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

• 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
• 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

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 在哺乳动物中再生组织的能力仍然难以捉摸。在使用干细胞种群的同时 在生物施加的情况下 病态组织，仍然存在重大挑战。另一种方法是试图唤起经典 在较低物种（例如newts）中看到的原位再生反应仿真。虽然这个特征被认为 要在进化中迷失，我们的观察（Heber-katz）是MRL鼠标和相关菌株具有 明显的赞助再生能力表明该性状保留在哺乳动物中。研究 在过去的近20年中 途径是小鼠进行再生的中央演员。早期HIF-1α显着升高 MRL小鼠中伤口愈合的阶段完全抑制Si-RNA阻滞的HIF-1α。什么时候 我们模仿了其他非再生瑞士韦伯斯特小鼠的HIF-1α响应 由忠实地替代与正常组织无法区分的组织结构所授予的。这 在新型的生物材料结构（Messersmith）中使用PHD抑制剂1,4-DPCA实现了 高水平的HIF-1α体内稳定。在当前的建议中，我们提供初步结果 表明在牙周疾病的小鼠模型中也可以看到令人印象深刻的愈合 细菌积累导致骨质流失（Hajishengallis模型）的炎症宿主反应。我们 证明骨骼恢复，牙周韧带（PDL）恢复，并且异常健壮的干细胞 发现牙齿果肉和牙周组织中的反应。我们将使用高级分子设计 产生能够实现单剂量和局部递送的生物材料与当前的三剂量递送 系统。除了产生一种新颖的软骨组织修订疗法外，我们认为该系统 提供了令人印象深刻的现象景观 口腔组织中的原位再生反应。 在AIM 1中，我们将创建新的生物材料以产生扩展的药物释放以提供单剂量治疗 含有快速降解的凝胶；在AIM 2中，我们将研究原始和新的药物制剂的效果， 关于骨骼和PDL损失以及使用MicroCT和分子分析后悔；在AIM 3中，我们将进一步探索 调节HIF水平后的代谢反应；在AIM 4中，我们将确定机械因素 参与炎症，总体免疫和干细胞反应。 总之，成功的原位药物诱导的再生疗法将显着提高 超出当前手术程序的牙周疾病的治疗。