A Biofabrication Strategy for a Custom-Shaped, Non-Synthetic Bone Graft Precursor with a Prevascularized Tissue Shell

Abstract

Critical-sized defects of irregular bones requiring bone grafting, such as in craniofacial reconstruction, are particularly challenging to repair. With bone-grafting procedures growing in number annually, there is a reciprocal growing interest in bone graft substitutes to meet the demand. Autogenous osteo(myo)cutaneous grafts harvested from a secondary surgical site are the gold standard for reconstruction but are associated with donor-site morbidity and are in limited supply. We developed a bone graft strategy for irregular bone-involved reconstruction that is customizable to defect geometry and patient anatomy, is free of synthetic materials, is cellularized, and has an outer pre-vascularized tissue layer to enhance engraftment and promote osteogenesis. The graft, comprised of bioprinted human-derived demineralized bone matrix blended with native matrix proteins containing human mesenchymal stromal cells and encased in a simple tissue shell containing isolated, human adipose microvessels, ossifies when implanted in rats. Ossification follows robust vascularization within and around the graft, including the formation of a vascular leash, and develops mechanical strength. These results demonstrate an early feasibility animal study of a biofabrication strategy to manufacture a 3D printed patient-matched, osteoconductive, tissue-banked, bone graft without synthetic materials for use in craniofacial reconstruction. The bone fabrication workflow is designed to be performed within the hospital near the Point of Care.

A dual osteoconductive-osteoprotective implantable device for vertical alveolar ridge augmentation

“…For comparative purposes, of particular importance is the patient defect-specific 3D design and printing with TCP/HA, a solid material as recently proposed (10), but also the dual ink strategy with TCP/HA for 3D printing of in vitro prevascularized bone scaffolds (12), or similarly with a human bone powder-based bioink (54).…”

Isolated Fragments of Intact Microvessels: Tissue Vascularization, Modeling, and Therapeutics

“…Over the years, iMVs have been used in countless applications, such as for studying angiogenesis-tissue biomechanics [36][37][38], stromal cell and vascular precursor dynamics [39,40], postangiogenesis microvascular maturation and patterning [41], imaging methods to assess neovascular behavior [42], whole-tissue modeling [43,44], and for prevascularization of tissue and cellular grafts [27,[45][46][47][48][49][50][51]. Intact microvessels have also served as a platform for evaluating the effect of angiogenic factors and agents [52][53][54][55][56][57][58], evaluating microvascular instability [59,60], assessing MMP-related angiogenic activity [52], and studying the dynamic role of the extracellular matrix during angiogenesis [37,42].…”

“…Following culture, prevascularized grafts were subcutaneously implanted into nude rats. Explanted grafts at 4 and 8 weeks were fully vascularized, having developed a supporting vascular leash, integrated with the surrounding tissue, and were ossified [45].…”