Multilayered Nanofiber Mimetic as a Functional Periosteum for Bone Tissue Repair and Reconstruction

Abstract

Periosteum harbors osteogenic and chondrogenic progenitors and demonstrates remarkable regenerative capacity in repair and reconstruction of injured bone. While an indispensable role of periosteum has been established, engineering of a flexible, transplantable periosteum that simulates the multilayered tissue structure of periosteum have not yet been realized. Utilizing a composite electrospun nanofiber mesh made of polycaprolactone, collagen and hydroxylapatite nanoparticles, we devised a layer-by-layer bottom-up approach to construction of a flexible 3D cellularized tissue graft that could function as a periosteum replacement for successful bone defect repair and reconstruction. Using an established segmental bone graft transplantation model in mice, we showed that the bone-marrow-stromal-cell (BMSC)-seeded, nanofiber-enabled tissue construct developed multiple-layered bone formation at the periosteum sites and further restored the inferior biomechanics of structural bone allograft healing after 6 week of implantation. Interestingly, depending upon the sites of implantation, donor BMSCs initiated either intramembraneous or endochondral bone formation and further recruited host cells to form chimeric bone. Using a windowed cranial defect chamber model that allows real-time, three-dimensional and longitudinal analyses of osteogenesis and angiogenesis of the multilayer periosteum mimetic at the site of defect via multiphoton laser scanning microscopy (MPLSM) in mice, we further showed that nanofiber constructs blocked exuberant angiogenesis and arteriogenesis originated from dura, facilitating host bone formation from the surrounding periosteum. Further seeding of nanofiber with BMSC reversed the aberrant vascular pattern and spatiotemporal changes associated with the chronic inflammatory responses elicited by electrospun nanofibrous materials, leading to marked bone formation and rapid defect closure. Taken together, our study demonstrated an effective engineering platform for construction of a multifunctional and multi-scaled periosteum mimetic for bone defect repair. Our data further revealed an intricate balance between osteogenesis and angiogenesis during nanofiber-mediated repair, underscoring the importance of development smart biomaterials capable of modifying host vascular microenvironment at multiple time scales for effective repair and regeneration. Tao Wang has nothing to disclose.