Injectable conductive hydrogel remodeling microenvironment and mimicking neuroelectric signal transmission after spinal cord injury.

Severe spinal cord injury (SCI) leads to dysregulated neuroinflammation and cell apoptosis, resulting in axonal die-back and the loss of neuroelectric signal transmission. While biocompatible hydrogels are commonly used in SCI repair, they lack the capacity to support neuroelectric transmission. To overcome this limitation, we developed an injectable silk fibroin/ionic liquid (SFMA@IL) conductive hydrogel to assist neuroelectric signal transmission after SCI in this study. The hydrogel can form rapidly in situ under ultraviolet (UV) light. The mechanical supporting and neuro-regenerating properties are provided by silk fibroin (SF), while the conductive capability is provided by the designed ionic liquid (IL). SFMA@IL showed attractive features for SCI repair, such as anti-swelling, conductivity, and injectability. In vivo, SFMA@IL hydrogel used in rats with complete transection injuries was found to remodel the microenvironment, reduce inflammation, and facilitate neuro-fiber outgrowth. The hydrogel also led to a notable decrease in cell apoptosis and the achievement of scar-free wound healing, which saved 45.6 ± 10.8 % of spinal cord tissue in SFMA@IL grafting. Electrophysiological studies in rats with complete transection SCI confirmed SFMA@IL's ability to support sensory neuroelectric transmission, providing strong evidence for its signal transmission function. These findings provide new insights for the development of effective SCI treatments.

A pathological joint-liver axis mediated by matrikine-activated CD4+ T cells.

The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4+ T cells in peripheral blood and spleen. Deletion of CD4+ T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4+ T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint-liver axis mediated by matrikine-activated CD4+ T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease. Intra-articular bleeding induces cartilage degradation through down-reulation of cartilage Akt pathway. During this process, the soluble COL II released from the damaged cartilage can activate peripheral CD4+ T cells, differention into Th17 cells and secretion of IL-17, which consequently induces liver impairment. Intra-articular application of sc79 (inhibitor of Akt pathway) can prevent the cartilage damage as well as its peripheral influences.

3D-printed biomimetic scaffolds with precisely controlled and tunable structures guide cell migration and promote regeneration of osteochondral defect.

Untreated osteochondral defects will develop into osteoarthritis, affecting patients' quality of life. Since articular cartilage and subchondral bone exhibit distinct biological characteristics, repairing osteochondral defects remains a major challenge. Previous studies have tried to fabricate multilayer scaffolds with traditional methods or 3D printing technology. However, the efficacy is unsatisfactory because of poor control over internal structures or a lack of integrity between adjacent layers, severely compromising repair outcomes. Therefore, there is a need for a biomimetic scaffold that can simultaneously boost osteochondral defect regeneration in both structure and function. Herein, an integrated bilayer scaffold with precisely controlled structures is successfully 3D-printed in one step via digital light processing (DLP) technology. The upper layer has both 'lotus- and radial-' distribution pores, and the bottom layer has 'lotus-' pores to guide and facilitate the migration of chondrocytes and bone marrow mesenchymal stem cells, respectively, to the defect area. Tuning pore sizes could modulate the mechanical properties of scaffolds easily. Results show that 3D-printed porous structures allow significantly more cells to infiltrate into the area of 'lotus- and radial-' distribution pores during cell migration assay, subcutaneous implantation, andin situtransplantation, which are essential for osteochondral repair. Transplantation of this 3D-printed bilayer scaffold exhibits a promising osteochondral repair effect in rabbits. Incorporation of Kartogenin into the upper layer of scaffolds further induces better cartilage formation. Combining small molecules/drugs and precisely size-controlled and layer-specific porous structure via DLP technology, this 3D-printed bilayer scaffold is expected to be a potential strategy for osteochondral regeneration.

Hyperplastic Human Macromass Cartilage for Joint Regeneration.

Cartilage damage affects millions of people worldwide. Tissue engineering strategies hold the promise to provide off-the-shelf cartilage analogs for tissue transplantation in cartilage repair. However, current strategies hardly generate sufficient grafts, as tissues cannot maintain size growth and cartilaginous phenotypes simultaneously. Herein, a step-wise strategy is developed for fabricating expandable human macromass cartilage (macro-cartilage) in a 3D condition by employing human polydactyly chondrocytes and a screen-defined serum-free customized culture (CC). CC-induced chondrocytes demonstrate improved cell plasticity, expressing chondrogenic biomarkers after a 14.59-times expansion. Crucially, CC-chondrocytes form large-size cartilage tissues with average diameters of 3.25 ± 0.05 mm, exhibiting abundant homogenous matrix and intact structure without a necrotic core. Compared with typical culture, the cell yield in CC increases 2.57 times, and the expression of cartilage marker collagen type II increases 4.70 times. Transcriptomics reveal that this step-wise culture drives a proliferation-to-differentiation process through an intermediate plastic stage, and CC-chondrocytes undergo a chondral lineage-specific differentiation with an activated metabolism. Animal studies show that CC macro-cartilage maintains a hyaline-like cartilage phenotype in vivo and significantly promotes the healing of large cartilage defects. Overall, an efficient expansion of human macro-cartilage with superior regenerative plasticity is achieved, providing a promising strategy for joint regeneration.

Biomaterial based implants caused remote liver fatty deposition through activated blood-derived macrophages.

Understanding the biocompatibility of biomaterials is a prerequisite for the prediction of its clinical application, and the present assessments mainly rely on in vitro cell culture and in situ histopathology. However, remote organs responses after biomaterials implantation is unclear. Here, by leveraging body-wide-transcriptomics data, we performed in-depth systems analysis of biomaterials - remote organs crosstalk after abdominal implantation of polypropylene and silk fibroin using a rodent model, demonstrating local implantation caused remote organs responses dominated by acute-phase responses, immune system responses and lipid metabolism disorders. Of note, liver function was specially disturbed, defined as hepatic lipid deposition. Combining flow cytometry analyses and liver monocyte recruitment inhibition experiments, we proved that blood derived monocyte-derived macrophages in the liver underlying the mechanism of abnormal lipid deposition induced by local biomaterials implantation. Moreover, from the perspective of temporality, the remote organs responses and liver lipid deposition of silk fibroin group faded away with biomaterial degradation and restored to normal at end, which highlighted its superiority of degradability. These findings were further indirectly evidenced by human blood biochemical ALT and AST examination from 141 clinical cases of hernia repair using silk fibroin mesh and polypropylene mesh. In conclusion, this study provided new insights on the crosstalk between local biomaterial implants and remote organs, which is of help for future selecting and evaluating biomaterial implants with the consideration of whole-body response.

Seamless and early gap healing of osteochondral defects by autologous mosaicplasty combined with bioactive supramolecular nanofiber-enabled gelatin methacryloyl (BSN-GelMA) hydrogel.

Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice. Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regeneration without uneven surface, graft necrosis and sclerosis. However, poor gap integration is a serious concern, which eventually leads to deterioration of joint function. To deal with such complications, this study has developed a strategy to effectively enhance integration of the gap region following mosaicplasty by applying injectable bioactive supramolecular nanofiber-enabled gelatin methacryloyl (GelMA) hydrogel (BSN-GelMA). A rabbit osteochondral defect model demonstrated that BSN-GelMA achieved seamless osteochondral healing in the gap region between plugs of osteochondral defects following mosaicplasty, as early as six weeks. Moreover, the International Cartilage Repair Society score, histology score, glycosaminoglycan content, subchondral bone volume, and collagen II expression were observed to be the highest in the gap region of BSN-GelMA treated group. This improved outcome was due to bio-interactive materials, which acted as tissue fillers to bridge the gap, prevent cartilage degeneration, and promote graft survival and migration of bone marrow mesenchymal stem cells by releasing bioactive supramolecular nanofibers from the GelMA hydrogel. This study provides a powerful and applicable approach to improve gap integration after autologous mosaicplasty. It is also a promising off-the-shelf bioactive material for cell-free in situ tissue regeneration.

Effects of arabinoxylan and chlorogenic acid on the intestinal microbiota in dextran sulfate sodium-treated mice.

Dietary non-starch polysaccharides and phenolics are usually ingested at the same time. They are both regarded as prebiotics, and they regulate the intestinal microbiota through various mechanisms. Notably, however, reports of their combined or synergistic effects are rare. Arabinoxylan (AX), a polysaccharide, and chlorogenic acid (CA), a polyphenol, are widely consumed, and their effects on the microbiota have previously been discussed. In the present study, they were given to dextran sulfate sodium (DSS)-treated mice, separately and together, and the intestinal microbiota were investigated by high-throughput sequencing. The data showed that CA attenuated body weight loss, colon shortening, and histological damage in DSS-treated mice, while neither AX nor the AX+CA combination exhibited any ameliorating potential. AX+CA had less of a modulating effect on intestinal microbiota profiles than did CA. AX+CA administration increased the relative abundance of Flavonifractor, Coprobacillus, and Clostridium_XlVa, and decreased the abundance of Robinsoniella and Lactobacillus. Compared to AX and CA, AX+CA contributed to a more complicated shift in the biological functions of the intestinal microbiotaAX seemed to weaken the beneficial effects of CA, at least in the present experimental model of DSS-induced colitis. The combined effects and mechanisms of dietary polysaccharides and phenolic compounds on the intestinal microbiota and on overall health still need to be further investigated.

Msx1+ stem cells recruited by bioactive tissue engineering graft for bone regeneration.

Critical-sized bone defects often lead to non-union and full-thickness defects of the calvarium specifically still present reconstructive challenges. In this study, we show that neurotrophic supplements induce robust in vitro expansion of mesenchymal stromal cells, and in situ transplantation of neurotrophic supplements-incorporated 3D-printed hydrogel grafts promote full-thickness regeneration of critical-sized bone defects. Single-cell RNA sequencing analysis reveals that a unique atlas of in situ stem/progenitor cells is generated during the calvarial bone healing in vivo. Notably, we find a local expansion of resident Msx1+ skeletal stem cells after transplantation of the in situ cell culture system. Moreover, the enhanced calvarial bone regeneration is accompanied by an increased endochondral ossification that closely correlates to the Msx1+ skeletal stem cells. Our findings illustrate the time-saving and regenerative efficacy of in situ cell culture systems targeting major cell subpopulations in vivo for rapid bone tissue regeneration.

High-efficient engineering of osteo-callus organoids for rapid bone regeneration within one month.

Large bone defects that cannot form a callus tissue are often faced with long-time recovery. Developmental engineering-based strategies with mesenchymal stem cell (MSC) aggregates have shown enhanced potential for bone regeneration. However, MSC aggregates are different from the physiological callus tissues, which limited the further endogenous osteogenesis. This study aims to achieve engineering of osteo-callus organoids for rapid bone regeneration in cooperation with bone marrow-derived stem cell (BMSC)-loaded hydrogel microspheres (MSs) by digital light-processing (DLP) printing technology and stepwise-induction. The printed MSC-loaded MSs aggregated into osteo-callus organoids after chondrogenic induction and showed much higher chondrogenic efficiency than that of traditional MSC pellets. Moreover, the osteo-callus organoids exhibited stage-specific gene expression pattern that recapitulated endochondral ossification process, as well as a synchronized state of cell proliferation and differentiation, which highly resembled the diverse cell compositions and behaviors of developmentally endochondral ossification. Lastly, the osteo-callus organoids efficiently led to rapid bone regeneration within only 4 weeks in a large bone defect in rabbits which need 2-3 months in previous tissue engineering studies. The findings suggested that in vitro engineering of osteo-callus organoids with developmentally osteogenic properties is a promising strategy for rapid bone defect regeneration and recovery.

Chemical-Empowered Human Adipose-Derived Stem Cells with Lower Immunogenicity and Enhanced Pro-angiogenic Ability Promote Fast Tissue Regeneration.

Mesenchymal stem cells (MSCs) have been widely used as functional components in tissue engineering. However, the immunogenicity and limited pro-angiogenic efficacy of MSCs greatly limited their pro-regenerative ability in allogenic treatment. Herein, utilizing a chemically defined cocktail in the culture system, including cytokines, small molecules, structural protein, and other essential components, we generated the immunoprivileged and pro-angiogenic cells (IACs) derived from human adipose tissues. Conventional adipose-derived MSCs (cADSCs) were used as a control in all the experiments. IACs show typical MSC properties with enhanced stemness capacity and a robust safety profile. IACs induce a significantly milder immune response of allogenic peripheral blood mononuclear cells in an H3K27me3-HLA axis-dependent manner. IACs, through superior paracrine effects, further promote nitric oxide production, anti-apoptotic ability, and the tube formation of human vein endothelial cells. Embedded in a photo-reactive hydrogel (Gel) termed as GelMA/HA-NB/LAP for tissue engineering treatment, IACs promote faster tissue regeneration in a xenogeneic full-thickness skin defect model, eliciting a milder immune response and enhanced blood vessel formation in IACs-treated defect areas. Together with its excellent pro-regenerative potential and robust safety, our findings suggest that IACs may be a promising candidate for clinically relevant stem cell and tissue engineering therapeutics.

Mesenchymal Stem Cells-Hydrogel Microspheres System for Bone Regeneration in Calvarial Defects.

The repair of large bone defects in clinic is a challenge and urgently needs to be solved. Tissue engineering is a promising therapeutic strategy for bone defect repair. In this study, hydrogel microspheres (HMs) were fabricated to act as carriers for bone marrow mesenchymal stem cells (BMSCs) to adhere and proliferate. The HMs were produced by a microfluidic system based on light-induced gelatin of gelatin methacrylate (GelMA). The HMs were demonstrated to be biocompatible and non-cytotoxic to stem cells. More importantly, the HMs promoted the osteogenic differentiation of stem cells. In vivo, the ability of bone regeneration was studied by way of implanting a BMSC/HM system in the cranial defect of rats for 8 weeks. The results confirmed that the BMSC/HM system can induce superior bone regeneration compared with both the HMs alone group and the untreated control group. This study provides a simple and effective research idea for bone defect repair, and the subsequent optimization study of HMs will provide a carrier material with application prospects for tissue engineering in the future.

Polyglutamic Acid-Based Elastic and Tough Adhesive Patch Promotes Tissue Regeneration through In Situ Macrophage Modulation.

Adhesive patches are advanced but challenging alternatives to suture, especially in treating fragile internal organs. So far there is no suture-free adhesive patch based on metabolizable poly(amino acid) materials with excellent mechanical strength as well as immunomodulation functionality. Here, a polyglutamic acid-based elastic and tough adhesive patch modified by photosensitive groups on the surface to achieve robust light-activated adhesion and sealing of flexible internal organs is explored. With the porous internal morphology and excellent biodegradability, the patches promote regeneration through a macrophage-regulating microenvironment. Treated rabbits achieve rapid full-thickness gastric regeneration with complete functional structure within 14 d, suggesting its robust tissue adhesion and repair-promoting ability.

Identification of an Ultrathin Osteochondral Interface Tissue with Specific Nanostructure at the Human Knee Joint.

Cartilage adheres to subchondral bone via a specific osteochondral interface tissue where forces are transferred from soft cartilage to hard bone without conferring fatigue damage over a lifetime of load cycles. However, the fine structure and mechanical properties of the osteochondral interface tissue remain unclear. Here, we identified an ultrathin ∼20-30 µm graded calcified region with two-layered micronano structures of osteochondral interface tissue in the human knee joint, which exhibited characteristic biomolecular compositions and complex nanocrystals assembly. Results from finite element simulations revealed that within this region, an exponential increase of modulus (3 orders of magnitude) was conducive to force transmission. Nanoscale heterogeneity in the hydroxyapatite, coupled with enrichment of elastic-responsive protein-titin, which is usually present in muscle, endowed the osteochondral tissue with excellent mechanical properties. Collectively, these results provide novel insights into the potential design for high-performance interface materials for osteochondral interface regeneration.

Biomimetic Joint Paint for Efficient Cartilage Repair by Simultaneously Regulating Cartilage Degeneration and Regeneration in Pigs.

Irregular partial-thickness cartilage defect is a common pathogenesis of osteoarthritis (OA) with no available treatment in clinical practice. Currently, cartilage tissue engineering is only suitable for a limited area of full-thickness cartilage defect. Here, we design a biomimetic joint paint for the intractable partial-thickness cartilage defect repair. The joint paint, composed of a bridging layer of chondroitin sulfate and a surface layer of gelatin methacrylate with hyaluronic acid, can quickly and tightly adhere to the cartilage defect by light activation. Being treated by the joint paint, the group of rabbit and pig models with partial-thickness cartilage defects showed a restoration of a smooth cartilage surface and the preservation of normal glycosaminoglycan content, whereas the untreated control group exhibited serious progressive OA development. This paint treatment functions by prohibiting chondrocyte apoptosis, maintaining chondrocyte phenotype, and preserving the content of glycosaminoglycan in the partial-thickness cartilage defects. These findings illustrated that the biomimetic joint paint is an effective and revolutionary therapeutics for the patients with noncurable partial-thickness cartilage defects.

Advanced Strategies of Biomimetic Tissue-Engineered Grafts for Bone Regeneration.

The failure to repair critical-sized bone defects often leads to incomplete regeneration or fracture non-union. Tissue-engineered grafts have been recognized as an alternative strategy for bone regeneration due to their potential to repair defects. To design a successful tissue-engineered graft requires the understanding of physicochemical optimization to mimic the composition and structure of native bone, as well as the biological strategies of mimicking the key biological elements during bone regeneration process. This review provides an overview of engineered graft-based strategies focusing on physicochemical properties of materials and graft structure optimization from macroscale to nanoscale to further boost bone regeneration, and it summarizes biological strategies which mainly focus on growth factors following bone regeneration pattern and stem cell-based strategies for more efficient repair. Finally, it discusses the current limitations of existing strategies upon bone repair and highlights a promising strategy for rapid bone regeneration.

Rapid printing of bio-inspired 3D tissue constructs for skin regeneration.

It is still a challenge for existing bioprinting technologies to fabricate organs suitable for implantation, mainly due to the inability to recapitulate the organs' complex anatomical structures, mechanical properties, and biological functions. Additionally, the failure to create 3D constructs with interconnected microchannels for long-range mass transportation that limits the clinical applications of 3D printing technologies. Here, a new method was developed to print functional living skin (FLS) using a newly designed biomimetic bioink (GelMA/HA-NB/LAP) and digital light processing (DLP)-based 3D printing technology. The FLS possess interconnected microchannels that facilitates cell migration, proliferation and neo-tissue formation. The GelMA/HA-NB/LAP bioink, composed of gelatin methacrylate (GelMA), N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide (NB) linked hyaluronic acid (HA-NB) and photo-initiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). The bioink demonstrated its rapid gelation kinetics, tunable mechanical properties, good biocompatibility and tissue adhesion. The DLP-based 3D printing technology provides a rapid method to precisely position clusters of human skin fibroblasts (HSFs) and human umbilical vein endothelial cells (HUVECs) with high cell viability to form FLS. The FLS promotes skin regeneration and efficient neovascularization by mimicking the physiological structure of natural skin, and it can also be easily handled and implanted onto the wound site due to its strong mechanical and bio-adhesive properties. Moreover, in vivo study demonstrated that the living skin exhibited instant defense function and had superior performance in promoting dermal regeneration with skin appendages in large animals. This study provides a rapid and mass production method of functional living organs for future clinical applications.

Nanomaterial-based scaffolds for bone tissue engineering and regeneration.

The global incidence of bone tissue injuries has been increasing rapidly in recent years, making it imperative to develop suitable bone grafts for facilitating bone tissue regeneration. It has been demonstrated that nanomaterials/nanocomposites scaffolds can more effectively promote new bone tissue formation compared with micromaterials. This may be attributed to their nanoscaled structural and topological features that better mimic the physiological characteristics of natural bone tissue. In this review, we examined the current applications of various nanomaterial/nanocomposite scaffolds and different topological structures for bone tissue engineering, as well as the underlying mechanisms of regeneration. The potential risks and toxicity of nanomaterials will also be critically discussed. Finally, some considerations for the clinical applications of nanomaterials/nanocomposites scaffolds for bone tissue engineering are mentioned.

Tissue-Adhesive Paint of Silk Microparticles for Articular Surface Cartilage Regeneration.

Current biomaterials and tissue engineering techniques have shown a promising efficacy on full-thickness articular cartilage defect repair in clinical practice. However, due to the difficulty of implanting biomaterials or tissue engineering constructs into a partial-thickness cartilage defect, it remains a challenge to provide a satisfactory cure in joint surface regeneration in the early and middle stages of osteoarthritis. In this study, we focused on a ready-to-use tissue-adhesive joint surface paint (JS-Paint) capable of promoting and enhancing articular surface cartilage regeneration. The JS-Paint is mainly composed of N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide (NB)-coated silk fibroin microparticles and possess optimal cell adhesion, migration, and proliferation properties. NB-modified silk fibroin microparticles can directly adhere to the cartilage and form a smooth layer on the surface via the photogenerated aldehyde group of NB reacting with the -NH2 groups of the cartilage tissue. JS-Paint treatment showed a significant promotion of cartilage regeneration and restored the smooth joint surface at 6 weeks postsurgery in a rabbit model of a partial-thickness cartilage defect. These findings revealed that silk fibroin can be utilized to bring about a tissue-adhesive paint. Thus, the JS-Paint strategy has some great potential to enhance joint surface regeneration and revolutionize future therapeutics of early and middle stages of osteoarthritis joint ailments.

High-Resolution Dissection of Chemical Reprogramming from Mouse Embryonic Fibroblasts into Fibrocartilaginous Cells.

Articular cartilage injury and degeneration causing pain and loss of quality-of-life has become a serious problem for increasingly aged populations. Given the poor self-renewal of adult human chondrocytes, alternative functional cell sources are needed. Direct reprogramming by small molecules potentially offers an oncogene-free and cost-effective approach to generate chondrocytes, but has yet to be investigated. Here, we directly reprogrammed mouse embryonic fibroblasts into PRG4+ chondrocytes using a 3D system with a chemical cocktail, VCRTc (valproic acid, CHIR98014, Repsox, TTNPB, and celecoxib). Using single-cell transcriptomics, we revealed the inhibition of fibroblast features and activation of chondrogenesis pathways in early reprograming, and the intermediate cellular process resembling cartilage development. The in vivo implantation of chemical-induced chondrocytes at defective articular surfaces promoted defect healing and rescued 63.4% of mechanical function loss. Our approach directly converts fibroblasts into functional cartilaginous cells, and also provides insights into potential pharmacological strategies for future cartilage regeneration.

Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis.

Changes in the stiffness of chondrocyte extracellular matrix (ECM) are involved in the pathological progression of osteoarthritis (OA). However, the downstream responses of cartilage ECM stiffness are still unclear. YAP (Yes-associated protein) has been extensively studied as a mechanotransducer, we thus hypothesized that by targeting the downstream molecule activity of ECM stiffness could maintain chondrocyte phenotype and prevent cartilage degeneration in OA. Here, we showed that human cartilage matrix stiffened during pathological progression of OA, and the chondrocyte YAP activity was associated with ECM stiffness. We then mimicked the physiological and pathological stiffness of human cartilage by using PDMS-based substrates, and found that YAP was activated in chondrocytes seeded on stiff substrate, gradually losing their phenotype. In addition, it was observed that YAP was also significantly activated in mice OA development, and conditional knockout (cKO) of YAP in mice preserved collagen II expression and protected cartilage from degeneration in the OA model. Furthermore, intra-articular injection of YAP-selective inhibitor, Verteporfin, significantly maintained cartilage homeostasis in mice OA model. This study indicates that the application of mechanotransducer-targeted drugs could be a potential therapeutic approach for cartilage repair in OA.