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Regenerative Medicine in the United States – The Current State & Future Outlook

Article by Corey W Hunter, MD, FIPP & Yashar Eshraghi, MD
“Regenerative medicine” is a widely used term these days – while it is meant to encompass a treatment methodology for disease states ranging from Parkinson’s and paralysis to autoimmune states, it is more commonly known in for its utility in pain management.

Unlike neuromodulation or regional anesthesia where there are set standards for learning and standardized curriculums within academic institutions and residency programs, regenerative medicine has no such criteria and largely relies on individual opinions over fact.

Currently, the only means for one to learn about regenerative medicine is weekend courses or a breakout session at an annual meeting. And despite this extremely limited training, there are more and more physicians each year who refer to themselves as “regenerative medicine experts” leaving the general public with no means to tell the difference.

Despite this grim state of affairs, the future of regenerative medicine is extremely bright with Level-I data and standardization on the horizon.

How do I Tell Who is an Expert & Who Isn’t?
Unfortunately, many doctors will take weekend courses and then market themselves as “experts” in the field of regenerative medicine or “world leaders in stem cell therapy” the following Monday and patients have no way of knowing that they are being deceived. 

Patients tend to trust that their doctor is telling the truth and believe what they are being told.  Making matters even worse, there are a number of chiropractors now who are marketing themselves as stem cell experts which is totally unethical as they are not legally allowed to draw blood or perform injections of any kind…but once again, patients do not know the difference.

There are a couple of key points to keep in mind when researching stem cell therapy to make sure the person you are considering is really an expert and not just another would-be scam artist.

  1. Stem cells cannot be grown or expanded anywhere in the United States and then be injected back into you outside of a clinical trial.  Period.  If someone tells you that they are going to culture your cells and make more, they are breaking the law.
  2. If the person tells you that they are performing a clinical trial or have “IRB approval” that allows them to grow the stem cells, ask for the name of the clinical trial and then go to www.clinicaltrials.gov and see if the study is there.  Many times physicians will get very preliminary approvals to conduct a “study” to create a loophole that will allow them to grow a person’s stem cells.  These “studies” are complete scams and nothing more than a way to get around the system.  These laws are in place to protect patients – just growing stem cells in a makeshift-lab and not testing those cells to make sure they have not mutated or changed in any way is reckless.  There are a number of FDA-approved clinical trials out there.  If it is your intention to join one, make sure it is a real study being conducted and not a scam.
  3. Adipose (Fat) Stem Cells are not as clear cut as some would have you believe.  About 10-years ago, it was discovered that fat is rich with stem cells – this is called the “stromal vascular fraction” or SVF.  In fact, this area appears to have more stem cells than bone marrow (BMAC).  So, many physicians interested in regenerative medicine began to use this as a way to harvest stem cells by performing a quick liposuction. There are 2 problems with this approach that most will not tell you. 1) Stem cells from fat tend to want to turn into more fat cells – this means that if you get an injection into your knee with stem cells that were harvested from a liposuction, rather than becoming cartilage to repair the “bone-on-bone” they will prefer to turn into fat cells and do nothing to fix your knee.  The sequence of events that needs to take place to “convince” these cells to become cartilage is still being investigated in clinical trials and is the trade secret of a company called JOINTSTEM.  2) When stem cells from fat are being processed, many technicians will turn to a drug called “lipase” to digest the fat and leave the stem cells behind.  This is a very grey area within the law as that is considered a drug and cannot be administered to a human without a special license.  Furthermore, the cells will need to be washed several times to remove the lipase – after all of the necessary washes, the cell count is virtually the same as what would be harvested from bone marrow.  MORAL: Stem cells from fat should be avoided outside of a real, FDA-approved clinical trial.
  4. Stem cells cannot be transported from one location to another.  The law clearly states that once a stem cell is removed from the physical location where it was harvested, it cannot be injected back into a human outside of a clinical trial.  As was stated in #2, many scam artists will create a fake study to give them a loophole so they can transport the stem cell to another location.  Avoid individuals that want to expand your cells and/or move your cells to a different location to be injected back into you.
  5. While there is no standardized training program for stem cell therapy or regenerative medicine, many have made the study of the field a life’s work and will routinely lecture on the topic and publish.  These are the real experts.  Simply calling yourself an expert doesn’t make you one. 

Here are some questions to ask: 

  1. How long have you been practicing regenerative medicine?  An expert is someone with YEARS of experience to their credit.
  2. Are you a doctor of medicine or a nurse practitioner? This will make it clear if the person sitting across from you is an MD, DO, NP or someone else who shouldn’t be practicing regenerative medicine
  3. What training do you have in regenerative medicine?  If the person says they took a weekend course a month ago, you have your answer
  4. What is your primary specialty? If someone is a vascular surgeon or family practice doctor by training, that person has had no training in musculoskeletal medicine, ultrasound-guided injections nor the basic foundations of the medical science necessary to be good at regenerative medicine.  They basically transitioned to regenerative medicine because they wanted to pursue a more lucrative specialty where they can charge cash.  Stick with pain doctors, physiatrists, and anesthesiologists who have had basic training in joint pain, ligament tears and the like.
  5. Have you lost your license in any state or been subject to any disciplinary actions?  There are more than a few doctors that got into trouble in one state and then moved to another to avoid scrutiny and used cash-based business of regenerative medicine to get started
  6. Is it safe and is there evidence to support what you are proposing?  Stem cells are not pixie dust – it doesn’t work on everything.  Even though it is not covered by insurance, it has been studied for decades and there is a ton of evidence to support it…on certain things.  There are a few doctors who have blinded patients by sticking stem cells in people’s eyes because the patient didn’t know any better than to simply ask.
  7. How many regenerative medicine procedures do you perform in an average month?  If a person does 2-3 injections a year, they are not an expert.

What is REAL Regenerative Medicine?
Stem Cell TherapyBroadly speaking, regenerative medicine (RM) describes the replacement or regeneration of human cells, tissue or organs (through organic means) to restore, establish or re-establish normal function.[1] While many consider William Haseltine to be the “forefather” of RM as he was the first to ponder its utility at a 1999 conference on Lake Como [2], the term “regenerative medicine” was initially coined in a 1992 paper by Leland Kaiser which described the emerging treatments and technologies of the time that were poised to make the most significant impacts on the field of medicine. [3] The crux of the world’s interest in RM, ever since, was always centered around its potential utility within the central nervous system – the one area of the body that lacked the ability to repair itself after an injury or insult.

Conditions like Parkinson’s and paralysis are well understood and could be easily treated if one could only induce the neural tissue correct itself – i.e. manufacture dopamine producing cells in the nigrostriatal pathway or having neurons reconnect across a spinal cord injury to make useful connections. [4] Early efforts in RM were focused on using embryonic stem cell cells to accomplish these goals.[5] However these particular cells were fragile, difficult to “convince” to accomplish their goals, more likely to become fibroblasts than neurons, and generally controversial due to their needing to be acquired from fetal tissue.[6, 7] Overtime, scientists recognized these deficiencies and looked to stromal stem cells as the next opportunity. These were considered more robust, easy to manipulate, more intuitive and could be self-harvested thus eliminating the ethical debate that surrounded embryonic cells.[8,9] Years later, these cells are commonplace in the field of pain medicine and go by the more recognizable name “mesenchymal stem cells.” While there is a great deal of research being done on them, their use in for pain and orthopedics remains largely unstandardized – as such, it is not a covered service by any insurance carrier.

The concept of platelet rich plasma (PRP) was initially described much earlier than stem cells by hematologists in the 1970s to describe plasma with a platelet count higher than that of peripheral blood, which was primarily utilized as a transfusion product for the treatment of thrombocytopenia.[10] Years later, maxillofacial surgeons began using PRP and (PRF) platelet rich fibrin matrix for their procedures like tooth avulsion or extraction, mucogingival surgery, Guided Tissue Regeneration (GTR) or bone filling of periodontal intrabony defects, and regeneration of alveolar ridges.[11-14] Over time, the utility of PRP expanded use with orthopedics and eventually pain medicine.[15-20] Initially, physicians were able to utilize PRP through insurance by billing for “autologous transplant.” Unfortunately, PRP became considered “experimental” due to a lack of standardization and was no longer covered by insurance companies.

The fact that RM is a cash procedure puts it out of reach for a great many patients, however it should not be considered any less credible when used in an evidence-based fashion. Fortunately there are a number of companies who recognize the utility of RM and are investing hundreds of millions in research money in an attempt to standardize the practice and gain insurance coverage to bring this truly remarkable therapy to the masses.

Intradiscal pain has always been the “white whale” for pain doctors and spine surgeons, alike. Much like the central nervous system, it is a structure that lacks the ability to regenerate itself and will remain pathologic for the remainder of one’s life. At present, companies like Mesoblast and Vivex are developing stem cell lines to be injected into the nucleus fibrosis of degenerative discs in an effort to reverse the deterioration and eliminate the pain. Both companies have completed recruitment for their respective Phase-III clinical trials and are the process of collecting their 12-month data. Once completed, these stem cell lines would be available “off-the-shelf” for physicians to utilize and covered by insurance carriers (ideally) like a drug or medication. In theory, this treatment would compete with lumbar fusions.[21-23]

The knee is another area of great interest for RM and could change the face of medicine should a viable product being developed. At present, RM for the knee is limited to PRP and non-standardized injections of stem cells. Studies on PRP for osteoarthritis (OA) of the knee have been variable with studies showing it to be no better than viscosupplementation [ref].

Stem cell therapy is all over the place with no 2 people using them the same way (i.e. with or without vehicle, with or without scaffold, with or without augmentation, etc).

Currently, there are companies like Kolon TissueGene and JOINTSTEM working to standardize the RM-treatment algorithm for knee OA. Kolon TissueGene has developed a cell line called “juvenile chondrocytes” which are meant to not only rebuild the lost and degenerative material of the knee but combat the effects of inflammation within the joint.

A Phase-III clinical trial is set to begin this year (2018) to study the potential for these cells at 12-months. Much like Vivex and Mesoblast, this will be an “off-the-shelf” treatment that physicians can purchase and inject like a hyaluronic acid of sorts. JOINTSTEM is taking a different approach by using autologous-derived stem cells from adipose tissue.

These patients will undergo a liposuction where adipose tissue will be harvested then isolated and cultured to acquire what is known as the stromal vascular fraction (VCF) – a concentrated supply of mesenchymal stem cells located within adipose tissue. These cells will then be expanded and shipped back to the physician to then inject back into the patient. JOINTSTEM is completing their Phase-I in the United States at the time of this manuscript.

Amniotic tissue is another potential regenerative product on the market that has shown promise, and like PRP and stem cell therapy, it is cash only. The principle is similar to PRP whereby the operator’s hand delivers growth factors to an area of need to “jump start” the regenerative process. Also like PRP and stem cell therapy, this has yet to be standardized.

TissueTech is a company who holds patents on their proprietary human placental and amniotic tissue products with plans to produce Level-I evidence for their use – one such use is on facet-mediated pain with plans to potentially study this in 2019.

The adoption of RM has been widespread and increasing despite the fact that some question its validity due to its “experimental” labeling and lack of standardization. However, there is an abundance of data for a number of indications, which shows the overall legitimacy of RM…for the right indications. As companies continue to work toward gathering Level-I evidence and the goal of gaining insurance coverage, not only will the overall access to RM improve, but the variability with which it is currently used should lessen.

REFERENCES

  1. Mason, C. and P. Dunnill, A brief definition of regenerative medicine. Regen Med, 2008. 3(1): p. 1-5.
  2. GM., F., Dr. William Haseltine on regenerative medicine, aging and human immortality. . Life Ext, 2002. 8(July (7)):58.
  3. Kaiser, L.R., The future of multihospital systems. Top Health Care Financ, 1992. 18(4): p. 32-45.
  4. Shroff, G., J. Dhanda Titus, and R. Shroff, A review of the emerging potential therapy for neurological disorders: human embryonic stem cell therapy. Am J Stem Cells, 2017. 6(1): p. 1-12.
  5. Fu, Y.S., et al., Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells, 2006. 24(1): p. 115-24.
  6. Stice, S.L., et al., Human embryonic stem cells: challenges and opportunities. Reprod Fertil Dev, 2006. 18(8): p. 839-46.
  7. Gershon, D., Complex political, ethical and legal issues surround research on human embryonic stem cells. Nature, 2003. 422(6934): p. 928-9.
  8. Bakshi A, Hunter C, Swanger S, Lepore A, Fischer I. Minimally invasive delivery of stem cells for spinal cord injury: advantages of the lumbar puncture technique. J Neurosurg Spine. 2004 Oct;1(3):330-7.
  9. Trohatou, O. and M.G. Roubelakis, Mesenchymal Stem/Stromal Cells in Regenerative Medicine: Past, Present, and Future. Cell Reprogram, 2017. 19(4): p. 217-224.
  10. Andia, I. and M. Abate, Platelet-rich plasma: underlying biology and clinical correlates. Regen Med, 2013. 8(5): p. 645-58.
  11. Del Corso, M., et al., Current knowledge and perspectives for the use of platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) in oral and maxillofacial surgery part 1: Periodontal and dentoalveolar surgery. Curr Pharm Biotechnol, 2012. 13(7): p. 1207-30.
  12. Marx RE, Carlson ER, Eichstaedt RM, Schimmele SR, Strauss JE, Georgeff KR. Platelet-rich plasma: Growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol. 1998; 85:638–646
  13. Landesberg R, Roy M, Sleichman RS. Quantification of growth factor levels using a simplified method of platelet rich plasma gel preparation. J Oral Maxillofac Surg 2000;58:297-300.
  14. Marx RE, Platelet-Rich Plasma – Evidence to support its use. J Oral Maxillofac Surg. 2004;62:489-496.
  15. Tetschke E, Rudolf M, Lohmann, CH, et al. Autologous proliferative therapies in recalcitrant lateral epicondylitis. Am J Phys Rehabil. 2014; Am J Phys Med Rehabil. 2015 Sep;94(9):696-706
  16. Al-Ajlouni J, Awidi A, Samara O, et al. Safety and efficacy of autologous intra-articular platelet lysates in early and intermediate knee osteoarthritis in humans: a prospective open-label study. Clin J Sport Med. 2014; Clin J Sport Med. 2015 Nov;25(6):524-8.
  17. Hussain, N., H. Johal, and M. Bhandari, An evidence-based evaluation on the use of platelet rich plasma in orthopedics – a review of the literature. SICOT J, 2017. 3: p. 57.
  18. Filardo, G., et al., Use of platelet-rich plasma for the treatment of refractory jumper’s knee. Int Orthop, 2010. 34(6): p. 909-15.
  19. Liddle, A.D. and E.C. Rodriguez-Merchan, Platelet-Rich Plasma in the Treatment of Patellar Tendinopathy: A Systematic Review. Am J Sports Med, 2015. 43(10): p. 2583-90.
  20. Foster TE, Puskas BL, Mandelbaum BR, et al. Platelet-rich plasma: From basic science to clinical applications. Am J Sports Med. 2009;37:2259-72.
  21. Safety and Preliminary Efficacy Study of Mesenchymal Precursor Cells (MPCs) in Subjects With Lumbar Back Pain. https://clinicaltrials.gov/ct2/show/NCT01290367. ClinicalTrials.gov Identifier: NCT01290367.
  22. Placebo-controlled Study to Evaluate Rexlemestrocel-L Alone or Combined With Hyaluronic Acid in Subjects With Chronic Low Back Pain (MSB-DR003). https://clinicaltrials.gov/ct2/show/NCT02412735. ClinicalTrials.gov Identifier: NCT02412735.
  23. Viable Allograft Supplemented Disc Regeneration in the Treatment of Patients With Low Back Pain (VAST). https://clinicaltrials.gov/ct2/show/NCT03709901?term=vivex&rank=1. ClinicalTrials.gov Identifier: NCT03709901.

Corey Hunter, M.D.

Founder at Ainsworth Institute
Dr. Corey Hunter is a nationally recognized interventional pain physician and the founder of Ainsworth Insitute. His publications have appeared in textbooks on treating pain and he is a regular contributor in leading pain management journals.