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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Bone marrow mesenchymal stem cell­derived exosomes: A novel therapeutic agent for tendon­bone healing (Review).

In sports medicine, injuries related to the insertion of tendons into bones, including rotator cuff injuries, anterior cruciate ligament injuries and Achilles tendon ruptures, are commonly observed. However, traditional therapies have proven to be insufficient in achieving satisfactory outcomes due to the intricate anatomical structure associated with these injuries. Adult bone marrow mesenchymal stem cells possess self­renewal and multi­directional differentiation potential and can generate various mesenchymal tissues to aid in the recovery of bone, cartilage, adipose tissue and bone marrow hematopoietic tissue. In addition, extracellular vesicles derived from bone marrow mesenchymal stem cells known as exosomes, contain lipids, proteins and nucleic acids that govern the tissue microenvironment, facilitate tissue repair and perform various biological functions. Studies have demonstrated that bone marrow mesenchymal stem cell­derived exosomes can function as natural nanocapsules for drug delivery and can enhance tendon­bone healing strength. The present review discusses the latest research results on the role of exosomes released by bone marrow mesenchymal stem cells in tendon­bone healing and provides valuable information for implementing these techniques in regenerative medicine and sports health.

The relationship between neuropathic pain and the outcomes of minimally invasive pain management in rotator cuff ruptures.

This study aimed to investigate how the presence of neuropathic pain related to partial rotator cuff tears affects the short-term results of subacromial injection and suprascapular nerve blockade therapy in patients with chronic shoulder pain. In this prospective observational study, shoulder pain via verbal numeric pain rating (VNPR, 0-10) and functional status through simple shoulder test (SST) were evaluated before and second week after procedure. After dividing as neuropathic pain and non-neuropathic pain groups, pre-procedural and follow-up scores concerning pain intensity, functional status, and whether there were those of patients with minimal clinically important change (MCIC) in areas of pain and function were evaluated. Between the groups including 140 patients, while there was no statistical difference in baseline pain intensity and functional status (P = .14,.11, respectively), outcomes of those without neuropathic pain were favored at the follow-up (P = .02,.01, respectively). Given baseline pain scores, the reduction (%) was significantly lower in neuropathic pain group (P = .03). There was no significant difference in patients with MCIC in pain intensity and functional status between the groups (P = .08,.59, respectively). An improvement was determined in pain intensity and functional status at the follow-up in both groups (P < .001). The improvement in pain intensity and functional status is poorer in patients with partial rotator cuff rupture-related neuropathic pain than in those without neuropathic pain. However neuropathic pain has no negative effect on the response to treatment.

[Progress and prospect of biological treatment for rotator cuff injury repair].

Objective: To review the research progress in biotherapy of rotator cuff injury in recent years, in order to provide help for clinical decision-making of rotator cuff injury treatment. Methods: The literature related to biotherapy of rotator cuff injury at home and abroad in recent years was widely reviewed, and the mechanism and efficacy of biotherapy for rotator cuff injury were summarized from the aspects of platelet-rich plasma (PRP), growth factors, stem cells, and exosomes. Results: In order to relieve patients' pain, improve upper limb function, and improve quality of life, the treatment of rotator cuff injury experienced an important change from conservative treatment to open surgery to arthroscopic rotator cuff repair. Arthroscopic rotator cuff repair plus a variety of biotherapy methods have become the mainstream of clinical treatment. All kinds of biotherapy methods have ideal mid- and long-term effectiveness in the repair of rotator cuff injury. The biotherapy method to promote the healing of rotator cuff injury is controversial and needs to be further studied. Conclusion: All kinds of biotherapy methods show a good effect on the repair of rotator cuff injury. It will be an important research direction to further develop new biotherapy technology and verify its effectiveness.

Assessment of a Synergistic Effect of Platelet-Rich Plasma and Stem Cell-Seeded Hydrogel for Healing of Rat Chronic Rotator Cuff Injuries.

Outcomes after repair of chronic rotator cuff injuries remain suboptimal. Type-1 collagen-rich tendon hydrogel was previously reported to improve healing in a rat chronic rotator cuff injury model. Stem cell seeding of the tendon hydrogel improved bone quality in the same model. This study aimed to examine whether there was a synergistic and dose-dependent effect of platelet-rich plasma (PRP) on tendon-bone interface healing by combining PRP with stem cell-seeded tendon hydrogel. Human cadaveric tendons were processed into a hydrogel. PRP was prepared at two different platelet concentrations: an initial concentration (initial PRP group) and a higher concentration (concentrated PRP group). Tendon hydrogel was mixed with adipose-derived stem cells and one of the platelet concentrations. Methylcellulose, as opposed to saline, was used as a negative control due to comparable viscosity. The supraspinatus tendon was detached bilaterally in 33 Sprague-Dawley rats (66 shoulders). Eight weeks later, each detached tendon was repaired, and a hydrogel mixture or control was injected at the repair site. Eight weeks after repair, shoulder samples were harvested and assigned for biomechanical testing (n = 42 shoulders) or a combination of bone morphological and histological assessment (n = 24 shoulders). Biomechanical testing showed significantly higher failure load and stiffness in the concentrated PRP group than in control. Yield load in the initial and concentrated PRP groups were significantly higher than that in the control. There were no statistically significant differences between the initial and concentrated PRP groups. The addition of the highly concentrated PRP to stem cells-seeded tendon hydrogel improved healing biomechanically after chronic rotator cuff injury in rats compared to control. However, synergistic and dose-dependent effects were not seen.

Editorial Commentary: Platelet-Rich Plasma Injections Produced a Significant Improvement in Most Patients With Rotator Cuff Tendinopathy.

Platelet-rich plasma (PRP) is an autologous blood product containing a high concentration of platelets, growth factors, and cytokines, which basic science studies have shown may improve tendinopathy. However, there is controversy over its clinical efficacy with randomized controlled trials and subsequent meta-analysis finding mixed results when treating shoulder rotator cuff tendinopathy. The effect of leukocyte concentration on PRP has been shown to be paramount, with different concentrations being favored for different pathologies. In those with tendinopathy, it is unclear whether leukocyte-rich or leukocyte-poor PRP is superior. Recent research shows that PRP injections produced a significant improvement in most patients with rotator cuff tendinopathy. However, improvement in symptoms and functional outcomes is worse in patients who have a partial-thickness rotator cuff tear compared with isolated tendinopathy without a partial tear. PRP may be more advantageous than corticosteroids. Both function as anti-inflammatories, but PRP may be potentially anabolic, whereas as corticosteroids have a catabolic effect on tendons, which may reduce repairability if patients proceed with surgery. Additionally, there are higher infection rates if patients ultimately go on to surgery within 3 months after corticosteroid injections. Ultimately, we must refine the indications for best use for PRP shoulder injections and determine the 5 R's: right patient, right drug, right dose, right route, and right time. Finally, we must remember that patients can first try conservative management, including physical therapy.

Efficacy of five-step shoulder manipulation for rotator cuff-related shoulder pain: protocol for a multicenter randomized controlled trial.

BACKGROUND: Rotator cuff-related shoulder pain (RCRSP) is the most common cause of shoulder disorders. In China, manipulation has been used extensively for the treatment of patients with RCRSP. However, high-quality clinical evidence to support the therapeutic effect of manipulation is still limited. METHODS: A multicenter, participant-, outcome assessor-, and data analyst-blinded, randomized, placebo-controlled trial will be conducted. A total of 280 participants with RCRSP will be recruited from three hospitals and randomly assigned to a five-step shoulder manipulation (FSM) group or a sham manipulation (SM) group. Each group will receive four weekly treatment sessions, with all participants performing exercises at home for 12 weeks. Assessments, namely the Constant-Murley score, visual analog scale, range of motion, and 36-Item Short Form Survey, will be made at baseline, 4, 12, 18, and 24 weeks. Adverse events during the study will also be recorded. DISCUSSION: This is a pragmatic clinical trial to evaluate the efficacy and safety of FSM in patients with RCRSP. The findings of this study will provide worthy clinical evidence for manual therapy for RCRSP. TRIAL REGISTRATION: China Registered Clinical Trial Registration Center ChiCTR2000037577. Registered on 29 August 2020.