Platelet-rich plasma is “a volume of plasma that has a platelet count above baseline.”21 Simplified, PRP comprises an increased concentration of platelets suspended in a small quantity of plasma. These platelets release a directly proportional quantity of cytokines, which are delivered to the injury to facilitate healing.21 Consequently, PRP has been promoted as a means to accelerate the biological healing cascade and optimize tissue repair and regeneration through the release of growth factors.
When activated, platelets release cytokines, such as platelet-derived growth factor,22 transforming growth factor-β,23 insulin-like growth factor-1 and -2,23 epidermal growth factor,23 vascular endothelial growth factor,23 and fibroblast growth factor.23 Recent research has confirmed that these bioactive molecules are capable of inducing angiogenesis and accelerating tendon healing.24,25
Despite the proven safety of PRP in the rotator cuff,16 the efficacy of PRP application during rotator cuff repair remains to be elucidated. The findings of Castricini et al19 suggest that PRP provides no clinical or structural advantage compared with traditional rotator cuff repair. Conversely, Barber et al26 reported that suturing 2 PRP fibrin matrices during rotator cuff repair reduced the incidence of re-tear rates and improved clinical outcomes. However, these discrepancies may be attributable to variations in PRP preparation. As PRP popularized, the heterogeneity of PRP increased, potentially altering its effectiveness.27 Nevertheless, the possibility exists that a specific PRP preparation may optimize the healing response of the rotator cuff.
Mesenchymal Stem Cells
Mesenchymal stem cells are nonhematopoietic multipotent cells that differentiate into tissue-forming cell lineages, such as osteoblasts, adipocytes, chondrocytes, tenocytes, and myocytes.28,29 To date, no specific marker for stem cells has been isolated, although positive and negative markers have been identified. Positive markers include CD44, -73, -90, -105, -166 and STRO-1, whereas negative markers are CD34 and -45 and HLA-DR.30 It is important to note that CD45 is not only expressed on hematopoietic cells but is also required for T- and B-cell activation. In the absence of CD45 and MHC-II,30,31 MSCs do not have an antigenic component, which allows allogenic MSCs to be applied without subsequent immunogenic reactions.
Bone marrow is the traditional source of human MSCs, but recently placental tissue has been studied as an alternative. Compared with bone marrow–derived MSCs, placenta-derived MSCs present with similar morphology, size, cell surface phenotype, characteristic MSC markers, and growth characteristics32,33 with no detection of the hematopoietic markers CD34, CD45, and HLA-DR.32,34,35 Furthermore, placenta-derived MSCs are capable of providing multipotent differentiation32,36,37 and possess beneficial immunosuppressive capabilities.32,35 In contrast with bone marrow derived MSCs, placenta-derived MSCs less readily differentiate into adipogenic cells, favor osteogenic differention, and consistently grow faster and more robustly.33 The characteristics of placenta derived MSCs may advance tendon healing.
Mesenchymal stem cells improve tissue repair through 2 suggested mechanisms: direct differentiation and paracrine signaling. Although MSCs regenerate damaged tissue by differentiating into tenocytes, chondrocytes, and osteoblasts, paracrine signaling regulates the local cellular environment by releasing biologically active molecules, such as growth factors.
During the inflammatory and proliferative phases of wound healing, growth factors regulate cell migration, proliferation, differentiation, and matrix synthesis. Shortly after tendon damage, platelet-derived growth factor is produced, which has been shown to stimulate the production of additional growth factors and play a role in tissue remodeling.38 During the early inflammatory phase, insulin-like growth factor-1 and transforming growth factor-β increase activity. Increased expression of insulin-like growth factor-1 and transforming growth factor-β has been shown to aid in cellular migration and proliferation, which subsequently increases collagen production.39
Directly following the inflammatory phase, vascular endothelial growth factor is produced at its highest levels. At this time, both vascular endothelial growth factor and basic fibroblast growth factor potently stimulate angiogenesis.39 Basic fibroblast growth factor regulates cellular migration and proliferation.40 With these dynamic properties, MSCs are ideal candidates to promote repair and healing. Given their potential to catalyze healing and tissue repair, MSCs have spiked an increasing interest.
Recent animal studies have demonstrated that MSCs can facilitate tendon healing.41–44 In rabbit Achilles tendon models, MSCs were shown to improve load and material properties through the reorganization of collagen fibers.42,45 Furthermore, in a rabbit anterior cruciate ligament model enhanced with MSCs, biomechanical and histological testing revealed restoration of normal cartilage histology and resulted in higher failure loads.43,44 However, only 1 known study has researched the use of MSCs to augment rotator cuff repair.46
As opposed to previous studies, MSC activity did not translate into improved biomechanical strength or organized cartilage structure and composition. However, the animals were only evaluated at 2 and 4 weeks, negating all long-term benefits. Encouragingly, Gulotta et al46 suggested that a combination of MSCs and mechanical reinforcement or growth factors may influence success rates.
Dermal allografts are derived from human skin recovered from either live or cadaveric donation. Donor tissue screening and preparation processes are performed to meet the guidelines established by sources such as the American Association of Tissue Banks to reduce the risk of disease transmission and to minimize contamination and cross-contamination. Typically, allograft tissue undergoes serological and nucleic acid testing prior to release for transplantation. The skin is processed to remove cellular components to prevent host rejection while maintaining the native biomechanical, biochemical, and collagen matrix structure. Lysis of cells, removal of cellular debris, and decontamination are essential to the process. The acellular nature of the tissue decreases the chances of immunogenic reactions.47 By retaining the natural collagen structure and mechanical properties, the final dermal allografts are designed to provide strength and serve as an extracellular matrix scaffold that allows for cell attachment, cell proliferation, and neovascularization for tissue remodeling.48,49 Despite the wide application of dermal allografts in areas such as general surgery and plastic and reconstructive surgery, few studies have investigated its use in rotator cuff repairs.49–52
Preliminary studies confirmed the safety and effectiveness of dermal allograft application to augment human rotator cuff healing.50,51 Magnetic resonance imaging indicated full incorporation of the graft into native tissue.51 In a subsequent histological evaluation of a biopsy specimen obtained 3 months after rotator cuff augmentation with a human dermal scaffold, Snyder et al49 reported cellular infiltration, alignment of collagen fibers, and blood vessel ingrowth. These results show that dermal allografts elicit histologic and morphologic remodeling in rotator cuff repair.
Barber et al52 conducted a randomized, controlled trial to evaluate acellular human dermal matrix application to repair large (>3 cm) rotator cuff tears involving 2 tendons. Acellular human dermal allograft application resulted in a higher percentage of intact repairs. Presumably, rotator cuff repair coupled with biologic augmentation offers a safe and effective treatment for large and massive rotator cuff tears.