Enhance Tendon Healing Research Articles

Challenges in tendon–bone healing: emphasizing inflammatory modulation mechanisms and treatment

Tendons are fibrous connective tissues that transmit force from muscles to bones. Despite their ability to withstand various loads, tendons are susceptible to significant damage. The healing process of tendons and ligaments connected to bone surfaces after injury presents a clinical challenge due to the intricate structure, composition, cellular populations, and mechanics of the interface. Inflammation plays a pivotal role in tendon healing, creating an inflammatory microenvironment through cytokines and immune cells that aid in debris clearance, tendon cell proliferation, and collagen fiber formation. However, uncontrolled inflammation can lead to tissue damage, and adhesions, and impede proper tendon healing, culminating in scar tissue formation. Therefore, precise regulation of inflammation is crucial. This review offers insights into the impact of inflammation on tendon–bone healing and its underlying mechanisms. Understanding the inflammatory microenvironment, cellular interactions, and extracellular matrix dynamics is essential for promoting optimal healing of tendon–bone injuries. The roles of fibroblasts, inflammatory cytokines, chemokines, and growth factors in promoting healing, inhibiting scar formation, and facilitating tissue regeneration are discussed, highlighting the necessity of balancing the suppression of detrimental inflammatory responses with the promotion of beneficial aspects to enhance tendon healing outcomes. Additionally, the review explores the significant implications and translational potential of targeted inflammatory modulation therapies in refining strategies for tendon–bone healing treatments.

Growth Differentiation Factor 5-Induced Mesenchymal Stromal Cells Enhance Tendon Healing.

Mesenchymal stromal cells (MSCs) have immense potential for use in musculoskeletal tissue regeneration; however, there is still a paucity of evidence on the effect of tenogenic MSCs (TMSCs) in tendon healing invivo. This study aimed to determine the effects of growth differentiation factor 5 (GDF5)-induced rabbit MSCs (rbMSCs) on infraspinatus tendon healing in a New Zealand white rabbit model. In this study, bone marrow-derived rbMSCs were isolated, and 100 ng/mL GDF5 was used to induce tenogenic differentiation in rbMSC. The effects of GDF5 on rbMSC in vitro were assessed by total collagen assay, gene expression analysis, and immunofluorescence staining of tenogenic markers; native tenocytes isolated from rabbit tendon were used as a positive control. In invivo, a window defect was created on the infraspinatus tendons bilaterally. After 3 weeks, the rabbits (n = 18) were randomly divided into six groups and repaired with various interventions: (1) surgical suture; (2) fibrin glue (FG); (3) suture and FG; (4) suture, FG, and rabbit tenocytes (rbTenocyte); (5) suture, FG, and rbMSCs, and (6) suture, FG, and TMSC. All animals were euthanized at 6 weeks postoperatively. The in vitro GDF5-induced rbMSCs (or TMSC) showed increased total collagen expression, augmented scleraxis (SCX), and type-I collagen (COL1A1) mRNA gene expression levels. Immunofluorescence showed similar expression in GDF5-induced rbMSC to that of rbTenocyte. In vivo histological analysis showed progressive tendon healing in the TMSC-treated group; cells with elongated nuclei aligned parallel to the collagen fibers, and the collagen fibers were in a more organized orientation, along with macroscopic evidence of tendon callus formation. Significant differences were observed in the cell-treated groups compared with the non-cell-treated groups. Histological scoring showed a significantly enhanced tendon healing in the TMSC- and rbMSC-treated groups compared with the rbTenocyte group. The SCX mRNA expression levels, at 6 weeks following repair, were significantly upregulated in the TMSC group. Immunofluorescence showed COL-1 bundles aligned in parallel orientation; this was further confirmed in atomic force microscopy imaging. SCX, TNC, and TNMD were detected in the TMSC group. In conclusion, GDF5 induces tenogenic differentiation in rbMSCs, and TMSC enhances tendon healing invivo compared with conventional suture repair. Impact Statement Tendon tears and degeneration are debilitating clinical conditions. To date, the suture method is the only gold standard for repairing tendons. Mesenchymal stromal cells (MSCs) have been suggested for many years for their potential in tissue regeneration, especially in tendon-degenerative conditions. Growth differentiation factor 5 (GDF5) has been reported to induce human MSC into a tenogenic lineage (or TMSC), hence a potential cell source for tendon regeneration. This study reported on the potential of rabbit MSC to differentiate into TMSC via GDF5 induction and the potential of TMSC in tendon healing in a New Zealand white rabbit infraspinatus tendon model fulfilled with the 3R principle (reduce, reuse, and replace).

Long head of biceps tendon augmentation in rotator cuff repair enhances tendon healing, shoulder function and patient-reported outcomes one-year post-surgery.

The aim is to determine the effect on healing and functionality of patients after 1 year of biceps augmentation of a rotator cuff repair (RCR) compared to RCR plus long head of the biceps (LHB) tenotomy. In addition, to analyse the main factors involved in the recovery after the surgery. A prospective, comparative, non-randomized study (Level of Evidence III) was conducted. Patients with repairable rotator cuff tears were allocated to either the control group, with a double row transosseous equivalent RCR with LHB tenotomy, or the RCR+augmentation with LHB group. Patients were evaluated for radiological (MRI), clinical (cuff size, Patte and Goutallier scales) and functional variables (Constant and American Shoulder and Elbow Surgeons [ASES] scales) before the intervention. At 1-year follow-up cuff healing was confirmed through MRI and functional evaluation with Constant, ASES, simple shoulder test [SST] and Disabilities of the Arm, Shoulder and Hand scales. Seventy-seven patients underwent control or RCR+augmentation with LHB, there were no preoperative differences between the groups. After 1 year of the surgery, re-rupture occurred in 38.5% and 16% of the patients in control and RCR+augmentation with LHB groups, respectively (p = .026). Total functionality was higher (p < .05) in RCR+augmentation with LHB than in the control group: Constant, SST and ASES scales. Among the explored factors involved in healing, re-rupture occurred in 100% of the cases with high fatty degeneration. Besides, higher initial functionality (Constant scale) and RCR+augmentation with LHB increased the odds of healing (odds ratio [OR] = 1.12 [1.04-1.21]; OR = 5 [1, 61], respectively), while higher cuff length had a detrimental effect (OR = 0.92 [0.85-0.99]). RCR+augmentation with LHB achieves a higher healing percentage and a better functional evolution than RCR+LHB tenotomy, 1 year after cuff repair. Fatty degeneration, cuff length and initial functionality are the main factors involved in cuff healing. Level III randomized controlled trial.

Circadian Rhythm-Regulated ADSC-Derived sEVs and a Triphasic Microneedle Delivery System to Enhance Tendon-to-Bone Healing.

Modulating the inflammatory microenvironment to reconstruct the fibrocartilaginous layer while promoting tendon repair is crucial for enhancing tendon-to-bone healing in rotator cuff repair (RCR), a persistent challenge in orthopedics. Small extracellular vesicles (sEVs) hold significant potential to modulate inflammation, yet the efficient production of highly bioactive sEVs remains a substantial barrier to their clinical application. Moreover, achieving minimally invasive local delivery of sEVs to the tendon-to-bone interface presents significant technical difficulties. Herein, the circadian rhythm of adipose-derived stem cells is modulated to increase the yield and enhance the inflammatory regulatory capacity of sEVs. Circadian rhythm-regulated sEVs (CR-sEVs) enhance the cyclic adenosine monophosphate signaling pathway in macrophage (Mφ) via platelet factor 4 delivery, thereby inhibiting Mφ M1 polarization. Subsequently, a triphasic microneedle (MN) scaffold with a tip, stem, and base is designed for the local delivery of CR-sEVs (CR-sEVs/MN) at the tendon-to-bone junction, incorporating tendon-derived decellularized extracellular matrix in the base to facilitate tendon repair. CR-sEVs/MN mitigates inflammation, promotes fibrocartilage regeneration, and enhances tendon healing, thereby improving biomechanical strength and shoulder joint function in a rat RCR model. Combining CR-sEVs with this triphasic microneedle delivery system presents a promising strategy for enhancing tendon-to-bone healing in clinical settings.

Antioxidant Carbon Dots and Ursolic Acid Co-Encapsulated Liposomes Composite Hydrogel for Alleviating Adhesion Formation and Enhancing Tendon Healing in Tendon Injury.

The formation of adhesion after tendon injury represents a major obstacle to tendon repair, and currently there is no effective anti-adhesion method in clinical practice. Oxidative stress, inflammation, and fibrosis can occur in tendon injury and these factors can lead to tendon adhesion. Antioxidant carbon dots and ursolic acid (UA) both possess antioxidant and anti-inflammatory properties. In this experiment, we have for the first time created RCDs/UA@Lipo-HAMA using red fluorescent carbon dots and UA co-encapsulated liposomes composite hyaluronic acid methacryloyl hydrogel. We found that RCDs/UA@Lipo-HAMA could better attenuate adhesion formation and enhance tendon healing in tendon injury. RCDs/UA@Lipo-HAMA were prepared and characterized. In vitro experiments on cellular oxidative stress and fibrosis were performed. Reactive oxygen species (ROS), and immunofluorescent staining of collagens type I (COL I), collagens type III (COL III), and α-smooth muscle actin (α-SMA) were used to evaluate anti-oxidative and anti-fibrotic abilities. In vivo models of Achilles tendon injury repair (ATI) and flexor digitorum profundus tendon injury repair (FDPI) were established. The major organs and blood biochemical indicators of rats were tested to determine the toxicity of RCDs/UA@Lipo-HAMA. Biomechanical testing, motor function analysis, immunofluorescence, and immunohistochemical staining were performed to assess the tendon adhesion and repair after tendon injury. In vitro, the RCDs/UA@Lipo group scavenged excessive ROS, stabilized the mitochondrial membrane potential (ΔΨm), and reduced the expression of COL I, COL III, and α-SMA. In vivo, assessment results showed that the RCDs/UA@Lipo-HAMA group improved collagen arrangement and biomechanical properties, reduced tendon adhesion, and promoted motor function after tendon injury. Additionally, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the RCDs/UA@Lipo-HAMA group increased; the levels of cluster of differentiation 68 (CD68), inducible Nitric Oxide Synthase (iNOS), COL III, α-SMA, Vimentin, and matrix metallopeptidase 2 (MMP2) decreased. In this study, the RCDs/UA@Lipo-HAMA alleviated tendon adhesion formation and enhanced tendon healing by attenuating oxidative stress, inflammation, and fibrosis. This study provided a novel therapeutic approach for the clinical treatment of tendon injury.

The addition of mesenchymal stem cells in a bioabsorbable scaffold does not enhance tendon healing after a repair of rotator cuff tear.

The purpose of the study is to evaluate the healing potential of a full-thickness tendon defect in the rotator cuff of rabbits using a bioabsorbable scaffold impregnated with bone marrow-mesenchymal stem cells (BM-MSCs) or rotator cuff-derived mesenchymal stem cells (RC-MSCs). Sixteen adult rabbits were subjected to a full-thickness rotator cuff deficit. Rabbits were randomly assigned to four groups of four animals. In Group 0 (control), the deficit was left untreated. In Group 1, the deficit was treated with a single synthetic scaffold alone. In Group 2, the deficit was treated with the previous scaffold loaded with allogeneic BM-MSCs. In Group 3, the deficit was treated with the previous scaffold loaded with allogenic RC-MSCs. After animal sacrifice, tissue samples were subjected to histological and immunohistochemical analysis. Group 1 showed the highest mean tendon maturing score (15.3 ± 0.9) postoperatively, being significantly higher, in comparison to groups 0, 2 and 3 (p = 0.01, 0.02 and 0.01, respectively). Group 1 showed the highest mean collagen I/collagen III ratio (1.4 ± 0.8) postoperatively but without any statistical significance. The utilization of MSCs in rotator cuff repair in a rabbit model has not been associated with an enhancement in tendon healing in 16 weeks postoperatively, in comparison to controls and bioabsorbable scaffolds. The addition of MSCs does not result in better rotator cuff healing. Not applicable. This is an animal study.

Searching for Ways to Enhance Tendon Healing in Revision Rotator Cuff Surgery: Letter to the Editor.

Searching for Ways to Enhance Tendon Healing in Revision Rotator Cuff Surgery: Letter to the Editor.

Searching for Ways to Enhance Tendon Healing in Revision Rotator Cuff Surgery: Response.

Searching for Ways to Enhance Tendon Healing in Revision Rotator Cuff Surgery: Response.

A Mesoporous Silica-Loaded Multi-Functional Hydrogel Enhanced Tendon Healing via Immunomodulatory and Pro-Regenerative Effects.

Tendon injuries are pervasive orthopedic injuries encountered by the general population. Nonetheless, recovery after severe injuries, such as Achilles tendon injury, is limited. Consequently, there is a pressing need to devise interventions, including biomaterials, that foster tendon healing. Regrettably, tissue engineering treatments have faced obstacles in crafting appropriate tissue scaffolds and efficacious nanomedical approaches. To surmount these hurdles, an innovative injectable hydrogel (CP@SiO2), comprising puerarin and chitosan through in situ self-assembly, is pioneered while concurrently delivering mesoporous silica nanoparticles for tendon healing. In this research, CP@SiO2 hydrogel is employed for the treatment of Achilles tendon injuries, conducting extensive in vivo and in vitro experiments to evaluate its efficacy. This reults demonstrates that CP@SiO2 hydrogel enhances the proliferation and differentiation of tendon-derived stem cells, and mitigates inflammation through the modulation of macrophage polarization. Furthermore, using histological and behavioral analyses, it is found that CP@SiO2 hydrogel can improve the histological and biomechanical properties of injured tendons. This findings indicate that this multifaceted injectable CP@SiO2 hydrogel constitutes a suitable bioactive material for tendon repair and presents a promising new strategy for the clinical management of tendon injuries.

Chiral Arginine Modified Electrospun Membrane for Enhancing Tendon Healing

AbstractTendon injury is a common motor system disease, impairing joint mobility, and lowering quality of life. Once damaged, tendon has a limited capacity for regeneration. Clinically, available therapeutic strategies have not achieved satisfactory outcomes. Chiral biomaterials can effectively regulate cell behaviors and tissue healing, but have not been applied to injured tendon yet. Here, chiral arginine is attached to electrospun membrane to fabricate chiral scaffolds. L‐chiral scaffold, rather than D‐chiral or R‐chiral scaffold, promotes cell adhesion, proliferation, and tenogenic differentiation. The vinculin/FAK/YAP pathway is discovered to have a significant impact on the processes mentioned above. Additionally, L‐arginine efficiently eliminates reactive oxygen species (ROS) and generates nitric oxide (NO), safeguarding tendon stem/progenitor cells (TSPCs) against oxidative stress. The use of L‐chiral scaffold in a rat model of Achilles tendon injury increases the expression of markers related to tendons and the deposition of collagen. Moreover, L‐chiral scaffold improves tendon structural, functional, and mechanical properties. This L‐chiral scaffold comprehensively enhances tendon healing, providing a promising therapeutic strategy for tendon injury. As a simple and effective method, modification by chiral molecules enriches biomaterial functions and offers a novel option for tissue regeneration.

Biologic augmentation of rotator cuff repair with microfragmented autologous subacromial bursal tissue enveloped in a patch of compressed autologous long head of biceps tendon tissue: the Bio-Ravioli technique

Rotator cuff repair is one of the most frequently performed procedures in orthopedic surgery. However, considering the limited healing potential of rotator cuff tendons, several augmentation strategies have evolved to enhance tendon healing. The purpose of this article was to present a new surgical technique called Bio-Ravioli. Patients with repairable full-thickness posterosuperior rotator cuff tear and a moderate-to-high risk of healing failure were chosen as candidates for the Bio-Ravioli procedure. It is a biologic augmentation strategy to increase healing potential of arthroscopic rotator cuff repair by use of a biologic graft fixed at the bone-tendon interface. The Bio-Ravioli consists of microfragmented autologous subacromial bursal tissue enveloped in a patch of compressed autologous long head of biceps tendon tissue. The rotator cuff is then repaired to the bone and over the graft using a transosseus equivalent configuration. The Bio-Ravioli technique represents an easy and reliable way to increase the healing potential at the bone-tendon interface by using autologous mesenchymal stem cells from different sources: subacromial bursa and long head of the biceps tendon.

Dermal Allograft Augmentation for Large and Massive Rotator Cuff Tears and Revisions: A Case Series.

Introduction Arthroscopic advancements have notably improved rotator cuff repair, yet the healing of tendons and retear risks still pose significant challenges, especially with massive and large tears. These larger tears have shown a quadruple increase in retear rate when the tear size grows from 1-3 cm. The prevalent cause of failure, particularly in tears with fatty degeneration, is suture tearing.As such, techniques that enhance tendon healing are pivotal due to their correlation with improved functional outcomes. Dermal allograft augmentation (DAA) is one method that has demonstrated improvements in rotator cuff repair biomechanics, as well as the promotion of vascularization and neotendon formation. This study evaluates the efficacy of DAA in the postoperative healing of large and massive rotator cuff tears, assessed through patient-reported outcomes and functional range of motion. Methods This retrospective study reviewed a single surgeon's database, selecting patients who underwent arthroscopic surgery for full-thickness rotator cuff tears measuring at least 3 cm, or those with maximum stage II fatty infiltration of the supraspinatus or infraspinatus muscle on MRI. We used three validated patient-reported outcome (PRO) measures, American Shoulder and Elbow Surgeon Score (ASES), Single Assessment Numeric Evaluation (SANE), and Simple Shoulder Test (SST), alongside a range of motion metrics, external rotation (ER), and forward flexion (FF). These were recorded pre-operatively and, at minimum, one year post-operatively, with a standard student t-test employed for comparative analysis. Results Out of 18 total patients, the average age was 61 years, and 83% were male. The cause of injury was mostly traumatic in nature (n=11), with the remainder being chronic (n=7). All three PROs (n=11) demonstrated a statistically significant increase in score including ASES (p=0.003), SANE (p=0.004), and SST (p=0.039). External rotation also significantly improved pre- to post-operative function (46 vs 58, p=0.049).Three patients (17%) suffered from a retear within three months of their rotator cuff repair. Two patients (11%) required a reverse shoulder arthroplasty within a year. Conclusion Our study demonstrated that DAA in rotator cuff repair yielded notable functional and clinical advancements, with a moderately low retear rate as confirmed by ultrasound. These outcomes suggest that DAA is a promising intervention for large and historically difficult rotator cuff tears, offering significant implications for future treatment protocols.

ADVANCED TENDON REPAIR STRATEGIES: FROM EVS TO MRNA-BASED APPROACHES

Approximately 30% of general practice consultations for musculoskeletal pain are related to tendon disorders, causing substantial personal suffering and enormous related healthcare costs. Treatments are often prone to long rehabilitation times, incomplete functional recovery, and secondary complications following surgical repair. Overall, due to their hypocellular and hypovascular nature, the regenerative capacity of tendons is very poor and intrinsically a disorganized scar tissue with inferior biomechanical properties forms after injury. Therefore, advanced therapeutic modalities need to be developed to enable functional tissue regeneration within a degenerative environment, moving beyond pure mechanical repair and overcoming the natural biological limits of tendon healing.Our recent studies have focused on developing biologically augmented treatment strategies for tendon injuries, aiming at restoring a physiological microenvironment and boosting endogenous tissue repair. Along these lines, we have demonstrated that the local application of mesenchymal stromal cell-derived small extracellular vesicles (sEVs) has the potential to improve rotator cuff tendon repair by modulating local inflammation and reduce fibrotic scarring. In another approach, we investigated if the local delivery of the tendon ECM protein SPARC, which we previously demonstrated to be essential for tendon maturation and tissue homeostasis, has the potential to enhance tendon healing. Finally, I will present results demonstrating the utility of nanoparticle-delivered, chemically modified mRNAs (cmRNA) to improve tendon repair.

FGF-2 enriched nanofiber scaffold for advancing achilles tendon healing: a comparative experimental investigation.

Achilles tendon rupture is a common and debilitating injury that significantly impacts mobility and quality of life. Effective treatment options that promote faster and more complete healing are needed. Fibroblast growth factor-2 (FGF-2) has shown potential in enhancing tendon repair. This study aims to investigate the efficacy of FGF-2 in promoting tendon healing in a rat model of Achilles tendon rupture, providing insights into its potential as a therapeutic option. Forty-eight rat hind legs with complete Achilles tendon ruptures were divided into four equal groups: the Sham (S) group (tendon repair only), the Polymer (P) group (tendon repair with scaffold wrapping), the Produced FGF-2 (PF) group (scaffold coated with lab-produced FGF-2), and the Commercial FGF-2 (CF) group (scaffold coated with commercially sourced FGF-2). Histological analyses at two and four weeks post-surgery evaluated healing based on nuclear morphology, vascularity, fibril organization, inflammation, and adipogenesis. At the end of the second week, no macroscopic healing was observed in one rat each from the S and P groups. By the end of the fourth week, macroscopic healing was observed in all groups. The S and P groups exhibited similarly severe fibril disorganization, pathological adipogenesis, and sustained inflammation, particularly at the fourth week. In contrast, the CF group demonstrated improved tendon healing with increased vascularity and extracellular matrix, lower inflammatory cell infiltration, and better fibril organization. Pathological adipogenesis was absent in the CF group, especially at the fourth week. The PF group showed comparable improvements at the second week but experienced a relapse by the 4th week, with increased inflammation and adipogenesis. FGF-2 coated scaffolds significantly enhanced tendon healing in a rat Achilles tendon rupture model by improving fibril organization, increasing vascularity, and reducing inflammation and pathological adipogenesis. These findings suggest that FGF-2 could be a promising therapeutic option for accelerating tendon repair. Future perspectives on tendon repair will focus on enhancing FGF-2 delivery using innovative scaffolds, paving the way for more effective therapies and improved patient outcomes.

Interleukin-6 upregulates extracellular matrix gene expression and transforming growth factor β1 activity of tendon progenitor cells

BackgroundProlonged inflammation during tendon healing and poor intrinsic healing capacity of tendon are causal factors associated with tendon structural and functional degeneration. Tendon cells, consisting of mature tenocytes and tendon progenitor cells (TPC) function to maintain tendon structure via extracellular matrix (ECM) synthesis. Tendon cells can succumb to tissue cytokine/chemokine alterations during healing and consequently contribute to tendon degeneration. Interleukin-(IL-)1β, IL-6 and TNFα are key cytokines upregulated in injured tendons; the specific effects of IL-6 on flexor tendon-derived TPC have not been discerned.MethodsPassage 3 equine superficial digital flexor tendon (SDFT)-derived TPC were isolated from 6 horses. IL-6 impact on the viability (MMT assay with 0, 1, 5 and 10 ng/mL concentrations), migration (scratch motility assay at 0, 10ng/mL concentration) of TPC in monolayer culture were assessed. IL-6 effect on tendon ECM and chondrogenic gene expression (qRT-PCR), TGFβ1 gene expression and activity (ELISA), and MMP-1, -3 and − 13 gene expression of TPC was evaluated.ResultsIL-6 decreased TPC viability and migration. IL-6 treatment at 10 ng/mL significantly up-regulated TGFβ1 gene expression (6.3-fold; p = 0.01) in TPC, and significantly increased the TGFβ1 concentration in cell culture supernates. IL-6 (at 10 ng/mL) significantly up-regulated both tendon ECM (COL1A1:5.3-fold, COL3A1:5.4-fold, COMP 5.5-fold) and chondrogenic (COL2A1:3.9-fold, ACAN:6.2-fold, SOX9:4.8-fold) mRNA expression in TPC. Addition of SB431542, a TGFβ1 receptor inhibitor, to TPC in the presence of IL-6, attenuated the up-regulated tendon ECM and chondrogenic genes.ConclusionIL-6 alters TPC phenotype during in vitro monolayer culture. Pro- and anti-inflammatory roles of IL-6 have been implicated on tendon healing. Our findings demonstrate that IL-6 induces TGFβ1 activity in TPC and affects the basal TPC phenotype (as evidenced via increased tendon ECM and chondrogenic gene expressions). Further investigation of this biological link may serve as a foundation for therapeutic strategies that modulate IL-6 to enhance tendon healing.

Local Injection of Rapamycin-Loaded Pcl-Peg Nanoparticles for Enhanced Tendon Healing in Rotator Cuff Tears via Simultaneously Reducing Fatty Infiltration and Drug Toxicity.

As a common cause of shoulder pain, rotator cuff tears (RCTs) are difficult to treat clinically because of their unsatisfactory prognosis due to the fatty infiltration caused by muscle-derived stem cells (MDSCs). Previous studies have found that rapamycin (RAPA) can inhibit fatty infiltration. However, systemic administration of RAPA may cause complications such as infection and nausea, while local administration of RAPA may lead to the cytotoxicity of tendon cells, affecting the healing of rotator cuffs. In this study, biocompatible and clinically approved polycaprolactone-polyethylene glycol (PCL-PEG) is formulated into an injectable nanoparticle for the sustained release of RAPA. The results indicate that the RAPA/PCL-PEG nanoparticles (NPs) can efficiently prolong the release of RAPA and significantly reduce the cytotoxicity of tendon cells caused by RAPA. Thestudy of the fatty infiltration model in rats with delayed rotator cuff repair shows that weekly intraarticular injection of RAPA/PCL-PEG NPs can more effectively reduce the fatty infiltration and muscle atrophy of rat rotator cuffs and leads to better mechanical properties and gait improvements than a daily intraarticular injection of RAPA. These findings imply that local injection of RAPA/PCL-PEG NPs in the shoulder joints can be a potential clinical option for RCTs patients with fatty infiltration.

Macrophages regulated by cyclooxygenases promote tendon healing via Pla1a/Etv1 axis

Tendon injuries are often accompanied by limited self-healing and common complications, such as re-rupture and adhesion formation. In our previous studies, we discovered that inhibiting cyclooxygenases (COXs) through a sustainable nanoparticle/hydrogel released system prevented adhesion formation. Additionally, we observed a decrease in M1/M2 polarization in the microenvironment. To investigate the mechanism underlying M2 macrophage polarization, we developed a rat flexor tendon injury model and injected macrophages transfected with COX siRNAs. The results confirmed the positive effects of this treatment and identified important targets, namely phospholipase A1 member A (Pla1a) and ETS variant transcription factor 1 (Etv1). We conducted in vivo and in vitro studies based on Pla1a and Etv1. In the in vivo studies, Pla1a/nanoparticle/hydrogel treatment improved the ultimate strength of injured tendons and inhibited flexor tendon adhesion formation. In the in vitro studies, upregulation of Pla1a promoted tendon cell proliferation and suppressed cell apoptosis. Stimulation of Pla1a also downregulated the level of Etv1. Tendon cells transfected with Etv1 siRNAs demonstrated better cell viability and less cell apoptosis. Furthermore, adhesion formation was reduced by treatment with Etv1 siRNAs/nanoparticle/hydrogel. These findings suggest that COX siRNAs-regulated macrophages could enhance tendon healing via the Pla1a/Etv1 axis.

Momordica charantia Enhances Tendon Healing in Rats: An Experimental Study

Momordica charantia (MC) is a traditional plant widely used since ancient times for wound healing. This study evaluated its potential effects on tendon healing. Adult male Wistar albino rats (n = 32, 8 rats in each group) were anesthetized, and their Achilles tendons were prepared for surgical procedures. Group 1 (Cont = control group) was not subjected to any surgery and was used as a control group for baseline values. Group 2 (PR = primary repair group) underwent primary repair (PR) with a monofilament suture after a full-thickness incision of the Achilles tendon. A full-thickness incision was also made to the Achilles tendon of group 3 (CT = collagen tube-administered group), followed by PR and collagen tube insertion. In group 4 (MC = M. charantia-administered group), 1 mL of MC extract was applied locally on the collagen tube in addition to the surgical procedure applied to group 3. The Achilles tendons were excised on the postoperative 40th day and examined stereologically, histologically, and bioinformatically. Data showed that the total volume of the collagen fibers was higher in MC and CT groups than in the PR group. The total volume of the tendon was decreased in MC and CT groups than in the Cont group. The ratios between the volumes of the collagen fibers and total tendon in the MC and CT groups were significantly different from PR, but not different from the Cont group. Additionally, MC improved tenoblastic activity, collagen production, and neovascularization. Bioinformatic interactions showed that the proteases of MC could trigger the signals playing a role on vasculogenesis, reducing inflammation, and contributing to tenoblast activation and collagen remodeling. MC extract ameliorates the healing of injured tendon and can provide satisfactory tendon repair. Further works are recommended to explore the healing capacity of MC.

Adductor longus and brevis lesion in an amateur soccer player: platelet rich plasma and multifractioned hyaluronic acid injections to enhance clinical recovery.

Groin pain is a common issue in athletes, with a particularly high incidence in male soccer players. Adductor muscles are the most involved site of the groin, accounting for up to one-fourth of muscle injuries of that region. Physical therapy and rehabilitation programs for adductor-related groin pain using active exercises are effective in getting athletes back to sport. However, the return-to-play time varies according to the injury severity. Minor lesions can recover in 1-2 weeks, while severer injuries require 8-12 weeks. To enhance tendon healing and shorten the return to play time, intrandentinous injections of Platelet Rich Plasma (PRP) have been proposed. An increasing body of evidence in literature have shown efficacy of platelet rich plasma in aiding the healing process in tendinopathies. Similarly, more recent evidences have proven hyaluronic (HA) acid to have anti-inflammatory, proliferative, repairing, and analgesic effects. This case report presents the clinical application of combined PRP and a multifractioned (a mixture of different molecular weights) HA in a 24-year-old athlete suffering from a hip adductor rupture.

Nanofiber matrix formulations for the delivery of Exendin-4 for tendon regeneration: In vitro and in vivo assessment.

Tendon and ligament injuries are the most common musculoskeletal injuries, which not only impact the quality of life but result in a massive economic burden. Surgical interventions for tendon/ligament injuries utilize biological and/or engineered grafts to reconstruct damaged tissue, but these have limitations. Engineered matrices confer superior physicochemical properties over biological grafts but lack desirable bioactivity to promote tissue healing. While incorporating drugs can enhance bioactivity, large matrix surface areas and hydrophobicity can lead to uncontrolled burst release and/or incomplete release due to binding. To overcome these limitations, we evaluated the delivery of a peptide growth factor (exendin-4; Ex-4) using an enhanced nanofiber matrix in a tendon injury model. To overcome drug surface binding due to matrix hydrophobicity of poly(caprolactone) (PCL)-which would be expected to enhance cell-material interactions-we blended PCL and cellulose acetate (CA) and electrospun nanofiber matrices with fiber diameters ranging from 600 to 1000nm. To avoid burst release and protect the drug, we encapsulated Ex-4 in the open lumen of halloysite nanotubes (HNTs), sealed the HNT tube endings with a polymer blend, and mixed Ex-4-loaded HNTs into the polymer mixture before electrospinning. This reduced burst release from ∼75% to ∼40%, but did not alter matrix morphology, fiber diameter, or tensile properties. We evaluated the bioactivity of the Ex-4 nanofiber formulation by culturing human mesenchymal stem cells (hMSCs) on matrix surfaces for 21 days and measuring tenogenic differentiation, compared with nanofiber matrices in basal media alone. Strikingly, we observed that Ex-4 nanofiber matrices accelerated the hMSC proliferation rate and elevated levels of sulfated glycosaminoglycan, tendon-related genes (Scx, Mkx, and Tnmd), and ECM-related genes (Col-I, Col-III, and Dcn), compared to control. We then assessed the safety and efficacy of Ex-4 nanofiber matrices in a full-thickness rat Achilles tendon defect with histology, marker expression, functional walking track analysis, and mechanical testing. Our analysis confirmed that Ex-4 nanofiber matrices enhanced tendon healing and reduced fibrocartilage formation versus nanofiber matrices alone. These findings implicate Ex-4 as a potentially valuable tool for tendon tissue engineering.