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.
Chondral injury is a particularly important subject given the limited potential of chondrocytes to replicate or migrate to the site of pathology.49 Stem cell use in this setting assists with programmed growth factor release and alteration of the anatomic microenvironment to facilitate regeneration and repair of the chondral surface. Autologous stem cell use through microfracture provides a perforation into the bone marrow and a subsequent fibrin clot formation containing platelets, growth factors, vascular elements, and MSCs.50 A similar concept to PRP is currently being explored with bm-MSCs. Isolated bm-MSCs are commonly referred to as bone marrow aspirate or bone marrow aspirate concentrate (BMAC). Commercially available systems are now available to aid in the harvesting and implementation of BMAC. One of the more promising avenues for BMAC implementation is in articular cartilage repair or regeneration due to chondrogenic potential of BMAC when used in isolation or when combined with microfracture, chondrocyte transfer, or collagen scaffolds.19,51 Synovial-derived stem cells as an additional source for stem cell use has demonstrated excellent chondrogenic potential in animal studies with full-thickness lesion healing and native-appearing cartilage histologically.52 Incorporation of a-MSCs into scaffolds for surgical implantation has demonstrated success in repairing full-thickness chondral defects with continuous joint surface and extracellular proteins, surface markers, and gene products similar to the native cartilage in animal models.53,54 In light of the promising basic science and animal studies, clinical studies have begun to emerge.55-57
Fortier and colleagues58 found MRI and histologic evidence of full-thickness chondral repair and increased integration with neighboring cartilage when BMAC was concurrently used at the time of microfracture in an equine model. Fortier and colleagues58 also demonstrated greater healing in equine models with acute full-thickness cartilage defects treated by microfracture with MSCs than without delivery of MSCs. Kim and colleagues59,60 similarly reported superiority in clinical outcomes for patients with osteochondral lesions of the talus treated with marrow stimulation and MSC injection than by the former in isolation.
In humans, stem cell use for chondral repair has additionally proven promising. A systematic review of the literature suggested good to excellent overall outcomes for the treatment of moderate focal chondral defects with BMAC with or without scaffolds and microfracture with inclusion of 8 total publications.61 This review included Gobbi and colleagues,62 who prospectively treated 15 patients with a mean focal chondral defect size of 9.2 cm2 about the knee. Use of BMAC covered with a collagen I/III matrix produced significant improvements in patient-reported outcome scores and MRI demonstrated complete hyaline-like cartilage coverage in 80%, with second-look arthroscopy demonstrating normal to nearly normal tissue. Gobbi and colleagues55 also found evidence for superiority of chondral defects treated with BMAC compared to matrix-induced autologous chondrocyte implantation (MACI) for patellofemoral lesions in 37 patients (MRI showed complete filling of defects in 81% of BMAC-treated patients vs 76% of MACI-treated patients).
Meniscal Repair
Clinical application of MSCs in the treatment of meniscal pathology is evolving as well. ASCs have been added to modify the biomechanical environment of avascular zone meniscal tears at the time of suture repair in a rabbit, and have demonstrated increased healing rates in small and larger lesions, although the effect lessens with delay in repair.63 Angele and colleagues64 treated meniscal defects in a rabbit model with scaffolds with bm-MSCs compared with empty scaffolds or control cohorts and found a higher proportion of menisci with healed meniscus-like fibrocartilage when MSCs were utilized.
In humans, Vangsness and colleagues30 treated knees with partial medial meniscectomy with allogeneic stem cells and reported an increase in meniscal volume and decrease in pain in those patients when compared to a cohort of knees treated with hyaluronic acid. Despite promising early results, additional clinical studies are necessary to determine the external validity and broad applicability of stem cell use in meniscal repair.
Rotator Cuff Repair
The number of local resident stem cells at the site of rotator cuff tear has been shown to decrease with tear size, chronicity, and degree of fatty infiltration, suggesting that those with the greatest need for a good reparative environment are those least equipped to heal.65 The need for improvement in this domain is related to the still relatively high re-tear rate after rotator cuff repair despite improvements in instrumentation and surgical technique.66 The native fibrocartilaginous transition zone between the humerus and the rotator cuff becomes a fibrovascular scar tissue after rupture and repair with poorer material properties than the native tissue.67 Thus, a-MSCs have been evaluated in this setting to determine if the biomechanical and histological properties of the repair may improve.68
