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

利用免疫调节因子生物制造 3D 骨组织类似物以诱导新血管形成和成骨

• 批准号: 2722891
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2722891
• 关键词: Biofabrication; 3D; bone; tissue; analogue

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.

在英国，每年进行的50,000多个骨手术涉及自体移植(1)。自体移植的严重局限性，如有限的组织供应，供区发病率，感染或疾病传播的可能性，以及骨整合不良，导致了许多骨组织工程方法[2]。然而，临界尺寸的3D工程化组织的一个主要挑战是缺乏足够的血管供应，导致细胞坏死和组织衰竭。我们已经开发出骨髓来源的间充质干细胞(MSC)球体，形成富钙结节(3)，并开发了一种在胶原凝胶中内皮细胞和MSC共培养的方法，用于预防工程结构的血管形成(4)，与天然水凝胶相结合，诱导血管生成和成骨。当植入生物材料时，宿主组织会产生反应，这可能会导致持续的炎症。这反过来又会导致受损的愈合和修复。因此，生物材料的骨和血管免疫调节特性可以影响骨再生的结果(5)。越来越多的证据表明，巨噬细胞分泌的炎性细胞因子是介导组织-生物材料整合所必需的。在这里，我们的目标是通过将骨祖细胞(骨髓来源的间充质干细胞)的细胞球体/有机体嵌入到天然水凝胶(胶原、明胶或海藻酸盐)中来丰富血管化骨构建。在这方面，将使用悬浮层添加剂制造(SLAM)方法对胶原凝胶中的内皮细胞和间充质干细胞进行生物打印，以创建悬浮血管网络。这些细胞将在含有或不含有巨噬细胞释放的活性骨免疫调节因子的情况下进行培养，以促进骨再生。