Regenerative Medicine Options for Chronic Musculoskeletal Conditions: A Review of the Literature Sean W. Mulvaney, MD1; Paul Tortland, DO2; Brian Shiple, DO3; Kamisha Curtis, MPH4 1 Associate Professor of Medicine, Uniformed Services expected to be over 67 billion dollars in spending on University, Bethesda, MD biologics and cell therapies by 2020 (1). 2 FAOASM, Associate Clinical Professor of Medicine, University of Connecticut, Farmington, CT Specifically, regenerative medicine also stands 3 CAQSM, RMSK, ARDMS; The Center for Sports Medicine & in contrast to treatment modalities that impair Wellness, Glen Mills, PA the body’s ability to facilitate endogenous repair 4 Regenerative and Orthopedic Sports Medicine, Annapolis, MD mechanisms such as anti-inflammatory drugs (2,3); destructive modalities (e.g., radio frequency ablation of nerves, botulinum toxin injections) (4); Abstract and surgical methods that permanently alter the functioning of a joint, including joint fusion, spine egenerative medicine as applied to fixation, and partial or total arthroplasty. When musculoskeletal injuries is a term compared to other allopathic options (including knee used to describe a growing field of R and hip arthroplasty with a 90-day mortality rate of musculoskeletal medicine that concentrates 0.7% in the Western hemisphere) (5), regenerative on evidence-based treatments that focus on medicine treatment modalities have a lower and augment the body’s endogenous repair incidence of adverse events with a growing body of capabilities. These treatments are targeted statistically significant medical literature illustrating at the specific injury site or region of injury both their safety and efficacy (6). by the precise application of autologous, allogeneic or proliferative agents. Focusing on When evaluating regenerative treatment options, the repair of chronic musculoskeletal injuries, it is reasonable to start by evaluating the medical this paper will discuss both background and evidence for currently accepted medical options for emerging theories in regenerative medicine, subacute and chronic musculoskeletal injuries. as well as specifically address developments in the clinically-relevant literature on specific Non-steroidal anti-inflammatory drugs (NSAIDs), treatments including: prolotherapy, platelet- as well as corticosteroid preparations, are widely rich plasma, autologous mesenchymal stems prescribed for acute and chronic pain conditions. cells, alpha 2 macroglobin, and human tissue- However, according to the Cochrane Database derived allograft products. Systemic Reviews, there is poor justification in the medical literature to indicate they promote improved Keywords: Regenerative medicine, platelet- long-term tissue healing (7,8). NSAIDs may interfere rich plasma, mesenchymal stem cells, with tissue healing (9,10). In 2017, a well-executed prolotherapy, micro-fragmented adipose, bone randomized controlled trial (RCT) with two-year marrow concentrate, alpha 2 macroglobin follow-up comparing intra-articular injection of corticosteroids to normal saline injections for the treatment of knee osteoarthritis showed no association Introduction with improvement in pain. In addition, the steroid treated knees showed MRI evidence of accelerated The term “regenerative medicine,” as applied osteoarthritis (11). The combination of local anesthetic to musculoskeletal injuries, describes a rapidly and corticosteroid has substantial evidence showing growing field of musculoskeletal medicine that that corticosteroids are toxic to chondrocytes both employs evidence-based treatments that focus in vivo and in vitro (12,13). Regarding the use of on augmenting the body’s endogenous repair corticosteroids in treating tendinopathy, in 2010 capabilities both at the specific injury site and Coombes and colleagues published a meta-analysis at the region of injury by the precise application of 41 RCTs that concluded that “at four weeks post- of autologous, allogeneic or proliferative agents. injection, the non-injection groups had better pain and World-wide, the market for regenerative medicine is function” (14). In addition, a randomized controlled trial Endurance and Sports Medicine • Fall/Winter 2018 6 comparing corticosteroid to placebo (saline) injections 1) The body fails to recognize an injury and mounts demonstrated worse outcomes in the corticosteroid an effective healing response. injection group after one year (15). 2) The repair mechanism is overwhelmed by The physiologic argument for using anti-inflammatory ongoing tissue insults such as chronic repetitive medications for the treatment of tendinopathies was movements without adequate recovery, called into question, if not refuted, in a landmark ligamentous laxity resulting in pathologic joint publication by Kraushaar and Nirschl in 1999. Using movement, and functional movement disorders electron microscopy sections of human lateral resulting in pathologic movement. epicondyle tendons clinically identified as tendinitis, they demonstrated that there was a conspicuous 3) The repair mechanisms are inhibited by a sub- absence of cells associated with inflammation optimal healing milieu. Factors contributing to a present in what previously, and inaccurately, had been catabolic, sub-optimal healing milieu include, but called “tendinitis” (a term implying inflammation). are not limited to: exposure to toxins (including They successfully demonstrated that the underlying many pharmaceuticals), poor diet, obesity, lack of pathology, instead, represented a chronic degenerative regular exercise, chronic systemic inflammation, condition referred to as “tendinosis” (16). chronic infection, poor sleep, hormonal deficiencies, and chronic stress (22,23). In the case of spine injections, including epidural steroid injections in the setting of subacute and chronic Each of these reasons for failure to self-repair is lumbar pain, an updated 2009 Cochrane review of a potential target for regenerative medicine and 18 RCTs concluded “there is currently insufficient counseling. evidence to support the use of [corticosteroid] injection In addition, as we age, the body moves towards therapy in subacute and chronic low-back pain” (17). senescence with a slow shift from a balanced Many standard orthopedic surgeries, including catabolic/anabolic environment to one that slightly arthroscopic surgery for the repair of knee meniscal favors catabolism, thus resulting in gradual tissue tears in patients over the age of 40, have been degeneration. At some point, this slow senescence shown in a recent meta-analysis of nine RCTs to becomes clinically manifested in the form of chronic be no better than sham surgery or conservative injuries. One goal of regenerative medicine treatment treatment (18,19). is to augment the anabolic environment through the stimulation of native and natural processes. Opioid therapy has also long been a mainstay of treatment for chronic non-neoplastic musculoskeletal pain. However, chronic narcotic therapy has inadvertently contributed to a national epidemic of opioid-related deaths (20) in addition to the known adverse effects of opioid-induced hyperalgesia, constipation, and lack of long-term efficacy or improved quality of life (21). These publications in high-impact peer reviewed medical journals may cause physicians treating musculoskeletal disorders to consider potential alternative treatments, including safe, physiologically sound treatment options that are supported by reasonable medical evidence. The regenerative medicine treatment model focuses on shifting the balance from catabolism and tissue degeneration towards anabolism and tissue repair on a local and regional level. The body is capable of self-repair. In the setting of chronic injury there are several reasons for inadequate or failed self-repair: Dr. Sean Mulvaney performing an ultrasound-guided bone marrow aspirate concentrate injection. Endurance and Sports Medicine • Fall/Winter 2018 7 Many regenerative medicine techniques rely on chronic repetitive actions) allows the joints and spine precise injections of autologous, allogeneic or to move beyond their intended physiologic parameters. proliferative agents that initiate (or re-initiate) a This disproportionate motion then leads to pathologic productive healing cascade by stimulating a repair responses such as annular ligament tears resulting response. Often this is accomplished by initiating an in vertebral disc bulges, or cartilage degradation and acute inflammatory reaction in the target tissue. This osteophyte generation resulting in osteoarthritis. focuses the body’s ability to heal itself by providing In typical scenarios that produce chronic pain, this initial injury debridement through the action of slowly progressive ligamentous laxity does not induce macrophages and induces the proliferative phase of a productive healing response. Prolotherapy has tissue repair, among many other key functions (24). generally been used as a regional modality, insofar as This inflammatory phase lasts for 10 days. This is many ligaments work in concert to prevent abnormal followed by the proliferative healing phase, lasting joint motion. It is also used in tendinopathies (31). 30 days, and that involves chemical messengers released from the injury site that recruit fibroblasts to The most studied “proliferant” solution is 15% the injury site and induce angiogenesis at the site to dextrose, although other agents have been used. facilitate tissue repair. The final phase of tissue healing When injected in or