The effect of adipose-derived stem cells on enthesis healing after repair of acute and chronic massive rotator cuff tears in rats.

BACKGROUND: Chronic massive rotator cuff tears heal poorly and often retear. This study investigated the effect of adipose-derived stem cells (ADSCs) and transforming growth factor-ß3 (TGF-ß3) delivered in 1 of 2 hydrogels (fibrin or gelatin methacrylate [GelMA]) on enthesis healing after repair of acute or chronic massive rotator cuff tears in rats. METHODS: Adult male Lewis rats underwent bilateral transection of the supraspinatus and infraspinatus tendons with intramuscular injection of botulinum toxin A (n = 48 rats). After 8 weeks, animals received 1 of 8 interventions (n = 12 shoulders/group): (1) no repair, (2) repair only, or repair augmented with (3) fibrin, (4) GelMA, (5) fibrin + ADSCs, (6) GelMA + ADSCs, (7) fibrin + ADSCs + TGF-ß3, or (8) GelMA + ADSCs + TGF-ß3. An equal number of animals underwent acute tendon transection and immediate application of 1 of 8 interventions. Enthesis healing was evaluated 4 weeks after the repair by microcomputed tomography, histology, and mechanical testing. RESULTS: Increased bone loss and reduced structural properties were seen in chronic compared with acute tears. Bone mineral density of the proximal humerus was higher in repairs of chronic tears augmented with fibrin + ADSCs and GelMA + ADSCs than in unrepaired chronic tears. Similar improvement was not seen in acute tears. No intervention enhanced histologic appearance or structural properties in acute or chronic tears. CONCLUSIONS: Surgical repair augmented with ADSCs may provide more benefit in chronic tears compared with acute tears, although there was no added benefit to supplementing ADSCs with TGF-ß3.

Technical Considerations in Revision Anterior Cruciate Ligament (ACL) Reconstruction for Operative Techniques in Orthopaedics.

As the incidence of anterior cruciate ligament (ACL) reconstruction continues to increase, the rate of revision surgery continues to climb. Revision surgery has inherent challenges that must be addressed in order to achieve successful results. The cause of the primary ACL reconstruction failure should be determined, and careful preoperative planning should be performed to address the cause(s) of failure. Each patient undergoing revision surgery should undergo a thorough history and physical examination, receive full length alignment radiographs, lateral radiographs, 45-degree flexion weight-bearing postero-anterior radiographs, and patellofemoral radiographs. 3-dimensional computed topography (CT) scan should be performed to assess tunnel position and widening. Magnetic resonance imaging (MRI) should be used to assess for intra-articular soft tissue pathology. Meniscal tears, meniscal deficiency, anterolateral capsule injuries, bony morphology, age, activity level, connective tissue diseases, infection, graft choice, and tunnel position can all impact the success of ACL reconstruction surgery. Meniscal lesions should be repaired, and in cases of persistent rotatory instability, extra-articular procedures may be indicated. Furthermore, osteotomies may be needed to correct malalignment or excess posterior tibial slope. Depending on the placement and condition of the original femoral and tibial tunnels, revision surgery may be performed in a single procedure or in a staged manner. In most cases, the surgery can be performed in one procedure. Regardless, the surgeon must communicate with the patient openly regarding the implications of revision ACL surgery and the treatment plan should be developed in a shared fashion between the surgeon and the patient.

Systematic Review of Surgical Literature from Resource-Limited Countries: Developing Strategies for Success.

BACKGROUND: Injuries and surgical diseases are leading causes of global mortality. We sought to identify successful strategies to augment surgical capacity and research endeavors in low-income countries (LIC's) based on existing peer-reviewed literature. METHODS: A systematic review of literature from or pertaining to LIC's from January 2002 to December 2011 was performed. Variables analyzed included type of intervention performed, research methodology, and publication demographics such as surgical specialty, partnerships involved, authorship contribution, place and journal of publication. FINDINGS: A total of 2049 articles met the inclusion criteria between 2002 and 2011. The two most common study methodologies performed were case series (44%) and case reports (18%). A total of 43% of publications were without outcome measures. Only 21% of all publications were authored by a collaboration of authors from low-income countries and developed country nationals. The five most common countries represented were Nepal (429), United States (408), England (170), Bangladesh (158), and Kenya (134). Furthermore, of countries evaluated, Nepal and Bangladesh were the only two with a specific national journal. INTERPRETATION: Based on the results of this research, the following recommendations were made: (1) Describe, develop, and stimulate surgical research through national peer-reviewed journals, (2) Foster centers of excellence to promote robust research competencies, (3) Endorse partnerships across regions and institutions in the promotion of global surgery, and (4) Build on outcome-directed research.

Resolution of Confusion Over Compartment Syndrome After Tibial Osteotomy With Continuous Pressure Measurements.

Compartment syndrome (CS) can occur in a variety of clinical scenarios. Reperfusion injury and tissue swelling are common causes across etiologies. Trauma is recognized as a common cause, but CS is also seen after limb alignment correction for extremities. CS is a difficult diagnosis to make in any scenario. Timely diagnosis is also difficult. Correct diagnosis is inexact, with many false positives and some false negatives being the normal outcome. This case represents a scenario where it was inherently difficult to make the diagnosis. The patient was a young patient with an underlying neurodevelopmental disorder where physical and clinical examination was impossible to accomplish. Any intervention to decrease pain was also difficult and actively refused by the patient and the family. Leaving open wounds after a fasciotomy was also undesirable for wound care and infection. Previous care maps have high false-positive rates or a need for fasciotomy as the treatment arm when diagnosis is uncertain. This usually results in fasciotomy being performed in many legs without CS. These false positives and resultant prophylactic releases are costly because of protracted hospital stay, high rate of deep infection, and decreased operating room availability for other cases. The desirable tool for surgeons would be the one that decreased false positives and false negatives while ensuring diagnosis in a timely fashion for true-positive cases. Technology for monitoring continuous pressure has been shown to aid in diagnosis. In this report, we illustrate the use of a continuous pressure monitoring system in a case of a pediatric patient post-osteotomy of a lower limb presenting with unremitting pain and a difficult clinical examination.

Patellofemoral Instability Part II: Surgical Treatment.

Treatment of patellofemoral instability in skeletally mature patients remains an important area of clinical and research interest. Both nonsurgical and surgical interventions are used to treat the underlying causes. Surgical management is the mainstay of treatment of recurrent PFI that fails nonsurgical treatment, and it is broadly classified into bony and soft-tissue procedures. Proximal bony procedures include femoral trochleoplasty, derotational osteotomies, and coronal alignment correction of the femur. Distal bony procedures include tibial tubercle transfer and derotational (supratubercle and infratubercle) osteotomies. Soft-tissue procedures consist of medial patellofemoral ligament repair or reconstruction and lateral lengthening procedures. This article is the second part of our two-article review on PFI, which focuses on surgical treatment options, their indications, outcomes, and potential complications.

Equation predicting tibial-tuberosity to trochlear-groove distance following supratubercle osteotomy: Radiographic proof of concept.

BACKGROUND: Supratubercle tibial rotational osteotomies are useful in patellar stabilizing procedures with high tibial-tuberosity to trochlear-groove distance caused by excessive external tibial torsion. An investigation determined one degree of internal tibial rotation results in 0.68 mm reduction of tibial-tuberosity to trochlear-groove distance, but did not account for anatomical variability. METHODS: This is a radiographic proof of concept for equation validation. We compared two different derived equations, a complex four-variable and simplified two-variable equation, to the literature relationship and true measured value from CT imaging. Bilateral pre-operative CTs of 37 patients, evaluated for malalignment, were reviewed retrospectively. We virtually simulated derotations of five, ten and fifteen degrees, and compared the reduction in tibial-tuberosity to trochlear-groove distance measured radiologically from CTs to the one predicted by our equation. FINDINGS: The difference between the true change in tibial-tuberosity to trochlear-groove distance and that obtained using our four-variable was statistically insignificant for all derotation angles (p > 0.05), and the two-variable equation it was statistically insignificant for five and fifteen degrees of derotation (p > 0.05). Conversely, the true values were statistically different from those found using the published relationship (p < 0.05 for all). INTERPRETATION: This new equation accounts for individual patient anatomy, for a more accurate relationship between internal rotation of the distal segment of the tibia and the subsequent decrease in the tibial-tuberosity to trochlear-groove distance. The change was overestimated using the linear relationship, which may result in under correction. Future studies will assess true post-operative distance change following osteotomy.

Patellofemoral Instability Part I: Evaluation and Nonsurgical Treatment.

Patellofemoral instability (PFI) is a prevalent cause of knee pain and disability. It affects mostly young females with an incidence reported as high as 1 in 1,000. Risk factors for instability include trochlear dysplasia, patella alta, increased tibial tubercle-to-trochlear groove distance, abnormal patella lateral tilt, and coronal and torsional malalignment. Nonsurgical and surgical options for PFI can treat the underlying causes with varied success rates. The goal of this review series was to synthesize the current best practices into a concise, algorithmic approach. This article is the first in a two-part review on PFI, which focuses on the clinical and radiological evaluation, followed by nonsurgical management. The orthopaedic surgeon should be aware of the latest diagnostic protocol for PFI and its nonsurgical treatment options, their indications, and outcomes.

Variable expressivity in a family with an aggrecanopathy.

BACKGROUND: Osteochondritis dissecans is a condition wherein there is a subchondral bone lesion that causes pain, inflammation, and cartilage damage. Dominant Familial Osteochondritis Dissecans is a rare and severe form of osteochondritis dissecans (OCD). It is caused by heterozygous pathogenic variants in the gene encoding Aggrecan; ACAN. Aggrecan, a proteoglycan, is an essential component of the articular and growth plate cartilage. METHODS: Herein, we report three individuals from one family; the proband who presented with short stature, a lower limb bone exostosis, and bilateral knee and elbow OCD at the age of 13 years old. His twin brother presented with isolated short stature and his father with short stature and lumbar disc herniation. RESULTS: Next-generation sequencing of the ACAN gene in the proband identified a frameshift variant which is also present in the brother and father with short stature. The proband was treated surgically with bilateral elbow microfracture, after the failure of conservative therapy. CONCLUSION: To the best of our knowledge, this is the first patient with an aggrecanopathy who presents with osteochondritis dissecans due to a frameshift variant. This family presents with variable expressivity which might be attributed to modifier genes.

Limited evidence for graft selection in pediatric ACL reconstruction: a narrative review.

Anterior cruciate ligament reconstruction is the preferred treatment to anterior cruciate ligament injury. With the increase in anterior cruciate ligament injuries in both adults and skeletally immature patients comes the need for individualized anterior cruciate ligament reconstruction graft selection whether it is the type of graft (auto vs. allograft) or the harvesting site (hamstrings, iliotibial band, quadriceps, patella). Several factors need to be considered preoperatively in order to optimize the patients' recovery and restore anterior cruciate ligament strength and function. These include age and bone maturity, preoperative knee flexor/extensor strength, sport participation, patient's needs and anatomical characteristics. This paper aims at bringing evidence supporting the use of a personalized approach in graft selection for faster and more efficient return to sport and propose a theoretical framework to support the approach.

Emergency surgical care delivery in post-earthquake Haiti: Partners in Health and Zanmi Lasante experience.

BACKGROUND: The earthquake that struck Haiti on 12 January 2010 caused significant devastation to both the country and the existing healthcare infrastructure in both urban and rural areas. Most hospital and health care facilities in Port-au-Prince and the surrounding areas were significantly damaged or destroyed. Consequently, large groups of Haitians fled Port-au-Prince for rural areas to seek emergency medical and surgical care. In partnership with the Haitian Ministry of Health, Partners in Health (PIH) and Zanmi Lasante (ZL) have developed and maintained a network of regional and district hospitals in rural Haiti for over twenty-five years. This PIH/ZL system was ideally situated to accommodate the increased need for emergent surgical care in the immediate quake aftermath. The goal of the present study was to provide a cross-sectional assessment of surgical need and care delivery across PIH/ZL facilities after the earthquake in Haiti. METHODS: We conducted a retrospective review of hospital case logs and operative records over the course of three weeks immediately following the earthquake. RESULTS: Roughly 3,000 patients were seen at PIH/ZL sites by a combination of Haitian and international surgical teams. During that period 513 emergency surgical cases were logged. Other than wound debridement, the most commonly performed procedure was fixation of long bone fractures, which constituted approximately one third of all surgical procedures. CONCLUSIONS: There was a significant demand for emergent surgical care after the earthquake in Haiti. The PIH/ZL hospital system played a critical role in addressing this acutely increased burden of surgical disease, and it allowed for large numbers of Haitians to receive needed surgical services. Our experiences reinforce that access to essential surgery is an essential pillar in public health.

Can a Knee Brace Prevent ACL Reinjury: A Systematic Review.

This systematic review aimed to investigate whether the use of a knee brace when returning to sport (RTS) could prevent a second injury after anterior cruciate ligament reconstruction (ACLR). This study was registered with the PROSPERO database and followed PRISMA guidelines. A systematic search of PubMed, Ovid Medline, Ovid All EBM Reviews, Ovid Embase, EBSCO Sportdiscus and ISI Web of Science databases for meta-analysis, randomized controlled trials and prospective cohort studies published before July 2020 was undertaken. The inclusion criteria were: (1) Comparing with and without a brace at RTS, (2) follow up of at least 18 months after ACLR, (3) reinjury rates included in the outcomes. Two reviewers independently extracted the data. Quality appraisal analyses were performed for each study using the Cochrane Collaboration tools for randomized and nonrandomized trials. A total of 1196 patients in three studies were included. One study showed a lower rate of reinjury when wearing a knee brace at RTS. One study found the knee brace to have a significant protective effect for younger patients (≤17 years). The effectiveness of knee bracing when RTS remains ambiguous. Current data cannot support that using a knee brace when RTS will decrease the rate of reinjury after ACL reconstruction.

Arthroscopy Association of Canada Position Statement on Exercise for Knee Osteoarthritis: A Systematic Review of Guidelines.

BACKGROUND: Exercise is widely regarded to improve pain and function in patients with knee osteoarthritis (OA) through building supportive muscle mass, facilitating weight loss, and through the other beneficial effects associated with it. PURPOSE: To explore literature that presents clinical guidelines for the use of exercise in the treatment of knee OA to inform an evidence-based position statement for the Arthroscopy Association of Canada. STUDY DESIGN: Position statement. METHODS: PubMed, MEDLINE, Embase, and Cochrane databases were searched for guidelines commenting on the role of exercise for knee OA. The search was limited to guidelines published in the last 10 years. Articles were screened for relevance, focusing on recently published research with clinical guidelines. Inclusion criteria involved all articles providing clinical guidelines for exercise and knee OA. RESULTS: Eight guidelines were identified. All eight recommended exercise as an important component of treatment for knee OA, with 6/8 strongly recommending it. CONCLUSION: Exercise is an effective and important component of the non-pharmacological management of knee OA. The Arthroscopy Association of Canada strongly recommends the use of exercise in the management of knee OA.

Management of common elective paediatric orthopaedic conditions during the COVID-19 pandemic: the Montreal experience.

PURPOSE: To explore safe delays for the treatment of common paediatric orthopaedic conditions when faced with a life-threatening pandemic, COVID-19, and to propose a categorization system to address this question. METHODS: Review of the literature related to acceptable delays for treatment of common orthopaedic conditions, experience of healthcare professionals from low resource communities and expertise of experienced surgeons. RESULTS: Guidelines for the management of cancellations of elective surgeries during a period of resource reallocation are proposed. Elective cases must not be postponed indefinitely as adverse outcomes may result. Triage of waiting lists should include continuous monitoring of the patient and close communication with families despite social distancing and travel restrictions. Telehealth becomes a necessity. Common orthopaedic conditions are triaged into four groups according to urgency and safe and acceptable delay. Categories proposed are Emergent (life and limb threatening conditions), Urgent (within seven days), Semi-elective (postponed for three months) and Elective (postponed for three to 12 months). In total, 25 common orthopaedic conditions are reviewed and categorized. CONCLUSION: Given the uncertainty within healthcare during a pandemic, it is necessary to determine acceptable delays for elective conditions. We report our experience in developing guidelines and propose categorizing elective cases into four categories, based on the length of delay. Telemedicine plays a key role in determining the gravity of each situation and hence the amount of delay. These guidelines will assist others dealing with elective cases in the midst of a crisis. This paper initiates a coordinated effort to develop a consensus statement on safe delays.Published without peer review.

Knee Morphological Risk Factors for Anterior Cruciate Ligament Injury: A Systematic Review.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction incidence has increased substantially in the past 25 years. Recently, there has been a focus on knee morphology as a contributor to ACL injury risk. The purpose of this study was to systematically review the literature to assess the influence of knee morphology on ACL injury. METHODS: In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, Embase, and MEDLINE were searched in September 2017 for studies reporting on knee morphology and ACL injury. The search was updated in June 2018. The following inclusion criteria were used: English language; full text available; Level-I, II, or III evidence; human studies; and skeletally mature patients. RESULTS: After systematically screening 6,208 studies, 65 studies met the inclusion/exclusion criteria. Three additional studies were identified in the search update, for a total of 68 studies comprising 5,834 ACL-injured knees. Intercondylar notch stenosis, most commonly defined by an "A-shaped" notch, decreased notch width, or decreased notch width index, was the most commonly reported femoral morphological risk factor for ACL injury. Increased femoral condylar offset ratio (>63%) and decreased condylar radius of curvature also were associated with an increased risk of ACL injury. Increased medial and lateral tibial slopes were the most commonly reported tibial risk factors. A smaller tibial eminence, reduced ACL size, and poor tibiofemoral congruity were also associated with increased injury risk. CONCLUSIONS: Intercondylar notch stenosis, variations in sagittal condylar shape, increased tibial slope, reduced tibial eminence size, poor tibiofemoral congruity, and reduced ACL size are substantial risk factors for ACL injury. In future research, it would be valuable to identify a slope beyond which slope correction should be performed concomitantly with ACL reconstruction, and to determine whether an optimal relationship of notch size to graft size exists. To achieve optimal outcomes, the osseous morphological risk factors should be considered in individualized anatomic ACL reconstructions. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure.

Transient receptor potential vanilloid 4 (TRPV4) channels have been implicated as mediators of calcium influx in both endothelial and vascular smooth muscle cells and are potentially important modulators of vascular tone. However, very little is known about the functional roles of TRPV4 in the resistance vasculature or how these channels influence hemodynamic properties. In the present study, we examined arterial vasomotor activity in vitro and recorded blood pressure dynamics in vivo using TRPV4 knockout (KO) mice. Acetylcholine-induced hyperpolarization and vasodilation were reduced by approximately 75% in mesenteric resistance arteries from TRPV4 KO versus wild-type (WT) mice. Furthermore, 11,12-epoxyeicosatrienoic acid (EET), a putative endothelium-derived hyperpolarizing factor, activated a TRPV4-like cation current and hyperpolarized the membrane of vascular smooth muscle cells, resulting in the dilation of mesenteric arteries from WT mice. In contrast, 11,12-EET had no effect on membrane potential, diameter, or ionic currents in the mesenteric arteries from TRPV4 KO mice. A disruption of the endothelium reduced 11,12-EET-induced hyperpolarization and vasodilatation by approximately 50%. A similar inhibition of these responses was observed following the block of endothelial (small and intermediate conductance) or smooth muscle (large conductance) K(+) channels, suggesting a link between 11,12-EET activity, TRPV4, and K(+) channels in endothelial and smooth muscle cells. Finally, we found that hypertension induced by the inhibition of nitric oxide synthase was greater in TRPV4 KO compared with WT mice. These results support the conclusion that both endothelial and smooth muscle TRPV4 channels are critically involved in the vasodilation of mesenteric arteries in response to endothelial-derived factors and suggest that in vivo this mechanism opposes the effects of hypertensive stimuli.

Validation of an objective device for assessing circumductive wrist motion.

PURPOSE: Circumduction of the wrist consists of a circular motion combining flexion, extension, and radioulnar deviation without simultaneous supination or pronation of the forearm. This pattern of flexion-extension and radial-ulnar deviation coupling is vital in common tasks; however, its evaluation in hand clinics is limited by the availability and ease of current tools. We present the construct, criterion, test-retest, and inter-rater validity of a new circumduction measurement device. METHODS: Splint volunteers (n = 42) and hand clinic patients (n = 51) were studied to assess different aspects of validity and reliability for the circumduction jig. Known-group validation was used to assess construct validity and demonstrate the ability of the device to differentiate between patients with lesser or greater circumduction values. Criterion validity was demonstrated by comparing the circumduction measures of the device to flexion, extension, ulnar deviation, and radial deviation. Test-retest reliability was established by comparing the results of repeated circumduction measures for the hand clinic patients by 2 blinded, independent researchers, and inter-rater reliability was determined by evaluating the correlation in circumduction measures taken on the same patient by different blinded, independent researchers. RESULTS: Circumduction measurements significantly decreased (test for trend, p < .01) across the 3 different treatments that represented progressively reduced range of motion, establishing construct validity of the device. Flexion, extension, and radioulnar deviation all correlated significantly with circumduction; the correlation values ranged from 0.46 to 0.82 (p < .01) among all subjects (93 subjects, 228 measurements). Intra-rater reliability was 0.98 (p < .01) for both evaluators, and inter-rater reliability was 0.94 (p < .01). CONCLUSIONS: The present validation study demonstrated criterion, construct, test-retest, and inter-rater reliability for a newly designed circumduction measurement device.

Structural Properties of the Anterolateral Complex and Their Clinical Implications.

The role of the anterolateral complex of the knee in providing static and rotatory knee stability has been a source of renewed interest in the literature. Several studies have established a role of the anterolateral complex in controlling knee rotational stability. Although the objective quantification of knee kinematics and stability has been investigated, understanding of the structural properties of the anterolateral complex is evolving. This article highlights recent evidence pertaining to the structural properties of the anterolateral structures. The biomechanical evaluation of the structural properties of the anterolateral complex of the knee yielded minimal involvement in controlling knee rotational stability.

Genetic and fluorescence studies of affinity maturation in related antibodies.

Affinity maturation, the process by which an organism's response to infection becomes more specific and more effective over time, occurs after somatic hypermutation of antibody genes in B-cells. This increase in affinity might be a result of the evolution of either specific interactions between antigen and antibody over time (enthalpic factors) or antibody binding site rigidification (entropic factors) or both. Here, monoclonal antibodies, derived from antibodies elicited at different points in the murine immune response after inoculation with the same diketone hapten, have been characterized both genetically and functionally. Though this hapten has previously been shown to produce the catalytic aldolase antibody 38C2, antibodies described here are not catalytic and unlike 38C2, form no covalent enzyme-substrate complex. Thus, they provide a system in which to assess contributions to the evolution of binding affinity. The genes for these non-catalytic antibodies have been sequenced and analyzed both with regard to their relationships to germ line genes, to each other, and to two commercially available catalytic aldolase antibodies. Consequences of particular mutations for antigen binding behavior are discussed. The protein products of these genes have been expressed, purified, and binding properties measured by two complementary techniques: the hapten-induced quenching of the native antibody fluorescence and the changes in the anisotropy of Prodan (6-propionyl-2-(dimethylamino)naphthalene), a fluorescent hapten analogue. Differences in binding affinity are related back to differences in the lengths and amino acid sequences of the complementary determining region 3 (CDR3) binding loop. Taken together with our earlier results on binding site heterogeneity from tryptophan lifetime analysis [Mohan, G.S., Chiu, P.T., Southern, C.A., O'Hara, P.B., 2004. Steady-state and multifrequency phase fluorometry studies of binding site flexibility in related antibodies. J. Phys. Chem. A 108, 7871-7877], affinity appears to be modulated by a combination of entropic and enthalpic factors, and not dominated by one or the other. Because these antibodies are not related to the same germ line gene, however, these results do not provide evidence for the dominance of enthalpy or entropy in evolving binding affinity in this system.

The Rotator Cuff Organ: Integrating Developmental Biology, Tissue Engineering, and Surgical Considerations to Treat Chronic Massive Rotator Cuff Tears.

The torn rotator cuff remains a persistent orthopedic challenge, with poor outcomes disproportionately associated with chronic, massive tears. Degenerative changes in the tissues that comprise the rotator cuff organ, including muscle, tendon, and bone, contribute to the poor healing capacity of chronic tears, resulting in poor function and an increased risk for repair failure. Tissue engineering strategies to augment rotator cuff repair have been developed in an effort to improve rotator cuff healing and have focused on three principal aims: (1) immediate mechanical augmentation of the surgical repair, (2) restoration of muscle quality and contractility, and (3) regeneration of native enthesis structure. Work in these areas will be reviewed in sequence, highlighting the relevant pathophysiology, developmental biology, and biomechanics, which must be considered when designing therapeutic applications. While the independent use of these strategies has shown promise, synergistic benefits may emerge from their combined application given the interdependence of the tissues that constitute the rotator cuff organ. Furthermore, controlled mobilization of augmented rotator cuff repairs during postoperative rehabilitation may provide mechanotransductive cues capable of guiding tissue regeneration and restoration of rotator cuff function. Present challenges and future possibilities will be identified, which if realized, may provide solutions to the vexing condition of chronic massive rotator cuff tears.