VetCell Therapeutics Blog
The main objective for a successful cell therapy treatment is to show a significant improvement as compared to the standard treatment regimen. This is actually a key decision point the FDA uses in consideration of approving a therapy. A given cell therapy from a biological perspective may in fact work, but it could be more expensive or less effective than the standard treatment. If this is the case, then it would be a large uphill battle to justify its clinical application.
The principal question that clinicians, scientists, regulators, and the general public is asking is: what are the cells actually doing? Each group in the above parties is very interested in the question, since it would provide an understanding of how the cells function. Clinicians are interested on how the cells can modulate a disease or contribute to a cure. Scientists are interested in the mechanisms on how the stem cells undertake their regenerative traits. Regulators are interested in the safety and effectiveness of cell therapies. Whereas the general public want reliable, easy to digest information about the general features of therapies and how they could be useful for treating diseases.
Although there is no absolute confirmation on what stem cells actually do, there has been a lot of research in this area with substantial data. The potentially confusing inkling here is that different types of stem cells used for therapy may have different mechanisms of action. For example, CD34 hematopoietic stem cells would be have much differently than, say neuronal stem cells. This may feel quite obvious, but it has to be recognized that different cells have different mechanisms and could be used for different applications.
Today’s blog will focus on adipose MSCs and their apparent interactions. Overall, there are five generally agreed upon mechanisms of integration which have been reported for adipose MSCs.
1 – Trophic Support. MSCs release several factors and cytokines which support resident cells and they respond to an injury or tissue damage. –These growth factors are secreted by MSCs support cell survival and contribute to wound healing. Other cellular activities include complex mechanisms such as anti-scarring, angiogenesis, anti-apoptosis, nascent stem cell recruitment and cellular growth (1). A couple of interesting cases of MSC trophic support are described with the use of islet survival and function after transplantation and for neurodegenerative diseases (2, 3)
2 – Anti-Inflammatory. In line to trophic support, MSCs secrete cytokines which are anti-inflammatory in nature which help to balance production of inflammation brought on by T cells. The immunosuppressive effects mediated by MSCs mainly involve interactions with T cells. When T cells are activated, they secrete pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-12. MSCs have shown the ability to inhibit the secretion of TNF-α, IFN-γ, and IL-12, mediated by the type 1 helper T cell pathway. (4, 5)
3 – Differentiation into tissue. The hope and promise of stem cells center on their potential capability of differentiating into many different types of tissues. This particular function for the stem cells is quite significant and requires strong evidence that this process actually occurs, in vivo. In an in vitro system, mesenchymal stem cells from adipose tissue in particular differentiate into chondrocytes (cartilage cells), osteocytes (bone cells) and adipocytes (fat cells). In fact, the International Society for Cell Therapy (ISCT) uses trilineage differentiation as a characteristic of human MSCs. The same criteria may be applied to growing and testing MSCs from any animal In an in vivo system, the task is challenging to provide evidence to the scientific community regarding differentiation. To do this successfully depends on the ability to monitor transplanted cells over a long period of time.
4 –MSC homing to an injury site. MSCs are capable of locating injured sites by homing to them. However, the dynamics and molecular mechanisms of MSCs trafficking to sites of injury have not been fully described. The therapeutic delivery of MSCs is typically performed via intravenous systemic injection into a major vessel. Some time is required to allow the MSCs to home and engraft within sites of injury. Not all the MSCs will actually end up at the injury site. Initially, intravenous injected MSCs are rapidly cleared from the circulation and become entrapped within the lungs. After 1–5 days post injection, MSCs begin to exit the lungs and are found within the liver, spleen, kidneys, and bone marrow.
The apprehension with this feature is the MSCs do have the inherent ability to migrate. Although most of the MSCs will home into a site of injury, a large proportion of them will migrate to other tissues. An example of this was noted in dogs where repeated injections into the periocular and intra-articular regions showed migration and subsequent engraftment of MSCs in the thymus as well as the gastrointestinal tract. (6) Although in this situation the migrating MSCs did not contribute to any harm, some regulatory agencies could cite this as a safety concern. The burden of proof to show that the cells will not harm the patient is a difficult task and tends to require large clinical trials and an exhausting cell tracking long term study. As this group showed, after two weeks post injection, the MSCs were able to deliver favorable immunomodulatory support and demonstrated the potential for a therapeutic benefit using MSCs.
5 – Immune system modulation. The most anticipated function of stem cells and widely studied are the effects that these cells have on the immune system. An immunomodulatory effect is well described with treatments which involve MSCs. This effect can be broad, from direct inhibition of lymphocyte proliferation, induction of regulatory T and B cells, to resetting the immune system. Although MSCs are not part of the immune system according to the established definitions (7), they interact with all immune cell types. They secrete a large range of anti-inflammatory as well as pro-inflammatory factors, among them cytokines, chemokines and prostaglandins, which target immune cells and affect their function. (8) In addition to paracrine interactions, MSCs express cell surface molecules that undergo interaction with various immune cells. The expression of certain adhesion markers, such as ICAM-1, increase the recruitment of activated immune cells to allow the immune cells to interact with the MSCs (9).
The current hypothesis for cell therapy is that the therapeutic cells can either progress in these possible pathways: (a) the injected cells home towards the damaged area, differentiate into several cell types and actively regenerate the damaged tissue, or (b) the injected cells respond to signaling factors, such as cytokines or cell to cell interactions, and behave in a paracrine support role to reduce inflammation and allow resident cells to repair the damaged area. A third scenario could include a combination of both pathways to some extent.
The first scenario is in line to what regenerative medicine is all about. Even though this mechanism is not fully defined, some of the recent data support the notion of MSCs secrete cytokines and contribute to lowering levels in inflammation.(10, 11) The idea here Is that the MSCs are able to home into the damaged areas and integrate into the area to some extent.
If cell therapy is to be fully and officially adopted, more data is needed to show what the cells do after they are administered. The other substantial component to figuring out how MSCs work is their localization patterns. The mechanism of the cells would be an intense exercise in some type of cell tracking experiments.
- Caplan A, J. et al., Cell. Biochem. 98: 1076–1084, 2006
- Joyce N, et al., Regenerative Medicine, Vol. 5, No. 6, Pages 933-946, Nov 2010
- Park, K, et al., Transplantation, Vol 89 – Issue 5 – pp 509-517, Mar 2010
- Abreu S, et al, A109. REMODELING AND THE MATRIX. May 1, 2016, A2828-A2828
- Manning C, et al, Stem Cell Research & Therapy20156:74
- Wood A, et al, Journal of Ocular Pharmacology and Therapeutics. June 2012, 28(3): 307-317.
- Hoogduijn MJ. Arthritis Res Ther (2015) 17(1):88.
- Soleymaninejadian E, et al., Am J Reprod Immunol (2012) 67(1):1–8
- Augello A, et al., Eur J Immunol (2005) 35(5):1482–90
- Yanez R, et al, Stem Cells, 24, (11), P 2582–2591, Nov 2006
- Jung W, et al, Tissue and Cell, 47, (1), P 86–93 Feb 2015
Earlier this year we hosted a documentary about stem cell therapy for canine Osteoarthritis for the British Veterinary Association. Check out the video segment from their visit to our US office and partner vet clinic in Irvine, CA.
Stem cell therapy is gaining traction here in the US and abroad, especially in the veterinary space, and VetCell Therapeutics is a pioneer of this exciting new veterinary medicine. Osteoarthritis, is a chronic degenerative disease that affects the soft tissues and the bones of joints of dogs – it’s a painful condition and one that can cause severe lameness. VetCell Therapeutics is pioneering stem cell therapeutics and research across the globe to offer vets and their patients a new, innovative treatment.
Stem cell transplants for dogs are making the news! Recently a story aired on the news in Arlington, Washington about a 150 pound three-year-old Newfoundland named Harley who was suffering from arthritis that set in following an ACL surgery. Instead of prescribing Harley with a lifetime of daily medications that could have harsh side effects, Harley’s veterinarian recommended something different – a stem cell therapy from VetCell Therapeutics called ReGen OA.
To understand why we at VetCell Therapeutics are so passionate about the future of using stem cell therapies for treating diseases in ailing pets, VetCell Therapeutics’ Chief Medical Officer Chad Maki discusses how stem cells interact with the body, his experience with treating patients with stem cells and his outlook on the future of treating various diseases with stem cells.
Dr. Maki explains, “I believe that our companion animals should have similar high quality medical care that their owners receive in human medicine and that we should embrace innovative and emerging cell therapy technologies. It is quite remarkable how the body is made up of many different cell types which all serve a particular and specific function. The body has the ability to provide us with energy, perform thoughts and mechanical movements, feel and react to our environment, grow and develop, fight off infections, and to heal and maintain homeostasis. All of these cell types and mechanisms begin with a single cell which replicates and morphs into the three germ layers which make up the many specialized cells and tissues in our bodies. As adults each organ houses its own stem cell populations that are known as precursor cells. Some are more prolific than others, but each tissue has the ability to heal and regenerate to a certain capacity. These cells know when and how to act through complex signaling with cytokines in their local environment.”
“The benefit of utilizing certain cells types for specific diseases is that they have a chance to control the disease and to rebuild functional tissue. With canine osteoarthritis (OA) for example, it is postulated that mesenchymal stem cells perform many functions to control the disease, two of which are of utmost importance; anti-inflammation and cartilage regeneration. These two features alone are enough to make stem cell therapy for OA very enticing. They have the potential to reduce inflammation which in turn will reduce pain, and also to rebuild damaged cartilage to produce a more functional joint. Together, these features provide the chance to stop or reverse the progression of osteoarthritis. I understand the promise of stem cell therapy and have seen the benefit it can have on my patients, but I want to stress on the importance of evidence based medicine and the need for rigorous clinical trials to prove that they are safe and effective. At VetCell Therapeutics we are committed and dedicated to this endeavor for scientific and therapeutic rigor.”
“Through my experience in the stem cell field and in the clinical practice setting, I see the great potential that stem cell therapy can have for various ailments. My aim is to provide state of the art stem cell therapies for our pet patients suffering from various degenerative conditions such as osteoarthritis and chronic kidney disease. My ambition is to have a life-changing impact on these patients that have a great need to eliminate their pain and suffering and improve their quality of life through regenerative therapy technologies. I envision regenerative therapies as the mainstay of animal and human medicine and I am excited to be at the forefront in this field.”
In his spare time Dr. Maki can be found with his wife, two little boys and their rescue dog Ava. He greatly values time spent outdoors and in nature and enjoys snowboarding, backpacking, hiking, running, swimming, basketball and many other activities especially when he is with his family. He grew up always loving animals and has had many pets including snakes, guinea pigs, rabbits, ducks, turtles, fish, dogs and cats. He has always been drawn to science, anything from biochemistry to cosmology. He feels lucky to have the ability not only to work with animals daily, but also to help them when they are suffering. The ability to apply his scientific knowledge to create innovative stem cell therapies for our pets is a privilege and an honor.
Dr. Maki earned his undergraduate degree in Biochemistry from the University of California, Berkeley and his internationally accredited DVM at the University of Edinburgh, Scotland. Since 2005 he has worked extensively in the field of stem cell research and has produced numerous peer reviewed scientific publications. While pursuing his veterinary degree he continued his scientific interests at Roslin Institute by investigating the role of canine cancer stem cells and the biomechanics of bone growth. After graduating with his DVM he moved back to his home town in Orange County, California and has been practicing veterinary medicine for our furry family companions ever since. He is the Chief Medical Officer at VetCell Therapeutics, an associate veterinarian at Irvine Pet Complex in Irvine, CA, as well as a member of the SCVMA, CVMA, AVMA, VOS, AAFP and iCatCare.
While navigating the potential path of treating a pet with cell therapies, one could find a lot of claims and promises of the therapeutic action of stem cells. Almost every disease occurrence is now, in some ways, tied to a stem cell treatment. The scientific perspective from this is highly positive, as it does indicate that progress is steadily being made in the science. A lot of the basic research conducted at academic institutions and at some companies are driving the treatment of diseases with stem cells. This is evident with the existence of such facilities at UC Irvine, UCLA, and USCF to just name a few (apologies for the California bias). On a very progressive note, UC Davis has a veterinarian regenerative medicine program which focuses on a variety of diseases in animals. Other admirable universities with veterinary regenerative medicine programs are University of Georgia and Virginia Tech in conjunction with U Maryland.
All of this is very exciting and instrumental in keeping the momentum moving strong in developing future stem cell therapies for both humans and animals. On the human side, the progress of clinical trials is listed on the www.clinicaltrials.gov website. A search of “stem cells” or “cell therapy” would result in the many different types of trials either getting started or in process. A review of the listing of the trials signifies that studies of this type of therapy are ongoing. Many believers are taking bold moves to see if stem cells will have a substantial effect on the future of medicine.
The veterinary side of clinical trials is not so clear. There is no central information source to search or to track the types of veterinary clinical trials that are ongoing. Any of the trials being conducted are confidential in nature and typically managed through university centers. The only chance we have to learn anything about these types of trials is through networking and asking the right people the right questions. However, this strategy may not provide much due to the confidential nature of the work.
Both of these approaches of stem cell based clinical trials are focused on one thing, ensuring cell therapy is safe and effective. The trials themselves are lengthy, costly and are subjected to a final decision bestowed upon it by the FDA. Yes, going through a process like this is challenging and daunting, but it is a necessary step in providing the treatments which are supposed to impact the future of medicine.
As the trials progress and conclude, the results will ultimately determine the applications of cell therapy. In looking at these trials, one must have a solid understanding of the expectations of the therapies. The days of the overhyped promises of stem cells should be behind us. Science has progressed enough during the last decade to reveal that stem cells are more complex than originally supposed and that they are not the cure-all. The most challenging part is the fact that the cells are living and they metabolize with their own energy demands. The debate is still ongoing whether the cells will incorporate into the damaged site or if they will settle to become support types of active cells that serve an anti-inflammatory function by secreting cytokines. Regardless, injecting something living into a body will require close scrutiny.
The progress of stem cell biology has, at least, guided researchers to focus on particular stem cells for treating particular diseases. For example, MSCs which easily differentiate into bone, cartilage and fat, tend to be used for skeletomuscular related types of injuries. Could these be used for cardiac and neurological diseases? As of now there is no answer, but they are in trials. Only the data will ultimately reveal the true power of certain types of stem cells.
The ultimate goal for companies and universities to pursue this science is to generate natural biological cures for diseases. Currently common autologous treatments of platelet rich plasma (PRP) and adipose stromal vascular fraction (SVF) are used to treat various cases. Some of the results are promising even though repeated treatments are needed. These types of applications are great first steps to generate case studies and to produce clinical data for cell treatments. These efforts, plus clinical trials, will eventually give rise to the outcomes the cell therapy industry needs to confidently state that particular types of stem cells are able to provide a cure, not just a treatment for the symptoms.
VetCell Therapeutics explains how it works in Modern Dog Magazine
Hey there, fellow pet fanatics! If you subscribe to Modern Dog Magazine, make sure you read the summer issue! VetCell Therapeutics is featured in an article called “Revolutionary New Treatment for Canine Arthritis”!
Revolutionary New Treatment for Canine Arthritis
Osteoarthritis affects up to 1 in 5 dogs. The good news is there’s something you can do about it.
Osteoarthritis, also known as degenerative joint disease, is the progressive and permanent long-term deterioration of the cartilage surrounding the joints. It causes chronic joint inflammation and is the most common cause of lameness in dogs. Thought to affect up to one in five dogs, with older dogs being at the highest risk, it is a painful and progressive disease resulting in cartilage destruction and bone changes that can drastically affect a dog’s quality of life. A veterinary examination can determine if your dog has this disease.
Over the past decade, stem cell use in the field of veterinary medicine has continued to evolve rapidly both experimentally and clinically. Stem cells derived from adipose and blood are most commonly used in clinical veterinary medicine in therapeutic applications for the treatment of musculoskeletal injuries in horses and dogs. The hope with using stem cell therapies is that patients will forego harsh drug treatments or invasive surgeries and instead rely on the healing potential of the body’s’ own cells. Recent research backs up the benefits of stem-cell treatments in some applications to combat the symptoms and reverse the damaging effects of autoimmune and degenerative diseases. (1, 2), The recent growth of university veterinary regenerative medicine departments, independently or through spin-off companies, and the plethora of clinical trials with human stem cells indicate that the industry is just barely scratching the surface of what is possible to accomplish with stem cell therapies.
The expansion of the many regenerative medicine facilities and the emergence of cell therapy, supports the notion that stem cells will have an impact on the future of medicine. The FDA is also becoming involved in the oversight of veterinarian use of stem cells, as evident with the creation of the Center for Veterinary Medicine (CVM) and its release of Guidance 218. (3)
VetCell Therapeutics, and our parent company PrimeGen Biotech, can excitedly say the fruits of the numerous years of research have resulted in the production and development of cell therapy products for the veterinary industry. VCT’s goal is to make a difference in the lives of pets suffering from various ailments, starting with osteoarthritis. The initial focus of our therapies will be on dogs and we began commercial production of these therapies in April of this year. In the two months of operation since announcing the therapies, we have experienced general interest from pet owners and veterinarians alike. The trend we noticed is while there is interest in stem cell use, there is also a fair amount of caution from our visitors. As a result, VCT aims to spread awareness of the safety and efficacy of stem cell therapies, in addition to supporting evidence based medicine.
Our initial product offering consists of two cell therapies, an autologous SVF stem cell therapy derived from a dog’s own fat tissue called ReGen OA, and a platelet rich plasma derived from the patient pet’s blood called EvoluGen OA, each offering unique therapeutic value for treating OA.
OA a painful disease, especially for dogs, that causes the smooth cartilage and bone tissues in joints to degenerate. Over time, the disease progresses causing a lot of pain and discomfort, which limits a pet’s activity and ability to enjoy doing the things they love most, like running and playing. Even a short walk could leave them in severe discomfort for days after. Clinical results of human trials have supported the use of stem cells for OA (4). Similarly, autologous stem cell applications have also benefitted dogs (5).
What is EvoluGen OA?
For platelet rich plasma treatments like our EvoluGen OA, a veterinarian collects tubes of blood from the pet patient and sends them to VetCell Therapeutics’ processing facility, where scientists separate the components of the blood. The process is customizable which allows the scientists to specifically prepare the therapy with a specific concentration of platelets tailored for the patient. The platelets within the plasma are rich in growth factors which have been shown to trigger a healing response within the body. The idea is that when a concentrated amount of PRP is injected into an osteoarthritic joint, the healing response initiated by the platelets reduces swelling and pain.
What is ReGen OA?
Stem Cell therapy is a unique type of treatment, with greater short- to long-term benefits. VCT offers a stromal vascular fraction (SVF) stem cell autologous therapy called ReGen OA that is made from fat tissue from the pet patient. A veterinarian extracts the required amount of fat tissue from the pet and sends to VetCell Therapeutics where we process the tissue and isolate the SVF stem cells. The stem cells are concentrated to the required dose, loaded into a syringe and sent back to the veterinarian for injection into the damaged joint. The stem cells when injected into the affected joint initiate a healing response that reduces pain and swelling. Over time the ability for stem cells to differentiate into other types of tissue cells is where the regenerative nature of the therapy comes into play. The clinical result for the stem cells injected into the joint is to leverage their anti-inflammatory properties for relief from the pain, and for those cells to become cartilage tissue cells and bone tissue cells, which contributes to restoring the pet’s mobility.
If you have a pet suffering from osteoarthritis, be sure to ask your vet about stem cell therapy. If your vet is not familiar with this type of therapy, kindly ask them to visit the VetCell Therapeutics website or to give us a call. Currently, VetCell Therapeutics only offers cell therapies for osteoarthritis, and we have been researching the potential of stem cells found in other tissues for treating more complex diseases for more than 10 years. In the coming years, we believe that stem cell therapies will be proven effective at treating a large variety of diseases suffered by our pets from heart disease to renal failure, offering them a safer alternative to costly surgeries and harsh drug treatments.
- Black, L. L. et al. Vet. Ther. 8, 272–284 (2007).
- Fortier, A. et al. Stem Cell Res Ther. 2011; 2(1): 9.
- Jo, C. et al. Stem Cells. 2014 May;32(5):1254-66
- Guercio, A. Cell Biol Int. 2012 Feb;36(2):189-94
Cell therapy is an innovative biological technology that has made large strides in the recent decade. Just 5 – 10 years ago, it was uncommon to consider a cell therapy option for damaged joints or neurodegenerative diseases. It is not to say cell therapy has not had a medical impact. To the contrary, the medical institutions have been using cell therapy for decades with the application of bone marrow transplants for treatments of cancer or hematological diseases. The expanded uses of cell therapy are a result of growing understanding of biological concepts of tissue regeneration and research on various cell types. The goal of cell therapy is a passionate search for “biological solutions to biological problems.”
As such, cell therapy is defined as the administration of live whole cells or maturation cell populations in a patient for the treatment of a disease. The types of cells used in this application can be mature cells, such a T cells or dendritic cells, to adult stem cells isolated from a fresh tissue source. An exciting up and coming use of mature cells is that of regulatory T cells in therapeutic applications. Regulatory T cells confer long-term protection against auto-inflammatory diseases in mouse models and have been shown to be effective in suppressing alloimmunity in models of graft-versus-host disease.  Regulatory T cell therapy is now at the point of evaluating its safety and efficacy within preclinical testing in humans. [2, 3]
Another interesting mature cell type being explored for cell therapy is the dendritic cell. Dendritic cells are highly-specialized, bone marrow-derived antigen-presenting cells that induce or regulate innate and adaptive immunity. Since the mid-1990s, dendritic cells have been used in clinical trials as cellular mediators for therapeutic vaccinations of patients with cancer. Dendritic cell based therapeutic immunotherapies with oncogene inhibitors in patients appear to be the method of choice. Human clinical trials investigating targetable tumors are underway in renal cell carcinoma, prostate cancer, breast cancer, and melanoma. [4, 5]
A large proportion of cell therapy is in development with various types of stem cells. Recent advances in stem cell biology and cell culture techniques have facilitated the development of cell therapy for translational medicine. Adult stem cells have been used in pilot studies as potential cell-based therapy for various diseases. Certain types of adult stem cells are better candidates for therapeutic applications, as compared to other stem cell types. To date, the most common types of adult stem cells used are bone marrow stem cells (i.e. CD34+), mobilized hematopoietic stem cells and adipose stem cells. These particular stem cell lineages are easily harvested from patients, have a high capacity of cell proliferation in culture, are able to migrate to host target tissues and have the ability to integrate into host tissues to interact with the surrounding tissues. [6, 7]
Cell therapy is challenging and should surprise no one by its pace of approval and acceptance. A sense of caution must also be taken when considering cell therapy for use. Many of the applications are still experimental and still require more safety testing. Autologous applications of cell therapy where the cells are from the same lineage tend to be safer and effective than using donor cells or a mismatched cell type. The cell therapies currently offered by VetCell Therapeutics are autologous and also within the same tissue lineage of the tissues effected by the diseases we can currently treat. It is well established that adipose stem cells routinely support growth of bone and cartilage. However, one must carefully critique the production of cell therapies as well as the delivery of the therapy for it to be safe and effective.
While cell therapy adoption is on an upswing, not all cell therapies are created equal, and it’s certainly beneficial for medical practitioners to know the contents of the cell therapies they administer. At VetCell Therapeutics, we treat each case differently. By knowing the specifics about each patient and the complexity of the disease being treated, we are able to craft cell therapies containing a guaranteed count of specific cell types, ensuring the patient receives exactly what they need and nothing they don’t.
- Qizhi Tang, Jeffrey A. Bluestone and Sang-Mo Kang. CD4+Foxp3+ regulatory T cell therapy in transplantation. J Mol Cell Biol (2012) 4 (1): 11-21.
- Hiroyoshi Nishikawa, Shimon Sakaguchi. Regulatory T cells in cancer immunotherapy. Current Opinion in Immunology, Volume 27, April 2014, Pages 1–7
- Theresa L. Whiteside. Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunology, Immunotherapy. January 2014, Volume 63, Issue 1, pp 67-72
- Jashodeep Datta, Erik Berk, Jessica A. Cintolo, Shuwen Xu, Robert E. Roses, and Brian J. Czerniecki, Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy. Front Immunol. 2015; 6: 271-81
- Sébastien Anguille, Evelien L Smits, Eva Lionb, Viggo F van Tendeloo, Zwi N Berneman, Clinical use of dendritic cells for cancer therapy. The Lancet Oncology, Vol 15, Issue 7, June 2014, Pages e257–e267
- Barker RA, Jain M, Armstrong RJ, Caldwell MA. Stem cells and neurological disease. J Neurol Neurosurg Psychiatry. 2003;74:553–7.
- Roopa R Nadig. Stem cell therapy – Hype or hope? A review. J Conserv Dent. 2009 Oct-Dec; 12(4): 131–138.
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