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

项目总结 在美国，四肢损伤、烧伤和肿瘤等肌肉骨骼疾病是主要原因 每两个人中就有一个受到残疾和死亡的影响。然而，直到现在，还没有有效的植入物 可以替代受损的骨骼和肌肉组织的结构和功能，可能是因为 调节复杂的异质骨-肌肉连接结构。结果，肌肉损伤 在肌肉骨骼手术中很大程度上被忽视了，这往往会导致组织脱节和纤维 组织形成，导致暂时性或永久性肌肉骨骼残疾。事实上，在人类中 肌肉骨骼系统，在骨骼和肌肉组织之间存在着广泛的直接连接 骨骼，形成一个“骨-肌肉单位”。基于这种结构的接近，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相连。因此，损坏 骨骼或肌肉都会恶化另一种组织类型的健康和功能。出于这个原因，有 迫切需要开发一种创新的肌肉骨骼植入物，它可以整合不同的 以空间控制的方式显示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制造第一个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，可同时挤出多种组织模拟生物墨水 和连续不断的态度。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 生物可降解药物载体提供肌肉和成骨生长因子的控释动力学 行为，以帮助组织恢复。此外，我们还将调整生物打印的参数，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3D 利用压缩和松弛技术在定制的生物反应器系统中植入打印的肌肉-骨骼器官 模仿活体肌肉骨骼运动的循环。最后，我们将对肌肉骨骼再生进行评估。 我们的3D打印肌骨植入物在小鼠容积性肌肉丢失和骨缺损模型中的容量。这 研究将提出第一个3D打印肌肉-骨组织，在体外具有连续结构，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。 我们进一步期待我们的3D打印肌肉-骨组织平台将有助于了解 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.