Biomimetic Approaches for Bone Tissue Engineering

Abstract

Bone tissue engineering is an attractive alternative to transplanting harvested tissue for bone defect repair. Various signals are involved in the regulation of stem/progenitor cell behavior, development and healing, which could be beneficially utilized in bone tissue engineering. However, bone tissue engineering research has very limited success in translation into the clinic, which often stems from the inappropriate administration of these signaling molecules due to the lack of optimal delivery systems. Therefore, this project is aimed at the development of new approaches to bone tissue engineering by mimicking advantageous features of the native extracellular matrix and signaling processes involved in development and natural healing. The author first develops preprogrammed drug delivery systems to achieve long-term pulsatile delivery of parathyroid hormone (PTH). A series of techniques, including polymer synthesis, drug formulation and device fabrication are developed to control the physical and chemical properties of the delivery devices so as to achieve spatiotemporal controlled drug release. Systemic pulsatile PTH release from the delivery device is demonstrated to increase bone volume and mineralized bone density, thereby providing a promising complying-friendly alternative to the standard daily PTH injection treatment for osteoporosis. Then PTH is repurposed successfully for local bone regeneration in a mouse calvarial bone defect regeneration model by using the pulsatile delivery system in combination with a biomimetic nanofibrous PLLA scaffold developed in our lab. Such system could possibly be utilized to regenerate various bone defects. Considering that the native bone defect healing process is initiated by macrophages via engulfing dead cells, the author develops a novel bioconjugation strategy to fabricate biodegradable microspheres to mimic apoptotic cells to target macrophages to initiate a biomimetic bone healing process. The biodegradable apoptotic cell-mimicking microspheres (BAM) are decorated with “eat me signal” and are shown to significantly enhance macrophage phagocytosis and enhance bone marrow stromal cell (BMSCs) migration via increased secretion of chemokines. Implanting a 3D space-defining biomimetic nanofiberous (NF) scaffold loaded with BAM results in a drastic increase in endogenous mesenchymal stem/progenitor cell recruitment into the scaffold compared to the same scaffold loaded with control microspheres, leading to critical-sized bone defect repair. This novel biomimetic approach opens a potential new avenue for bone regeneration without the need for exogenous cells.