Translational Research on Orthobiologics in the Treatment of Rotator Cuff Disease: From the Laboratory to the Operating Room.

Rotator cuff disease is one of the most common human tendinopathies and can lead to significant shoulder dysfunction. Despite efforts to improve symptoms in patients with rotator cuff tears and healing rates after rotator cuff repair, high rates of failed healing and persistent shoulder morbidity exist. Increasing interest has been placed on the utilization of orthobiologics-scaffolds, cell-based augmentation, platelet right plasma (platelet-rich plasma), and small molecule-based strategies-in the management of rotator cuff disease and the augmentation of rotator cuff repairs. This is a complex topic that involves novel treatment strategies, including patches/scaffolds, small molecule-based, cellular-based, and tissue-derived augmentation techniques. Ultimately, translational research, with a particular focus on preclinical models, has allowed us to gain some insights into the utility of orthobiologics in the treatment of rotator cuff disease and will continue to be critical to our further understanding of the underlying cellular mechanisms moving forward.

Effect of extracorporeal shock wave therapy for rotator cuff injury: Protocol for a systematic review and meta-analysis.

BACKGROUND: Rotator cuff injury (RCI) is a common musculoskeletal ailment and a major cause of shoulder pain and limited functionality. The ensuing pain and restricted movement significantly impact overall quality of life. This study aims to systematically review the effects of extracorporeal shock wave therapy (ESWT) on RCI. METHODS: This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. A literature search, spanning inception to November 1, 2023, will include databases such as PubMed, Web of Science, the Cochrane Library, Scopus, MEDLINE, EMBASE, EBSCO, and China National Knowledge Infrastructure (CNKI) to identify ESWT studies for RCI treatment. Excluding retrospectives, bias risk will be assessed with the Cochrane tool. Two researchers will independently screen, extract data, and evaluate bias risk. Revman 5.3 software will be used for data analysis. RESULTS: This study aims to objectively and comprehensively evaluate the effectiveness and safety of randomized controlled trials of ESWT in the treatment of RCI, and analyze in detail the effect of ESWT in the treatment of RCI. Results will be analyzed using the Pain Visual Analogue Scale (VAS), Constant-Murley score, University of California Los Angeles score (UCLA), and American Shoulder and Elbow Surgeons form (ASES). If applicable, subgroup analysis will also be performed to divide patients into groups according to the energy level of ESWT, the time of intervention, and the degree of tearing of RCI. Finally, the results are submitted for publication in a peer-reviewed journal. DISCUSSION AND CONCLUSION: There is existing evidence suggesting that ESWT may contribute to the amelioration of pain and functional limitations associated with Rotator Cuff Injury (RCI). This systematic review aims to update, consolidate, and critically evaluate relevant evidence on the effects of ESWT for RCI. The anticipated outcomes may serve as a valuable reference for clinical ESWT practices, covering treatment methods, timing, and intensity. Moreover, this review aspires to provide high-quality evidence addressing the impact of ESWT on RCI-related pain. Simultaneously, the findings of this systematic review are poised to offer guidance to clinicians and rehabilitation therapists. This guidance is intended to enhance the management of pain and functional impairments experienced by individuals with RCI, ultimately leading to improvements in their physical well-being. TRIAL REGISTRATION: Protocol registration number CRD42023441407. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023441407.

Platelet-rich plasma in the management of rotator cuff tendinopathy.

Platelet-rich plasma (PRP) is an autologous blood-derived product that has gained significant attention in the treatment of tendinopathies as one of many treatment modalities in the field of regenerative medicine. Rotator cuff pathologies are the leading cause of shoulder pain. Despite the high success rate with conservative treatment and arthroscopic surgical repair, the search for a nonsurgical treatment has made PRP a trending topic recently. The purpose of this article is to review the recent literature data on the possible role of PRP in different rotator cuff pathologies. The limited data in the literature about isolated tendinopathies without a tear (tendonitis and tendinosis) suggests potential benefit from conservative treatment with PRP. Many studies exist for the treatment of rotator cuff tears solely using PRP or as an augmentation to arthroscopic repair. Despite the large number of randomized clinical trials and meta-analyses about the topic, there is no consensus in favor of routine application of PRP in this patient population. The existing reliable evidence of benefit seems to be restricted to its use in only inflammatory tendinopathies with preserved tendon integrity.

Regenerative Medicine Solutions for Rotator Cuff Injuries in Athletes: Indications and Outcomes.

Rotator cuff (RC) injuries include a wide range of pathologic states. Athletes are perhaps the most susceptible to RC injuries ranging from tendinopathy to partial or full-thickness tears, due to functional overload and repetitive movements, causing abstention from sports for long periods. Regenerative medicine keeps giving us multiple choices to fight the disability caused by these pathologies. A literature search was performed, and findings related to the structure-function of rotator cuff units, pathophysiology of injuries, regenerative medicine treatments, and future strategies were outlined. Platelet-rich plasma (PRP) has a greater number of articles and clinical trials, accompanied by stem cells progenitor, prolotherapy, and new approaches such as microfragmented adipose tissue and exosomes. RC injuries in athletes can cause pain, functional impotence, and the risk of recurrence, and can lead them to stop playing sports. Regenerative medicine offers a range of treatments, but some of them need further studies to underline their actual validity.

Arthroscopic rotator cuff repair combined with platelet-rich plasma products can reduce the rate of retearing and improve clinical outcomes: A meta-analysis of randomized controlled trials.

BACKGROUND: Although several studies on the potential benefits of protein-rich plasma (PRP) therapy for rotator cuff injuries have been published, the results have been conflicting. Therefore, this study aimed to determine whether PRP is beneficial for the prevention of retears after arthroscopic rotator cuff repair (ARCR). METHODS: Two reviewers conducted independent literature searches based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized controlled trials (RCTs) comparing a PRP treatment group with a control group were included. The quality of evidence was assessed using the Cochrane Collaboration Risk of Bias Tool. Clinical outcomes were compared using the risk ratio (RR) for dichotomous variables and weighted mean difference (WMD) for continuous variables. Statistical significance was set at P < .05. RESULTS: This review included 21 RCTs (1359 patients). Significant results were noted in favor of PRP treatment compared with controls based on retearing rates (16.5% vs 23.6%, respectively; P = .002) and the Constant score in the short term (WMD: 1.98; 95% confidence interval [CI], 0.27-3.70; I2 = 0%; P = .02), medium term and long term (WMD: 2.56 [95% CI: 1.57-3.55]; I2 = 2%; P < .001); the University of California, Los Angeles score in the short term (WMD: 1.14 [95% CI: 0.43-1.85]; I2 = 25%; P = .002) but not in the medium and long term (WMD: 0.66 [95% CI: -0.16 to 1.48]; I2 = 57%; P = .11); and the visual analog scale score in the short term (WMD: -0.63 [95% CI: -0.83 to-0.43]; I2 = 41%; P < .001), medium and long term (WMD: -0.12 [95% CI: -0.19 to-0.05]; I2 = 0%; P = .008). There was no significant difference in American Shoulder and Elbow Surgeons scores between the treatment and control groups in the short term (WMD: -0.48 [95% CI: -2.80 to 1.85]; I2 = 22%; P = .69) or medium and long term (WMD: 0.92 [95% CI: -1.56 to 3.39]; I2 = 40%; P = .47). CONCLUSION: Intraoperative use of PRP reduces the risk of rotator cuff repair failure, improves clinical outcomes, and reduces recurrence rates.

Effect of extracorporeal shockwave therapy for rotator cuff tendinopathy: a systematic review and meta-analysis.

BACKGROUND: Rotator cuff tendinopathy (RCT) is a widespread musculoskeletal disorder and a primary cause of shoulder pain and limited function. The resulting pain and limited functionality have a detrimental impact on the overall quality of life. The purpose of this study was to perform a systematic review of the effects of extracorporeal shock wave therapy (ESWT) for RCT. METHODS: The literature search was conducted on the following databases from inception to February 20, 2024: PubMed, Web of Science, the Cochrane Library, Scopus, MEDLINE, EMBASE, EBSCO, and China National Knowledge Infrastructure (CNKI) were checked to identify the potential studies exploring the effect of ESWT for the treatment of Rotator cuff tendinopathy (Calcification or non-calcification), control group for sham, other treatments (including placebo), without restriction of date, language. Two researchers independently screened literature, extracted data, evaluated the risk of bias in the included studies, and performed meta-analysis using RevMan 5.3 software. RESULTS: A total of 16 RCTs with 1093 patients were included. The results showed that compared with the control group, ESWT for pain score Visual Analogue Scale/Score (VAS) (SMD = -1.95, 95% CI -2.47, -1.41, P < 0.00001), function score Constant-Murley score (CMS) (SMD = 1.30, 95% CI 0.67, 1.92, P < 0.00001), University of California Los Angeles score (UCLA) (SMD = 2.69, 95% CI 1.64, 3.74, P < 0.00001), American Shoulder and Elbow Surgeons form (ASES) (SMD = 1.29, 95% CI 0.93, 1.65, P < 0.00001), Range of motion (ROM) External rotation (SMD = 1.00, 95% CI 0.29, 1.72, P = 0.02), Total effective rate (TER) (OR = 3.64, 95% CI 1.85, 7.14, P = 0.0002), the differences in the above results were statistically significant. But ROM-Abduction (SMD = 0.72, 95% CI -0.22, 1.66, P = 0.13), the difference was not statistically significant. CONCLUSION: Currently limited evidence suggests that, compared with the control group, ESWT can provide better pain relief, functional recovery, and maintenance of function in patients with RCT.

Assessment of description and implementation fidelity of clinical trials involving exercise-based treatment in individuals with rotator cuff tears: a scoping review.

BACKGROUND: For evidence-based practice, clinicians and researchers can rely on well-conducted randomized clinical trials that exhibit good methodological quality, provide adequate intervention descriptions, and implementation fidelity. OBJECTIVE: To assess the description and implementation fidelity of exercise-based interventions in clinical trials for individuals with rotator cuff tears. METHODS: A systematic search was conducted in PubMed, Embase, CINAHL, LILACS, Cochrane Library, Web of Science, SCOPUS and SciELO. Randomized clinical trials that assessed individuals with rotator cuff tears confirmed by imaging exam were included. All individuals must have received an exercise-based treatment. The methodological quality was scored with the Physiotherapy Evidence Database (PEDro) scale. The Template for Intervention Description and Replication (TIDieR) checklist and the National Institutes of Health Behaviour Change Consortium (NIHBCC) were used to assess intervention description and implementation fidelity, respectively. RESULTS: A total of 13 studies were included. Despite their adequate methodological quality, the description of the intervention was poor with TIDieR scores ranging from 6 to 15 out of 24 total points. The TIDieR highest-scoring item was item 1 (brief name) that was reported in all studies. Considering fidelity, only one of the five domains of NIHBCC (i.e., treatment design) reached just over 50%. CONCLUSION: Exercise-based interventions used in studies for individuals with rotator cuff tears are poorly reported. The description and fidelity of the intervention need to be better reported to assist clinical decision-making and support evidence-based practice.

Cell-Based Therapies for Rotator Cuff Injuries: An Updated Review of the Literature.

This review focuses on non-surgical treatment options for rotator cuff injuries and highlights the potential of mesenchymal stem cells (MSCs) as a potential regenerative approach. MSCs, sourced from various tissues like bone marrow and adipose tissue, exhibit promising mechanisms in vitro, influencing tendon-related gene expression and microenvironment modulation. Animal studies support this, showcasing MSCs' ability to reduce inflammation, improve tissue remodeling, and enhance repaired tendon strength. Human trials, while varied and limited, suggest that MSCs might lower retear rates and enhance post-repair outcomes, but randomized controlled trials yield mixed results, emphasizing the necessity for standardized investigations. Ultimately, while cell-based therapies demonstrate an excellent safety profile, more rigorous clinical trials are necessary to determine their efficacy in improving patient outcomes and achieving lasting structural changes in rotator cuff injuries.

Experimental Study of Autologous Platelet-rich Plasma Combined With Sodium Hyaluronate on Tendon-bone Healing After Rotator Cuff Injury Repair in Rabbits.

OBJECTIVE: To investigate the therapeutic effects of autologous platelet-rich plasma (PRP) combined with sodium hyaluronate on tendon healing following rotator cuff injury repair in rabbits. METHODS: New Zealand white rabbits were randomly assigned to five groups: sham operation group, control group, PRP group, sodium hyaluronate group, and combined group, each comprising 12 rabbits. A rotator cuff injury model was established in all groups except the sham operation group. At 8 weeks post-surgery, 12 lateral rotator cuff specimens were taken from each group. Four specimens were randomly selected from each group for biomechanical testing, and analyses were conducted on the expression of vascular endothelial growth factor (VEGF), the fiber area ratio of COL-I and COL-III, and tissue morphology. RESULTS: The combined group exhibited the highest biomechanical strength in the cuff tissue of white rabbits (P < 0.05). There was no significant difference in VEGF levels among the five groups (F = 0.814, P = 0.523). However, a significant difference was observed in the ratio of fiber area between COL-I and COL-III groups (F = 11.600, P < 0.001), with the combined group scoring the highest (3.82 ± 0.47 minutes). The inflammatory infiltration in tendon-bone tissue was minimal, and histological morphology was optimal. CONCLUSION: The combination of PRP and sodium hyaluronate effectively promotes the repair of rotator cuff injuries and accelerates tendon-bone healing.

Management of rotator cuff injuries using allogenic platelet-rich plasma.

Rotator cuff injuries are a major cause of shoulder pain, affecting the quality of life and producing a significant burden on healthcare systems. Conservative management modalities are prioritized, resorting to surgery only when required. The field of regenerative medicine involving the use of biologics, such as platelet-rich plasma (PRP), has evolved and shown potential for managing rotator cuff injuries. Nonetheless, limitations including subpar outcomes have led clinicians to question the efficacy of autologous PRP. To circumvent this, the possibility of utilizing a standardized and well-characterized allogenic PRP for RCI has been explored. In this manuscript, we qualitatively present the evidence from in vitro, pre-clinical, clinical and ongoing studies investigating the applications of allogenic PRP in the context of rotator cuff disorders. Administration of allogenic PRP is safe and potentially efficacious to manage rotator cuff injuries, though more adequately powered randomized controlled trials with longer follow-ups are warranted to further establish the efficacy of allogenic PRP and justify its routine clinical use.

Dosage of joint mobilization for the management of patients with rotator cuff-related shoulder pain: A scoping review.

BACKGROUND: Evidence supporting type and dosage of joint mobilizations and rationale for selecting joint mobilization dosage for patients with rotator cuff-related shoulder pain are limited. OBJECTIVES: This scoping review aimed to systematically map the type and dosage of joint mobilizations used in previous trials for managing patients with rotator cuff-related shoulder pain; and summarize the rationale for adopting a specific joint mobilization dosage. METHODS: We searched six databases. We included randomised controlled trials using joint mobilization for patients with rotator cuff-related shoulder pain. We extracted data regarding technique, treatment joint mobilization dosages and rationale for a specific dosage. RESULTS: We included 32 studies. Most studies did not or partially report technique (67%) and within-session dosage (64%) of passive joint mobilization. Overall treatment was fully reported in 95% of studies. The dosage used for passive joint mobilization was heterogeneous (ranging from grade I to grade V). Most studies (85%) did not or partially report technique of mobilization with movement (MWM), whereas within-session and overall treatment dosages were fully reported in more than 85% of studies. Three sets of 10 repetitions were commonly used within-session dosage for MWM. We found very limited information on the rationale for selecting dosage of joint mobilization. CONCLUSION: We found limited information about the dosage or the rationale for selecting joint mobilization, with a heterogeneous dosage being tested across trials. Our findings highlight the importance of detailed reporting for dosage and rationale for selecting a specific dosage of joint mobilization.

'If he thought that I was going to go and hurt myself, he had another thing coming': Treatment experiences of those with large to massive rotator cuff tears and the perspectives of healthcare practitioners.

OBJECTIVE: To explore the treatment experiences of those diagnosed with large to massive rotator cuff tears and the perspectives of healthcare practitioners providing their care. DESIGN: A qualitative descriptive study using reflexive thematic analysis. SETTING: In-person focus groups were undertaken in a clinical setting (private practice [n = 1]; public outpatient [n = 2]). Semi-structured interviews were conducted online via Microsoft Teams. PARTICIPANTS: Patients diagnosed with these tears (n = 12) and healthcare practitioners (n = 11). RESULTS: Two interlinking themes were identified based on the care received and provided for patients with symptomatic large to massive rotator cuff tears:1) Positive treatment experiences and management: Education, clear communication and reassurance around prognosis were the foundation of positive patient-clinician care. Sub-themes of pain relief, exercise prescription and confidence in their pathway underpinned this experience. This proficiency in care was affirmed by some healthcare practitioners who spoke about the importance of confidence and experience in their management plan even in times of poor progress.2) Negative treatment experiences and management: Uncertainty, delays and exacerbation of pain flawed the patient-clinician care. Sub-themes of inappropriate pain relief, inappropriate exercise prescription and uncertainty impacted their care. Some healthcare practitioners acknowledged knowledge gaps led to uncertainty especially when choosing the next step of care and were quick to escalate care to deflect this uncertainty. CONCLUSIONS: The findings suggest discordance exists between the patient's experiences and expectations when the delivery of care was by less experienced and confident healthcare practitioners in the management of this condition. This highlights the need for improved education and support for healthcare practitioners.

Natural History of Quantitative Fatty Infiltration and 3D Muscle Volume After Nonoperative Treatment of Symptomatic Rotator Cuff Tears: A Prospective MRI Study of 79 Patients.

BACKGROUND: The severity of fatty infiltration (FI) predicts the treatment outcome of rotator cuff tears. The purpose of this investigation was to quantitatively analyze supraspinatus (SSP) muscle FI and volume at the initial presentation and after a 3-month minimum of conservative management. We hypothesized that progression of FI could be predicted with initial tear size, FI, and muscle volume. METHODS: Seventy-nine shoulders with rotator cuff tears were prospectively enrolled, and 2 magnetic resonance imaging (MRI) scans with 6-point Dixon sequences were acquired. The fat fraction within the SSP muscle was measured on 3 sagittal slices, and the arithmetic mean was calculated (FI SSP ). Advanced FI SSP was defined as ≥8%, pathological FI SSP was defined as ≥13.5%, and relevant progression was defined as a ≥4.5% increase in FI SSP . Furthermore, muscle volume, tear location, size, and Goutallier grade were evaluated. RESULTS: Fifty-seven shoulders (72.2%) had normal FI SSP , 13 (16.5%) had advanced FI SSP , and 9 (11.4%) had pathological FI SSP at the initial MRI scan. Eleven shoulders (13.9%) showed a ≥4.5% increase in FI SSP at 19.5 ± 14.7 months, and 17 shoulders (21.5%) showed a ≥5-mm 3 loss of volume at 17.8 ± 15.3 months. Five tears (7.1%) with initially normal or advanced FI SSP turned pathological. These tears, compared with tears that were not pathological, had significantly higher initial mediolateral tear size (24.8 compared with 14.3 mm; p = 0.05), less volume (23.5 compared with 34.2 mm 3 ; p = 0.024), more FI SSP (9.6% compared with 5.6%; p = 0.026), and increased progression of FI SSP (8.6% compared with 0.5%; p < 0.001). An initial mediolateral tear size of ≥20 mm yielded a relevant FI SSP progression rate of 81.8% (odds ratio [OR], 19.0; p < 0.001). Progression rates of 72.7% were found for both initial FI SSP of ≥9.9% (OR, 17.5; p < 0.001) and an initial anteroposterior tear size of ≥17 mm (OR, 8.0; p = 0.003). Combining these parameters in a logistic regression analysis led to an area under the receiver operating characteristic curve (AUC) of 0.913. The correlation between FI SSP progression and the time between MRI scans was weak positive (ρ = 0.31). CONCLUSIONS: Three risk factors for relevant FI progression, quantifiable on the initial MRI, were identified: ≥20-mm mediolateral tear size, ≥9.9% FI SSP , and ≥17-mm anteroposterior tear size. These thresholds were associated with a higher risk of tear progression: 19 times higher for ≥20-mm mediolateral tear size, 17.5 times higher for ≥9.9% FI SSP , and 8 times higher for ≥17-mm anteroposterior tear size. The presence of all 3 yielded a 91% chance of ≥4.5% progression of FI SSP within a mean of 19.5 months. LEVEL OF EVIDENCE: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Improved joint function when reaching behind the back is associated with patient reported outcomes in individuals with rotator cuff tears following exercise therapy.

BACKGROUND: Reaching behind the back is painful for individuals with rotator cuff tears. The objectives of the study were to determine changes in glenohumeral kinematics when reaching behind the back, passive range of motion (RoM), patient reported outcomes and the relationships between kinematics and patient reported outcomes following exercise therapy. METHODS: Eighty-four individuals with symptomatic isolated supraspinatus tears were recruited for this prospective observational study. Glenohumeral kinematics were measured using biplane radiography during a reaching behind the back movement. Passive glenohumeral internal rotation and patient reported outcome measures were collected. Depending on data normality, appropriate tests were utilized to determine changes in variables. Spearman's correlations were utilized for associations, and Stuart-Maxwell tests for changes in distributions. FINDINGS: Maximum active glenohumeral internal rotation increased by 3.2° (P = 0.001), contact path length decreased by 5.5% glenoid size (P = 0.022), passive glenohumeral internal rotation RoM increased by 4.9° (P = 0.001), and Western Ontario Rotator Cuff Index and American Shoulder and Elbow Surgeons scores increased by 29.8 and 21.1 (P = 0.001), respectively. Changes in Western Ontario Rotator Cuff Index scores positively associated with changes in maximum active glenohumeral internal rotation and negatively associated with changes in contact path lengths (P = 0.008 and P = 0.006, respectively). INTERPRETATION: The reaching behind the back movement was useful in elucidating in-vivo mechanistic changes associated with patient reported outcomes. Glenohumeral joint function and patient reported outcomes improved, where changes in Western Ontario Rotator Cuff Index scores were associated with kinematics. These findings inform clinicians of functional changes following exercise therapy and new targetable treatment factors.

Rotator Cuff Injuries in the Pediatric Population: A Retrospective Review of Patient Characteristics and Treatment at a Single Center.

BACKGROUND: As youth participation in contact and overhead sports has increased in recent decades, so has the occurrence of injuries of the shoulder. Rotator cuff injury (RCI) is an infrequent shoulder pathology in pediatric patients and its description in the literature has been scarce. A greater understanding of RCI characteristics and treatment outcomes in children and adolescents would improve our understanding of this pathology and help to better guide clinical decision-making. HYPOTHESIS: To identify pediatric patients with magnetic resonance imaging-confirmed RCI treated at a single center to summarize injury characteristics, treatment, and outcomes. It was hypothesized that injuries would occur predominantly in overhead throwing athletes and would demonstrate good outcomes among both operatively and nonoperatively treated patients. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: A retrospective review of pediatric patients (<18 years old) diagnosed with and treated for an RCI between January 1, 2011 and January 31, 2021. Patient demographics, injury mechanism and type, treatment, and outcomes were collected. Descriptive statistics were performed. Bivariate testing was used to compare operatively and nonoperatively treated cohorts. RESULTS: A total of 52 pediatric patients treated for a rotator cuff avulsion, partial tear, or complete tear were identified. Mean age was 15 years and 67% of patients were male. Injuries were related most commonly to participation in throwing sports. Operative management occurred in 23% of patients, while 77% were managed nonoperatively. Treatment cohorts differed based on tear type, with all complete tears being managed operatively (P < 0.01). Associated shoulder pathology was common, with the most frequent finding being anterior shoulder instability pathology. Return to play was longer for operatively managed patients (7.1 vs 4.5 months; P < 0.01). CONCLUSION: The present study expands the limited data available regarding RCIs in pediatric patients. Most injuries are associated with sports and involve the supraspinatus tendon. RCIs were associated with good outcomes and low rates of reinjury in patients managed both nonoperative and operatively. RCI should be considered in throwing athletes with shoulder pain, even in skeletally immature patients. CLINICAL RELEVANCE: This retrospective study fills the hole in the literature by detailing the patterns associated with RCI characteristics and treatment outcomes. In contrast to studies of adult RCIs, our results suggest that outcomes are good regardless of treatment type.

Bone Marrow Mobilization and Local Stromal Cell-Derived Factor-1α Delivery Enhances Nascent Supraspinatus Muscle Fiber Growth.

Rotator cuff tear is a significant problem that leads to poor clinical outcomes due to muscle degeneration after injury. The objective of this study was to synergistically increase the number of proregenerative cells recruited to injure rotator cuff muscle through a novel dual treatment system, consisting of a bone marrow mobilizing agent (VPC01091), hypothesized to "push" prohealing cells into the blood, and localized delivery of stromal cell-derived factor-1α (SDF-1α), to "pull" the cells to the injury site. Immediately after rotator cuff tendon injury in rat, the mobilizing agent was delivered systemically, and SDF-1α-loaded heparin-based microparticles were injected into the supraspinatus muscle. Regenerative and degenerative changes to supraspinatus muscle and the presence of inflammatory/immune cells, mesenchymal stem cells (MSCs), and satellite cells were assessed via flow cytometry and histology for up to 21 days. After dual treatment, significantly more MSCs (31.9 ± 8.0% single cells) and T lymphocytes (6.7 ± 4.3 per 20 × field of view) were observed in supraspinatus muscle 7 days after injury and treatment compared to injury alone (14.4 ± 6.5% single cells, 1.2 ± 0.7 per 20 × field of view), in addition to an elevated M2:M1 macrophage ratio (3.0 ± 0.5), an indicator of a proregenerative environment. These proregenerative cellular changes were accompanied by increased nascent fiber formation (indicated by embryonic myosin heavy chain staining) at day 7 compared to SDF-1α treatment alone, suggesting that this method may be a promising strategy to influence the early cellular response in muscle and promote a proregenerative microenvironment to increase muscle healing after severe rotator cuff tear.

Platelet-rich plasma-derived exosomes promote rotator cuff tendon-bone healing.

BACKGROUND: Rotator cuff tear (RCT) is the most common type of shoulder joint injury, platelet-rich plasma-derived exosomes (PRP-exos) are highly promising in tissue repair and regeneration. The purpose of this study was to determine the function of PRP-exos in rotator cuff tendon-bone healing. METHODS: PRP-exos were isolated from the rabbit whole blood by differential ultracentrifugation and characterized through transmission electron microscopy assay, nanoparticle tracking analysis, and western blotting. Alkaline phosphatase and Von Kossa staining were used to show tendon-derived stem cell (TDSC) differentiation. RT-qPCR and western blotting were performed to detect COL II, SOX-9, and TIMP-1. To determine the therapeutic effects of PRP-exos in vivo. Thirty New Zealand white rabbits were divided into control, model, and PRP-exos groups. The RCT animal model was constructed. The changes in tendon-bone tissue were determined by HE staining. Contents of COL-II, SOX-9, and TIMP-1 were determined by immunohistochemistry staining. RESULTS: PRP-exos were successfully isolated from rabbit blood. PRP-exos promoted TDSC proliferation and differentiation and also induced tendon-specific markers COL II, SOX-9, and TIMP-1 production. In vivo study revealed that PRP-exos promoted early healing of injured tendons. Rabbits treated with PRP-exos had better tissue arrangement in the tear site. Additionally, the contents of COL II, SOX-9, and TIMP-1 were also increased in the RCT rabbit model after PRP-exos treatment. CONCLUSIONS: PRP-exos enhanced tendon-bone healing by promoting TDSC proliferation and differentiation. This finding indicates that PRP-exos can serve as a promising strategy to treat rotator cuff tendon-bone healing.

Individuals with rotator cuff tears unsuccessfully treated with exercise therapy have less inferiorly oriented net muscle forces during scapular plane abduction.

Exercise therapy for individuals with rotator cuff tears fails in approximately 25.0 % of cases. One reason for failure of exercise therapy may be the inability to strengthen and balance the muscle forces crossing the glenohumeral joint that act to center the humeral head on the glenoid. The objective of the current study was to compare the magnitude and orientation of the net muscle force pre- and post-exercise therapy between subjects successfully and unsuccessfully (e.g. eventually underwent surgery) treated with a 12-week individualized exercise therapy program. Twelve computational musculoskeletal models (n = 6 successful, n = 6 unsuccessful) were developed in OpenSim (v4.0) that incorporated subject specific tear characteristics, muscle peak isometric force, in-vivo kinematics and bony morphology. The models were driven with experimental kinematics and the magnitude and orientation of the net muscle force was determined during scapular plane abduction at pre- and post-exercise therapy timepoints. Subjects unsuccessfully treated had less inferiorly oriented net muscle forces pre- and post-exercise therapy compared to subjects successfully treated (p = 0.039 & 0.045, respectively). No differences were observed in the magnitude of the net muscle force (p > 0.05). The current study developed novel computational musculoskeletal models with subject specific inputs capable of distinguishing between subjects successfully and unsuccessfully treated with exercise therapy. A less inferiorly oriented net muscle force in subjects unsuccessfully treated may increase the risk of superior migration leading to impingement. Adjustments to exercise therapy programs may be warranted to avoid surgery in subjects at risk of unsuccessful treatment.

Age-different BMSCs-derived exosomes accelerate tendon-bone interface healing in rotator cuff tears model.

BACKGROUND: Rotator cuff tears (RCTs) are culprit of shoulder pain and dysfunction. Tendon-bone interface (TBI) mal-healing is an essential contributor to retear after RCTs. Consequently, present project was conducted to investigate the role of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on TBI healing. METHOD: Young BMSCs (Y-BMSCs) and Aged BMSCs (A-BMSCs) were isolated from Young (3-month-old) and old (24-month-old) SD rats, and their-derived exosomes (A-BMSCs-exo and Y-BMSCs-exo) were identified. RCTs model was established, and A-BMSCs-exo and Y-BMSCs-exo were injected at the rotator cuff using hydrogel as a vehicle. Pathological changes of TBI were observed by HE, Sirius Red and Oil Red O staining. Western blotting and RT-qPCR were applied to assess the expression of extracellular matrix (ECM)-, tendon cell (TCs)-, osteogenic-, tendon-derived stem cell (TDSCs)- and angiogenic-associated proteins and mRNAs in TBI. RESULT: Y-BMSCs exhibited increased activity, osteogenic and lipogenic abilities than A-BMSCs. After A-BMSCs-exo and Y-BMSCs-exo treatment, TBI displayed massive sharpey's fibers growing along the tendon longitudinally, and a collagen fiber-chondrocyte migration zone forming a typical tendon-noncalcified fibrocartilage-calcified fibrocartilage-bone structure. A-BMSCs-exo and Y-BMSCs-exo significantly upregulated the expression of collagen Col I/II/III, Aggrecan, TNMD, SCX, Runx2, OPN, CD45, Sox2, CD31 and VEGFR2 in TBI. In vitro, A-BMSCs-exo and Y-BMSCs-exo significantly enhanced the activity of TCs and TDSCs, TDSCs stemness, and reduced the osteogenic and lipogenic capacity of TDSCs. The effect of Y-BMSCs-exo was significantly stronger than that of A-BMSCs-exo. CONCLUSION: BMSCs-derived exosomes facilitate ECM remodeling, osteogenic differentiation, angiogenesis, and stemness of TDSCs, thereby accelerating TBI healing in RCTs, with better outcomes using young individual-derived BMSCs.

From Platelet-Rich Plasma to Mesenchymal Stem Cells: Cartilage, Tendon, and Bone Regeneration With Orthobiologics.

The use of orthobiologics such as platelet-rich plasma, bone marrow aspirate, and stem cells has been proposed as a biologic augmentation for treatment of various conditions of cartilage, tendon, and bone. Although the published evidence is not conclusive, the safety of these treatments and benefits in improving the biologic condition of treated tissues have been confirmed. Osteoarthritis, rotator cuff injuries, and osteonecrosis of the femoral head are three common musculoskeletal conditions associated with the use of orthobiologics in patients with cartilage, tendon, and bone injuries. When reviewing the use of platelet-rich plasma, bone marrow aspirate, and mesenchymal stem cells in patients with these conditions, there is evidence of high safety and positive, but variable, efficacy. Recent studies have shown promising results and have paved the way for research being conducted at many specialized centers around the world.