Shape Memory Polymer Scaffolds to Treat Bone Defects in Patients with Alzheimer's Disease

抽象的。阿尔茨海默病(AD)是一种具有全身性影响的破坏性神经退行性疾病。 例如，即使在疾病的早期，阿尔茨海默病患者通常也患有低骨密度， 因此，与普通人群相比，他们更容易发生骨折。由于骨质密度的丧失， 对于AD患者群体，自体骨移植通常不是骨折修复的一种选择。此外， 阿尔茨海默病的骨折愈合通常是缓慢的，通常会导致延迟或不完全愈合。这种延迟的愈合 是在已经很高的与缺陷修复相关的高并发症发生率之上的。骨矿物质的流失 阿尔茨海默病的密度似乎部分是由于异常的外周交感神经(SN)激活 与这种疾病有关。特别是，骨质疏松性AD骨骼中肿瘤坏死因子α水平的升高与 SNS异常激活，已知会严重影响骨愈合、吸收、血管形成， 和动态平衡。因此，在嵌入型SNS中刺激更正常表型的生物材料支架可以 促进AD骨折修复中的成骨和骨愈合。最近，我们提出了一种新的支架设计方案 基于一类新型形状记忆聚合物(SMPS)。避免使用外生因素--这可能 产生不想要的偏离目标的效果-这些支架通过所结合的 黏附配体(S)和已知支持成骨的纳米多巴胺涂层以及 羟基磷灰石的形成。有趣的是，多聚多巴胺涂层最近也被证明 刺激SN样细胞的延伸和表型成熟，就像纤维连接蛋白和层粘连蛋白衍生的整合素一样 粘附性配体。此R03提案侧重于定制基于SMP的整合素粘附性环境 在骨诱导和神经诱导的背景下促进所需SN细胞和MSC表型的支架 多巴胺碱基。这一建议的独特之处在于它侧重于将内生SN细胞的表型调整为 改善MSC的成骨能力，并在类似疾病的“发炎”环境中做到这一点。

ABSTRACT. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder which has systemic effects. For instance, AD patients generally suffer from low bone mineral density even in early stages of the disease, and as such are more prone to bone fractures relative to the general population. Due to the loss in bone density, autologous bone grafts are generally not an option in fracture repair for the AD patient population. Furthermore, healing of fractures in AD is usually slow and often results in delayed or incomplete healing. This delayed healing is on top of the already high complication rates often associated with defect repair. The loss in bone mineral density in AD appears to be due in part to the abnormal peripheral sympathetic nerve (SN) activation often associated with the disease. In particular, elevated levels of TNFα in the osteoporotic AD bone are correlated with abnormally activate SNs, which are known to critically influence bone healing, resorption, vascularization, and homeostasis. Thus, a biomaterial scaffold which stimulates a more normal phenotype in ingrowing SNs may enhance osteogenesis and bone healing in AD fracture repair. Recently, we proposed a new scaffold design based on a novel class of shape memory polymers (SMPs). Avoiding the use of exogenous factors – which can cause undesired off-target effects - these scaffolds provide intrinsic osteoinductivity through the incorporated adhesion ligand(s) and a nanoscale polydopamine coating known to support osteogenesis as well as the formation of hydroxyapatite. Interestingly, polydopamine coatings have also recently been demonstrated to stimulate extension and phenotypic maturation in SN-like cells, as have fibronectin- and laminin-derived integrin adhesion ligands. This R03 proposal focuses on tailoring the integrin adhesion-based landscape of SMP scaffolds to promote desired SN cell and MSC phenotypes within the context of an osteo- and neuro-inductive polydopamine base. This proposal is unique in its focus on tailoring the phenotype of ingrowing SN cells toward improving MSC osteogenesis and doing so within a disease-mimetic “inflamed” environment.