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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

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。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，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，委员会认为， 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。这种延迟愈合是在已经很高的并发症发生率之上，通常与缺陷修复有关。骨矿物质的流失 AD中的高密度似乎部分是由于异常的外周交感神经（SN）激活，与疾病有关。特别是，AD骨中TNFα水平的升高与AD的发病相关。与异常活化的SN，已知其严重影响骨愈合、再吸收、血管形成，和体内平衡。因此，在向内生长的SN中刺激更正常表型的生物材料支架可以促进AD骨折修复中的骨生成和骨愈合。最近，我们提出了一种新的支架设计，基于一类新型的形状记忆聚合物（SMP）。避免使用外部因素-这可能引起不期望的脱靶效应-这些支架通过结合的骨诱导性提供内在的骨诱导性。粘附配体和已知支持骨生成的纳米级聚多巴胺涂层，羟基磷灰石的形成。有趣的是，聚多巴胺涂层最近也被证明刺激SN样细胞中延伸和表型成熟，如具有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SMP的基于整合素粘附的前景在骨和神经诱导的环境中促进期望的SN细胞和MSC表型的支架聚多巴胺碱该提案的独特之处在于其专注于定制向内生长的SN细胞的表型，改善MSC成骨，并在疾病模拟“发炎”环境中这样做。