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Tendon repair remains challenging due to its poor intrinsic healing capacity, and stem cell therapy has emerged as a promising strategy to promote tendon regeneration. Nevertheless, the inflammatory environment following acute tendon injuries disrupts stem cell differentiation, leading to unsatisfied outcomes. Our study recognized the critical role of NF-κB signaling in activating inflammation and suppressing tenogenic differentiation of stem cells after acute tendon injury via multiomics analysis. TPCA-1, a selective inhibitor of IKKβ/NF-κB signaling, efficiently restored the impaired tenogenesis of stem cells in the inflammatory environment. By developing a microsphere-incorporated hydrogel system for stem cell delivery and controlled release of TPCA-1, we successfully engineered a pro-tenogenic niche to initiate tenogenesis for tendon regeneration. Collectively, we recognize NF-κB signaling as a critical target to tailor a pro-tenogenic niche and propose the combined delivery of stem cells and TPCA-1 as a potential strategy for acute tendon injuries.

Abstract Background Osteosarcopenia is a geriatric syndrome associated with an increased risk of frailty, falls, fractures, disability, and death. Calf circumference (CC) has been used as a simple and practical skeletal muscle marker to diagnose sarcopenia. This study aimed to explore the relationship of calf circumference and osteoporosis (OP) and hip fractures (HF) in middle-aged and older adults. This is important for screening OP and HF in the community and improving the quality of life of older adults. Methods This study was based on the National Health and Nutrition Examination Survey (NHANES) 1999–2006. Logistic regression analysis and restricted cubic spline were used to investigate the correlation of CC with OP and HF. The receiver operating characteristic (ROC) curve was utilized to determine the optimal cut-off value for CC. Finally, logistic regression model analysis was applied to test the predictive efficacy of CC. Results Among 4575 individuals with a mean age of 63.0 ± 11.5 years, the OP group had higher proportions of females (P

Highlights A systematic review of recent advances of microrobots applied in the musculoskeletal system with an emphasis on design strategies of microrobotic systems for tissue regeneration. The fabrication, motion and control, and image-guided delivery of microrobots in the musculoskeletal system are reviewed based on the up-to-date works. Prospects and challenges for future clinical translation of microrobots in the musculoskeletal system and regenerative medicine are discussed.

Background: Osteosarcopenia is a syndrome coexisting sarcopenia and osteopenia/osteoporosis, with a high fracture risk. Recently, skeletal muscle and bone have been recognized as endocrine organs capable of communication through secreting myokines and osteokines, respectively. With a deeper understanding of the muscle-bone crosstalk, these endocrine signals exhibit an important role in osteosarcopenia development and fracture healing. Methods: This review summarizes the role of myokines and osteokines in the development and treatment of osteosarcopenia and fracture, and discusses their potential for osteosarcopenia-related fracture treatment. Results: Several well-defined myokines (myostatin and irisin) and osteokines (RANKL and SOST) are found to not only regulate skeletal muscle and bone metabolism but also influence fracture healing processes. Systemic interventions targeting these biochemical signals has shown promising results in improving the mass and functions of skeletal muscle and bone, as well as accelerating fracture healing processes. Conclusion: The regulation of muscle-bone crosstalk via biochemical signals presents a novel and promising strategy for treating osteosarcopenia and fracture by simultaneously enhancing bone and muscle anabolism. We propose that myostatin, irisin, RANKL, and SOST may serve as potential targets to treat fracture patients with osteosarcopenia. The translational potential of this article: Osteosarcopenia is an emerging geriatric syndrome where sarcopenia and osteoporosis coexist, with high fracture risk, delayed fracture healing, and increased mortality. However, no pharmacological agent is available to treat fracture patients with osteosarcopenia. This review summarizes the role of several myokines and osteokines in the development and treatment of osteosacropenia and fracture, as well as discusses their potential as intervention targets for osteosarcopenia-related fracture, which provides a novel and promising strategy for future osteosarcopenia-related fracture treatment.

Abstract Stiffness is an important physical property of biomaterials that determines stem cell fate. Guiding stem cell differentiation via stiffness modulation has been considered in tissue engineering. However, the mechanism by which material stiffness regulates stem cell differentiation into the tendon lineage remains controversial. Increasing evidence demonstrates that immune cells interact with implanted biomaterials and regulate stem cell behaviors via paracrine signaling; however, the role of this mechanism in tendon differentiation is not clear. In this study, polydimethylsiloxane (PDMS) substrates with different stiffnesses are developed, and the tenogenic differentiation of mesenchymal stem cells (MSCs) exposed to different stiffnesses and macrophage paracrine signals is investigated. The results reveal that lower stiffnesses facilitates tenogenic differentiation of MSCs, while macrophage paracrine signals at these stiffnesses suppress the differentiation. When exposed to these two stimuli, MSCs still exhibit enhanced tendon differentiation, which is further elucidated by global proteomic analysis. Following subcutaneous implantation in rats for 2 weeks, soft biomaterial induces only low inflammation and promotes tendon‐like tissue formation. In conclusion, the study demonstrates that soft, rather than stiff, material has a greater potential to guide tenogenic differentiation of stem cells, which provides comprehensive evidence for optimized bioactive scaffold design in tendon tissue engineering.

Abstract Background With the development of tissue engineering, enhanced tendon regeneration could be achieved by exploiting suitable cell types and biomaterials. The accessibility, robust cell amplification ability, superior tendon differentiation potential, and immunomodulatory effects of human periodontal ligament stem cells (hPDLSCs) indicate their potential as ideal seed cells for tendon tissue engineering. Nevertheless, there are currently no reports of using PDLSCs as seed cells. Previous studies have confirmed the potential of silk scaffold for tendon tissue engineering. However, the biomimetic silk scaffold with tendon extracellular matrix (ECM)-like structure has not been systematically studied for in situ tendon regeneration. Therefore, this study aims to evaluate the effects of hPDLSCs and biomimetic silk scaffold on in situ tendon regeneration. Methods Human PDLSCs were isolated from extracted wisdom teeth. The differentiation potential of hPDLSCs towards osteo-, chondro-, and adipo-lineage was examined by cultured in different inducing media. Aligned and random silk scaffolds were fabricated by the controlled directional freezing technique. Scaffolds were characterized including surface structure, water contact angle, swelling ratio, degradation speed and mechanical properties. The biocompatibility of silk scaffolds was evaluated by live/dead staining, SEM observation, cell proliferation determination and immunofluorescent staining of deposited collagen type I. Subsequently, hPDLSCs were seeded on the aligned silk scaffold and transplanted into the ruptured rat Achilles tendon. Scaffolds without cells served as control groups. After 4 weeks, histology evaluation was carried out and macrophage polarization was examined to check the repair effects and immunomodulatory effects. Results Human PDLSCs were successfully isolated, and their multi-differentiation potential was confirmed. Compared with random scaffold, aligned silk scaffold had more elongated and aligned pores and promoted the proliferation and ordered arrangement of hPDLSCs. After implantation into rat Achilles tendon defect, hPDLSCs seeded aligned silk scaffold enhanced tendon repair with more tendon-like tissue formation after 4 weeks, as compared to the scaffold-only groups. Higher expression of CD206 and lower expression of iNOS, IL-1β and TNF-α were found in the hPDLSCs seeded aligned silk scaffold group, which revealed its modulation effect of macrophage polarization from M1 to M2 phenotype. Conclusions In summary, this study demonstrates the efficacy of hPDLSCs as seed cells and aligned silk scaffold as a tendon-mimetic scaffold for enhanced tendon tissue engineering, which may have broad implications for future tendon tissue engineering and regenerative medicine researches.

Endogenous repair of osteochondral defect is usually limited by the insufficient number of cells in the early stage and incomplete cell differentiation in the later stage. The development of drug delivery systems for sequential release of pro-migratory and pro-chondrogenic molecules to induce endogenous bone marrow-derived mesenchymal stem cells (BMSCs) recruitment and chondrogenic differentiation is highly desirable for in situ osteochondral regeneration. In this study, a novel, all-silk-derived sequential delivery system was fabricated by incorporating the tunable drug-loaded silk fibroin (SF) nanospheres into a SF porous matrix. The loading efficiency and release kinetics of biomolecules depended on the initial SF/polyvinyl alcohol (PVA) concentrations (0.2%, 1% and 5%) of the nanospheres, as well as the hydrophobicity of the loaded molecules, resulting in controllable and programmed delivery profiles. Our findings indicated that the 5% nanosphere-incorporated matrix showed a rapid release of E7 peptide during the first 120 h, whereas the 0.2% nanosphere-incorporated matrix provided a slow and sustained release of Kartogenin (KGN) longer than 30 days. During in vitro culture of BMSCs, this functional SF matrix incorporated with E7/KGN nanospheres showed good biocompatibility, as well as enhanced BMSCs migration and chondrogenic differentiation through the release of E7 and KGN. Furthermore, when implanted into rabbit osteochondral defect, the SF nanosphere matrix with sequential E7/KGN release promoted the regeneration of both cartilage and subchondral bone. This work not only provided a novel all-silk-derived drug delivery system for sequential release of molecules, but also a functional tissue-engineered scaffold for osteochondral regeneration.

In osteochondral defects, oxidative stress caused by elevated levels of reactive oxygen species (ROS) can disrupt the normal endogenous repair process. In this study, a multifunctional hydrogel composed of silk fibroin (SF) and tannic acid (TA), the FDA-approved ingredients, was developed to alleviate oxidative stress and enhance osteochondral regeneration. In this proposed hydrogel, SF first interacts with TA to form a hydrogen-bonded supramolecular structure, which is subsequently enzymatically crosslinked to form a stable hydrogel. Furthermore, TA had multiple phenolic hydroxyl groups that formed interactions with the therapeutic molecule E7 peptide for controlled drug delivery. In vitro investigations showed that SF-TA and SF-TA-E7 hydrogels exhibited a multitude of biological effects including scavenging of ROS, maintaining cell viability, and promoting the proliferation of bone marrow mesenchymal stem cells (BMSCs) against oxidative stress. The proteomic analysis indicated that SF-TA and SF-TA-E7 hydrogels suppressed oxidative stress, which in turn improved cell proliferation in multiple proliferation and apoptosis-related pathways. In rabbit osteochondral defect model, SF-TA and SF-TA-E7 hydrogels promoted enhanced regeneration of both cartilage and subchondral bone as compared to hydrogel without TA incorporation. These findings indicated that the multifunctional SF-TA hydrogel provided a microenvironment suitable for the endogenous regeneration of osteochondral defects.

Tendon injury is the most common disease in the musculoskeletal system. The current treatment methods have many limitations, such as poor therapeutic effects, functional loss of donor site, and immune rejection. Tendon tissue engineering provides a new treatment strategy for tendon repair and regeneration. In this review, we made a retrospective analysis of applying mechanical stimulation in tendon tissue engineering, and its potential as a direction of development for future clinical treatment strategies. For this purpose, the following topics are discussed; (1) the context of tendon tissue engineering and mechanical stimulation; (2) the applications of various mechanical stimulations in tendon tissue engineering, as well as their inherent mechanisms; (3) the application of magnetic force and the synergy of mechanical and biochemical stimulation. With this, we aim at clarifying some of the main questions that currently exist in the field of tendon tissue engineering and consequently gain new knowledge that may help in the development of future clinical application of tissue engineering in tendon injury.