Bioactive, "Self-fitting" Shape Memory Polymer (SMP) Scaffolds to Treat Cranial Bone Defects

摘要 我们的研究目标是开发一种生物活性的、自适应的形状记忆聚合物(SMP)。 联合骨髓间充质干细胞修复局限性颅骨缺损的实验研究 细胞(BMSCs)。自体移植与漫长的采集程序、供体部位发病率以及 难以成形和定位移植物到缺损处。组织工程是一种很有前途的替代方案，但 需要一种目前尚未满足的需求--一种生物材料支架，它同时提供：(1)能够 (2)生物活性，(3)骨诱导性 以及(4)高度连通的毛孔和细胞迁移所必需的受控生物降解性、营养 扩散和肿瘤组织聚集，同时避免脆性机械性能。它的意义和 这种方法的创新之处在于一种新的“自适应”的、涂有多巴胺的SMP支架设计，它实现了所有 这些财产的价值。由PI开发，建议的混合SMP支架由有机 链段[聚(ε-己内酯)，PCl]和无机含硅链段[聚二甲基硅氧烷， 聚二甲基硅氧烷或聚硅醚，PSE]。脚手架设计满足关键功能要求：(1)骨水泥- 集成：由于其形状记忆行为，SMP支架将具有自适应功能，从而实现 短时间暴露于温盐水中并锁定新的临时牙合适形修复不规则的缺损 冷却至体温后的形状。(2)生物活性和(3)成骨活性：一种纳米级的生物活性 聚多巴胺涂层将应用于SMP支架孔表面，以支持祖细胞成骨 以及骨整合所需的羟基磷灰石的形成。(4)相互连通的毛孔，受控 生物可降解性和坚固的机械性能：SMP支架制造策略实现了高 孔隙率和孔的相互连通性，同时避免脆性的机械行为。脚手架的速度 生物降解将受无机链段类型(即PDMS或PSE)和相对分子质量(MN)(即 交叉链接密度)。SMP支架的愈合潜力将在临界大小的大鼠颅骨模型中进行评估 采用组织学检测、显微CT和生物力学检测。 该小组由拟议工作的所有关键领域的专家组成。Melissa Grunlan教授(PI)将 带头努力制备包覆多巴胺的SMP支架和未包覆的对照(目标1-3)。玛丽亚教授 Hahn(Co-I)将领导体外组织工程研究，将大鼠和人的BMSCs整合到 脚手架(目标2)。Brian Saunders教授(Co-I)将细胞支架植入大鼠颅骨缺损区(AIM 3)。迈克尔·莫雷诺教授将领导研究支架、天然组织和 植骨构建(目标1-3)。愈合情况将通过组织学/免疫组织化学进行评估(Roy教授 Pool和Saunders，Co-is)，微型CT(Saunders)和生物力学测试(Moreno)。输入将由以下人员提供 两位颅面整形外科医生，雷蒙德·哈什巴格博士和凯文·霍普金斯(顾问)。

ABSTRACT Our research goal is the development of a bioactive, “self-fitting” shape memory polymer (SMP) scaffold to repair confined cranial defects by associated bone marrow-derived mesenchymal stem cells (BMSCs). Autografts are associated with lengthy harvesting procedures, donor site morbidity as well as difficulties in shaping and positioning the graft into the defect. Tissue engineering is a promising alternative but requires a currently unmet need - a biomaterial scaffold which simultaneously provides: (1) the ability to conformally fit into an irregular defect to enhance osseointegration, (2) bioactivity, (3) osteoinductivity and (4) highly interconnected pores and controlled biodegradability necessary for cell migration, nutrient diffusion and neotissue accumulation while avoiding brittle mechanical properties. The significance and innovation of this approach is a new “self-fitting”, polydopamine-coated SMP scaffold design that achieves all of these properties. Developed by the PI, the proposed hybrid SMP scaffolds are comprised of an organic segment [poly(ε-caprolactone), PCL] and an inorganic silicon-containing segment [polydimethylsiloxane, PDMS or poly(silyl ether), PSE]. The scaffold design meets key functional requirements: (1) Osseo- integration: The SMP scaffold will be “self-fitting” as a result of its shape memory behavior, enabling conformal fitting into an irregular defect by brief exposure to warm saline and locking of the new temporary shape upon cooling to body temperature. (2) Bioactivity and (3) Osteoinductivity: A nanothick, bioactive polydopamine coating will be applied to the SMP scaffold pore surfaces to support progenitor cell osteogenesis as well the formation of hydroxyapatite necessary for osseointegration. (4) Interconnected Pores, Controlled Biodegradability, and Robust Mechanical Properties: The SMP scaffold fabrication strategy enables high porosities and pore interconnectivity while avoiding brittle mechanical behavior. The rate of scaffold biodegradation will be controlled by inorganic segment type (i.e. PDMS or PSE) and molecular weight (Mn) (i.e. crosslink density). The healing potential of SMP scaffolds will be evaluated in a critical size-rat calvarial model using histological testing, micro-CT and biomechanical testing. The team is comprised of experts in all key areas of the proposed work. Prof. Melissa Grunlan (PI) will lead efforts to prepare polydopamine-coated SMP scaffolds and uncoated controls (Aims 1-3). Prof. Mariah Hahn (Co-I) will lead in vitro tissue engineering studies with rat- and human-BMSCs incorporated into the scaffolds (Aim 2). Prof. Brian Saunders (Co-I) will implant cell-laden scaffolds into rat calvarial defects (Aim 3). Prof. Michael Moreno will lead efforts to study biomechanical properties of scaffolds, native tissues and bone-graft constructs (Aims 1-3). Healing will be evaluated by histology/immunohistochemistry (Prof. Roy Pool and Saunders, Co-Is), micro-CT (Saunders) and biomechanical tests (Moreno). Input will be provided by two craniofacial plastic surgeons, Drs. Raymond Harshbarger and Kevin Hopkins (consultants).