The British Heart Foundation announced the winner of its $36 million Big Beat Challenge, one of the largest non-commercial awards ever given for heart research.

The winning team, CureHeart, brings together researchers from the U.K., U.S. and Asia, including Eric Olson, professor and chair of the Department of Molecular Biology at UT Southwestern Medical Center.

Olson is the founding chair of the department and directs the Hamon Center for Regenerative Science and Medicine and the Wellstone Center for Muscular Dystrophy Research. He holds the Robert A. Welch Distinguished Chair in Science and the Annie and Willie Nelson Professorship in Stem Cell Research.

He has spent his career investigating heart and muscle development and disease, leading to his participation on the CureHeart team. The Olson Lab at UTSW has been incredibly successful in muscular research, most recently providing a new way to correct the mutation that causes Duchenne muscular dystrophy through gene editing.

CureHeart made the top of the list with its gene editing therapy aimed at curing inherited heart muscle diseases, known as cardiomyopathies.

A BHF release said the technology will seek to develop the first cures for inherited heart muscle diseases by pioneering revolutionary and ultra-precise gene therapy technologies that could edit or silence the faulty genes that cause these deadly conditions.

The project will use gene-editing technology CRISPR to complete base and prime editing in the heart for the first time.

It works by correcting or silencing a faulty gene in the pumping machinery of the heart, either by re-writing the DNA at a single location or by switching off the entire copy of the faulty gene.

The technique was described as molecules that act like tiny pencils to rewrite the single mutations that are buried within the DNA of heart cells in people with heart conditions.

It can also help the heart produce enough proteins to function normally, again by fixing or stimulating the faulty gene.

With ultra-precise base editing technology, we hope to be able to correct a single letter and larger errors in the genetic code. This would mark a breakthrough for not only genetic cardiomyopathies, but for many heart conditions, said Olson in the release.

The project is the next step toward a real-world application, having already proved successful in animals with cardiomyopathies and in human cells. Members of the team believe therapies could be delivered through an arm injection, slowing or stopping the progression of cardiomyopathies, or even curing the disease entirely.

If successful, the research could have enormous impacts.

Every year in the US, around 2,000 people under the age of 25 die of a sudden cardiac arrest, often caused by one of these inherited muscle diseases, said the release. Current treatments do not prevent the condition from progressing, and around half of all heart transplants are needed because of cardiomyopathy.

The researchers believe it could also be successful in preventing the disease from being expressed if inherited. Children who receive the faulty gene from their parents could receive the injection and never develop cardiomyopathy in the first place.

Over the last 30 years, we have made extraordinary advancements in our understanding of the genetic mistakes that cause cardiomyopathy. CureHeart is a once-in-a-generation opportunity to transform this knowledge into a cure, said Olson in the release.

The technology is still in the research and development phase, but Olson said the funds will be used to optimize the method and expand it to a larger number of genetic diseases of the heart, and could move to clinical trials in the next few years.

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UTSW researcher part of team awarded $36 million heart research grant - The Dallas Morning News

Stem Cells Market: Introduction

According to the report, the globalstem cells marketwas valued at US$11.73Bn in 2020 and is projected to expand at a CAGR of10.4%from 2021 to 2028. Stem cells are defined as specialized cells of the human body that can develop into various different kinds of cells. Stem cells can form muscle cells, brain cells and all other cells in the body. Stem cells are used to treat various illnesses in the body.

North America was the largest market for stem cells in 2020. The region dominated the global market due to substantial investments in the field, impressive economic growth, increase in incidence of target chronic diseases, and technological progress. Moreover, technological advancements, increase in access to healthcare services, and entry of new manufacturers are the other factors likely to fuel the growth of the market in North America during the forecast period.

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Asia Pacific is projected to be a highly lucrative market for stem cells during the forecast period. The market in the region is anticipated to expand at a high CAGR during the forecast period. High per capita income has increased the consumption of diagnostic and therapy products in the region. Rapid expansion of the market in the region can be attributed to numerous government initiatives undertaken to improve the health care infrastructure. The market in Asia Pacific is estimated to expand rapidly compared to other regions due to shift in base of pharmaceutical companies and clinical research industries from developed to developing regions such as China and India. Moreover, changing lifestyles and increase in urbanization in these countries have led to a gradual escalation in the incidence of lifestyle-related diseases such as cancer, diabetes, and heart diseases.

Technological Advancements to Drive Market

Several companies are developing new approaches to culturing or utilizing stem cells for various applications. Stem cell technology is a rapidly developing field that combines the efforts of cell biologists, geneticists, and clinicians, and offers hope of effective treatment for various malignant and non-malignant diseases. The stem cell technology is progressing as a result of multidisciplinary effort, and advances in this technology have stimulated a rapid growth in the understanding of embryonic and postnatal neural development.

Adult Stem Cells Segment to Dominate Global Market

In terms of product type, the global stem cells market has been classified into adult stem cells, human embryonic stem cells, and induced pluripotent stem cells. The adult stem cells segment accounted for leading share of the global market in 2020. The capability of adult stem cells to generate a large number of specialized cells lowers the risk of rejection and enables repair of damaged tissues.

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Autologous Segment to Lead Market

Based on source, the global stem cells market has been bifurcated into autologous and allogenic. The autologous segment accounted for leading share of the global market in 2020. Autologous stem cells are used from ones own body to replace damaged bone marrow and hence it is safer and is commonly being practiced.

Regenerative Medicines to be Highly Lucrative

In terms of application, the global stem cells market has been categorized into regenerative medicines (neurology, oncology, cardiology, and others) and drug discovery & development. The regenerative medicines segment accounted for major share of the global market in 2020, as regenerative medicine is a stem cell therapy and the medicines are made using stem cells in order to repair an injured tissue. Increase in the number of cardiac diseases and other health conditions drive the segment.

Therapeutics Companies Emerge as Major End-users

Based on end-user, the global stem cells market has been divided into therapeutics companies, cell & tissue banks, tools & reagents companies, and service companies. The therapeutics companies segment dominated the global stem cells market in 2020. The segment is driven by increase in usage of stem cells to treat various illnesses in the body. Therapeutic companies are increasing the utilization of stem cells for providing various therapies. However, the cell & tissue banks segment is projected to expand at a high CAGR during the forecast period. Increase in number of banks that carry out research on stem cells required for tissue & cell growth and elaborative use of stem cells to grow various cells & tissues can be attributed to the growth of the segment.

Regional Analysis

In terms of region, the global stem cells market has been segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa. North America dominated the global stem cells market in 2020, followed by Europe. Emerging markets in Asia Pacific hold immense growth potential due to increase in income levels in emerging markets such as India and China leading to a rise in healthcare spending.

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Competition Landscape

The global stem cells market is fragmented in terms of number of players. Key players in the global market include STEMCELL Technologies, Inc., Astellas Pharma, Inc., Cellular Engineering Technologies, Inc., BioTime, Inc., Takara Bio, Inc., U.S. Stem Cell, Inc., BrainStorm Cell Therapeutics, Inc., Cytori Therapeutics, Inc., Osiris Therapeutics, Inc., and Caladrius Biosciences, Inc.

Stem Cells Market, by Application

Stem Cells Market, by End-user

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Stem Cells Market to Expand at a CAGR of 10.4% from 2021 to 2028 Travel Adventure Cinema - Travel Adventure Cinema

In brief

In 2020, the European Commission began a review of the EUs rules on blood, tissues and cells (BTC) used for medical treatments and therapies. Now the Commission haspublisheda draft legislative proposal to amend the rules.

The proposal does not recommend a complete overhaul: the EU will not change its definitions of blood, tissue and cell products. Yet it does promise a significant update to the two Directives published in the early 2000s that continue to govern the use of BTC components in the EU. Most importantly, the proposed legislation would be packaged as a Regulation rather than a Directive, meaning it would have a direct effect in the Member States.

The legislation sets out quality and safety requirements for allactivitiesfrom donation to human application (unless the donations are used to manufacture medicinal products or medical devices, in which case the legislation only applies to donation, collection and testing).

In its press release, the European Commission states that every year, EU patients are treated with 25 million blood transfusions (during surgery, emergency, cancer or other care), a million cycles of medically assisted reproduction, over 35,000 transplants of stem cells (mainly for blood cancers) and hundred thousands of replacement tissues (e.g., for orthopedic, skin, cardiac or eye problems). These therapies are only available thanks to the willingness of fellow citizens to make altruistic donations.

In the EU, the collection, processing and supply of each individual unit is typically organized on a local small-scale by public services, (academic) hospitals and non-profit actors.

Afteralmost 20years in place, the legislationno longer addressesthe scientific and technicalstate of the art and needs to be updated to take into account developments that have taken place in the sector.

How is the Commission planning to change BTC legislation in the EU? Here are three key takeaways from the draft proposal.

Compensating Doctors

The tissue and cell directive currently in force explicitly permits the Member States to compensate donors of tissue and cell products for their trouble. The corresponding blood Directive, however, contains no such provision: in its absence, different countries have developed their own guidelines on blood donor compensation.

That disparity is addressed in the draft Regulation, which would allow the Member States to reimburse donors of all human-derived products for losses related to their participation in adonation through fixed-rate allowances. Improving access to plasma donation, advocates of compensation schemes hope, could help the EU to bolster its patchy stockpiles of the essential fluid.

Emergency Planning

The Covid-19 pandemic demonstrated the fragility of healthcare networks that rely heavily on external sources for their products. Supply chain disruptions are a particular threat to the availability of plasma-derived medicines in the bloc since much of the EUs plasma is imported from the USA.

With this in mind, the Commission wants the Member States to develop emergency plans to cope with supply shocks. Countries would be required to maintain lines of communication that could be used in emergencies, establish authorities responsible for distribution in critical situations, and detect risks to their continued access to substances of human origin.

Detecting Risks

As might be expected, the draft Regulation introduces measures to protect the health and privacy of donors and donees. Screening is mandated to prevent patients from receiving diseased blood or cancerous cells. Technical systems should be in place to preserve the anonymity of all parties to a BTC transfer.

The burden of safeguarding is particularly heavy where assisted reproduction is concerned. It would be up to the Member States, under the draft legislation, to detect and mitigate genetic risks posed by donated reproductive cells.

If approved, it is thought that the revisions will be endorsed by 2023, with implementation beginning in 2024.

For further information, please contact Julia Gillert of our London office.

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EU: New Blood? Proposed Revisions to the EUs Blood, Tissues and Cells Rules - GlobalComplianceNews

Shortly after I was told I would need a heart transplant, in August 2014, a cardiac nurse visited my house. She scanned the room and noticed my exercise equipment. "You're not going to use that are you?", she asked me. "Yes", I replied, "why?"

My heart was operating at 13 percent and I was firmly told I couldn't be doing that sort of thing in my condition. The nurse said she would send round a physiotherapist called Nikki Simpson to tell me what I could and couldn't do while doctors tried to figure out what was going on with my heart.

"Nikki Simpson?" I asked. It couldn't be. The woman I had once known with the same name was training to be a hairdresser, plus she'd married and moved away.

We had first met as teenagers at a club in the north of England in 1984. I had wavy shoulder length hair and she always had some sort of red leather gear on. Usually, I'm not the sharpest knife in the drawer when it comes to flirting, but I could tell she liked me straight away.

We dated for about six months. I didn't drink much so we would go on long drives and spend time with mutual friends, but for some reason the relationship just fizzled out. Nothing bad happened, we just drifted apart.

I lived a bachelor life for a while. Eventually I got married and had my son, Robert. Nikki got married and had a baby girl. We only lived a village away from each other but I never saw her once.

When my son was eight my first marriage broke down and I cared for Robert. It was the hardest thing to do, but we had the best time of our lives. I did date when my son was younger, but nobody seemed to understand that Robert came first.

For years I'd been extremely fit, I was a plasterer by trade and had always had physical jobs. But in February, 2014, when I was doing some work putting up billboards in Leeds, I couldn't breathe and kept falling to my knees.

I visited the emergency room with my sister. I was told I had pneumonia and given a course of antibiotics. I took them for two weeks but still couldn't breathe properly, so I was told it was likely I had a respiratory condition and to visit my doctor.

After months of being referred to and from the hospital, my doctor told me he thought I had heart failure. He organized an MRI scan which showed my heart was globally dilated and operating at a fraction of its normal function. They said it was likely down to a virus, but had no idea which one.

I went back the next week and the doctor sat there, clicking away on his keyboard. He glanced across at me and said: "We need to discuss a heart transplant." There I was, this strapping Yorkshireman who doesn't drink, doesn't smoke, doesn't do anything untoward, who has a dodgy heart. I stopped listening to anything he said. I went back to my doctor who told me to stop whatever I was doing, go home and watch TV on the sofa.

I started going for various scans and a cardiac nurse began to visit me and curate my drugs, which is when she mentioned about a physio helping me.

One day in August 2014, this nurse she knocked on the door and said "The physio is on her way, but I need to ask your permission for her to treat you because you have a history." I said it was fine.

When Nikki knocked on my door, I swung it open and shouted "f*** off!" I grabbed her, sat her on the kitchen table and gave her a big kiss on the cheek.

It just sort of took off from there. We started seeing each other when she came round to treat me. I would go to the gym with her to do exercises and she would call round for a cup of tea in the evenings.

Robert was doing his first year at university studying aeronautical engineering and I was concerned because he was driving a fair distance home every day just so I wasn't at home by myself. Eventually, Nikki said she'd move in with me so Robert could go and live the dream.

It was ace having her around. Even at this point, when I thought I was dying and there was no cure for me, it was like this angel had walked through the door and made my life better.

The relationship with Nikki was great, but I was going to the hospital a lot. The tablets used to steady you and make you comfortable I just couldn't tolerate. I got to the stage where I spent so much time in the hospital the porters recognised me.

It looked like I was going to die. I had a mate who had his suit washed three times for my funeral. Whenever I saw him he would say: "Are you still here?"

In October 2017, we were watching TV when an interview with the Heart Cells Foundation came on. They'd created a stem-cell procedure which took bone marrow from a patient's pelvis then injected it straight into the heart. I wanted it.

The next day I phoned them and they said to come down for some tests. I qualified for the procedure and in November 2018 went down to St Bartholomew's Hospital in London and had the treatment. It changed my life overnight.

This horrific thing I was thinking about; someone dying and me taking their heart, wasn't going to happen anymore. That was three and a half years ago. I had thought I was going to be dead in months without a transplant.

From day one of leaving the hospital, I haven't had any problems at all. I go down for a yearly check up and the consultant wants me to have the treatment again. They've never done it twice but think they might get some good results.

Nikki has been ace throughout all of this. We're looking to get married next year. I didn't want to get married before the treatment. I didn't want to be pushed down the aisle in a wheelchair or go for a meal after and end up in an ambulance. But, now, I'm getting fit, strong and strapping, so we want to go with it.

Looking back, it seems so strange that Nikki and I parted ways. I don't know if I believe in fate, but since I was first told I'd need a heart transplant we've lost my dad, my brother, two aunties and Nikki's dad. All these people who have gone, I was supposed to go before them. My perspective on life has always been to live it today, because you don't know what's going to come tomorrow.

Barry Newman, 55, from Wakefield, was a plasterer before undergoing pioneering treatment with the Heart Cells Foundation, an independent charity which has run a small unit at St Bartholomew's Hospital since 2016. Earlier this year he carried the baton at the Commonwealth Games relay.

All views expressed in this article are the author's own.

As told to Monica Greep

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'My Teen Sweetheart And I Drifted Apart. 30 Years Later I Made a Shocking Discovery' - Newsweek

Wilmington, Delaware, United States, July 18, 2022 (GLOBE NEWSWIRE) -- Transparency Market Research Inc.: The market value of the global cell separation technologies market is estimated to be over US$ 20.3 Bn by 2031, according to a research report by Transparency Market Research (TMR). Hence, the market is expected expand at a CAGR of 11.9% during the forecast period, from 2022 to 2031.

According to the TMR insights on the cell separation technologies market, the prevalence of chronic disorders including obesity, diabetes, cardiac diseases, cancer, and arthritis is being increasing around the world. Some of the key reasons for this situation include the sedentary lifestyle of people, increase in the older population, and rise in cigarette smoking and alcohol consumption across many developed and developing nations. These factors are expected to help in the expansion of the cell separation technologies market during the forecast period.

Players in the global cell separation technologies market are increasing focus on the launch of next-gen products. Hence, they are seen increasing investments in R&Ds. Moreover, companies are focusing on different strategies including acquisitions and strengthening their distribution networks in order to stay ahead of the competition.

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As per the Imperial College London, chronic diseases are expected to account for approximately 41 million deaths per year, which seven out of 10 demises worldwide. Of these deaths, approximately 17 million are considered to be premature. Hence, surge in cases of chronic diseases globally is resulting into increased need for cellular therapies in order to treat such disease conditions, which, in turn, is boosting the investments toward R&Ds, creating sales opportunities in the cell separation technologies market.

Cell Separation Technologies Market: Key Findings

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Cell Separation Technologies Market: Growth Boosters

Cell Separation Technologies Market: Regional Analysis

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Cell Separation Technologies Market: Key Players

Some of the key players profiled in the report are:

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Cell Separation Technologies Market Segmentation

Modernization of healthcare in terms of both infrastructure and services have pushed the healthcare industry to new heights, Stay Updated with Latest Healthcare Research Reports by Transparency Market Research:

Cell Culture Market: Rise in outsourcing activities and expansion of biopharmaceutical manufacturers are expected to drive the cell culture market during the forecast period

Cell Culture Media, Sera, and Reagents Market: The global cell culture media, sera, and reagents market is majorly driven by growth and expansion of biotechnology & pharmaceutical companies and academic & research institutes.

Stem Cells Market: The global stem cells market is majorly driven by rising applications of stem cells in regenerative medicines. Increase in the number of chronic diseases such as cardiac diseases, diabetes, cancer, etc.

Cell Line Authentication and Characterization Tests Market: Increase in the geriatric population and surge in incidence of chronic diseases are projected to drive the global cell line authentication and characterization tests market.

CAR T-cell Therapy Market: The CAR T-cell therapy market is expected to clock a CAGR of 30.6% during the assessment period. The CAR T-cell therapy is known as a revolutionary treatment option for cancer, owing to its remarkably effective and durable clinical responses.

Cell & Tissue Preservation Market: Rise in investments in the field of regenerative medicine research is estimated to propel the market. Human blood, tissues, cells, and organs own the capability to heal damaged tissues and organs with long-term advantages.

Placental Stem Cell Therapy Market: Placental stem cell therapy market is driven by prominence in treatment of age-related disorders/diseases and increase in awareness about stem cell therapies are projected to drive the global market in the near future.

Biotherapeutics Cell Line Development Market: The market growth will be largely driven by research and development activities due to which, new solutions and technologies have gradually entered the market.

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Transparency Market Research, a global market research company registered at Wilmington, Delaware, United States, provides custom research and consulting services. Our exclusive blend of quantitative forecasting and trends analysis provides forward-looking insights for thousands of decision makers. Our experienced team of Analysts, Researchers, and Consultants use proprietary data sources and various tools & techniques to gather and analyze information.

Our data repository is continuously updated and revised by a team of research experts, so that it always reflects the latest trends and information. With a broad research and analysis capability, Transparency Market Research employs rigorous primary and secondary research techniques in developing distinctive data sets and research material for business reports.

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Cell Separation Technologies Market Expands with Rise in Prevalence of Chronic Diseases, States TMR Study - GlobeNewswire

WILMINGTON, Del., July 21, 2022 /PRNewswire/ --An in-depth demand analysis of dental membrane and bone graft substitutes found that massive demand for resorbable bone grafting materials presents value-grab opportunity. Companies in the dental membrane and bone graft substitutes market are actively leaning on development of novel biomaterials to meet the needs of bone grafting procedures. The TMR study projects the size of the market to surpass worth of US$ 1,337 Mn by 2031.

Advancements in periodontology are catalyzing introduction of new soft tissue regeneration, as emerging trends of the dental membrane and bone graft substitutes market underscore. Moreover, dental membrane and bone graft substitutes market projections in the TMR study have found that the use of xenograft for dental bone regeneration is anticipated to rise rapidly, and will unlock lucrative avenues. The fact that xenografts are cost-effective and show good results in bone tissue regeneration will spur the popularity of products in the segment.

Increasing number of bone regeneration procedures has led to the commercialization of novel biomaterials and dental bone grafts. The application of human cell sources in bone graft substitutes is growing, thus extending the canvas for companies in the dental membrane and bone graft substitutes market. Rise in oral disorders and injuries has impelled the need for bone substitute materials that can promise long-term survival rates in the patients.

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Key Findings of Dental Membrane and Bone Graft Substitutes Market Study

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Dental Membrane and Bone Graft Substitutes Market: Key Players

High degree of fragmentation has characterized the competition landscape in the dental membrane and bone graft substitutes market, mainly due to presence of several prominent players. Some of the key players are Zimmer Biomet, OPKO Health, Inc., NovaBone Products, LLC., Nobel Biocare Services AG, Geistlich Pharma AG, Dentsply Sirona, Collagen Matrix, Inc., BioHorizons, and Institut Straumann AG.

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Dental Membrane and Bone Graft Substitutes Market Segmentation

Regions Covered

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Modernization of healthcare in terms of both infrastructure and services have pushed the healthcare industry to new heights, Stay Updated withLatest Healthcare Research Reportsby Transparency Market Research:

Non-Invasive Prenatal Testing Market: Non-invasive prenatal testing market was worth around US$ 1.3 Bn in 2018. The market is likely to develop at a CAGR of 16.4% during the forecast period, from 2019 to 2027.

Cell Culture Media, Sera, and Reagents Market: The global cell culture media, sera, and reagents market is majorly driven by growth and expansion of biotechnology & pharmaceutical companies and academic & research institutes.

Stem Cells Market: The global stem cells market is majorly driven by rising applications of stem cells in regenerative medicines. Increase in the number of chronic diseases such as cardiac diseases, diabetes, cancer, etc.

Cell Line Authentication and Characterization Tests Market: Increase in the geriatric population and surge in incidence of chronic diseases are projected to drive the global cell line authentication and characterization tests market.

CAR T-cell Therapy Market: The CAR T-cell therapy market is expected to clock a CAGR of 30.6% during the assessment period. The CAR T-cell therapy is known as a revolutionary treatment option for cancer, owing to its remarkably effective and durable clinical responses.

Cell & Tissue Preservation Market: Rise in investments in the field of regenerative medicine research is estimated to propel the market. Human blood, tissues, cells, and organs own the capability to heal damaged tissues and organs with long-term advantages.

mHealth Monitoring Diagnostic Medical Devices Market: The global mHealth monitoring diagnostic medical devices market was valued at US$ 29.05 Bn in 2018 and is projected to expand at a CAGR of 20.5% from 2019 to 2027.

Pediatric Medical Devices Market: The global pediatric medical devices market was valued at US$ 21,000 Mn in 2017 and is projected to expand at a CAGR of 8.0% from 2018 to 2026.

About Transparency Market Research

Transparency Market Research, a global market research company registered at Wilmington, Delaware, United States, provides custom research and consulting services. Our exclusive blend of quantitative forecasting and trends analysis provides forward-looking insights for thousands of decision makers. Our experienced team of Analysts, Researchers, and Consultants use proprietary data sources and various tools & techniques to gather and analyze information.

Our data repository is continuously updated and revised by a team of research experts, so that it always reflects the latest trends and information. With a broad research and analysis capability, Transparency Market Research employs rigorous primary and secondary research techniques in developing distinctive data sets and research material for business reports.

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Dental Membrane and Bone Graft Substitutes Market to Exceed Value of US$ 1,337 Mn by 2031 - PR Newswire UK

Affecting one in 5,000 male births worldwide, Duchenne Muscular Dystrophy (DMD) is a fatal genetic disorder that currently doesnt have a cure, but published research conducted at the University of Nevada, Reno School of Medicine shows promise and may lead to the eventual development of a new molecular therapeutic.

The latest, significant research finding, published in Human Molecular Genetics, February 2022, involves the small-molecule sunitinib which has been shown to mitigate DMD-related skeletal muscle disease in a number of ways.

As patients with DMD grow older, muscular dystrophy worsens, causing respiratory and cardiac muscle failure resulting in premature death. There are no effective treatments to prevent DMD-related cardiac failure, however continued research in the lab of UNR Med Professor of Pharmacology Dean Burkin is pointing to protein and molecular-based solutions, including sunitinib which is already FDA approved and used in cancer treatments.

Burkin conducted the latest research with Ph.D. student Ariany Oliveira-Santos. Based on a mouse model, they found that sunitinib improved major negative symptoms that stem from DMD, such as cardiac muscle damage, without depressing the immune system completely. Oliveira-Santos was lead author on the published results. The study was supported by a grant from the Muscular Dystrophy Association and the National Institutes of Health.

Burkins lab focuses mainly on studying two key proteins 71 integrinand laminin and understanding the role they play in muscle development and disease. The lab primarily studies two muscle-damaging diseases: DMD and Laminin-2 related congenital muscular dystrophy (LAMA2-CMD).

Were interested in the biology of the 71 integrin, that's really the central focus of [our research], Burkin said. But we also have other big interests in these muscle diseases where the integrin [protein] is normally found.

Burkin explains that through this translational research, which he also calls the lab bench to bedside approach, researchers attempt to understand the biology of a system as much as possible, and then continue through the development steps that lead to therapeutic treatments.

Patients with DMD lack dystrophin which causes progressive muscle degeneration and weakness. This means the more these muscles are used, the more damage occurs. While there are repair cells in muscles, these cells eventually tire out. Burkin and Oliveira-Santos noted that the heart, an organ being used all the time, does not have this repair system, making the damage severe in cardiac muscles as well. Currently some therapeutic approaches have been beneficial for skeletal muscles but not for the heart; therefore, its important to have a drug or treatment that can target and be beneficial to skeletal and cardiac muscle at the same time, Oliveira-Santos explained.

We looked to the electrical and mechanical function of the heart and both were improved, Oliveira-Santos said. Sunitinib helped the cardiac function [and reduced] cardiac damage, and inflammation. I don't think theres really many drugs out there that do that right now.

Oliveira-Santos remembers wanting to be a scientist as early as eight years old. She went on to earn degrees in Brazil, including a bachelors in biomedicine and a masters in the scientific fields of immunology and pharmacology as they relate to transplant rejection. While earning her masters degree, Burkin was invited to Brazil by Oliveira-Santoss supervisor to give a talk, and the two met in-person and discussed her masters project. At the time, they were studying the same molecule, but in different models, so Oliveira-Santos had read some of Burkins papers.

Oliveira-Santos had always been interested in the physiology and pathology of disease and thought it would be a great area to study for a doctoral degree. She knew Burkin was working in this field, so about five years after their in-person meeting, Oliveira-Santos reached out to Burkin. He told her about an open position in his lab for a Ph.D. student, and their project of understanding the role of an FDA-approved small molecule for the treatment of DMD cardiomyopathy. She felt this project was a good match for what she was looking for and joined the lab in January 2019.

Oliveira-Santos said the mentorship and support shes received from Burkin and the rest of the lab has been invaluable.

Dean is always available to discuss and very happy to help [the lab members] with everything we need, Oliveira-Santos said. Everyone had an important opinion about the project and that was essential for the projects success.

While working in science oftentimes can come with struggles, Oliveira-Santos expressed how much these experiences have taught her.

Being in science is a big challenge, because you have to learn how to deal with problems all the time, she said. There are more failures than success [so] it teaches you how to deal with failure. Failure is normal. You just need to try to find a way around to get a solution.

Oliveira-Santos is set to finish her Ph.D. in Cellular and Molecular Pharmacology & Physiology in the fall 2022.

When I bring a student to the lab, I say I can supply everything but enthusiasm. And that's one thing that Ariany brings in abundance, Burkin said. I'm putting my students in contact with other principal investigators that I know to try and make sure that the next level on their career is achieved. She can go anywhere right now and move forward. The world is her oyster.

Continued here:
Promising solution to fatal genetic-disorder complications discovered by University professor and Ph.D. candidate - Nevada Today

Stem Cells. Author manuscript; available in PMC 2020 Jul 1.

Published in final edited form as:

PMCID: PMC6658105

NIHMSID: NIHMS1024291

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA

Author contributions:

Barbara Lukomska: Conception and design, financial support, collection and/or assembly of data, final approval of manuscript

Miroslaw Janowski: Conception and design, financial support, collection and/or assembly of data, manuscript writing, final approval of manuscript

It was shown as long as half a century ago that bone marrow is a source of not only hematopoietic stem cells, but also stem cells of mesenchymal tissues. Then the term of mesenchymal stem cells (MSCs) has been coined in early 1990s and over a decade later the criteria for defining MSCs have been released by International Society for Cellular Therapy. The easy derivation from a variety of fetal and adult tissues and not demanding cell culture conditions made MSCs an attractive research object. It was followed by the avalanche of reports from preclinical studies on potentially therapeutic properties of MSCs such as immunomodulation, trophic support and capability for a spontaneous differentiation into connective tissue cells, and differentiation into majority of cell types upon specific inductive conditions. While ontogenesis, niche and heterogeneity of MSCs are still under investigation, there is a rapid boost of attempts in clinical applications of MSCs, especially for a flood of civilization-driven conditions in so quickly aging societies in not only developed countries, but also very populous developing world. The fields of regenerative medicine and oncology are particularly extensively addressed by MSC applications, in part due to paucity of traditional therapeutic options for these highly demanding and costly conditions. There are currently almost 1000 clinical trials from entire world registered at clinicaltrials.gov and it seems that we are starting to witness the snowball effect with MSCs becoming a powerful global industry, however spectacular effects of MSCs in clinic still need to be shown.

Keywords: Mesenchymal stem cells, clinical, differentiation, immunomodulation, paracrine activity, history

Friedenstein was one of the pioneers of the theory that bone marrow is a reservoir of stem cells of mesenchymal tissues in adult organisms. It was based on his observation at the turn of the 1960s and 1970s., that ectopic transplantation of bone marrow into the kidney capsule, results not only the proliferation of bone marrow cells, but also the formation of bone [1] (). This indicated the existence in the bone marrow of a second, in addition to hematopoietic cells, stem cell population giving rise to bone precursors. Due to the ability of these cells to create osteoblasts, Friedenstein gave them the name of osteogenic stem cells. Friedenstein was also the first to isolate from bone marrow adherent fibroblast-like cells with the ability to grow rapidly in vitro in the form of clonogenic colonies (CFU-F; colony forming unit-fibroblast). These cells derived from CFU-F colonies were characterized by the ability to differentiate in vitro not only to osteocytes, but also to chondrocytes and adipocytes. After transplantation of CFU-F colonies into the recipient, they were capable of co-formation of the bone marrow micro-environment [2,3]. The term mesenchymal stem cells has been proposed by Caplan in 1991 because of their ability to differentiate into more than one type of cells that form connective tissue in many organs [4]. This name has become very popular and is currently the most commonly used, even though it raised doubts about the degree of their stemness [5]. Today, there are many substitutes in the literature for the abbreviation of MSCs, including Multipotent Stromal Cells, Marrow Stromal Cells, Mesodermal Stem Cells, Mesenchymal Stromal Cells and many more. In its latest work, Caplan recommends renaming these cells to Medicinal Signaling Cells due to the emphasis on the mechanism of their therapeutic effects after transplantation, which is believed to be based mainly on the secretion of factors facilitating regenerative processes [6].

The roots of research on bone marrow-derived stem cells of connective tissue, which has been then named: mesenchymal stem cells

Due to the growing controversy regarding the nomenclature, the degree of stemness and the characteristics of the cells discovered by Friedenstein, the International Society for Cellular Therapy (ISCT) in 2006 published its position specifying the criteria defining the population of MSCs, which was accepted by the global scientific community. These guidelines recommend the use of the name multipotent mesenchymal stromal cells, however, the name mesenchymal stem cells still remains the most-used. The condition for the identification of MSCs is the growth of cells in vitro as a population adhering to the substrate, as well as in the case of cells of human origin, a phenotype characterized by the presence of CD73, CD90, CD105 surface antigens and the lack of expression of proteins such as: CD45, CD34, CD14, CD11b, CD79a or CD19 or class II histocompatibility complex antigens (HLA II, human leukocyte antigens class II). Moreover, these cells must have the ability to differentiate towards osteoblasts, adipocytes and chondroblasts [7,8]. In addition to the markers mentioned in the ISCT guidelines, the following antigens turned out to be useful in isolating the human MSCs from the bone marrow: STRO-1 (antigen of the bone marrow stromal-1 antigen, cell surface antigen expressed by stromal elements in human bone marrow-1), VCAM / CD106 (vascular cell adhesion molecule 1) and MCAM / CD146 (melanoma cell adhesion molecule), which characterizes cells growing in vitro in a adherent form, with a high degree of clonogenicity and multidirectional differentiation ability [911].

The common mesenchymal core in both versions of MSC abbreviation comes from the term mesenchyme, which is synonymous with mesenchymal tissue or embryonic connective tissue. It is used to refer to a group of cells present only in the developing embryo derived mainly from the third germ layer - mesoderm. During the development these cells migrate and diffuse throughout the body of the embryo. They give rise to cells that build connective tissue in adult organisms, such as bones, cartilage, tendons, ligaments, muscles and bone marrow. The view about the differentiation of MSCs during embryonic development from mesenchymal cells is widely spread [4]. This is due, inter alia, to the observed convergence in the expression of markers such as: vimentin, laminin 1, fibronectin and osteopontin, which are typical for mesoderm cells during embryonic development, as well as characteristic for in vitro adherent bone marrow stroma cells [12]. However, the true origin of MSCs is unknown. In the literature, we can find also reports indicating that they are ontogenetically associated with a group of cells derived from ectoderm, which originate from Sox1 + cells (SRY - sex determining region Y) that appear during the development of embryonic neuroectoderm and neural crest. These cells inhabit newborn bone marrow and meet the criteria corresponding to their designation as MSCs. However, with the development of animals, the population of these cells disappears and is replaced by cells with a different, unidentified origin [13]. It has also been shown that in the bone marrow of the developing mouse embryo, at least two MSCs populations with distinct expression of the nestin protein and the intensity of cell divisions can be distinguished. The former one originates from mesoderm that does not express nestin, and is characterized by intense proliferation and is involved in the process of creating the embryo skeleton. The latter one is derived from the cells of the neural crest, which expresses nestin and is non-dividing and remains passive during bone formation while in the adult organism contributes to a niche of hematopoietic cells [14]. It seems, therefore, that the ontogenesis of MSCs is associated with cells belonging to different germ layers and their original source determines the role and functions that they play in the adult body.

In 1978, the concept of a niche was defined as a place in the body that is settled by stem cells and whose environment allows them to be maintained in an undifferentiated state [15]. MSCs were first obtained from the bone marrow stroma where they constitute an element of stromal cells, participating in the production of signals modulating the maturation of hematopoietic cells. However, the precise location of the niche for MSCs has not been known so far. In the context of research results indicating that MSCs can be isolated from many mesoderm-derived tissues during embryonic development, a common element was sought for all sources from which MSCs can be isolated and a theory was proposed about the existence of their niche within the blood vessels that are present in all structures from which these cells were isolated.

Crisan and colleagues have shown that cells inhabiting the perivascular space of blood vessels, isolated from human tissues such as skeletal muscle, pancreas, adipose tissue and placenta, with the phenotype CD146 +, NG2 + (neuroglycan-2), PDGF-R + (-type platelet-derived growth factor receptor), ALP + expressing endothelial, hematopoietic and muscle cell markers described as pericytes were precursors for cells that after in vitro expansion meet the criteria for determining them as MSCs [16]. Analogously to the described by Friedenstein MSCs, CD146 + cells colonizing the perivascular space of sinusoidal sinus vessels, are responsible for the production of signals allowing the reconstruction of the bone marrow microenvironment after transplantation to heterotopic location [11]. Whats more, tracing the fate of pericytes in the process of rebuilding a damaged tooth in rodents has shown that they are transforming into odontoblasts, which arise from MSCs found in the pulp. However, the same studies showed that in the process of reconstruction of incisors in mice, a different population of odontoblasts, which is not formed from pericytes, but from MSCs of different origin migrating to the area of damage, prevailed quantitatively [17]. The second cell population associated with blood vessels, proposed as a counterpart of MSCs in the body is advent building cells with the CD34+ CD31- CD146- phenotype, which after isolation and in vitro culture meet the criteria defining the population as MSCs. However, these cells also have the ability to differentiate into pericytes [18,19]. Although pericytes and MSCs have a very similar gene expression profile as well as an analogical capacity for differentiation, it has been shown that the functionality of these cells varies. In vitro studies of endothelial cell interactions in co-culture with MSCs or pericytes have shown that only pericytes are able to form highly branched, dense, cylindrical structures with large diameter, typical for well-organized blood vessels, while isolated from the bone marrow MSCs do not have such abilities. Currently, it is believed that there is a link between pericytes and MSCs, but their mutual relations are not well defined. There are speculations that MSCs are an intermediate form of pericytes or their subpopulation, but there is still no conclusive evidence confirming this hypothesis [20,21].

While the cells fulfilling criteria for MSCs can be harvested from various tissues at all developmental stages (fetal, young, adult and aged) using their plastic adherence property, there are profound differences between obtained MSC populations [22,23]. Bone marrow was historically the first source from which MSCs were obtained, however, over time, there have been reports of the possibility of isolation from other sources of cells with similar properties. Mesenchymal cells are obtained from both tissues and secretions of the adult body, such as adipose tissue, peripheral blood, dental pulp, yellow ligament, menstrual blood, endometrium, milk from mothers, as well as fetal tissues: amniotic fluid, membranes, chorionic villi, placenta, umbilical cord, Wharton jelly, and umbilical cord blood [2437]. MSCs of fetal origin as compared to cells isolated from tissues of adult organisms are characterized by a faster rate of proliferation as well as a greater number of in vitro passages until senescence [38]. However, MSCs derived from bone marrow and adipose tissue are able to create a larger number of CFU-F colonies, which indirectly indicates a higher degree of their stemness. The comparison of gene expression typical for pluripotent cells shows that only in cells isolated from the bone marrow we can observe the expression of the SOX2 gene, the activation of which is associated with the self-renewal process of stem cells as well as with neurogenesis during embryonic development [39]. Discrepancies in the ability of MSCs obtained from various sources to differentiate have also been described. The lack of differentiation of MSCs derived from umbilical cord blood towards adipocytes as well as the greater tendency of MSCs from bone marrow and adipose tissue to differentiate towards osteoblasts were observed [39,40].

In addition to the diverseness observed between MSCs from different sources, there are also differences associated with obtaining them from individual donors. Among the cells isolated from the bone marrow from donors of different ages and sexes, up to 12-fold differences in the rate of their proliferation and osteogenesis were found, combined with a 40-fold difference in the level of bone remodeling marker activity - ALP (alkaline phosphatase). At the same time, no correlations were found resulting from differences in the sex or age of donors [41]. However, the results of studies by other authors indicate that the properties of MSCs isolated from the bone marrow are strongly associated with the age of the donor. Cells collected from older donors are characterized by an increased percentage of apoptotic cells and slower rate of proliferation, which is associated with an increased population doubling time. There is also a weakened ability of MSCs from older donors to differentiate towards osteoblasts [42]. Heo in his work shows the different ability of MSCs to osteogenesis combining it with different levels of DLX5 gene expression (transcription factor with the homeodomain 5 motif) in individual donors, however independent of the type of tissue from which the cells were isolated [39].

The next stage in which we can observe diversity among the MSCs population is in vitro culture. The morphology of cultured cells that originate from the same isolation allows for differentiation into three sub-populations. There are observed spindle-shaped proliferating cells resembling fibroblasts (type I); large, flat cells with a clearly marked cytoskeleton structure, containing a number of granules (type II) and small, round cells with high self-renewal capacity [43,44]. The original hypothesis assumed that all cells that make up the MSCs population are multipotent, and each colony of CFU is capable of differentiating into adipocytes, chondrocytes and osteoblasts, as confirmed by appropriate studies [45]. However, in the literature we can find reports that cell lines derived from a common colony of CFU-F differ in their properties, characterized by uni-, di- or multipotence [46]. Some of the authors showed the division of clonogenic MSCs colonies into as much as eight groups distinct in their potential for differentiation. At the same time, it is suggested that there is a hierarchy within which cells subordinate to each other are increasingly directed towards osteo- chondro- or adipocytes and gradually lose their multipotential properties to di- and unipotential ones. This transformation may also be associated with a decrease in the rate of cell proliferation and the level of CD146 protein expression (CD; cluster of differentiation) - proposed as a marker of multipotency [47].

One of the main advantages of MSCs are their immunomodulatory properties. MSCs grown in vitro have the ability to interact and regulate the function of the majority of effector cells involved in the processes of primary and acquired immune response () [48]. They exert their immunomodulatory effects by inhibiting the complement-mediated effects of peripheral blood mononuclear cell proliferation [49,50], blocking apoptosis of native and activated neutrophils, as well as reducing the number of neutrophils binding to vascular endothelial cells, limiting the mobilization of these cells to the area of damage [51,52]. In addition, cytokines synthesized by activated MSCs stimulate neutrophil chemotaxis and secretion of pro-inflammatory chemokines involved in recruitment and stimulation of phagocytic macrophage properties [53]. Moreover MSCs limit mast cell degranulation, secretion of pro-inflammatory cytokines by these cells as well as their migration towards the chemotactic factors [54]. Native MSCs have the ability to block the proliferation of de novo-induced NK cells, but they are only able to partially inhibit the proliferation of already activated cells [55]. They also contribute to the reduction of cytotoxic activity of NK cells [56]. Moreover MSCs can block the differentiation of CD34 + cells isolated from the bone marrow or blood monocytes into mature dendritic cells both by direct contact as well as by secreted paracrine factors [57,58]. They inhibit the transformation of immature dendritic cells into mature forms and limit the mobilization of dendritic cells to the tissues [59]. Under their influence, M1 (pro-inflammatory) macrophages are transformed into M2 type cells with an anti-inflammatory phenotype, and the IL-10 (IL, interleukin) secreted by them inhibits T-cell proliferation [60,61]. In vitro studies have demonstrated a direct immunomodulatory effect of MSCs on lymphocytes. During the co-culture of MSCs with lymphocytes, suppression of activated CD4 + and CD8 + T cells and B lymphocytes was observed [62]. In addition, MSCs reduce the level of pro-inflammatory cytokines synthesized by T-lymphocytes, such as TNF- (tumor necrosis factor ) and IFN- (interferon ) [63], and increase synthesis of anti-inflammatory cytokines, e.g. IL-4. In the presence of MSCs, the inhibition of the differentiation of naive CD4 + T lymphocytes to Th17 + lymphocytes (Th; T helper cells) was observed, while the percentage of T cells differentiating towards CD4 + CD25 + regulatory T cells was found to increase [64,65]. Glennie et al. described this condition as anergy of activated T cells in the presence of MSCs [62]. MSCs also have the ability to limit the synthesis of immunoglobulins like IgM, IgG and IgA (Ig; immunoglobulin) classes secreted by activated B cells, thereby blocking the differentiation of these cells to plasma cells. They also reduce the expression of chemokines and their receptors on the surface of B lymphocytes, which probably have a negative effect on their ability to migrate [66].

The schematic representation of immunomodulatory capabilities of MSCs

Mesenchymal stem cells secrete a wide range of paracrine factors, collectively referred to as the secretome, which support regenerative processes in damaged tissues. They comprise the components of the extracellular matrix, proteins involved in the adhesion process, enzymes as well as their activators and inhibitors, growth factors and binding proteins, cytokines and chemokines, and probably many more [67]. These factors can have distinct impact on the processes they regulate (). MSCs secrete factors promoting angiogenesis, such as: vascular endothelial growth factor (VEGF) but they may also inhibit this process, through expression of monokine induced by interferon and tissue inhibitors of metalloproteinases 1 and 2 [68,69]. An important role is also played by chemokines secreted by MSCs in the process of blocking or stimulating cell chemotaxis, such as: CCL5 (RANTES, regulated by activation, expression and secretion by normal T lymphocytes), CXCL12 (SDF-1, stromal cell-derived factor 1) or CCL8 (MCP-2; monocyte chemoattractant protein 2). An essential group of factors from the point of view of regeneration processes are growth factors with an anti-apoptotic effect, including: HGF (hepatocyte growth factor), IGF-1 (insulin-like growth factor 1), VEGF, CINC-3 (cytokine induced by a chemoattractant for neutrophil chemoattractant), TIMP-1 (tissue inhibitor of metalloproteinases 1), TIMP-2 (tissue inhibitor of metalloproteinases 2), osteopontin, growth hormone, FGF-BP (bFGF binding protein), and BDNF (brain-derived growth factor; -derived neurotrophic factor) and stimulating proliferation as: TGF- (transforming growth factor ), HGF, EGF (epidermal growth factor), NGF (nerve growth factor; nerve growth factor), bFGF (basic fibroblast growth factor), IGFBP-1, IGFBP-2 (IGFBP; insulin-like growth factor 1 binding protein, IGF-Protein-1 protein) and M-CSF (stimulant factor t molar macrophage colony; macrophage colony-stimulating factor) [68,70,71]. Growth factors secreted by MSCs have also ability to reduce fibrosis of tissues during regeneration. These include KGF (keratinocyte growth factor), HGF, VEGF, and Ang-1 (angiopoietin-1), SDF1, IGF-1, EGF, HGF, NGF, TGF- [71,72]. There are reports about the antibacterial properties and interaction of the MSC secretome with cancer cells. Data on the impact of MSCs on neoplasia are not conclusive, however, it is assumed that both the tumor type and the origin of MSCs are of great importance for the final effect [73]. It was shown that factors enclosed within the MSCs secretome are able to reduce the proliferation, viability and migration of certain types of cancer cells (such as non-small-cell lung carcinoma) [74]. Others have shown that factors released by MSCs may increase motility, invasiveness and the ability to form metastases (including, for example, breast cancer cells) [75]. In response to bacteria, levels of cytokines such as IL- 6, IL-8, CCL5, PGE2, TNF-, IL-1, IL-10, VEGF and SDF-1 secreted by MSCs are subject to change [76]. MSCs contain also substances with antibacterial, anti-parasitic and antiviral activity [77].

The mechanisms mediating MSC-dependent trophic support

Another broad and dynamically developing field in recent years which is related to paracrine MSCs activity is their ability to secrete extracellular vesicles (EVs), which include exosomes, microvesicles and apoptotic bodies. Their composition largely coincides with the components contained in the cells from which they originate. Physiologically they play an important role in the regulation of biological functions, homeostasis and the immune response of the body. It is also postulated that the biological activity of microvesicles is comparable to that of MSCs [78]. Experiments conducted using supernatant derived from in vitro culture of MSCs showed that the factors contained in their secretome are responsible for a large part of the effects exerted by MSCs during the regeneration of the damaged area including the protection of other cells against apoptosis, induction of their proliferation, prevention of excessive fibrosis of tissues, stimulation of the angiogenesis process and immunomodulatory effects, as well as the induction of endogenous stem cells differentiation [65,68,69,7982].

As mentioned above, the ability to differentiate into three types of cells such as: osteocytes, chondrocytes and adipocytes is one of the criterion for MSCs [8]. This phenomenon can be traced in vitro by placing MSCs in a medium containing specific supplements, for the adipogenesis process they are mainly dexamethasone, indomethacin, insulin and isobutylmethylxanthin [83], for chondrogenesis cell culture in DMEM medium (Dulbecco / Vogt Modified Eagles Minimal Essential Medium) supplemented with insulin, transferrin, selenium, linoleic acid, selenium acid, pyruvate, ascorbic phosphate, dexamethasone and TGF- III [84], which may additionally be aided by the addition of IGF-1 and BMP-2 (BMP; bone morphogenetic proteins) [85]. In turn the osteogenesis is induced by the presence of ascorbic acid, -glycerophosphate and dexamethasone [86]. Differentiation of MSCs in the appropriate cell type is assessed by identifying the production of respectively: fat droplets (adipogenesis), proteoglycans and type II collagen synthesis (chondrogenesis) or mineralization of calcium deposits and the increase of alkaline phosphatase expression (osteogenesis). However, many literature reports indicate that by the treatment with appropriate factors MSCs might be also a source of other cell types. Caplan and Dennis in their work from 2006 present a process that they call mesengenesis, in which MSCs give also rise to myoblasts, bone marrow stromal cells, fibroblasts, cells co-creating connective tissue of the body as well as ligaments and tendons [87]. Addition of 5-azacytidine to MSCs allows to obtain muscle cells, including cardiomyocytes and myoblasts having the ability to create multinucleated miotubes and expressing markers such as: -myosin heavy chain, -actin cardiac form and desmin [88]. In addition, in vitro studies have made it possible to obtain from MSCs at least two types of cells derived from the endoderm through their transdifferentiation into hepatocytes and -cells of pancreatic islets. The liver cells are obtained from MSCs in two stages by culturing them in modified Dulbeccos medium supplemented with EGF, bFGF and nicotinamide, and in the next stage with the addition of oncostatin M, dexamethasone, insulin, transferrin and selenium. The resulting cells show the presence of markers typical for hepatocytes such as albumin, -fetoprotein and hepatocyte nuclear factor 4 (HNF-4) [89]. By the treatment with a mixture of growth factors secreted by regenerating cells of the pancreas as well as by the use of acitin A, sodium butyrate, taurine and nicotinamide the pancreatic islets of -cells capable of producing insulin were obtained from MSCs [90,91]. It has also been shown that stimulation with appropriate factors may result in the differentiation of MSCs into cells derived ontogenetically from ectoderm, such as neurons. The use of BME stimulation in vitro (-mercaptoethanol) followed by NGF leads to the differentiation of MSCs into cholinergic nerve cells expressing their typical proteins such as NF-68 neurofilaments (68 kDa Neurofilament protein with 68 kDa molecular mass), NF-200 (neurofilament protein with a molecular weight 200kDa, 200kDa neurofilament protein), NF-160 (neurofilament protein molecular weight 160kDa, 160kDa neurofilament protein), choline acetyltransferase and synapsin I [92]. Other factors mentioned as compounds inducing the transformation of MSCs into nerve cells are insulin, retinoic acid, bFGF, EGF, valproic acid, BME and hydrocortisol [93]. In addition, GNDF (glial cell-derived neurotrophic factor), BDNF (brain-derived neurotrophic factor), retinoic acid, 5-azacytidine, isobutylmethylxanthine and indomethacin stimulate the transformation of MSCs into mature neurons that express markers of nervous systems cells such as: nestin, -III tubulin, microtubule associated protein - MAP2 (microtubule associated protein 2) and neuron-specific enolase (ENO2; enolase 2) [94]. These studies show that under strictly controlled conditions prevailing during in vitro culture, in the presence of chemicals and growth factors, MSCs are able to turn into cells derived from all three embryonic germ layers ().

The differentiation potential of MSCs

It has been more than half a century since the curiosity has been revealed that not only hematopoietic cells, but also those capable of forming connective tissue reside in the bone marrow. Subsequent studies have begun to reveal the increasingly fascinating properties of these cells, which go far beyond forming connective tissue. This, combined with their easy derivation from various tissues, made them an attractive research object. Immunomodulatory properties, aiding repair of various tissues as well as differentiation potential to practically any types of cells stunned a whole host of scientists and established MSCs as a driving force of regenerative medicine and began also to play an increasingly important role in oncology [95]. We are currently observing a flood of clinical trials with the use of MSCs, and their number doubles every few years and currently reaches almost 1000 registered items on the clinicaltrials.gov website.

MSCs compose a negligible fraction of cells derived from in vivo tissues and there is no effective method to capture them directly. Therefore, MSCs need to be subjected to the process of in vitro expansion, which in clinical context is called biomanufacturing and biobanking and both terms are frequently used interchangeably to describe the process from procurement of cell source to deliver cells to the patients bed. The processing of MSCs must be performed according to current Good Manufacturing Practice (cGMP) as any other therapeutic agent and is subjected to extensive regulatory effort. Food and Drug Administration (FDA) is the main authority responsible for acceptance of medical products including those containing living cells such as MSCs in the USA. FDA has issued a perspective on MSC-based product characterization [96] and up-dated it in FDA Grand Round delivered by Steven Bauer, PhD, Chief of Cell and Tissue Therapies Branch at FDA on March 08, 2018. Both sources are an excellent overview of regulatory challenges related to the biobanking of MSCs. In general, any new product must obtain investigational new drug status (INDs) to be used in clinical trial before filing application for marketing, and there were 66 INDs submitted to FDA between 2006 and 2012. Based on that FDA engaged into regulatory research project called MSC consortium to characterize MSC based-products with an output of 16 research papers. The main organ responsible for the regulation of medical market in all Member States is European Medicines Agency (EMA) consisting of seven smaller committees. The MSCs-containing products should be classified as Advanced Therapy Medical Product (ATMP) and in detail considered as Somatic Cell Therapy Medicinal Product (CTMP) [97]. Its release on medical market has to be first accredited by Committee for Advanced Therapies (CAT) which creates the general opinion and evaluates the quality, safety and efficiency of the product. After CAT assessment the final acceptance should be then approved by Committee for the Medicinal Products for Human Use (CHMP). This type of legalization is called Centralized Marketing Authorization and it allows to use ATMP products in all European Union countries. Currently, there is a variety of protocols used for biomanufacturing and biobanking of MSCs, and once the successful stories become strong, the landscape of MSC production will probably solidify with predicted reduction of MSC production approaches due to economic and regulatory pressures.

Summing up, it seems that the MSCs are becoming a powerful global industry, ready to respond to the unmet needs of modern medicine struggling with the proper care and quality of life of rapidly aging societies, which is already affecting not only developed countries, but also very populous developing countries. In conclusion, we are beginning to observe the effect of the snowball in which ever new discoveries related to MSC are increasingly stimulating clinical applications of the MSC, which is beginning to contribute to the transformation of medical care.

Significance Statement

The research on bone marrow-derived stem cells of connective tissue is evolving and continuously expanding with a recent boost of interest in clinical applications reflected by an avalanche of nearly 1000 registered clinical trials. While, the current name: mesenchymal stem cells (MSCs) have been coined as late as early 90-ies, it is important to commemorate of the fiftieth anniversary of research on them and provide a big picture from roots of first paper in 1968, through identification of their various potential therapeutic activities such as immunomodulation, trophic support and capability for differentiation and taking role in cell replacement strategies.

This work was funded by NCR&D grant EXPLORE ME within the STRATEGMED I program and by NIH R01 NS091100-01A1.

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Mesenchymal stem cells: from roots to boost - PMC

Wilmington, Delaware, United States, Transparency Market Research Inc.: Cell line development is an important technology in life sciences. Stable cell lines are used for various applications including monoclonal antibody and recombinant protein productions, gene functional studies, and drug screening

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Manual screening method is a traditional method used for cell line development. This method is tend to be disadvantageous as it is labor-intensive and time-consuming. Automation in tools used for cell line development is likely to replace manual methods of cell line development.

Cell line development and culturing is being rapidly adopted in areas of biological drug developments for various chronic diseases, regenerative medicines such as stem cells & cell-based therapies, recombinant protein, and other cellular entities for pharmaceuticals, diagnostics, and various other industries.

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Key Drivers and Opportunities of Global Cell Line Development Market

Rise in focus on research & development, owing to increase in prevalence of cancer and other chronic diseases is anticipated to drive the market. Several institutes, such as Cancer Research Institute, National Cancer Institute, Advanced Centre for Treatment, Research and Education in Cancer (Cancer Research Centre [ICRC]), and NCI Community Oncology Research Program (NCORP), are engaged in research & development for cancer diagnosis and treatment. Hence, the initiative of government and non-government organizations is likely boost the growth of the market.

Mammalian cell lines are widely used as production tools for various biologic drugs. Technological advancement in cell line development in mammalian cell culturing is likely to fuel the growth of the market. For instance, according to an article published in Pharmaceuticals (Basel), the U.S. Food and Drug Administered approved 15 novel recombinant protein therapeutics from 2005 to 2011 on an average.

Advances in bioinformatics and recombinant technologies have led to development of new cell lines for synthesis or production of essential peptides, enzymes, saccharides, and other molecules which are being used in pharmaceuticals and various other industries.

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North America to Capture Major Share of Global Cell Line Development Market

North America is expected to account for major share of the global cell line development market due to well-established health care infrastructure and rise in government initiatives. Furthermore, adoption of innovative technologies is likely to augment the market in the region.

The cell line development market in Asia Pacific is expected to grow at a rapid pace during the forecast period, owing to increasing risk of communicable diseases, cancer, and chronic & rare diseases and surge in geriatric population. For instance, according to an article published in BioMed Central Ltd, in 2018, 2.9 million cancer deaths occurred and 4.3 million new cancer cases were recorded in China.

Key Players Operating in Global Cell Line Development Market

The global cell line development market is highly concentrated due to the presence of key players. A large number of manufacturers hold major share in their respective regions. Key players engaged in adopting new strategies are likely to drive the global cell line development market. Key players are developing new, cost-effective biologic products. This is anticipated to augment the market.

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Major players operating in the global cell line development market are:

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Cell Line Development Market: Increase in Prevalence of Cancer and Other Chronic Diseases to Drive the Market - BioSpace

The parents of a 12-year-old boy who's on life support are appealing the decision of the UK Royal Courts of Justice to remove his oxygen and other life-sustaining treatment. They're taking their case to a Court of Appeal hearing in London on Wednesday.

As CBN News reported earlier this month, Family Division of the High Court Judge Emma Arbuthnot ruled "on the balance of probabilities" Archie Battersbee had already died after doctors told the court "it was highly likely" he was "brain stem dead."

Archie's mother and father, Holly Dance and Paul Battersbee are trying to give their son every chance at life after he was found unconscious on April 7 with a cord around his neck. He reportedly had participated in what is believed to be an online blackout challenge, according to watchdog Christian Concern.

The boy has remained on life support at the Royal London Hospital and has not regained consciousness.

Judge Arbuthnot ordered, "Medical professionals at the Royal London Hospital (1) to cease to ventilate mechanically Archie Battersbee; (2) to extubate Archie Battersbee; (3) to cease the administration of medication to Archie Battersbee, and (4) not to attempt any cardio or pulmonary resuscitation on Archie Battersbee when cardiac output ceases or respiratory effort ceases."

"The steps I have set out above are lawful," the judge contended. But she also gave Archie's mother and father, Holly Dance and Paul Battersbee permission to appeal her ruling.

Arbuthnot said there was a "compelling reason" why appeal judges should consider the case, according to ITV News.

According to Christian Concern, this is believed to be the first time that someone in the UK has been declared 'likely' to be dead based on an MRI test.

At a High Court hearing about Archie's case on June 20, Christian Legal Centre attorney Edward Devereux QC argued that evidence should instead show 'beyond reasonable doubt', as in criminal proceedings, that Archie is dead, rather than using a balance of probabilities test.

Archie's parents have been fighting a legal battle to give their son more time and to allow him to have more medical tests to assess whether his condition improves before making the decision about withdrawing his life support.

In a statement, Archie's mother, Hollie, and sister-in-law, Ella Carter, asked: "If Archie can be pronounced dead via an MRI, which is outside the bounds of the law, then what's going to be next?"

They also thanked everyone for the support the family has received from around the world.

"Archie's words, if he was sitting next to me right now, would be 'it melts my heart' and I'll use those words now, because everyone's support does melt my heart. So, thank you and please continue to support us in this fight," the statement said.

Proof of Life?

Archie's parents say a video of him gripping his mother's fingers is proof that he's still alive and his brain is functioning.

But his doctors believe there's no hope for the boy to recover since they believe his brain stem is dead. Scans reportedly show blood is not flowing to the area, according to Sky News. The stem lies at the base of the brain above the spinal cord. It is responsible for regulating most of the body's automatic functions essential for life. Doctors previously said Archie's stem is 50% damaged and that 10% to 20% of the stem is in necrosis where cells have died and/or are decaying.

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Lawyers for the Barts Health NHS Trust said that doctors have repeatedly recreated the moment of the boy holding a clinician's hand, but the hospital workers said it was just "friction" not a grip, which the doctors say is consistent with muscle stiffness.

Eminent Pediatric Neurologist Testified About Cases of Persons Diagnosed as 'Brain Dead' Who Later Recovered

Dr. D. Alan Shewmon, M.D., professor emeritus of Neurology and Pediatrics at the University of California, gave expert testimony about numerous documented cases where persons diagnosed as 'brain dead' subsequently recovered.

When asked whether there was sufficient evidence for a reliable diagnosis of death in Archie's case, Shewmon replied, "Absolutely not."

An online petition to the hospital's chief executive officer has been created to ask that legal action be withdrawn in Archie's case. So far, more than 89,000 people have signed it.

A GoFundMe page has also been set up on the boy's behalf. So far, the account has raised 29,042 GBP (or approximately $35,479 in U.S. dollars).

Archie's mom told Christian Concern earlier this month that the judge's ruling that he's "likely" to be dead is not good enough.

"Basing this judgment on an MRI test and that he is 'likely' to be dead, is not good enough. This is believed to be the first time that someone has been declared 'likely' to be dead based on an MRI test," she explained.

"The medical expert opinion presented in Court was clear in that the whole concept of 'brain death' is now discredited, and in any event, Archie cannot be reliably diagnosed as brain-dead," Dance continued.

She reiterated that she does not believe her son has been given enough time to heal.

"I do not believe Archie has been given enough time. From the beginning, I have always thought 'why the rush?' His heart is still beating, he has gripped my hand, and as his mother, I know he is still in there," she noted.

"Until it's God's way, I won't accept he should go. I know of miracles when people have come back from being brain dead," Dance said.

Andrea Williams, chief executive of the Christian Legal Centre, said in a statement that Archie's case has raised "significant moral, legal and medical questions as to when a person is dead."

"Archie's parents believe that the time and manner of his death should be determined by God and claim a right to pray for a miracle until and unless that happens. That belief must be respected. The ideology of 'dignity in death', meaning a planned time of death as fixed and carried out by the doctors, should not be brutally imposed on families who do not believe in it," Williams said.

"We will continue to stand with the family as they appeal the ruling and continue to pray for a miracle," she concluded.

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Parents of 12-Year-Old Boy Praying for a Miracle, Appealing UK Judge's Decision to Remove Life Support - CBN.com

Global Surgical Mesh Market Is Estimated To Be Valued At US$ 1.29 Bn In 2022, And Is Forecast To Surpass US$ 2.2 Bn Valuation By The End Of 2032

Sales of surgical meshes are expected to account for more than 21 Mn units by 2032-end, owing to their increasing application in untapped markets, says a Fact.MR analyst.

Fact.MR A Market Research and Competitive Intelligence Provider: The global surgical mesh market is estimated to exceed a valuation of US$ 1.29 Bn in 2022, and expand at a significant CAGR of 5.5% by value over the assessment period (2022-2032).

The availability of surgical meshes in absorbable and non-absorbable forms has expanded their application for temporary as well as permanent reinforcement. In recent years, demand for surgical meshes has escalated in aiding breast reconstruction as they reduce the exposure risk of the implant. Increasing health literacy in North America and Europe will create ample opportunities for surgical mesh manufacturers over the coming years.

Sedentary lifestyle and increasing obesity among the population have resulted in several chronic health issues. The consequent weakening of the muscles extends space for organ prolapse and hernia. Putting these organs back in place by stitching the muscles together can result in muscle tearing and the recurrence of prolapse. However, reinforcing the weakened muscles with the help of a surgical mesh has shown to decrease recurrence and increase the longevity of the repair.

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Winning Strategy

To attract new customers, market players are focusing on portfolio enhancement. Robust investments in R&D are driving product innovation for key market players. Meshes inhibiting the growth of bacterial films and preventing tissue adhesions are luring new consumers. Collaboration of manufacturers with scientific personnel and operating surgeons have enabled bespoke designing of meshes to best fit patients needs.

Manufacturers are also aiming for portfolio expansion through acquisition and partnerships. Partnering with companies that offer a well-aligned portfolio has significantly increased consumer penetration for key manufacturers. However, augmenting relations with local players and operating surgeons will be a key determinant of the products commercial success.

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Scientific collaborations and robust R&D investments have also guided product innovation and became a common strategic approach adopted by leading surgical mesh manufacturing companies to upscale their market presence.

For instance:

Surgical Mesh Industry Research by Category

Surgical Mesh Market by Product Type:

Surgical Mesh Market by Nature:

Surgical Mesh Market by Surgical Access:

Surgical Mesh Market by Use Case:

Surgical Mesh Market by Raw Material:

Surgical Mesh Market by Region:

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Fact.MR, in its new offering, presents an unbiased analysis of the global surgical mesh market, presenting historical market data (2017-2021) and forecast statistics for the period of 2022-2032.

The study reveals essential insights on the basis of product type (synthetic, biosynthetic, biologic, hybrid/composite), nature of mesh (absorbable, non-absorbable, partially absorbable), surgical access (open surgery, laparoscopic surgery), use case (hernia repair, pelvic floor disorder treatment, breast reconstruction, others), and raw material (polypropylene, polyethylene terephthalate, expanded polytetrafluoroethylene, polyglycolic acid, decellularized dermis/ECM, others), across seven major regions (North America, Latin America, Europe, East Asia, South Asia & ASEAN, Oceania, MEA).

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With a repertoire of over thousand reports and 1 million-plus data points, the team has analysed the healthcare domain across 50+ countries for over a decade. The team provides unmatched end-to-end research and consulting services.

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Technical Advancements & Innovative Products Likely to Expand Application of Surgical Meshes in Untapped Domains, States Fact.MR - BioSpace

A paper recently published in the journal Biomaterials reviewed the new advances in three-dimensional bioprinting (3DBP) for regenerative therapy in different organ systems.

Study:Advances in 3D bioprinting of tissues/organs for regenerative medicine and in-vitro models. Image Credit:luchschenF/Shutterstock.com

Organ/tissue shortage has emerged as a significant challenge in the medical field due to patient immune rejections and donor scarcity. Moreover, mimicking or predicting the human disease condition in the animal models is difficult during preclinical trials owing to the differences in the disease phenotype between animals and humans.

3DBP has gained significant attention as a highly-efficient multidisciplinary technology to fabricate 3D biological tissue with complex composition and architecture. This technology allows precise assembly and deposition of biomaterials with donor/patients cells, leading to the successful fabrication of organ/tissue-like structures, preclinical implants, and in vitro models.

In this study, researchers reviewed the 3DBP strategies currently used for regenerative therapy in eight organ systems, including urinary, respiratory, gastrointestinal, exocrine and endocrine, integumentary, skeletal, cardiovascular, and nervous systems. Researchers also focused on the application of 3DBP to fabricate in vitro models. The concept of in situ 3DBP was discussed.

In this extensively used low-cost bioprinting method, rotating screw gear or pressurized air is used without or with temperature to extrude a continuous stream of thermoplastic or semisolid material. Different materials can be printed at a high fabrication speed using this technology. However, low cell viability and the need for post-processing are the major drawbacks of extrusion bioprinting.

In this method, liquid drops are ejected on a substrate by acoustic or thermal forces. High fabrication speed, small droplet volume, and interconnected micro-porosity gradient in the fabricated 3D structures are the main advantages of this technique. However, limited printed materials and clogging are the biggest drawbacks of inkjet bioprinting.

A laser is used to induce the forward transfer of biomaterials on a solid surface in the laser-assisted bioprinting method. High cell viability and nozzle-free noncontact process are the biggest advantages of laser-assisted bioprinting, while metallic particle contamination and the time-consuming nature of the printing process are the major disadvantages.

Several studies were performed involving the development of neuronal tissues using the 3DBP method. The pressure extrusion/syringe extrusion (PE/SE) bioprinting technique was used for central nervous tissue (CNS) tissue replacement. The layered porous structure was fabricated using glial cells derived using human induced pluripotent stem cell (iPSC) and a novel bioink based on agarose, alginate, and carboxymethyl chitosan (CMC) formed synaptic networks and displayed a bicuculline-induced enhanced calcium response.

Similarly, stereolithography (SLA) was used to fabricate a 3D scaffold for CNS and the viability of the scaffold was evaluated for regenerative medicine application. Layered linear microchannels were printed using poly(ethylene glycol) diacrylate-gelatin methacrylate (PEGDA-GelMA) and rat E14 neural progenitor cells (NPCs). The 3D scaffold restored the synaptic contacts and significantly improved the functional outcomes. Cyclohexane was used to bond polystyrene fibers to matrix bundle terminals during crosslinking.

Multiphoton excited 3-dimensional printing (MPE-3DP) was employed for the regeneration of myocardial tissue. A layer-by-layer structure was fabricated using GelMA/ sodium 4-[2-(4-morpholino)benzoyl-2-dimethylamino]-butylbenzenesulfonate (MBS) and human hciPSC-derived cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs). The crosslinking was performed by photoactivation. The structure promoted electromechanical coupling and improved cell proliferation, vascularity, and cardiac function.

Fused deposition modeling (FDM) and PE/SE bioprinting method were used for complex tissue and organ regeneration. A micro-fluid network heart shape structure was fabricated using polyvinyl alcohol (PVA), agarose, sodium alginate, and platelet-rich plasma and rat H9c2 cells and human umbilical vein endothelial cells (HUVECs). 2% calcium dichloride was used during the crosslinking mechanism. The fabricated structure possessed a valentine heart with hollow mechanical properties and a self-defined height.

SE printing was utilized to fabricate a capillary-like network using collagen type1/ xanthan gum and human fibroblasts and ECs for applications in blood vessels. The fabricated network possessed endothelial networks and sprouting between the fibroblast layers.

Bone, cartilage, and skeletal muscle tissue can be repaired and regenerated using the 3DBP technique. For instance, FDM printing was used to print multifunctional therapeutic scaffolds for the treatment of bone. Filopodial projections were fabricated using polylactic acid (PLA) platform loaded with hyaluronic acid (HA)/ iron oxide nanoparticles (IONS)/ minocycline and human MG-63 and human bone marrow stromal cells (hBMSCs), which improved the osteogenic stimulation of the IONS and HA.

PE/SE method was used to fabricate disks and cuboid-shaped scaffolds using - tricalcium phosphate (TCP) microgel and human fetal osteoblast (hFOB) and bone marrow-derived mesenchymal stem cell (BM-MSC) for bone repair, multicellular delivery, and disease model. The fabricated structures promoted osteogenesis.

PE/SE bioprinting was also utilized to fabricate complex porous layered cartilage-like structures using alginate/gelatin/HA, rat bone marrow mesenchymal stem cells (BMSCs), and cow cardiac progenitor cells (CPCs) for hyaline cartilage regeneration. The CPCs upregulated gene expression of proteoglycan 4 (PRG4), SRY-box transcription factor 9 (SOX9), and collagen II.

PE/SE printing was also used to fabricate multinucleated, highly-aligned myotube structures using polyurethane (PU), poly(-caprolactone) (PCL), and mouse C2C12 myoblasts and NIH/3T3 fibroblasts for in-situ expansion and differentiation of skeletal muscle tendon. The fabricated constructs demonstrated more than 80% cell viability with initial tissue differentiation and development.

SLA bioprinting technique was used to fabricate bi-layered epidermis-like structure using collagen type I, mouse NIH 3T3 fibroblast cells, and human keratinocyte cells for tissue model and engineering. The fabricated constructs effectively imitated the tissue functions.

Similarly, PE was employed to fabricate microporous structures using human amniotic mesenchymal stem cells (AFSCs) and heparin-HA-PEGDA for wound healing. The construct improved the wound closure and reepithelialization, increased extracellular matrix synthesis and vascularization, and prolonged the cell paracrine activity.

PE technique was utilized to prepare a multilayered cornea-like structure using human keratocytes and methacrylated collagen (ColMA)-alginate. The cell viability of the keratocytes decreased from 90% to 83% after printing.

PE/SE bioprinting was utilized to bioprint multilayered liver-like structures using GeIMA and human HepG2/C3A for liver tissue engineering. Similarly, hepatocytes were also bioprinted to fabricate multiple organ precursors with branching vasculature. A small intestine model with improved intestinal function and high cell proliferation was fabricated using caco-2 cell-loaded polyethylene vinyl acetate (PEVA) scaffold.

Spheroids of mesenchymal stem cells (MSCs) and chondrocytes and lung endothelial cells were utilized to fabricate scaffold-free tracheal transplant. After implantation in the rat model, the matured spheroids displayed excellent vasculogenesis, chondrogenesis, and mechanical strength. FDM technique was used to fabricate a glomerular structure for kidneys using human iPSCs and hydrogel and a hollow porous network using poly(lactic-co-glycolic acid (PLGA)/PCL/tumor-associated endothelial cells (TECs) for the urethra.

In in-situ bioprinting, the tissue is directly printed on the specific defect or wound site in the body for regenerative and reparative therapy. This method provides a well-defined structure and reduces the gap between host-implant interfaces. In-situ bioprinting is better than in vitro bioprinting techniques as the patients body, as a natural bioreactor, provides a natural microenvironment.

Several studies have evaluated this technique for tissue regeneration. For instance, PE/SE method was used for skin tissue regeneration in pigs and mice using fibrin/collagen/HA and human fibroblast cells. Skin-laden sheets of consistent composition, thickness, and width were formed upon rapid crosslinking of biomaterial. PE/SE technique was also used for neural tissue regeneration in mice using agarose/CMC/alginate and human iPSCs.

In vitro models provide significant assistance in understanding the mechanism of therapeutics and disease pathophysiology. Recently, in vitro models of human tissues and organs were engineered using 3DBP technology for safety assessment and drug testing.

In the 3DBP of organs and tissues, biomaterials play a crucial role in maintaining cellular viability, providing support, and long-term acceptance. Specifically, bioinks must possess unique properties, such as cell growth promotion and structural stability, that can be optimized for clinical use. Additionally, bioinks must be compatible with printers for high-precision rapid prototyping.

Bioinks fulfilling all of these requirements are yet to be identified. Moreover, managing the time during the bioprinting of the constructs is another major challenge, as the time required to fabricate them is often more than the survival time of cells. A bioreactor platform that supports organoid growth and provides time for tissue remodeling can be used to overcome this challenge. Ethical challenges and issues are also a hurdle since fabricating internal tissues/organs can lead to liability and biosafety concerns.

In the future, 3DBP can provide novel solutions to engineer organs/tissues and revolutionize modern healthcare and medicine if these challenges can be addressed.

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Jain, P., Kathuria, H., Dubey, N. Advances in 3D bioprinting of tissues/organs for regenerative medicine and in-vitro models. Biomaterials 2022. https://www.sciencedirect.com/science/article/abs/pii/S0142961222002794?via%3Dihub

Disclaimer: The views expressed here are those of the author expressed in their private capacity and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the Terms and conditions of use of this website.

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What New Advances are there in 3D Bioprinting Tissues? - AZoM

Second-line lisocabtagene maraleucel (liso-cel; Breyanzi) provides an earlier CAR T-cell treatment option that improves survival outcomes and produces a manageable safety profile in patients with relapsed/refractory large B-cell lymphoma (LBCL), including those who are older and have comorbidities, according to Nilanjan Ghosh, MD, PhD.

On June 24, 2022, the FDA approved liso-cel in the second line for patients with relapsed/refractory LBCL, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal LBCL, follicular lymphoma grade 3B, and high-grade B-cell lymphoma. This approval was supported by data from the phase 3 TRANSFORM trial (NCT03575351) and the phase 2 TRANSCEND-PILOT-017006 study (NCT03483103).

Liso-cel is a fantastic option, because it has a great efficacy profile and is also a safe product amongst the available CAR T-cell products, with a relatively low incidence of cytokine release syndrome [CRS] and neurological events [NEs], the majority of which are low grade, Ghosh said.

In an interview with OncLive, Ghosh, director of the Lymphoma Program at the Levine Cancer Institute of Atrium Health, discussed the significance of the liso-cel approval in this patient population. He also highlighted how liso-cel will influence current treatment sequencing, which patients might derive the most benefit from this therapy, and the adverse effects (AEs) to be aware of and try to mitigate when prescribing liso-cel.

Ghosh: This approval is highly significant. The majority of patients with primary refractory DLBCL and early relapsed DLBCL do not derive benefit from standard-of-care [SOC] salvage chemotherapy followed by ASCT [autologous stem cell transplant], [which had been the best option until now].

The data from the TRANSFORM study showed liso-cel to be superior to high-dose salvage chemotherapy and ASCT. This approval will allow earlier access to CAR T-cell therapy for this group of patients.

Most patients with LBCL receive frontline therapy in the community setting. In addition to making our community aware of this indication, we need to educate our community about the time it takes to receive CAR T-cell therapy. The process includes many steps, such as gaining financial clearance and setting a date for T-cell collection, or leukapheresis. This date must be acceptable to both the institution [providing the treatment] and the company manufacturing the CAR T cells. [We also need to factor in] the time spent manufacturing the CAR T cells, often known as the vein-to-vein time. This entire process can take 6 weeks or more.

We often focus on just the vein-to-vein time, but there are many other steps even before leukapheresis. These patients are also refractory or have early relapsed disease that must be controlled while they are waiting to receive CAR T-cell therapy. Early referral to a CAR T-cell center is crucial to get the process going while discussing with the referring physician ways and means to control the disease in the interim. Those might include strategies like bridging therapy, which was allowed on the TRANSFORM study.

Insome patients, liso-cel may end up being a third-line therapy, despite its indication as a second-line therapy, because you may have to give another therapy to control the disease while the patients are waiting to receive CAR T cells. That discussion would best be done with the treating center and the referring physician, because some treatments can be toxic to lymphocytes, and you may want to avoid those kinds of treatments prior to collecting the lymphocytes. At the same time, we must make sure we control the disease so the patients can receive the treatment they may benefit from in the future.

Many factors must be taken into account before giving liso-cel. We look at the ECOG performance status [PS], as well as cardiac function and renal function.

Looking at comorbidities, fortunately, the TRANSCEND-PILOT-017006 trial included patients with comorbidities who were not considered good candidates for ASCT. To enroll in the study, the investigators needed to verify that the patients were not good candidates for transplant. [They also needed to meet at least 1 of the criteria], which included being over 70 years of age, having impaired renal function, having impaired cardiac function, or having a decrease in [diffusing capacity of the lungs for carbon monoxide], which is reflective of pulmonary function. The investigators also looked at hepatic function.

The outcomes of this study were good. The bottom line is that patients who are going to receive liso-cel need not only be candidates you would otherwise consider for ASCT. The eligibility for liso-cel is much broader than standard transplanteligibility in terms of age, comorbidities, and disease status. That is the most important thing. A patient who is older, has some comorbidities, and has relapsed or refractory LBCL can still benefit from liso-cel with high efficacy and low toxicity, which is what liso-cel offers in this patient population.

TRANSFORM was a randomized study of patients with DLBCL not otherwise specified, which includes de novo DLBCL and those who have transformed from indolent non-Hodgkin lymphoma; high-grade B cell lymphoma, which includes double-hit and triple-hit lymphoma; follicular lymphoma grade 3B; primary mediastinal B-cell lymphoma; and T-cell or histiocyte-rich DLBCL. Eligible patients needed to have either developed refractory disease from frontline therapy or relapsed within 12 months after frontline therapy. The frontline therapy should have included an anthracycline anda CD20 agent, which is the SOC. In addition, these patients should have been otherwise considered to be eligible for ASCT and had an ECOG PS of 0 to 1.

Eligible patients underwent leukapheresis and then were randomized to receive liso-cel or SOC, which was salvage chemotherapy followed by ASCT for those who responded to salvage chemotherapy. Importantly, this study included crossover from the SOC arm to the liso-cel arm. This was allowed for those who failed to respond to SOC by 9 weeks post-randomization, those who progressedat any time, or those who started a new antineoplastic therapy after transplant.

The primary end point was event-free survival [EFS]. Events were defined as death from any cause, progressive disease, failure to achieve complete response [CR] or partial response by 9 weeks post randomization, or the start of an antineoplastic therapy, whichever occurred first. The median EFS with liso-cel was 10.1 months compared with 2.3 months with SOC. At 12 months, the EFS rates were 44.5% with liso-cel and 23.7% with SOC. That was a significant margin of benefit.

In terms of responses, in this recent population, were most interested in CR. A total of 66% of the patients who received liso-cel achieved a CR compared with 39% of those who received SOC.

Progression-free survival [PFS] was also a secondary end point. The median PFS was 14.8 months with liso-cel and 5.7 months with SOC. Efficacy-wise, liso-cel hit all the marks. Overall survival [OS] data is maturing, so well need some longer follow-up, but we are starting to see trends in the right direction.

We have to remember that this study included crossover. Of the 91 patients in the SOC arm, 50 [crossed over to receive] CAR T-cell therapy with liso-cel. Those data will affect the OS data, but even so, were starting to see some separation of the OS curves in the TRANSFORM study.

The TRANSCEND-PILOT-017006 study is a little different because its a single-arm study. It was not intended for patients who would be otherwise considered transplant candidates. These patients did not need to relapse within 1 year [of frontline therapy], and they could have relapsed or refractory disease. A total of 25% of patients had late relapses as well, which was not the case in TRANSFORM. Otherwise, they all had 1 prior line of therapy, [like in TRANSFORM].

This is also a second-line study but in a different population of patients. This was an elderly population. Compared with the TRANSFORM study, the median age in the TRANSCEND-PILOT-017006 study was 74 years, with the oldest patient being 84 years of age. In total, 33% of patients in this study had double-hit and triple-hit disease, which I want to highlight because this is the toughest group of patients to treat. A total of 54% of the patients had primary refractory disease, [and many patients had comorbidities].

Additionally, 44% of the patients had an HCT-CI [Hematopoietic Cell Transplantation-Specific Comorbidity Index] score of 3 or more. We dont know the relevance [of this score] for CAR T-cell therapy, but outcomes are typically poor in patients who have an HCT-CI score of 3 or higher who undergoallogeneic transplant or ASCT.

[In this trial], the overall response rate was great, at 80%, with 54% achieving CR. Responses were seen in all prespecified subgroups, including patients with high-risk features, with no notable differences in efficacy or safety outcomes based on HCT-CI score. Investigators did separate out patients who had scores of less than 3 vs 3 or higher, and they didnt see any differences.

The median duration of response [DOR] was [11.2 months in patients with an HCT-CI score under 3, and not reached in patients with an HCT-CI score of 3 or higher].In patients who achieved a CR, the median DOR was 21.7 months.

The median PFS was [7.4 months in patients with an HCT-CI score under 3, and NR in patients with an HCT-CI score of 3 or higher]. The median OS was not reached.

Importantly, 32.8% of the patients were monitored as outpatients in this study, and 35% of those needed to be hospitalized for concerns of CRS and neurotoxicity after receiving liso-cel. Most of the patients who received liso-cel as outpatients did not need hospitalization within 3 days of receiving it. These results support liso-cel as a second-line treatment in patients with LBCL in whom transplant is not intended.

In general, the acute AEs that occur with any CAR T-cell therapy, but which are much lower with liso-cel, are CRS and NEs. These occur immediately post-CAR T-cell therapy, within days.

However, the incidence of CRS and NEs was low in both [TRANSFORM and TRANSCEND-PILOT-017006]. Most CRS events were grade 1 or grade 2. In total, 1 patient in each study had grade 3 CRS, and there were no instances of grade 4 CRS [in either study].

The incidence of neurotoxicity was also quite low. [A total of 4% of patients in the TRANSFORM study and 5% of patients in the TRANSCEND-PILOT-017006 study experienced] grade 3 neurotoxicity. Most of the neurotoxicity that was seen was grade 1 or grade 2. Importantly, the utilization of tocilizumab [Actemra] and steroids was also low [in both trials].

However, there are other AEs which we need to monitor. For example, by the time a patient is out of that CRS and neurotoxicity window and thinking of going back to their referring physician, they may still [be at risk for AEs such as] prolonged cytopenias, [which some patients exhibited in these trials]. In the [TRANSFORM] study, prolonged cytopenias were defined as [grade 3 cytopenias that persisted] at day 35 or beyond. [In the TRANSCEND-PILOT-017006 study, prolonged cytopenias were defined as grade 3 or higher cytopenias that persisted at day 29 or beyond.]

We should also monitor for hypogammaglobulinemia. This is important because if a patient has hypogammaglobulinemia or lymphopenia, and neutropenia, they are more prone to infection. Preventing infection, providing supportive care, and giving treatment medications [as early as possible] is important, and monitoring AEs is crucial.

The field of LBCL has exploded with new treatments over the past few years, including what we saw recently in the frontline setting. CAR T-cell therapy, in general, is a huge advancement within this field.

Having said that, its important to be aware of and monitor the AEs. A question that comes up is: How accessible are CAR T-cell therapies going to be? We need to work as a community to make them more accessible to patients, cut down the time from when we first consider CAR T-cell therapy to when we deliver it, and make that process more efficient, so more patients can benefit from it.

We also need to be aware of the many other treatments that have come out in the space, such as bispecific antibodies that are in development and antibody-drug conjugates. Over the next few years, we need to figure out how to sequence thesetherapies so that we can maximize the benefits and help our patients who still have unmet needs. We do have to recognize that even though CAR T-cell therapy has excellent outcomes, there are many patients who are still refractory to CAR T-cell therapy and relapse after CAR T-cell therapy. [We need to find] the best way to sequence the other treatments that are out there to help these patients. Thats an area of active investigation.

I hope we are in a much better place in the years to come. However, weve made huge strides in the past several years, and its been great to be a part of that research.

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Liso-cel Approval Provides Earlier, Expanded Access to CAR T-cell Therapy in Second-line LBCL - OncLive

Stem cell technology will transform medical practice. While stem cell research has already elucidated many basic disease mechanisms, the promise of stem cellbased therapies remains largely unrealized. In this review, we begin with an overview of different stem cell types. Next, we review the progress in using stem cells for regenerative therapy. Last, we discuss the risks associated with stem cellbased therapies.

There are three major types of stem cells as follows: adult stem cells (also called tissue-specific stem cells), embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells.

A majority of adult stem cells are lineage-restricted cells that often reside within niches of their tissue of origin. Adult stem cells are characterized by their capacity for self-renewal and differentiation into tissue-specific cell types. Many adult tissues contain stem cells including skin, muscle, intestine, and bone marrow (Gan et al, 1997; Artlett et al, 1998; Matsuoka et al, 2001; Coulombel, 2004; Humphries et al, 2011). However, it remains unclear whether all adult organs contain stem cells. Adult stem cells are quiescent but can be induced to replicate and differentiate after tissue injury to replace cells that have died. The process by which this occurs is poorly understood. Importantly, adult stem cells are exquisitely tissue-specific in that they can only differentiate into the mature cell type of the organ within which they reside (Rinkevich et al, 2011).

Thus far, there are few accepted adult stem cellbased therapies. Hematopoietic stem cells (HSCs) can be used after myeloablation to repopulate the bone marrow in patients with hematologic disorders, potentially curing the underlying disorder (Meletis and Terpos, 2009; Terwey et al, 2009; Casper et al, 2010; Hill and Copelan, 2010; Hoff and Bruch-Gerharz, 2010; de Witte et al, 2010). HSCs are found most abundantly in the bone marrow, but can also be harvested at birth from umbilical cord blood (Broxmeyer et al, 1989). Similar to the HSCs harvested from bone marrow, cord blood stem cells are tissue-specific and can only be used to reconstitute the hematopoietic system (Forraz et al, 2002; McGuckin et al, 2003; McGuckin and Forraz, 2008). In addition to HSCs, limbal stem cells have been used for corneal replacement (Rama et al, 2010).

Mesenchymal stem cells (MSCs) are a subset of adult stem cells that may be particularly useful for stem cellbased therapies for three reasons. First, MSCs have been isolated from a variety of mesenchymal tissues, including bone marrow, muscle, circulating blood, blood vessels, and fat, thus making them abundant and readily available (Deans and Moseley, 2000; Zhang et al, 2009; Lue et al, 2010; Portmann-Lanz et al, 2010). Second, MSCs can differentiate into a wide array of cell types, including osteoblasts, chondrocytes, and adipocytes (Pittenger et al, 1999). This suggests that MSCs may have broader therapeutic applications compared to other adult stem cells. Third, MSCs exert potent paracrine effects enhancing the ability of injured tissue to repair itself. In fact, animal studies suggest that this may be the predominant mechanism by which MSCs promote tissue repair. The paracrine effects of MSC-based therapy have been shown to aid in angiogenic, antiapoptotic, and immunomodulatory processes. For instance, MSCs in culture secrete hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) (Nagaya et al, 2005). In a rat model of myocardial ischemia, injection of human bone marrow-derived stem cells upregulated cardiac expression of VEGF, HGF, bFGF, angiopoietin-1 and angiopoietin-2, and PDGF (Yoon et al, 2005). In swine, injection of bone marrow-derived mononuclear cells into ischemic myocardium was shown to increase the expression of VEGF, enhance angiogenesis, and improve cardiac performance (Tse et al, 2007). Bone marrow-derived stem cells have also been used in a number of small clinical trials with conflicting results. In the largest of these trials (REPAIR-AMI), 204 patients with acute myocardial infarction were randomized to receive bone marrow-derived progenitor cells vs placebo 37 days after reperfusion. After 4 months, the patients that were infused with stem cells showed improvement in left ventricular function compared to control patients. At 1 year, the combined endpoint of recurrent ischemia, revascularization, or death was decreased in the group treated with stem cells (Schachinger et al, 2006).

Embryonic stem cells are derived from the inner cell mass of the developing embryo during the blastocyst stage (Thomson et al, 1998). In contrast to adult stem cells, ES cells are pluripotent and can theoretically give rise to any cell type if exposed to the proper stimuli. Thus, ES cells possess a greater therapeutic potential than adult stem cells. However, four major obstacles exist to implementing ES cells therapeutically. First, directing ES cells to differentiate into a particular cell type has proven to be challenging. Second, ES cells can potentially transform into cancerous tissue. Third, after transplantation, immunological mismatch can occur resulting in host rejection. Fourth, harvesting cells from a potentially viable embryo raises ethical concerns. At the time of this publication, there are only two ongoing clinical trials utilizing human ES-derived cells. One trial is a safety study for the use of human ES-derived oligodendrocyte precursors in patients with paraplegia (Genron based in Menlo Park, California). The other is using human ES-derived retinal pigmented epithelial cells to treat blindness resulting from macular degeneration (Advanced Cell Technology, Santa Monica, CA, USA).

In stem cell research, the most exciting recent advancement has been the development of iPS cell technology. In 2006, the laboratory of Shinya Yamanaka at the Gladstone Institute was the first to reprogram adult mouse fibroblasts into an embryonic-like cell, or iPS cell, by overexpression of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 under ES cell culture conditions (Takahashi and Yamanaka, 2006). Yamakana's pioneering work in cellular reprogramming using adult mouse cells set the foundation for the successful creation of iPS cells from adult human cells by both his team (Takahashi et al, 2007) and a group led by James Thomson at the University of Wisconsin (Yu et al, 2007). These initial proof of concept studies were expanded upon by leading scientists such as George Daley, who created the first library of disease-specific iPS cell lines (Park et al, 2008). These seminal discoveries in the cellular reprogramming of adult cells invigorated the stem cell field and created a niche for a new avenue of stem cell research based on iPS cells and their derivatives. Since the first publication on cellular reprogramming in 2006, there has been an exponential growth in the number of publications on iPS cells.

Similar to ES cells, iPS cells are pluripotent and, thus, have tremendous therapeutic potential. As of yet, there are no clinical trials using iPS cells. However, iPS cells are already powerful tools for modeling disease processes. Prior to iPS cell technology, in vitro cell culture disease models were limited to those cell types that could be harvested from the patient without harm usually dermal fibroblasts from skin biopsies. However, mature dermal fibroblasts alone cannot recapitulate complicated disease processes involving multiple cell types. Using iPS technology, dermal fibroblasts can be de-differentiated into iPS cells. Subsequently, the iPS cells can be directed to differentiate into the cell type most beneficial for modeling a particular disease process. Advances in the production of iPS cells have found that the earliest pluripotent stage of the derivation process can be eliminated under certain circumstances. For instance, dermal fibroblasts have been directly differentiated into dopaminergic neurons by viral co-transduction of forebrain transcriptional regulators (Brn2, Myt1l, Zic1, Olig2, and Ascl1) in the presence of media containing neuronal survival factors [brain-derived neurotrophic factor, neurotrophin-3 (NT3), and glial-conditioned media] (Qiang et al, 2011). Additionally, dermal fibroblasts have been directly differentiated into cardiomyocyte-like cells using the transcription factors Gata4, Mef2c, and Tb5 (Ieda et al, 2010). Regardless of the derivation process, once the cell type of interest is generated, the phenotype central to the disease process can be readily studied. In addition, compounds can be screened for therapeutic benefit and environmental toxins can be screened as potential contributors to the disease. Thus far, iPS cells have generated valuable in vitro models for many neurodegenerative (including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis), hematologic (including Fanconi's anemia and dyskeratosis congenital), and cardiac disorders (most notably the long QT syndrome) (Park et al, 2008). iPS cells from patients with the long QT syndrome are particularly interesting as they may provide an excellent platform for rapidly screening drugs for a common, lethal side effect (Zwi et al, 2009; Malan et al, 2011; Tiscornia et al, 2011). The development of patient-specific iPS cells for in vitro disease modeling will determine the potential for these cells to differentiate into desired cell lineages, serve as models for investigating the mechanisms underlying disease pathophysiology, and serve as tools for future preclinical drug screening and toxicology studies.

Despite substantial improvements in therapy, cardiovascular disease remains the leading cause of death in the industrialized world. Therefore, there is a particular interest in cardiovascular regenerative therapies. The potential of diverse progenitor cells to repair damaged heart tissue includes replacement (tissue transplant), restoration (activation of resident cardiac progenitor cells, paracrine effects), and regeneration (stem cell engraftment forming new myocytes) (Codina et al, 2010). It is unclear whether the heart contains resident stem cells. However, experiments show that bone marrow mononuclear cells (BMCs) can repair myocardial damage, reduce left ventricular remodeling, and improve heart function by myocardial regeneration (Hakuno et al, 2002; Amado et al, 2005; Dai et al, 2005; Schneider et al, 2008). The regenerative capacity of human heart tissue was further supported by the detection of the renewal of human cardiomyocytes (1% annually at the age of 25) by analysis of carbon-14 integration into human cardiomyocyte DNA (Bergmann et al, 2009). It is not clear whether cardiomyocyte renewal is derived from resident adult stem cells, cardiomyocyte duplication, or homing of non-myocardial progenitor cells. Bone marrow cells home to the injured myocardium as shown by Y chromosome-positive BMCs in female recipients (Deb et al, 2003). On the basis of these promising results, clinical trials in patients with ischemic heart disease have been initiated primarily using bone marrow-derived cells. However, these small trials have shown controversial results. This is likely due to a lack of standardization for cell harvesting and delivery procedures. This highlights the need for a better understanding of the basic mechanisms underlying stem cell isolation and homing prior to clinical implementation.

Although stem cells have the capacity to differentiate into neurons, oligodendrocytes, and astrocytes, novel clinical stem cellbased therapies for central and peripheral nervous system diseases have yet to be realized. It is widely hoped that transplantation of stem cells will provide effective therapy for Parkinson's disease, Alzheimer's disease, Huntington's Disease, amyloid lateral sclerosis, spinal cord injury, and stroke. Several encouraging animal studies have shown that stem cells can rescue some degree of neurological function after injury (Daniela et al, 2007; Hu et al, 2010; Shimada and Spees, 2011). Currently, a number of clinical trials have been performed and are ongoing.

Dental stem cells could potentially repair damaged tooth tissues such as dentin, periodontal ligament, and dental pulp (Gronthos et al, 2002; Ohazama et al, 2004; Jo et al, 2007; Ikeda et al, 2009; Balic et al, 2010; Volponi et al, 2010). Moreover, as the behavior of dental stem cells is similar to MSCs, dental stem cells could also be used to facilitate the repair of non-dental tissues such as bone and nerves (Huang et al, 2009; Takahashi et al, 2010). Several populations of cells with stem cell properties have been isolated from different parts of the tooth. These include cells from the pulp of both exfoliated (children's) and adult teeth, the periodontal ligament that links the tooth root with the bone, the tips of developing roots, and the tissue that surrounds the unerupted tooth (dental follicle) (Bluteau et al, 2008). These cells probably share a common lineage from neural crest cells, and all have generic mesenchymal stem cell-like properties, including expression of marker genes and differentiation into mesenchymal cells in vitro and in vivo (Bluteau et al, 2008). different cell populations do, however, differ in certain aspects of their growth rate in culture, marker gene expression, and cell differentiation. However, the extent to which these differences can be attributed to tissue of origin, function, or culture conditions remains unclear.

There are several issues determining the long-term outcome of stem cellbased therapies, including improvements in the survival, engraftment, proliferation, and regeneration of transplanted cells. The genomic and epigenetic integrity of cell lines that have been manipulated in vitro prior to transplantation play a pivotal role in the survival and clinical benefit of stem cell therapy. Although stem cells possess extensive replicative capacity, immune rejection of donor cells by the host immune system post-transplantation is a primary concern (Negro et al, 2012). Recent studies have shown that the majority of donor cell death occurs in the first hours to days after transplantation, which limits the efficacy and therapeutic potential of stem cellbased therapies (Robey et al, 2008).

Although mouse and human ES cells have traditionally been classified as being immune privileged, a recent study used in vivo, whole-animal, live cell-tracing techniques to demonstrate that human ES cells are rapidly rejected following transplantation into immunocompetent mice (Swijnenburg et al, 2008). Treatment of ES cell-derived vascular progenitor cells with inter-feron (to upregulate major histocompatibility complex (MHC) class I expression) or in vivo ablation of natural killer (NK) cells led to enhanced progenitor cell survival after transplantation into a syngeneic murine ischemic hindlimb model. This suggests that MHC class I-dependent, NK cell-mediated elimination is a major determinant of graft survivability (Ma et al, 2010). Given the risk of rejection, it is likely that initial therapeutic attempts using either ES or iPS cells will require adjunctive immunosuppressive therapy. Immunosuppressive therapy, however, puts the patient at risk of infection as well as drug-specific adverse reactions. As such, determining the mechanisms regulating donor graft tolerance by the host will be crucial for advancing the clinical application of stem cellbased therapies.

An alternative strategy to avoid immune rejection could employ so-called gene editing. Using this technique, the stem cell genome is manipulated ex vivo to correct the underlying genetic defect prior to transplantation. Additionally, stem cell immunologic markers could be manipulated to evade the host immune response. Two recent papers offer alternative methods for gene editing. Soldner et al (2011) used zinc finger nuclease to correct the genetic defect in iPS cells from patients with Parkinson's disease because of a mutation in the -Synuclein (-SYN) gene. Liu et al (2011) used helper-dependent adenoviral vectors (HDAdV) to correct the mutation in the Lamin A (LMNA) gene in iPS cells derived from patients with HutchinsonGilford Progeria (HGP), a syndrome of premature aging. Cells from patients with HGP have dysmorphic nuclei and increased levels of progerin protein. The cellular phenotype is especially pronounced in mature, differentiated cells. Using highly efficient helper-dependent adenoviral vectors containing wild-type sequences, they were able to use homologous recombination to correct two different Lamin A mutations. After genetic correction, the diseased cellular phenotype was reversed even after differentiation into mature smooth muscle cells. In addition to the potential therapeutic benefit, gene editing could generate appropriate controls for in vitro studies.

Finally, there are multiple safety and toxicity concerns regarding the transplantation, engraftment, and long-term survival of stem cells. Donor stem cells that manage to escape immune rejection may later become oncogenic because of their unlimited capacity to replicate (Amariglio et al, 2009). Thus, ES and iPS cells may need to be directed into a more mature cell type prior to transplantation to minimize this risk. Additionally, generation of ES and iPS cells harboring an inducible kill-switch may prevent uncontrolled growth of these cells and/or their derivatives. In two ongoing human trials with ES cells, both companies have provided evidence from animal studies that these cells will not form teratomas. However, this issue has not been thoroughly examined, and enrolled patients will need to be monitored closely for this potentially lethal side effect.

In addition to the previously mentioned technical issues, the use of ES cells raises social and ethical concerns. In the past, these concerns have limited federal funding and thwarted the progress of this very important research. Because funding limitations may be reinstituted in the future, ES cell technology is being less aggressively pursued and young researchers are shying away from the field.

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The benefits and risks of stem cell technology - PMC

Stem Cells 101

Every cell type in the body that makes up organs and tissues arose from a more primitive cell type called a stem cell. Stem cells are the foundation of living organisms, with the unique ability to self-renew and differentiate into specialised cell types. There are three different types of stem cell, classified by the number of specialised cell types they can produce: i) pluripotent stem cells (e.g. embryonic stem cells) can generate any specialised cell type; ii) multipotent stem cells (e.g. mesenchymal stem cells) are able to generate multiple, but not all, specialised cell types; and, iii) unipotent stem cells (e.g. epidermal stem cells that produce skin) give rise to only one cell type. It was long believed that stem cell differentiation into specialised cell types only occurs in one direction. There have been many exciting advances in stem cell biology, most notable the discovery of induced pluripotent stem cells (iPSCs) that demonstrated a mature differentiated specialised cell can be reverted to a primitive pluripotent stem cell (Takahashi K, 2006). This discovery transformed our understanding of stem cell biology enabling exciting and substantial advances in stem cell tools, technologies and applications. This article focuses on pluripotent stem cells, as they offer the most promising future applications.

To harness the power of stem cells, they must first be maintained in vitro tissue culture. Culture expansion of stem cells is tricky because they must be maintained in an undifferentiated state and not permitted to differentiate into other cell types until desired. In short, if stem cells are not dividing in log phase growth, they are differentiating. Historically, pluripotent stem cells were notoriously difficult to work with in the lab largely because of the of inherent variability of reagents derived from animal tissues.

An important concept affecting current and future innovations in stem cell technologies is Good Manufacturing Practice (GMP). This is governed by formal regulations administered by drug regulatory agencies (for example the FDA) that control the manufacture processes of medicines. The use of stem cells as therapeutic agents has necessitated specialised drug regulations known as Advanced Therapeutic Medicinal Products (ATMPs). Unlike chemically synthesised medicines where the final product can be defined through chemical analysis, ATMPs are complex biological living entities whereby the entire manufacturing process defines the final product. In simple terms, every reagent that touches the stem cells in the manufacturing process throughout the entire lifetime of the stem cell becomes a component of the final product. As such, in the real world the quality and consistency of the reagents used in a stem cell manufacturing process is paramount for downstream clinical applications, even if the project is still in the R&D or preclinical phase. Once reserved for clinical applications, GMP has become a dominating concept that affects all aspects of stem cell research and applications. Researchers and clinical developers benefit alike from GMP-focused innovations in stem cell technologies that deliver consistent growth properties and high-quality results.

Significant advances that overcome the challenges of the past have been made in all aspects of in vitro stem cell culture. These include advances in tissue culture medium, extracellular matrix, 3D synthetic cell culture plastic, growth factors, dissociation enzymes, cryopreservation agents and differentiation technologies. The workflow to culture stem cells in vitro is not a linear process but rather a continuous circle that can be broken down into 6 steps: 1) Extracellular Matrix coating of tissue culture plasticware; 2) Revival/seeding of tissue culture flasks; 3) Expansion of the cell culture in an incubator; 4) Culture medium change; 5) Subculture or passaging one flask to many; and 6) Cryopreservation of the stem cell culture. The stem cell workflow is shown in Figure 1.

The art of culturing stem cells is a lot easier today than in the past. Stem cells grow as adherent cultures on the surface of tissue culture flasks or dishes (image shown in Figure 1, Step 3). For the stem cells to adhere to the surface it must be coated with extracellular matrix. In the early days, it was an effort to maintain stem cells in culture because the cultures needed to be grown on a feeder layer of fibroblast cells. The requirement for a second cell culture combined with the stem cell culture is laborious to set up and severely limited experiments and applications (due to the contaminating fibroblasts mixed with the stem cells). Extracellular matrix isolated from mouse tumours removed the need for feeder layer cultures but can be variable in consistency and contain contaminants. Today, researchers benefit from recombinantly expressed extracellular matrix containing laminin-511 fragments that provides highly efficient adherence of a broad range of cell types and is easy to use (with only 1 hour coating time required that saves time and cost). Exceptional pluripotent stem cell adherence is achieved with laminin-511 fragments. The recombinant extracellular matrix laminin-511 is expressed in mammalian cell culture (e.g. CHO cells) or insect culture (e.g. silkworm) that eliminates the need for animal derived products in the extracellular matrix. Alternatively, synthetic 3D plastic scaffolds (e.g. Alvetex) are also available that offer a rigid defined matrix that is non-biological.

Early stem cell culture media required the medium to be replenished daily. This means 7 days a week in the lab tending to the stem cell cultures. Optimisation of tissue culture medium composition enables cultures to be maintained over the weekend without a medium change, enabling feeder-free, weekend-free stem cell culture. This may sound insignificant but does have a huge impact on the lifestyle of researchers working with stem cells. Unlike early tissue culture media, the composition of the culture media are fully defined and contain no animal derived products. Removal of animal-derived products offers important advantages by removing variability inherent in animal-derived products and guaranteeing consistent cell growth. Furthermore, animal-free formulations eleminate the risk of infection arising from the animal product (e.g. TSE risk). Growth factors are a critical component of the culture medium to maintain the stem cells in an undifferentiated state. Products available on the market contain growth factors that are expressed and isolated from barley.

Stem cells undergo cellular division in the culture vessel. As they expand, they will eventually outgrow their home and must be subcultured to separate flasks to provide space for further growth. Common practice is to use a digestive enzyme to free the stem cells from the culture surface. Trypsin isolated from bovine is commonplace in the tissue culture laboratory. Advances in the products available today use trypsin expressed in maize that is stable at room temperature in solution. Collagenase is an alternative dissociation reagent that is gentle and efficient on a wide range of cells and is available both animal-free and GMP grade - again enabling robust consistent culture conditions, and removing the dependence on animal derived products that are inherently variable.

The stem cells harvested from cultures can be frozen and stored (or cryopreserved) safely for several decades. When required, the cryopreserved stem cells may be defrosted, revived and expanded in culture providing a renewable source of stem cells. During cryopreservation of stem cells, it is critical to prevent cell death and changes in genotype/phenotype. Todays cryopreservation media can maintain consistent high cell viability after thawing; maintaining cell pluripotency, normal karyotype and proliferation even after long term cell storage. Traditionally, the cryopreservation process involved a rate-controlled freezer or a specialised container to freeze the cells at -1C/min. Advances in cryopreservation agents have removed the need for rate-controlled freezing. The process is now simple - you just place the stem cell suspension into a -80C freezer. Moreover, cryopreservation agents are available in GMP grade and with no animal-derived ingredients.

The power of stem cells lies in their ability both to self-renew and to differentiate into specialised cell types. The process of differentiation removes the stem cells from the workflow towards applications. Directed differentiation of stem cells into specific cell types enables the number of applications to grow. A typical differentiation protocol uses stepwise changes in culture medium, cytokines, growth factors and extracellular matrix over several weeks to direct the stem cells into a particular lineage and fate. Today, innovative technologies use genetic reprogramming factors that rapidly (< 1 week) differentiate stem cells into mature cell phenotypes. This advance significantly reduces time to experiment and increases manufacturing capacity for differentiated cell types.

Table 1. Advances in Stem Cell Technologies.Description Area of Innovation Examples of Innovative ProductsExtracellular Matrix Recombinant Laminin Expressed in CHO and Silkworm iMatrix-511Culture Medium No medium change required over the weekend, GMP grade, animal free StemFit MediumGrowth Factors Recombinant, GMP grade, animal free StemFit PuroteinDissociation Reagents Trypsin enzyme recombinantly expressed in maize. Collagenase & Neutral Protease expressed in Clostridium histolyticum TrypLECollagenase NBNeutral Protease NBCryopreservation Rate-controlled freezing not required. GMP grade, animal free and available for clinical use. Suitable for all cell types. STEM-CELLBANKERDifferentiation Rapid directed differentiation through genetic reprogramming Quick-Skeletal MuscleQuick-EndotheliumQuick-Neuron

There are unlimited applications that arise from a renewable source of mature cell types. One exciting area of innovation using differentiated stem cells is in disease modelling. Studying a disease state in an organ or tissue has in the past been limited to using in vivo animal models; whereas, differentiated stem cells opened the opportunity to create disease states in specific cell types in vitro. In addition, current technologies enable organoids or mini organs to be generated in the laboratory. Disease specific induced pluripotent stem cells can also be used to create disease models in vitro that are valuable tools for the study of disease and drug development without the need for in vivo animal models. In theory, any tissue is possible to create in vitro. In an exciting example of stem cell disease modelling, Dr Takayama from the CiRA in Kyoto, Japan has successfully modelled the life cycle of SARS-CoV-2 in both organoids and undifferentiated pluripotent stem cells (Takayama, 2020) (Sano, 2021) (Figure 2). In another example, the Skeletal Muscle Differentiation Kit was used to produce skeletal muscle myotubes from stem cells to create an in vitro disease model (Figure 3). In a direct application, pluripotent stem cell models of skeletal muscle have also been successfully used to develop a novel treatment for Duchenne muscular dystrophy (Moretti, 2020).

Promising progress is being made to create meat in the laboratory or what is commonly called cultured meat. Environmental concerns are driving the need for more sustainable meat production over traditional farming methods. Stem cell research in itself is reducing the need for the use of animals across multiple aspects as highlighted here. Producing cultured meat is straightforward in principle but faces many challenges in practice, for example maintaining the correct environment and stimuli for cultured cells to produce meat with the correct consistency and characteristics of the animal derived product. Stem cell cultures are expanded at scale in bioreactors and differentiated into skeletal muscle cells. These can be structured, using an edible scaffold for example, or used unstructured as the raw material to produce meat products (Figure 4). Tools and technologies are readily available to achieve this goal: expansion and differentiation of stem cells is highly efficient. However, a key consideration is the cost of goods. Current technologies are too costly but these are pioneering times and research is moving at an exciting pace.

The promise and potential of stem technologies to advance biology, medicine and food production can only be fulfilled if stem cell culture conditions are consistent, and accessible to research scientists and commercial operations alike. Exciting advances across multiple aspects of the stem cell workflow have streamlined processes to deliver products that are fully defined and animal-free. Furthermore, clinical translation of stem cell therapies and drug discovery are accelerated by the availability of GMP compliant reagents. The foundations are set for a bright future of discoveries and applications emerging from stem cell technologies.

Dr William Hadlington-Booth is the business unit manager for stem cell technologies and the extracellular matrix at AMSBIO. Erik Miljan, PhD, is a pioneer in the development of cellular therapies for a range of degenerative and disease conditions. He holds a PhD in biochemistry from Hong Kong University. For further information please contact:William@amsbio.com

Moretti, A. F., et al. (2020). Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy. Nature Medicine, 26, 207214.Takahashi K., et al. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. . Cell, 126, 663-676.Takayama, K. (2020). In Vitro and Animal Models for SARS-CoV-2 research. Trends in Pharmacological Sciences, 41. 513-517.Sano, E., et al. (2021). Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells. Iscience, 24(5), 102428.

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Current and Future Innovations in Stem Cell Technologies - Labmate Online

Owing to Rising Demand for Less Invasive Treatments Among Heart Patients, Fact.MR Study Opines the Global Bioabsorbable Stents Market Share is Estimated to Reach a Value of Nearly US$ 1 Billion by 2032 from US$ 372 Million in 2021

Growing incidences of physicians and healthcare professionals preferring bioabsorbable stents over conventional stents is believed to have rapidly surged the bioabsorbable stent market growth in the global market.

Fact.MR, a Market Research and Competitive Intelligence Provider - The global bioabsorbable stents market is predicted to witness a moderate growth rate of 9.6% during the forecast years 2022 to 2032. The net worth of the bioabsorbable stents market share is expected to be valued at around US$ 1 Billion by the year 2032, growing from a mere US$ 372 Million recorded in the year 2021.

The growing prevalence of cardiovascular disease is sighted to be the leading cause of heart-related mortality worldwide. Around 17.5 million people die each year as a result of cardiovascular disease as a consequence of changing lifestyles, dietary habits, and rising blood pressure difficulties. All these factors have boosted the demand for bioabsorbable stents in the global market.

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Cardiovascular illnesses were responsible for more than 32% of fatalities in 2015, and this number is anticipated to grow to 45 per cent by 2030. The number of people diagnosed with diabetes has increased. Obesity, which is the leading cause of type 2 diabetes in adults, has increased as a result of changes in trends, food patterns, and regular exercise. The proliferation of such correlated diseases is suggested to be the major driving factor for the sales of bioabsorbable stents across the globe.

However, due to an increase in the prevalence of coronary artery disease, increased knowledge of bioabsorbable stents, increased demand for minimally invasive surgery, and increased adoption of unhealthy lifestyles, Asia-Pacific is predicted to have the highest CAGR from 2021 to 2032.

What is the Bioabsorbabale Stents Market Outlook in Asia Pacific Region?

As per the global market study on bioabsorbable stents, Asia Pacific is predicted to develop at the quickest rate. The rising number of cardiac patients in the Asia Pacific countries with the highest population count is predicted to drive the demand for bioabsorbable stents in the regional market.

During the projected period, the China bioabsorbable stents market is predicted to lead at the fastest rate of 8.8% in this geographical region. The net worth of the market is estimated to be around US$ 28 Million in 2022 and is projected to reach a total valuation of US$ 71.6 Million in the year 2032.

Other than that, bioabsorbable stents market opportunities in Japan and South Korea are also quite promising for the forecasted years, with an estimated growth rate of 8.1% and 7.3%, respectively. This new market research report on bioabsorbable stents also sheds light on the growth prospects in Indian Market as well.

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Recent Developments in the Market

Fact.MRs Domain Expertise in Healthcare Sector

Our healthcare consulting team guides organizations at each step of their business strategy by helping you understand how the latest influencers account for operational and strategic transformation in the healthcare sector. Our expertise in recognizing the challenges and trends impacting the global healthcare industry provides indispensable insights and support - encasing a strategic perspective that helps you identify critical issues and devise appropriate solutions.

Point of Care Diagnostics Market - Shipments of point of care test (POCT) kits are projected to surge at a CAGR of around 7% from 2021 to 2028, as per this new analysis. In 2020, the global point of care diagnostics market stood at US$ 34.1 Bn, and is anticipated to surge to a valuation of US$ 66 Bn by the end of 2028.

Spectrometry Market - The global spectrometry market is projected to increase from a valuation of US$ 7.1 Bn in 2020 to US$ 13.8 Bn by 2028, expanding at a CAGR of 6.4% during the forecast period, Demand for mass spectrometry is set to increase faster at a CAGR of 7.4% over the forecast period 2021-2028.

Coronary Stents Market- Worldwide sales of coronary stents were valued at around US$ 10.1 Bn in 2020. The global coronary stents market is projected to register 12.9% CAGR and reach a valuation of US$ 25.7 Bn by the end of 2028.

Osteoporosis Therapeutics Market- The global osteoporosis therapeutics market stands at a valuation of US$ 12.7 Bn currently, and is predicted to reach US$ 14.2 Bn by the end of 2026. Consumption of osteoporosis therapeutic drugs is anticipated to increase at a CAGR of 2.9% from 2022 to 2026.

CNS Therapeutics Market- The CNS therapeutics market stands at a valuation of US$ 116.7 Bn in 2022, and is expected to reach US$ 142.1 Bn by the end of 2026. CNS drug sales are projected to rise at a steady CAGR of 4.9% from 2022 to 2026.

Induced Pluripotent Stem Cell (iPSC) Market- The global induced pluripotent stem cell (iPSC) market stands at a valuation of US$ 1.8 Bn in 2022, and is projected to climb to US$ 2.3 Bn by the end of 2026. Over the 2022 to 2026 period, worldwide demand for induced pluripotent stem cells is anticipated to rise rapidly at a CAGR of 6.6%.

Doxorubicin Market- Demand for doxorubicin is anticipated to increase steadily at a CAGR of 5.3% from 2022 to 2026. At present, the global doxorubicin market stands at US$ 1.1 Billion, and are projected to reach a valuation of US$ 1.3 Billion by the end of 2026.

Heart Attack Diagnostics Market- The heart attack diagnostics market is predicted to grow at a moderate CAGR of 7.1% during the forecast period of 2022 to 2032. The global heart attack diagnostics market is estimated to reach a value of nearly US$ 22.2 Billion by 2032 by growing from US$ 10.4 Billion in 2021.

Smart Implants Market- The global smart implants market is estimated at US$ 3.9 billion in 2022, and is forecast to surpass a market value of US$ 22.2 billion by 2032. Smart implants are expected to contribute significantly to the global implants market, with demand surging at a CAGR of 19% from 2022 to 2032.

Facial Implants Market- The global facial implant market was valued at US$ 2.7 Billion in 2022, and is expected to rise at a 7.7% value CAGR, likely to reach US$ 5.6 Billion by the end of the 2022-2032 forecast period.

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Bioabsorbable Stents Market to Grow at a Fine CAGR of 9.6% through 2032: Improvements in Healthcare Infrastructure and Growing Geriatric Population to...

According to reports, currently, 64.34 million people suffer from heart failure worldwide[1]. Furthermore, the number of patients with end-organ heart failure is rising, leading to an all-time high in the number of people waiting for an organ transplant[2]. Several strategies have been devised to increase this strained supply of heart for transplantation, including expanding donor criteria[3], use of advanced perfusion machines such as organ care systems (OCS) to improve viability[4], use of normothermic regional perfusion (NRP) in donor from cardiac death (DCD) hearts, and xenotransplantation. Recently, the focus has shifted to new procedures using regenerative cells, angiogenesis factors, biological matrices, biocompatible synthetic polymers, and online registry systems that utilize bioimplants. These advanced technologies are collectively referred to as tissue engineering[5-8]. Ultimately, the goal is to grow a heart de novo. In addition to the unlimited organ supply, the new organ would be antigenically identical to the recipient as the recipients cells would be used, eliminating the need for immunosuppressive agents.

Even though bioengineering a fully functioning heart is in its infancy, huge strides have been made in achieving this goal. Scientists have been able to bioengineer models of the heart, lungs, pancreas, liver, and kidney. An important strategy for supporting the recipients cells and creating an autologous tissue/organ is to create a mechanical, geometrical, and biological environment that closely mimics the native organs properties. The breakthrough in growing an artificial heart was the invention of the decellularization of extracellular matrix (ECM), which maintains the native vascular network[9]. Numerous tissues and organs have been engineered using decellularization, including livers [10], lungs[11], kidneys[12], corneas[13], bladders[14], vasculature[15], articular cartilage[16], intestines[17], and hearts[18]. There has been some success in engineering a heart in the lab. Although technological innovations and biological model systems have resulted in great progress, constructing such complicated tissue structures effortlessly remains a challenge. This review aims to outline the techniques involved in bioengineering a heart in the lab and the challenges involved in developing it into a viable organ for transplantation (Figure 1).

The human heart comprises various cells, each specialized to perform a specific task. A human heart contains roughly 2-3 billion cardiomyocytes, making up only about one-third of its total cells [19]. Additionally, other cells include endothelial cells, fibroblasts, and specialized conducting cells like Purkinje fibers. On top of that, structural scaffolds support the functions of cells arranged into structures, such as vessels, muscles, and nerves. These scaffolds mainly consist of polysaccharides and proteoglycans embedded in complex sugars and chemokines matrix, allowing the heart to coordinate its mechanical and electrical functions [20,21]. Sprawled around this is a collection of protein fibers such as collagen and elastin, which confers mechanical strength to the heart and allow for the constant loading and unloading forces[22,23]. Thus, it is necessary to construct a scaffold around which the specialized cells can grow and maintain vitality through blood perfusion to recreate a functioning heart in a laboratory [24] (Figure 2).

Extracellular matrix (ECM) and cells in an organ display a dynamic reciprocity, whereby the ECM constantly adapts to the demands of the cells[25], and selecting the appropriate scaffold is the key component for growing a viable organ in the lab. Researchers have also studied various synthetic scaffolds as potential surrogates for the ECM, but none can replicate its intricacy or structure compared to native ECM. It is possible to vascularize synthetic materials such as polylactic acid (PLLA) and polylactic glycolic acid (PLGA) and to produce them consistently[26,27]. The significant advantage of synthetic ECM is its production scalability as it does not require to be harvested from living tissue, but these do not match the native myocardiums tensile strength. Hydrogels have also been studied extensively and even accepted by the Food and Drug Administration for drug delivery and adjunct for cell therapy. Hydrogels consist of a cross-linked hydrophilic polymer matrix with over 30% water content [28]. However, they have poor cell retention [29] or poor tensile strength [30]; hence, they are not feasible as a primary scaffold for constructing an organ. Decellularizing the whole heart and leaving the ECM serves as a potential solution to this problem with the particular advantage of having a balanced composition of all the proteins present physiologically [31].

The Badylak laboratory developed the first technique for decellularizing tissue[32]. This process involved the removal of the cell, leaving only the ECM, which retained its composition, architecture, and mechanical properties. There are several methods for removing cells from the ECM. These methods include physical methods (e.g., freeze/thaw cycles), enzymatic degradation (e.g., trypsin), and removal by using chemicals (e.g., sodium dodecyl sulfate)[33]. Ott et al. noted that decellularization could be achieved with different detergent solutions. Comparative studies on decellularization methods have mixed results regarding the superiority of different techniques [34-37]. Based on the results, the sodium dodecyl sulfate (SDS) solution was found to be the best [18]. However, a few studies have suggested that SDS treatment causes degradation of the ECM with a reduction in elastin, collagen, and glycosaminoglycans (GAG) content [34]. The decellularization process utilizes 1% SDS perfused through the coronary circulation, followed by washing it with de-ionized water and subsequently 1% Triton-X-100 (Sigma). Finally, the organ remnant is washed with phosphate-buffered saline (PBS) wash buffer, antibiotic, and protease, leaving a decellularized ECM[38,39]. Using this technique, they decellularized the heart, reseeded it with neonatal cardiac cells, and grew the first beating rodent heart in the lab [18]. Decellularized tissue provides a dynamic environment for the orientation and coupling of cells and facilitates the exchange of nutrients and oxygen throughout the depth of the tissue. Moreover, this process efficiently removes both allogeneic and xenogeneic antigens, possibly preventing the need for immunosuppressants [33], which is especially important as one of the causes of heart failure in transplanted hearts is myocardial fibrosis from chronic rejection [40]. This process can be potentially avoided by using a decellularized heart to generate an ECM scaffold which can then be repopulated using the recipients cells.

Researchers have used animal heart ECM and human heart ECM scaffolds to provide this decellularized ECM scaffold. The porcine heart has often been deemed suitable for its similarity with the human heart [41]. As decellularization removes most of the cells, much of the antigen load is removed. However, the porcine heart ECM contains -1,3-galactose epitope (-gal), which can stimulate an immune response [42,43]. One way to circumvent this is to use pigs lacking -gal epitope, but this technique needs further research. Another possible problem with using a porcine heart is the possible risk of horizontal transmission of porcine viruses like the porcine endogenous retrovirus, cytomegalovirus, HSB, circovirus, etc. [44,45]. Although a few tests can detect the presence of these viruses, they have poor sensitivity, and hence further work has to be done [46].

A cadaveric heart that is unfit for transplant can also be used to harvest an ECM scaffold [47]. The only drawback to this is that it may not always be possible to achieve the desired level of tissue engineering fidelity with these matrices because they may be damaged or diseased. Moreover, there is an assumption that they are superior for the growth and differentiation of human cells, but there is no robust evaluation to support this assumption. The method for decellularization of the cadaveric human heart is similar to that of other animals, utilizing 1% SDS and 1% Triton X-100, with the only difference being a longer perfusion time for these chemicals [48,49].

These cells are highly specialized and terminally differentiated, and hence, they do not proliferate normally. Therefore, to repopulate a human-sized scaffold, autologous human cardioblasts must be isolated or expanded in large quantities. Hence, for the recellularization of ECM, a method of inducing progenitor cells had to be devised. Thus, the discovery of methods to reprogram or induce adult cells into pluripotent stem cells was a significant milestone in stem cell biology and tissue bioengineering[50-52].

Once we have the cells for repopulation of ECM, recellularization is required to achieve a functional organ product for implantation. For recellularization to be achieved, choosing appropriate cell sources, seeding cells optimally, and cultivating them using organ-specific cultures are needed [24]. Cells from fetuses and adults, embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs) have all been used[24]. Obtained with ease and ethically, stem cells from bone marrow stroma or adipose tissue (MSC) have shown promise as the ideal cells for recellularization [53]. In addition, human somatic cells can be reprogrammed to produce iPSCs, and they exhibit properties similar to ESCs [54].

A potential solution to the problem of getting a large number of human cells for tissue engineering or other regenerative medicine approaches is the ability to produce iPSCs from readily available autologous cells such as fibroblasts or blood cells[55,56]. The only drawback to using iPSCs is the possibility of teratoma formation due to its pluripotent nature [48,57]. However, the potential solution to this problem is to allow controlled differentiation toward a cardiac lineage before implantation into the ECM [58]. Although previously any attempts to produce iPSCs would result in karyotype instability [59], recent advances have been made with iPSCs maintaining chromosomal integrity [60]. These advances have ushered astep forward in the pursuit of creating viable organs in the lab.

Cell seeding techniques depend on the type of organ being engineered, and, for the heart, it usually involves seeding by perfusion through the vascular tree [24]. This step is called re-endothelization and is usually the first step to recellularization. A dynamic communication between endothelial cells and cardiomyocyte populations occurs via direct cell interactions and the secretion of various factors[61,62]. It is evident from multiple reports that seeding endothelial cell populations and cardiomyocyte populations simultaneously provides functional benefits that aid in maintaining the recellularization process [63]. Interestingly, endothelial cells have also demonstrated the ability to differentiate into cardiomyocytes in other cardiomyocyte cells [64], which may aid in more efficient recellularization. Moreover, besides the advantage, the recellularization of both the vascular tree and the heart parenchyma must be uniform to prevent two key issues in the heart, namely, thrombogenesis[65] and arrhythmogenesis[66].

Improved cell concentration and diffusion over the scaffold can be achieved by optimizing the mechanical environment, scaffold coating, and cell perfusion systems by using multiple perfusion routes simultaneously, which for the heart involves both direct intramyocardial injections and perfusion of the vascular tree [67]. However, the potential problem with intramyocardial injections is that even though the injection site shows dense cellularity, the cells are generally poorly distributed throughout the scaffold [58]. Moreover, sequential injections of cardiac cells will likely be required to rebuild the chamber parenchyma, which may compromise matrix integrity [48]. Nevertheless, given that cardiac cells include fibroblasts, in which ECM is produced and secreted, there is a possibility that endogenous matrix repair may occur after cell seeding to help resolve this issue [62].

While sourcing cells for recellularization using stem cells is a work in progress, multiple studies have explored ways to develop mature cardiomyocytes derived from iPSCs that are more physiologically similar to native cardiomyocytes [68,69]. One of the most recent cardiac constructs was engineered using PSC-derived cardiac cells in a ratio of equal cardiomyocyte and noncardiomyocyte cells, cultured in serum-free media [70]. Cardiomyocytes cultivated in this method were elongated, had organized sarcomeres and distinguished bands, and exhibited increased contractility [70]. It is encouraging to see these results that stem cells can be used to produce cardiomyocytes similar to native mature cells, reinforcing the notion that stem cells can be a cardiac cell source.

After enough cells have been seeded onto an organ scaffold, cell culture is required. A bioreactor is required for perfusion and provides a nutrient-rich environment that encourages organ-specific cell growth [24]. Bioreactors should allow nutrient-rich oxygen to be pumped with adjustable rates of flow and pressure and monitor and control the pH and temperature of the media. Moreover, mechanical stimulation is also an essential component for engineering organs of the musculoskeletal and cardiovascular systems [71]. A wide range of mechanical properties is employed in the design of bioreactors, including substrate stiffness and dynamic changes in stiffness throughout culture, pulsatile flow, and providing stretch to enhance cell maturation, alignment, and generation of force in engineered constructs [72]. Presently, there are several types of bioreactors available, with Radnoti [73] and BIOSTAT B-DCU II [74], to name a few. In addition, there has been an increase in bioreactor designs incorporating real-time monitoring to assess the status of engineered tissues. These designs may incorporate biochemical probes to assess transmural pressure changes or sampling ports to test cells viability and biochemical composition after recellularization [75,76]. The incorporation of sampling methods within bioreactor designs will keep constructs sterile, allowing for modifications in stimuli to be made while maintaining a closed system, and providing researchers with valuable feedback on cell responses throughout bioengineering. Further research is being conducted to make bioreactors that can be used to maintain the perfect milieu for growing these bioengineered tissues and organs.

For an organ to be viable for transplant, three things must be ensured: sterility of the process, structural integrity, and, lastly, patency for surgical anastomosis. Biological tissues are sterilized by gamma radiations or peracetic acid at low concentrations before the ECM is repopulated with cells[77]. Once the cells are added, antibacterial, antifungals, and other antibiotic drugs can be utilized. It is re-evaluated for integrity before the ECM is recellularized and only gets the green light for cell seeding if structural integrity is maintained. Interestingly, with the aid of endoscopy, decellularized constructs can be easily manipulated and visualized for macro and microstructure defects at the level of chambers, papillary muscle, and valves[47]. One of the most important aspects of evaluating the integrity of ECM is to check for intact coronary vasculature, which can be done by micro-optical coherence tomography [48].

Heart constructs engineered in the lab have been demonstrated to undergo cyclical muscular contraction but also have been shown to respond to drugs and exhibit electrical activity. However, electrocardiography analysis of the bioengineered hearts has shown irregular wave morphology due to loss of coupling between cardiomyocytes [78]. Therefore, it will be crucial to develop continuous monitoring of cardiac electrophysiology, function, and even vascular patency if these artificial constructs can be transplanted into patients.

Over the past decade, research in regenerative medicine has enabled us to understand better the challenges associated with developing a bioartificial heart. The first challenge was creating a biocompatible scaffold which has already been resolved with the development of various decellularization techniques, making it possible to generate an anatomically accurate and vascularized heart scaffold. With the advent of newer techniques for iPSC generation of stable karyotype, cell generation is also potentially resolved. Presently, research has to be aimed to address the challenges in reseeding the ECM scaffold. A potential solution might be the advancement in 3D-printed matrixes with embedded cells. However, decellularized ECM remains the gold standard for now as 3D-printed matrixes cannot replicate the complexity and structural integrity of the natural component of ECM.

Another potential problem is the creation of a bioreactor that can efficiently maintain the environment required for the growth of cardiac and other differentiated cells around the decellularized ECM scaffold. Constructing organs is no easy feat and involves much technical expertise. Hence, many resources are required in every step of artificially reproducing tissues and organs. Thus, even if bioengineering a heart is a possibility in the near future, it may not be financially feasible to use them for transplantation until the cost of making such constructs is lowered. Additionally, we do not know the long-term viability of such constructs. These constructs use chemicals to decellularize ECM as well as induce the conversion of adult cells into pluripotent cells. Some questions arise on how the complex network of cells and ECM would interact over the long run. The heart is a complex organ that requires a highly specialized conduction system to ensure efficient, coordinated, and purposeful contraction of the heart chambers. Any deviance may lead to fatal arrhythmia or thrombus formation. We are yet to reproduce a perfect conduction system in the lab, let alone test its long-term functionality. Furthermore, the use of induced pluripotent cells also raises the prospect of long-term tumorigenesis and malignancy. Despite rapid advances in bioengineering and artificial hearts, research and clinical trials must be conducted to determine the long-term feasibility of using these organs.

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Is a Bioengineered Heart From Recipient Tissues the Answer to the Shortage of Donors in Heart Transplantation? - Cureus

DUBLIN--(BUSINESS WIRE)--The "Heart Failure - Pipeline Insight" clinical trials has been added to ResearchAndMarkets.com's offering.

This "Heart Failure - Pipeline Insight, 2022" report provides comprehensive insights about 90+ companies and 90+ pipeline drugs in Heart Failure pipeline landscape. It covers the pipeline drug profiles, including clinical and nonclinical stage products. It also covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space.

"Heart Failure - Pipeline Insight, 2022" report outlays comprehensive insights of present scenario and growth prospects across the indication. A detailed picture of the Heart Failure pipeline landscape is provided which includes the disease overview and Heart Failure treatment guidelines.

The assessment part of the report embraces, in depth Heart Failure commercial assessment and clinical assessment of the pipeline products under development. In the report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, collaborations, licensing, mergers and acquisition, funding, designations and other product related details.

Report Highlights

Heart Failure Emerging Drugs

Tirzepatide: Eli Lilly and Company

Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for chronic weight management and heart failure with preserved ejection fraction (HFpEF). It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH). Both the FDA and EMA have accepted Eli Lilly's marketing approval applications for its type 2 diabetes treatment, tirzepatide.

Finerenone (BAY94-8862): Bayer

Finerenone (BAY 94-8862) is an investigational novel, non-steroidal, selective mineralocorticoid receptor antagonist (MRA) that has been shown to block the harmful effects of the overactivated mineralocorticoid receptor (MR) system. MR overactivation is a major driver of heart and kidney damage. Current steroidal MRAs on the market have proven to be effective in reducing cardiovascular mortality in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, they are often underutilized due to the incidence of hyperkalemia, renal dysfunction, and anti-androgenic/ progestogenic side effects.

CardiAMP Cell Therapy: BioCardia

CardiAMP Cell Therapy uses a patient's own (autologous) bone marrow cells delivered to the heart in a minimally invasive, catheter-based procedure to potentially stimulate the body's natural healing response. The CardiAMP Cell Therapy Heart Failure Trial is the first multicenter clinical trial of an autologous cell therapy to prospectively screen for cell therapeutic potency in order to improve patient outcomes. CardiAMP Cell Therapy incorporates three proprietary elements not previously utilized in investigational cardiac cell therapy, which the company believes improves the probability of success of the treatment: a pre-procedural diagnostic for patient selection, a high target dosage of cells, and a proprietary delivery system that has been shown to be safer than other intramyocardial delivery systems and more successful for enhancing cell retention.

Rexlemestrocel-L (Revascor): Mesoblast

Revascor consists of 150 million mesenchymal precursor cells (MPCs) administered by direct injection into the heart muscle in patients suffering from CHF and progressive loss of heart function. MPCs release a range of factors when triggered by specific receptor-ligand interactions within damaged tissue. Based on preclinical data, it is believed that these factors induce functional cardiac recovery by simultaneous activation of multiple pathways, including induction of endogenous vascular network formation, reduction in harmful inflammation, reduction in cardiac scarring and fibrosis, and regeneration of heart muscle through activation of tissue precursors.

BMS-986231: Bristol-Myers Squibb

Cimlanod (development codes CXL-1427 and BMS-986231) is an experimental drug for the treatment of acute decompensated heart failure. HNO gas (nitroxyl) is a chemical sibling of nitric oxide. Although nitric oxide and HNO appear to be closely related chemically, the physiological effects and biologic mechanisms of HNO and nitric oxide action are distinct. The biologic effects of HNO are mediated by direct post-translational modification of thiol residues in target proteins, including SERCA2a, phospholamban, the ryanodine receptor, and myofilament proteins in cardiomyocytes. In vitro, HNO increases the efficiency of calcium cycling and improves myofilament calcium sensitivity, which enhances myocardial contraction and relaxation. HNO also mediates peripheral vasodilation through endothelial soluble guanylate cyclase. HNO does not induce tachyphylaxis in peripheral vessels, unlike nitric oxide.

Elamipretide: Stealth BioTherapeutics

Elamipretide (MTP-131, Bendavia) is a novel tetra-peptide that targets mitochondrial dysfunction in energydepleted myocytes. Elamipretide crosses the outer membrane of the mitochondria and associates itself with cardiolipin, which is a phospholipid expressed only in the inner membrane of mitochondria. Cardiolipin has an integral role in mitochondrial stability and organization of respiratory complexes into super complexes for oxidative phosphorylation.Thus, elamipretide helps to enhance ATP synthesis in multiple organs of the body. Elamipretide has been shown to improve left ventricular ejection fraction (LVEF), LV end diastolic pressure, cardiac hypertrophy, myocardial fibrosis, and myocardial ATP synthesis in both animal models and humans.

FA relaxin: Bristol Myers Squibb

BMS-986259 is a next-generation version of Relaxin that is enabled with our technology and currently in Phase 1 clinical trials for ADHF. Relaxin, a peptide hormone, has been reported to reduce fibrosis in the multiple organs and to exert cardioprotective effects in preclinical studies. However, the therapeutic potential of Relaxin has been partially limited by its short half-life in humans. BMS-986259 has exhibited a prolonged half-life and therefore has the potential to enhance clinical benefit as a novel therapeutic for ADHF.

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Its a symbol of love and courage. It flutters with excitement and panic. It knows when to rest and when to quicken. But, most importantly, the heart is an extraordinary machine. These doors inside your heart [the valves] have to flap open and closed 100,000 times a day, says cardiologist James Wong. If you did that to your front door it would be gone in the afternoon.

Yet, as with all complex machinery, over time the heart can develop issues. One of the more insidious problems lies in its plumbing the coronary arteries which, when blocked, cause a heart attack.

One in every 25 deaths in Australia in 2020 was due to a heart attack. Thats the equivalent of 18 deaths a day, or one every 80 minutes. Sometimes, heart attacks are sudden and brutal. Other times, people dont realise they are having one. And they are often different for women and men.

So, how do you know if you are having a heart attack? What does a massive heart attack mean? Can you test for signs? And to what extent can you prevent them?

Credit:Artwork Matt Davidson

The heart is a pump made of muscle with its own electrical circuits and plumbing. Its job is to bring oxygen and nutrients to all our organs in just the right amount. It normally beats up to 100 times a minute more when you exercise. With each beat, it squeezes to circulate blood from the lungs to the rest of body then back again. Valves keep blood flowing in the right direction, pieces of thin, strong tissue like parachute material. Its amazing how resilient they are to withstand pressure without tearing, says Wong, an associate professor of medicine, who is director of the Royal Melbourne Hospitals echocardiography laboratory.

Its the best pump that Professor Garry Jennings knows of and the most hardy. Not many pumps work for 90 years, 100,000 times a day, says Jennings, the Heart Foundations chief medical adviser.

Its a lot of responsibility for an organ the size of a fist, but it has its own electrical system to help.

Tiny electrical impulses trigger each heartbeat, beginning in the sinus node at the top of the heart before travelling, like a Mexican wave, through the hearts four chambers two atria and two ventricles with the atria contracting a fraction of a second before the ventricles to push the blood. Wong likens the sinus node to the guy that beats the drum, which the rest of the heart follows, thereby controlling the heart rate.

Researchers have found that every time the heart beats, the brain pulses in sync ever so slightly.

An electrocardiogram, or ECG, produces the pulsing graph you see on screens at hospitals (and much beloved by makers of TV dramas). It detects the hearts contractions by reading its electrical activity via electrodes on the skin.

The heart contracts automatically, but the brains autonomic nervous system regulates the strength and pace of the contractions. The brain and heart depend on each other: the brain supports the hearts pumping, and the heart keeps the brain oxygenated. In fact, researchers have found that every time the heart beats, the brain pulses in sync ever so slightly.

But to do its job, the heart relies on having a rich blood supply, which is where its plumbing comes in: the coronary arteries are the blood vessels that wrap around the heart to nourish it with oxygenated blood. A heart attack occurs when that supply is impeded, cutting off nourishment and preventing the heart from keeping up with the demands of the body. The heart has to work pretty hard, and if you cut off the blood supply to a part of the muscle then it runs into trouble, says Jennings.

A heart attack is a medical event where blood flow in the coronary arteries becomes restricted, resulting in irreversible damage to the heart muscle. Because theres no blood flow being delivered to that part of the heart muscle, that part dies, Wong says.

The extent of the damage will vary but the consequences can be devastating, leading to a life sentence of chronic heart failure, or death.

What tends to determine a heart attacks severity is the location of the artery blockage and the time taken to clear it, as these two factors will dictate how much irreversible scarring is left behind.

You might hear that someone died of a massive heart attack. Picture the coronary arteries as being made up of three major freeways then side streets, avenues and laneways. Wong explains: If the blockage happened very much downstream and one of the side streets is blocked off, were not talking about a big volume of heart [thats low on supply]. Compare that to the start of the freeway being blocked then everything downstream is going to get wiped out because the narrowing happened to be at the wrong spot.

Blocked at the start of the freeway, the heart simply cant pump the blood out to the brain and other organs, and that can result in life-threatening cardiac shock. Wong says there is a particularly bad zone for a blockage, which is the left main stem where blood vessels lead into the heart. If it blocks off, probably two-thirds of the heart will go. That is not sustainable at all.

Its estimated that more than half of people killed by a heart attack die suddenly. In other cases, a blockage can harm the hearts electrical system causing cardiac arrhythmia, which can be fatal too: the hearts rhythm goes berserk and cant pump. The heart doesnt have time to fill then it cant empty properly. So its just fluttering instead of a regular beat in and out, Jennings says.

This can then lead to cardiac arrest, which is not the same as a heart attack, although heart attack is a common cause of cardiac arrest. You might think of a heart attack as more of a plumbing-related issue caused by a blockage while cardiac arrest is due to a malfunctioning of the hearts electrical system, prompting the heart to beat erratically thats where defibrillators come in, as an arrest is treated with electric shock.

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A heart attack is usually a result of coronary heart disease (also called ischaemic heart disease or coronary artery disease), an umbrella term for a range of conditions that can affect the heart when blood flow in the coronary arteries is compromised.

For some people, a heart attack is the first time a person realises they have the disease. Its Australias biggest killer overall; the leading cause of death in men, and, in women, it is the second-leading cause after dementia. Heart attacks are responsible for two-fifths of all coronary heart disease deaths.

Another important distinction: coronary heart disease is just one form of heart disease. Heart disease and cardiovascular disease are the same thing and are broad terms that include any disease of the heart or blood vessels, such as stroke and congenital heart conditions.

Angina, meanwhile, is a short-lived chest pain caused by blood flow issues its a sign of coronary heart disease but less intense than heart attack pain.

Most of us probably have an image in our heads of someone clutching their chest and collapsing. Wong says the textbooks dont always reflect real life but theyre the best place to start. People often get chest pains across the front of the chest, which radiate to their jaw or down their left arm. Its also associated with some breathlessness, sweatiness or nausea, he says.

Its not always like that, though. Women, for example, are less likely to have chest pains, more likely to have breathlessness, excessive sweating, dizziness or neck and back pain. One day in 2020, disability support worker Kath Moorby felt discomfort in her right shoulder and hand followed by tingling in her arms and fingers. Then she felt hot, clammy and sweaty. There was no chest pain, just a heaviness.

It was a surreal moment. Really? Im 44 and Im having a heart attack?

Paramedics eventually determined she was having a heart attack. It was a surreal moment, she recalls. Really? Im 44 and Im having a heart attack?

Moorby had two stents implanted. She says the effect was instant: the pressure in her upper-body reduced and her blood could flow freely again. They said I had a 20 per cent chance of surviving had I not made it to hospital when I did, she recalls.

Other people experience tightness rather than crushing pain.

People usually become cold, white and clammy, Jennings says. But symptoms can be variable.

Andrew van Vloten, a 53-year-old Victorian park ranger, had his first heart attack in 2014. With a family history of heart disease, he says, looking back, there had been signs for months that something was off: he felt occasional chest and jaw pain, especially when exercising, as well as shortness of breath. One day at work, the chest pains returned and wouldnt subside. It was getting quite intense, the pressure right on the centre of my chest I then started to get pins and needles in my fingers and toes. It was full-on, van Vloten says.

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He had a stent put in that day.

To avoid a repeat, he set about exercising more and ate less saturated fat, red meat and processed food. Six months down the track, I felt as fit as Id been in 10 years.

Its why he was so shocked when he had a second heart attack in 2020. This time he had no symptoms in the lead-up other than feeling a bit unwell. Then, as he was loading up timber into a ute, he was hit by nausea, breathlessness and chest pains. It just came on really quickly and intensely, he says. Everything started coming back to me.

It can be easy to mix up heart attack symptoms with heartburn, oesophageal spasms or angina. If the pain lasts more than 10 minutes, its worth seeking urgent medical attention. Its a heart attack when an artery blocks off and nothing a patient does makes it better, Jennings says.

Sometimes a heart attack can happen when the heart is under more pressure, such as during exercise or even following a big fright.Other times, theres no particular exertion. To complicate matters, one-sixth of people experience silent heart attacks no symptoms. This is more likely in people who have diabetes because their nerve endings can be blunted.

Sometimes we do ECGs on people for insurance purposes, and we find that theyve had an old heart attack somewhere along the way, Wong says. Its like if you damaged any part of you, you would scar, with scar tissue replacing the damaged tissue. The same thing happens in the heart.

Credit:Artwork Getty/Marija Ercegovac

They might seem to come out of the blue but a heart attack often reflects a process that has been going on throughout a persons life. Atherosclerosis is the narrowing and hardening of arteries. It starts in adolescence, if not before, brought on by a build-up of plaque (made of cholesterol and other substances) on the inner wall of the arteries. Once it gets underneath that inner lining of the vessel wall, its really hard to get out again, Wong says, so its almost like a one-way street.

By the time the guy whos been doing absolutely nothing, sitting all day, comes to you with chest pain, thats really late.

You wont be aware of much of the gradual narrowing because the body manages fine until it reaches a particular point. Its only once a coronary artery narrows by between 60 and 70 per cent that blood flow falls off noticeably and someone might begin to tire more easily or feel bursts of chest discomfort. That partly explains why some people feel great one week and dont feel good the next, Wong says.

This is also when coronary heart disease is in full swing. The artery wall becomes more unstable, so a blob of plaque can crack off and lead to clotting. This is the most common way a blockage happens before a heart attack but there are others. Sometimes, heart attacks occur in people without significantly clogged arteries, Wong says. There might be a spasm of the muscle lining in the artery that causes it to clamp down or, in rare cases (about 2 per cent of heart attacks) mainly in women, there can be a tear in the inner artery wall that peels off and blocks circulation (this is called spontaneous coronary artery dissection, or SCAD). Or plaque might simply be unstable, slough off and clog an artery more common in smokers.

Credit:Artwork Stephen Kiprillis

If someones exercise capacity is consistently worsening, it can be a sign their arteries are narrowing dangerously. It means when the heart is being asked to do more work, its not getting enough blood flow to it, Wong says. Maybe you used to be fine walking five kilometres, three the next month, then two; or walking room to room becomes too much. It will be unrelenting, its not something that would come and go away, Wong says. People need to be honest with themselves by the time the guy whos been doing absolutely nothing, sitting all day, comes to you with chest pain, thats really late. The artery is likely to be quite narrowed.

There are various tests you can do. As a first step, Wong advises his patients to try an online calculator such as cvdcalculator.com, where you punch in your data (for example, age, smoking status, cholesterol levels) to get an understanding of your risk and how making small lifestyle changes can make a big difference.

You dont have to have symptoms of heart disease to get a heart health check. Any patient over 30 is eligible.

A basic heart health check, usually done by a GP, can determine risk levels and help work out whether you are harbouring artery disease. You dont have to have symptoms of heart disease to get a heart health check. Any patient over 30 is eligible. Its covered by Medicare once in a 12-month period and is recommended for adults aged 45 and over, or Aboriginal and Torres Strait Islander people aged 30 and over.

A patient might have further tests if its appropriate, such as a calcium-score CT scan (more calcium deposits in the coronary arteries means theres a higher chance theyre narrowed) or an ECG or a cardiac stress test, which examines how the heart responds to exercise. These tests can cost a few hundred dollars, which Medicare generally covers only if someone has heart disease symptoms.

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To check to what extent someones arteries have narrowed, a coronary angiogram involves injecting dye into the hearts blood vessels, which is picked up using an X-ray machine.

Depending on the patient, they might be prescribed medication to treat cholesterol, blood pressure or clotting. Or a doctor might recommend inserting a stent or doing coronary artery bypass surgery to redirect blood flow by grafting a healthy blood vessel.

Its difficult not to be alarmed by the stories of fit, healthy people who collapse suddenly with a heart attack. Wong says these are rare events often caused by inherited, underlying heart disease. But anyone who has concerns can talk to their doctor about tests that will help them ascertain their hearts health, and what level of physical activity is safe for them.

Twice as many men are admitted to hospital with a heart attack compared to women, although the disparity in deaths is slimmer: in 2020, 2800 women and 3700 Australian men. This is, in large part, because of differences between how these events present in the two sexes studies having long shown that many women have their symptoms dismissed or misdiagnosed.

The average age of a first heart attack is 72 for women about 10 years older than men.

The average age of a first heart attack is 72 for women about 10 years older than men and theyre more likely to have a spontaneous artery tear, a blockage in a small coronary blood vessel or a mini heart attack where a smaller artery doesnt open up properly, despite no significant narrowing. The biology that causes heart attacks can be a bit more varied in women than men, Jennings says.

Women with a history of pre-eclampsia or gestational diabetes during pregnancy or endometriosis also have a higher risk of coronary heart disease.

There are some inequalities in who suffers most from heart attacks. The rate of hospitalisations and deaths is about 1.5 times higher for people in remote or lower socioeconomic areas, the Australian Institute of Health and Welfare reports. For Indigenous Australians, the rate is double that of non-Indigenous Australians.

People with diabetes are roughly four times more likely to have a heart attack. And mental health is important for the heart: depression can increase your risk of developing coronary heart disease just as much as smoking and high blood pressure.

Phone triple zero. While you wait for an ambulance, it helps to focus on breathing steadily to try to calm yourself. With any heart attack, Wong says the key is to have as short a door-to-needle time as possible. Normally, paramedics alert a hospital of a heart attack patient before arrival.

Sometimes theyll be given clot-dissolving medication, or a catheter tube is threaded up the arm or leg and a tiny balloon widens the narrowed coronary artery to leave behind a wire mesh, called a stent, to prop it open. Every minute counts in doing that, Jennings says, because the longer you wait, the more the heart muscle cells will be dying.

The part of the heart not affected by the blockage will keep working to contract, but it will be strained and the damage can spread. There is a risk of chronic heart failure, where the hearts pump mechanism is weakened long-term. They could be fine sitting or lying down but when they start walking up a hill, they cant do it. They have a limit and their lifestyle has to be adjusted to what the heart allows them to do, Wong explains. In severe heart failure cases, an artificial pacemaker or organ transplant may be needed.

Weve seen some horrendous things that could have been dealt with a lot sooner.

Treatment involves looking after the other arteries because you cant afford to lose any more heart muscle with another heart attack.If we get them from their home to hospital within two to three hours then we have a very high chance of salvaging their heart muscle and keeping them alive. If its five to six hours after the onset of the heart attack, even if you unblock the artery, the amount thats salvaged is much less, says Wong.

There have been too many preventable heart attack deaths from patients who stayed away from hospital during the pandemic, Wong says. Weve seen some horrendous things that could have been dealt with a lot sooner, he says. Having ambulances ramped outside emergency rooms is a particular concern in heart attack cases.

When treatment is swift, you can go on to lead a normal life, with medication and lifestyle adjustments to help keep your arteries open. Still, its estimated that about 20 per cent of heart attack patients will be hospitalised with a second one within five years, a reality that Wong says can make people feel very anxious.

Its why cardiac rehabilitation is so important as it involves structured physical activity and education on lifestyle and medicines, Jennings says, urging people to speak to their doctor about enrolling in a program or use the Heart Foundations directory to find one.

The heart does age and wear out eventually, Wong says. Sometimes I have to say to patients, Its more a case of youve had too many birthdays. That said, a heart attack is eminently preventable, Jennings says, particularly under the age of 80. The goal is to slow the rate at which the coronary arteries are narrowing and stiffening.

First, its good to understand what we can control. We cant change our age nor our genetics, both of which are unavoidable factors in our risk of heart disease. Some people can do all the wrong things [for their health] and never have a heart problem. Other people barely infringe and suffer from heart disease, says Jennings.

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Some people have a family history of heart disease. Wong starts to treat such patients about five years before their close relative who had heart trouble started having issues. Some people might have naturally high cholesterol (called familial hypercholesterolemia). Here, heart complications tend to occur in someones 20s.

Health issues such as high cholesterol or blood pressure have effective medications. But whatever your genetic background, youll still be better off with a better lifestyle, so never give up, Jennings says. Poor nutrition, low physical activity, drinking alcohol, smoking and being overweight: these are all major risk factors that can be improved. A 2019 study of more than 26,000 people aged over 18 found that a healthy lifestyle was linked to a 44 per cent lower risk of coronary heart disease.

This might sound a bit airy-fairy, but I say thank you to my heart every day. I am in absolute awe of my heart.

Sometimes people become scared of putting pressure on their heart with exercise but Jennings urges people to ditch the fear. Theres nothing better you can do for your heart than being physically active, he says. Sensible exercise, where people build up a program and get fit, is one of the healthiest things.

The Mediterranean diet remains the gold standard for a healthy heart, he says, and instead of focusing on food components, such as fat and cholesterol, there is increasing emphasis on healthy food combinations so, lots of fruit and vegetables, olive oil, fish and chicken because people eat food, not polyunsaturated fat .

Kath Moorby had many risk factors, from family history to years of weight struggles. Before her heart attack she had lost 100 kilograms but her diet remained unhealthy, and she was smoking 50 cigarettes a day. What you do in your younger years comes back to bite you on the bum, Moorby says. Today, she eats better, walks, doesnt drink and no longer smokes.

While coronary heart disease kills more Australians than any cancer (lung cancer is the fourth-leading cause of death in men and women), Jennings observes that cancer tends to be more feared in society, not least because people fade away in front of us, whereas with a heart attack [often] theyre just gone [suddenly].

He says there is a degree of unfair blame that is heaped on heart disease patients too. Its not necessarily their fault if theyre overweight or have undetected risk factors. We just need to help them a bit more, he says.

Andrew van Vloten, who had two heart attacks, urges people to learn about their bodies and their limits and take any heart disease risk factors seriously by visiting a doctor. Today, hes a proud 10-kilometre race finisher, and he connects with his heart through meditation. This might sound a bit airy-fairy, but I say thank you to my heart every day, van Vloten says. I am in absolute awe of my heart, the function it does and what its capable of doing.

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Whats a heart attack? How can you tell if youre on the edge of one? - Sydney Morning Herald

Dr. Sara Vasconcelos in the laboratory at Toronto General Hospital on May 11.Christopher Katsarov/The Globe and Mail

When Sara Vasconcelos talks about her work, it sounds as if shes in the restoration business. But instead of repairing damaged buildings, the researcher at Torontos University Health Network wants to fix damaged hearts by using stem cells to rebuild cardiovascular tissue.

Now, Dr. Vasconcelos is one step closer to achieving that goal with a $3-million grant from the Stem Cell Network, a Canadian research funding organization. Her effort is one of 32 projects across the country that rose to the top in a competition for in the largest outlay of federal funding for regenerative medicine in 20 years.

On Thursday, the Ottawa-based network announced a total of $19.5-million in awards, which together with matching funds from various partners, will translate into $42-million for research and clinical trials over the next three years. The funding will enable the work of more than 400 scientists, clinicians and trainees, the organization said.

Its a big step, said Dr. Vasconcelos, who said she will use her award to build on preliminary findings obtained using rats. She will next work with pig hearts, which offer a much closer analogue to the human organ.

While doing so, she also hopes to overcome a barrier that has stood in the path of those who are trying to repair hearts using cardiomyocytes heart tissue cells that are grown from embryonic stem cells. The problem is that the replacement cells wither away if they are not nourished and kept alive by blood vessels.

As part of her project Dr. Vasconcelos aims to use a technique in which small sections of microscopic blood vessels are harvested from human fat and implanted along with the heart cells.

The microvessels that are like Lego pieces, she said. You can put a whole bunch of them in with the stem cell-derived cardiomyocytes and they will connect to each other and connect to the host vessels that carry blood.

With her grant secured, Dr. Vasconcelos said she is assembling the team that will test the method on pig hearts later this year. Ultimately, her goal is to develop the technique into a therapy that can restore cardiac function in human patients following a heart attack, she said.

Among the other projects to win funding are some that are already heading for clinical studies. That includes a large study led by Guy Sauvageau, a hematologist at Maisonneuve-Rosemont Hospital in Montreal, that involves developing engineered blood stem cells to treat leukemia.

Working with a group of clinical sites in the U.S., Dr. Sauvageau and his team have already had success at treating patients with leukemia who relapse. The new project will involve introducing genetical engineered stem cells into people who are better able to withstand cancer treatment and facilitate recovery.

Between 10,000 and 20,000 patients a year would benefit from this kind of therapy, Dr. Sauvageau said.

In the future, he added, the study could open the door to teaching the body to continually produce and replenish its own cancer-killing immune cells rather than having those cells created externally and infused in a form of treatment know as CAR T-cell therapy.

As part of another of the funded projects, David Thompson at the Vancouver Coastal Health Research Institute will conduct clinical trials for one of the worlds first genetically engineered cell replacement therapies for type 1 diabetes.

Dr. Sara Vasconcelos points to an image of vascular tissue in the laboratory at Toronto General Hospital where they engineer cell and tissue regeneration.Christopher Katsarov/The Globe and Mail

The diversity of the projects highlights the increasing prominence of stem cells in multiple domains of health research, an area where Canada has a long track record of success ever since University of Toronto researchers James Till and Ernest McCullough established the existence of stem cells cells which can differentiate into more specialized types in bone marrow in 1961.

Tania Bubela, dean of health sciences at Simon Fraser University in Burnaby, B.C., said the kind of funding the Stem Cell Network provides helps bridge a crucial gap between fundamental laboratory research and proven therapies for patients.

What weve realized over time is that where you get public sector investments to close the funding gap is exactly in that translational space from preclinical into early stage clinical trials, Dr. Bubela said. Once you have that proof that things are going to work and that they can be taken up by the health system, thats when venture capital starts to get interested.

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Heart, cancer and diabetes projects among winners of funding boost for stem cell therapies - The Globe and Mail