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.
In rat models, Valencia Mora and colleagues68 reported on the application of a-MSCs in a rat rotator cuff repair model compared to an untreated group. They found no differences between those treated rats and those without a-MSCs use in terms of biomechanical properties of the tendon-to-bone healing, but those with stem cell use had less inflammation shown histologically (diminished presence of edema and neutrophils) at 2- and 4-week time points, which the authors suggested may lead to a more elastic repair and less scar at the bone-tendon healing site. Oh and colleagues1 evaluated the use of a-MSCs in a rabbit subscapularis tear model, and reported significantly reduced fatty infiltration at the site of chronic rotator cuff tear after repair with its application at the repair site; while the load-to-failure was higher in those rabbits with ASCs administration, it was short of reaching statistical significance. Yokoya and colleagues69 demonstrated regeneration of rotator cuff tendon-to-bone insertional site anatomy and in the belly of the cuff tendon in a rabbit model with MSCs applied at the operative site. However, Gulotta and colleagues70 did not see the same improvement in their similar study in the rat model; these authors failed to see improvement in structure, strength, or composition of the tendinous attachment site despite addition of MSCs.
Clinical studies on augmented rotator cuff repair have also found mixed results. MSCs for this purpose have been cultivated from arthroscopic bone marrow aspiration of the proximal humerus71 and subacromial bursa72 with successful and reproducibly high concentrations of stem cells. Hernigou and colleagues73 found a significant improvement in rate of healing (87% intact cuffs vs 44% in the control group) and repair surface tendon integrity (via ultrasound and MRI) for patients at a minimum of 10 years after rotator cuff repair with MSC injection at the time of surgery. The authors found a direct correlation in these outcomes with the number of MSCs injected at the time of repair. Ellera Gomes and colleagues74 injected bm-MSCs obtained from the iliac crest into the tendinous repair site in 14 consecutive patients with full-thickness rotator cuff tears treated by transosseous sutures via a mini-open approach. MRI demonstrated integrity of the repair site in all patients at more than 1-year follow-up.
Achilles Tendon Repair
The goal with stem cell use in Achilles repair is to accelerate the healing and rehabilitation. Several animal studies have demonstrated improved mechanical properties and collagen composition of tendon repairs augmented with stem cells, including Achilles tendon repair in a rat model. Adams and colleagues75 compared suture alone (36 tendons) to suture plus stem cell concentrate injection (36 tendons) and stem cell loaded suture (36 tendons) in Achilles tendon repair with rat models. The suture-alone cohort had lower ultimate failure loads at 14 days after surgery, indicating biomechanical superiority with stem cell augmentation means. Transplantation of hypoxic MSCs at the time of Achilles tendon repair may be a promising option for superior biomechanical failure loads and histologic findings as per recent rat model findings by Huang and colleagues.76 Yao and colleagues77 demonstrated increased strength of suture repair for Achilles repair in rat models at early time points when using MSC-coated suture in comparison to standard suture, and suggested that the addition of stem cells may improve early mechanical properties during the tendon repair process. A-MSC addition to PRP has provided significantly increased tensile strength to rabbit models with Achilles tendon repair as well.78
In evaluation of stem cell use for this purpose with humans, Stein and colleagues79 reviewed 28 sports-related Achilles tendon ruptures in 27 patients treated with open repair and BMAC injection. At a mean follow-up of 29.7 months, the authors reported no re-ruptures, with 92% return to sport at 5.9 months, and excellent clinical outcomes. This small cohort study found no adverse outcomes related to the BMAC addition, and thus proposed further study of the efficacy of stem cell treatment for Achilles tendon repair.
Anterior Cruciate Ligament Reconstruction
Bm-MSCs genetically modified with bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) have shown great promise in improvement of the formation of mechanically sound tendon-bone interface in anterior cruciate ligament (ACL) reconstruction.80 Similar to the other surgical procedures mentioned in this review, animal studies have successfully evaluated the augmentation of osteointegration of tendon to bone in the setting of ACL reconstruction. Jang and colleagues3 investigated the use of nonautologous transplantation of human umbilical cord blood-derived MSCs in a rabbit ACL reconstruction model. The authors demonstrated a lack of immune rejection, and enhanced tendon-bone healing with broad fibrocartilage formation at the transition zone (similar to the native ACL) and decreased femoral and tibial tunnel widening as compared to a control cohort at 12-weeks after surgery. In a rat model, Kanaya and colleagues81 reported improved histological scores and slight improvements in biomechanical integrity of partially transected rat ACLs treated with intra-articular MSC injection. Stem cell use in the form of suture-supporting scaffolds seeded with MSCs has been evaluated in a total ACL transection rabbit model; the authors of this report demonstrated total ACL regeneration in one-third of samples treated with this augmentation option, in comparison to complete failure in all suture and scaffold alone groups.82
