A new model of regenerative healing via inflammation-modulating biomaterials

通过炎症调节生物材料实现再生愈合的新模型

基本信息

批准号：
9982904
负责人：
Georgios Hajishengallis
金额：
$ 70.51万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982904
关键词：
Address Affect Agonist Architecture Bacteria Biocompatible Materials Biological Biological Models Blood Vessels Bone Regeneration Bone Tissue Cells Chemistry Chronic Connective Tissue Data Dental Dental Pulp Development Disease Disease model Dose Drug Compounding Drug Modulation Ear Environment Evolution Exhibits Fiber Fibroblasts Formulation Gel Genes Glycolysis Goals Grant Health Histologic Human Hydrogels Hydrolysis Hypoxia-Inducible Factor Pathway Immune Immune response Immunology In Situ Inflammation Inflammatory Injectable Injury Lead Lesion Ligaments Ligation Ligature Luciferases Mammals Measures Mechanics Mediating Medicine Metabolic Microbial Biofilms Modeling Modification Molecular Molecular Analysis Mouse Strains Mus Nanostructures Natural Immunity Natural regeneration Newts Normal tissue morphology Operative Surgical Procedures Osteoblasts Osteoclasts Osteoporosis Oxidative Phosphorylation Patients Periodontal Diseases Periodontal Ligament Pharmaceutical Preparations Phase Polymers Population Prodrugs Proteins Publishing RNA Recovery Regenerative response Reporter Rheumatoid Arthritis System T-Lymphocyte Testing Thinness Time Tissues Tooth Loss Tooth structure alveolar bone bone bone healing bone loss cytokine design drug release kinetics economic impact healing human disease human model in vivo inhibitor/antagonist microCT molecular marker mouse model multidisciplinary novel oral condition oral tissue regenerative regenerative therapy response scaffold self assembly soft tissue standard of care stem stem cell population stem cells tissue regeneration trait translational model wound closure wound healing

项目摘要

Abstract The ability to regenerate tissue in mammals has remained elusive. While the use of stem cell populations in the context of bio-scaffolds has shown promise as a potential means of replacing lost, damaged, or diseased tissue, significant challenges remain. An alternative approach is to attempt to evoke a classical in situ regenerative response emulating that seen in lower species such as newts. While this trait was thought to be lost in evolution, our observation (Heber-Katz) that the MRL mouse and related strains have a significant spontaneous regenerative capability demonstrates that the trait is retained in mammals. Studies over the past almost 20 years have culminated in the identification of the HIF-1α (hypoxia inducible factor) pathway as the central actor regulating regeneration in mice. HIF-1α is significantly elevated during the early phases of wound healing in MRL mice and inhibiting HIF-1α with si-RNA blocks regeneration entirely. When we mimicked this HIF-1α response in otherwise non-regenerating Swiss Webster mice the regeneration trait was conferred with the faithful replacement of tissue architecture indistinguishable from normal tissue. This was achieved using the PHD inhibitor 1,4-DPCA in a novel biomaterial construct (Messersmith) leading to the stabilization of high levels of HIF-1α in vivo. In this current proposal, we provide preliminary results suggesting that impressive healing is also seen in a mouse model of periodontal disease, ligature-induced bacterial accumulation leading to an inflammatory host response with bone loss (Hajishengallis model). We show that bone recovers, the periodontal ligament (PDL) is restored, and an unusually robust stem cell response in the tooth pulp and in periodontal tissue is found. We will use advanced molecular design to produce a biomaterial capable of achieving single dose and local delivery vs. the current three-dose delivery system. In addition to yielding a novel soft and bone tissue regeneration therapy, we believe that this system provides an impressive landscape of phenomena that will yield important mechanistic information about in- situ regenerative responses in oral tissues. In Aim 1, we will create new biomaterials to yield extended drug release to provide a single-dose treatment with rapidly degradable gels; in Aim 2, we will examine the effect of drug preparations, both original and new, on bone and PDL loss and regrowth using microCT and molecular analysis; in Aim 3, we will further explore the metabolic response after modulating HIF levels; and in Aim 4, we will determine mechanistic factors involved in the inflammatory, overall immune, and stem cell responses. In conclusion, a successful in-situ drug-induced regenerative therapy would significantly advance the treatment of periodontal disease beyond current surgical procedures.

抽象的哺乳动物的组织再生能力仍然难以捉摸，而干细胞群的使用仍然难以捉摸。在生物支架的背景下，已显示出作为替代丢失、损坏或损坏的潜在手段的希望患病组织，仍然存在重大挑战，另一种方法是尝试唤起经典。模仿蝾螈等低等物种的原位再生反应，而这种特征被认为是。为了在进化中迷失，我们的观察（Heber-Katz）认为 MRL 小鼠和相关品系具有显着的自发再生能力表明该特征在哺乳动物中得以保留。在过去近 20 年里，HIF-1α（缺氧诱导因子）的鉴定达到顶峰 HIF-1α 通路作为调节小鼠再生的核心因子在早期显着升高。在 MRL 小鼠伤口愈合阶段，用 si-RNA 抑制 HIF-1α 可以完全阻断再生。我们在其他不可再生的瑞士韦伯斯特小鼠中模仿了这种 HIF-1α 反应被赋予了与正常组织无法区分的组织结构的忠实替换。在新型生物材料结构（Messersmith）中使用 PHD 抑制剂 1,4-DPCA 实现了在当前的提议中，我们提供了体内高水平 HIF-1α 的稳定性。这表明在结扎诱导的牙周病小鼠模型中也观察到令人印象深刻的愈合细菌积累导致炎症宿主反应并导致骨质流失（Hajishengallis 模型）。显示骨骼恢复，牙周膜（PDL）恢复，并且异常强健的干细胞我们将使用先进的分子设计来发现牙髓和牙周组织的反应。生产一种能够实现单剂量和局部递送的生物材料，而不是目前的三剂量递送除了产生一种新型的软组织和骨组织再生疗法之外，我们相信该系统。提供了令人印象深刻的现象景观，这些现象将产生有关内部的重要机械信息口腔组织的原位再生反应。在目标 1 中，我们将创造新的生物材料来延长药物释放，从而提供单剂量治疗使用可快速降解的凝胶；在目标2中，我们将检查原始和新的药物制剂的效果，在目标 3 中，我们将使用 microCT 和分子分析进一步探讨骨和 PDL 的损失和再生；调节 HIF 水平后的代谢反应；在目标 4 中，我们将确定机制因素参与炎症、整体免疫和干细胞反应。总之，成功的原位药物诱导再生疗法将显着促进超越当前外科手术的牙周病治疗。