Tendon Disorders Research Articles

Safety analysis of fluoroquinolone drugs in elderly patients over 65 based on FAERS

ABSTRACT Objective This study investigates adverse drug event (ADE) reports from the FAERS related to FQs drugs in patients aged 65 and older. The findings aim to guide the rational clinical use of these drugs in elderly patients. Methods We employed Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods to analyze ADE reports for the representative FQ drugs from Q1 2015 to Q4 2023, covering 36 quarters. Results The analysis identified 6883 ADE cases for ciprofloxacin, 5866 for levofloxacin, 1498 for moxifloxacin, and 317 for ofloxacin. Moxifloxacin showed higher incidences of Cardiac disorders and Psychiatric disorders ADEs (4.01%, 23.11%). Ciprofloxacin and levofloxacin showed higher ADE rates in musculoskeletal and connective tissue diseases (20.18% and 26.97%) compared to moxifloxacin (3.62%) and ofloxacin (9.25%). Additionally, moxifloxacin and ofloxacin showed higher ADE rates for eye disorders (10.61% and 15.03%). Conclusion Different FQs exhibit varying ADE profiles across cardiovascular, vascular and lymphatic, renal and urinary, psychiatric, musculoskeletal and connective tissue, and ocular systems. Patients with underlying systemic diseases should avoid FQs with higher ADE risks for their conditions. Personalized medication plans for elderly patients should also be strengthened.

Evaluation of Functional Outcome of Single Dose Intralesional Autologous Blood Vs Corticosteroid Injection in Chronic Plantar Fascitis

Introduction: Plantar fascitis is one of the main underlying causes of acute and chronic heel pain. Diagnosis is mainly based on clinical symptoms and most of the time diagnostic imaging is not required routinely. Corticosteroid injection and autologous blood injection has been a possible means of treatment. Injection of autologous blood can help stimulate a healing response in chronic tendon disorders. Aims: To compare the functional outcome of single dose intra-lesional injection of autologous blood and corticosteroid in chronic plantar fascitis. Methods: This study was done in Nepalgunj medical college and teaching hospital during the period of March 2023 to August 2023 in the department of orthopedics. Sixty patients were enrolled in the study with 30 patients in each group. The patients were selected according to our inclusion and exclusion criteria and diagnosis made on clinical examination alone. The pain status was noted on the visual analog scale and the activity level noted based on the Nirschl stage. The final outcome was based on our scoring system based on the pain status and the activity level at two, four- and twelve-weeks’ duration and graded into four categories as excellent, good, and acceptable and poor. Results: We found that in chronic plantar fascitis, local intralesional steroid injection gives better pain relief and faster return to activities of daily living compared to autologous blood injections. In our study we found that 17.85% had excellent outcome, 35.72% had good outcome and 12% had acceptable outcome in steroid group, whereas in autologous blood group 7.40% had excellent, 22.22% had good and 70.37% had acceptable outcome respectively. Conclusion: Intralesional steroid injection in chronic plantar fascitis have shown to achieve better functional outcome than autologous blood injection.

Clinical Outcomes After Mini-Open Subpectoral Biceps Tenodesis

Background Long head of the biceps tendon pathology is a common cause of shoulder pain. Current surgical treatment options for long head of the biceps tendon disorders include tenotomy and tenodesis. Younger and high-demand patients are usually treated with tenodesis since tenotomy is associated with increased biceps pain and cramping, cosmetic deformity and patient dissatisfaction. Previous studies have shown biomechanical advantages of subpectoral open approach over arthroscopic suprapectoral approach, with less biceps over tension and increased ultimate load to failure. Despite this, there is a lack of consensus in the literature regarding the management of biceps-related pathology. Methods We retrospectively reviewed all patients who underwent subpectoral biceps tenodesis with unicortical endo-button fixation between January 2015 and December 2019. Only patients who had a minimum of 24 months follow-up were included in the study. We reviewed patient demographics. The American Shoulder and Elbow Surgeons and Visual Analogue score were assessed and complications were recorded. Results A total of thirty-two patients were enrolled in this study. 15 were young patients and sports athletes with SLAP (Superior Labrum from Anterior to Posterior) lesions or isolated biceps instability and the remaining 17 were middle-age patients with degenerative biceps disease and concomitant pathology. The mean follow-up time was 36 months. SLAP lesions group average age was 24,3 and degenerative group average age was 53,8. The ASES score and the VAS score and were statically significative better in the isolated subpectoral tenodesis due to SLAP lesions 99,8 and 0,1 respectively in comparison with the degenerative group, 85,7 and 1,5 respectively. We recorded two complications. One case of superficial infection and one case of a patient that was concomitant submitted to arthroscopic rotator cuff tear repair with persisting shoulder pain. There was no case of failure of fixation or associated Popeye deformity. Conclusions Subpectoral biceps tenodesis with unicortical endo-button fixation is a viable treatment option for patients with symptomatic biceps disease. Anterior shoulder pain and biceps symptoms were resolved with this technique. Patients with coexistent rotator cuff lesion may have less favorable outcomes.

Effects of Pulsed Electromagnetic Field Treatment on Skeletal Muscle Tissue Recovery in a Rat Model of Collagenase-Induced Tendinopathy: Results from a Proteome Analysis.

Tendon disorders often result in decreased muscle function and atrophy. Pulsed Electromagnetic Fields (PEMFs) have shown potential in improving tendon fiber structure and muscle recovery. However, the molecular effects of PEMF therapy on skeletal muscle, beyond conventional metrics like MRI or markers of muscle decline, remain largely unexplored. This study investigates the metabolic and structural changes in PEMF-treated muscle tissue using proteomics in a rat model of Achilles tendinopathy induced by collagenase. Sprague Dawley rats were unilaterally induced for tendinopathy with type I collagenase injection and exposed to PEMFs for 8 h/day. Gastrocnemius extracts from untreated or PEMF-treated rats were analyzed with LC-MS/MS, and proteomics differential analysis was conducted through label-free quantitation. PEMF-treated animals exhibited decreased glycolysis and increased LDHB expression, enhancing NAD signaling and ATP production, which boosted respiratory chain activity and fatty acid beta-oxidation. Antioxidant protein levels increased, controlling ROS production. PEMF therapy restored PGC1alpha and YAP levels, decreased by tendinopathy. Additionally, myosins regulating slow-twitch fibers and proteins involved in fiber alignment and force transmission increased, supporting muscle recovery and contractile function. Our findings show that PEMF treatment modulates NAD signaling and oxidative phosphorylation, aiding muscle recovery through the upregulation of YAP and PGC1alpha and increasing slow myosin isoforms, thus speeding up physiological recovery.

Validation and reliability of the Simple Achille Value (SAV) in Achilles tendon disorders

BackgroundAchilles tendon (AT) disorders significantly impact patient life, necessitating accurate assessment tools. Current methods are often complex and time-consuming. This study aims to validate the Simple Ankle Value (SAV) for AT disorders. MethodsA multicenter study was conducted involving 101 participants, including a surgical, a conservative, and a control group. Participants completed the SAV, VISA-A, and EFAS scores. The study assessed correlations among scores, reliability, responsiveness to change, threshold and ceiling effect and discriminative ability of the SAV. ResultsThere was a significant strong correlation with the EFAS and a significant moderate to strong correlation with the VISA-A. The score showed excellent reliability (ρ = 0.95, 95 %CI: [0.913; 0.976], p < 0.001). Responsiveness to change was significant between preoperative and postoperative SAV (37.99 ± 25.73 vs 70.86 ± 21.26). The SAV discriminated between patient and controls with no threshold or ceiling effect. ConclusionThe SAV provides a valid, reliable, and responsive method for assessing AT disorders. It offers a simplified and effective alternative to more complex scores. Study DesignCohort study (Diagnosis); Level of evidence, 2.

Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats

BackgroundTendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study.MethodsHerein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats.ResultsWe discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence.ConclusionIn conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.

Vertical pelvic movement asymmetry and lameness location in ipsilateral combined forelimb and hindlimb lameness cases.

Compensatory vertical head and pelvis movement asymmetry may occur in trotting horses with a primary cause of lameness in one end of the body due to the weight shifting between limbs, leading to apparent combined forelimb and hindlimb lameness (CFHL). Little is known about CFHL patterns observed with body-mounted inertial sensors (BMIS) and regardless of their underlying mechanisms, compensatory and secondary lameness may complicate the definitive identification of the primary causes of lameness. Determine associations between vertical pelvic movement asymmetry and location of primary lameness in ipsilateral CFHL cases where hindlimb lameness is solely impact or push-off type. Retrospective cohort. From a body-mounted inertial sensor (BMIS) evaluated equine lameness database, we identified cases with a consistent, low-variability ipsilateral impact (IpI) or ipsilateral pushoff (IpP) hindlimb lameness in a straight-line trot and that had definitive diagnoses. Cases were categorised by lameness location to the limb(s), diagnosis, and ratio of the amplitude of forelimb to hindlimb lameness (Forea/Hinda). Differences in the numbers of IpI and IpP cases in these categories were analysed with chi-square tests, effect sizes, and odds ratios. Among the 2375 total lameness cases screened, 49 IpI and 36 IpP cases met the criteria for consistency, low variability, and definitive diagnosis. IpI cases were more likely than IpP cases to have forelimb-only lameness causes when Forea/Hinda >1 (OR = 43, 95% CI = 2.3-798). IpP cases were more likely than IpI cases to have hindlimb-only causes at both Forea/Hinda >1.0 (OR = 20, 95% CI = 2.2-200) and <1.0 (OR = 14, 95% CI = 2.9-66.7). Compared with IpI, IpP cases were more frequently diagnosed with tendon, suspensory ligament, or high-motion joint disorders in hindlimbs (OR = 3.6, 95% CI = 1.1-12.3) and less with unknown causes (OR = 13.2, 95% CI = 3.2-75.2). In IpI cases, positive forelimb regional anaesthesia often reduced hindlimb lameness, whereas in IpP cases, positive hindlimb regional anaesthesia typically lessened forelimb lameness. Most cases were Quarter Horses. The likelihood of location and cause of lameness may be different for other breeds. The type of pelvic movement asymmetry observed in IpI and IpP cases is linked to the location and underlying cause of the primary lameness.

The roles and mechanisms of the NF-κB signaling pathway in tendon disorders.

Both acute and chronic tendon injuries are the most frequently occurring musculoskeletal diseases in human and veterinary medicine, with a limited repertoire of successful and evidenced-based therapeutic strategies. Inflammation has been suggested as a key driver for the formation of scar and adhesion tissue following tendon acute injury, as well as pathological alternations of degenerative tendinopathy. However, prior efforts to completely block this inflammatory process have yet to be largely successful. Recent investigations have indicated that a more precise targeted approach for modulating inflammation is critical to improve outcomes. The nuclear factor-kappaB (NF-κB) is a typical proinflammatory signal transduction pathway identified as a key factor leading to tendon disorders. Therefore, a comprehensive understanding of the mechanism or regulation of NF-κB in tendon disorders will aid in developing targeted therapeutic strategies for human and veterinary tendon disorders. In this review, we discuss what is currently known about molecular components and structures of basal NF-κB proteins and two activation pathways: the canonical activation pathway and the non-canonical activation pathway. Furthermore, we summarize the underlying mechanisms of the NF-κB signaling pathway in fibrosis and adhesion after acute tendon injury, as well as pathological changes of degenerative tendinopathy in all species and highlight the effect of targeting this signaling pathway in tendon disorders. However, to gain a comprehensive understanding of its mechanisms underlying tendon disorders, further investigations are required. In the future, extensive scientific examinations are warranted to full characterize the NF-κB, the exact mechanisms of action, and translate findings into clinical human and veterinary practice.

Orthobiologics Injection Therapies in the Treatment of Muscle and Tendon Disorders in Athletes: Fact or Fake?

Orthobiologics Injection Therapies in the Treatment of Muscle and Tendon Disorders in Athletes: Fact or Fake?

Exploring the impact of vitamin D on tendon health: a comprehensive review.

Tendons are vital components of the musculoskeletal system, facilitating movement and supporting mechanical loads. Emerging evidence suggests that vitamin D, beyond its well-established role in bone health, exerts significant effects on tendon physiology. The aim of this manuscript is to review the impact of vitamin D on tendons, focusing on its mechanisms of action, clinical implications, and therapeutic applications. A comprehensive search of scientific electronic databases was conducted to identify articles on the effects of vitamin D ontendon health. Fourteen studies were included in this review. Five studies were performed invitro, and nine studies were conducted invivo. Despite some conflicting results, the included studies showed that vitamin D regulates collagen synthesis, inflammation, and mineralization within tendons through its interaction with vitamin D receptors. Epidemiological studies link vitamin D deficiency with tendon disorders, including tendinopathy and impaired healing. Supplementation with vitamin D shows promise in improving tendon strength and function, particularly in at-risk populations such as athletes and the elderly. Future research should address optimal supplementation strategies and explore the interplay between vitamin D and other factors influencing tendon health. Integrating vitamin D optimization into clinical practice could enhance tendon integrity and reduce the burden of tendon-related pathologies.

Is the Tendon-to-Groove Ratio Associated with Elevated Risk for LHB Tendon Disorders?-A New Approach of Preoperative MR-Graphic Analysis for Targeted Diagnosis of Tendinopathy of the Long Head of Biceps.

Background: Pathologies of the long head of the biceps (LHB) tendon are a common cause of anterior shoulder pain. While the influence of the anatomical morphology of the intertubercular groove (ITG) on the development of LHB tendon instability has been investigated with ambiguous results, the relationship of the LHB to ITG anatomy has not yet been considered in this context. The objective of this study was to reliably extract the tendon-to-groove ratio from MRI scans of symptomatic patients and examine its potential influence on the occurrence of certain causes for LHB-associated symptoms. Methods: In this retrospective study, preoperative MRI scans of 35 patients (mean age of 46 ± 14 years) presenting with anterior shoulder pain and clinical indications of LHB tendinopathy were analyzed in transversal planes. Long and short diameters of the LHB tendon and ITG were measured, cross-sectional areas of the LHB tendon and ITG were calculated from these measurements, and the ratio of cross-sectional areas (LHB/ITG) was introduced. All measurements were repeated independently by three investigators and inter-rater reliability was assessed using intraclass correlation coefficient (ICC). Thereafter, tendon-to-groove ratios were compared in patients with and without intraoperative signs of LHB tendon instability. Results: All patients exhibited intraoperative signs of LHB tendinitis, with additional findings including pulley lesions and SLAP lesions. Analysis revealed variations in the dimensions of the LHB tendon and ITG cross sections, with the tendon-to-groove ratio decreasing from 37% at the pulley to 31% at the deepest point of the sulcus. Very good inter-rater reliability was observed for all measurements. The tendon-to-groove ratio did not significantly differ (p > 0.05) in patients with or without pulley lesions or SLAP lesions. Conclusions: Our study introduced the novel parameter of the tendon-to-groove ratio of cross-sectional areas as a reproducible parameter for the description of local anatomy in the field of targeted diagnosis of LHB tendon disorders. While our findings do not yet support the predictive value of the tendon-to-groove ratio, they underscore the importance of further research with larger cohorts and control groups to validate these observations.

OUTCOMES OF PERONEAL TENDOSCOPY: THE BRISTOL EXPERIENCE

Tendoscopy in the treatment of peroneal tendon disorders is becoming an increasingly safe, reliable, and reproducible technique. Peroneal tendoscopy can be used as both an isolated procedure and as an adjacent procedure with other surgical techniques. The aim of our study was to review all peroneal tendoscopy that was undertaken at the AOC, by the senior authors (IGW, SH), and to determine the safety and efficacy of this surgical technique.MethodsFrom 2000 to 2017 a manual and electronic database search was undertaken of all procedures by the senior authors. Peroneal tendoscopy cases were identified and then prospectively analysed.Results51 patients (23 male, 28 female) were identified from 2004–2017 using a manual and electronic database search. The mean age at time of surgery was 41.5 years (range 16–83) with a mean follow-up time post operatively of 11.8 months (range 9–64 months). The main indications for surgery were lateral and/or postero-lateral ankle pain and lateral ankle swelling. The majority of cases showed unstable peroneal tendon tears that were debrided safely using tendoscopy. Of the 51 patients, 23 required an adjacent foot and ankle operation at the same time, 5 open and 17 arthroscopic (12 ankle, 5 subtalar). Open procedures included 2 first ray osteotomies, 2 open debridements of accessory tissue, one PL to PB transfer. One patient also had an endoscopic FHL transfer. Complication rates to date have been low: 2 superficial wound infections (4%) and one repeat tendoscopy for ongoing pain. A small proportion of patients with ongoing pain were treated with USS guided steroid injections with good results.ConclusionOur series of peroneal tendoscopy has a low complication rate with high patient satisfaction at discharge. Results of tendoscopic treatment are similar to open techniques, however its advantages make tendoscopic procedures an excellent method to treat peroneal tendon disorders.

Ultrasound measurements of the normal peroneal tubercle: validation of the normal anatomical measurements and evaluation of the intra- and interobserver reliability.

The aim of this study was to investigate if ultrasound could be a reliable and accurate tool to measure the size of the peroneal tubercle. This study measured the width, length, and height of the peroneal tubercle in 100 asymptomatic patients, comparing the measurements to prior radiographs of the foot (if available) and previously reported anatomical data. This study also assessed the intra- and interrater reliability of ultrasound as a measurement tool. Our findings show that ultrasound measurements of the peroneal tubercle were consistent with values reported in the literature and prior radiographs concerning width. Both intra- and inter-observer measurements were reliable. This study highlights the potential of ultrasound imaging as a promising tool to measure the peroneal tubercle, and it could contribute to a better understanding of peroneal tendon disorders.

AOFAS Diabetic Foot Survey Results

Introduction: Foot and ankle pathology in patients with diabetes mellitus is prevalent in the United States and may be associated with significant morbidity. Patient outcomes can be improved by optimal medical management; deformity management and correction to limit the development of infection and ulceration; and timely, appropriate treatment of infection and ulceration when it occurs. Orthopaedic foot and ankle surgeons are well-qualified to treat these patients, either individually or as members of a healthcare professional team. However, there are some healthcare professionals and members of the public who are under the impression that orthopaedic foot and ankle surgeon are either unwilling or uninterested in treating this patient population. The authors hypothesized that this impression was a misconception and this study was designed to address this question. Methods: An online survey was sent to 1376 AOFAS members practicing in the United States. There were six questions, two of which were demographic and one that asked for additional comments. The survey was completed by 297 (22%) members from 45 states and the District of Columbia. Results: Nonoperative treatment of foot and ankle disorders in patients with diabetes mellitus was performed by 98.7% of responders including 98.7% for fractures; 97.6% for common disorders (e.g., bunions, hammer toes, flatfeet, plantar fasciitis, osteoarthritis, tendon disorders); 89.9% for Charcot arthropathy; 77.1% for infections; and 69.0% for ulcers. Operative treatment of foot and ankle disorders in patients with diabetes mellitus was performed by 98.7% of responders including 97.0% for fracture fixation; 96.3% for gastrocnemius recession and/ or Achilles tendon lengthening; 94.6% for arthrodesis for osteoarthritis; 94.3% for hammer toe surgery; 92.6% for bunion surgery; 89.6% for Charcot exostectomy; 83.8% for Charcot reconstruction; 83.5% for amputations within foot; 81.1% for below knee amputations; 74.8% for operative debridement of infections/ ulcers; and 57.9% for total ankle replacement. When asked which healthcare professionals treat diabetic patients in their community, 96.6% listed podiatrists; 91.3% listed orthopaedic foot and ankle surgeons; 69.0% listed other MD/ DO surgeons (e.g. general, plastics, vascular); 64.0% listed nurses (e.g., APRN, wound care specialist); 37.4% listed other orthopaedic surgeons; 31.7% listed non- surgeon MD/ DO physicians; 32.3% listed physician assistants; and 2% listed other. Conclusion: The vast majority of orthopaedic foot and ankle surgeons practicing in the United States who responded to the survey provide operative and nonoperative treatment to patients with diabetes mellitus and foot and ankle disorders. Given the extensive medical education and training of orthopaedic foot and ankle surgeons, their knowledge and surgical skill, and the benefits patients with diabetes receive from appropriate and timely foot and ankle care, efforts should be made to educate the public and other healthcare professionals of the availability of most orthopaedic foot and ankle surgeons to provide this care.

The Heel Complex: Anatomy, Imaging, Pathologic Conditions, and Treatment.

The differential diagnosis for heel pain is broad but primarily involves abnormalities of the Achilles tendon, calcaneus, and plantar fascia. Achilles tendon disorders include tendinosis, tendinitis, and partial or complete tears. Tendinosis refers to tendon degeneration, while tendinitis is inflammation after acute overload. Untreated tendinosis can progress to partial or complete tears. Tendon disorders can be accompanied by paratenonitis or inflammation of the loose sheath enclosing the tendon. Initial management involves rehabilitation and image-guided procedures. Operative management is reserved for tendon tears and includes direct repair, tendon transfer, and graft reconstruction. The calcaneus is the most commonly fractured tarsal bone. The majority of fractures are intra-articular; extra-articular fractures, stress or insufficiency fractures, medial process avulsion, and neuropathic avulsion can also occur. Posterosuperior calcaneal exostosis or Haglund deformity, retrocalcaneal bursitis, and insertional Achilles tendinosis form the characteristic triad of Haglund syndrome. It is initially managed with orthotics and physiotherapy. Operative management aims to correct osseous or soft-tissue derangements. The plantar fascia is a strong fibrous tissue that invests the sole of the foot and contributes to midfoot stability. Inflammation or plantar fasciitis is the most common cause of heel pain and can be related to overuse or mechanical causes. Acute rupture is less common but can occur in preexisting plantar fasciitis. Conservative treatment includes footwear modification, calf stretches, and percutaneous procedures. The main operative treatment is plantar fasciotomy. Plantar fibromatosis is a benign fibroblastic proliferation within the fascia that can be locally aggressive and is prone to recurrence. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Adenylate cyclase activates the cAMP signalling pathway to enhance platelet-rich plasma-treated Achilles tendon disease, a theoretical bioinformatics-based study.

The effectiveness of platelet-rich plasma (PRP) for the treatment of Achilles tendon disorders still needs to be evaluated through a series of prospective studies, but genomic analysis can reveal the existence of complementary PRP treatment options. Based on the 96 platelet activation-related genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we performed Gene Ontology functional enrichment analysis and KEGG enrichment analysis, pathway correlation analysis, and enrichment mapping to determine the enrichment results of the gene set enrichment analysis and found that the cAMP signalling pathway may be the key to enhancing the effectiveness of PRP treatment. The cAMP signalling pathway interacts with the Rap1 signalling pathway and cGMP-PKG signalling pathway to mediate the entire pathophysiological process of Achilles tendon disease. Moreover, ADCY1-9 may be the key to the activation of the cAMP signalling network. Further based on the data in the Gene Expression Omnibus database, it was found that ADCY4 and ADCY7 may be the players that play a major role, associated with the STAT4-ADCY4-LAMA5 axis and the GRbeta-ADCY7-SEMA3C axis, which is expected to be a complementary target for enhancing the efficacy of PRP in the treatment of Achilles tendon disease.

Chondroitin sulfate and caseinophosphopeptides doped polyurethane-based highly porous 3D scaffolds for tendon-to-bone regeneration

Tendon disorders are common injuries, which can be greatly debilitating as they are often accompanied by great pain and inflammation. Moreover, several problems are also related to the laceration of the tendon-to-bone interface (TBI), a specific region subjected to great mechanical stresses. The techniques used nowadays for the treatment of tendon and TBI injuries often involve surgery. However, one critical aspect of this procedure involves the elevated risk of fail due to the tissues weakening and the postoperative alterations of the normal joint mechanics. Synthetic polymers, such as thermoplastic polyurethane, are of special interest in the tissue engineering field as they allow the production of scaffolds with tunable elastic and mechanical properties, that could guarantee an effective support during the new tissue formation. Based on these premises, the aim of this work was the design and the development of highly porous 3D scaffolds based on thermoplastic polyurethane, and doped with chondroitin sulfate and caseinophosphopeptides, able to mimic the structural, biomechanical, and biochemical functions of the TBI. The obtained scaffolds were characterized by a homogeneous microporous structure, and by a porosity optimal for cell nutrition and migration. They were also characterized by remarkable mechanical properties, reaching values comparable to the ones of the native tendons. The scaffolds promoted the tenocyte adhesion and proliferation when caseinophosphopetides and chondroitin sulfate are present in the 3D structure. In particular, caseinophosphopeptides’ optimal concentration for cell proliferation resulted 2.4 mg/mL. Finally, the systems evaluation in vivo demonstrated the scaffolds’ safety, since they did not cause any inflammatory effect nor foreign body response, representing interesting platforms for the regeneration of injured TBI.

PLATELET-DERIVED EXTRACELLULAR VESICLES PROMOTE STEM CELL TENOGENIC COMMITMENT IN A BIOENGINEERED TENDON 3D MODEL

Worldwide, tendon disorders are one of the main causes of disability that decrease the quality of life of individuals and represent a substantial economic burden on society. Currently, the main therapies used for tendon injuries are not able to restore tendon functionality, and due to tendons' hypovascular and hypocellular nature, they present a reduced healing capacity, which also limits the success of the available therapies. In order to discover new therapies, extracellular vesicles (EVs), key players in cell-cell communication, have been widely explored for tissue engineering and regenerative medicine applications. Thus, the aim of this study is to assess the role of EVs derived from platelets in stem cell tenogenic commitment using a bioengineered tendon in vitro model for potential use as tendon therapeutic agents. Biomimetic platelet-derived EVs were produced by freeze-thaw cycles of platelets and isolation at different centrifugation speed. To recreate the architecture of tendons, a 3D system consisting of electrospun anisotropic nanofiber scaffolds coated with collagen encapsulating human adipose stem cells (hASCs) and different types of platelet-derived EVs, were produced. Then, the influence of the tendon-mimetic constructs and the distinct EVs populations in the hASCs tenogenic differentiation were assessed over culture time. We observed that the hASCs on the nanofibrous tendon scaffolds, show high cytoskeleton anisotropic organization that is characteristic of tenocytes. Moreover, acting as biological cues, platelet-derived EVs boosted hASCs tenogenic commitment, supported by the increased gene expression of tendon-related markers (SCX and TNMD). Additionally, EVs enhanced the deposition of tendon like extracellular matrix (ECM), as evidenced by the increased gene expression of ECM-related markers such as COL1, COL3, DCN, TNC, and MMP-3, which are fundamental for ECM synthesis and degradation balance. Moreover, EVs induced lower collagen matrix contraction on hASCs, which has been related with lower myofibroblast differentiation. Overall, the results revealed that EVs are capable of modulating stem cells' behavior boosting their tenogenic commitment, through the increased expression of healthy tendon cell markers, potentiating ECM deposition and decreasing cell contractility. Therefore, platelet EVs are a promising biochemical tool, worthy to be further explored, as paracrine signaling that might potentiate tendon repair and regeneration.

HIF-1A INITIATES VASCULAR RECRUITMENT AND IRREVERSIBLE FIBROSIS IN TENDON

Tendinopathy is the most common form of chronic tendon disorders, accounting for up 30% of all musculoskeletal clinic visits [1]. In tendon disease, the largely avascular tendon tissue often becomes hypervascularized and fibrotic [2]. As blood vessel growth and angiogenic signaling molecules are often induced by the lack of adequate nutrients and oxygen, hypoxic signaling is speculated to be a root cause of tendon neovascularization and tendinopathy [3,4,5]. However, how the vascular switch is initiated in tendons, and how vascularization contributes to tendon pathology remains unknown. In this talk, we provide evidence that HIF-1α is implicated in tendon disease and HIF-1α stabilization in human tendon cells induces vascular recruitment of endothelial cells via VEGFa secretion. More interesting, HIF-1α stabilization in tendon cells in vivo, seems to recapitulate all main features of fibrotic human tendon disease, including vascular ingrowth, matrix disorganization, changes in tissue mechanics, cell proliferation and innervation. Surprisingly, in vivo knock-out of VEGFa rescued angiogenesis in the tendon core but it did not affect tendon mechanical properties and tissue pathophysiological changes, suggesting that blood vessels ingrowth might not be a primary cause but a consequence of HIF-1α activation.

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.