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

摘要 阿尔茨海默病（Alzheimer's disease，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，AD患者通常即使在疾病的早期阶段也患有低骨矿物质密度，并且 因此相对于普通人群更容易骨折。由于骨密度的损失， 自体骨移植通常不是AD患者群体的骨折修复的选择。 此外，AD中骨折的愈合通常是缓慢的，并且经常导致延迟愈合或不完全愈合。这 延迟愈合是在通常与缺损修复相关的已经很高的并发症发生率之上。的损失 AD患者的骨矿物质密度似乎部分归因于异常的外周交感神经（SN） 激活通常与疾病有关。特别是，AD骨中TNFα水平升高， 与异常活性的SN相关，已知其严重影响骨愈合，再吸收， 血管化和体内平衡。因此，可以提供一种在哺乳动物中刺激更正常表型的生物材料支架。 生长的SN可以增强AD骨折修复中的骨生成和骨愈合。最近，我们提出了一个新的 基于一类新型形状记忆聚合物（SMP）的支架设计。避免使用外源性 这些支架提供了内在的骨诱导性， 通过结合的粘附配体和纳米级聚多巴胺涂层， 骨生成以及羟基磷灰石的形成。有趣的是，聚多巴胺涂层也 最近被证明可以刺激SN样细胞的延伸和表型成熟， 纤连蛋白和层粘连蛋白衍生的整联蛋白粘附配体。该R 03提案侧重于定制整合素 SMP支架的基于粘附的景观，以促进所需的SN细胞和MSC表型内， 骨和神经诱导聚多巴胺基地的背景下。这一提案的独特之处在于它注重量身定制 向内生长SN细胞的表型有助于改善MSC成骨，并在疾病中这样做- 模拟“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.