Engineering the Corneal Wound Bed to Promote Healing

设计角膜创面以促进愈合

基本信息

批准号：
8026319
负责人：
Sara Michelle Thomasy
金额：
$ 17.58万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8026319
关键词：
Address Animals Anti-Inflammatory Agents Anti-inflammatory Beds Binding Biodegradation Blindness Caring Cells Characteristics Chemistry Chronic Cicatrix Clinical Management Collagen Complex Cornea Corneal Diseases Corneal Injury Cost Savings Cues Data Defensins Elective Surgical Procedures Elements Engineering Ensure Environment Epidermal Growth Factor Epithelial Extracellular Matrix Eye Failure Frequencies Grant Growth Factor Healed Homeostasis Hospitals Human Immobilization Impaired wound healing In Vitro Infection Investigation Keratoplasty Kinetics Laminin Lead Link Medical Membrane Modeling Operative Surgical Procedures Outcome Patients Peptides Pharmaceutical Preparations Probability Process Proteins Relative (related person)Research Safety Science Signal Transduction Silver Solutions Structure Surface Surgical complication Technology Testing Therapeutic Therapeutic Agents Time Topical Antibiotic Trauma Ulcer United States Visual Wound Healing antimicrobial biophysical chemistry conventional therapy corneal scar cost cytotoxicity extracellular healing improved insight interfacial nano nanoscience novel novel strategies prevent residence submicron wound

项目摘要

DESCRIPTION (provided by applicant): Worldwide, corneal diseases primarily resulting from infection, trauma, and surgical complications are responsible for 6 to 8 million cases of blindness in human patients. In all of these cases, wound healing is an essential element to maintaining or restoring homeostasis and ensuring optimal visual outcomes. Corneal wound healing is a complex process wherein cells must simultaneously integrate multiple cues provided by the cytoactive factors in the soluble extracellular signaling environment as well as biophysical cues supplied by the extracellular matrix. Dysregulation or delay of this process can result in chronic non-healing wounds, haze formation, and visual compromise. Conventional medical and surgical treatments are sometimes insufficient in producing optimal outcomes. There is an urgent need for improved therapies in the treatment of corneal wounds. Therefore, a novel, versatile and generalizable engineering approach is proposed to promote favorable corneal wound healing outcomes. By utilizing recent advances in protein-conjugation chemistry, interfacial science, and nano-submicron fabrication technologies, I propose to fundamentally change the corneal wound to promote healing. Compared to conventional topical treatment of a corneal wound with therapeutic agents, the direct integration of cytoactive factors into the corneal wound bed enables the use of significantly less compound, an approach that provides a much lower likelihood of cytotoxicity, has a much greater safety margin, and presents significant cost savings in the execution of the therapeutic plan. Biodegradable materials will be used to gain temporal control over cytoactive factor persistence in the corneal wound. Direct integration of cytoactive factor(s) into the corneal wound will minimize the probability of deleterious effects resulting from long-standing, persistent cytoactive factor signaling. Antimicrobial factors such as silver and human b-defensin-3, a naturally occurring host peptide, will be used to test the novel proposition that their direct integration into the corneal wound can provide antimicrobial activity without impairing healing. The overall purpose of this proposal is to determine how novel approaches to interfacial materials engineering can be utilized to fundamentally alter the surface chemistry and biophysical characteristics of the corneal wound bed to promote favorable healing outcomes. In hypothesis 1, polyelectrolyte multilayers (PEMs) loaded with nano-submicron beads will be utilized to integrate antimicrobial compounds and cytoactive factors into the corneal wound bed. Exciting preliminary data already have documented the feasibility of transferring functionalized PEMs into wound beds by stamping and shown that submicron beads within the PEMs are required for efficient transfer to soft materials such as corneal wound beds. By optimizing the biodegradation of PEMs and bead materials, transient residence of antimicrobial and cytoactive factors integrated into the corneal wound bed can be achieved. The kinetics, antimicrobial activity, and cytotoxicity of silver and b-defensin-3 will then be investigated following incorporation into beads and/or PEMs. In hypothesis 2, protein linkage chemistries will directly integrate antimicrobial compounds and cytoactive factors into the corneal wound bed. Recent studies have demonstrated the ability to covalently immobilize cytoactive factors on various model surfaces while preserving their bioactivity. First, the safety of various protein linkage chemistries for use with corneal cells will be determined. Then, the optimal linkage chemistry to enable tuning or transient residence of a cytoactive factor, EGF, will be determined as well as the best process for immobilizing EGF to the corneal wound bed. Lastly, the efficacy of covalently immobilized EGF will be compared to traditional topical treatment of EGF. If successful, the outcomes of this grant will have a dramatic impact on the management of corneal wounds in humans and animals. PUBLIC HEALTH RELEVANCE: Corneal trauma and infection are common and responsible for 6 to 8 million cases of blindness worldwide. Poor corneal wound healing can result in permanent loss of corneal transparency, and there are limited medical and surgical treatments available to address this problem. The purpose of this proposal is to develop novel treatments to aid in corneal wound healing using an engineering-inspired approach; these new therapies may profoundly alter how we treat corneal wounds in people and animals.

描述（由申请人提供）：在世界范围内，主要由感染、创伤和手术并发症引起的角膜疾病导致 6 至 800 万人类患者失明。在所有这些情况下，伤口愈合是维持或恢复体内平衡并确保最佳视觉效果的重要因素。角膜伤口愈合是一个复杂的过程，其中细胞必须同时整合由可溶性细胞外信号环境中的细胞活性因子提供的多种信号以及由细胞外基质提供的生物物理信号。这一过程的失调或延迟可能会导致慢性不愈合伤口、雾霾形成和视力损害。传统的药物和手术治疗有时不足以产生最佳结果。迫切需要改进治疗角膜伤口的疗法。因此，提出了一种新颖、通用且可推广的工程方法来促进良好的角膜伤口愈合结果。通过利用蛋白质结合化学、界面科学和纳米亚微米制造技术的最新进展，我建议从根本上改变角膜伤口以促进愈合。与使用治疗剂对角膜伤口进行传统的局部治疗相比，将细胞活性因子直接整合到角膜伤口床中可以使用显着更少的化合物，这种方法提供了低得多的细胞毒性可能性，具有更大的安全裕度，并在治疗计划的执行中显着节省成本。可生物降解材料将用于暂时控制角膜伤口中细胞活性因子的持久性。将细胞活性因子直接整合到角膜伤口中将最大限度地减少长期持续的细胞活性因子信号传导造成的有害影响的可能性。银和人β-防御素-3（一种天然存在的宿主肽）等抗菌因子将用于测试这一新主张，即它们直接整合到角膜伤口中可以提供抗菌活性而不损害愈合。该提案的总体目的是确定如何利用界面材料工程的新方法从根本上改变角膜创面床的表面化学和生物物理特性，以促进有利的愈合结果。在假设 1 中，载有纳米亚微米珠的聚电解质多层 (PEM) 将用于将抗菌化合物和细胞活性因子整合到角膜创面床中。令人兴奋的初步数据已经证明了通过冲压将功能化质子交换膜转移到创面床的可行性，并表明质子交换膜内的亚微米珠是有效转移到软材料（例如角膜创面床）所必需的。通过优化 PEM 和珠材料的生物降解，可以实现整合到角膜创面床中的抗菌和细胞活性因子的短暂停留。银和 b-defensin-3 掺入珠子和/或 PEM 后，将研究其动力学、抗菌活性和细胞毒性。在假设 2 中，蛋白质连接化学将直接将抗菌化合物和细胞活性因子整合到角膜伤口床中。最近的研究表明能够将细胞活性因子共价固定在各种模型表面上，同时保留其生物活性。首先，将确定用于角膜细胞的各种蛋白质连接化学的安全性。然后，将确定能够调节或短暂驻留细胞活性因子 EGF 的最佳连接化学，以及将 EGF 固定到角膜伤口床的最佳过程。最后，将共价固定 EGF 的功效与传统的 EGF 局部治疗进行比较。如果成功，这笔资助的结果将对人类和动物角膜伤口的治疗产生巨大影响。公共卫生相关性：角膜创伤和感染很常见，导致全球 6 至 800 万例失明。角膜伤口愈合不良会导致角膜透明度永久丧失，并且可用于解决此问题的医疗和手术治疗方法有限。该提案的目的是利用工程启发的方法开发新的治疗方法来帮助角膜伤口愈合；这些新疗法可能会深刻改变我们治疗人和动物角膜伤口的方式。