3D printed muscle-bone organ implant for treating large injuries

项目摘要 在美国，肌肉骨骼疾病，如肢体损伤，烧伤和肿瘤是一个主要原因 残疾和死亡，影响到两个人中的一个。然而，直到现在，还没有有效的植入物 它可以替代受损骨骼和肌肉组织的结构和功能，这可能是由于 调节复杂的异质性骨-肌肉连接结构。因此，肌肉损伤 在肌肉骨骼手术中，这在很大程度上被忽视了，这通常会导致组织分离和纤维化。 组织形成，导致暂时或永久性肌肉骨骼残疾。事实上，在人类 在肌肉骨骼系统中，在广泛的骨和肌肉组织之间存在直接附着， 骨，形成“骨-肌肉单元”。基于这种结构上的紧密性，骨骼的生长和发育 和肌肉通过生长因子信号和细胞串扰紧密耦合。因此，损害 骨骼或肌肉中的任何一种都可能使另一种组织类型的健康和功能恶化。为此， 一直强烈需要开发一种创新的肌肉骨骼植入物， 以空间受控的方式测量硬组织和软组织的物理化学性质。 为了解决这个问题，我们的目标是设计和建立第一个3D打印肌肉骨骼植入物，通过利用状态- 最先进的3D多材料生物打印，可以同时挤出多种类型的组织模拟生物墨水。 连续的方式。我们将控制生物墨水的物理化学性质，如粘度和孔隙率， 为每种细胞类型的生长和分化提供优化的人工生态位。我们还将包括 提供具有控释动力学的肌生成和成骨生长因子的可生物降解的药物载体 行为，以帮助组织恢复。此外，我们将调整生物打印的参数，例如气动 压力以及注射和光交联条件来构建3D结构。然后我们将成熟的3D 通过施加压缩和松弛在定制的生物反应器系统中打印的肌肉-骨器官植入物 模拟体内肌肉骨骼运动的周期。最后，我们将评估肌肉骨骼再生 我们的3D打印肌肉-骨植入物在小鼠体积肌肉损失和骨缺损模型中的容量。这 研究将展示第一个3D打印的肌肉-骨骼组织，其具有体外连续结构，可以提供 开创性的临床解决方案，用于治疗严重的肌肉骨骼损伤和预防临床残疾。 我们进一步期望我们的3D打印肌肉-骨骼组织平台将有助于理解 肌肉骨骼系统的发育原理和病理机制。

PROJECT SUMMARY In the United States, musculoskeletal diseases such as extremity injuries, burns, and tumors are a leading cause of disabilities and death, affecting one in two individuals. However, until now, there has been no effective implant that can replace the structure and function of damaged bone and muscle tissues, likely due to the difficulty of regulating the sophisticated heterogeneous bone-muscle junction structure. As a result, muscle damage has been largely ignored during musculoskeletal surgeries, which often results in disconnected tissues and fibrous tissue formation, leading to temporal or permanent musculoskeletal disability. In fact, in the human musculoskeletal system, there exists a direct attachment between bone and muscle tissues at a wide area of bone, forming a “bone-muscle unit.” Based on this structural closeness, the growth and development of bone and muscle are tightly coupled through growth factor signaling and cellular cross-talk. Therefore, damage to either bone or muscle can deteriorate health and function of the other tissue type. For this reason, there has been a strong need for developing an innovative musculoskeletal implant, which can integrate the distinguished physicochemical properties of hard tissue and soft tissue in a spatially controlled manner. To address this problem, we aim to design and build the first 3D printed muscle-bone implant, by utilizing state- of-the-art 3D multimaterial bioprinting that can extrude multiple types of tissue mimetic bioinks in a simultaneous and continuous manner. We will control the physicochemical properties of bioinks, such as viscosity and porosity, to provide an optimized artificial niche for the growth and differentiation of each cell type. We will also include biodegradable drug carriers to supply musculogenic and osteogenic growth factors with controlled release kinetic behavior, to aid tissue recovery. In addition, we will regulate the parameters for bioprinting, such as pneumatic pressure, and the injection and photocrosslinking conditions to build a 3D structure. We will then mature the 3D printed muscle-bone organ implant in a customized bioreactor system by applying compression and relaxation cycles that mimic musculoskeletal movement in vivo. Finally, we will evaluate the musculoskeletal regeneration capacity of our 3D printed muscle-bone implant in a mouse volumetric muscle loss and bone defect model. This research will present the first 3D print muscle-bone tissues with continuous structures ex vivo that can provide a groundbreaking clinical solution for curing severe musculoskeletal injuries and preventing disabilities in the clinic. We further expect that our 3D printed muscle-bone tissue platform will be beneficial for understanding developmental principles and pathological mechanisms of the musculoskeletal system.