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

形状记忆聚合物支架治疗阿尔茨海默病患者的骨缺损

• 批准号: 10263155
• 负责人: Melissa Grunlan
• 金额: $ 7.53万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263155
• 关键词: 3-Dimensional; Address; Adhesions; Alzheimer' s Disease; Alzheimer' s disease patient; Animal Disease Models; Autologous; Biocompatible Materials; Biomimetics; Body Temperature; Bone Density; Bone Diseases; Bone Regeneration; Bone Tissue; Bone Transplantation; Cell Adhesion; Cell Culture Techniques; Cell Differentiation process; Cells; Coculture Techniques; Complication; Defect; Disease; Environment; Exogenous Factors; Fibronectins; Formulation; Fracture; Fracture Healing; Future; General Population; Homeostasis; Hydroxyapatites; Impaired healing; Infiltration; Integrins; Laminin; Ligands; Maintenance; Memory; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modulus; Mutation; Nerve; Neurodegenerative Disorders; Neurons; Neuropathy; Osseointegration; Osteoblasts; Osteogenesis; Osteoporotic; Patients; Peripheral; Phenotype; Polymers; Porosity; Property; Research; Role; Saline; Shapes; TNF gene; Tissue Engineering; Vascularization; Work; base; bone; bone healing; comorbidity; design; embryonic stem cell; healing; improved; induced pluripotent stem cell; member; mimetics; nanoscale; novel; patient population; physical property; presenilin-1; repaired; scaffold

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.

抽象的。阿尔茨海默氏病（AD）是一种具有全身作用的毁灭性神经退行性疾病。 例如，AD患者即使在疾病的早期，也通常患有低骨矿物质密度， 因此，相对于一般人群，更容易骨折。由于骨密度损失 自体骨移植通常不是AD患者人群断裂修复的选择。此外， AD中骨折的愈合通常很慢，通常会导致延迟或不完整的愈合。这延迟了治愈 是通常与缺陷修复有关的已经很高的并发症率。骨粉骨的损失 AD中的密度似乎部分归因于异常的外周交感神经（SN）激活 与疾病有关。特别是，骨质疏松AD骨中TNFα的水平升高是相关的 具有绝对激活的SNS，已知会严重影响骨骼愈合，分辨率，血管形成， 和稳态。这是一个生物材料支架，在刺激SNS中刺激更正常的表型的脚手架可能 在AD断裂修复中增强成骨和骨愈合。最近，我们提出了一种新的脚手架设计 基于新型的形状记忆聚合物（SMP）。避免使用外源性因素 - 可以 导致不想要的脱靶效应 - 这些支架通过融合提供了内在的骨诱导率 粘附配体（S）和纳米级多胺涂料已知支持成骨的作用以及 羟基磷灰石的形成。有趣的是，最近还证明了多巴胺涂层 与纤连蛋白衍生的整联蛋白一样，刺激SN样细胞中的延伸和表型成熟 粘附配体。该R03提案重点是量身定制基于整合素的基于SMP的景观 在骨和神经诱导的背景下促进所需的SN细胞和MSC表型的脚手架 聚多巴胺基碱。该提议的重点是调整呈沉积SN单元的表型的独特 改善MSC成骨的作用，并在模拟疾病的“发炎”环境中这样做。