홍합 모사 소재 기반의 세포 유도/치료제 플랫폼 개발

Abstract

Stem cell therapy has become an emerging branch of medicine for treating chronic diseases and organ transplantation. However, one of the major challenges in stem cell therapies is how transplanted stem cells remain and survive, and further functions what we expect. Another major challenge of stem cell therapy is the possibility to induce new blood vessels after cell transplantation. The hostile environments with which grafted cells confront, such as hypoxic and ischemic environments, result in a deficient supply of nutrients and oxygen for stem cells, leading to cell death. Therefore, new insights into a therapeutic angiogenesis derived from stem cell therapies have been encouraged for better grafted cell survival and high therapeutic efficacy. In this research, the novel platforms were be developed by employing bio-inspired protein biomaterials to overcome the limitations of conventional stem cell therapies. Numerous strategies have been devised and evaluated for alleviating deterioration and recovering dysfunctional tissues. These strategies can be divided into two general approaches: bioactive molecule-based therapies including growth factor and cytokines, and physically supporting-based therapies by mimicking physical characteristics of tissue to be regenerated. The former strategy is the therapeutic approach to induce paracrine effect for tissue regeneration, including angiogenesis and anti-fibrosis, based on employing bioactive molecules to recruit and stimulate stem cells. On the other hand, physically supporting-based strategy to mimic the surrounding tissue structurally and mechanically can make resident cells survive due to various adverse environments. The most optimal approaches need to be developed with the combination of appealing advantages in these two approaches. Thus, in our strategies, the optimal platform will be combined with bioactive approaches, such as cell cluster formation and stem cell signal transduction, and structural supporting approaches, such as cell adhesive utilizing adhesion modality found in nature organism, high elastic and delicate cell patch fabricated by 3D printing, and super adhesive cell scaffolds, based on marine-inspired structural proteins including mussel adhesive proteins (MAPs) and sea anemone-derived silk protein (Aneroin). In addition, crucial modalities were additionally conjugated to a biocompatible polymer to impart functionality such as adhesion or conductivity to the materials. In these studies, MAP-based underwater bioadhesive easily encapsulated stem cells and delivered them to the target site, in which cells not only survived for a long time but also induced angiogenesis with high cell retention, resulting in high therapeutic efficacy in rat myocardial infarction model. As the further strategy, we developed the MAP-based platform that combined the strategy of spatially separating bioactive molecules according to the releasing profile of material formulation and the physical supporting strategy by attaching materials possessing similar mechanical properties with surrounding tissue to be grafted and applied it to rat skin defects and myocardial infarction models to demonstrate its efficacy. In addition, we have also developed materials with special properties, including elasticity and conductivity. As for elasticity, we employed Aneroin having high elasticity. We developed 3D printed scaffolds using MAP and Aneroin to demonstrate the possibility of stem cell therapy platform by attaching various cells to proliferate and differentiate into osteoblast and chondrocyte with great elastic and cell favorable micro-environments. Finally, we developed a high-strength hydrogel that simultaneously imparted adhesiveness and conductivity to hyaluronic acid, and implanted it in mouse to demonstrate its biocompatibility. The platform was applied to bio-sensor or conductive hydrogel as a bio-grafting platform. Consequently, we could apply our novel stem cell platform to treat in vivo chronic diseases, including myocardial infarction, bone and cartilage defect, and skin defect. Therefore, our bio-inspired structural protein material-based stem cell therapy platform could be used as a promising regenerative medicine in diverse internal body applications requiring high therapeutic efficacy.