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Regenerative medicine (RM) is a widely used term meant to encompass a treatment methodology for disease states ranging from Parkinson’s disease and paralysis to autoimmune states, including a utility in pain management. Unlike neuromodulation or regional anesthesia that have set standards for learning and standardized curriculums within academic institutions and residency programs, RM largely relies on individual opinions over fact. Currently, most learn about regenerative medicine at weekend courses or breakout sessions at annual meetings. Despite this extremely limited training, more and more physicians each year refer to themselves as RM experts, leaving the general public with no means to tell the difference. Despite this grim state of affairs, RM’s future is extremely bright with Level I data and standardization on the horizon.

The crux of the world’s interest in regenerative medicine . . . has centered around its potential utility in the central nervous system—the one area of the body that lacks the ability to repair itself after an injury or insult.

Broadly speaking, RM describes the replacement or regeneration of human cells, tissue, or organs (through organic means) to restore, establish or re-establish normal function.^[1] Although many consider William Haseltine to be the forefather of RM—he was the first to ponder its utility at a 1999 conference in Lake Como—the term was initially coined in a 1992 article by Leland Kaiser.^[2] Kaiser described emerging treatments and technologies of the time that were poised to have the most significant effects on the field of medicine.^[3] The crux of the world’s interest in RM, ever since, has centered around its potential utility in the central nervous system—the one area of the body that lacks the ability to repair itself after an injury or insult.

Conditions such as Parkinson’s and paralysis are well understood and could be easily treated if the neural tissue could correct itself (ie, manufacture dopamine-producing cells in the nigrostriatal pathway or induce neurons to reconnect and make useful connections across a spinal cord injury).^[4] Early efforts in RM were focused on using embryonic stem cell cells to accomplish these goals.^[5] However, the cells were fragile, difficult to trigger to achieve their goals, more likely to become fibroblasts than neurons, and generally controversial because they were acquired from fetal tissue.^[6],[7] Over time, scientists looked to stromal stem cells as the next opportunity. Stromal cells are considered more robust, easier to manipulate, and more intuitive; they could be self-harvested, thus eliminating the ethical debate that surrounded embryonic cells.^[8],[9] Years later, those cells are commonplace in the field of pain medicine and go by the more recognizable name “mesenchymal stem cells.” Although a great deal of research is being conducted on them, their use in pain and orthopedics remains largely unstandardized and, as such, is not covered by any insurance carrier.

The concept of platelet-rich plasma (PRP) was initially used by hematologists in the 1970s to describe plasma with a platelet count higher than that of peripheral blood and primarily served as a transfusion product for the treatment of thrombocytopenia.^[10] Years later, maxillofacial surgeons began using PRP and platelet-rich fibrin matrix for their procedures such as tooth avulsion or extraction, mucogingival surgery, guided tissue regeneration or bone filling of periodontal intrabony defects, and regeneration of alveolar ridges.^[11-14] Over time, PRP expanded into the field of orthopedics and eventually pain medicine.^[15-20] Initially, physicians billed PRP through insurance for autologous transplant. Unfortunately, PRP became considered experimental because of a lack of standardization and is no longer covered by insurance companies.

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

Managing intradiscal pain has always been a challenge 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 often remains pathologic for the remainder of a patient’s life. At present, some companies are developing stem cell lines to inject into the nucleus fibrosis of degenerative discs to reverse the deterioration and eliminate the pain. They are currently in phase III clinical trials and, if approved, would be available off the shelf for physicians and ideally covered by insurance carriers like a drug or medication. In theory, this treatment would compete with lumbar fusions.^[21-23]

The knee is another area of opportunity for RM and could change the face of medicine once a viable product is developed. At present, RM for the knee is limited to PRP and nonstandardized injections of stem cells. Studies on PRP for osteoarthritis (OA) of the knee have been variable, and some show it to be no better than viscosupplementation.^[24] Stem cell therapy is associated with a wide range of clinical use strategies for knee OA (eg, with or without vehicle, with or without scaffold, with or without augmentation), and companies are working to standardize the RM treatment algorithm. An experimental cell line called “juvenile chondrocytes,” currently in a phase III clinical trial. It is meant not only to rebuild the lost and degenerative material of the knee but also combat inflammation within the joint. This would also be an off-the-shelf treatment that physicians can purchase and inject like hyaluronic acid. Another company is taking a different approach by using autologous-derived stem cells from adipose tissue, currently in phase I clinical trials. Patients will undergo liposuction where adipose tissue is harvested, isolated, and cultured to acquire what is known as the “stromal vascular fraction”—a concentrated supply of mesenchymal stem cells located within adipose tissue. Those cells are expanded and shipped to the physician to inject back into the patient.

Amniotic tissue is another potential regenerative product on the market that has shown promise but, like PRP and stem cell therapy, is cash only. The principle is similar to PRP in that it delivers growth factors directly to an area to trigger the regenerative process. Also like PRP and stem cell therapy, it has yet to be standardized. RM’s adoption has been widespread and increasing despite its validity still being under question because of experimental labeling and lack of standardization. However, data are abundant for its use in certain situations, demonstrating its validity for the right indications. As companies continue to work toward gathering Level I evidence and gaining insurance coverage, overall access will continue to improve and the variability with which it is currently used should lessen.

References

1. Mason C, Dunnill P. A brief definition of regenerative medicine. Regen Med. 2008;3(1): 1–5. https://doi.org/10.2217/17460751.3.1.1
2. Fahy GM. Dr. William Haseltine on regenerative medicine, aging and human immortality. Life Ext. 2002;8(7):58. https://www.lifeextension.com/Magazine/2002/7/report_haseltine/Page-02?p=1
3. Kaiser LR. The future of multihospital systems. Top Health Care Financ. 1992;18(4):32–45.
4. Shroff G, Dhanda Titus J, Shroff R. A review of the emerging potential therapy for neurological disorders: human embryonic stem cell therapy. Am J Stem Cells. 2017;6(1):1–12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435646/
5. Fu YS, Cheng YC, Lin MY, 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):115–124. https://doi.org/10.1634/stemcells.2005-0053
6. Stice SL, Boyd NL, Dhara SK, Gerwe BA, Machacek DW, Shin S. Human embryonic stem cells: challenges and opportunities. Reprod Fertil Dev. 2006;18(8):839–846.
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9. Trohatou O, Roubelakis MG. Mesenchymal stem/stromal cells in regenerative medicine: past, present, and future. Cell Reprogram. 2017;19(4):217–224. https://doi.org/10.1089/cell.2016.0062
10. Andia I, Abate M. Platelet-rich plasma: underlying biology and clinical correlates. Regen Med. 2013;8(5):645–658. https://doi.org/10.2217/rme.13.59
11. Del Corso M, Vervelle A, Simonpieri A, 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):1207–1230.
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(6):638–646.
13. Landesberg R, Roy M, Glickman RS. Quantification of growth factor levels using a simplified method of platelet rich plasma gel preparation. J Oral Maxillofac Surg. 2000;58(3):297–300.
14. Marx RE. Platelet-rich plasma—evidence to support its use. J Oral Maxillofac Surg. 2004;62(4):489–496.
15. Tetschke E, Rudolf M, Lohmann, CH, Stärke C. Autologous proliferative therapies in recalcitrant lateral epicondylitis. Am J Phys Med Rehabil. 2015;94(9):696–706. https://doi.org/10.1097/PHM.0000000000000234
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. 2015;25(6):524–528. https://doi.org/10.1097/JSM.0000000000000166
17. Hussain N, Johal H, Bhandari M. An evidence-based evaluation on the use of platelet rich plasma in orthopedics - a review of the literature. SICOT J. 2017;3:57. https://doi.org/10.1051/sicotj/2017036
18. Filardo G, Kon E, Della Villa S, Vincentelli F, Fornasari PM, Marcacci M. Use of platelet-rich plasma for the treatment of refractory jumper's knee. Int Orthop. 2010;34(6):909–915. https://doi.org/10.1007/s00264-009-0845-7
19. Liddle AD, Rodriguez-Merchan EC. Platelet-rich plasma in the treatment of patellar tendinopathy: a systematic review. Am J Sports Med. 2015;43(10):2583–2590. https://doi.org/10.1177/0363546514560726
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21. Safety and preliminary efficacy study of mesenchymal precursor cells (MPCs) in subjects with lumbar back pain. https://clinicaltrials.gov/ct2/show/NCT01290367. Accessed June 11, 2019.
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. Accessed June 11, 2019.
23. Viable allograft supplemented disc regeneration in the treatment of patients with low back pain (VAST). https://clinicaltrials.gov/ct2/show/NCT03709901. Accessed June 11, 2019.
24. Zhang HF, Wang CG, Li H, Huang YT, Li ZJ. Intra-articular platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: a meta-analysis. Drug Des Devel Ther. 2018;12:445–453. https://doi.org/10.2147/DDDT.S156724