Rotator cuff disease accounts for >4.5 million annual visits to a physician, and >75,000 rotator cuff repairs are performed each year in the United States.1 Authors of a cadaver study found a 6% incidence of full-thickness rotator cuff tears in persons aged <60 years and a 30% incidence of full-thickness rotator cuff tears in those aged >60 years.2 Despite improvements in pain and function following rotator cuff repair, tendon failure has historically been reported to be 11% to 95% at 2-year follow-up, with higher failure rates associated with biomechanically inferior techniques as well as massive tears.3–8 Although a variety of biologic and pharmacologic adjuvants has been suggested in an attempt to improve rotator cuff tendon healing, the efficacy of many of these agents has not been proved.
The rotator cuff tendon is composed primarily of type I collagen; the basic cellular unit is the tenocyte, also known as the fibroblast. The blood supply to the rotator cuff tendon is dense at its origin in the muscle belly, but the size and number of vessels decrease closer to the humeral insertion.9 As the rotator cuff tendon inserts to the proximal humerus, there is the transition of four distinct tissue zones: tendon, nonmineralized fibrocartilage, mineralized fibrocartilage, and bone. None of the current repair strategies replicates this normal transitional zone, a fact that may par- tially explain why healing does not always occur after rotator cuff repair.
Tendon heals in three overlapping stages by both intrinsic (cells from within the tendon) and extrinsic (cells from the paratenon) mechanisms: inflammatory, fibroblastic, and remodeling.10,11 The inflammatory stage occurs within the first week after repair. It is characterized by deposition of fibrin and fibronectin by platelets. These platelets secrete insulin-like growth factor-1, plateletderived growth factor (PDGF), and transforming growth factor (TGF)-β, which recruit macrophages and neutrophils. Macrophages then secrete TGF-β1, which promotes the formation of scar tissue. The fibroblastic stage begins within 48 hours of repair and lasts approximately 8 weeks. During this period, fibroblasts produce primarily type III collagen. Finally, during the remodeling stage, some of the type III collagen is remodeled to type I, resulting in a more organized matrix. Although these three stages predictably occur following rotator cuff repair, the tissue formed is inferior in quality compared with that of the native rotator cuff.11,12 Instead of four distinct zones, as in the native tendon, the repaired tendon is largely composed of fibrovascular scar tissue with a large proportion of type III collagen.13
A successful repair of the rotator cuff ideally requires ingrowth of the tendon into bone;14 however, a modestly organized fibrovascular scar tissue layer likely remains between the tendon and bone, serving as a bridge between these structures.
Despite improvements in surgical techniques and postoperative management, failure of rotator cuff repair is common.3,4,6 Failure to restore normal histology at the repair site, intrinsic tendon degeneration, fatty infiltration of tendon and muscle, and muscle atrophy may contribute to failure after rotator cuff repair. Surgical techniques that seek to improve tendon-to-bone healing through better fixation devices, pattern of suture repair, and improved arthroscopic knots have been developed to increase repair strength; still, a rerupture rate of 12% has been observed.5
In addition to improving the strength of the repair construct, investigators have explored novel adjuvants to aid rotator cuff healing in hopes of reducing failure rates. One field of investigation has been the use of growth factors to aid in cell chemotaxis and proliferation, matrix synthesis, and cell differentiation. Würgler-Hauri et al15 studied the temporal expression of eight different growth factors by means of immunoassays in the repair of the supraspinatus in the Sprague-Dawley in vivo rat model. They investigated basic fibroblastic growth factors (bFGFs); bone morphogenetic protein (BMP)-12, -13, and -14; cartilage oligomeric matrix protein; connective tissue growth factors (CTGFs), PDGF, and TGF-β1.
The results of this study showed an initial increase in growth factor expression, with a return to basal levels over time. Of note, bFGF peaked at 1 week and then increased again at 8 weeks postoperatively, suggesting both an early and a late increase in tenocyte proliferation. BMP-12 and CTGF were moderately expressed across all time points. Cartilage oligomeric matrix protein peaked at 1 week and then decreased in expression by 2 weeks. During the remodeling phase, growth factor expression increased again, particularly in the midsubstance of the tendon. This elevation of growth factors in the later stage is thought to be the result of increased load at the tendon-bone junction with mobilization and stress on the repair.15
BMP has been analyzed as a biologic adjuvant for rotator cuff repairs. Rodeo et al16 investigated the use of a mixture of osteoinductive growth factors (ie, BMPs 2 through 7, TGF-β1-3, FGF) to improve the healing of tendon to bone in an in vivo sheep model. Despite the presence of gapping between the rotator cuff tendon and bone on MRI, histology revealed an increase in bone and soft-tissue formation at the repair site, and biomechanical testing demonstrated a stronger repair at both 6 and 12 weeks in the experimental group. This was one of the first rotator cuff studies to show that a biologic adjuvant could increase tissue formation between tendon and bone.
BMP-12 and -13 have been shown to play a role in normal tendon regeneration.17 Seeherman et al18 inves- tigated the role of recombinant human BMP-12 (rhBMP-12) in the in vivo repair of rotator cuffs in sheep. These growth factors are expressed during development to form tendons and their insertions.19 The investigators found that animals treated with rhBMP-12 delivered via a type I/III collagen sponge had rotator cuffs with greater maximal tensile load and stiffness compared with the sponge carrier alone or with untreated repairs. They postulated that the carrier allows for a more controlled retention and release of osteoinductive growth factors, in addition to serving as a scaffold for cellular and vascular ingrowth. Histologic analysis showed collagen fiber continuity between bone and fibrovascular interface scar tissue, with an increase in glycosaminoglycan levels. There was a positive correlation between the amount of glycosaminoglycan and the maximum load to failure.18
FGFs are known for their role in angiogenesis and mesenchymal cell mitogenesis. FGF-2 induces early inflammatory cells to form granulation tissue and promote soft-tissue remodeling. It has been hypothesized that FGF-2 induces the TGF-β gene in vivo and, in doing so, initiates the release of TGF-β and BMP, which may aid in bony ingrowth. Ide et al20 showed that FGF-2 accelerated bone ingrowth at the supraspinatus repair site in an in vivo Sprague-Dawley rat model. Rats treated with FGF-2 demonstrated improved biomechanical properties and better histologic scores at 2 weeks compared with the untreated group. However, these differences were not confirmed at 4 and 6 weeks after repair.20
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that maintain and remodel the extracellular matrices of connective tissue. They work intimately with tissue inhibitors of matrix metalloproteinases to maintain homeostasis of the extracellular matrices between reparative and degradative states. When these inhibitors are not present, homeostasis is lost, which may lead to degenerative tendinopathy of the rotator cuff. In an in vivo rat model, Bedi et al21 performed two investigations with two separate tissue inhibitors of matrix metalloproteinases (doxycycline and recombinant α-2-macroglobulin [A2M] protein). The group treated with doxycycline had higher MMP levels immediately after surgery, but MMP expression decreased to basal levels by week 4.21 The group treated with doxycycline was also found to heal with increased fibrocartilage and collagen organization at the rotator cuff repair site and had increased biomechanical load-to-failure compared with the control group. Rats treated with A2M showed a decrease in local collagen degradation, an increase in new fibrocartilage at 2 weeks, and greater collagen organization at 4 weeks.22 Despite this improved histologic makeup, biomechanical testing did not demonstrate a difference in strength, suggesting that better collagen organization does not necessarily translate into improved strength.
Several studies have investigated the use of platelet-rich plasma (PRP) during rotator cuff repair. Randelli et al23 examined the safety and efficacy of in vivo PRP augmentation in 14 patients undergoing arthroscopic rotator cuff repairs. Following irrigation, PRP with thrombin was injected onto the footprint of the tendon. There were no adverse events with these injections, and the authors found that patients had improvements in Constant, visual analog scale (VAS), and University of California Los Angeles shoulder scores at a mean follow-up of 2 years com pared with preoperative values. In this study, there was no control group of repair without PRP augmentation; therefore, it is unclear whether the PRP was the variable that improved function and rotator cuff healing24 (Table 1).
Rodeo et al25 investigated the in vivo application of platelet-rich fibrin matrix (PRFM), a PRP variant created by using calcium chloride and a second round of centrifugation that activates the fibrin-clotting cascade, thus theoretically allowing for a sustained release of cytokines. Sixty-seven patients were randomized to receive either PRFM with rotator cuff repair (36 patients) or rotator cuff repair without biologic augmentation (31 patients). The PRFM was placed on the suture at the interface between the tendon and the greater tuberosity. Patients were evaluated at 6 and 12 weeks by ultrasonography to assess tendon healing and vascularity. The PRFM group repairs were intact in 24 of 36 shoulders (67%), compared with 25 of 31 shoulders (81%) in the control group (P = 0.03), suggesting that PRFM may actually be detrimental to healing of the rotator cuff. Additionally, there was no difference in vascularity between the two groups. American Shoulder and Elbow Surgeons and L'Insalata scores increased with time in both groups, but there was no statistical difference between the groups.
Weber and Kauffman26 also evaluated PRFM in a prospective, randomized in vivo trial with 60 patients. PRFM was not found to significantly increase perioperative morbidity. Additionally, postoperative MRI studies in both groups showed structural integrity with residual defects that were similar. Early VAS scores and postoperative narcotic use did not demonstrate a significant difference. Finally, the average surgical time was longer in the PRFM group (P < 0.02).
Castricini et al27 performed a randomized controlled trial that assessed the efficacy of in vivo PRFM in 87 patients with small and medium-sized tears with a minimum 16-month follow-up. The authors evaluated their patients with Constant shoulder scores and assessed the integrity of the repair by MRI. Their study did not demonstrate superior clinical or structural performance in the group that received PRFM compared with those who did not. Anderson and Anziano28 retrospectively explored the clinical outcomes of patients treated with in vivo PRFM to augment arthroscopic rotator cuff repair. Compared with patients in the control group, those in the experimental group were found to have reduced pain and improved sleep.
Previous investigation has shown that, in the setting of supraspinatus tendon injury, accelerated bone loss occurs at the insertion site, particularly with delayed repairs.29 This deterioration in bone density is thought to play a significant factor in poor rotator cuff healing. Cadet et al30 performed bilateral ovariectomies in 24 Sprague-Dawley rats. Twelve of the subjects were treated with diphosphonates, and 12 were used for control. Estrogen deficiency in the control rats caused bone loss at the footprint but did not affect the overall bone mineral density. The control rats had an increase in stiffness of the supraspinatus. Enthesis changes were noted to mimic earlier stages of embryologic development, suggesting that the enthesis responds to hormonal effects. Additionally, it was found that diphosphonates increased bone mineral density at the footprint, which allowed for an improved load to failure despite poor fibrocartilage organization on histologic analysis. The presence of bone loss in the control group did not show a decrease in load to failure.30 Further investigation is necessary to determine whether diphosphonates favorably affect the enthesis and allow for a stronger repair.
Tissue Engineering, Stem Cells, and the Future
Gene therapy is the transfer of a specific gene from one cell into another so that the second cell will upregulate the expression of the desired gene.31 By placing gene-modified pluripotent muscle-derived cells into a rotator cuff repair site (Figure 1), it may be possible to modify the supraspinatus tendon and cause accelerated regeneration. Pelinkovic et al32 examined the ability to deliver muscle-derived cells into the supraspinatus in an in vivo athymic rat model. These cells were isolated from a neonatal mdx mouse, replicated, and injected into the supraspinatus tendon. The native supraspinatus tissue was able to differentiate the muscle-derived cells to form fibroblasts. Although these results are encouraging, it remains to be seen whether they can be safely and effectively used in humans.
Uggen et al33 transduced rat tendon fibroblasts with the genes for either insulin-like growth factor-1 or PDGF-β via retroviral vectors in an ex vivo Sprague-Dawley rat model. These cells were cultured and then seeded onto a bioabsorable scaffold. Rats underwent surgical transection of the supraspinatus; 2 weeks later, the supraspinatus was repaired with either a basic suture repair (control) or a tissue-engineered scaffold (experimental). PDGF-β scaffold with suture showed near complete restoration of the tendon, suggesting that therapeutic growth factors can be engineered to deliver restorative peptides and stimulate a healing response.
Although previous studies have shown that mesenchymal stem cells (MSCs) from bone marrow aid in the healing of tendon in a bone tunnel,34,35 Gulotta et al36 were not able to demonstrate superior healing when MSCs were used in an in vivo rat rotator cuff repair model. It appears that simply adding MSCs to a repair site does not improve the structure or strength of rotator cuff repair. Rather, the authors felt that improved cellular signaling to induce appropriate differentiation of the stem cells might be able to improve fibrocartilage formation.
By combining stem cells with tissue engineering in an ex vivo rat model, Gulotta et al37 evaluated MSCs and MSCs treated with adenoviral-mediated gene transfer of human BMP-13 (Ad-BMP-13). It was hypothesized that the Ad-BMP-13 would improve fibrocartilage proliferation and collagen organization at the footprint. However, histologic and biomechanical analysis did not show a difference in the amount of cartilage formed, collagen organization, or improvement in strength, load to failure, or stiffness.
Scleraxis (Scx) is a transcription factor for tendon development and regeneration in utero. Additionally, it is believed that overexpression of Scx in osteoblastic cell lines may induce chondrocyte-specific gene expression. These properties offer a potential way to improve rotator cuff repairs because the transition zone consists of both tendon and cartilage. Gulotta et al38 transduced MSCs with adenoviral-mediated scleraxis (Ad-Scx) and compared this to rats treated with MSCs alone. Results at 2 weeks showed no histologic difference, although improved biomechanical properties of the Ad-Scx-treated rats were demonstrated. Compared with the controls at 4 weeks, there was more fibrocartilage at the insertion site that resembled the native rotator cuff, in addition to better biomechanical properties.
Moffat et al39 investigated the use of a biphasic nanofiber scaffold to assist rotator cuff repairs in an in vivo Lewis rat model. This scaffold contained both nonmineralized and mineralized regions. Analysis of the repair site showed that chondrocytes were viable. Additionally, a collagen/proteoglycan matrix was deposited on both phases of the scaffold. Immunostaining showed that types I and II collagen were present in this healing tissue. The rats repaired with the scaffold showed an organized fibrocartilage-like transition zone, whereas fibrovascular tissue was observed in the control group, suggesting that a biphasic scaffold may aid in rotator cuff repair.
Rotator cuff tendon healing is one of the unsolved problems facing orthopaedic surgeons. Recent animal studies have demonstrated that growth factors and stem cells might play a role in rotator cuff healing and have the potential to revolutionize the manage ment of rotator cuff tears. Further clinical and laboratory investigation is necessary to delineate how these factors can best be modulated. Despite its prevalent use, PRP has failed to show clinical benefits. The future of management of rotator cuff disease will likely rely on optimizing the biologic environment for rotator cuff healing in hopes of improving patient outcomes following rotator cuff repair.
Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, references 1 and 25-27 are level II studies. References 3-8 and 30 are level III studies. References 2, 23, and 28 are level IV studies. References 24 and 31 are level V expert opinion.
References printed in bold type are those published within the past 5 years.
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26. Weber SC, Kauffman JI: Platelet-rich fibrin matrix in arthroscopic rotator cuff repair: A prospective, randomized study. Presented at the 77th Annual Meeting of the American Academy of Orthopaedic Surgeons, New Orleans, Louisiana, March 9-13, 2010.
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33. Uggen JC, Dines J, Uggen CW, et al: Tendon gene therapy modulates the local repair environment in the shoulder. J Am Osteopath Assoc
34. Lim JK, Hui J, Li L, Thambyah A, Goh J, Lee EH: Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction. Arthroscopy
35. Ouyang HW, Goh JC, Lee EH: Use of bone marrow stromal cells for tendon graft-to-bone healing: Histological and immunohistochemical studies in a rabbit model. Am J Sports Med
36. Gulotta LV, Kovacevic D, Ehteshami JR, Dagher E, Packer JD, Rodeo SA: Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am J Sports Med
37. Gulotta LV, Kovacevic D, Packer JD, Ehteshami JR, Rodeo SA: Adenoviralmediated gene transfer of human bone morphogenetic protein-13 does not improve rotator cuff healing in a rat model. Am J Sports Med
38. Gulotta LV, Kovacevic D, Packer JD, Deng XH, Rodeo SA: Bone marrowderived mesenchymal stem cells transduced with scleraxis improve rotator cuff healing in a rat model. Am J Sports Med
39. Moffat KL, Zhang X, Greco S, et al: In vitro and in vivo evaluation of a biphasic nanofiber scaffold for integrative rotator cuff repair. Transactions of the Orthopaedic Research Society