Synthetic hydrogels represent an exciting avenue in the field of regenerative biomaterials given their injectability, orthogonally tunable mechanical properties, and potential for modular inclusion of cellular cues. Separately, recent advances in soluble factor release technology have facilitated control over the soluble milieu in cell microenvironments via tunable microparticles. A composite hydrogel incorporating both of these components can robustly mediate tendon healing following a single injection. Here, a synthetic hydrogel system with encapsulated electrospun fiber segments and a novel microgel-based soluble factor delivery system achieves precise control over topographical and soluble features of an engineered microenvironment, respectively. It is demonstrated that three-dimensional migration of tendon progenitor cells can be enhanced via combined mechanical, topographical, and microparticle-delivered soluble cues in both a tendon progenitor cell spheroid model and an ex vivo murine Achilles tendon model. These results indicate that fiber reinforced hydrogels can drive the recruitment of endogenous progenitor cells relevant to the regeneration of tendon and, likely, a broad range of connective tissues.

This review highlights the promise of fiber-reinforced hydrogel composites (FRHCs) for augmenting tendon and ligament repair and regeneration. Composed of reinforcing fibers embedded in a hydrogel, these scaffolds provide both mechanical strength and a conducive microenvironment for biological processes required for connective tissue regeneration. Typical properties of FRHCs are discussed, highlighting their ability to simultaneously fulfill essential mechanical and biological design criteria for a regenerative scaffold. Furthermore, features of FRHCs are described that improve specific biological aspects of tendon healing including mesenchymal progenitor cell recruitment, early polarization to a pro-regenerative immune response, tenogenic differentiation of recruited progenitor cells, and subsequent production of a mature, aligned collagenous matrix. Finally, the review offers a perspective on clinical translation of tendon FRHCs and outlines key directions for future work.

UNASSIGNED: Unrepairable massive rotator cuff tears (UMRCTs) are challenging to surgeons owing to the severely retracted rotator cuff musculotendinous tissues and extreme defects in the rotator cuff tendinous tissues.
UNASSIGNED: To fabricate a tendon stem cell-derived exosomes loaded scaffold (TSC-Exos-S) and investigate its effects on cellular bioactivity in vitro and repair in a rabbit UMRCT model in vivo.
UNASSIGNED: Controlled laboratory study.
UNASSIGNED: TSC-Exos-S was fabricated by loading TSC-Exos and type 1 collagen (COL-I) into a 3-dimensional bioprinted and polycaprolactone (PCL)-based scaffold. The proliferation, migration, and tenogenic differentiation activities of rabbit bone marrow stem cells (BMSCs) were evaluated in vitro by culturing them in saline, PCL-based scaffold (S), COL-I loaded scaffold (COL-I-S), and TSC-Exos-S. In vivo studies were conducted on a rabbit UMRCT model, where bridging was repaired with S, COL-I-S, TSC-Exos-S, and autologous fascia lata (FL). Histological and biomechanical analyses were performed at 8 and 16 weeks postoperatively.
UNASSIGNED: TSC-Exos-S exhibited reliable mechanical strength and subcutaneous degradation, which did not occur before tissue regeneration. TSC-Exos-S significantly promoted the proliferation, migration, and tenogenic differentiation of rabbit BMSCs in vitro. In vivo studies showed that UMRCT repaired with TSC-Exos-S exhibited significant signs of tendinous tissue regeneration at the bridging site with regard to specific collagen staining. Moreover, no significant differences were observed in the histological and biomechanical properties compared with those repaired with autologous FL.
UNASSIGNED: TSC-Exos-S achieved tendinous tissue regeneration in UMRCT by providing mechanical support and promoting the trend toward tenogenic differentiation.
UNASSIGNED: The present study proposes a potential strategy for repairing UMRCT with severely retracted musculotendinous tissues and large tendinous tissue defects.

OBJECTIVE: The purpose of this study was to compare the regeneration of semitendinosus and gracilis tendons from two different graft harvesting techniques, which are the stump preservation and conventional graft harvesting techniques. We hypothesised that the stump preservation graft harvesting technique, which preserved the distal attachment of tendons at their insertion, would facilitate anatomical regeneration to the pes anserinus.
METHODS: This is a prospective, randomised, double-blinded study whereby thirty consecutive patients who underwent single bundle anterior cruciate ligament reconstruction with ipsilateral semitendinosus and gracilis autografts were recruited. The patients were randomly assigned to the stump preservation group (14 patients) or conventional group (16 patients). Magnetic resonance imaging (MRI) evaluation was performed preoperatively and at six months post-operatively.
RESULTS: At 6-month follow-up, MRI evaluations showed a higher percentage of insertion of regenerated semitendinosus and gracilis at the pes anserinus in the stump preservation group (75.0%) than that in the conventional group (68.8%). There was a significantly higher proximal shift of the musculotendinous junction of semitendinosus (5.70 ​cm versus 3.36 ​cm, p ​= ​0.029) and gracilis (5.28 ​cm versus 3.16 ​cm, p ​= ​0.045) in the conventional group post-operatively.
CONCLUSIONS: The stump preservation technique yields a higher percentage of anatomical insertion of regenerated tendons and a lesser amount of proximal shift of the musculotendinous junction.
METHODS: III - Prospective study with up to two negative criteria.

Musculoskeletal disorders are the leading causes of physical disabilities worldwide. The poor self-repair capacity of musculoskeletal tissues and the absence of effective therapies have driven the development of novel bioengineering-based therapeutic approaches. Adipose-derived stem cell (ADSC)-based therapies are being explored as new regenerative strategies for the repair and regeneration of bone, cartilage, and tendon owing to the accessibility, multipotency, and active paracrine activity of ADSCs. In this review, recent advances in ADSCs and their optimization strategies, including ADSC-derived exosomes (ADSC-Exos), biomaterials, and genetic modifications, are summarized. Furthermore, the preclinical and clinical applications of ADSCs and ADSC-Exos, either alone or in combination with growth factors or biomaterials or in genetically modified forms, for bone, cartilage, and tendon regeneration are reviewed. ADSC-based optimization strategies hold promise for the management of multiple types of musculoskeletal injuries. The timely summary and highlights provided here could offer guidance for further investigations to accelerate the development and clinical application of ADSC-based therapies in musculoskeletal regeneration.

Tendon regeneration is greatly influenced by the oxidant and the inflammatory microenvironment. Persistent inflammation during the tendon repair can cause matrix degradation, tendon adhesion, and excessive accumulation of reactive oxygen species (ROS), while excessive ROS affect extracellular matrix remodeling and tendon integration. Herein, we used tannic acid (TA) to modify a decellularized tendon slice (DTS) to fabricate a functional scaffold (DTS-TA) with antioxidant and anti-inflammatory properties for tendon repair. The characterizations and cytocompatibility of the scaffolds were examined in vitro. The antioxidant and anti-inflammatory activities of the scaffold were evaluated in vitro and further studied in vivo using a subcutaneous implantation model. It was found that the modified DTS combined with TA via hydrogen bonds and covalent bonds, and the hydrophilicity, thermal stability, biodegradability, and mechanical characteristics of the scaffold were significantly improved. Afterward, the results demonstrated that DTS-TA could effectively reduce inflammation by increasing the M2/M1 macrophage ratio and interleukin-4 (IL-4) expression, decreasing the secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β), as well as scavenging excessive ROS in vitro and in vivo. In summary, DTS modified with TA provides a potential versatile scaffold for tendon regeneration.

A significant clinical challenge in large-to-massive rotator cuff tendon injuries is the need for sustaining high mechanical demands despite limited tissue regeneration, which often results in clinical repair failure with high retear rates and long-term functional deficiencies. To address this, an innovative tendon substitute named \"BioTenoForce\" is engineered, which uses (i) tendon extracellular matrix (tECM)\'s rich biocomplexity for tendon-specific regeneration and (ii) a mechanically robust, slow degradation polyurethane elastomer to mimic native tendon\'s physical attributes for sustaining long-term shoulder movement. Comprehensive assessments revealed outstanding performance of BioTenoForce, characterized by robust core-shell interfacial bonding, human rotator cuff tendon-like mechanical properties, excellent suture retention, biocompatibility, and tendon differentiation of human adipose-derived stem cells. Importantly, BioTenoForce, when used as an interpositional tendon substitute, demonstrated successful integration with regenerative tissue, exhibiting remarkable efficacy in repairing large-to-massive tendon injuries in two animal models. Noteworthy outcomes include durable repair and sustained functionality with no observed breakage/rupture, accelerated recovery of rat gait performance, and >1 cm rabbit tendon regeneration with native tendon-like biomechanical attributes. The regenerated tissues showed tendon-like, wavy, aligned matrix structure, which starkly contrasts with the typical disorganized scar tissue observed after tendon injury, and was strongly correlated with tissue stiffness. Our simple yet versatile approach offers a dual-pronged, broadly applicable strategy that overcomes the limitations of poor regeneration and stringent biomechanical requirements, particularly essential for substantial defects in tendon and other load-bearing tissues.

Risk for rupture of the Achilles tendon, and other tendons increases with age. Such injuries of tissues that function in high load environments generally are believed to heal with variable outcome. However, in many cases, the healing does not lead to a good outcome and the patient cannot return to the previous level of participation in active living activities, including sports. In the past few years, using proteomic approaches and other biological techniques, reports have appeared that identify biomarkers that are prognostic of good outcomes from healing, and others that are destined for poor outcomes using validated criteria at 1-year post injury. This review will discuss some of these recent findings and their potential implications for improving outcomes following connective tissue injuries, as well as implications for how clinical research and clinical trials may be conducted in the future where the goal is to assess the impact of specific interventions on the healing process, as well as focusing the emphasis on regeneration and not just repair.

OBJECTIVE: The aims of the study were to document the outcomes of percutaneous Achilles tenotomy (pAT) performed in older children with clubfoot, by assessing the clinical, functional and ultrasonographic evidence of Achilles tendon regeneration.
METHODS: A retrospective case series of older children with clubfoot treated between August 2011 and July 2020 was studied. Clinical assessment of ankle range of motion and calf strength, functional assessment of triceps surae muscle endurance by single leg heel-rise test, and ultrasonographic assessment of Achilles tendon echotexture and dimensions to assess tendon regeneration were performed.
RESULTS: Percutaneous Achilles tenotomy was performed on 31 children (48 clubfeet) at a mean age of 5.24 ± 2.14 years (1-10.2 years). At a mean follow-up of 4.86 ± 1.97 years, all children demonstrated normal calf strength with mean dorsiflexion range of 13.64° (0-25°) and mean plantarflexion range of 37.95° (10-40°). The heel-rise endurance test was completed by 27 children with mean 25.85 heel rises/minute (range 17-30) and mean height of heel rise of 6.29 cm (range 4-10 cm). Normal fibrillar tendinous echotexture with homogenous echogenicity was seen on ultrasonography in 41 feet (85.4%) with mean tendon width of 9.7 mm (3.3-16 mm) and thickness of 5.1 mm (1.8-15 mm), comparable with unaffected feet.
CONCLUSIONS: Clinical, functional and ultrasonographic parameters unequivocally demonstrate complete regeneration of the Achilles tendon, when pAT is performed in older children with delayed-presenting idiopathic clubfoot treated using Ponseti principles.

Over the past few decades, hydrogels have attracted considerable attention as promising biomedical materials. However, conventional hydrogels require improved mechanical properties, such as brittleness, which significantly limits their widespread use. Recently, hydrogels with remarkably improved toughness have been developed; however, their low biocompatibility must be addressed. In this study, we developed a tough graphene hybrid hydrogel with nanostructures. The resultant hydrogel exhibited remarkable mechanical properties while representing an aligned nanostructure that resembled the extracellular matrix of soft tissue. Owing to the synergistic effect of the topographical properties, and the enhanced biochemical properties, the graphene hybrid hydrogel had excellent stretchability, resilience, toughness, and biocompatibility. Furthermore, the hydrogel displayed outstanding tissue regeneration capabilities (e.g., skin and tendons). Overall, the proposed graphene hybrid tough hydrogel may provide significant insights into the application of tough hydrogels in tissue regeneration.