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Skin wound is always accompanied with nerve destruction. Due to the limited clinical treatment option, loss of skin sensation with unsatisfactory nerve regeneration is remained to be a challenge for wound therapy. Endogenous mesenchymal stem cells (MSCs) based in situ regeneration, of which, MSCs recruited by chemokines and directed for neuronal differentiation by biological and electrical signals have been thought a novel strategy with potential to accelerate the nerve regeneration and sensory functions recovery. However, most current therapeutic systems usually deliver the chemokines, biological and electrical signals separately and statically, resulting in limited nerve regeneration and sensory functions recovery. Moreover, most of the devices for providing electrical signals need external energy input and complicated practice, leading to poor compliance in patients. To address these issues, we propose a self-powered smart patch (PRG-G-C) to provide chemokine and biological-electrical cues in program. PRG-G-C was composed of a flexible piezoelectric generator to supply electrical stimulation and a conductive gel, which served as the reservoir of chemokine and neural directing exosomes as well as the electrode to transfer electric cue. PRG-G-C was shown to efficiently accelerate rapid nerve regeneration and sensation restoration at the wound site within 23 days. This study demonstrates a proof-to-concept in organizing chemokine, neural directing biological-electrical heterogeneous cues within a self-powered smart patch for accelarating nerve regeneration and sensation restoration, possessing great potential in neural repair applications.

Strategies to direct the differentiation of endogenous bone marrow derived mesenchymal stem cells (BMSCs) in vivo following recruitment to the injured site are critical to realizing the potential of stem cell-based therapies. But the differentiation efficiency of BMSCs remains limited without direction. Here we demonstrated a novel strategy to promote neuronal differentiation of BMSCs using cross-linked polyethylenimine (PEI) grafted graphene oxide (GO) as the enzyme responsive vector for delivering active genes to BMSCs. In vivo, a core–shell microfiber arrayed hydrogel with a chemokine (SDF-1α) and the cross-linked GO-PEI/pDNAs-bFGF microparticles incorporated into the shell and core, respectively, were constructed. The arrayed hydrogel was shown to recruit and stimulate the neural-like differentiation of BMSCs effectively by delivering the CXCL12 and GO-PEI/pDNAs-bFGF in a self-controlled manner. With this strategy, both in vitro and in vivo neuronal differentiation of BMSCs with function were accelerated significantly. The cross-linked GO-PEI mediated gene transfection together with a multi-functional microfiber arrayed hydrogel provide a translatable approach for endogenous stem cell-based regenerative therapy.