We report here an injectable, self-healing coordinative hydrogel with antibacterial and angiogenic properties for diabetic wound regeneration. The hydrogel was prepared by coordinative cross-linking of multi-arm thiolated polyethylene glycol (SH-PEG) with silver nitrate (AgNO3). Due to the dynamic nature of Ag-S coordination bond and bacteria-killing activity of Ag+, the resultant coordinative hydrogel featured self-healing, injectable and antibacterial properties. In this study, we synchronously loaded an angiogenic drug, desferrioxamine (DFO), in the coordinative hydrogel during cross-linking. We finally obtained a multifunctional hydrogel that is manageable, resistant to mechanical irritation, antibacterial and angiogenic in vitro. Our in vivo studies further demonstrated that the injectable self-healing hydrogel could efficiently repair diabetic skin wounds with low bacteria-infection and enhance angiogenic activity. In short, besides diabetic skin wound repair, such dynamic multifunctional hydrogel scaffolds would show great promise in the regeneration of different types of exposed wounds, in particular, in situations with disturbed physiological functions, high risk of bacterial infections, and external mechanical irritation.

Distal necrosis of random skin flap is always clinical problematic in plastic surgery. The development of 3D functional vascular networks is fundamental for the survival of a local random skin flap. Herein, an effective technique on constructing 3D fibrous scaffolds for accelerated vascularization is demonstrated using a photocrosslinkable natural hydrogel based on gelatin methacryloyl (GelMA) by electrospinning. It is found that the ultraviolet (UV) photocrosslinkable gelatin electrospun hydrogel fibrous membranes exhibit soft adjustable mechanical properties and controllable degradation properties. Furthermore, it is observed that the optimized hydrogel scaffolds can support endothelial cells and dermal fibroblasts adhesion, proliferation, and migration into the scaffolds, which facilitates vascularization. Importantly, a rapid formation of tubes is observed after 3 d seeding of endothelial cells. After GelMA fibrous scaffold implantation below the skin flap in a rat model, it is found that the flap survival rate is higher than the control group, and there is more microvascular formation, which is potentially beneficial for the flap tissue vascularization. These data suggest that GelMA hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues.

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Mesenchymal stem cells (MSCs) represent an attractive source for stem cell-based regenerative therapy, but they are vulnerable to oxidative stress-induced premature senescence in pathological conditions. We previously reported antioxidant and antiarthritic effects of melatonin on MSCs against proinflammatory cytokines. In this study, we hypothesized that melatonin could protect MSCs from premature senescence induced by hydrogen peroxide (H2O2) via the silent information regulator type 1 (SIRT1)-dependent pathway. In response to H2O2 at a sublethal concentration of 200 μM, human bone marrow-derived MSCs (BM-MSCs) underwent growth arrest and cellular senescence. Treatment with melatonin before H2O2 exposure cannot significantly prevent premature senescence; however, treatment with melatonin subsequent to H2O2 exposure successfully reversed the senescent phenotypes of BM-MSCs in a dose-dependent manner. This result was made evident by improved cell proliferation, decreased senescence-associated β-galactosidase activity, and the improved entry of proliferating cells into the S phase. In addition, treatment with 100 μM melatonin restored the osteogenic differentiation potential of BM-MSCs that was inhibited by H2O2-induced premature senescence. We also found that melatonin attenuated H2O2-stimulated phosphorylation of p38 mitogen-activated protein kinase, decreased expression of the senescence-associated protein p16INK4α, and increased SIRT1. Further molecular experiments revealed that luzindole, a nonselective antagonist of melatonin receptors, blocked melatonin-mediated anti-senescence effects. Inhibition of SIRT1 by sirtinol counteracted the protective effects of melatonin, suggesting that melatonin reversed senescence in cells through the SIRT1-dependent pathway. Together, these findings lay new ground for understanding oxidative stress-induced premature senescence and open perspectives for therapeutic applications of melatonin in stem cell-based regenerative medicine.

Molecular imprinting is a versatile and straightforward method for the preparation of polymer receptors with tailor-made recognition sites. [1,2] Despite the tremendous progress made in this field, many challenges still remain to be addressed. In particular, it has been shown that the presently developed molecularly imprinted polymers (MIPs) are normally only organic solvent compatible and they mostly fail to show specific template bindings in pure aqueous solutions, thus significantly limiting their practical applications in the field of biotechnology.[2b] Although some approaches, which either use specifically designed functional monomers [3] or apply the conventional imprinting protocol, [4] have been developed for the preparation of MIPs with molecular recognition ability under aqueous conditions, versatile approaches for the preparation of MIPs that are applicable in pure aqueous environments are still rare. Herein, we report a new and efficient one-pot approach to obtain pure-water-compatible and narrowly dispersed MIP microspheres with surface-grafted hydrophilic polymer brushes by facile reversible addition/fragmentation chaintransfer (RAFT) precipitation polymerization (RAFTPP), [5] mediated by hydrophilic macromolecular chain-transfer agents (Macro-CTAs; Scheme 1). The presence of hydrophilic polymer brushes on MIP microspheres significantly improved their surface hydrophilicity and dramatically reduced their hydrophobic interactions with template molecules in pure aqueous media, thus leading to their water compatibility.[5b,c] The easy availability of many different hydrophilic Macro-CTAs (by either RAFT polymerization of hydrophilic monomers or hydrophilic polymer end group modification), [6] together with the versatility of RAFTPP for the controlled preparation of MIP microspheres, [5] makes this strategy highly applicable for the design of hydrophilic and water-compatible MIPs. Two strategies have been developed for the synthesis of water-compatible MIPs by improving their surface hydrophilicity; these strategies involve the use of a hydrophilic comonomer, [7] functional monomer, [8] or crosslinker [9] in the molecular imprinting process, and the postmodification of the preformed MIPs. [10, 11] Although simple in principle, the former strategy either requires time-consuming optimization of MIP formulation components [7,12] or can only be applied in some special systems. [8,9] In comparison, the latter strategy, which involves the surface grafting of hydrophilic polymer layers, has proven highly attractive because it not only significantly improves the MIPs surface hydrophilicity, but also provides a protective layer to prevent protein molecules from blocking their imprinting sites in biological solutions.[10] Very recently, we have successfully prepared pure-water-compatible MIP microspheres by the controlled grafting of hydrophilic polymer layers onto the preformed MIP particles. [5b,c] Compared with this two-step approach, the new strategy presented herein allows the more efficient controlled s...