Search Results (388)

Background/Objectives: Photobiomodulation Therapy (PBMT) is widely used in musculoskeletal rehabilitation. Although its clinical use continues to expand, the dose-dependent metabolic responses on specific musculoskeletal cell populations remain undefined. This study assessed the effects of 1064 nm PBMT on primary human tenocytes and bursa-derived cells across varying fluence and irradiance. Methods: Primary tenocytes and bursa-derived cells were cultured in 24-well plates and exposed to Hiro TT 1064 nm laser at fluences ranging from 1.5 to 6.0 J/cm² and irradiance levels of 90 or 125 mW/cm². Treatments were administered once daily for three consecutive days. Cellular activity was assessed using an XTT assay and bright field microscopy was performed to assess cell morphology and confluency. Statistical analysis was compared to evaluate dose-dependent effects. Results: PBMT demonstrated tissue-dependent effects on cellular metabolic activity and proliferation. In tenocytes, moderate fluence (4.5–6.0 J/cm²) significantly increased metabolic activity compared with control. In contrast, bursa-derived cells exhibited smaller magnitude changes, with most treatment groups demonstrating neutral or modest deviations from control. Conclusions: PBMT of 1064 nm wavelenght produced distinct dose-dependent responses in musculoskeletal cell types, with tenocytes demonstrating a threshold-dependent response and bursa-derived cells showing attenuated effects. These findings support the need for tissue-specific parameters when applying PBMT in clinical tendon-related applications. Full article

At the dawn of the 20th century, seminal studies revealed that muscle fibers produce less heat and generate greater force during elongation than during shortening actions, laying the foundation for contemporary research on eccentric exercise. Today, eccentric exercise is widely used by athletes to enhance strength and by older adults to maintain functional capacity, yet it may cause muscle damage, particularly in unaccustomed muscles. Despite more than a century of investigation, the precise mechanisms of eccentric exercise-induced muscle damage remain incompletely resolved. Nevertheless, eccentric exercise serves as a valuable model for studying muscle injury and repair and adaptation. This review organizes current evidence into nine key themes: (1) eccentric exercise-induced muscle damage and flawed biomarkers, (2) satellite cell-mediated and alternative repair pathways, (3) high-force, low-cost contractions and metabolic impact, (4) repeated bout effect and protective adaptations, (5) architectural remodeling of fascicles, sarcomeres and tendon, (6) distinct neural control, proprioception, and cross-education adaptations, (7) mitochondrial, sarcoplasmic reticulum, and cytoskeletal stress remodeling, (8) connective tissue perturbation, remodeling, and joint stability, and (9) targeted, cautious use of antioxidant supplementation. Rather than offering a comprehensive overview, this review highlights pivotal experiments, concepts, and controversies within these themes to guide readers to the most impactful discoveries in eccentric exercise and muscle damage. Full article

The in vivo effect of platelet-rich plasma (PRP) on supraspinatus tendon morphology and subacromial bursa cell gene expression in degenerative rotator cuff tears remains unclear. This randomized controlled trial evaluated the effect of preoperative leukocyte-poor PRP (LP-PRP) subacromial injection on supraspinatus tendon histology and subacromial bursa gene expression. Sixteen patients with full-thickness supraspinatus tears were randomized to receive an ultrasound-guided LP-PRP injection (n = 8) or no injection (n = 8) six weeks before arthroscopic repair. Tendon biopsies were assessed using the modified Movin score. Gene expression of collagen type I, II and III, metalloproteinase 3 and 13, and interleukin 1β and 6 genes from subacromial bursa cells was quantified using quantitative real-time PCR. The results of the two groups were compared to determine any statistically significant difference regarding all the examined parameters. The PRP group demonstrated a significantly lower total modified Movin score than controls (6.5 vs. 12.1, p = 0.002), with lower scores for fiber structure, fiber arrangement, nuclear rounding, inflammation and cell density (all p < 0.003), while angiogenesis did not differ (p = 0.149), indicating an architecture closer to that of normal tendon. No statistically significant differences in gene expression were observed (all p > 0.05), although collagen II and metalloproteinase 3 and 13 showed biologically relevant downregulation [fold change 0.23 (95%CI 0.05–1.09), 0.24 (95%CI 0.002–26.10), and 0.26 (95%CI 0.02–2.76), respectively]. The LP-PRP injection was associated with improved supraspinatus tendon histological characteristics and biologically relevant reductions in selected bursal genes, in the setting of supraspinatus tendon tear. Full article

Tendon-derived stem cells (TDSCs) are a unique cell population found in tendons, exhibiting both mesenchymal stem cell (MSC)-like phenotypes and tendon-specific markers. They have emerged as a promising research tool in tendon-related tissue engineering studies. However, there is currently no well-characterized TDSC line with MSC-related phenotypes for investigating tendon biology or developing therapeutics. Here, we established an immortalized monoclonal TDSC, named iTDSC#6, from the Achilles tendon of an adult male Sprague-Dawley rat. Cell clones were characterized for MSC-associated cell surface markers, colony formation capacity, and trilineage differentiation potentials, tenogenic potential and SV40LT expression at both early (passage < 10) and late (passage > 30) stages. iTDSC#6 showed stable expression of Simian virus 40 large T antigen (SV40LT) and demonstrated similar MSC-like phenotypes as its wild-type counterpart at both early and late passages, including colony formation capability and multi-lineage differentiation potentials. iTDSC#6 was positive for the MSC markers CD90, CD44, CD29 and CD73 (≥95%) and negative for the hematopoietic markers CD34 and CD45 (<1%). Regarding its utility for basic research and therapeutic development, iTDSC#6 showed potential for modelling cells with increased levels of senescence-associated beta-galactosidase activity in response to hydrogen peroxide and for bioengineering scaffold-free, tendon-like 3D constructs as evidenced by its upregulation of tendon-related markers, high nuclear aspect ratio, and aligned collagen organization. In conclusion, an immortalized TDSC line was successfully established that shows promise as a useful research tool to study tendon biology and aid the development of therapeutics for tissue engineering and regenerative medicine. Full article

Tendon and ligament injuries are frequent in sport horses and are prone to recurrence due to incomplete healing. Platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) are increasingly used, but data controlled on the early effects of autologous MSCs remain limited. A prospective randomized, double-blind, placebo-controlled trial was conducted in horses with naturally occurring tendinopathies. After standardized PRP pretreatment, non-responders were randomized to receive intralesional autologous muscle-derived MSCs (mdMSCs, n = 17) or placebo (n = 6). Clinical and ultrasonographic parameters were evaluated at the recruitment period (T0) before the administration of the local treatment (T1), 4 (T2) and 8 weeks later (T3). Eighteen horses from both groups received at T2 a second intralesional injection of mdMSCs at the investigator’s discretion; this phase was not randomized. Horses treated with mdMSCs showed significant improvements from T1 to T2 across both clinical and ultrasonographic parameters, whereas no significant changes were observed in the placebo group. Between-group comparison at T2 confirmed the significant superiority of mdMSCs. Further improvements were observed between T2 and T3 in the 18 horses that received a second injection. No systemic adverse events were recorded, and local reactions were mild and transient. This randomized controlled trial demonstrates early clinical and ultrasonographic efficacy of autologous mdMSCs in equine tendinopathy, with additional benefit from a second injection. The autologous approach combines efficacy and safety while avoiding the immunological and logistical constraints of allogeneic strategies. Full article

Background/Objectives: Tenosynovial giant cell tumours (TGCT) are a group of mesenchymal tumours involving the synovium, bursae, and tendon sheaths, comprising two subtypes: nodular and diffuse. Although predominantly benign, diffuse forms can be locally aggressive, resulting in bone destruction. The pathogenesis of TGCTs is still poorly understood. The aim of this study was to systematically review the current literature on the factors, mechanisms, and markers involved in TGCT disease, focussing on their potential role in bone destruction. Methods: This systematic review was conducted using the PRISMA guidelines. A search was performed using PubMed, Scopus, and Cochrane Library, and all original scientific research into mechanisms/pathways/signalling involving TGCTs was included. Results: After the review process, 51 studies were included for data extraction. Extracted data included authorship, publication year, patient numbers and aetiology (nTGCT/dTGCT), demographics, investigative methods, and studied biological factors, mechanisms, and markers. Cross-tabulation of reported elements revealed 159 unique factors, with most appearing only once. Eight elements were reported five or more times: CSF1, CD68, Ki-67, MMP9, CD163, TRAP, TNF-α, and IL-1β. Although representing just 5% of all identified factors, these appeared in 69% of the included studies, highlighting their prominence in the literature. Conclusions: Apart from the well-known osteoclastogenesis factor CSF1, inflammatory cytokines (TNF-α and IL-1β) and monocyte–macrophage lineage makers (CD68, CD163) are signalling pathways key to TGCT disease progression and associated bone destruction. Full article

Orthobiologic treatments such as platelet-rich plasma and stem cell therapies are increasingly used to support the healing of tendons, ligaments, and joints. This perspective proposes applying periodization—a structured, progressive model borrowed from athletic training—to rehabilitation following orthobiologic interventions in order to improve functional outcomes. The framework is organized into sequential phases that align with biological stages of healing. Early phases emphasize pain control, inflammation management, and safe, controlled mobility. Rehabilitation then progresses toward gradually increasing load bearing and strength, and toward more specific exercises to promote tissue regeneration while reducing the risk of re-injury. In later phases (mesocycles), the model highlights the importance of neuroplastic adaptations for sustained functional recovery, including neurogenesis, synaptic plasticity, and functional remodeling to safer RTP for athletes. A key advantage of this approach is its adaptability: progression can be individualized according to a patient’s recovery trajectory and response to loading. By aligning rehabilitation progression with intrinsic healing processes and integrating physiological and neuromuscular goals, the proposed model aims to maximize regenerative potential across both athletic and non-athletic populations. Overall, this neuroplastic periodized approach offers a practical, evidence-informed structure to guide clinicians in delivering patient-centered regenerative rehabilitation and may help standardize care after orthobiologic procedures. Full article

Achilles tendon rupture often leads to poor functional recovery due to limited self-healing, with mitochondrial dysfunction in tendon stromal cells (TSCs) being a key factor in disease progression. Here, we developed adipose-derived stromal cell (ADSC) membrane-coated mitochondria (Mito-NPs) to target this dysfunction and evaluate their therapeutic potential for tendon repair. Mito-NPs exhibited uniform size, stable surface charge, and effective membrane coating. In lipopolysaccharide-induced inflammatory TSCs, Mito-NPs enhanced oxidative phosphorylation, improved mitochondrial metabolic homeostasis, and reshaped gene expression profiles to normalize TSC functional phenotypes, including inflammation, migration, and collagen synthesis. When encapsulated in a reactive oxygen species (ROS)-responsive hydrogel (Mito-NPs@HG) and implanted into rat Achilles tendon injuries, Mito-NPs@HG improved gait function, decreased local inflammation, and promoted histological repair of damaged tendons by enhancing collagen organization and reducing inflammation. Our findings demonstrate that ADSC membrane-coated mitochondria effectively rescue TSC dysfunction and facilitate tendon regeneration, providing a promising translational strategy for treating tendon injuries. Full article

Shoulder calcific tendinopathy is a common condition affecting adults and is has a higher incidence in women. This condition is due to a multifactorial process and is characterized by the deposition of hydroxyapatite crystals in the rotator cuff tendons. The disease shows a phenotypic transformation of tenocytes into chondrocyte-like cells, likely caused by metabolic and inflammatory changes and mechanical stress. Risk factors promoting this pathology include hyperlipidemia, advanced age, diabetes, female gender, and thyroid dysfunction. Recent studies highlight that metalloproteinases, oxidative stress, inflammatory mediators, bone morphogenetic proteins (BMPs), genetic and post-transcriptional alterations play a significant role in the pathogenesis of the disease. New therapeutic strategies are currently available that aim to modulate inflammation, osteogenic differentiation, and calcium homeostasis, showing promising results, especially in preclinical models. The aim of this review is to explore the different pathogenetic mechanisms and highlight future therapeutic developments for the treatment of shoulder calcification. Full article

Background: Well-known risk factors for soft tissue heterotopic ossification (HO) include aging and mechanical stress, which may be linked to oxidative stress and downstream nucleotide metabolites. Thus, we investigated the involvement of extracellular ATP (ex-ATP) and its metabolites in the oxidative stress-induced mineralization of TT-D6 cells and primary mouse tendon cells. Methods: An osteogenic culture with the intermittent addition of hydrogen peroxide was monitored for two weeks using metabolomic and gene expression analyses. Results: Calcium deposition was significantly enhanced by 0.3 mM hydrogen peroxide in the osteogenic media after 2 weeks, with minimal calcification in its absence. Similar results were observed in a medium transfer experiment using 3-day-old hydrogen peroxide-treated conditioned medium, which led to an increased expression of osterix and alkaline phosphatase. Metabolomic analysis revealed a gradual increase in ex-ATP and its metabolites, including ADP, AMP, and adenosine, in the medium. The metabolite increase was enhanced by hydrogen peroxide after 12 h. Moreover, exogenous adenosine (100 μM) increased mineralization in osteogenic media. Additionally, 1 μM dipyridamole, an inhibitor of equilibrative nucleoside transporter 1 (Ent1), also increased it in response to low-dose (0.1 mM) hydrogen peroxide. Conclusions: The enhanced osteogenic calcification of the tendon cell culture by hydrogen peroxide was associated with an increase in extracellular nucleotide metabolites, especially adenosine, with some evidence of causality. Full article

Campanacci grade III giant cell tumors of the distal radius frequently require en bloc resection to achieve adequate oncologic control. Reconstruction of the resulting defect remains challenging, particularly with respect to preservation of distal radioulnar joint stability and forearm rotation. Although proximal fibular autograft reconstruction is well established, ligamentous stabilization of the distal radioulnar joint is rarely incorporated in oncologic settings. This technical note describes an integrated reconstructive strategy combining proximal fibular autograft with distal oblique bundle reconstruction, illustrated by a representative clinical case. The technique involves segmental en bloc resection of the distal radius followed by reconstruction using an ipsilateral, nonvascularized proximal fibular autograft including the fibular head. Distal radioulnar joint stability is addressed through reconstruction of the distal oblique bundle using an autologous palmaris longus tendon graft. Surgical indications, operative steps, donor site stabilization, and perioperative management are detailed. Functional evolution was assessed using the Musculoskeletal Tumor Society scoring system and range-of-motion measurements. Histopathological examination confirmed negative oncologic margins. Early postoperative events included donor-site common peroneal nerve dysfunction and radiocarpal instability requiring temporary Kirschner wire stabilization. At nine months, the Musculoskeletal Tumor Society score reached 80%, with forearm rotation preserved at 68.8% pronation and 81.3% supination of normal values. Combined osseous and ligamentous reconstruction following distal radius resection is technically feasible and may allow preservation of distal forearm mechanics while maintaining oncologic principles. Broader validation will require application in larger clinical series and longer follow-up. Full article

Macrophages and other phagocytic cells are central regulators of tendon immunobiology, orchestrating inflammation, tissue repair, and extracellular matrix (ECM) remodeling in the tendons. They derive from circulating monocytes and resident tendon-specific populations, including tenophages. Macrophage polarization along the M1/M2 axis exerts a decisive influence on tendon healing trajectories. Activated M1 macrophages promote the early healing phase for debris clearance initiating the reparative cascade. However, their sustained activity leads to inflammation, ECM degradation, impaired healing, tendinopathy, and heterotopic ossification (HO). Conversely, a timed shift toward activated M2 macrophages promotes resolution of inflammation, angiogenesis, ECM deposition, and fibrocartilage formation, whereas excessive or prolonged M2 activity facilitates adhesion formation, fibrosis, scarring and HO. Recent single-cell and spatial profiling studies showed macrophage heterogeneity across tendon compartments, thereby extending the classical M1/M2 paradigm and underscoring the relevance of macrophages/resident tendon cell’s interaction in tendon-specific local niches. Mechanobiological stimuli (depending on magnitude, frequency and duration) further modulate macrophage phenotypes and tendon healing. Emerging coculture models and human tendon-on-chip systems provide high-resolution platforms for dissecting these spatiotemporal interactions. Promising therapeutic approaches comprise the application of extracellular vesicles, controlled mechanoloading regimens, and immunomodulatory biomaterials demonstrating potential to induce regenerative macrophage signatures for improved healing outcomes. Notably, platelet-rich plasma (PRP) formulations shape macrophage responses: leukocyte-rich PRP preferentially promotes M1 activity whereas leukocyte-poor PRP supports M2 polarization. Thus, mechano- and immunomodulatory strategies can offer precise control over macrophage dynamics. Regarding the Achilles tendon pathologies, such approaches are helpful by directing macrophage-mediated inflammation towards effective tendon healing outcomes. Full article

Tendon healing is often hindered by unresolved inflammation and dysregulated immune responses, highlighting the need for innovative regenerative strategies. This study developed an immune-informed platform by functionalizing validated 3D tendon-mimetic poly(lactide-co-glycolide) (PLGA) scaffolds with immunomodulatory conditioned media (CM), referred to as CM_INF to emphasize its anti-inflammatory and immunomodulatory properties, derived from ovine amniotic epithelial stem cells (AECs), offering a potential cell-free therapeutic solution. Three functionalization methods were compared: physical adsorption, and hydrochloric acid (HCl) or sodium hydroxide (NaOH) pre-treatments. FT-IR spectroscopy and protein adsorption analyses identified NaOH as the most effective method, enhancing retention and release of Amphiregulin (AREG), an AEC key immunomodulatory protein. Kinetic studies revealed a sustained, controlled release of AREG over 7 days (d) from CM_INF-functionalized scaffolds (3D-CM_INF), preserving bioactivity. Functionally, 3D-CM_INF scaffolds significantly suppressed T-cell activation and peripheral blood mononuclear cell (PBMC) proliferation. The released CM from 3D-CM_INF (CM_R) exhibited time-dependent immunomodulatory effects: early T-cell inhibition (6–72 h) and delayed suppression of PBMC proliferation (48 h–7 d). Macrophage polarization analysis revealed a shift towards the pro-regenerative M2 phenotype, with increased expression of M2 over M1 markers in 3D-CM_INF-adherent cells. Flow cytometry confirmed a preferential induction of regulatory M2b macrophages alongside reductions in pro-inflammatory M1 and pro-fibrotic M2a subsets. These results demonstrate that 3D-CM_INF scaffolds can finely modulate immune responses, balancing inflammatory and reparative cues relevant to early tendon healing processes. This platform, integrating structural and immunomodulatory elements, presents a promising, cell-free, and translational immunoengineering strategy to control inflammation and support tendon repair. Full article

The tendon-to-bone enthesis is a multiphasic structure with four structurally continuous and compositionally distinct regions: tendon, uncalcified fibrocartilage, calcified fibrocartilage and bone. Our study aimed to develop 3D scaffold-free in vitro spheroids and macro-tissues of the enthesis for applications as experimental tools to understand the development and repair of enthesis injury. This study hypothesises that integrating tendon and bone cell spheroids with bone marrow mesenchymal stem cell spheroids will facilitate the production of a fibrocartilaginous interface. 3D Spheroids: The biphasic (tendon–bone) and triphasic co-culture (tendon–stem cell–bone) of spheroids in growth media and chondrogenic media were investigated to establish fusion kinetics, and the cellular and ECM components produced via histology and immunohistochemistry. Complete fusion between spheroids occurred within 6-to-8 days in biphasic co-culture, and 15-to-20 days in triphasic co-culture. Compared to biphasic, the triphasic co-culture in chondrogenic media showed a continuous interface connecting the tendon and bone regions. The presence of collagen I, sulphated proteoglycans and collagen type II in the interface region of triphasic co-culture indicates fibrochondrogenic differentiation. 3D macro-tissues: The modular tissue engineering strategy was used in this study to produce enthesis macro-tissues using spheroids as building blocks. Spheroids were bio-assembled in the triphasic manner (12 tendon spheroids, 12 stem cell spheroids and 8 bone spheroids) in the custom-designed and 3D-printed temporary supports (Formlabs Clear Resin^®) using a customised spheroid bio-assembly system. The fusion of spheroids occurred by day 8 after bio-assembly, and they were removed from temporary supports and cultured in scaffold-free conditions. Although the bio-assembly methodology was successful in producing fused scaffold-free macro-tissues, the histological analysis revealed the presence of an extensive necrotic core due to the large-sized constructs. To conclude, the findings support the hypothesis that a triphasic co-culture has the potential to produce a structurally continuous fibrocartilaginous interface but requires further optimisation to produce macro-tissues with anatomical morphologies and reduced necrotic cores. Full article

Tendinopathy is a common musculoskeletal disorder that increases the risk of tendon rupture if not properly treated. Current local injection therapies require frequent administration, and no fully effective drug is yet available. Curcumin (Cur) exhibits excellent anti-inflammatory and antioxidant effects, but its poor water solubility and low stability limit its clinical application. To overcome these challenges, this study encapsulated Cur into pluronic F127-based nanomicelles (Cur-F127) to improve its aqueous solubility and stability. Subsequently, the micelles were incorporated into a hydrogel network (Cur-F127&gel) formed by oxidized hyaluronic acid (oxi-HA) and adipic acid dihydrazide (ADH) to achieve sustained release. The resulting Cur-F127 micelles had a particle size of 20.14 ± 0.287 nm, an encapsulation efficiency (EE%) of 89.95 ± 0.60%, and a drug loading (DL%) of 5.57 ± 0.05%. The composite hydrogel possessed a loose, porous three-dimensional network, excellent biocompatibility, and favorable degradation behavior. The system enabled sustained release of Cur for over 20 days without an initial burst. In a rat model of tendinopathy, Cur-F127&gel significantly promoted tendon repair, as evidenced by reduced inflammatory cell infiltration, improved collagen fiber alignment, restored expression of key mitochondrial-related proteins (Ndufs3, Uqcrq, Uqcr10, Atp5mc3), and alleviated oxidative stress damage demonstrated by increased SOD activity and decreased MDA content in tendon tissue, thereby suppressing disease progression. This injectable sustained-release hydrogel system for poorly soluble drugs provides an effective approach for the local, long-acting delivery of Cur and long-term repair of tendinopathy, highlighting its potential value for clinical application. Full article