Bryan M. Saltzman, MD, Benjamin D. Kuhns, MD, MS, Alexander E. Weber, MD, Adam Yanke, MD, and Shane J. Nho, MD, MS
Authors’ Disclosure Statement: Dr. Saltzman reports that he receives royalties from Nova Science Publishers and Postgraduate Institute for Medicine. Dr. Yanke reports that he receives research support from Arthrex and NuTech. Dr. Nho reports that he receives research support from Allosource, Arthrex, Athletico, DJ Orthopaedics, Linvatec, Miomed, Smith & Nephew, and Stryker; is on the editorial/governing board of The American Journal of Orthopedics; is on the board of the American Orthopaedic Society for Sports Medicine and the Arthroscopy Association of North America; is a paid consultant for Ossur and Stryker; and receives publishing royalties from Springer. The other authors report no actual or potential conflict of interest in relation to this article.
Following harvesting, isolation, and expansion, MSC delivery methods for treatments typically consist of either cell-based or tissue engineering approaches. Cell-based techniques involve the injection of MSCs into damaged tissues. Purely cell-based therapy has shown success in limited clinical trials involving knee osteoarthritis, cartilage repair, and meniscal repair.28-30 However, additional studies with longer follow-up are required to validate these preliminary findings. Tissue engineering approaches involve the construction of a 3-dimensional scaffold seeded with MSCs that is later surgically implanted. While promising in theory, limited and often conflicting data exist regarding the efficacy of tissue-engineered MSC implantation.31-32 Suboptimal scaffold vascularity is a major limitation to scaffold design, which may be alleviated in part with the advent of 3-dimensional printing and the ability to more precisely alter scaffold architecture.14,33 Additional limitations include ensuring MSC purity and differentiation potential following harvesting and expansion. At present, the use of tissue engineering with MSCs is promising but it remains a nascent technology with additional preclinical studies required to confirm implant efficacy and safety.
Clinical Entities
Osteoarthritis
MSC therapies have emerged as promising treatment strategies in the setting of early osteoarthritis (OA). In addition to their regenerative potential, MSCs demonstrate potent anti-inflammatory properties, increasing their attractiveness as biologic agents in the setting of OA.34 Over the past decade, multiple human trials have been published demonstrating the efficacy of MSC injections into patients with OA.35,36 In a study evaluating a-MSC injection into elderly patients (age >65 years) with knee OA, Koh and colleagues29 found that 88% demonstrated improved cartilage status at 2-year follow-up, while no patient underwent a total knee arthroplasty during this time period. In another study investigating patients with unicompartmental knee OA with varus alignment undergoing high tibial osteotomy and microfracture, Wong and colleagues37 reported improved clinical, patient-reported, and magnetic resonance imaging (MRI)-based outcomes in a group receiving a preoperative MSC injection compared to a control group. Further, in a recent randomized control trial of patients with knee osteoarthritis, Vega and colleagues38 reported improved cartilage and quality of life outcomes at 1 year following MSC injection compared to a control group receiving a hyaluronic acid injection. In addition to knee OA, studies have also reported improvement in ankle OA following MSC injection.39 While promising, many of the preliminary clinical studies evaluating the efficacy of MSC therapies in the treatment of OA are hindered by small patient populations and short-term follow-up. Additional large-scale, randomized studies are required and many are ongoing presently in hopes of validating these preliminary findings.36
Tendinopathy
The quality of repaired tissue in primary tendon-to-tendon and tendon-to-bone healing has long been a topic of great interest.40 The healing potential of tendons is inferior to that of other bony and connective tissues,41 with tendon healing typically resulting in a biomechanically and histologically inferior structure to the native tissue.42 As such, this has been a particularly salient opportunity for stem cell use with hopes of recapitulating a more normal tendon or tendon enthesis following injury. In addition to the acute injury, there is great interest in the application of stem cells to chronic states of injury such as tendinopathy.
In equine models, the effect of autologous bm-MSCs treatment on tendinopathy of the superficial digital flexor tendon has been studied. Godwin and colleagues43 evaluated 141 race horses with spontaneous superficial digital flexor tendinopathy treated in this manner, and reported a reinjury percentage in these treated horses of just 27.4%, which compared favorably to historical controls and alternative therapeutics. Machova Urdzikova and colleagues44 injected MSCs at Achilles tendinopathy locations to augment nonoperative healing in 40 rats, and identified more native histological organization and improved vascularization in comparison to control rat specimens. Oshita and colleagues45 reported histologic improvement of tendinopathy findings in 8 rats receiving a-MSCs at the location of induced Achilles tendinopathy that was significantly superior to a control cohort. Bm-MSCs were used by Yuksel and colleagues46 in comparison with platelet-rich plasma (PRP) for treatment of Achilles tendon ruptures created surgically in rat models. They demonstrated successful effects with its use in terms of recovery for the tendon’s histopathologic, immunohistochemical, and biomechanical properties, related to significantly greater levels of anti-inflammatory cytokines. However, these aforementioned findings have not been uniform across the literature—other authors have reported findings that MSC transplantation alone did not repair Achilles tendon injury with such high levels of success.47
Human treatment of tendinopathies with stem cells has been scarcely studied to date. Pascual-Garrido and colleagues48 evaluated 8 patients with refractory patellar tendinopathy treated with injection of autologous bm-MSCs and reported successful results at 2- to 5-year follow-up, with significant improvements in patient-reported outcome measures for 100% of patients. Seven of 8 (87.5%) noted that they would undergo the procedure again.
