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：阿尔茨海默氏病（AD）是一种具有系统性影响的破坏性神经退行性疾病。例如，AD 患者即使在疾病早期，骨密度也普遍较低，因此，由于骨密度下降，相对于普通人群更容易发生骨折。自体骨移植通常不是 AD 患者骨折修复的选择。 AD 骨折的愈合通常很慢，并且常常导致愈合延迟或不完全。除了与骨缺损修复相关的并发症发生率已经很高之外，骨矿物质的流失也很常见。 AD 中的密度似乎部分归因于周围交感神经 (SN) 的异常激活特别是，骨质疏松性 AD 骨中 TNFα 水平升高相关。异常激活的 SN，已知会严重影响骨愈合、吸收、血管化，因此，刺激 SN 内生长更正常表型的生物材料支架可能会起作用。最近，我们提出了一种新的支架设计。基于一类新型形状记忆聚合物（SMP），避免使用外源因素。导致不良的脱靶效应 - 这些支架通过整合的材料提供内在的骨诱导性粘附配体和纳米级聚多巴胺涂层已知支持成骨以及最近还证明了羟基磷灰石的形成。刺激 SN 样细胞的延伸和表型成熟，如纤连蛋白和层粘连蛋白衍生的整联蛋白该 R03 提案的重点是定制基于整合素粘附的 SMP 景观。在骨和神经诱导的背景下促进所需的 SN 细胞和 MSC 表型的支架该提案的独特之处在于其重点是调整向内生长的 SN 细胞的表型。改善 MSC 成骨，并在模拟疾病的“发炎”环境中实现这一点。