Oxygen generating bioinks for 3D printed bone implants

用于 3D 打印骨植入物的产氧生物墨水

• 批准号: 10212963
• 负责人: Su Ryon Shin
• 金额: $ 39.02万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212963
• 关键词: 3-Dimensional; Address; Alginates; Anastomosis - action; Autologous Transplantation; Behavior; Biocompatible Materials; Blood Vessels; Bone Tissue; Bone Transplantation; Cell Death; Cell Survival; Cells; Clinical; Defect; Development; Diffusion; Endothelial Cells; Engineering; Excision; Failure; Fracture; Fracture Healing; Gelatin; Goals; Gold; Hospitalization; Human; Hydrolysis; Hydrophobicity; Hypoxia; Implant; In Vitro; Intuition; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Musculoskeletal; Nature; Orthopedic Procedures; Osteogenesis; Oxygen; Pain; Patients; Phase; Polymers; Recovery; Research; Safety; Silicates; Site; Solid; Starvation; Stress; Structure; System; Techniques; Technology; Time; Tissue Engineering; Tissues; Ultraviolet Rays; United States; Vascular Endothelial Cell; Vascular System; Vascularization; behavioral construct; bioprinting; blood vessel development; bone; bone engineering; clinical efficacy; clinically relevant; cost; crosslink; design; disability; healing; implantation; improved; in vivo; innovation; long bone; nanoparticle; novel; osteogenic; physically handicapped; prevent; sample fixation; standard care; subcutaneous; tissue injury

Abstract Musculoskeletal tissue injuries are a leading cause of disability in the United States (US), yet there are only a few viable options for patients suffering from bone degeneration. One of the major challenges in this field is nonunion formation, which is the permanent failure of bone fracture healing. Current therapies such as bone fixation or bone grafting are often ineffective, painful, invasive, costly, and do not result in recovery of full function. To overcome this grand challenge, much research has been dedicated to the development of engineered three- dimensional (3D) bone tissue, which typically is composed of a biomaterial containing human mesenchymal stem cells (hMSCs) for bone formation and endothelial cells for blood vessel formation. Although these approaches accelerate implant anastomosis, it is inherently still associated with a prevascular phase that causes significant amounts of starvation induced cell death. Here, we propose an innovative solution to solve this important problem. We aim to achieve this by developing an oxygen generating biomaterial that can be used to 3D bioprint a vascularized bone implant for critical bone defect treatments. To this end, we set-out to explore two of our recently developed technologies: oxygen generating biomaterials and embedded sacrificial 3D bioprinting. To maintain cell survival during the implant’s pre-anastomosis phase, we will develop hydrophobic micromaterials containing molecules that release oxygen upon hydrolysis, which can be controlled via tuning the micromaterial’s hydrophobicity. These microparticles will be combined with our 3D printable and bone forming nanoparticle incorporated biomaterial matrix (Silicate-nanoparticles/GelMA) that is laden with human mesenchymal stem cells to effectively create an oxygenating bone forming bioink. This bioink will be used as a viscous medium in which a 3D vascular structure will be printed using embedded bioprinting; a novel 3D bioprinting technique that we are pioneering. Specifically, we will endow constructs with a 3D vascular structure of endothelial cell laden alginate bioink. Crosslinking the oxygenating bioink using low levels of UV light will yield a fully solid 3D construct. Upon sacrificing the internal alginate structure, an open 3D vascular network will be instantly formed. The pre-laden endothelial cells will coat the 3D network and thus provide a functional early vascularity that will accelerate anastomosis and thus minimize the implant’s prevascular phase. After in depth in vitro characterization using normoxic and hypoxic cultures, we will investigate the construct’s in vivo behavior using a subcutaneous and a critical defect model.

抽象的 肌肉骨骼组织损伤是美国 (US) 残疾的主要原因，但 对于患有骨退化的患者来说，只有少数可行的选择。 该领域的主要挑战是骨不连形成，即骨的永久性衰竭 目前的治疗方法如骨固定或骨移植通常无效， 克服这一重大问题是痛苦的、侵入性的、成本高昂的，并且不会导致完全功能的恢复。 挑战，许多研究致力于开发工程三 三维（3D）骨组织，通常由含有人类的生物材料组成 用于骨形成的间充质干细胞（hMSC）和用于血管的内皮细胞 尽管这些方法加速了种植体吻合，但本质上仍然是这样。 与导致大量饥饿诱导细胞的血管前阶段相关 在这里，我们提出了一个创新的解决方案来解决这个重要问题。 通过可用于 3D 生物打印的产氧生物材料来实现这一开发 为此，我们开始探索用于关键骨缺损治疗的血管化骨植入物。 我们最近开发的两项技术：产氧生物材料和嵌入式 为了在植入物的预吻合阶段维持细胞存活， 我们将开发含有释放氧气的分子的疏水性微材料 水解，可以通过调节微材料的疏水性来控制。 微粒将与我们的 3D 打印和骨形成纳米颗粒相结合 掺入生物材料基质（硅酸盐纳米颗粒/GelMA），其中充满了人类 间充质干细胞可以有效地创建含氧骨形成生物墨水。 将用作粘性介质，其中将使用 3D 血管结构进行打印 嵌入式生物打印；我们正在开创的一种新颖的 3D 生物打印技术。 将赋予构建体以充满内皮细胞的藻酸盐生物墨水的 3D 血管结构。 使用低水平的紫外线交联氧化生物墨水将产生完全固态的 3D 牺牲内部藻酸盐结构后，将形成开放的 3D 血管网络。 预先装载的内皮细胞将覆盖 3D 网络，从而提供一个 功能性早期血管分布将加速吻合，从而最大限度地减少植入物 使用常氧和低氧培养物进行深入的体外表征后， 我们将使用皮下和关键缺陷来研究构建体的体内行为 模型。