INTRODUCTION
Rotator cuff disease is a common and debilitating condition, frequently seen in clinical practice as a significant source of shoulder pain and disability [1]. It is the third most common cause of pain and functional impairment in the general population, following neck and back pain. Within this spectrum, partial-thickness rotator cuff tears (PTRCTs) are particularly challenging due to their high prevalence and propensity to worsen over time [2]. Another common condition associated with rotator cuff disease is subacromial impingement syndrome [3]. Impingement syndrome can exacerbate rotator cuff pathology and is often treated with nonoperative and operative approaches, including injections and physical therapy. Rotator cuff tears (RCTs) often develop without any obvious trauma, gradually becoming symptomatic and leading to chronic pain and disability.
Management of rotator cuff tears, including PTRCTs, involves both nonoperative and operative approaches [2]. The choice of treatment depends on factors such as the severity and size of the tear, symptoms, and functional impairment. However, considerable debate remains about the most effective treatment strategy, particularly for partial-thickness tears. Nonoperative treatments such as physical therapy, exercises, and various injection therapies are commonly used, but their effectiveness in preventing tear progression and promoting tendon healing remains uncertain.
Advances in biologic therapies have introduced a variety of new treatment options for enhancing tissue regeneration and repair. Platelet-rich plasma (PRP) is an autologous blood product enriched with platelets, which release growth factors (GFs) and cytokines that can facilitate tissue healing [4]. Atelocollagen, a highly purified form of collagen with low immunogenicity, has shown promising preclinical results for promoting tendon repair, though clinical evidence is limited [5].
Other injection therapies such as polydeoxyribonucleotide (PDRN), corticosteroids, hyaluronic acid (HA), and prolotherapy are being explored for their potential benefits in treating rotator cuff disease. PDRN, derived from salmon sperm, is thought to promote tissue repair and regeneration by activating adenosine A2A receptors [6]. Corticosteroids are widely used for their powerful anti-inflammatory effects; they provide symptomatic relief, but their potential to weaken tendon tissue is a concern [1]. HA, an essential component of the extracellular matrix (ECM), is used for its viscoelastic properties and ability to improve tendon gliding and reduce pain [7]. Prolotherapy, which involves injecting irritant solutions to stimulate tissue repair, is also being investigated for its role in tendon healing and pain relief [8].
Recent developments in cell therapy have shown promise for the treatment of RCTs. Bone marrow (BM) aspirate concentrate (BMAC) and stem cell therapies are emerging as potential regenerative treatments [9]. BMAC, which is rich in mesenchymal stem cells (MSCs), GFs, and cytokines, has demonstrated potential to enhance tendon healing and tissue regeneration. Stem cell therapy, involving the use of MSCs derived from sources such as BM and adipose tissue, aims to repair and regenerate damaged tendon tissue through differentiation and paracrine effects.
This scoping review consolidates the existing evidence, rationale, and methodology for various injection therapies used to treat rotator cuff disease: PRP, collagen, BMAC, PDRN, corticosteroids, HA, prolotherapy, and cell therapy. By synthesizing data from high-quality studies, we provide a comprehensive overview of the current landscape for these biologic treatments and their role in managing rotator cuff disease. This review will guide clinical decision-making and inform future research directions to optimize treatment outcomes for patients suffering from these shoulder conditions.
METHODS
Search Strategy
This study is a scoping review of injection therapy for treatment of rotator cuff disease. Using a protocol designed by an independent medical librarian (NJK), we performed a systematic search of three electronic databases in May 2024: PubMed, Embase, and Cochrane Library. As search terms, we used MeSH terms in PubMed and the Cochrane Library and Emtree terms in Embase. In addition, related natural languages were added, and Boolean operators (AND, OR, NOT) were combined with the search terms to convert them into search expressions. We used the search terms listed in the Supplementary Material 1 to gather data from the three electronic databases.
Eligibility Criteria
After all publications were identified, duplicates were removed, and study selection was performed by four independent reviewers in two phases. During the first phase, titles and abstracts were reviewed for relevance. In the second phase, full-text articles were examined. A senior author was consulted in cases of disagreement over study inclusion, and all disagreements were resolved by consensus. The references of the included studies were screened using the aforementioned method to identify additional relevant articles.
The selected studies satisfied the following criteria: (1) basic science studies, comparative clinical studies, or systematic reviews, (2) included patients who received injection treatment for rotator cuff disease, (3) had rotator cuff disease as their main subject, and (4) were written in English. This scoping review excluded (1) case series and case reports, (2) letters to editors, (3) studies without rotator cuff disease as the main subject, (4) studies not written in English, and (5) studies without full-text availability. Studies were assessed for eligibility against the criteria summarized in Table 1.
Screening and Data Extraction
After screening the titles and abstracts, discrepancies were discussed until consensus was reached. The full-text articles were then reviewed to determine final study selection based on the inclusion and exclusion criteria. From the sorted articles, only those specifically related to injection therapies were extracted from the EndNote library for further analysis.
RESULTS
Corticosteroids
Studies on corticosteroids for rotator cuff tendinopathy
Rotator cuff tendinopathy is a chronic overuse disease in which inflammation is not characterized pathologically. However, in vitro studies have shown that corticosteroids provide therapeutic effects to the tendon and surrounding connective tissues by inhibiting the production of collagen, ECM molecules, and granulation tissue, in addition to suppressing inflammation [1]. These positive effects of corticosteroid use are relevant only in the early period. One systemic review reported that the long-term harmful effects of glucocorticoids on tendon cells in vitro were reduced cell viability, proliferation, and mechanical properties of the tendon. Another potential adverse effect is an increasing possibility of tendon rupture [10]. Although tendon and fascial ruptures have been reported as complications of injected corticosteroids, the literature does not provide the precise estimates needed to calculate a complication rate.
One systematic review with a meta-analysis of 18 randomized controlled trials comparing various injections for rotator cuff tendinopathy showed that corticosteroids play a role in pain reduction and functional improvement in the short term (3–6 weeks), but not in the long-term (more than 24 weeks) [11]. On the other hand, PRP and prolotherapy yield better outcomes in the long term (more than 24 weeks). In that review, no tendon rupture occurred. Of the 23 trials included, only 8 randomized controlled trials reported minor transient complications from corticosteroid use, such as facial flushing, dizziness with vasovagal reaction, pain, and skin pigmentation.
Another meta-analysis of 11 randomized controlled trials about corticosteroid injection in rotator cuff tendinosis reported that corticosteroid injections provide minimal transient pain relief in a small number of patients with rotator cuff tendinosis, and that they cannot modify the natural course of the disease [12]. Given the discomfort, cost, and potential to accelerate tendon degeneration associated with corticosteroids, they have limited appeal. Their wide use could be attributable to habit, underappreciation of the placebo effect, incentive to satisfy rather than discuss a patient’s desire for physical intervention, or a drive for remuneration, rather than their utility.
Another systematic review of 41 randomized controlled trials about corticosteroid injection and other injections to manage tendinopathy included an analysis of 13 randomized controlled trials about corticosteroid injection to manage rotator cuff tendinopathy [4]. In comparisons with nonsteroidal anti-inflammatory drugs (NSAIDs) and NSAIDs plus placebo injections, no differences in pain or function were found (three studies); nor were differences found when NSAIDs were administered in addition to corticosteroid and placebo injections (four studies). Corticosteroid injections and physiotherapy did not differ in effectiveness (two studies), although one study found greater short-term overall improvement and function after a corticosteroid injection.
Characteristics of corticosteroids and other treatments
Strong evidence has been presented to show that corticosteroid injections are beneficial for treating rotator cuff tendinopathy in the short term [4]. The use of corticosteroid injections, which are potent anti-inflammatories, poses a clinical dilemma because consistent findings suggest good short-term effects despite lack of an inflammatory pathogenesis in tendinopathy. Altered release of toxins and inhibition of collagen, ECM molecules, and granulation tissue might provide a biological basis for this effect.
PRP effectively provided functional improvement in the long term. Several in vitro studies of human samples documented the beneficial anabolic abilities of certain GFs from PRP to promote tendon matrix repair [4]. For rotator cuff disease, the value of adjunct PRP with rotator cuff repair (RCR) surgery is still debated, with no clear improvement reported [8]. In one meta-analysis, older patients did not receive greater benefits from PRP injections, but positive evidence supporting the long-term clinical utility of PRP in patients with rotator cuff tendinopathy was shown [1]. A previous study correspondingly showed that age did not influence the platelet count or GF concentrations in PRP [13].
Regarding prolotherapy, hypertonic dextrose, which is inexpensive, readily available, and reported to be safe, is the solution most used for prolotherapy [14]. Both inflammatory and non-inflammatory pathways for stimulating tissue healing have been demonstrated in basic science studies. The clinical use of prolotherapy is effective in lower limb tendinopathy and fasciopathy [15]. More studies are needed to confirm its role in rotator cuff tendinopathy.
According to one meta-analysis, injections of botulinum toxin, HA, and an NSAID could all be ineffective for rotator cuff tendinopathy. Animal models have demonstrated that the direct analgesic effects of botulinum toxin occur by inhibiting neurotransmitters such as glutamate and substance P [16]. A recent meta-analysis supported the use of botulinum toxin for shoulder pain [17]. Different etiologies and the limited number of studies might contribute to the lack of positive effects of botulinum toxin injection in our review. Similarly, many studies support the beneficial effects of intraarticular HA injection for osteoarthritis of the knee and shoulder [15,16]. However, most of the reported mechanisms of action, such as the promotion of chondrocyte HA synthesis and reduction of matrix metalloproteinases, are specific to osteoarthritis [7]. The clinical value of subacromial HA injection for rotator cuff tendinopathy remained inconclusive in our meta-analysis. According to the previous literature, NSAIDs are inferior to corticosteroid injections for rotator cuff tendinopathy [17].
According to the reviewed studies, corticosteroid injections to treat rotator cuff tendinopathy can be beneficial in the short term, but they are worse than other treatments in the intermediate and long term.
Prolotherapy
Prolotherapy, which involves injections of a hyperosmolar dextrose solution, was initially introduced in the 1950s to manage ligament laxity and related musculoskeletal and arthritic disorders through its potential to enhance tissue healing and promote fibrosis [11]. During the past decade, research on prolotherapy for rotator cuff tendinopathy has gained traction by exploring different injection protocols and techniques that could reinforce tendon structures, promote the repair of tendon defects, and alleviate pain [18-21]. However, robust clinical evidence is lacking, and consensus is needed on optimal treatment parameters, such as the dextrose concentration, injection volume, number of sites to inject, and appropriate dosing schedules. Prolotherapy is a minimally invasive injection treatment designed to address chronic musculoskeletal pain by stimulating the body’s natural healing mechanisms [22]. The therapy involves the injection of small volumes of an irritant solution—most commonly hyperosmolar dextrose—at multiple painful tendon and ligament insertions where they attach to the bone, administered over several treatment sessions. When the hyperosmolar dextrose solution is injected, it triggers a localized inflammatory response at the site of injury. This controlled inflammatory reaction leads to the release of GFs, such as platelet-derived growth factor (PDGF) and fibroblast GF, which activate fibroblast proliferation [23]. As a result, new collagen fibers are synthesized, strengthening the tendon or ligament and enhancing its structural integrity. Through this regenerative mechanism, prolotherapy promotes tissue remodeling and restores tendon resilience, indicating its promise for treating various tendinopathies, including rotator cuff tendinopathy, lateral epicondylitis, Achilles tendinopathy, and plantar fasciitis [22,24].
Randomized clinical trials on prolotherapy for rotator cuff tears
Lin et al. [25] conducted a double-blind randomized controlled study evaluating the effects of hypertonic dextrose injection on pain and shoulder function in patients with chronic supraspinatus tendinopathy. They randomly assigned 57 participants to either the dextrose prolotherapy group (n=29) or a control group receiving injections of normal saline (n=28). Ultrasound-guided injections were administered once. The results showed that the dextrose group experienced a significant reduction (P<0.001) in visual analog scale (VAS) and shoulder pain and disability index (SPADI) scores compared with the control group after 2 weeks, but those improvements were not sustained beyond 6 weeks (P>0.05). On the other hand, the study group exhibited more frequent changes in the echogenicity ratio and mean gray-scale value of the supraspinatus region of interest as a reference to the deltoid muscle region of interest at weeks 6 (P=0.012) and 12 (P=0.002) compared with the control group [25].
Nasiri et al. [26] compared ultrasound-guided dextrose prolotherapy with corticosteroid injections in a randomized clinical trial involving 33 patients with chronic rotator cuff tendinopathy. Both groups exhibited significant improvement in VAS and SPADI scores at 3 and 12 weeks posttreatment. However, no significant difference was observed between the groups. The study concluded that prolotherapy is a safe and effective alternative to corticosteroids for managing chronic rotator cuff pain [26].
Kazempour Mofrad et al. [27] conducted a randomized clinical trial comparing neurofascial dextrose prolotherapy and physiotherapy in 65 patients with chronic rotator cuff tendinopathy. Participants were divided into two groups: prolotherapy (n=32) and physiotherapy (n=33). The results showed that the dextrose prolotherapy group had better pain reduction and functional improvement than the physiotherapy group at 2 weeks and 3 months, though physiotherapy showed more sustained benefits in pain reduction [27].
Seven et al. [19] investigated the efficacy of prolotherapy versus physiotherapy for chronic refractory rotator cuff lesions in a prospective randomized study. They divided 101 patients into two groups: prolotherapy (n=57) and physiotherapy (n=44). The prolotherapy group showed significant improvements in VAS, SPADI, and Western Ontario Rotator Cuff scores at 3, 6, and 12 weeks, with 92.9% of participants reporting good or excellent outcomes, compared with 56.8% in the physiotherapy group [19].
Bertrand et al. [18] performed a triple-blind randomized trial to compare the effects of dextrose prolotherapy and two control injections in patients with painful rotator cuff tendinopathy. Seventy-three participants with chronic shoulder pain due to ultrasound-confirmed supraspinatus tendinosis or tears were divided into three groups. Three monthly injections were performed either (1) onto painful entheses with dextrose (Enthesis-Dextrose), (2) onto entheses with saline (Enthesis-Saline), or (3) above entheses with saline (Superficial-Saline). All solutions included 0.1% lidocaine. All participants received concurrent programmed physical therapy. The study found that the Enthesis-Dextrose group showed better long-term pain reduction and patient satisfaction than the saline groups at the 9-month follow-up [18].
Prolotherapy has demonstrated potential as an effective treatment for rotator cuff tendinopathy, offering pain reduction and functional improvement comparable or superior to conventional therapies. Recent studies support short- and long-term benefits of prolotherapy, but variability in protocols indicates the need for more standardized procedures. Overall, it is a promising alternative, but further high-quality trials are needed to solidify its clinical use.
Hyaluronic Acid
Recently, HA has garnered attention as a potential treatment option for rotator cuff diseases, particularly for its potential for intra-articular injection and its role in promoting tissue regeneration [28,29]. However, previous studies have not reached consensus on its efficacy, and the outcomes appear to vary depending on the application method, molecular weight, and characteristics of the treated lesion.
Molecular biology
HA is an important glycosaminoglycan constituent of the ECM and is composed of repeated disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine [30]. During the healing process after RCR, inflammatory cells accumulate, leading to the formation of fibrotic tissue, which hinders tendon regeneration and impairs tendon healing [31]. HA has anti-inflammatory effects and can alleviate H2O2-induced oxidative stress by decreasing the proportion of apoptotic cells and reversing the activation of caspases 3 and 7 [29]. In addition, by binding to specific cell-associated receptors such as CD44, HA promotes tissue regeneration, enhancing tendon-to-bone healing [32].
Studies on HA for RCTs
Animal studies on rotator cuff tendons
Honda et al. [28] conducted an experiment using a rabbit RCT model and found that applying HA after RCR significantly increased the volume of cartilaginous pellets produced by MSCs compared with the untreated group. Also, the ultimate load-to-failure was significantly greater in the HA group than in the control group (45.61±9.0 N vs. 32.42±9.4 N at 4 weeks, 90.7±16.0 N vs. 66.97±10.0 N at 8 weeks; both P<0.05) [28]. Rhee et al. [33] recently reported an animal experiment using a chronic RCT model, revealing that HA significantly increased the proliferation of fibroblasts. Consequently, an injection mixture of HA and human dermal fibroblasts enhanced the healing of RCTs [33].
Clinical studies on rotator cuff tendons
Ko et al. [34] conducted a double-blind randomized trial comparing the effects of subacromial HA injections and HA combined with extracorporeal shockwave therapy (ESWT) in patients with rotator cuff lesions but without complete tear. Sixty-three patients were assigned to three groups (HA only, HA + ESWT once, and HA + ESWT twice). They reported that combining HA with ESWT significantly improved muscle power and the Constant-Murley score [35] compared with HA alone, and HA + ESWT twice showed better range of motion (ROM) improvements [34].
Jeong et al. [36] conducted a prospective randomized trial on patients with full-thickness RCTs to evaluate the effects of combining atelocollagen and HA injections versus HA alone relative to a control group. Eighty patients were divided into three groups (atelocollagen + HA: 28, HA: 26, control: 26). The results indicated that the combined atelocollagen and HA group had lower retear rates and reduced need for steroid injections than the other groups [36].
Mohebbi et al. [37] conducted a triple-blind randomized trial to compare the effects of high molecular weight and low molecular weight HA in patients with rotator cuff tendinopathy. Fifty-six patients were enrolled and randomly assigned to receive either high molecular weight or low molecular weight HA injections. Both groups showed significant improvement in pain and ROM at 3 months, but the pain, induration (P=0.007), and inflammation at the site of injection were less prominent in the LMW group [37].
On the other hand, Huang et al. [38] performed a prospective, non-randomized comparative study to evaluate the clinical efficacy of PRP injections versus HA injections for PTRCTs. Forty-eight patients were divided into two groups (PRP: 24, HA: 24), and both experienced significant improvement. However, the PRP group exhibited superior passive abduction ROM and Constant-Murley shoulder scores at 3 months [38].
HA shows significant promise in enhancing rotator cuff healing by reducing inflammation, mitigating oxidative stress, and promoting tissue regeneration through interactions with cellular receptors such as CD44. Animal and clinical studies corroborate HA efficacy, indicating improved structural integrity and pain reduction in RCRs.
Collagen
A previous review article [39] explained tendon architecture in terms of type-1 collagen and its significance in managing rotator cuff tendinopathies. Derangements in the tendon matrisome are pathognomonic for musculoskeletal disorders, including RCT. Collagen type-1 accounts for more than 85% of the dry weight of tendon ECM. Current understanding of basic tendon physiology, organization of the ECM, the structure and function of component biomolecules of the matrisome, and underlying regulatory mechanisms explains the pathological events associated with RCT. Histomorphological evidence from RCT patients and animal models illustrates ECM disorganization as the major hallmark of tendinopathy in which a significant decrease in type-1 collagen is prevalent.
Two animal studies explored the effects of injecting collagen into a repaired chronic RCT. Kaizawa et al. [40] explored how an injectable, thermoresponsive, type I collagen-rich hydrogel (tHG) derived from decellularized human tendon affected RCR. They used human cadaveric flexor tendons to prepare the tHG. After bilateral resection of supraspinatus tendons in animals, one shoulder was repaired with a transosseous suture alone (control group) and the other with the same suture plus tHG injection (tHG group). Eight weeks post-repair, the tHG joints showed significantly better biomechanical properties, including greater load to failure, stiffness, energy to failure, strain at failure, and toughness. Additionally, the tHG group had more new cartilage formation. Though bone morphometry at the tendon insertion site showed no significant differences between the groups, the tHG group performed slightly better overall.
Kim et al. [41] investigated the retention and therapeutic effects of injecting extracellular vesicles (EVs) from human umbilical cord-derived MSCs in a collagen gel on RCR. In an experiment with rabbits, four groups were compared: normal (N), repair-only (R), repair with injectable collagen (RC), and repair with EV-laden collagen (RCE). The results showed the presence of EVs at the application site for up to 4 weeks. The RCE group demonstrated significantly better healing at the bone–tendon interface, less fatty degeneration, and improved biomechanical properties (load-to-failure and stiffness) than the RC and R groups. That study concluded that EVs in injectable collagen enhance bone-to-tendon healing and prevent muscle degeneration, suggesting a potential clinical benefit for RCR.
One level 1 study examined the effects of atelocollagen in treating PTRCTs. Kim et al. [5] investigated the effectiveness of atelocollagen injections in treating partial tears of the supraspinatus tendon. The study divided 94 patients into three groups: group 1 received a 0.5 mL atelocollagen injection, group 2 received a 1 mL injection, and group 3 received no injection. Over an average follow-up of 24.7 months, clinical scores (American Shoulder and Elbow Surgeons [ASES], Constant-Murley Shoulder Outcome Score, VAS) improved significantly in the injection groups (groups 1 and 2) compared with pre-treatment, whereas no significant improvement was seen in the control group (group 3). Magnetic resonance imaging (MRI) scans 6 months posttreatment showed structural improvements in 36.7% of the patients in group 2 and 28.1% in group 1, versus only 6.3% in group 3.
Another level 1 study investigated the effectiveness of different treatments for PTRCTs [42]. Researchers compared 3 groups of 30 patients each who received weekly ultrasound-guided shoulder injections: group A received collagen with PRP, group B received collagen alone, and group C received PRP alone. Pain intensity and other health measures were evaluated at the start and at 6, 12, and 24 weeks. The study found no significant differences in pain relief among the groups, although groups A and C showed some improvement trends over time compared with group B. Rotator cuff regeneration and discontinuity were also monitored, with similar results across all groups. Overall, combined collagen and PRP therapy showed effectiveness comparable to that of either treatment alone.
Halm-Pozniak et al. [43] performed a prospective comparative study to investigate the effectiveness of combining autologous conditioned plasma with a recombinant human collagen scaffold injection with that of a corticosteroid/local anesthetic injection for treating external shoulder impingement syndrome. They also examined other factors that can influence treatment outcomes, such as GF concentration, age, and acromial morphology. The study included 58 patients and measured outcomes at intervals using various scores. Both treatment methods improved patient outcomes, with autologous conditioned plasma combined with a recombinant human collagen scaffold showing superior results in increasing shoulder strength. GF levels did not correlate with age, suggesting that autologous conditioned plasma combined with a recombinant human collagen scaffold could be effective for older patients. However, patients with a Bigliani type III acromion had a higher risk of therapy failure, regardless of treatment type.
One level 1 study and 4 level 3 studies investigated the effects of injecting collagen material after RCR. Jeong et al. [36] examined the effects of injecting atelocollagen and HA into repaired rotator cuffs in patients with full-thickness tears. Three groups were compared: one receiving both atelocollagen and HA, one receiving only HA, and one receiving no injections. After 1 year, clinical scores were similar across all groups. However, the group that received both atelocollagen and HA had significantly fewer cases of pain and limited movement requiring steroid treatment at 3 months and a significantly lower rate of rotator cuff retears after 1 year.
Kim et al. [44] compared the effects of atelocollagen injection during arthroscopic RCR in 121 patients with full-thickness RCTs. Group 1 received the injection, and group 2 did not. The results showed that pain levels (VAS scores) were significantly lower in the injection group in the immediate postoperative period. However, shoulder function Korean Shoulder Score did not differ significantly between the groups across 2 years. The retear rates at 6 months, as seen on MRI, also did not differ significantly between the groups.
Aldhafian et al. [45] investigated the safety and effectiveness of atelocollagen and acellular dermal matrix (ADM) allograft injections during arthroscopic repair of full-thickness RCTs. The research involved 129 patients divided into 3 groups: arthroscopic repair only (group 1), repair with atelocollagen injection (group 2), and repair with ADM allograft injection (group 3). During an average follow-up period of 20 months, all groups showed improvement in function and pain scores, with no significant differences among them. The nonhealing and retear rates were similar across the groups, and no adverse events were observed related to the injections. Overall, the study concluded that atelocollagen and ADM allograft injections did not provide outcomes superior to those of standard arthroscopic repair alone.
Ji et al. [46] evaluated the effects of atelocollagen insertion into the bone–tendon interface after arthroscopic RCR for high-grade partial articular supraspinatus tendon avulsion lesions. The study involved 301 patients divided into two groups: one treated with standard trans-tendon suture-bridge repair (group 1) and the other with the addition of atelocollagen (group 2). The outcomes, assessed across a minimum of 2 years, included pain, shoulder function, and tendon integrity measured via MRI. The results showed no significant differences between the groups in most clinical outcomes. However, group 2 had slightly better results in terms of forward flexion and abduction, and less residual discomfort at the final follow-up. Additionally, group 2 showed significantly greater tendon thickness on MRI at all measured time points. Overall, although atelocollagen did not significantly enhance the outcome scores, it did provide some benefits in ROM and tendon thickness.
Kim et al. [47] investigated the clinical and structural outcomes of injectable atelocollagen during arthroscopic RCR for small to medium-sized RCTs. The retrospective analysis included 181 pairs of patients matched by propensity score to reduce bias and compared those who received atelocollagen injections with those who did not. Both groups showed significant postoperative improvements in ROM, muscle strength, and functional outcomes. However, the atelocollagen group had slightly worse outcomes in forward elevation and external rotation compared with the control group at various follow-up points. The ASES score improvement was similar between the groups. The MRI evaluations indicated a slightly better Sugaya grade in the atelocollagen group, but no significant difference in tendon healing failure rates between the groups. Overall, atelocollagen injections did not significantly enhance clinical outcomes, though some differences were seen in the MRI findings.
The key findings of studies about collagen injection include the significant role of type-1 collagen in maintaining tendon structure and function, with its disruption being a hallmark of RCT. Studies using collagen hydrogels, EVs, and atelocollagen injections showed mixed results in improving biomechanical properties, reducing pain, and enhancing tendon healing, with many treatments failing to significantly outperform standard care. Overall, although some benefits were noted, particularly in tendon thickness and reduced degeneration, the clinical efficacy of collagen treatments remains variable. The optimal amount and frequency of collagen injection should be determined in future studies.
Polydeoxyribonucleotide
Research is actively being conducted on the use of percutaneous injections of PDRN to treat rotator cuff tendinopathy. PDRN consists of DNA fragments with LMW (from 50 to 1,500 kDa) and functions as a tissue regeneration promoter with thermostable properties. It binds to the adenosine A2 receptor, inducing the synthesis of vascular endothelial growth factor (VEGF) and causing fibroblasts to produce collagen fibers [48]. One of the most important mechanisms of PDRN is the activation of adenosine A2 receptors, which play a crucial role in regulating inflammation, ischemia, cell growth, and angiogenesis. In practice, PDRN promotes the binding of adenosine to A2A receptors, which increases VEGF expression, cell differentiation, fibroblast maturation, and collagen synthesis to accelerate granulation tissue formation and healing in wound treatment (Fig. 1) [6]. Therefore, PDRN is used in various wound healing and musculoskeletal disorder applications.
PDRN has been extracted from trout, salmon, and sturgeon [49] and used as a regeneration activator for rotator cuff tendinopathy. Studies on the effects of PDRN have reported that it increased tendon–bone healing and decreased fatty degeneration in a rat cuff repair model and improved functional scores for treated shoulders in humans [50-52].
Studies on PDRN for rotator cuff tendon injury
RCTs are a common cause of shoulder pain and functional impairment, with a prevalence of nearly 50% in individuals older than 70 years. When a RCT occurs, muscle fiber atrophy and fibrosis progress, and fat accumulation occurs, a condition known as fatty degeneration [53]. This fatty degeneration is a critical factor in the prognosis after RCR surgery [54]. Several studies have reported methods to biologically reduce fatty degeneration and promote tendon–bone healing at the tendon attachment site.
One study that evaluated histological and biological healing after RCR in a rat model reported that autologous PRP promoted tendon–bone healing [55]. However, another study reported that PRP does not improve tendon healing or functional recovery [56]. According to Hwang et al. [50], PDRN administration in the subacromial joint of a rat model enhanced tendon–bone healing of the infraspinatus tendon and reduced fatty degeneration. Moreover, a diabetic rat cuff repair model verified that PDRN increased mean plasma GF level [57]. A study using a rabbit cuff tear model reported that cuff healing significantly improved when PDRN treatment was combined with human umbilical cord blood (UCB)-derived MSCs with or without microcurrent [58]. Another rabbit study showed that tendon healing improved significantly when PDRN was combined with microcurrent treatment [59]. Another study reported that PDRN combined with human UCB-derived MSCs showed significantly greater improvement in tendon healing than human UCB-derived MSCs alone [60].
Clinical studies have reported that PDRN administration to treat rotator cuff tendinopathy effectively reduced pain and improved function. For example, 3 mL of PDRN and 1 mL of 1% lidocaine were injected into the rotator cuff tear area using ultrasound guidance, and progress was monitored for 3 months [51]. Significant improvements were observed in the VAS and SPADI scores. Other clinical studies have shown similar results. In a study of patients with chronic non-traumatic rotator cuff tendinopathy, the group treated with PDRN showed better improvements in VAS and SPADI scores and analgesic consumption than the group that did not receive PDRN [52].
In brief, PDRN enhances tendon–bone healing and reduces fatty degeneration in rotator cuff tendinopathy, and it has clinically positive effects on pain and function.
PDRN combined with other regenerative materials
PDRN stimulates fibroblasts or macrophages at an injury site to produce VEGF and collagen fibers. Collagen derivatives such as atelocollagen could be a helpful source of collagen for tendon healing when used with PDRN. However, because PRP is a type of concentrated GF, combined PRP and PDRN therapy could produce negative feedback. Further studies are needed to determine the best combinations of regenerative materials. In summary, PDRN is a tissue regeneration activator that enhances GFs and collagen synthesis through receptor–ligand interactions. Therefore, it can be used to treat rotator cuff injury. Because PDRN is a nucleotide-based material, immunogenicity should be rare, and it is suitable for injection.
BM Aspirate Concentrate
BMAC has emerged as an important biologic therapy in regenerative medicine, particularly valued for its potential to enhance tissue repair and recovery after musculoskeletal injuries [61]. BMAC is derived from BM aspirate and processed via centrifugation to concentrate key regenerative components such as MSCs, GFs, cytokines, and other progenitor cells [62]. This unique blend is thought to contribute to improved healing outcomes, especially in the treatment of RCTs and other shoulder disorders [61,63].
Components in BMAC
BM is responsible for producing red blood cells through hematopoiesis and is composed of hematopoietic cells, adipocytes, and supportive stromal cells [64]. Additionally, BM contains MSCs, though their quantity is typically small. MSCs are multipotent progenitor cells found in BM and other tissues and are capable of differentiating into osteoblasts, chondroblasts, and adipocytes [65]. The concentration of MSCs in BM aspirate has been estimated to be 0.001%–0.01% of the total cell population [66]. To address the scarcity of MSCs in BM, BMAC has been developed to offer a higher concentration of MSCs and GFs than are found in BM alone [65]. In BMAC, stem cells are accompanied by various bioactive molecules and GFs such as transforming growth factor beta (TGF-β), PDGF, and VEGF, which play essential roles in stimulating cell growth, differentiation, and tissue regeneration [67-69].
Differences in BMAC based on extraction site
Anz and Sherman [9] investigated the optimal extraction site for BMA to be used during arthroscopic RCR. BM was aspirated from both the posterior superior iliac spine (PSIS) and the proximal humerus, with 60 mL collected from each site in each of 12 patients younger than 80 years. The BMA was processed independently for comparison. BMA from the PSIS was found to contain 3 times the number of nucleated cells and 8.3 times the number of colony-forming units per mL compared with BMA from the proximal humerus. The average extraction time was 5.6 minutes for the PSIS and 11 minutes for the proximal humerus. Therefore, when a high cell yield is required for BMA products in RCR, the PSIS is the preferred extraction site [9].
Clinical studies
Several recent studies have reported a reduction in retear rates when BMAC is applied during RCR. Cole et al. [61] evaluated the clinical outcomes and healing effects of BMAC during arthroscopic RCR. Patients with isolated supraspinatus tears were randomly assigned to either a BMAC group or a placebo group, with clinical outcomes and MRI-determined structural integrity assessed during a 2-year period. The BMAC group demonstrated superior outcomes in terms of retear rates (18% vs. 57%, P<0.001) [61].
Voss et al. [70] conducted a retrospective analysis of the effect of biologic augmentation using BMA harvested from the humeral head and an autologous fibrin scaffold in revision arthroscopic RCR between 2014 and 2015. They analyzed data for 10 patients with a mean follow-up of 30.7 months. Clinical scores showed significant improvement post-surgery (ASES, pain VAS, Simple Shoulder Test), and ROM in flexion and abduction increased significantly, though external rotation did not. A higher number of nucleated cells was associated with greater pain reduction, but not with retear rates. However, 40% of the patients underwent revision surgery during the follow-up period [70].
The effects of BMAC and PRP on the rotator cuff tendon
Liu et al. [71] evaluated the effects of BMAC on tendon-to-bone healing in a chronic RCT model in rabbits. Forty rabbits were divided into five groups (control, saline injection, PRP injection, BMAC injection, PRP+BMAC injection) to analyze the efficacy of BMAC. The BMAC group showed significantly higher stiffness than both the saline and PRP groups (P=0.002 and P=0.006, respectively), with superior collagen fiber continuity and arrangement. The PRP+BMAC group demonstrated the highest mechanical strength. Furthermore, the BMAC contained higher levels of GFs such as insulin-like growth factor 1, TGF-β1, and VEGF than the PRP. In conclusion, BMAC is suggested as a potential therapy to enhance tendon-to-bone healing in RCR surgeries [71].
With partial RCTs, BMAC-PRP injections significantly enhanced pain relief and shoulder function. In Kim et al. [72], 24 patients with partial RCTs were treated with either BMAC-PRP injections (12 patients) or rotator cuff exercises (12 patients) to compare outcomes. At 3 months, the BMAC-PRP group showed a significant reduction in pain, with VAS scores improving more than in the exercise group (P=0.039). The ASES score in the BMAC-PRP group improved from 39.4±13.0 to 74.1±8.5 at 3 months, which was larger than the control group increase from 45.9±12.4 to 62.2±12.2 (P=0.011). Tear size decreased in both groups without a significant difference between them [72].
On the other hand, Spicer et al. [73] conducted a systematic review to assess whether RCRs using BMAC alone or combined with PRP resulted in better functional outcomes. A search of 5 databases yielded 3 studies (1 BMAC with PRP and 2 BMAC only) that met the criteria for inclusion. Functional outcomes were measured using the ASES shoulder score and the University of California Los Angeles shoulder score. The meta-analysis showed no significant difference between the groups, with effect sizes of Cohen's d=2.19 for BMAC with PRP and Cohen's d=2.35 for BMAC alone (P=0.76). The difference in functional outcomes between the two groups was Cohen's d=0.16, which was also not significant. They concluded that using BMAC alone might be more cost-effective [73].
Schoch et al. [74] used a national database to compare the effects of BMAC and PRP on revision surgery rates following arthroscopic RCR. They compared 760 patients who received biologic augmentation during RCR with 3,800 matched controls who underwent RCR without biologics. The results showed that patients treated with BMAC had a significantly lower rate of revision surgery within 2 years (odds ratio [OR], 0.36; 95% CI, 0.15–0.82; P=0.015), but PRP had no significant effect on revision rates (OR, 0.87; 95% CI, 0.62–1.23; P=0.183). They concluded that BMAC might reduce the need for revision surgery, whereas PRP does not appear to have a significant effect, and they suggested that further research be conducted to clarify the role of biologics in RCR [74].
In summary, BMAC has shown potential to improve tendon-to-bone healing and functional outcomes and reduce retear and revision rates in RCR. BMAC, alone or with PRP, provides better clinical outcomes, including pain relief and tissue regeneration, than the standard treatment used as the control. However, more studies are needed to fully understand its role, and further large-scale clinical trials are required to confirm its effectiveness in optimizing surgical outcomes.
Platelet-Rich Plasma
Three-hundred eighty-three studies about PRP were reviewed and categorized into 26 animal studies, 60 clinical studies related to conservative treatment, and 124 clinical studies related to postoperative augmentation, with the remaining studies deemed to be irrelevant. To obtain precise research results, various classification methods for PRP have been attempted [75-77]. Dohan et al. [76] classified platelet concentrates into four categories based on the leukocyte and fibrin content: pure platelet-rich plasma (P-PRP), leukocyte- and platelet-rich plasma (L-PRP), pure platelet-rich fibrin, and leukocyte- and platelet-rich fibrin [76]. Delong et al. [75] proposed the Platelet-Activating Factor classification, which considers the platelet count, activation method, and white cell presence. Jo et al. [77] described the characteristics of PRP applications based on the concentration, activation, and method of application [78]. Common important variables are the absolute number of platelets and the presence or absence of leukocytes.
Animal studies
Several animal studies have demonstrated that PRP promotes healing at the bone–tendon interface [55,79,80]. Peng et al. [80] studied the effects of leukocyte-rich platelet-rich plasma (LR-PRP) and leukocyte-poor platelet-rich plasma (LP-PRP) on bone–tendon interface healing in a rotator cuff injury model with 102 mice. They divided the mice into three groups: LP-PRP group, LR-PRP group, and a control group. Within the first 4 weeks, the LR-PRP group showed faster regeneration than the LP-PRP group, but at 8 weeks, the LP-PRP group exhibited better regeneration. In the LP-PRP group, M2 macrophages, which are known to reduce inflammation and promote healing, remained at the repair site for a longer period, and levels of inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor alpha were maintained at lower levels than in the LR-PRP group, which created a more favorable environment for late-stage bone–tendon healing.
Clinical studies
Conservative treatment
Tanpowpong et al. [81] reported that, in PTRCTs, intralesional PRP injection led to a reduction in tear size compared with corticosteroid injection and improved functional scores at 6 months. Huang et al. [38] demonstrated in patients with PTRCTs that PRP injection did not produce worse pain or functional scores compared with HA injection at the 3-month follow-up, and PRP injection showed superior ROM and Constant-Murley shoulder scores. Overall, in PTRCTs, PRP injections showed clinical outcomes that were comparable to or better than those of HA and corticosteroid injections. According to Pritem et al. [82], PRP injection demonstrated good pain and functional outcomes even in patients without tears. They conducted a study on 30 patients with rotator cuff tendinopathy, excluding those with MRI-confirmed tears. They found that 12 weeks after PRP injection, the VAS score improved from 7.4 to 1.9, and they also reported significant improvements in functional scores.
Pang et al. [83] published a meta-analysis of randomized controlled trials comparing PRP injections to corticosteroid injections for conservative treatment of rotator cuff disease. Compared with corticosteroids, PRP showed poorer short-term (<2 months) outcomes but better intermediate (2 to 6 months) and long-term (>6 months) outcomes. Jiang et al. [84] compared HA and PRP and reported that HA was superior for short-term (1 to 5 months) pain relief, but PRP was superior for long-term (>6 months) pain relief and functional outcomes. In summary, PRP injections generally show long-term outcomes (at least 6 months) that are superior to those from corticosteroid or HA injection.
No clear guidelines on the dosage regimen for PRP administration as a conservative treatment have been published. Among the 60 clinical studies related to conservative treatment using PRP, only seven specified the classification of PRP and number of cells used [85-91]. Most of them showed favorable outcomes. Among them, one study used LR-PRP, and the others used LP-PRP or pure PRP. In two studies, PRP with a concentration less than 800,000/mm3 was used, and in five studies, PRP with a concentration of 1,000,000/mm3 or more was used. The mean volume of PRP injected was 5 mL.
Augmentation for Surgery
PRP can be used in either liquid form or gel form as an augmentation to surgery. In a randomized clinical study, Zhang et al. [86] administered liquid LP-PRP 3 times: during surgery and on days 7 and 14 post-surgery. The group that received PRP showed a reduction in the retear rate and an improvement in fatty infiltration compared with the control group, but clinical scores and pain levels did not differ significantly. Jo et al. [77] achieved good structural outcomes, such as a reduction in retears and an increase in the cross-sectional area of the supraspinatus muscle, using pure-PRP gel augmentation during surgery for medium to massive tears [78]. When applying PRP during surgery, considerations include whether to use the gel or liquid form and determining the appropriate concentration and numbers of leukocytes and platelets. As shown above, both forms of PRP demonstrated effectiveness in improving the structural outcomes of surgery. Hurley et al. [92] conducted a meta-analysis of randomized controlled trials to evaluate the use of LP- or LR-PRP as an adjunct to arthroscopic RCR. LP-PRP was effective in reducing retears and improving patient-reported outcomes, compared with the control group, but it was not clearly superior to LR-PRP. Nunes et al. [93] conducted a systematic review and meta-analysis to examine the effect of PRP dosage on healing following RCR. Patients were divided into a high-concentration PRP group (approximately 106 cells/mm3), a low-concentration PRP group (approximately 5 ×105 cells/mm3), and a non-PRP group for analysis. The high-concentration group showed a 3.9 times higher chance of healing compared with the non-PRP group, and the low-concentration group did not differ significantly from the non-PRP group. Wang et al. [94] reported that PRP injection after RCR did not improve the quality of bone–tendon healing or functional recovery. However, they used a low concentration of PRP (470,000/mm3 in approximately 3 mL). In contrast, the two earlier studies that showed better results used higher concentrations of PRP, with 3 mL administered 3 times and 9 mL in a single administration [78,86]. Rossi et al. [95] obtained similar results using a single 5 mL injection of LP-PRP with a concentration of 1,750,000/mm3. In the three studies with favorable outcomes, the total number of platelets injected was approximately 9 ×109.
Overall, augmenting arthroscopic RCR with PRP improves structural outcomes according to several clinical trials [77,78,86,95]. However, it is unclear whether such supplementation produces significant differences in pain or functional outcomes. The research findings for LP-PRP are more significant than those for LR-PRP, and considering animal study results, LP-PRP is preferred for use as an augmentation after surgery [80,92]. High-concentration PRP demonstrated better structural outcomes than low-concentration PRP, and both the liquid and gel forms showed good results [77,78,86,93].
In summary, PRP injections can be used as a conservative treatment for rotator cuff disorders with the expectation of long-term outcomes, and they can be used as an augmentation to improve structural outcomes from surgical treatment. Although no clear guidelines are available, it can be recommended to use 5 to 10 mL of LP-PRP with a concentration of approximately 106 platelets/mm3.
Stem Cell Therapy
A significant issue in the current landscape of cell therapies is the frequent conflation or confusion between stem cell therapy and minimally manipulated cell therapy (MMCT). Stem cell therapy involves the use of MSCs, which are often cultured and extensively characterized to ensure their identity and functional potential. In contrast, MMCT, which includes treatments using BM mononuclear cells or the stromal vascular fraction, involves cells that are minimally processed and not necessarily enriched for stem cells. This distinction is crucial because MMCT can lead to variability and inconsistent therapeutic effects due to mixed cell populations, limited cell counts, and lack of standardization and characterization. Despite these differences, the terms are often used interchangeably, leading to misunderstandings about the efficacy and potential of these therapies.
In stem cell therapy, it is essential to verify stem cells after culture to ensure their purity, identity, and regeneration potential. However, studies that thoroughly report this process are scarce. Adipose-derived MSCs have been extensively studied for their potential in tendon repair. Jo et al. [96] used a clinical trial design, with patients receiving varying doses: low-dose (1.0 ×107 cells), mid-dose (5.0 ×107 cells), and high-dose (1.0 ×108 cells) [97]. The harvested fat tissues were enzymatically digested, and cells from the stromal vascular fraction were isolated and cultured. The cells were grown in keratinocyte-SFM (Invitrogen)–based medium containing 0.2 mM ascorbic acid, 0.09 mM calcium, 5 ng/mL recombinant epidermal GF, and 5% fetal bovine serum. The mid-dose group showed an 83% reduction in articular defect volume (P=0.022), and the high-dose group exhibited a 90% reduction in bursa side defect volume (P<0.001). Additionally, the high-dose group did not experience an increase in adverse effects, confirming that high-dose adipose-derived MSC injections are a safe and effective treatment option.
Chun et al. [98] reported a randomized controlled study in which they assessed the effectiveness of MSC injections in 24 patients with chronic shoulder pain from partial supraspinatus tendon tears. Patients were injected with stem cells in fibrin glue, a saline/fibrin glue mixture, or saline alone. Over a 2-year follow-up, the groups showed no significant differences in pain reduction, shoulder function, or tear size. They concluded that stem cell injections were not more effective than the control treatments. However, all participants experienced only transient injection site pain, with no persistent adverse events reported. Current research focuses on optimizing cell dosages, improving delivery methods, and understanding the long-term effects of these therapies. However, challenges remain, particularly regarding the consistency and long-term efficacy of such treatments.
Minimally manipulated cell therapy
Ellera Gomes et al. [99] reported that patients who received RCR with BM mononuclear cell transplantation, without the addition of stem cells, showed promising outcomes compared with historical data from patients who underwent the same surgical procedure. Otto et al. [100] indicated that biologically augmented arthroscopic RCR can improve clinical outcomes in both primary and revision surgeries for high-risk patients.
Hurd et al. [101] administered a single injection of an average of 11.4 ×10⁶ fresh, uncultured, unmodified, autologous adipose-derived regenerative cells and reported that, in patients with symptomatic PTRCTs, the treatment was safe and improved shoulder function without adverse effects. The intraoperative injection of autologous micro-fragmented adipose tissue was also demonstrated to be safe and effective in improving short-term clinical and functional outcomes following single-row arthroscopic RCR [102].
Current advances in MMCT, particularly in clinical settings, focus on optimizing techniques for cell harvesting and processing to enhance the therapeutic potential of the cells. Additionally, studies are investigating the most effective cell sources, such as BM or adipose tissue, to maximize treatment efficacy while minimizing procedure invasiveness. Despite those advances, challenges remain, particularly in regeneration outcomes and the long-term efficacy of these therapies.
Although cell therapies offer promising results in tendon repair, the variability in outcomes between stem cell therapy and MMCT needs to be acknowledged. The more controlled and characterized approach of stem cell therapy generally leads to more consistent outcomes, whereas the inherent variability of MMCT might limit its effectiveness and reproducibility. The limitations observed across the reviewed studies include small sample sizes, short follow-up periods, and a lack of standardization, particularly in MMCT studies. These factors constrain the generalizability and reliability of the findings. Therefore, future researchers should conduct large multicenter trials with extended follow-up to fully assess the long-term efficacy and safety of these therapies. The standardization of cell processing and administration protocols is essential to reduce variability and enhance therapeutic outcomes. Furthermore, investigating the interactions between cells and biomaterials is crucial to prevent adverse effects and optimize the safety of combined therapeutic approaches.
Authors' Perspective
Although their clinical availability is low, clinicians should consider using well-characterized MSCs, particularly in patients with tears of significant size, because these cells have shown the most consistent and effective results in experimental studies. Dosing and repeat strategies should be carefully optimized to balance efficacy and safety. MMCT remains a viable option at present. However, clinicians should be aware of the potential for variability in therapeutic outcomes and select their cell sources and harvesting techniques accordingly.
Future research should focus on optimizing protocols for both stem cell therapy and MMCT to improve their consistency and therapeutic efficacy. Larger, long-term studies are needed to confirm the safety and effectiveness of these therapies over extended periods. Additionally, further investigation into the interactions between cells and biomaterials is needed to enhance the safety and success of combined approaches.
DISCUSSION
This scoping review examined various injection therapies used in the treatment of rotator cuff disease, highlighting their mechanisms, clinical applications, and associated outcomes. Injection therapies, while diverse in approach, share a common goal of reducing pain, improving function, and addressing the underlying pathophysiology of rotator cuff disease. However, their relative efficacy, safety, and long-term benefits remain topics of considerable debate, necessitating a detailed exploration of their strengths and limitations.
Corticosteroid injections are widely used in the treatment of rotator cuff disease due to their potent anti-inflammatory properties and their ability to provide significant short-term pain relief and improve function by suppressing inflammation [1]. However, their long-term benefits are limited, with evidence suggesting that they neither prevent disease progression nor enhance tendon healing. Repeated injections pose risks such as tendon degeneration and rupture, raising concerns about their safety in chronic use [11]. Although they remain a valuable option for managing acute pain exacerbations, especially when combined with non-operative interventions, their application should be carefully weighed against the potential long-term complications [11].
PRP has gained significant attention as a regenerative therapy for rotator cuff disease due to its ability to concentrate platelets and GFs that enhance tissue healing and reduce inflammation [4]. Although there are no fixed guidelines for the use of PRP, several studies suggest that using LP-PRP with a concentration greater than 1,000,000/mm3 yields the best results [85,91,93]. As the data from using PRP with clear classifications and dosages increase, it is expected that more definitive guidelines for its use can be established. Recent reports suggest that PRP induces tissue regeneration through M2 macrophage polarization, and that it is possible to isolate exosomes from PRP. It has also been reported that PRP-derived exosomes can assist in tendon–bone healing in RCTs. Further in-depth research on these topics is needed [103]. HA injections have shown potential to improve joint lubrication and provide short-term relief from pain and improved shoulder function in patients with rotator cuff disease. However, the long-term efficacy of HA remains uncertain, with limited evidence supporting sustained benefits [104]. Although it is commonly used to treat osteoarthritis, its application in rotator cuff tendinopathy is less established. Combining HA with other treatments, such as collagen, has demonstrated promise in enhancing outcomes, highlighting the need for further studies to clarify its role and optimize therapeutic protocols.
Prolotherapy involves injecting irritant solutions, such as hypertonic dextrose, to stimulate the body’s natural healing mechanisms [18]. This therapy has demonstrated notable advantages, including long-term pain reduction and functional improvement through collagen synthesis and tendon strengthening [8]. Clinical studies suggest that prolotherapy might achieve short-term efficacy similar to corticosteroids while also providing additional long-term benefits [11,21,27]. However, challenges such as variability in injection protocols, lack of standardized dosing regimens, and limited high-quality research hinder its widespread adoption [12]. Addressing those limitations through rigorous clinical trials and standardized methodologies could enhance its clinical utility and accessibility.
BMAC is a rich source of MSCs, GFs, and cytokines and offers substantial regenerative potential for tendon repair [72]. Clinical and preclinical studies have demonstrated its ability to enhance tendon-to-bone healing, reduce retear rates, and improve functional outcomes in rotator cuff disease [61,70,71]. However, the high cost and complexity of BMAC preparation present significant barriers to its widespread clinical use [65]. Although its regenerative advantages make it a promising option, its challenges limit accessibility and necessitate further research to simplify extraction and delivery methods. Future studies should also explore cost-effective strategies to harness its benefits, aiming to balance its potential with practicality in clinical settings.
Collagen injections aim to restore the structural integrity of damaged tendons by providing a scaffold for tissue regeneration [5,71]. Studies on atelocollagen and other collagen formulations have demonstrated improvements in pain and function and reductions in tendon retear rates, highlighting the potential of this treatment to enhance tendon repair [5,46,47]. However, gaps remain in understanding its clinical efficacy relative to other therapies. Variability in outcomes and the lack of standardized protocols for dosing and application pose challenges to its widespread adoption. Further research is needed to establish optimal treatment parameters and confirm its comparative effectiveness, ensuring its place in the broader spectrum of rotator cuff disease management strategies.
PDRN, derived from DNA fragments, promotes tissue regeneration by activating adenosine A2A receptors and stimulating collagen production [48]. Its key advantages include the ability to enhance tendon healing and reduce fatty degeneration, as demonstrated in preclinical studies [6]. Early clinical trials have shown significant improvements in pain and function, suggesting its potential as a valuable addition to the therapeutic arsenal for rotator cuff disease [59]. However, challenges remain regarding its long-term safety and efficacy, which require further validation through well-designed clinical trials. Addressing these gaps will be critical to fully understanding and optimizing the role of PDRN in rotator cuff disease management.
Stem cell therapy is a cutting-edge approach to regenerative medicine that leverages the multipotent capacity of MSCs to repair and regenerate damaged tissues [97,105]. Early studies have shown promising results, particularly in improving tendon integrity and reducing retear rates in rotator cuff disease, highlighting its potential as a transformative treatment [68,96-98,101]. However, this promise comes with challenges, including high costs, complex regulatory frameworks, and the need for standardized cell preparation and delivery methods [63,65]. These factors currently limit the broad clinical application of stem cell therapy. Addressing these barriers through cost-effective strategies, streamlined regulatory processes, and well-designed clinical trials will be essential to unlocking its full potential and allowing it to become an accessible and reliable option in the management of RCR.
Although this scoping review provides a comprehensive overview of injection therapies for treatment of the rotator cuff, several limitations warrant acknowledgment. First, the variability in study design, population demographics, and methodologies among the included studies complicates direct comparisons and the generalizability of the findings. Specifically, the lack of uniformity in preparation methods and dosing protocols for biologic therapies such as PRP, BMAC, and PDRN introduces heterogeneity that limits definitive conclusions about their efficacy. Second, most studies reviewed were limited by short follow-up periods, which hinders the assessment of long-term outcomes, particularly for regenerative therapies aimed at structural tendon repair. Furthermore, many of the included studies lacked robust randomization, adequate sample sizes, or appropriate controls, raising concerns about potential bias and the reliability of the reported outcomes. Third, the relative paucity of high-quality clinical evidence for certain emerging therapies, such as PDRN and atelocollagen, highlights the need for further research to establish standardized protocols and clarify their role in rotator cuff management. Similarly, although corticosteroid injections are well studied, their reported risks of tendon degeneration underscore the need for studies evaluating safer and more effective alternatives. Last, this review focused on English-language publications, which might have excluded relevant studies published in other languages. Additionally, publication bias might have influenced the representation of positive findings over negative or inconclusive results.
Future research should prioritize large-scale, multicenter, randomized controlled trials with standardized protocols and longer follow-up durations to address these gaps and establish clearer guidelines for the use of injection therapies in rotator cuff disease management.
CONCLUSION
The variety of injection therapies for rotator cuff disease highlights the need for individualized treatment approaches as their effectiveness and long-term benefits remain under investigation. Future research should focus on addressing gaps and optimizing clinical applications by minimizing corticosteroid risks, standardizing PRP and prolotherapy protocols, clarifying the role of HA in symptom relief, refining BMAC delivery and its optimal clinical use, and validating the optimal dosage and regenerative mechanisms of PDRN and collagen-based injections. Stem cell research must overcome regulatory and cost barriers while standardizing its methods. This scoping review can play a crucial role in guiding shoulder clinicians as they select optimal treatment options for rotator cuff patients.
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