Resorbable, Phsophorylated Poly(ester urea) Surgical Adhesive to Enhance Fracture Healing

项目摘要 该提案提出了一个为期五年的研究职业发展计划，重点是优化物理 磷酸化聚酯脲（pPEU）用于肋骨固定和愈合的生物学特性 骨折该候选人目前是外科和急性和重症监护创伤助理教授 杜克大学的外科医生，以前在生物材料和组织工程方面有研究经验 research.他现在选择专注于材料科学和机械工程， 具有材料、聚合物、肌肉骨骼修复 和干细胞研究。拟议的实验和教学工作将为候选人提供 一套独特的技能，这将帮助他过渡到独立作为一个外科医生，科学家，使他能够填补一个 在肋骨骨折和伤口愈合的研究领域存在显著的“经验差距”。 肋骨骨折占每年所有骨折的近40%， 肋骨受伤这些伤害可能会产生长期影响，有时甚至是终身影响。超过一半的肋骨骨折患者 感染肺炎，近三分之二的人在多年后仍然会经历胸壁的明显疼痛。 持续的伤害。虽然骨折的稳定性促进了更快的愈合并降低了骨不连的发生率 （骨折无法愈合），肋骨骨折提出了一个独特的挑战，因为固定只能是 通过侵入性外科手术完成。因此，不像长骨骨折， 稳定是标准的，这是保留在肋骨骨折，只有最严重的情况下。聚酯脲（PEU） 是基于氨基酸的生物可降解聚合物，具有骨样机械性能。一个这样的磷酸化 基于磷酸丝氨酸（pSer）的PEU（pPEU）共聚物是乙醇可溶的，允许注射，具有强的 骨粘附力和高弹性模量，使pPEU成为理想的创新，非侵入性解决方案， 稳定肋骨骨折。然而，pSer化学计量对PEU共聚物骨诱导的影响仍然存在 未知，以及使用可吸收PEU粘合剂的临时弹性骨痂是否可以加速 通过早期骨折稳定实现骨愈合。该提案将确定 注射用pSer-PEU的物理和生物学特性，并测试其安全性和 pSer-PEU在大鼠肋骨骨折模型中的性能。本提案的工作将：1） PEU共聚物中pSer化学计量对生物力学（拉伸强度，弹性模量， 和硬度），和筋膜间粘附的pSer-PEU; 2）定量骨髓基质细胞（BMSC）细胞骨架 重组和骨诱导以增加刚度，以及3）评估骨折稳定性和骨痂形成 在大鼠肋骨骨折模型中具有最佳性能的pSer-PEU。这项工作的结果将作为 未来的项目集中在使用功能化生物材料来理解断裂的细胞机制 以优化高风险创伤患者的愈合。

PROJECT SUMMARY This proposal presents a five-year research career development program focused on optimizing the physical and biological characteristics of phosphorylated poly(ester ureas) (pPEU) for the stabilization and healing of rib fractures. The candidate is currently an Assistant Professor of Surgery and acute and critical care trauma surgeon at Duke University, with previous research experience in biologic materials and tissue engineering research. He has now chosen to focus on materials science and mechanical engineering with a diverse mentoring committee of investigators with expertise in materials, polymers, musculoskeletal reparative processes and stem cell research. The proposed experiments and didactic work will provide the candidate with a unique set of skills that will help him transition to independence as a surgeon-scientist and enable him to fill a significant “experience gap” in the field of research dedicated to rib fractures and wound healing. Rib fractures account for nearly 40% of all bone fractures sustained in the each year, with over a quarter million rib injuries. These injuries can have long-lasting effects, sometimes even for life. Over half of rib fracture patients contract pneumonia, and nearly two thirds will still experience significant pain in the chest wall years after sustaining the injury. While stabilization of a fracture promotes faster healing and decreased rates of non-union (failure of a broken bone to heal), rib fractures present a unique challenge in that immobilization can only be accomplished through invasive surgical intervention. Therefore, unlike long bone fractures where immediate stabilization is standard, this is reserved in rib fractures for only the most severe cases. Poly(ester ureas) (PEU) are amino acid based biodegradable polymers with bone like mechanical properties. One such phosphorylated PEU (pPEU) copolymer, based on phosphoserine (pSer) is ethanol soluble allowing for injection, with strong bone adhesion and high elastic moduli, making pPEU’s ideal as an innovative, non-invasive solution for the stabilization of rib fractures. However, the effect of pSer stoichiometry on PEU copolymer osteoinduction remains unknown, as well as if a provisional elastomeric callus using resorbable PEU based adhesive can accelerate bone healing through early fracture stabilization. This proposal will determine the relationships between the physical and biologic characteristics of injectable pSer-PEU for osteoinduction and test the safety and performance of pSer-PEU in a rat model of rib fracture. The work of this proposal will 1) characterize the relationship of pSer stoichiometry within the PEU copolymers on biomechanics (tensile strength, elastic modulus, and stiffness), and interfascial adhesion of pSer-PEU; 2) quantify bone marrow stromal cell (BMSC) cytoskeletal reorganization and osteoinduction to increased stiffness, and 3) evaluate fracture stability and callus formation in a rat rib fracture model with best performing pSer-PEU. The results of this work will serve as the basis for future projects focused on using functionalized biomaterials to understand the cellular mechanisms of fracture healing in order to optimize healing in the high risk trauma patient.