A decellularized extracellular matrix (dECM) is an excellent biomaterial in regenerative medicine, due to its biomimetic nature in targeting tissues and organs. In this study, we prepared cell-derived ECMs (CDM) derived from four different cell sources, characterized them individually, and found that intrinsic properties of each CDM were substantially different in terms of the fibrous matrix, total protein, and biochemical factors. Based on such information, we selected two ECM candidates, the human lung fibroblast derived matrix (hFDM) and the umbilical cord-blood mesenchymal stem cell derived matrix (UMDM) for the study of ECM-macrophage interactions in vitro and in vivo. In fact, UMDM was the richer in both total protein and angiogenic-related cytokines than any other CDM. When THP-1 cell-derived macrophages (M0) were seeded onto the UMDM or the hFDM, it showed a mixed cell morphology of macrophage phenotype and the macrophages (M0) preconditioned on UMDM presented more diverse cytokine release profiles. The treatment of conditioned medium obtained from CDM-seeded macrophages showed that UMDM could yield significantly advanced wound closure in 24 h via the human dermal fibroblast scratch model. To investigate the role of ECM on macrophage polarization in vivo, we prepared an ECM hydrogel, a mixture of each CDM and Pluronic F127/hyaluronan, and applied them onto a full-thickness mouse skin wound model for 2 weeks. The therapeutic efficacy as assessed via histology and immunofluorescence staining (α-SMA and CD206) revealed that the UMDM-treated group showed more effective wound healing compared to the other groups, as proven via the thinner epidermal layer, significant recovery of skin appendage, better neovascularization, and higher recruitment of myofibroblasts and larger number of macrophages (M2) at 7 days. The difference between UMDM and hFDM was marginal. Taken together, among the CDMs, UMDM and hFDM are promising resources of ECM, showing a great potential for wound healing. Although the mechanism is not fully understood, bioactive innate factors in UMDM may contribute individually and/or collectively to advance wound healing.

Bone tissue engineering materials are crucial for bone repair, but existing repair materials still face many challenges, including poor biocompatibility and bioactivity, slow self-repair processes, limited adaptability, inability to promote angiogenesis and so on. To address these issues, the development of third-generation bone repair materials, which are being designed to stimulate specific cellular responses at the molecular level, such as borate and borosilicate bioactive glasses (BBGs/BSBGs) that activate cells and genes, offers new potential for promoting bone tissue self-renewing. Their unique characteristic lies in a flow of life-giving energy, releasing beneficial ions such as boron, calcium and silicon to stimulate cell proliferation and differentiation, accelerating the regeneration of bones. Through this dynamic repair mechanism, these VitaFlux glasses operate like a "living system" within the body, not only speeding up the healing of damaged tissues but also interacting seamlessly with surrounding tissues during the repair process. In this review, we provide a comprehensive analysis of the current understanding of the osteogenesis mechanisms of BBGs/BSBGs, emphasizing their interactions with cells, including ion release and exchange, protein adsorption, and cell adhesion. We also examine key osteogenic signaling pathways related to the alkaline and ionic microenvironments of BBGs/BSBGs, such as the cell cycle, Wnt, MAPK, and BMP signaling pathways, along with macrophage polarization and angiogenesis. Additionally, strategies and future prospects for advancing BBGs/BSBGs research are discussed. Special attention is given to the NaBC1 and GPCR-mediated signaling pathways, which require further investigation.

Cell cultures of dispersed cells within hydrogels depict the interaction of the cell–extracellular matrix (ECM) in 3D, while the coculture of different cells within spheroids combines both the effects of cell–cell and cell–ECM interactions. In this study, the cell co-spheroids of human bone mesenchymal stem cells/human umbilical vein endothelial cells (HBMSC/HUVECs) are prepared with the assistance of a nanopattern, named colloidal self-assembled patterns (cSAPs), which is superior to low-adhesion surfaces. A phenol-modified gelatin/hyaluronan (Gel-Ph/HA-Ph) hydrogel is used to encapsulate the multicellular spheroids and the constructs are photo-crosslinked using blue light. The results show that Gel-Ph/HA-Ph hydrogels with a 5%-to-0.3% ratio have the best properties. Cells in HBMSC/HUVEC co-spheroids are more favorable for osteogenic differentiation (Runx2, ALP, Col1a1 and OPN) and vascular network formation (CD31+ cells) compared to HBMSC spheroids. In a subcutaneous nude mouse model, the HBMSC/HUVEC co-spheroids showed better performance than HBMSC spheroids in angiogenesis and the development of blood vessels. Overall, this study paves a new way for using nanopatterns, cell coculturing and hydrogel technology for the generation and application of multicellular spheroids.

Magnesium (Mg) alloys are popular biodegradable metals studied for orthopedic and cardiovascular applications, mainly because Mg ions are essential trace elements known to promote angiogenesis and osteogenesis. However, Mg corrosion consists of oxidation and reduction reactions that produce by-products, such as hydrogen gas, reactive oxygen species, and hydroxides. It is still unclear how all these by-products and Mg ions concomitantly alter the microenvironment and cell behaviors spatially and temporally. This study shows that Mg corrosion can enhance cell proliferation by reducing intracellular ROS. However, Mg cannot decrease ROS and promote cell proliferation in simulated inflammatory conditions, meaning the microenvironment is critical. Furthermore, cells may respond to Mg ions differently in chronic or acute alkaline pH or oxidative stress. Depending on the corrosion rate, Mg modulates HIF1α and many signaling pathways like PI3K/AKT/mTOR, mitophagy, cell cycle, and oxidative phosphorylation. Therefore, this study provides a fundamental insight into the importance of reduction reactions in Mg alloys.

Topographical cues on material surfaces are crucial for guiding the behavior of nerve cells and facilitating the repair of peripheral nerve defects. Previously, micron-grooved surfaces have shown great potential in controlling nerve cell alignment for studying the behavior and functions of those cells and peripheral nerve regeneration. However, the effects of smaller-sized topographical cues, such as those in the submicron- and nano-scales, on Schwann cell behavior remain poorly understood. In this study, four different submicron-grooved polystyrene films (800/400, 800/100, 400/400, and 400/100) were fabricated to study the behavior, gene expression, and membrane potential of Schwann cells. The results showed that all submicron-grooved films could guide the cell alignment and cytoskeleton in a groove depth-dependent manner. Cell proliferation and cell cycle assays revealed that there was no significant difference between the submicron groove samples and the flat control. However, the submicron grooves can direct the migration of cells and upregulate the expression of critical genes in axon regeneration and myelination (e.g., MBP and Smad6). Finally, the membrane potential of the Schwann cells was significantly altered on the grooved sample. In conclusion, this study sheds light on the role of submicron-grooved patterns in regulating the behavior and function of Schwann cells, which provides unique insights for the development of implants for peripheral nerve regeneration.