Rotator cuff tears (RCTs) are a common cause of shoulder pain resulting from overuse or injury, often requiring surgical repair. Unfortunately, the rate of persistent tears after surgery remains high due to the hostile biologic environment of the shoulder joint. Muscle atrophy, fibrosis, and fatty degeneration often develop after rotator cuff tears, contributing to high surgical failure rates and poor patient outcomes. In response to the high rate of persistent re-injury following rotator cuff repair, surgeons have employed biologic agents to improve healing at the bone-tendon junction, specifically, mesenchymal stem cells, adipose-derived stem cells, and synthetic and biological patches. While these agents may have some beneficial effects, the literature demonstrating the efficacy of these interventions is limited.
A multidisciplinary team of physician-scientists at Keck Medicine of USC, is investigating the potential of cellular and antifibrotic therapies to improve muscle quality, diminish atrophy, and improve rotator cuff healing. These studies are currently conducted in animal models with hopes of advancing them to clinical trials in the future.
Biological Basis of RCT Repair Failure
An estimated 10% of persons over 60 years are affected by rotator cuff tears, causing significant activity-related pain and decreased quality of life.[4] Over 75,000 rotator cuff repair surgical procedures are performed annually in the United States alone.[5]
While full-thickness rotator cuff tears will not heal on their own, they may become asymptomatic. As such, orthopedic surgeons like Keck Medicine’s Dr. Frank Petrigliano, associate professor of clinical orthopaedic surgery at the Keck School of Medicine of USC and chief of the USC Epstein Family Center for Sports Medicine at Keck Medicine of USC, recommend treating most non-traumatic rotator cuff injuries with a period of nonoperative care—especially considering the high rate of post-surgical anatomic failure. When rotator cuff tears heal via biological repair, it does so by secondary intention, forming scar tissue with biomechanical properties inferior to native tissue—increasing the likelihood of failure.
The subacromial space, which houses several soft tissues, including the rotator cuff, is a hostile biological environment for several reasons: there is no soft tissue envelope to provide a blood supply; the rotator cuff is relatively avascular, with its primary blood supply coming from the bone; and the synovial fluid is rich in matrix metalloproteinase proteins (MPPs).[15] These intrinsic biological factors contribute to rotator cuff pathology and inhibit healing.
Various patient factors adversely affect rotator cuff pathology and healing, including age, nicotine use, diabetes, osteoporosis, high cholesterol, NSAID use, low vitamin D, and tear size. However, advanced age is most closely associated with decreased heating rates after rotator cuff repair due to age-related degenerative changes, decreased microcirculation, and reduced bone healing potential.[10]
Although the patient reported outcomes of rotator cuff repair surgical procedures are generally positive, surgical failures lead to significant morbidity.[1] Failures often require costly revision surgery or salvage procedures such as reverse total shoulder arthroplasty.[2] Muscle atrophy, fatty degeneration, and fibrosis lead to decreased muscle strength and tissue compliance, complicating surgical repair and biological healing. Fibroadipogenesis, the process characterized by fatty degeneration and fibrotic scar formation, correlates with increasing tear size, patient age, and duration of the tear.[3]The leading cause of surgical failure, tendon retears, is strongly associated with muscle atrophy and fatty degeneration; moreover, fatty degeneration is implicated in up to 94% of massive rotator cuff tears.[6]
Biologic Strategies for RCT Repair Enhancement: Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) play a central supportive role in cell differentiation, secreting bioactive factors that are both tropic and anti-inflammatory, which can lead to the activation of local progenitor cell populations. [11] Researchers have attempted to leverage the supportive role of MSCs. Implanted MSCs may stimulate local or distant host cells and direct their participation in the repair process. This anti-inflammatory and immunomodulatory role may help improve tendon-to-bone and tendon-to-tendon healing, stimulate muscle regeneration, and reverse fatty infiltration and muscle atrophy.
Potential options for this cell-based approach include adult-derived stromal cells (bone marrow, adipose tissue, periosteum), induced pluripotent stem cells (formed by “transducing” adipose derived stem cells, bone marrow aspirate, or fibroblasts with transcription factors to encourage pluripotency gene expression), embryonic pluripotent stem cell, or using a stem cell from the tissue of interest.[16] However, cell-based therapies require further study to determine the optimal dose and delivery vehicle. In addition, although gene therapy holds great promise the identification of the ideal vector delivery system has not been determined.
There are a few human studies that use a cell-based approach. However, this approach does seem to be able to heal full-thickness tears. Thus, clinicians may use stem cell therapies to complement surgical repair.
Biologic Strategies for RCT Repair Enhancement: Synthetic and Biological Patches
There are currently a few FDA-approved patches meant to enhance RCT repair. However, these scaffolds only provide structural augmentation; they are not interposition grafts. Irrespective of the origin of the patch, its mechanical properties are inferior to that of the native tendon. Patch interventions work to decrease tension at the repair site by adding a robust scaffold.
Porcine small intestinal submucosa (SIS), a biological extracellular patch, is rarely recommended because of its high rates of incomplete healing, post-operative inflammation, and minimal clinical improvement. There are two classes of acellular dermal extracellular matrix patches---human and porcine. While acellular dermal ECM grafts have demonstrated efficacy in clinical reports, the lack of control groups limits the findings of these studies.[13]
Existing synthetic patches include polyester, Dacron, polypropylene, nylon, polyacrylamide, carbon, and silicon. Although synthetic patches are stronger than biological grafts, they are hardly biocompatible and induce inflammation. Furthermore, there is a lack of clinical studies, especially studies with long-term follow-up.[13]
A promising advancement in patch technology is a bioabsorbable acellular bovine collagen patch that has the potential to deliver biologic agents locally. While rotation patches have shown complete healing of partial articular supraspinatus tendon avulsion (PASTA) lesions, this evidence is limited, and again, the evidence is limited by the lack of a control group.[14] Another limitation of this intervention is that it is expensive, especially when compared to other interventions for RCT.
Experimental Biologic Strategies for RCT Repair Enhancement
The existing biologic strategies for RCT repair enhancement are promising, but hardly transformative as they merely complement surgical intervention. Physician-scientists at Keck Medicine are attempting to improve rotator cuff healing by leveraging cellular and antifibrotic therapies to enhance muscle quality, diminish atrophy, and ultimately improve rotator cuff healing. They seek USC biologic therapies to speed-up patient recovery for those treated non-operatively and improve rotator cuff healing for patients treated operatively. The aging global population, coupled with the high rates of surgical failure and poor patient outcomes, highlights the need to advance this critical research.
Intending to regenerate chronically injured skeletal muscle, the multidisciplinary team of researchers at Keck Medicine has prioritized three areas of study: 1) optimizing purified perivascular cells and related factors to regenerate muscle; 2) identifying the origin of cells that participate in degeneration and fibrosis; and 3) developing antifibrotic therapies to facilitate muscle regeneration. While these experimental therapies have not yet advanced to human trials, they may be more transformative than existing interventions.
About USC Orthopedic Surgery
At USC Orthopaedic Surgery, we provide our patients with exceptional medical care in treating a wide range of orthopaedic disorders, offering expertise in sports medicine; joint preservation and replacement; musculoskeletal oncology; spine care; fracture and trauma care; foot and ankle surgery; and hand surgery.
We have special protocols for pain and physical therapy to shorten length of stay and enhance recovery after surgery. We use robotic surgery to perform minimally invasive procedures to restore mobility and function to our patients. We offer a blend of orthopaedic and microsurgical expertise in the treatment of hand or upper extremity disorders. Our specialists also use a multidisciplinary approach to treat patients with musculoskeletal tumors.
Our focus is on our patients, and our goal is to provide the best care possible throughout Southern California and the West Coast. From diagnosis to rehabilitation, we provide our patients with comprehensive services across the continuum of care so that they can return to a full and healthy life.
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[2]: Shamsudin A., Lam P.H., Peters K., Rubenis I., Hackett L., Murrell G.A.C
Revision versus primary arthroscopic rotator cuff repair: a 2-year analysis of outcomes in 360 patients. Am J Sports Med. 2015; 43: 557-564. http://dx.doi.org/10.1177/0363546514560729
[3]Jensen AR, Kelley BV, Mosich GM, Ariniello A, Eliasberg CD, Vu B, Shah P, Devana SK, Murray IR, Péault B, Dar A, Petrigliano FA. Neer Award 2018: Platelet-derived growth factor receptor ? co-expression typifies a subset of platelet-derived growth factor receptor ?-positive progenitor cells that contribute to fatty degeneration and fibrosis of the murine rotator cuff. J Shoulder Elbow Surg. 2018 Jul;27(7):1149-1161. doi:10.1016/j.jse.2018.02.040. Epub 2018 Apr 10. PMID: 29653843
[4]Eljabu W, Klinger HM, von Knoch M. The natural history of rotator cuff tears: a systematic review. Arch Orthop Trauma Surg 2015;135:1055-61. http://dx.doi.org/10.1007/s00402-015-2239-1
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[6]: Randelli P, Spennacchio P, Ragone V, Arrigoni P, Casella A, Cabitza P. Complications associated with arthroscopic rotator cuff repair: a literature review. Musculoskelet Surg 2012;96:9-16. http://dx.doi.org/ 10.1007/s12306-011-0175-y
[7]: Uezumi A, Fukada S, Yamamoto N, Ikemoto-Uezumi M, Nakatani M, Morita M, et al. Identification and characterization of PDGFR?+ mesenchymal progenitors in human skeletal muscle. Cell Death Dis 2014;5:e1186. http://dx.doi.org/10.1038/cddis.2014.161
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[10]: Nho SJ, Brown BS, Lyman S, Adler RS, Altchek DW, MacGillivray JD. Prospective analysis of arthroscopic rotator cuff repair: prognostic factors affecting clinical and ultrasound outcome. J Shoulder Elbow Surg. 2009 Jan-Feb;18(1):13-20. doi: 10.1016/j.jse.2008.05.045. Epub 2008 Sep 16. PMID: 18799326.
[11]: Murray, I. R., & Péault, B. (2015). Q&A: Mesenchymal stem cells - where do they come from and is it important?. BMC biology, 13, 99. https://doi.org/10.1186/s12915-015-0212-7
[12]: Canapp Sherman O., Canapp Debra A., Ibrahim Victor, Carr Brittany Jean, Cox Catherine, Barrett Jennifer G.The Use of Adipose-Derived Progenitor Cells and Platelet-Rich Plasma Combination for the Treatment of Supraspinatus Tendinopathy in 55 Dogs: A Retrospective Study. Frontiers in Veterinary Science. 2016 Sept; 3. doi:10.3389/fvets.2016.00061
[13]:Ciampi P, Scotti C, Nonis A, et al: The benefit of synthetic versus biological patch augmentation in the repair of posterosuperior massive rotator cuff tears: A 3-year follow-up study. Am J Sports Med 2014;42(5):1169–1175.
[14]: Schlegel TF, Abrams JS, Bushnell BD, Brock JL, Ho CP. Radiologic and clinical evaluation of a bioabsorbable collagen implant to treat partial-thickness tears: a prospective multicenter study. J Shoulder Elbow Surg. 2018 Feb;27(2):242-251. doi: 10.1016/j.jse.2017.08.023. Epub 2017 Nov 20. PMID: 29157898.
[15]:Varacallo M, El Bitar Y, Mair SD. Rotator Cuff Syndrome. [Updated 2021 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK531506/
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