Osteoarthritis (OA) is a common joint disease characterized by progressive loss of cartilage and reduction in lubricating synovial fluid, which lacks effective treatments currently. Here, we propose a hydrogel-based miRNA delivery strategy to rejuvenate impaired cartilage by creating a regenerative microenvironment to mitigate chondrocyte senescence that mainly contributes to cartilage breakdown during OA development. An aging-related miRNA, miR-29b-5p, was first found to be markedly down-regulated in OA cartilage, and their up-regulation suppressed the expression of matrix metalloproteinases and senescence-associated genes ( P16 ^INK4a /P21 ) via ten-eleven-translocation enzyme 1 (TET1). An injectable bioactive self-assembling peptide nanofiber hydrogel was applied to deliver agomir-29b-5p, which was functionalized by conjugating a stem cell–homing peptide SKPPGTSS for endogenous synovial stem cell recruitment simultaneously. Sustained miR-29b-5p delivery and recruitment of synovial stem cells and their subsequent differentiation into chondrocytes led to successful cartilage repair and chondrocyte rejuvenation. This strategy enables miRNA-based therapeutic modality to become a viable alternative for surgery in OA treatment.

Conductive hydrogels have the potential to facilitate nerve regeneration through various mechanisms, including providing physical support, enabling electrical signal transmission, and stimulating nerve cells to release growth factors. Carbon-based conductive materials, such as carbon nanotubes (CNTs) and graphene oxide (GO), are widely used in the construction of conductive hydrogels due to their advantages in electrical conductivity and biosafety. Herein, we fabricated conductive hydrogels by incorporating CNTs or GO into gelatin or chitosan. The gelatin- and chitosan-based electrospun fiber hydrogels were synthesized at room temperature using acetic acid/hexafluoroisopropanol and acetic acid/water as solvents, respectively. Subsequently, we investigated the morphology, swelling properties, mechanical properties, and electrical performance of the hydrogels. Scanning electron microscopy (SEM) images verified the uniform distribution of CNTs and GO within the different hydrogel formulations. The network structure formed by CNTs enhanced the swelling rate of the hydrogels. The incorporation of CNTs and GO elevated the compression elastic moduli of the hydrogels. Conductivity experiments revealed that the conductivity of graphene oxide was significantly improved upon soaking with sodium ascorbate. Notably, chitosan hydrogels containing reduced graphene oxide exhibited the highest conductivity. Pheochromocytoma 12 (PC12) cells could adhere to and spread on the hydrogels surface. These findings suggest that conductive hydrogels hold great promise as candidates for nerve repair in the future.

Peripheral nerve injury is a debilitating condition that have a profound impact on the overall quality of an individual’s life. The repair of peripheral nerve defects continues to present significant challenges in the field. Iron oxide magnetic nanoparticles (IONPs) have been recognized as potent nanotools for promoting the regeneration of peripheral nerves due to their capability as biological carriers and their ability to template the hydrogel structure under an external magnetic field. This research used a fibrin nanofiber hydrogel loaded with IONPs (IONPs/fibrin) to promote the regeneration of peripheral nerves in rats. In vitro examination of PC12 cells on various concentrations of IONPs/fibrin hydrogels revealed a remarkable increase in NGF and VEGF expression at 2% IONPs concentration. The biocompatibility and degradation of 2% IONPs/fibrin hydrogel were assessed using the in vivo imaging system, demonstrating subcutaneous degradation within a week without immediate inflammation. Bridging a 10-mm sciatic nerve gap in Sprague Dawley rats with 2% IONPs/fibrin hydrogel led to satisfactory morphological recovery of myelinated nerve fibers. And motor functional recovery in the 2% IONPs/fibrin group was comparable to autografts at 6, 9 and 12 weeks postoperatively. Hence, the composite fibrin hydrogel incorporating 2% IONPs exhibits potential for peripheral nerve regeneration.

Aim: Our aim was to design an osteogenic extracellular matrix (ECM) coated bioscaffold and to apply it to critical bone defect repair with adipose-derived stem cells (ADSCs). Materials & methods: Morphology of scaffolds was scanned by scanning electron microscope. Cell adhesion, proliferation and osteogenic differentiation of ADSCs on ECM-small intestinal submucosa (SIS) were evaluated by immunofluorescences staining, cell counting kit-8 and real-time qPCR, respectively. A mouse calvarial defect model was used to assess effects on bone regeneration in vivo. Results: Abundant ECM was coated on SIS, which facilitated cell adhesion and proliferation of ADSCs. ECM-SIS induced osteogenic differentiation of ADSCs even without osteogenic inductive factors. Bone regeneration in vivo was enhanced by ECM-SIS + ADSCs via BMP/SMAD pathway. Conclusion: This work suggested a biofabricated SIS scaffold coated with osteogenic ECM-facilitated bone regeneration with ADSCs synergistically. Graphical abstract

Osteoarthritis (OA) is characterized by symptoms such as abnormal lubrication function of synovial fluid and heightened friction on the cartilage surface in its early stages, prior to evident cartilage damage. Current early intervention strategies employing lubricated hydrogels to shield cartilage from friction often overlook the significance of hydrogel-cartilage adhesion and enhancement of the cartilage extracellular matrix (ECM). Herein, we constructed a hydrogel based on dihydrazide-modified hyaluronic acid (HA) (AHA) and catechol-conjugated aldehyde-modified HA (CHA), which not only adheres to the cartilage surface as an effective lubricant but also improves the extracellular environment of chondrocytes in OA. Material characterization experiments on AHA/CHA hydrogels with varying concentrations validated their exceptional self-healing capabilities, superior injectability and viscoelasticity, sustained adhesion strength to cartilage, and a low friction coefficient. Chondrocytes exhibited robust adhesion and proliferation on the AHA/CHA hydrogel surface, with the upregulation of cartilage matrix protein expression. Intra-articular injection of AHA/CHA hydrogels was performed following destabilization of the medial meniscus (DMM) surgery in mice to assess its protective effect on cartilage. The AHA/CHA hydrogel effectively attenuated the degree of cartilage wear, facilitated chondrocytes' anabolic metabolism, and restored the ECM of cartilage. Therefore, the AHA/CHA hydrogel emerges as a promising therapeutic approach in clinical practices of OA treatment.

Critical‐sized bone defects remain a highly challenging clinical problem due to insufficient intrinsic self‐healing capacity. Bone marrow mesenchymal stem cell (BMSC)‐derived exosomes have emerged as promising cell‐free therapeutic candidates for bone regeneration, owing to their paracrine effects in regulating bone regeneration‐related processes. However, enhancing exosome bioactivity via biomimetic preconditioning and developing efficient delivery vectors remain key bottlenecks in this field. Herein, we developed a synergistic bone regenerative system composed of biomimetic preconditioned BMSC‐derived exosomes (BioPre‐Exos) and injectable porous polydopamine (PDA)‐modified gelatin methacryloyl (GelMA) microspheres. The biomimetic preconditioning strategy adopted 3% hypoxia combined with 3D GelMA microsphere culture, mimicking the bone marrow microenvironment to regulate BMSC functions and significantly boost exosome bioactivity. Functional experiments verified that BioPre‐Exos robustly promoted BMSC migration, osteogenic differentiation, angiogenesis, and macrophage polarization toward an anti‐inflammatory phenotype in vitro. Furthermore, in a rat femoral condyle defect model, the composite system markedly improved neovascularization density and bone volume fraction, thus achieving efficient vascularized bone regeneration. These findings indicate that this cell‐free biomimetic synergistic delivery system holds great application potential in the clinical treatment of bone defects.