Engineering anatomically shaped human bone grafts

Abstract

The ability to engineer anatomically correct pieces of viable and functional human bone would have tremendous potential for bone reconstructions after congenital defects, cancer resections, and trauma. We report that clinically sized, anatomically shaped, viable human bone grafts can be engineered by using human mesenchymal stem cells (hMSCs) and a "biomimetic" scaffold-bioreactor system. We selected the temporomandibular joint (TMJ) condylar bone as our tissue model, because of its clinical importance and the challenges associated with its complex shape. Anatomically shaped scaffolds were generated from fully decellularized trabecular bone by using digitized clinical images, seeded with hMSCs, and cultured with interstitial flow of culture medium. A bioreactor with a chamber in the exact shape of a human TMJ was designed for controllable perfusion throughout the engineered construct. By 5 weeks of cultivation, tissue growth was evidenced by the formation of confluent layers of lamellar bone (by scanning electron microscopy), markedly increased volume of mineralized matrix (by quantitative microcomputer tomography), and the formation of osteoids (histologically). Within bone grafts of this size and complexity cells were fully viable at a physiologic density, likely an important factor of graft function. Moreover, the density and architecture of bone matrix correlated with the intensity and pattern of the interstitial flow, as determined in experimental and modeling studies. This approach has potential to overcome a critical hurdle-in vitro cultivation of viable bone grafts of complex geometries-to provide patient-specific bone grafts for craniofacial and orthopedic reconstructions.biomimetic | bioreactor | craniofacial regeneration | mesenchymal stem cells | temporomandibular joint | tissue engineering

Image-Based, Fiber Guiding Scaffolds: A Platform for Regenerating Tissue Interfaces

“…[3][4][5][6] To overcome these therapeutic difficulties, multi-phasic scaffolds or physical gradient constructs have been designed and used for multiple tissue formation within a single system 7,8 as well as for bioactive molecule-induced tissue morphogenesis and regeneration. 9 Various in vitro approaches highlight the importance of geometric control on tissue regeneration/ morphogenesis using a variety of cell types, [10][11][12] but geometric influences on spatiotemporal tissue regeneration and functional healing have had limited assessment in vivo. 3,13 Dental-supportive connective tissue, known as periodontal ligament (PDL), is anchored between mineralized tissue surfaces and plays a key role in the transmission of biomechanical proprioception, 3,13,14 adaptive responses of masticatory cyclic movements, 13 shock absorption of external forces, and tooth movement.…”

The Potential Impact of Bone Tissue Engineering in the Clinic

“…Unlike entirely in vivo therapies, the use of bioreactors makes it easy to prevent the risk of pleiotropic effects of high doses of bioactive molecules and to avoid attachment of competing, undesirable cell types (e.g., fibroblasts). The goal of some bioreactor approaches is to create scaffolds coated with precultured bone extracellular matrix that may be perceived by the host as a bone graft [102][103][104]. Three types of bioreactors may be used for BTE.…”

Bioengineered tumors

“…Based on our previous studies on the bone niche, [7][8][9][10] we consider that-in addition to cancer cells-the most important component for building a bone tumor is the bone tissue context, with the bone cells and extracellular matrix. Together, these 2 components can be mimicked using the tissue engineering tools, such as scaffolds and bioreactors (Fig.…”

“…5 In recent years, many groups have made significant progress in creating advanced in vitro models that recapitulate some of the key factors of the native tumor microenvironment, with the aid of tissue engineering. 6 Our lab is applying the knowledge and techniques acquired over years in generating in vitro human bone tissue [7][8][9][10] to build specific niches for developing bone tumors. 11 …”