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Regenerative medicine

Regenerative medicine is an exciting advancement in the field of medicine that encompasses various techniques to promote the body’s healing response in targeted tissues to restore or establish normal function. The term is widely considered to have been coined by William Haseltine but was first used in 1992 in a paper by Leland Kaiser who listed technologies that would impact the future of medicine (Sampogna 2015).

In 1948 the first patient with rheumatoid arthritis was treated with corticosteroids thanks to the culmination of works of the laboratories of Kendall at Mayo Clinic and Reichstein in Zurich in the 1930s and 40s (Benedek 2011). Since then, corticosteroids have been applied to the treatment of pain in various orthopedic-related conditions.

At the turn of the century, researchers began discovering that many conditions for which corticosteroids were being used to treat were degenerative processes, not inflammatory like rheumatoid arthritis for which it was first used. The term ‘-itis’ signifies an inflammatory process, while the term ‘-osis’ signifies the disease state of a tissue. Thus, the medical community pushed to change the naming around such conditions to more accurately describe the pathologic process such as moving away from using ‘tendinitis’ and ‘osteoarthritis’ towards ‘tendinosis’ and ‘osteoarthrosis’ respectively (Andres 2008).

Parallel to this movement, the concepts and techniques in the field of wound care evolved to treat chronic, non-healing wounds by provoking bleeding to turn chronic wounds into acute ones. This would create an inflammatory response, triggering a complex signaling pathway of keratinocytes, macrophages, fibroblasts, endothelial cells, and platelets which contain numerous growth factors, cytokines, and chemokines involved in orchestrating wound healing (Barrientos 2008). This process of creating an inflammatory response is the complete opposite of what has been done in the field of orthopedics for over fifty years and this understanding is the fundamental basis of how regenerative medicine is now being utilized to revolutionize the field.

One of the many regenerative techniques in interventional orthopedics utilizes platelet-rich plasma or PRP. Platelets are covered in alpha-graunules which contain various healing factors and cytokines involved with initiating the body's healing cascade. Such factors include platelet-derived growth factor (PDGF), Transforming Growth Factor Beta (TGFB), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IF1) (Liu 2022). These factors and their respective platelets can be isolated, concentrated, and precisely delivered under ultrasound guidance into pathologic tissue, akin to a chronic non-healing wound, and restart the healing process, akin to turning it into an acute one. For this reason, it is generally discouraged to use anti-inflammatories such as Ibuprofen and Advil for at least 5 days (aspirin, 7 days) before and up to 6 weeks after such interventions (Wyles 2015). But the literature regarding PRP is mixed, right?

As it turns out not all PRP is created equal, or more specifically the process by which it is procured and processed. In 2004, the works of Waters and Roberts discussed several factors influencing the quality and quantity of platelets including shear stress, hemolysis, and the anticoagulant used during processing. A PRP platelet count of at least 1 to 1.5 x 10^9/mL is the generally accepted platelet concentration of therapeutic PRP (Dhurat 2014), although a more nuanced understanding in recent years has shown optimal concentrations varies by tissue (Collins et al 2021). A study in 2018 by Fadadu et al compared various FDA-cleared devices for concentrating PRP and found variations in the concentration among machines and found only a few machines on the market were able to concentrate platelets to the minimal accepted level to be medically efficacious. Furthermore, studies demonstrate PRP is most efficacious in younger patients and milder disease (Laver 2017, Barrientos 2008) compared to other regenerative techniques which must also be taken into account when deciding what treatment is best.

For all of these reasons, it is paramount that if you are undergoing any regenerative medicine procedure, the administering provider be fellowship trained in regenerative medicine. This is not only to have the experience to determine which patients and conditions are appropriate for certain procedures and have the proper equipment and training to procure and handle the specimens properly, but also the ability to set expectations regarding the post-interventional course, accurately deliver the intervention under direct image guidance and properly guide sport-specific, post-interventional physical therapy, which is a vital part tissue healing and reorganization.

At TSARO, our process minimizes hemolysis and shear stress on platelets during handling and utilizes the most efficacious anticoagulant and centrifuge to maximize yield. Additionally, we measure platelet counts before and after to ensure the concentration is at least 5-10 times the baseline concentration and appropriate concentration to the target tissue type (muscle, tendon, ligament, or intra-articular) . All interventions are performed under ultrasound guidance with evidence-based post-intervention rehabilitation coordinated with a physical therapist. Furthermore, decisions for treatment are personalized and the patient’s age, type of pathology, severity of disease, sport, competition dates, and social determinants of health are taken into account when making shared decisions regarding the best treatment options. In combination with the use of validated function outcome score surveys to monitor treatment response, we continue to improve our patients’ care, refine clinic processes, and contribute to the body of literature in the field of regenerative medicine.

Learn more here.

References

Sampogna G, Guraya SY, Forgione A. Regenerative medicine: Historical roots and potential strategies in modern medicine. J Microsc Ultrastruct. 2015 Jul-Sep;3(3):101-107. doi: 10.1016/j.jmau.2015.05.002. Epub 2015 May 18. PMID: 30023189; PMCID: PMC6014277.

Benedek TG. History of the development of corticosteroid therapy. Clin Exp Rheumatol. 2011 Sep-Oct;29(5 Suppl 68):S-5-12. Epub 2011 Oct 21. PMID: 22018177.

Andres BM, Murrell GA. Treatment of tendinopathy: what works, what does not, and what is on the horizon. Clin Orthop Relat Res. 2008 Jul;466(7):1539-54. doi: 10.1007/s11999-008-0260-1. Epub 2008 Apr 30. PMID: 18446422; PMCID: PMC2505250.

Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008 Sep-Oct;16(5):585-601. doi: 10.1111/j.1524-475X.2008.00410.x. PMID: 19128254.

Liu Y, Kalen A, Risto O, Wahlstrom O. Fibroblast proliferation due to exposure to a platelet concentrate in vitro is pH dependent.  Wound Repair Regen . 2002;10(5):336–340.

Wyles C.C, Houdek M.T, Wyles S.P, Wagner E.R, Behfar A, Sierra R.J. Differential cytotoxicity of corticosteroids on human mesenchymal stem cells.  Clin Orthop . 2015;473(3):1155–1164. doi: 10.1007/s11999-014-3925-y.

Waters JH, Roberts KC. Database review of possible factors influencing point-of-care platelet gel manufacture. J Extra Corpor Technol. 2004 Sep;36(3):250–4.

Dhurat R, Sukesh M. Principles and methods of preparation of platelet-rich plasma: a review and author′s perspective.  J Cutan Aesthetic Surg . 2014;7(4):189.

Collins T, Alexander D, Barkatali B. Platelet-rich plasma: a narrative review. EFORT Open Rev. 2021 Apr 1;6(4):225-235. doi: 10.1302/2058-5241.6.200017. PMID: 34040800; PMCID: PMC8142058.

Fadadu PP, Mazzola AJ, Hunter CW, Davis TT. Review of concentration yields in commercially available platelet-rich plasma (PRP) systems: a call for PRP standardization. Reg Anesth Pain Med. 2019 Apr 16:rapm-2018-100356. doi: 10.1136/rapm-2018-100356. Epub ahead of print. PMID: 30992411.

 Laver L, Marom N, Dnyanesh L, Mei-Dan O, Espregueira-Mendes J, Gobbi A. PRP for degenerative cartilage disease: a systematic review of clinical studies.  Cartilage . 2017;8(4):341–364. doi: 10.1177/1947603516670709.

Barrientos S, Stojadinovic O, Golinko M.S, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing.  Wound Repair Regen . 2008;16(5):585–601. doi: 10.1111/j.1524-475x.2008.00410.x.