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

摘要 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。为 例如，即使在疾病的早期阶段，阿尔茨海默病患者通常也患有低骨密度，并且 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，经常导致延迟或不完全愈合。这 愈合延迟是在与缺陷修复相关的本已很高的并发症发生率之上的。在中国的损失 阿尔茨海默病患者的骨密度似乎部分是由于异常的周围交感神经(SN)所致 激活通常与疾病有关。尤其是骨质疏松性AD骨组织中肿瘤坏死因子α水平升高 与异常活跃的SNS相关，众所周知，SNS对骨愈合、吸收、 血管形成和动态平衡。因此，一种能够刺激更正常的表型的生物材料支架 在AD骨折修复中，生长的SNS可能促进成骨和骨愈合。最近，我们提出了一个新的 基于新型形状记忆聚合物(SMPS)的支架设计。避免使用外源 这些支架具有内在的骨诱导性，这些因素可能会导致不受欢迎的脱靶效应。 通过结合的黏附配体(S)和已知支持的纳米级多巴胺涂层 成骨以及羟基磷灰石的形成。有趣的是，聚多巴胺涂层还具有 最近被证明可以刺激SN样细胞的伸展和表型成熟， 纤维连接蛋白和层粘连蛋白衍生的整合素黏附配体。此R03提案侧重于定制整合素 基于粘附性的SMP支架景观以促进所需的SN细胞和MSC表型 骨和神经诱导性多巴胺基础的背景。这项提议的独特之处在于它注重量身定做 植入SN细胞的表型有助于改善MSC的成骨，并在疾病中做到这一点- 模拟的“发炎”环境。

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. Particularly, elevated levels of TNFα in the osteoporotic AD bone are correlated with abnormally active SNs, which are known to critically influence bone healing, resorption, vascularization, and homeostasis. Thus, a biomaterial scaffold which stimulates a more normal phenotype in growing 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.