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Viewpoint: As New Zealand edges toward relaxing its ban on gene edited foods, experts weigh in – Genetic Literacy Project

September 13th, 2024 2:41 am

Viewpoint: As New Zealand edges toward relaxing its ban on gene edited foods, experts weigh in  Genetic Literacy Project

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Farmers in Brazil and Argentina ramp up growing of genetically-modified drought tolerant wheat that can grow in subtropical regions – Genetic Literacy…

September 13th, 2024 2:41 am

Farmers in Brazil and Argentina ramp up growing of genetically-modified drought tolerant wheat that can grow in subtropical regions  Genetic Literacy Project

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Scientist explains why we’ll never have a real Jurassic Park – and people are crestfallen – indy100

September 13th, 2024 2:41 am

Scientist explains why we'll never have a real Jurassic Park - and people are crestfallen  indy100

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More Precise Classifications of NonClear Cell RCC Are Required to Improve Personalized Treatment – OncLive

September 13th, 2024 2:40 am

More Precise Classifications of NonClear Cell RCC Are Required to Improve Personalized Treatment  OncLive

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Bahrain aims to provide residents with personalized healthcare – Healthcare IT News

September 13th, 2024 2:40 am

Bahrain aims to provide residents with personalized healthcare  Healthcare IT News

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Precision Medicine Market Is Expected To Reach Revenue Of – GlobeNewswire

September 13th, 2024 2:40 am

Precision Medicine Market Is Expected To Reach Revenue Of  GlobeNewswire

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An injectable HIV-prevention drug is highly effective but wildly expensive – NBC News

September 13th, 2024 2:40 am

An injectable HIV-prevention drug is highly effective but wildly expensive  NBC News

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Top preventive health tips your internist wants you to know – American Medical Association

September 13th, 2024 2:40 am

Top preventive health tips your internist wants you to know  American Medical Association

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National Falls Prevention Week: Turning awareness into action – McKnight’s Long-Term Care News

September 13th, 2024 2:40 am

National Falls Prevention Week: Turning awareness into action  McKnight's Long-Term Care News

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UToledo Health Mobile Clinic Takes Preventative Care on the Road – UToledo News

September 13th, 2024 2:40 am

UToledo Health Mobile Clinic Takes Preventative Care on the Road  UToledo News

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Twice-Yearly Injection Cuts HIV Risk by 96%, But Will Cost Cut Access? – The Mercury – Manhattan, Kansas

September 13th, 2024 2:40 am

Twice-Yearly Injection Cuts HIV Risk by 96%, But Will Cost Cut Access?  The Mercury - Manhattan, Kansas

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Von der Leyen to ramp up EU healthcare union and focus on preventative treatment – MedWatch

September 13th, 2024 2:40 am

Von der Leyen to ramp up EU healthcare union and focus on preventative treatment  MedWatch

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Kate Middleton’s preventative chemotherapy explained: The gruelling drugs that are proven to stop disease retu – Daily Mail

September 13th, 2024 2:40 am

Kate Middleton's preventative chemotherapy explained: The gruelling drugs that are proven to stop disease retu  Daily Mail

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Personalised prevention in England – The Health Foundation

September 13th, 2024 2:40 am

Personalised prevention in England  The Health Foundation

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Mayo Clinic offers unique regenerative medicine procedure for knee and …

September 13th, 2024 2:40 am

Aug. 29, 2023

This Q&A features Daniel B. F. Saris, M.D., Ph.D., an orthopedic surgeon specializing in knee surgery with a focus on cell-based surgical regenerative medicine at Mayo Clinic's campus in Minnesota. Here, he explains a regenerative medicine procedure for joint restoration that he believes addresses an unmet need. Dr. Saris discusses its background and future, and appropriate referral candidates.

A team of Mayo Clinic orthopedic and regenerative medicine researchers has continued development and testing of a knee joint restoration procedure, called recycled cartilage auto/allo implantation (RECLAIM). I brought RECLAIM with me from the University Medical Center Utrecht in the Netherlands, where we developed this procedure and called it IMPACT.

In this procedure, we debride the patient's knee defect. We remove cartilage from the knee or hip, mincing these pieces into smaller fragments and extracting cartilage cells through chemical digestion to the level of the chondron. We combine these recycled autologous chondrons with allogeneic donor mesenchymal stem cells (MSCs). The mixture of 10% to 20% of the patient's cells with 80% to 90% MSCs is placed into fibrin glue, which allows the surgeon to inject them into the patient's knee defect. This procedure enables the patient's body to repair the cartilage defect, something it otherwise would be unable to do.

RECLAIM is a one-stage innovative procedure for hip and knee that enables tissue growth and restoration of cartilage in the patient's joint. Within one year, the defect is filled. DNA analysis has shown this to be patient-derived new cartilage tissue without donor DNA remaining. I see it as the MSCs providing both immune modulatory signals as well as growth factor, reminding the cartilage to grow. Ultimately, RECLAIM may help preserve the joint by filling the "pothole" for a better "drive."

We have learned that combining native cartilage cells and allogeneic MSCs can be a good partnership. We consider the transplant successful if the joint is still viable in 13 to 20 years.

A depiction of the steps in the process of recycled cartilage auto/allo implantation (RECLAIM) knee cartilage regeneration.

[This animation shows RECLAIM knee cartilage regeneration. It is playing with no audio.]

RECLAIM for hip and knee is performed under FDA scrutiny as an investigational new drug in a phase 1 trial I led with a team of Mayo Clinic investigators, and it is not yet widely available. The trial began in September 2018 and ends in September 2024.

Indications for this therapy are precise. The patient must meet the following criteria:

Often, these cartilage defects are from trauma or athletic injury.

One of my biggest drivers is improving quality of life. People need to move in their lives and they need their joints to work. Patients' alternatives are usually to deal with discomfort or quit sports. We want to help them return to sports or their pre-injury lifestyles.

I am also passionate about helping patients with arthritis, one of the biggest quality-of-life threats.

My research team specifically is seeking solutions to treat defects in young patients with active lifestyles. This is a growing group, and age limits are changing. Someday, if people live to age 120, we need joint preservation solutions for individuals ages 30 to 60 and older.

We hope it will work with other joints, but that has not been studied yet. The need seems greatest for hip and knee, but we would like to explore hand, ankle, elbow and others.

We also hope RECLAIM will apply to the meniscus. We have a Ph.D. program working on that potential application.

Aaron J. Krych, M.D., an orthopedic surgeon at Mayo Clinic in Minnesota, is leading a phase 1 RECLAIM study in the hip joint. It's open for patient enrollment. We are doing a randomized controlled trial in the Netherlands for permission to enter this as standard of care.

Lucienne Vonk, Ph.D., and I developed the idea from the first experiments through completing the initial human trials. Dr. Vonk serves as a senior researcher in the Department of Orthopaedics, University Medical Center Utrecht, the Netherlands, and director of musculoskeletal diseases at Xintela AB, a biomedical company in Sweden. As we were working with RECLAIM in the Netherlands, evidence and international enthusiasm grew. It was showing promise. Mayo Clinic orthopedic and regenerative medicine leadership gave us the opportunity to continue developing RECLAIM using Mayo Clinic's stem cell bank and conduct U.S. RECLAIM clinical trials.

Also important to me was that Mayo Clinic had orthopedic surgeons who could perform the RECLAIM procedure and that Mayo had the brand respect needed to make a clinical trial happen in the U.S.

First, we will take good care of your patients. Second, it is a cell-based cartilage repair in a single surgical procedure and only available at Mayo Clinic in Minnesota in the U.S. Outside of the United States, it's also available at University Medical Center Utrecht.

If patients have cartilage defects, say, in the knee, they often have pain and swelling clinically, and the defect can be visible on MRI. Mayo Clinic has a specialized cartilage clinic. In the knee clinic, we jointly analyze those injuries with the whole team to develop one-visit solutions.

Mayo Clinic also has world leaders in orthopedic injectable therapy if our experts deem injectables best for patients' injuries.

We also have significant multidisciplinary expertise available at Mayo Clinic and have numerous clinical trials to offer.

If you have a question regarding sending a patient to Mayo Clinic, contact knee@mayo.edu or cartilage@mayo.edu.

We attempted a moonshot effort to put all elements of this procedure into one arthroscopic surgery, an important goal for our team. To now see that come to fruition after some years is exciting and rewarding for the team, and hopefully it is a valuable improvement for our patients.

Ultimately, we want RECLAIM to be available widely for many patients and to be able to apply this cell-cell combination for other joint challenges and even other organs.

Clinical trials: REcycled CartiLage Auto/Allo Implantation. Mayo Clinic.

Refer a patient to Mayo Clinic.

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Regenerative Medicine to the Rescue – Cleveland Clinic

September 13th, 2024 2:40 am

For Kevin Kelley, the bad news came out of nowhere. I woke up one morning, he recalls, and it felt like somebody had stuffed half a banana under the left side of my jaw. The IT data security analyst from the Cleveland suburb of Rocky River, Ohio, considered himself to be in good health, aside from the hypertension that ran in his family and a recent pulmonary embolism that was successfully treated. A competitive swimmer, he swam a couple of miles almost every day, either in Lake Erie or in a pool.

A biopsy of Kelleys swollen gland revealed an aggressive form of non-Hodgkins lymphoma, a malignant cancer that originates in the lymphatic system, a network of vessels, tissues and organs that helps remove toxins and waste from our bodies.

To fight the disease, Kelley and his oncologist, Brian Hill, MD, PhD, of Cleveland Clinic, turned to regenerative medicine not once, but twice. His case is compelling because it highlights where regenerative medicine has been and where regenerative medicine is heading, says Dr. Hill, Director of the Lymphoid Malignancies Program in Taussig Cancer Institute.

Kelley received a bone marrow transplant and CAR-T cell therapy. Bone marrow transplants, which have been used for decades, transfer healthy blood-forming cells into a person with blood cancer. CAR-T cell therapy, which the Food and Drug Administration initially approved in 2017, modifies a patients own immune cells to kill cancer cells.

First, though, Kelley underwent six cycles of chemotherapy. Through it all, he continued to swim as often as he could. His care team even timed the treatments so he and his new bride, Karen, could enjoy a Grand Cayman honeymoon.

Unfortunately, a few months later, a biopsy showed that Kelley wasnt cancer-free. The next step was a bone marrow transplant, immediately preceded by more chemotherapy. Very high doses of chemotherapy are delivered with the intention of eliminating the lymphoma, Dr. Hill says. In the process, though, the patients bone marrow is eradicated, too. So you have to collect their bone marrow ahead of time and then give it back to them after the chemotherapy.

In Kelleys case, the transplant was autologous, meaning he was his own donor. (Allogeneic transplants entail a matched donor.) During the transplant, more than 100 million hematopoietic stem cells were delivered directly into his bloodstream through a special type of IV. For good measure, a chaplain blessed the cells beforehand, at Kelleys request. I figured every little bit helps, he says.

Like salmon swimming upstream to spawn, the cells knew where to go and what to do when they got there, regenerating healthy marrow in the bones.

For Kelley, the road to recovery included a three-week stay in the hospital. After another month of rest at home, he began swimming again, slowly but surely regaining strength. He was declared in remission, although the respite was short-lived. Less than a year after the bone marrow transplant, a scan showed new activity. A lymph node biopsy confirmed it: The lymphoma was back.

Kelley didnt hesitate when Dr. Hill recommended a new line of attack: CAR-T cell therapy. To get the ball rolling, T cells which are white blood cells were collected from Kelley through a procedure called leukapheresis. The T cells were then shipped off to a lab, where they were genetically altered. New chimeric antigen receptors (CAR for short) on the surface of the T cells would allow them to carry out a seek-and-destroy mission against cancer cells. In the meantime, Kelley had another course of chemotherapy. When the manufactured CAR-T cells were ready, hundreds of millions of them were infused into his bloodstream. After a week in the hospital, he was back home and on the mend.

With CAR-T cell therapy, instead of just hammering away at the cancer cells with traditional chemotherapy drugs that poison the cells, the idea is to invoke the power of the bodys own immune response to attack the cancer, Dr. Hill says.

By way of an explanation, Kelley offers an analogy that any fan of old-school video games will appreciate: Suddenly, your body is playing Pac-Man. Once those manufactured T cells are put in you, theyre on the hunt. When they find a cancer cell, they destroy it. Theyre just gobbling it up.

CAR-T cell therapy isnt without side effects, which can include flu-like symptoms as well as neurologic events that can result in confusion. Nonetheless, this particular form of regenerative medicine shows great promise. Im very optimistic for the future of this treatment approach, Dr. Hill says.

As for Kelley, hes back in remission. He plans to swim in a couple of upcoming 8-mile, open-water races: one in the Florida Keys and one around Mackinac Island in Michigan. The latter will be a fundraiser for the Leukemia & Lymphoma Society.

I feel great, Kelley says. Now its time to go have some fun.

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Regenerative medicine applications: An overview of clinical trials

September 13th, 2024 2:40 am

Abstract

Insights into the use of cellular therapeutics, extracellular vesicles (EVs), and tissue engineering strategies for regenerative medicine applications are continually emerging with a focus on personalized, patient-specific treatments. Multiple pre-clinical and clinical trials have demonstrated the strong potential of cellular therapies, such as stem cells, immune cells, and EVs, to modulate inflammatory immune responses and promote neoangiogenic regeneration in diseased organs, damaged grafts, and inflammatory diseases, including COVID-19. Over 5,000 registered clinical trials on ClinicalTrials.gov involve stem cell therapies across various organs such as lung, kidney, heart, and liver, among other applications. A vast majority of stem cell clinical trials have been focused on these therapies safety and effectiveness. Advances in our understanding of stem cell heterogeneity, dosage specificity, and ex vivo manipulation of stem cell activity have shed light on the potential benefits of cellular therapies and supported expansion into clinical indications such as optimizing organ preservation before transplantation. Standardization of manufacturing protocols of tissue-engineered grafts is a critical first step towards the ultimate goal of whole organ engineering. Although various challenges and uncertainties are present in applying cellular and tissue engineering therapies, these fields prospect remains promising for customized patient-specific treatments. Here we will review novel regenerative medicine applications involving cellular therapies, EVs, and tissue-engineered constructs currently investigated in the clinic to mitigate diseases and possible use of cellular therapeutics for solid organ transplantation. We will discuss how these strategies may help advance the therapeutic potential of regenerative and transplant medicine.

Keywords: regenerative medicine, stem cells, extracellular vesicles, COVID-19, tissue engineering, transplantation, bioengineering

Regenerative medicine focuses on replenishing and repairing tissue or organs impaired by disease, trauma, or congenital issues. Cellular therapies, conditioned media, extracellular vesicles (EVs), and seeded cellular patches are promising therapeutic tools to combat various inflammatory conditions and diseases. A large body of pre-clinical research has shown that stem cell therapies can delay disease onset within multiple organs such as the kidney (Sedrakyan et al., 2012; Urt-Filho et al., 2016; Frank and Petrosyan, 2020), lung (Mei et al., 2007; Zhen et al., 2008, 2010; Garcia et al., 2013; Xu et al., 2018), heart (Wang et al., 2015; Galipeau et al., 2016; Miteva et al., 2017), and liver (Gilsanz et al., 2017; Tsuchiya et al., 2019) through immunomodulatory and paracrine mechanisms. Conditioned media and EVs derived from stem cells also demonstrate similar characteristics (Lener et al., 2015; Nassar et al., 2016; Bruno et al., 2017; Riazifar et al., 2017; Sedrakyan et al., 2017; Grange et al., 2019). Mesenchymal stromal cells (mesenchymal stem cells; MSCs), which are used mainly in clinical trials, have a potent self-renewal and differentiation capacity into multi-lineages and may be isolated from various adult tissues such as bone marrow (BM), adipose tissue, and fetal specimens (amniotic fluid and umbilical cord). Cellular therapies are also investigated for transplant medicine with the hopes of repairing marginal organs, minimizing ischemia-reperfusion injury (IRI), and inducing immune tolerance in solid organ transplantation (Leventhal et al., 2016; Sawitzki et al., 2020). In addition to stem cell therapies, immune cell therapies that specifically isolate and enrich anti-inflammatory immune cells are also investigated as a promising regenerative medicine tool towards treating inflammation, promoting tissue regeneration, and enhancing transplant tolerance (Zwang and Leventhal, 2017). Currently, clinicians and scientists have begun providing novel insights into optimizing cellular therapy in the clinical setting to provide a more deliverable, sustained, and impactful clinical benefit to patients (Okano and Sipp, 2020). However, further studies with larger patient cohorts are needed to show the efficacy of cellular therapies, conditioned media, extracellular vesicles (EVs), and seeded cellular patches for regenerative medicine. Here we will review results obtained from current clinical trials and novel cellular therapeutic options investigated towards clinical use. We will discuss how these findings and current novel techniques may help advance the potential therapeutic effects of cellular transplantations, EVs, and tissue-engineered constructs for regenerative medicine and transplantation.

Promising pre-clinical research studies have shown the potential of multipotent mesenchymal stem cells (MSCs) transplantation as a regenerative medicine therapy option (Vu et al., 2014; Wang et al., 2021). Currently, the U.S. Food and Drug Administration (FDA) has approved a small set of therapies for clinical use (). Clinical trials have focused on using MSCs immunomodulatory, immunosuppressive, and regenerative potentials with hopes of treating chronic diseases and immune resetting of autoimmune disorders (). MSCs immunoregulatory properties are attributed to their secretion of numerous cytokines (anti-inflammatory factors: iNOS, IDO, PGE2, TSG6, HO1 and galectins, cytokines: TGF, IL-10, CCL2, IL-6 and IL-7, chemokines: IL-6, CXCR3, CCR5, CCL5, CXCL9-11) and putative angiogenic proteins (VEGF, PDGF, TGF) (Shi et al., 2018). The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) has set standards to define multipotent mesenchymal stromal cells (MSC) for both laboratory-based scientific investigations and pre-clinical studies (Dominici et al., 2006). Three guidelines must be met for the designation of MSC. Firstly, MSC must be plastic-adherent (tissue culture flasks) in cultured under standard conditions. Secondly, MSC (measured by flow cytometry) must have specific surface antigen (Ag) expression (95% expression of CD105, CD73 and CD90, with absence (5/2%) in expression of CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA class II). Thirdly, MSC must exhibit differentiation capabilities towards osteoblasts, adipocytes, and chondroblasts under standard in vitro differentiating conditions. Not all published clinical trials have adhered to these guidelines, limiting our ability to compare and contrast study outcomes and hindering the fields progression ().

A list of cellular and tissue engineered products with the proposed treatments currently FDA approved. All of the approved cellular products are hematopoietic progenitor cell derived from Cord Blood approved for disorders affecting the hematopoietic system. The tissue engineered scaffolds are allowed for the treatment of mucogingival conditions, cartilage defects of the knee, and thermal burns.

A list of clinical trials using regenerative medicine applications. Each trial is identified by disease reference, patient gender, method of treatment, outcome, and International Society for Cellular Therapy Criteria Check (1, 2, 3). 1) MSC must be plastic-adherent when maintained in standard culture conditions. 2) MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. 3) MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. Most clinical trials using MSC appeared to have the 1st and 2nd criteria mentioned, and a large difference was noted between the trials regarding cell number, type, from of transplantation, and culture conditions. Such variation allows for the identification of different forms of effect per experimental group but shows little consistency in the trials performed. Thus, it would be beneficial if clinical trials followed a clearer guideline with minor changes per experimental group to understand better the applicability and efficacy of cellular and tissue engineered therapies.

In current clinical trials, similar to pre-clinical data, clinical administration of cellular therapies has shown angiogenic properties (active secretion of proangiogenic factors) and anti-inflammatory effects (reduced expression of pro-inflammatory markers and T cell proliferation) (Saad et al., 2017; Ye et al., 2017; Zhang et al., 2017). The angiogenic properties of autologous adipose tissue-derived MSCs are attributed to significantly increasing renal tissue oxygenation, cortical blood flow, and stabilizing glomerular filtration rates (GFR) up to 3months in patients with the atherosclerotic renovascular disease (RVD) (Saad et al., 2017). The anti-inflammatory effects of autologous hematopoietic stem cells are predicted to be beneficial for patients with type 1 diabetes mellitus by lowering the proportion of white blood cells, lymphocytes, T-cell proliferation, and pro-inflammatory cytokine production (Ye et al., 2017). Similarly, anti-inflammatory properties of allogeneic umbilical cord-derived MSCs, show improvements in patients with systemic sclerosis-associated, with better skin thickness scores, lung function, significantly decrease in anti-Scl70 autoantibody titers, and reduction of pro-inflammatory cytokine levels (including transforming growth factor- (TGF-) and vascular endothelial growth factor (VEGF) levels in serum) (Zhang et al., 2017). Although clinical trials show promising results for MSC use in the clinic, there are limitations in MSCs scalability, interdonor variability, clinical trial outcomes inconsistency, low engraftment rates, variation in immunomodulatory response, and potential regenerative limitations (Tanavde et al., 2015). Recently, induced pluripotent stem cells (iPSCs) derived MSCs (CPY-001) are shown to be safe and well-tolerated in a limited number of patients with steroid-resistant acute graft versus host disease (Bloor et al., 2020). This trial demonstrates for the first time, the possible applicability of iPSC-derived MSCs for a range of other clinical targets that may overcome the fundamental limitations of conventional, donor-derived MSC production processes. Although current clinical trials exhibit similar and limited anti-inflammatory beneficial effects with MSC treatments like previous pre-clinical trials, there is a large variation between each trial. Variations such as cell culture conditions, cell number transplantation, from of transplantation, cell type, and characterization limited the interpretation of each trial. Additional studies with larger cohorts are also needed to address the efficacy of cellular therapeutics in regenerative medicine.

MSCs preconditioned with either recombinant proteins, drugs, or ex-vivo cell culture conditions and techniques are also investigated to enhance their therapeutic potential before transplantation (). One form of enhancement strategy applied for cardiac regenerative cell therapy is using a guided cardiopoiesis approach to deliver BM-MSCs expanded and processed for lineage specification to derive cardiopoietic cells. In a Phase III Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) clinical trial, cardiopoietic stem cells were delivered via the endomyocardial route with a retention-enhanced catheter to patients with ischemic heart failure (Bartunek et al., 2017). However, after thirty-nine weeks, the primary outcome was neutral, except for a subset of patients with severe heart enlargement that appeared to have had a consistent beneficial effect. The results suggest that cardiopoietic cell treatment beneficial outcomes may vary depending on the type of cardiac damage present in patients. Another alternative method used to enhance MSC regenerative potential aside from preconditioning the cells with recombinant growth factors, cytokines, or drugs is the use of environmental stimuli, such as hypoxia. Preconditioned MSCs under chronic hypoxic conditions (itMSC) show enhanced immunomodulatory properties when transplanted in non-ischemic cardiomyopathy patients (Butler et al., 2017). After 90 days, the administration of itMSCs was associated with a reduced number of natural killer cells, and the magnitude of this reduction was correlated with improved left ventricular ejection fraction (Butler et al., 2017). However, a single injection of itMSC was not efficient in promoting significant cardiac structural or functional improvements, highlighting the need to investigate the efficacy of serial dosing of intravenously administered itMSCs to promote a sustained immunomodulatory effect along with structural and functional improvements in the clinic. Thus, clinicians have also carried out studies identifying how different dosages of stem cells and numbers of injections (transplants) may dictate their therapeutic potential. In the TRIDENT Study, Florea et al. have demonstrated in patients with ischemic cardiomyopathy that there are different beneficial outcomes when patients are administered either 20 million or 100 million allogeneic MSC via transendocardial injection (Florea et al., 2017). Both groups showed improvement in scar formation; however, improved ejection fraction was noted only in patients receiving 100 million cells. The authors stated that although the two doses of allogeneic MSC are safe for patients, it is crucial to design trials to evaluate optimal dosing for cell-based therapies. Clinical trials have also begun to understand how different cell types produce better results than single-cell transplantation. In pre-clinical studies (Park K.-S. et al., 2019), have recently demonstrated that delivering both cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) and human mesenchymal stem cell-loaded patch (hMSC-PA) to rats with myocardial infractions can amplify cardiac repair with enhanced vascular regeneration and improved cellular retention and engraftment (Park S.-J. et al., 2019). The combinatory cell delivery can also be applied to organ transplantations to enhance/preserve newly transplanted partial organ engraftment. Benomar et al. demonstrated that patients who were transplanted with pancreatic tissue comprising more than 50% of non-islet cells (likely enriched in ductal, acinar, and MSCs) had a statistically significant lower level of hemoglobin A1c and lower daily requirement of insulin even 5years after transplantation, compared to those who received islet transplant with more than 50% tissue purity (Benomar et al., 2018); thus, suggesting that non-endocrine cells have a beneficial effect on long-term islet graft metabolic function. The authors identified elevated expression of CA19-9 generally synthesized by pancreatic ductal cells and hypothesized that ductal cells must have been transplanted and continued to proliferate and contributed to the beneficial outcomes. These findings bring forth an important concept, the need to transplant multiple cell types for better long-term engraftment and function. These results suggest and warrant further investigation into the understanding and application of methods to enhance the therapeutic potential of MSC, either through improved cell culture techniques, the route of delivery, dosage specificity, or a combination of various cell types to further amplify their regenerative potential.

Current therapies are also designed to mobilize patients tissue-specific progenitor cells using various bioactive molecules such as growth factors, cytokines, and hormones to enhance endogenous regeneration. Activation of endogenous stem cells to promote regeneration or repair holds great promise for the future of translational medicine (Xia et al., 2018). Ansheles et al. demonstrated that using statins (Atorvastatin therapy) in patients with coronary heart disease could significantly increase the pool of endothelial progenitor cells by 72% in 3months (Ansheles et al., 2017). Patients also displayed a significant decrease in VEGF expression and various metabolic markers such as C-reactive protein, total cholesterol, LDL cholesterol, and triglycerides. Pantin et al. also investigated how to enhance endothelial cell mobilization from patients following allogeneic transplantation to sustain donor-derived hematopoiesis (Pantin et al., 2017). They identified that a high-dose (480mg/kg) Plerixafor is safe and effective in mobilizing CD31 expressing cells in healthy donors. These studies highlight the use of molecules to enhance tissue regeneration and restoration in disease by activating endogenous resident cells without the need for exogenous cellular infusions.

Cell-to-cell communication is vital to control wound healing and modulate chronic and acute diseases via paracrine signaling. Cells communicate via the secretion of numerous extracellular vesicles (EVs) which are a heterogeneous population and ranging from 40nm to a few mm in size under physiological and pathophysiological conditions. EV populations most widely studied and characterized are exosomes (derived from intracellular endosomal compartments and range from 30 to 120nm in diameter), microvesicles (also known as shedding vesicles are non-apoptotic EVs that originate from the plasma membrane and range from 50 to 1,000nm in diameter), and apoptotic bodies (originate from cells undergoing apoptosis and range from 50 to 2,000nm). Multiple pre-clinical studies have demonstrated that conditioned media of cultured stem cells and stem cell EVs show beneficial effects on various diseases (Lener et al., 2015; Bruno et al., 2017; Riazifar et al., 2017; Nguyen et al., 2020). The discovery of exosomes, microvesicles, and apoptotic bodies within the conditioned media has led to a new avenue of research exploring EVs for clinical use. Using EVs, most of the therapeutic effects of stem cells can be achieved with a reduced risk associated with live-cell injection late effects, such as neoplastic transformation and immune response activation (Nassar et al., 2016; Wang et al., 2017; Guo et al., 2020). A limited number of clinical trials have investigated EVs therapeutic potential in patients with cancer (Morse et al., 2005; Dai et al., 2008) and disease (Nassar et al., 2016). In chronic kidney disease patients (), EVs isolated from umbilical cord MSCs were shown to be safe and potentially effective in modulating the inflammatory immune reaction (Nassar et al., 2016). Patients who were given two doses of MSC-EVs showed improved eGFR, serum creatinine level, blood urea, and urinary albumin-creatinine ratio, possibly due to a significant plasma level increase in TGF-1 and IL-10 with a decrease in plasma levels of inflammatory cytokine, TNF-. Although patients saw a vast improvement after two dosages of therapy at 8weeks to 9months, the improvements were not sustained after 9months, and an additional administration of the EV might be needed (Nassar et al., 2016).

Further studies are also necessary to clarify fundamental questions regarding the generation, origin of isolation (body fluids: plasma, serum, blood, amniotic fluid, cell lines: MSCs, progenitor cells, IPSCs distribution, tissue derived) (Crescitelli et al., 2021) and uptake of EVs and how to scale up to cGMP manufacturing and improve associated quality control and batch tracking methods for the clinic (Riazifar et al., 2017). Another issue brought forth by the International Society for Extracellular Vesicles is the general lack of proper characterization of the different forms of EVs used in pre-clinical and clinical trials as each type contains different cargos and may promote different effects (Thry et al., 2018). There are currently multiple clinical trials initiated and recruiting patients to investigate EVs application in various diseased organs such as lung, liver, kidney, and heart. The potential use of EVs as a regenerative medicine therapeutic option is vast and promising. There are currently no FDA-approved EV products.

Cellular therapeutics have also been applied ex vivo to improve and recondition donor organ quality before transplantations. Thompson et al. show how ex vivo delivery of multipotent adult progenitor cells via normothermic machine perfusion in kidneys deemed un-transplantable prompted improved clinically relevant parameters (urine output, decreased expression of injury biomarker NGAL, improved microvascular perfusion) and decreased neutrophil recruitment and pro-inflammatory cytokines (downregulation of interleukin (IL)-1, upregulation of IL-10 and Indolamine-2, 3-dioxygenase) (Thompson et al., 2020). Brasile et al. also show how 24h ex vivo perfusion of MSC in an Exsanguinous Metabolic Support tissue-engineering can accelerate the repair of ischemic damage in human kidneys. Promoting regeneration identified by the increased synthesis of ATP (both in the renal cortex and medulla), a reduced inflammatory response (TNF-, RANTES, IL1-B, IL6), increased synthesis of growth factors (EGF, FGF-2, and TGF-), normalization of the cytoskeleton (ZO-1 expressed exclusively at the plasma membrane) and increased cellular proliferation (higher expression of PCNA and mitosis) (Brasile et al., 2019). The authors suggest a more prolonged warm reperfusion of a donors kidney may further improve and repair tubule damages attained from severe ischemic insult. The potential of MSCs to prevent or decrease injuries due to ischemia-reperfusion to further improve organ preservation has also been shown in various organs such as the lung (La Francesca et al., 2014; Lu et al., 2015), liver (Laing et al., 2020), and heart (Yano et al., 2018). Thus, these techniques involving reperfusion using various cell types provide a new avenue to significantly expanding donor criteria to offset current donor shortages. Future studies directed towards identifying the precise reperfusion media, the extent of reperfusion time, and the most suitable cell source can further enhance these techniques applicability in the clinic.

COVID-19, the disease attributed to the novel SARS-CoV-2 coronavirus, has given rise to a global pandemic. Although many patients do well, some present fever, dyspnea, hypoxia, and even exhibit moderate-to-severe acute respiratory distress syndrome (ARDS). This group of patients typically require intubation, which is associated with high mortality rates (up to 67%94%) (King et al., 2020). The detrimental effect of COVID-19 that causes multiple organ failure and even death is correlated with the presentation of a cytokine storm, which is identified as a maladaptive release of cytokines (Brodin, 2021). Elevated expression of inflammatory cytokines such as IL-1B, IFN-, IP-10, and monocyte chemoattractant protein 1 (MCP-1) detected in patients with COVID-19 is linked with Th1 cell response (Ye et al., 2020). Currently, MSC and their EVs are considered as a potential therapeutic option against COVID-19 (). MSC has the innate capacity to promote anti-inflammatory and immune regulatory functions by directly inhibiting abnormal activation of T lymphocytes and macrophages, pro-inflammatory cytokines, and secreting anti-inflammatory cytokines and growth factors such as IL-10 and VEGF to stimulate regeneration and repair. There are currently 16 clinical trials completed with over one thousand studies listed on ClinicalTrials.gov on the use of stem cells or stem cell exosomes to treat coronavirus-related injuries, such as acute kidney and lung injury and various inflammatory processes. Non-randomized case studies, phase 1 and phase 2 clinical trials have shown that human umbilical cord-derived mesenchymal stem cell (UC-MSCs) infusions in patients with moderate and severe COVID-19 pulmonary disease is safe and well-tolerated (Liang et al., 2020; Meng et al., 2020; Shu et al., 2020; Hashemian et al., 2021; Shi et al., 2021). A phase 1 and phase 2 clinical trial with limited patients shows that administration of UC-MSCs or clinical-grade MSCs may help reduce inflammatory cytokines (TNF-, IFN-, IL6, IL8, C-reactive protein) and promote lung recovery in surviving patients (Liang et al., 2020; Hashemian et al., 2021; Shi et al., 2021). Intravenous injection of clinical-grade MSCs (lacking ACE-2 receptor and TMPRSS2) led to increased levels of anti-inflammatory cytokine IL-10, and the normalized presence of immune cells. The patients presented an increase of peripheral lymphocytes, a decrease in C-reactive protein (CRP), a reduced activated cytokine-secreting immune cells (CXCR3+CD4+T-cells, CXCR3+CD8+Tcells, and CXCR3+NK-cells), and a restored levels of regulatory DC cell population (CD14+CD11c+CD11bmodregulatory DC cell) (Leng et al., 2020). The use of MSC with the absence of ACE-2 receptor and TMPRSS2 to prevent infection with SARS-Cov-2 may have enhanced the therapeutic effects of MSCs.

There are currently multiple studies listed on ClinicalTrials.gov on the use of EVs to treat COVID-19. Sengupta et al. show that a single dose of intravenous infusion of exosomes derived from BM-MSC (ExoFloTM) in patients presenting moderate-to-severe ARDS helps restore oxygenation, reduces the cytokine storm, to bring back a healthy immune system with no adverse effects (Sengupta et al., 2020). The authors state that exosomes may be used as a preventative measure against progression to invasive oxygen support and mechanical ventilation, which is associated with a high mortality rate. Further studies with randomized controlled trials (RCTs) are warranted to prove efficacy and address what type of EVs and what dosage of EVs are needed to treat COVID-19 patients. A short-term (84days) Phase 1 clinical trial of twenty-seven COVID-19 patients with pulmonary fibrosis treated with human embryonic stem cell-derived immunity and matrix-regulatory cells, which poses high expression of proliferative, immunomodulatory and anti-fibrotic genes, also show improvements in clinical symptoms (Wu et al., 2020). Additional multicenter randomized placebo-controlled Phase 2/3 trials are underway for further proof. Although these findings are promising, additional studies with larger cohorts are needed to assess the efficacy of MSCs and EVs therapeutic potential to treat and prevent the progression of COVID-19 related injuries in patients. While many clinical trials are listed, not all have begun, and only a few have been completed. Additionally, the completed trials consist of a small sample size, various cellular products, different culture methodology, and need more time for result interpretation. Leading to a discouraging notion that COVID-19 treatment with cellular therapies may not be available soon to treat a significant number of patients. COVID-19 clinical trial moving forward should focus on clear identification of cellular products used and improve quality of study design to further the future of cellular therapies in treatment of COVID-19.

Aside from using stem cells, the field of regenerative medicine also investigates the potential isolation and enrichment of specific anti-inflammatory immune cells to treat inflammation, promote tissue regeneration and transplant tolerance (). In non-acute stroke patients, administration of autologous M2 macrophages is shown to be safe and can modulate inflammatory responses, contributing to angiogenesis and tissue repair (Chernykh et al., 2016). However, the treatment appeared to be more effective in patients with lower endogenous immunosuppressive mechanisms (IL-10, FGF-, PDGF, VEGF) and increased pro-inflammatory activity (IL-1, TNF-, IFN-, IL-6). Infusion of autologous Treg cells has also been investigated for kidney transplantation patients to promote transplant tolerance in hopes of avoiding long-term use of toxic immunosuppressive agents that cause increased morbidity/mortality (Mathew et al., 2018). The administration of transplanted polyclonal Tregs (CD4+CD25+ T cells) derived from the thymus or peripheral tissues of the recipients and expanded in vitro into living donor kidney transplant recipients showed a reduction of total CD4+T and CD8+ T cells and a 520 fold increased circulating Tregs levels after 90 days. The authors aim to move into a phase II clinical trial to test Treg infusions efficacy for tolerance induction or drug minimization (Mathew et al., 2018). Chimeric antigen receptor transduced natural killer (CAR-NK) therapy (Liu et al., 2020), and pluripotent stem cell-derived immunosuppressive cells (macrophages) (Tsuji et al., 2020) are also investigated for use in solid organ transplantation as an alternative method of posttransplant management to improve allograft survival and minimize secondary complications. Recently, Tsuji et al. showed the successful generation of immunosuppressive cells from non-human primate ESCs that expressed several immunosuppressive molecules and significantly inhibited allogeneic mixed lymphocyte reaction (Tsuji et al., 2020). The future goal is to move into pre-clinical trials and demonstrate their potential to suppress allogeneic immune reactions against grafts derived from the same donor in transplantation models. Although advancements in surgical technique and immunosuppression regimens have progressed in transplant medicine, many limitations still exist. The chronic use of immunosuppression in transplant medicine promotes several side effects and increases the relative risk of infections, malignancy, cardiovascular morbidity, and organ damage (e.g., liver toxicity, nephrotoxicity, neurotoxicity, and diabetes mellitus). Thus, to further improve solid organ transplantation outcomes, discovering a novel immunoregulating strategy in regenerative medicine using pluripotent stem cells and engineered immune cells to enhance organ survival and tolerance is vital for the growth of transplant medicine.

In tissue engineering, a combination of cells, a scaffold, and biologically active molecules are used to reconstruct or regenerate damaged tissues or whole organs. The success of tissue engineering relies on the interplay between multiple scientific disciplines such as cell biology, biomedical engineering, and material science. The identification of proper scaffolds, bioreactors, cell sources, and biomolecules such as growth factors and chemokines are needed to reconstruct or regenerate organs correctly. Currently, contrary to 2D planar tissues, bioengineering solid organs for transplantation is still challenging. Advances have been made towards identifying novel scaffolds, biomolecules, and cells, but protocols towards combining the mixture for solid organs de novo reconstruction are still a limiting factor. Although scientific thinking and approaches towards fully realizing the exciting potential of whole organ engineering are still in their early phases, there have been advances in using novel technology with cell therapy to enhance tissue regeneration and function in the clinic ().

Tissue engineering is currently applied to creating alternative materials for the reconstruction of multiple organs. Ram-Liebig et al. show that manufactured tissue-engineered oral mucosa graft is safe and efficient in urethroplasty in male patients with surgically unsuccessful pretreated urethral stricture (Ram-Liebig et al., 2017). The procedure involves harvesting a small oral biopsy from the patients and sending it out to a Good Manufacturing Practice (GMP) laboratory manufacturing company, MukoCell, where the sample is used to create a tissue-engineered oral mucosa graft for the urethroplasty. The transplant success rate was 67.3% at 12 and 58.2% at 24 months and the authors hypothesize that the success rate may be higher if the patients are initially treated with the graft from the beginning. Nonetheless, the authors show that the bulbar and penile urethra reconstruction is feasible, safe, and efficacious in a heavily pretreated population using a tissue-engineered oral mucosa graft. This study demonstrates how current tissue engineering therapies could be successfully standardized and manufactured in a company to provide a constant viable product tailored to everyone.

Clinical studies are also exploring the mechanisms of how tissue-engineered constructs cross-communicate with the diseased milieu to promote healing of a chronic wound. Stone et al. used transcriptomics to understand mechanistically how an FDA-approved bilayer living cell construct (BLCC) promotes the healing of chronic non-healing venous leg ulcers (Stone et al., 2017). BLCC consists of a layer of the human foreskinderived neonatal fibroblasts in a bovine type I collagen matrix under a layer of the human foreskinderived neonatal epidermal keratinocytes. The authors identified that BLCC provides bioactive signals after transplant to the damaged tissue site to promote wound healing via modulation of inflammatory and growth factor signaling, keratinocyte activation, and attenuation Wnt/-catenin signaling. This study identifies mechanistically how tissue-engineered constructs can communicate at the site of injury to promote healing (Stone et al., 2017). The use of a cardiac patch has also garnered much attention, which provides cells a proper microenvironment for tissue development and maturation (Menasch et al., 2018). Bayes-Genis et al. have shown that autologous pericardial adipose graft transplanted within patients treated with coronary artery bypass graft surgery promotes a noticeable improvement in reducing the necrotic mass-sized ventricular volumes after 1year (Bayes-Genis et al., 2016). The authors used an autologous pericardial adipose graft directly obtained from the patients and surgical glued it in place over the necrotic zone after the coronary artery bypass. The surgeons harnessed the biological regenerative capacity of adipose tissue for patients with a chronic myocardial scar. However, no statistically significant difference was noted in necrosis size, possibly due to the limited patient numbers and the need to refine the surgical procedure (Bayes-Genis et al., 2016). Cardiac patches are also used to address the limitation in the retention and need of large cell numbers for cardiac regenerative therapy. In a phase I clinical trial, Menasche et al. assessed the safety and efficacy of transplanting human embryonic stem cell (hESC)-derived cardiovascular progenitors embedded in a fibrin patch in severe ischemic left ventricular dysfunction patients receiving a coronary artery bypass procedure (Menasch et al., 2018). The cardiac fibrin patch showed no evidence of tumor formation or arrhythmias during the 18 months follow-up. Although the feasibility of producing clinical-grade hESC-CM for transplantation was demonstrated, clinical trials assessing efficacy were not yet conducted due to the small sample size, lack of blinded assessment, and confounding effect of the associated coronary artery bypass grafting. Based on these results, there is still a need to identify the best source of stem or progenitor cells and extracellular matrix or biomaterial to promote tissue regeneration and repair in efficacy and safe manner.

Researchers have identified how stem cell heterogeneity, due to differences in source and donor to donor variations, may limit their clinical effectiveness. Autologous (isolated from and transplanted back into the same patient) and allogeneic (isolated from a different patient) stem cells have a different beneficial therapeutic potential based on disease and organ model. Hare et al. demonstrate that although transplantation of both autologous and allogeneic BM-MSCs is safe, feasible, and beneficial when applied in chronic non-ischemic dilated cardiomyopathy (NIDCM), there are slight differences in their beneficial outcomes (Hare et al., 2017). Allogeneic BM-MSCs transplants promote a more significant improvement in functional tests like Ejection Fraction (EF), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Six Minute Walk Test (6MWT), along with the better functional restoration of endothelium and reduction of pro-inflammatory cytokines (TNF-) 6 months after transplantation compared to autologous BM-MSCs. Similarly, Bhansali et al. also show that autologous bone-marrow or mononuclear cells (MNCs) transplanted in patients with type 2 diabetes mellitus effectively reduce the need for insulin after a year (Bhansali et al., 2017). However, patients with MNC transplants showed a significant increase in second-phase C-peptide response during the hyperglycemic clamp indicating insulin production, while MSC transplanted patients had a significant improvement in insulin sensitivity index and an increase in insulin receptor substrate-1 gene expression. Thus, demonstrating the need for more informative studies to distinguish the differential beneficial effects of different cell cellular therapies. Xiao et al. also compared the efficacy of intracoronary administration of BM-MNCs or BM-MSCs for patients with dilated cardiomyopathy (DCM) (Xiao et al., 2017). After 3months, both injections showed an improvement in New York Heart Association (NYHA) functional class and left ventricular ejection fraction (LVEF) in patients. However, after 12 months, BM-MSCs transplanted patients continued to significantly improve LVEF and NYHA, unlike BM-MNCs transplanted patients who showed a decrease in LVEF compared to their 3months follow-up. These results suggest that BM-MNCs provided a temporary improvement in LVEF and NYHA class and only accelerate cardiac function recovery while the improvement observed following BM-MSC therapy is sustained (Xiao et al., 2017). These studies provide novel insights and a comprehensive understanding of how various cell sources and cell types may deliver different therapeutic effects based on disease. Additionally, they highlight the need to tailor stem cell therapies specific to each patients need to enhance their regenerative potential. Further conformational studies with large, randomized, placebo-controlled clinical trials are needed to clarify the complexity of MSCs (based on origin and application) and their interaction with host tissue.

Although advancements are being made daily in cellular therapy, there are still many challenges in translating pre-clinical results regarding cellular therapy efficacy to promote tissue healing, reduce excessive inflammation, and improve the clinics survival (Galipeau et al., 2016; Chinnadurai et al., 2018). It has been shown that not all stem cell therapies are initially beneficial. Makhlough et al. show the safety and tolerability of autologous BM-MSC transplanted into six autosomal dominant polycystic kidney disease patients but with no physiological improvement detected after 1year (Makhlough et al., 2017). Patients exhibited a continuous decrease of GFR with a significant increase in serum creatinine levels. The study was limited to only six patients, and only a single cell transplant was administered, which may partially explain the limited beneficial effects detected (Makhlough et al., 2017). Stem cell therapys effectiveness may also be limited by the extent of chronic inflammation and fibrosis already present within the patients damaged tissue. In patients with decompensated (severe) alcoholic liver disease, transplantation of BM-MSCs showed no modification of the diseases progression after 4weeks (Lanthier et al., 2017) to 8weeks (Rajaram et al., 2017). Although patients showed an elevation of liver macrophages and upregulation of regenerative liver markers (SPINK1 and HGF), no difference was detected regarding proliferative hepatocyte numbers (Lanthier et al., 2017). There are also potential safety concerns with cellular therapy, such as the potential for malignant transformation of MSCs (Steinemann et al., 2013). A long-term follow-up study of patients with decompensated (severe) alcoholic liver disease transplanted with autologous BM-derived mononuclear cells showed improved liver function and decreased collagen levels in patients liver transiently 6months post-transplantation (Kim et al., 2017). Patients also displayed improved biochemical parameters, CP class, and increased liver volume, indicating liver regeneration. Although improved liver function was still evident at the five-year follow-up, patients who had received cell transplantation had an alarming increased risk of developing hepatocellular carcinoma (HCC). This relatively high incidence of HCC within 2years after autologous bone marrow cell infusion warrants further investigation (Kim et al., 2017). Other studies have also shown that a small group of hematopoietic cell transplant survivors may suffer from not only solid tumors but also from other significant late effects such as diseases of the cardiovascular, pulmonary, and endocrine systems, dysfunction of the thyroid gland, gonads, liver and kidneys, infertility, iron overload, bone diseases, infection, and neuropsychological effects (Inamoto and Lee, 2017). The leading cause of mortality in adult patients who had received hematopoietic cell transplants includes recurrent malignancy, lung diseases, infection, secondary cancers, and chronic graft-versus-host disease. Thus, long-term risk assessment studies of patients receiving stem cell transplantation are needed to understand the risk of developing cancer and other harmful late effects versus the long-term benefits of stem cell therapy. Another limitation preventing comparison of current clinical trials and their outcomes, is that not all clinical trials adhered to ISCT criteria in defining the cellular treatments. Moving forward, improved methodological quality, increased sample size, and extended trial duration are needed for a better comparison of clinical trial data and results amongst each study. Cossu et al. and others also emphasized the need for better science, funding models, governance, public and patient engagement to enhance cellular therapys efficacy and safety in the clinic (Cossu et al., 2018). Regulatory limitations are another hurdle for the application of cell therapies or new technologies. With growing innovations made in regenerative medicine, outdated regulations may not adequately address new challenges posed as technology advances. Thus, new regulations must be designed to protect the patients from unnecessary risk while encouraging investigators, funding bodies, and investors to support research and development and market commercialization of novel products.

Excerpt from:
Regenerative medicine applications: An overview of clinical trials

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The Progression of Regenerative Medicine and its Impact on Therapy …

September 13th, 2024 2:40 am

Clin Transl Sci. 2020 May; 13(3): 440450.

1Division of Cardiac Surgery, University of Ottawa Heart Institute, OttawaOntario, Canada

2School of Human Kinetics, University of Ottawa, OttawaCanada

1Division of Cardiac Surgery, University of Ottawa Heart Institute, OttawaOntario, Canada

3Department of Cellular & Molecular Medicine, University of Ottawa, OttawaCanada

1Division of Cardiac Surgery, University of Ottawa Heart Institute, OttawaOntario, Canada

2School of Human Kinetics, University of Ottawa, OttawaCanada

3Department of Cellular & Molecular Medicine, University of Ottawa, OttawaCanada

Received 2019 Nov 6; Accepted 2019 Nov 7.

Despite regenerative medicine (RM) being one of the hottest topics in biotechnology for the past 3decades, it is generally acknowledged that the fields performance at the bedside has been somewhat disappointing. This may be linked to the novelty of these technologies and their disruptive nature, which has brought an increasing level of complexity to translation. Therefore, we look at how the historical development of the RM field has changed the translational strategy. Specifically, we explore how the pursuit of such novel regenerative therapies has changed the way experts aim to translate their ideas into clinical applications, and then identify areas that need to be corrected or reinforced in order for these therapies to eventually be incorporated into the standardofcare. This is then linked to a discussion of the preclinical and postclinical challenges remaining today, which offer insights that can contribute to the future progression of RM.

In 1954, Dr. Joseph Murray performed the first transplant in a human when he transferred a kidney from one identical twin to another.1 This successful procedure, which would go on to have a profound impact on medical history, was the culmination of >50years of transplantation and grafting research. In the following years, organ replacement became more widespread but also led to a plateau in terms of landmark successes.1 The technology was working, but limitations were already being encountered; the most prominent of them being the lack of organ availability and the increasing need from the aging population.2 During the same time period, chronic diseases were on the rise and the associated process of tissue degeneration was becoming evident. Additionally, the available clinical interventions were merely capable of treating symptoms, rather than curing the disease, and, therefore, once a loss of tissue function occurred, it was nearly impossible to regain.3 Overall, the coupling of all these factors that took place in the 1960s and 1970s created urgency for disruptive technologies and led to the creation of tissue engineering (TE).

TE can be described as a field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ.4 TE is considered to be under the umbrella of regenerative medicine (RM) and, according to Dr. Heather Greenwood et al., regenerative medicine is an emerging interdisciplinary field of research and clinical applications focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any cause, including congenital defects, diseases, trauma and aging.5 It uses a combination of technological approaches that moves it beyond traditional transplantation and replacement therapies. These approaches may include, but are not limited to, the use of soluble molecules, gene therapy, stem cell transplantation, tissue engineering, and the reprogramming of cell and tissue types.3, 6, 7 A summary of the recent history of RM is presented in Figure.

A summary timeline of the recent history of regenerative medicine (RM). Selected milestones in the development of RM are presented starting from the 1950s all the way up to the present day.

Although RM may have seemed novel, the principles of regeneration are as old as humanity and are found in its many cultures.8 A common example used is the tale of Prometheus that appeared in 8th century BCE. Prometheus, an immortal Titan in Greek mythology, stole fire and gave it to humanity for them to use, defying the gods in consequence. As punishment, Zeus decreed that he was to be bound to a rock where an eagle would feast on his liver every day and said liver would regenerate itself every night, leading to a continuous loop of torture.9 RM came about at the time it did, not only because of the combining factors mentioned above, but also because researchers had been successfully keeping tissue alive in vitro and understanding the biological processes involved in regeneration and degeneration. Consequently, possible therapeutic outcomes came into fruition. Since the arrival of TE and RM, strides made on the benchside have been ever increasing with now >280,000 search results on PubMed relating to regeneration. Discoveries and advances made by cell/molecular biologists, engineers, clinicians, and many more led to a paradigm shift from treatmentbased to curebased therapies.10 In addition to Greenwoods definition, RMs arsenal now contains controlled release matrices, scaffolds, and bioreactors.5, 8 Despite this impressive profile on the benchside, RM has so far underperformed in terms of clinical applications (i.e., poor therapy translation).8 Simply put, a disappointing number of discoveries are making it through clinical trials and onto the market.11 Although some experts say that the field is reaching a critical mass in terms of potential therapies and that we will soon see results, others, like Dr. Harper Jr. from the Mayo Clinic in Minnesota, say that the transformative power of RM is well recognized, but the complexity of translating isnt.7, 8, 12

This brings us to the subject matter of the present paper: RM and translation. The goals of this historical review are twofold. The first is to understand how RM, over the past 50years or so, has changed the way discoveries/new technologies are transferred to the clinic. How has the translational strategy changed in response to these new therapies? The second is to identify challenges that have led to RMs modest performance on the bedside. Some articles have already documented these but have focused on the clinical and postclinical factors, and whereas they will be briefly discussed here, the focus will be on preclinical factors.13 To accomplish these objectives, we will begin by summarizing the historical development of RM (which has been extensively documented by other works2, 3, 14, 15), followed by a detailed look at the definition of translational medicine (TM). With this background information established, we then look at the various preclinical and clinical impacts of RM on TM, as well as some of its effects on the private sector. Limiting factors of the field are then described, again focusing on those that are preclinical. This endeavor was initiated via a librarianassisted literature search for original research and historical documentation of the field of RM and other related subjects. The documents were then screened for relevance and the analyzed information was categorized into the themes discussed below. Conclusions were then drawn based on the interplay among these themes.

As mentioned, the idea of regeneration first started in myths and legends. This is logical because, as Drs. Himanshu Kaul and Yiannis Ventikos put it, myths shape ideas, and ideas then shape technologies.8 In addition to the tale of Prometheus, there are many others. For example, there is the Hindu myth of Raktabeej whose blood drops could each form a clone of himself, or the Indian story of the birth of the Kaurava brothers where pieces of flesh were grown in pots and treated with herbs to grow fullsized humans.8 The idea of regeneration has persisted throughout history and started to become a possibility in the early 1900s when scientists like Alexis Carrel (who invented the technique of cell culture) were finally able to keep cells and tissues alive outside of the body. This allowed them to study the mechanisms of cell renewal, regulation, and repair.8 In addition, studying regeneration goes handinhand with developmental biology. Seminal work in experimental embryology began in the 1820s with the detailed description of the differentiation of embryonic germ layers.16 An increased understanding of basic embryological mechanisms led to Hans Spemanns Nobel Prize for his theory of embryonic induction; a field that was further elaborated by his students and others, advancing it toward the possibility of cloning and demonstrating how development and regeneration are intimately linked.16 Before this era, the study of regeneration was done through the study of animals, with scientists studying the phenomena in serpents, snails, and crustaceans, for example.17, 18 However, the modern study of regeneration is said to have started with Abraham Trembleys study of the hydra, which showed that it was possible for an entire organism to regenerate from its cut appendage.19 The 18th century on through to the 19th century is also when scientists became intrigued by the amphibian newts and axolotls for their astonishing regenerative capabilities, which are still used today as the gold standard models for studying regeneration along with certain fish, such as the zebrafish.20

Now, although the term RM as we know it today would only be coined in 1999 by William Haseltine, the field itself started in the late 1970s in the form of TE (pioneered by Drs. Joseph Vacanti and Robert Langer) in the city of Boston.2, 14, 21 To address the need for novel therapies, biomedical engineers, material scientists, and biologists at Harvard and MIT started working on regenerating parts of the largest and simplest organ of the human body: the skin. In 1979, the first cellbased TE product appeared and was named Epicel.15 Developed by Dr. Howard Green et al., this technology consisted of isolating keratinocytes from a skin biopsy and having them proliferate outside of the body to make cell sheets that were then used as an autologous treatment for burn patients.15 Another famous product (this time allogeneic), developed in 1981, was Apligraf, a composite skin invention capable of rebuilding both the dermis and epidermis of skin wounds.15 With these two therapies and many more being created, TE in the 1980s was booming. At the time, researchers were also developing therapies for cartilage regeneration.

Once the 1990s came around, TE strategies were combined with stem cells (which had just been discovered) to create RM.3, 8 At that time, RM was a hot topic. After the first products for skin were commercialized, scientists became more enthused and started trying other tissues.15 Startup companies were popping up left and right, private funding was abnormally high, and public hype was gaining lots of traction. However, governments were not so quick to fund this research and took their time before making decisions, whereas private investors saw this field as very promising and thought it was their ticket to the top.14 Given that 90% of the funding of RM came from the private sector, this greatly influenced the direction of the research and its timeframe.14 People were simply trying to copy tissue formation rather than understanding it, so as to make the development process quicker.3 As a result, many of the technologies that initially looked promising failed in clinical trials or on the market.

These disappointing results coupled with the dot.com crash meant that by the end of 2002, the capital value of the industry was reduced by 90%, the workforce by 80%, and out of the 20 US Food and Drug Administration (FDA) products with clinical trials, only 4 were approved and none had any success.22 This phenomenon has been extensively studied and, according to Lysaght and Hazlehurst, five factors contributed to the industry crash22:

The products were not much better than the existing treatment options and so making the switch was not worth it for clinicians.

Even if the science was good, lowcost manufacturing procedures did not exist.

The approval process for these novel therapies was unrealistically challenging and the regulatory cost was too high.

Companies lacked the skill to market their new products.

The reimbursement strategies were unclear.

Despite these events, the industry had 89 firms survive the crash and stem cell research was not affected. In fact, from 2000 to 2004, the number of companies increased but the number of jobs decreased, which means investors were supporting research in basic and applied science with smaller firms that were lower risk, and by 2004, the field was dominated by startup companies.22 Before the crash, RM was primarily happening in the United States, but in 2004, other countries like the United Kingdom and Japan started catching up.22 The industry slowly started growing again. In 2006, the first engineered tissue (bladder) was implanted, and by 2008, commercial successes were being achieved.3, 10 As an example, hematopoietic stem cell transplants were approved and are now a curative treatment for blood disorders and other immunodeficiencies.7 Now, the RM field had ironically regenerated itself.3 It has gained increased governmental attention (federal funding has increased) and has been recognized as being at the forefront of health care.7, 22 There is once again intense media coverage that is raising public expectations.23 The number and variety of clinical trials is also increasing everywhere.23 According to allied market research, RM is predicted to be worth US $67.5 billion by 2020.10

Unfortunately, regardless of these seemingly cheerful notes, the fact remains that cell therapies remain experimental, except for the aforementioned hematopoietic stem cell treatments.13 The market for RM is still small and will remain so until RM proves that its therapies are better and cheaper than the existing ones.15 Yet, the pressure for clinical translation is increasing through the needs of the population, investors that are eager to make a return on their investments, and scientists who believe that these technologies are the future.23 Moreover, there has been a growing appreciation of the magnitude and complexity of the obstacles the field is facing, but it remains to be seen how they will be solved; although initial steps have already been taken, which will be discussed further below.

Now that we have established the background for RM, there needs to be a proper understanding of TM before conclusions on how the two are related can be drawn, which is the purpose of the following section.

The European Society for Translational Medicine (EUSTM) has defined TM as an interdisciplinary branch of the biomedical field supported by three main pillars: benchside, bedside, and community. The goals of TM are to combine disciplines, resources, expertise, and techniques within these pillars to promote enhancements in prevention, diagnosis, and therapies.24 TMs goals can be split into two categories: T1 and T2. T1 is to apply research from bench to bedside and back, whereas T2 is to help move successful new therapies from a research context to an everyday clinical context.25 In other words, TM is a medical practice explicitly devoted to helping basic research attain clinical application. Conceptual medical research, preclinical studies, clinical trials, and implementation of research findings are all included within TM.26

Between basic science and the clinic is an area that is popularly referred to as the valley of death.25 This gap is fraught with not only scientific obstacles (like an unknown molecular mechanism), but social and economic ones as well. This is where many novel ideas die and, consequently, companies are weary of going through this valley for fear of wasted financial resources.25 For these reasons, many of the approved drugs we get now are derivatives of others that have been previously approved.25 This is the area that TM seeks to impact, to be the bridge between idea and cure, and to act as a catalyst to increase the efficiency between laboratory and clinic.25, 26 The term bench to bedside and back is commonly used. The cost of development for a therapy is very high (estimated at US $800 million to $2.6 billion for a drug) because of increasing regulatory demands and the complexity of clinical trials, among others. TM aims to streamline the early development stages to reduce the time and cost of development.24

What will be important to note for the discussion below is that TM focuses more on the pathophysiological mechanisms of a disease and/or treatment and favors a more trialanderror method rather than an evidencebased method. Dr. Miriam Solomon argues in his book chapter entitled What is Translational Medicine? that most medical innovations proceed unpredictably with interdisciplinary teams and with shifts from laboratory to patient and back again, and that freedom of trialanderror is what will lead to more therapeutic translation.25 Furthermore, for years, TM did not have any technical suggestions for improving translation, only two broad categories that were claimed to be essential for translatability: improving research infrastructure and broadening the goals of inquiry. This discrepancy has since been identified and efforts have been made to address it. For example, the EUSTM provided a textbook called Translational Medicine: Tools and Techniques as an initiative to provide concise knowledge to the fields stakeholders.24

Presently, TM has attracted considerable attention with substantial funding and numerous institutions and journals committed to its cause.25, 27 But before this, its arrival had to be incited. TM emerged in the late 1990s to offer hope in response to the shortcomings of evidencebased medicine and basic science research, such as the unsatisfactory results from the Human Genome Project, for instance.25 There were growing concerns that the explosion of biomedical research was not being translated in a meaningful manner proportionate with the expenditures and growing needs of the patients.27 The research had ignored what it took to properly disseminate new ideas.25 The difficulties of translation from bench to bedside have always been known, but what is different with TM is the amount of emphasis that is now put on translation and the recognition on how difficult and multifaceted it is to translate technologies.25 Over the past 20years, the role, power, and research volume of the field has increased, and TM is now a top priority for the scientific community.26 TM is also often used as common justification for research funding and conveys the message to politicians and taxpayers that research activities ultimately serve the public, which is also why it appeals to todays generation of students who want to work on big, realworld problems and make a meaningful difference.28, 29

As already mentioned, RM therapies are proving difficult to translate to the clinic.11 Although the basic research discoveries are never ceasing (books such as NewPerspectives in Regeneration by Drs. HeberKatz and Stocum30, and articles such as "Tissue Engineering and Regenerative Medicine: Past, Present, and Future" by Dr. Antnio Salgado et al.,31 provide comprehensive summaries of these advancements), therapy approval is practically nonexistent.30, 31, 32 This may be due, in part, to a tendency for people to blame the lack of translation of their technologies on extrinsic factors, thus removing responsibility.11 Additionally, the failures are not being studied. For example, stem cell research looks good in small animals but often fails in larger ones and then does not progress beyond phase II or III clinical trials because no benefits are found, and historically we have not been exploring why.11, 32 Consequently, the next therapies that are developed are improved by guesses rather than through a better understanding of the disease in mind (Figure).11

The negative feedback cycle currently present in most discovery and development processes of regenerative medicine. This cycle obstructs progression of the field.

RM has the potential to impact not only the quality of healthcare but also the economy, because the costs that could be avoided with curative therapies are immense.33 For this reason, analyzing the impact of RM on the translational strategy over time can help identify aspects that should be encouraged or discouraged to drastically improve translation. Reflecting on this history cannot only help us to avoid past mistakes but can also aid in redirecting the field to a onceproductive path.34 In the following section, the preclinical impact of RM on TM will be discussed, focusing on the shift from evidencebased medicine to trialanderror, the role of the basic scientist, and the emergence of the multidisciplinary approach. Clinical impact is also covered, concentrating on regulatory modifications. Last, changes in the private sector are considered as the shift in business models is detailed.

Because the RM field is essentially comprised of new ideas on cell renewal and tissue healing, it is logical that most of its impact would be on the preclinical side, as this is where ideas are tested, finetuned, and developed. Coincidentally, it is also where the translational strategy begins. Considering certain aspects early in the developmental process, such as realistic applications and ease of use, can help facilitate translation. RMs influence on TM can thus be separated into the three themes below.

Before the late 20th century, the majority of medical research was done using evidencebased medicine. This is a systematic approach to solving a clinical problem that integrates the best available research evidence together with clinical signs, patient values, and individual clinical experience all to support scientific decision making and research progression.35 As such, evidencebased medicine favors clinical trials and does not allow for much tinkering and only that which possesses highquality clinical evidence is to be pursued. This has its limitations, as it devalues mechanistic reasoning, and both in vitro and animal studies. Therefore, evidencebased medicine may have played a role in RMs downfall in the early 2000s. TE in the 1990s was using evidencebased medicine and was simply trying to copy tissue formation rather than trying to understand it.3 That most of the funding was coming from the private sector probably did not help either. Investors saw TE as an opportunity for quick returns on their investments, so therapies were rushed to clinical trials, which led to inconsistent results.14, 25, 32

As well, evidencebased medicine obscured the need for different methods of discovery. After RMs decline and the idea of TM came about, a trialanderror method was adopted. This technique favors a team effort, mechanistic reasoning, and seeks to change the social structure of research.25 Although clinical trials are still deemed important, the trialanderror method identifies that an idea needs to first be explored and should not necessarily require the confirmation of a hypothesis.11, 25 This new method is based more so on facts and has stimulated a more informed dialogue among stakeholders (whereas the confirmation or refusal of a hypothesis cannot always be made relevant to people outside the field). This, in turn, can help the regulatory agencies reduce the burden on their review boards in the evaluation and acceptance of novel strategies.11 Therefore, the failures of RM had helped to highlight the boundaries of evidencebased medicine and, combined with the rising intensity put on TM in the 1990s, assisted in defining the trialanderror based method.

Another thing that is changed with the historical development of RM has been the role of the basic scientist. Please see Figure for a summary of the differences between the traditional and modern scientist discussed in this review. Traditionally, basic scientists have worked with a discovery mindset, but without a noticeable regard for potential therapeutic applications. It has been noted that RM has made us realize how important it is to take the practical and industrializing aspects (like cost, for example) into account even at the basic research level.7, 14 The needs of the end users need to be considered during the developmental phase if RM is to establish a proper foothold within the market.15 In view of this, over the past 2decades, medical philosophy has changed in that it encourages basic scientists to communicate more with clinicians and vice versa. Experts like Barry Coller, MD, Vice President for Medical Affairs and PhysicianinChief at the Rockefeller University Medical Center, have identified various skills that a basic scientist must possess if translational research is to be improved.26, 28 Additionally, other researchers have commented that more and more basic scientists are motivated to have an impact on global health and this passion can be a source of inspiration that can help fuel interdisciplinary cooperation.28 Efforts have also been made to familiarize basic scientists with regulatory requirements. For example, the FDA publishes guide documents with recommendations on how to address these requirements.36 Despite this, much remains to be done, as there is still a lack of TM professionals and the current research environment hampers cooperation between experts (e.g., specialization is still encouraged, and achievement awards are individualized).26, 28

A comparison between the traditional and modern scientist. Although traditional scientists are more hypothesisdriven and rigid in terms of research methodology, if the concepts shown above are used, it can generate the modern scientist who is better suited for the translation of regenerative therapies. RM, regenerative medicine.

An additional point that can be argued is that because RM got basic scientists more involved in the translational process, this has consequently made them more realistic.37 As already mentioned, early RM therapies were comprised of complex cell therapies that were not fully understood. From 2004 onward, the field diversified to include research into simpler acellular products.38 Other avenues, such as induced pluripotent stem cells, endogenous repair, nanotechnology, and regenerative pharmacology, are also being explored.37, 39, 40, 41 Increasingly, experts are trying to spread this message; for instance, in the field of cardiology, Dr. Mark Sussman, a world renowned cardiac researcher, and his colleague Dr. Kathleen Broughton at the San Diego State University Heart Institute and the Integrated Regenerative Research Institute, recently stated that After over a decade of myocardial regenerative research studies, the initial optimism and enthusiasm that fueled rapid and widespread adoption of cellular therapies for heart failure has given way to more pragmatic, realistic, and achievable goals.9

The last preclinical impact of RM to be discussed is the arrival of the multidisciplinary approach. This now widespread notion identifies that to improve translation and accelerate technology development, it is better to have a team composed of experts from multiple disciplines, because the various backgrounds and schools of thought can be combined with each contributing to a project in a different way.25, 39 What has surely incited its evolution is that RM inherently requires contributions from biologists, chemists, engineers, and medical professionals. This need has led to the formation of institutions that house all the required expertise under the same roof (such centers have increased in number since 2003), which promotes more teamwork between laboratories and clinics.28 Dr. Jennifer Hobin et al.28 states that bringing dissimilar research expertise together in close proximity is the key to creating an environment that facilitates collaboration. In addition, it could be said that these collaborative environments help minimize the flaws of medical specialization, which occurred in the second half of the 19th century; where the ideological basis that the human body can be categorized combined with the rapid arrival of new medical technologies led to the specialization of medical practice, which, in turn, led to the segregation of medical professionals from each other and the patient.42 Coincidentally, if one recalls the definition of TM, it, along with the trialanderror based method, suggests that improved research infrastructures and team efforts can facilitate the translation of therapies.

We now look at the influence that RM has had on the clinical side of therapy development. Before the subject is discussed, it is important to note that the reason clinical research has been affected is because of the uniqueness of RM therapies. Their novelty does not fit within the current regulatory process or use in clinical trials, and although the latter has yet to adapt, the regulatory sector has attempted over the years to facilitate the journey from bench to bedside.7, 43, 44

Initially, when RM was in its infancy, its therapies were regulated by the criteria originally developed for drugs; and as we have seen, this was identified as a factor that led to its downfall. Now, in 2019, several regulatory changes have been implemented to rectify this. What has helped has been the input from other countries. As mentioned above, RM started in the United States, but after the crash, other countries like the United Kingdom and Japan caught up, and their less stringent regulatory procedures have allowed them to better adapt the framework for these new therapies.22 In 2007, the European Union passed the Advanced Therapy Products Regulation law, which defined regenerative therapies, categorized them, and provided them with separate regulatory criteria for advanced approval.13, 43 In 2014, public pressure and researcher demands led Japan to enact three new laws: the Regenerative Medicine Promotion Act, the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act, and the Act on the Safety of Regenerative Medicine. These unprecedented national policies now help therapies gain accelerated and conditional approval to better conduct clinical trials and to better meet the demands of the patients.7, 13, 44, 45 During this time, the United States has not stood idle. In 2012, the US Congress passed the FDA Safety and Innovation Act (FDASIA), which expanded its existing Accelerated Approval Pathway to include breakthrough therapies, a category created for new emerging technologies, including regenerative strategies.13, 46 Drs. Celia Witten, Richard McFarland, and Stephanie Simek provide a wellwritten overview on the efforts of the FDA to accommodate RM.36 By and large, it is safe to say that RM has spurred a drastic change in traditional regulatory pathways to not only better manage these novel therapies but also put more weight on efficient translation.

It is also important to discuss changes in the private sector because manufacturing and marketing is and will remain one of the greatest obstacles facing RM, and, once again, the novelty of the field is responsible. Although the bulk of the problems remain, there has nonetheless been a change in business strategies that is worth appreciating.

Throughout its history, RM research has been carried out by academic research institutions or small and mediumsized enterprises.23, 47 With this in mind, the business model used in the health industry varies depending on the type of company. The royalty model is the one primarily used by biotech companies.8, 14 Here, businesses will develop a therapy up to the clinical stage and then hand it off to a company with more resources (usually a pharmaceutical one) who can carry out the larger scale studies. With this model, biotech companies make money simply through royalties and this carries both pros and cons (Figure).

A comparison of both the royalty and integrated business models used by private companies in the biomedical industry. The pros and cons are listed with the assumption that they are for a startup company in regenerative medicine.

Because the market for regenerative therapies currently is not big enough for the royalty model, startups have had to shift to an integrated model where the discovery, development, approval, and manufacturing of a new therapy are all done internally (which is unusual for small startups).8 Using this strategy, the companies can reap all the rewards but obviously also assume all the risk.

The market for regenerative therapies has so far been small enough that smaller firms do not have to manufacture large quantities of their products (like they do in the pharmaceutical industry) and they can start making money in a quicker fashion.8 Whether the business model will change again as the market grows or if the original startups will grow in proportion remains to be seen.14 What is to be highlighted here is that those who seek to commercialize regenerative therapies have had to shift to an integrated business model (that was not previously the norm for smaller ventures), which has affected translation by letting them have more influence in determining how their therapy is being developed, marketed, and manufactured.

Having detailed RMs relationship with the translation strategy and the aspects that changed in conjunction with the fields development, the remainder of the review will summarize the challenges that are contributing to RMs modest performance in the clinic.

With increased funding and a growing number of committed institutions, many countries have become increasingly invested in RMs success. For example, the US Department of Health and Human Services recognizes RM as being at the forefront of healthcare.7 As well, the UK government has identified RM as a field in which they can become global leaders and that will generate significant economic returns.44 The literature indicates that RM is reaching a critical mass and is on the verge of a significant clinical transition. The optimism is as high as it has ever been and the rush to succeed with clinical trials is equally felt.23 However, the bottom line is that the clinical and market performance is still very poor. Being that a gold standard for treatment in RM remains elusive, clinicians are often illinformed about current applications, and studies on safety and efficacy are lacking.23, 44, 48, 49 The National Institute of Health estimates that 8090% of potential therapies run into problems during the preclinical phase.28 Naturally, scientists have offered various explanations for these results, such as deficiencies in translational science and poor research practices in the clinical sciences.50 Shockingly, in a 2004 analysis, 101 articles by basic scientists were found that clearly promised a product with major clinical application, and yet 20years later, only 5 were licensed and only 1 had a major impact.50 Therefore, it is easily deducible that many challenges still lie ahead. The perceived riskbenefit ratio remains high and, as a consequence, clinical trials have been proceeding with caution.13, 23, 33 Numerous reviews have been published on these challenges but with an emphasis on those relating to the clinical phase.11, 13, 22, 51 Although these will be summarized below, the present study highlights the identification and analysis of the preclinical challenges. Please see Figure for a summary of the preclinical and clinical obstacles discussed herein.

Summary of the preclinical and postclinical challenges discussed. Even though preclinical obstacles to the translation of regenerative medicine therapies are more elusive, they are just as significant as their counterparts.

To begin, a possible explanation for the preclinical obstacles being underrepresented in the literature is because of the pliability of the phase itself. Although the clinical phase is composed of numerous subphases and strict protocols, the preclinical research is much less structured with less oversight. Whereas rigorous scientific method is applied to the experiments themselves, which usually consist of in vitro followed by in vivo experiments, the basic scientist has more flexibility regarding experimental organization, structure, and backtracking; thus, making explicit challenges possibly harder to recognize.

Some researchers have nevertheless attempted to do so. For example, Dr. Jennifer Hobin et al. have identified three major risks associated with RM technologies as being tumorigenicity, immunogenicity, and risks involved with the implantation procedure.13 The first two relate to arguably the largest preclinical challenge, which have been identified as needing a better understanding of the mechanism of action.12 Although the difficulties of identifying a mechanism are appreciated in the scientific community, it is imperative that improvements in this area are made as it will affect application and manufacturing decisions. Hence, greater emphasis on identifying the mechanism of action(s) will need to be adopted by basic scientists who are looking to develop a technology.

Another significant preclinical challenge is the lack of translation streamlining for basic scientists. Although basic scientists have become more involved in the translational process and more pragmatic over the years, there is, in general, still a lack of incentive and available resources to help a scientist translate their research. Academic faculty members are given tenure and promotion based on funding success (grants) and intellectual contributions (publications).28 Thus, researchers who have received money to conduct research and publish their work on a promising new therapy might stop short of translation as there may be no additional recognizable accomplishment or motivation for such an endeavor. For example, Jennifer Hobin et al. described the case of Dr. Daria MochlyRosen at Stanford Universitys Translational Research Program, who sought help for an interesting idea for a heart rate regulation therapy.13 She was turned down by numerous companies that found the clinical challenges too daunting and her colleagues offered no support but rather discouraged her from pursuing the idea saying that it would not be worthwhile for her career.

Last, a very important preclinical challenge that has gained recognition over the past few years is the lack of appropriate preclinical testing models. It is often reported that novel therapies that do well in the laboratory but then fail in larger animal studies or clinical trials. This is partly due to a lack of mechanistic insight, but also because of a shortage of appropriate in vitro, in vivo, and ex vivo models.9, 36 With properly validated preclinical models, we would be better able to gauge the performance of novel therapies and predict their future clinical success, but instead we are misidentifying the potential of therapies. Notably, the lack of appropriate models also contributes to the difficulty in obtaining reliable data on the underlying mechanism(s) of action of RM therapies, as differences may exist between the preclinical and clinical settings.

As far as clinical challenges go, they are numerous. Stem cell trials in particular have received criticism from a perceived lack of rigor and controlled trials.23 Related to this, a potent point that has arisen over the past few years is the absence of longterm followup studies for clinical trials, which is clearly necessary to establish the safety and efficacy of these interventions.13, 33 Unfortunately, they are costly and they are timeconsuming. Efforts are nonetheless being made to overcome these obstacles. For example, in 2015, the Mayo Clinic released an RM buildout perspective offering a blueprint for the discovery, translation and application of regenerative medicine therapies for accelerated adoption into standard of care.7 Institutions, such as Canadas Center for Commercialization of Regenerative Medicine, have been launched to help researchers mitigate the risks of cell therapy development by offering technical as well as business services.12, 51 Experts are also stepping up; for example, Drs. Arnold Caplan and Michael West proposed a new regulatory pathway that incorporates large postmarket studies into clinical trials.33

In terms of manufacturing, it is difficult to engage industry because the necessary technology to produce RM therapies at an industrial level does not exist yet. Scaleout and automated production methods for the manufacturing of regenerative therapies are needed.7, 10, 12, 23, 52, 53 This challenge stems from the complexity and natural intrinsic variation of the biological components, which makes longterm stability difficult to achieve and increases manufacturing costs.13, 44 Now, if RM therapies could establish their superiority over conventional treatments, then this would potentially alleviate costs and increase the likelihood of being reimbursed, but it remains to be seen.13 A hot topic at the moment is the choice between autologous or allogeneicbased products, which would entail either a centralized or decentralized manufacturing model, respectively (although hybrid models have been proposed).7, 23, 54 Autologous products, being patientspecific, have the advantage of having smaller startup costs, simpler regulations, and point of care processing.47 As for allogeneic products, they are more suitable for an off the shelf product, for a scaleout model and quality controls can be applied in bulk.47, 54 Dr. Yves Bayon et al.51 provided a thorough description of this topic while simultaneously indicating areas that have been identified for improvement.

As mentioned above, regulatory challenges are what have been most addressed thus far through scientific and public pressure. Moving forward, the goal identified by expert thinktank sessions is to harmonize RMspecific regulations across agencies and countries.7, 36 Reimbursement is the last of the regulatory challenges to be considered. In order for RM treatments to become broadly available, reimbursement is a necessity and both public and private healthcare need to determine how the regulations will be modified for disruptive therapies coming down the pipeline.13, 23, 44

RM has had an undeniable influence on the process of bench to bedside research. Preclinically, it has helped identify the limitations of evidencebased medicine and contributed to the paradigm shift to the trialanderror method. Likewise, the field has changed its mindset and the basic scientist is adopting new responsibilities becoming more motivated, pragmatic, and involved in TM, rivaling researchers in the applied sciences. The multidisciplinary approach has also been promoted by RM over the years and institutions dedicated to fostering collaborative research in RM have increased in numbers. Clinically, regulatory pathways that were developed for drugs and biomedical devices, and which have been in place for decades, have been adapted to aid RMs disruptive technologies, leading to new guidelines that favor translation. In the private sector, the novel nature of RM therapies has led to startup companies using an alternative business model that provides them toptobottom authority over the development of their products and it is yet to be seen if the business strategy in place will be sufficient as the industry grows.

If the translation of RM therapies is to be improved, many of the challenges to be overcome lie in the early stages of therapy development, such as identifying the mechanism(s) of action, validating preclinical experimental models, and incentivizing translational research for basic scientists. In later stages, regulatory changes have been made, but much still needs to be addressed. This includes the adoption of clinical trials that are more rigorous and include longterm followup studies, the development of appropriate manufacturing technology, the synchronization of regulatory agencies, and a clear plan for reimbursement strategies. Once again, these challenges have been discussed in greater detail in previous works.2, 3, 7, 12, 13, 15, 22, 23, 26, 31, 38, 44, 48, 51, 52 While it seems that the field may be at a tipping point with many challenges remaining, the fact that translation has been influenced in a positive way gives promise to the future progression of RM therapies.

This work was supported by a Collaborative Research Grant from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC; CPG158280 to E.J.S.), and the Hetenyi Memorial Studentship from the University of Ottawa (to E.J.).

All authors declared no competing interest for this work.

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Immune cell injection significantly boosts healing of bone, muscle & skin

September 13th, 2024 2:40 am

Injecting regulatory T cells or Tregs, which control the bodys immune responses, directly into damaged bone, muscle and skin significantly boosts healing, according to new research. The door is now open to developing a universal cell-based method of enhancing healing after an injury.

A few months ago, we reported on research by the University of Cambridge in the UK that overturned traditional thinking about regulatory T cells or Tregs, finding that these active controllers of the bodys immune response have the potential to be used as an army of healers for almost everything.

Now, researchers from the Immunology Frontier Research Center (IFReC) at Osaka University, Japan, and Monash University in Melbourne, Australia, have investigated that potential as part of a new study and found that its true.

We began exploring administering Tregs for regenerative medicine purposes because they can directly impact other immune cell types called monocytes and macrophages, said Mikal Martino, an associate professor at Monash who also held a cross-appointment position at Osaka University, and the studys corresponding author. Additionally, Tregs can secrete signaling molecules that support tissue healing. Despite their strong potential, few studies have explored using Tregs for such applications.

Monocytes are white blood cells responsible for fighting certain infections and helping other white blood cells remove dead or damaged cells. Macrophages, another type of white blood cell of the immune system, engulf and digest (phagocytose) pathogens like microbes, cancer cells, cellular debris and foreign substances.

Essential to healing and tissue restoration post-injury is the bodys ability to transition from a pro-inflammatory to an anti-inflammatory state. Theres plenty of scientific evidence about what can occur when the inflammatory response is not switched off and becomes chronic. Understandably, regenerative medicine therapies seek to capitalize on the main immune system players in this pro- and anti-inflammatory process. Thats where Tregs come in.

Nayer et al.

In the present study, the researchers locally administered a fibrin hydrogel containing Tregs into the injured tissue of mice to see to what extent they promoted tissue healing in bone, muscle and skin. Specifically, they chose three models of acute injury: severe skull defects, loss of skeletal muscle resulting in impaired function, and full-thickness skin wounds. Fibrin is a protein thats naturally involved in wound healing; its the end product of the bodys blood clotting pathway and can also act as a medium for regenerative cells like Tregs.

Compared to those administered fibrin hydrogel without Tregs, mice given Tregs showed enhanced bone volume and coverage over injured cranial areas, higher amounts of muscle tissue and large muscle fiber size, and faster skin wound closure, said Shizuo Akira, a professor from IFReC and a senior author on the study.

Examining the mechanics of the Treg-promoted healing, the researchers observed that the cells adopted an injury-specific phenotype a phenotype is an observable trait after being introduced to the damaged area. The Tregs showed increased levels of expression in genes related to immune system modulation and tissue healing. Further experiments showed that the Tregs caused monocytes and macrophages in damaged tissue to switch to an anti-inflammatory state, specifically by secreting signaling molecules like interleukin-10 (IL-10).

Interestingly, we observed that when the gene encoding IL-10 is knocked out of the Tregs, their pro-healing effects are lost, Martino said. This finding indicates the key role of IL-10 in how these Tregs support tissue repair and regeneration.

The studys findings demonstrate the strong potential for using Tregs as a cell-based regenerative medicine therapy after tissue injury. Although this study examined the effect of Tregs administered immediately post-injury, future studies will determine the time frame in which Tregs need to be administered to damaged tissue to effectively aid healing.

The study was published in the journal Nature Communications.

Source: IFReC

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Regenerative Medicine Foundation

September 13th, 2024 2:40 am

Regenerative cellular therapies represent the next generation of groundbreaking treatments that are showing great promise in cardiology, neurology, oncology, orthopedics, ophthalmology, and other areas. Several well-designed clinical trials are being conducted under FDA investigational new drug (IND) protocols. At the same time, a handful of clinics have caused patient harm or made questionable claims, taking advantage of vulnerable patients and casting a negative light on this emerging science and industry.

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Regenerative Medicine Foundation

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