Going below and beyond the surface: Microneedle structure, materials, drugs, fabrication, and applications for wound healing and tissue regeneration.

Microneedle, as a novel drug delivery system, has attracted widespread attention due to its non-invasiveness, painless and simple administration, controllable drug delivery, and diverse cargo loading capacity. Although microneedles are initially designed to penetrate stratum corneum of skin for transdermal drug delivery, they, recently, have been used to promote wound healing and regeneration of diverse tissues and organs and the results are promising. Despite there are reviews about microneedles, few of them focus on wound healing and tissue regeneration. Here, we review the recent advances of microneedles in this field. We first give an overview of microneedle system in terms of its potential cargos (e.g., small molecules, macromolecules, nucleic acids, nanoparticles, extracellular vesicle, cells), structural designs (e.g., multidrug structures, adhesive structures), material selection, and drug release mechanisms. Then we briefly summarize different microneedle fabrication methods, including their advantages and limitations. We finally summarize the recent progress of microneedle-assisted wound healing and tissue regeneration (e.g., skin, cardiac, bone, tendon, ocular, vascular, oral, hair, spinal cord, and uterine tissues). We expect that our article would serve as a guideline for readers to design their microneedle systems according to different applications, including material selection, drug selection, and structure design, for achieving better healing and regeneration efficacy.