A review of regulated self-organizing approaches for tissue regeneration

Tissue and organ regeneration is the dynamic process by which a population of cells rearranges into a specific form with specific functions. Traditional tissue regeneration utilizes tissue grafting, cell implantation, and structured scaffolds to achieve clinical efficacy. However, tissue grafting methods face a shortage of donor tissue, while cell implantation may involve leakage of the implanted cells without a supportive 3D matrix. Cell migration, proliferation, and differentiation in structured scaffolds may disorganize and frustrate the artificially pre-designed structures, and sometimes involve immunogenic reactions. To overcome this limitation, the self-organizing properties and innate regenerative capability of tissue/organism formation in the absence of guidance by structured scaffolds has been investigated. This review emphasizes the growing subfield of the regulated self-organizing approach for neotissue formation and describes advances in the subfield using diverse, cutting-edge, inter-disciplinarity technologies. We cohesively summarize the directed self-organization of cells in the micro-engineered cell-ECM system and 3D/4D cell printing. Mathematical modeling of cellular self-organization is also discussed for providing rational guidance to intractable problems in tissue regeneration. It is envisioned that future self-organization approaches integrating biomathematics, micro-nano engineering, and gene circuits developed from synthetic biology will continue to work in concert with self-organizing morphogenesis to enhance rational control during self-organizing in tissue and organ regeneration.