Biofabrication of a 3D bone tissue analogue with immunomodulatory factors to induce neovascularization and osteogenesis

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Over 50,000 bone procedures performed annually in the UK involve autografts (1). Serious limitations in autologous-grafts, such as limited tissue supply, donor site morbidity, potential for infection or disease transmission and poor osseointegration, has led to many bone tissue engineering approaches (2). However, a major challenge of critically-sized 3D engineered tissues is the lack of adequate vascular supply which results in cell necrosis and tissue failure. We have developed bone marrow derived mesenchymal-stem-cells (MSC) spheroids that form calcium rich nodules (3) and an endothelial and MSC coculture methodology in collagen gel for the prevascularisation of engineered constructs (4) that combined with natural hydrogels induce angiogenesis and osteogenesis. When a biomaterial is implanted a response is initiated by the host tissue which could result in persistent inflammation. This in turn results in impaired healing and repair. Therefore the osteo- and angio-immunomodulatory properties of biomaterials can affect the outcomes of bone regeneration (5). Increasing evidence suggest that the inflammatory cytokines secreted by macrophages are necessary for mediating tissue-biomaterial integration. Here we aim to biofabricate vascularised-bone-constructs by embedding cellular spheroids/organoids of osteoprogenitor-cells (bone marrow derived mesenchymal-stem-cells) in a natural hydrogel (collagen, gelatin or alginate). In that, ECs and MSCs in collagen gel will be bioprinted using the suspended layer additive manufacture (SLAM) method for the creation of a suspended vascular network. These will be cultured with or without active osteo-immunomodulatory factors released by macrophages to increase bone regeneration.