Microengineering vascularized and innervated bone-like scaffolds as an alternative to autologous bone grafts

PROJECT SUMMARY
A wide range of skeletal conditions require assisted bone repair, including trauma, cancer resections, and bone
augmentation for oral implant therapy. Current methods to treat these conditions rely on procedures to harvest
and implant bone autografts, which are costly, invasive and difficult to scale up. The other alternatives are
synthetic bone replacement materials, which show high failure rates and fail to mimic the native bone structure,
composition and osteogenic properties. Stem cell-based tissue engineering has long been proposed as a
promising alternative for the repair of bone defects. However, treating large bony structures remains problematic.
It is generally believed that scaffold materials that closely approximate the characteristics of native bone
represent improved materials for bone regeneration. However, the development of in-vitro scaffolds mimicking
the highly vascularized, innervated, and mineralized cell-rich bone matrix down to the nanoscale has remained
elusive to date. Here, we will develop a new bone scaffold biomanufacturing process where osteoprogenitor cells
are three-dimensionally embedded in controlled nano-mineralized, pre-vascularized and innervated bone-like
injectable microgels, thus mimicking the mineralized nanostructure, cellular and extracellular microenvironment
of native bone. (aim 1) We will determine the mechanistic characteristics enabling the differentiation of hMSCs
into osteogenic phenotypes as influenced by bone-like microenvironments, and engineer cell-laden mineralized
injectable microgels that approximate the regenerative potential of autologous bone grafts. We will then adapt
this strategy to engineer (aim 2) pericyte-supported vascular capillaries and (aim 3) neuronal networks, that are
embedded in nanoscale mineralized hydrogels, to determine the mechanisms that enable vasculature and
innervation enhancement of osteogenesis in-vitro and regeneration in-vivo. We argue that this multi-pronged
strategy will enable the engineering of highly innovative bone scaffold materials and in-vitro bone model systems
that will share great nanostructural and physical similarities to native bone. Ultimately, this will lead to
biomaterials that closely approximate the regenerative potential of autologous bone in the clinic.

Grant Number: 5R01DE029553-05
NIH Institute/Center: NIH
Principal Investigator: Luiz Bertassoni