Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation in accumulated senescent cells (SnCs) with aging is essential for tissue homeostasis, and adequate ATP is important in cell activation for aged tissue repair. Strategies for ATP metabolism intervention hold prospects for therapeutic advances. Here, we found energy metabolic changes in aging skin from patients and mice. Our data show that metformin engineered EV (Met-EV) can enhance aged mouse skin repair, as well as ameliorate cellular senescence and restore cell dysfunctions. Notably, ATP metabolism was remodeled as reduced glycolysis and enhanced OXPHOS after Met-EV treatment. We show Met-EV rescue senescence-induced mitochondria dysfunctions and mitophagy suppressions, indicating the role of Met-EV in remodeling mitochondrial functions via mitophagy for adequate ATP production in aged tissue repair. Our results reveal the mechanism for SnCs rejuvenation by EV and suggest the disturbed energy metabolism, essential in age-related defects, to be a potential therapeutic target for facilitating aged tissue repair.

The osteogenic function of mesenchymal stem cells (MSCs) is mainly attributed to the paracrine effect of extracellular vesicles. MSC-derived exosomes are interesting candidates as biopharmaceuticals for drug delivery and for the engineering of biologically functionalized materials, and have emerged as cell-free regenerative medicine in recent years. In this study, bone marrow mesenchymal stem cell (BMSC)-derived exosomes were loaded with photothermal material layered black phosphorus (BP) modified poly(N-isopropylacrylamide) (PNIPAAm) thermosensitive hydrogels to explore their effects on bone defect repair. In vitro, it was confirmed that the local high heat of nano-BP irradiated using a near-infrared (NIR) laser could trigger the reversible cascade reaction of hydrogels, and that the mechanical contraction of hydrogels led to the controllable release of a large number of exosomes along with the release of water molecules. Furthermore, in vitro investigations demonstrated that BP hydrogels loaded with BMSC-derived exosomes had favourable biocompatibility and could promote the proliferation and osteogenic differentiation of MSCs. Experiments conducted in vivo confirmed that this system significantly promoted bone regeneration. Therefore, the results of our study indicated that the nanoplatform based on BP thermosensitive hydrogels could provide a new clinical treatment strategy for controlled release and on-demand drug delivery, while the cell-free system composed of BMSC-derived exosomes had great application potential in bone tissue repair with the synergism of BP.

Background: The synergistic effect of chemical element doping and surface modification is considered a novel way to regulate cell biological responses and improve the osteoinductive ability of biomaterials. Methods: Hydroxyapatite (HAp) bioceramics with micro-nano-hybrid (a mixture of microrods and nanorods) surfaces and different strontium (Sr) doping contents of 2.5, 5, 10, and 20% (Sr_x-mnHAp, x: 2.5, 5, 10 and 20%) were prepared via a hydrothermal transformation method. The effect of Sr_x-mnHAp on osteogenesis and angiogenesis of bone marrow stromal cells (BMSCs) was evaluated in vitro, and the bioceramics scaffolds were further implanted into rat calvarial defects for the observation of bone regeneration in vivo. Results: HAp bioceramics with micro-nano-hybrid surfaces (mnHAp) could facilitate cell spreading, proliferation ability, ALP activity, and gene expression of osteogenic and angiogenic factors, including COL1, BSP, BMP-2, OPN, VEGF, and ANG-1. More importantly, Sr_x-mnHAp (x: 2.5, 5, 10 and 20%) further promoted cellular osteogenic activity, and Sr₁₀-mnHAp possessed the best stimulatory effect. The results of calvarial defects revealed that Sr₁₀-mnHAp could promote more bone and blood vessel regeneration, with mnHAp and HAp bioceramics (dense and flat surfaces) as compared. Conclusion: The present study suggests that HAp bioceramics with micro-nano-hybrid surface and Sr doping had synergistic promotion effects on bone regeneration, which can be a promising material for bone defect repair.

Introduction: Achieving a successful reconstruction of alveolar bone morphology still remains a challenge because of the irregularity and complex microenvironment of tooth sockets. Biological materials including hydroxyapatite and collagen, are used for alveolar ridge preservation. However, the healing effect is often unsatisfactory.Methods: Inspired by superwetting biomimetic materials, we constructed a 3D actively-spreading bone repair material. It consisted of photocurable polyether F127 diacrylate hydrogel loaded with mixed spheroids of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs).Results: Biologically, cells in the spheroids were able to spread and migrate outwards, and possessed both osteogenic and angiogenic potential. Meanwhile, ECs also enhanced osteogenic differentiation of MSCs. Mechanically, the excellent physical properties of F127DA hydrogel ensured that it was able to be injected directly into the tooth socket and stabilized after light curing. In vivo experiments showed that MSC-EC-F127DA system promoted bone repair and preserved the shape of alveolar ridge within a short time duration.Discussion: In conclusion, the novel photocurable injectable MSC-EC-F127DA hydrogel system was able to achieve three-dimensional tissue infiltration, and exhibited much therapeutic potential for complex oral bone defects in the future.

Chirality, a fundamental design feature at all levels of life organization, has shown great capability in guiding cell‐fate determination and tissue regeneration. Chirality‐directed differentiation programs involve remarkable changes in transcriptional networks, yet whether epigenetic regulatory events are also required is less well understood. Herein, by combining high‐throughput m⁶A MeRIP sequencing, RIP‐qPCR, and gene modulation techniques, it is demonstrated that biomimetic chiral nanofibrils can bidirectionally regulate wilms tumor 1 associated protein (WTAP)‐mediated m⁶A RNA methylation to guide macrophages polarization for tissue regeneration. The biomimic chiral nanofibril hydrogels are fabricated using a self‐assembly approach based on C2‐symmetric phenylalanine derivatives. In vitro and in vivo studies indicated that the L‐nanofibrils exhibit a greater propensity to promote M2‐macrophage polarization than D‐nanofibrils, thereby favoring osteogenesis. Then, m⁶A‐MeRIP sequencing revealed a unique chirality‐dependent m⁶A methylation level in macrophages, which was gated by a competitive pair of CCM3‐FAK through enantioselectively integrin recognition. L‐nanofibrils considerably suppressed WTAP‐mediated m⁶A methylation by promoting Itgα3‐FAK expression and paxillin‐driven mechanotransduction, whereas D‐nanofibrils induced WTAP‐mediated m⁶A methylation by favoring ItgαV‐CCM3 expression and suppressing mechanotransduction. Furthermore, the gain‐of‐function and loss‐of‐function experiments and RIP‐qPCR demonstrate that the WTAP expression could direct macrophage polarization via manipulating the functional molecule B7‐H3 (CD276). Thus, a mechano‐epigenetic mechanism of chirality‐mediated cell‐fate determination is unveiled, which holds remarkable promise in the realm of assisted regenerative material design.