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

可吸收的磷酸化聚（酯脲）手术粘合剂可促进骨折愈合

• 批准号: 10283703
• 负责人: Joseph S. Fernandez-Moure
• 金额: $ 16.73万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283703
• 关键词: Actins; Adhesions; Adhesives; Amino Acids; Award; Biocompatible Materials; Biologic Characteristic; Biomechanics; Biomedical Engineering; Bone Marrow; Bone Marrow Stem Cell; Bone callus; Breathing; Calcium; Cartilage; Cells; Chemicals; Chest wall structure; Chondrocytes; Clinical; Collagen; Contracts; Critical Care; Cues; Cytoskeletal Modeling; Data; Deposition; Development; Engineering; Esters; Ethanol; Exhibits; External Fixation Devices; Failure; Flail Chest; Focal Adhesions; Formulation; Foundations; Fracture; Fracture Healing; Future; Generations; Glycols; Goals; Immobilization; In Vitro; Incidence; Injectable; Injections; Injury; Investigation; Laboratory Research; Life; Mechanics; Mentors; Metabolic; Modeling; Modification; Modulus; Musculoskeletal; Operative Surgical Procedures; Orthopedics; Osteoblasts; Pain; Patients; Performance; Phosphorylation; Phosphoserine; Play; Pneumonia; Polymers; Positioning Attribute; Program Development; Property; Public Health; Rattus; Research; Research Personnel; Rib Fractures; Scientist; Stem Cell Research; Stromal Cells; Surface; Surgeon; Tensile Strength; Testing; Tissue Engineering; Trauma; Trauma patient; Traumatic injury; United States; United States National Institutes of Health; Universities; Urea; Vertebral column; Work; acute care; base; biodegradable polymer; bone; bone healing; career; career development; clinical practice; copolymer; cortical bone; density; elastomeric; experience; experimental study; healing; high risk; improved; in vivo; innovation; inorganic phosphate; insight; interfacial; long bone; materials science; mechanical properties; minimally invasive; monomer; novel; novel therapeutics; polymerization; professor; pulmonary function; repaired; reparative process; rib bone structure; safety testing; skills; stoichiometry; surgery material; trauma care; treatment strategy; wound healing

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.

项目摘要 该建议提出了一项五年的研究职业发展计划，旨在优化物理 磷酸化聚（酯尿素）（PPEU）的生物学特征，用于肋骨的稳定和愈合 断裂。候选人目前是手术，急性和重症监护创伤的助理教授 杜克大学的外科医生，在生物材料和组织工程方面具有先前的研究经验 研究。他现在选择专注于潜水员的材料科学和机械工程 研究人员指导委员会具有材料，聚合物，肌肉骨骼的专业知识的专业知识委员会 过程和干细胞研究。拟议的实验和教学工作将为候选人提供 一套独特的技能，可以帮助他作为外科医生过渡到独立性，并使他能够填补 专门用于肋骨骨折和伤口愈合的研究领域的重要“经验差距”。 肋骨骨折占每年持续的所有骨折的近40％，超过25万 肋骨受伤。这些伤害可能会产生持久的影响，有时甚至是生命。超过一半的肋骨受伤患者 几年后，肺炎合同，近三分之二仍会在胸壁上遭受重大疼痛 维持伤害。骨折的稳定促进了更快的愈合和提高非工会的速度 （断骨骨折的未能治愈），肋骨骨折提出了一个独特的挑战，因为固定只能是 通过侵入性手术干预完成。因此，与立即的长骨骨折不同 稳定是标准的，仅在最严重的情况下保留在肋骨分数中。聚（酯尿素）（PEU） 是基于氨基酸的可生物降解聚合物，具有机械性能。一种这样的磷酸化 PEU（PPEU）共聚物，基于磷serine（PSER）是乙醇固体，可以注射，并具有强烈​​的注射 骨粘合剂和高弹性模量，使PPEU成为一种创新的，无创的解决方案 肋骨骨折的稳定。但是，PSER化学计量对PEU共聚物骨诱导的影响仍然存在 未知，以及使用基于可吸收PEU粘合剂的临时弹性愈伤组织是否可以加速 骨骼通过早期骨折稳定进行愈合。该建议将决定 可注射pser-PEU的物理和生物学特征，用于骨诱导并测试安全性和 pser-peu在肋骨骨折模型中的性能。该提议的工作将为1）表征 PEU共聚物在生物力学上的PSER化学计量法（拉伸强度，弹性模量， 和刚度）和pser-peu的界面粘附； 2）量化骨髓基质细胞（BMSC）细胞骨架 重组和骨诱导以增加刚度，3）评估断裂稳定性和愈伤组织形成 在具有最佳性能PSER-PEU的大鼠肋骨断裂模型中。这项工作的结果将作为 未来的项目着重于使用功能化的生物材料来了解骨折的细胞机制 为了优化高风险创伤患者的愈合。