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残疾的主要原因，但 患有骨变性的患者只有少数可行的选择。中的一个 该领域的主要挑战是骨不连的，这是骨头的永久失败 断裂愈合。当前的疗法（例如骨骼固定或骨移植）通常无效， 痛苦，侵入性，昂贵，并且不会导致完整功能的恢复。克服这个盛大的 挑战，许多研究都致力于开发工程的三 - 尺寸（3D）骨组织，通常由包含人的生物材料组成 间充质干细胞（HMSC）用于血管的骨形成和内皮细胞 地层。尽管这些方法加速了植入物吻合术，但仍在 与引起大量饥饿诱导细胞的前期相关 死亡。在这里，我们提出了一种创新的解决方案来解决这个重要问题。我们的目标 通过开发可用于3D Bioprint A的氧气产生生物材料来实现这一目标 临界骨缺损治疗的血管植入物。为此，我们设定探索 我们最近开发的两种技术：产生生物材料并嵌入的氧气 牺牲3D生物打印。为了维持植入物前剂量阶段中的细胞存活， 我们将开发含有含有分子的疏水微材料，这些分子在 水解，可以通过调整微材料的疏水性来控制。这些 微粒将与我们的3D可打印和骨形成纳米颗粒结合 掺入生物材料基质（硅酸盐 - 纳米颗粒/胶质），载有人类 间充质干细胞有效地产生形成生物学的氧化骨。这个生物界 将用作使用3D血管结构的粘性介质 嵌入生物打印；我们正在开创的一种新颖的3D生物打印技术。具体来说，我们 将赋予内皮细胞Lady Alginate Bioink的3D血管结构。 使用低水平的紫外线将氧合生物互联交联将产生完全实心的3D 构造。牺牲内部藻酸盐结构后，开放的3D血管网络将是 立即形成。预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，将加速吻合，从而最大程度地减少植入物 前期期。在使用常氧和低氧培养物进行深入的体外表征之后， 我们将使用皮下和关键缺陷研究结构的体内行为 模型。