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：
8815316
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 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8815316
关键词：
Address Animals Anti-Inflammatory Agents Anti-inflammatory Beds Binding Biodegradation Blindness Caring Cells 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 properties 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.

描述（由申请人提供）：全球，主要是由于感染，创伤和手术并发症引起的角膜疾病，导致人类患者失明的6至800万例。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结果的重要因素。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细胞活性因子提供的多个提示，并在可溶的细胞外信号传导环境中以及细胞外基质提供的生物物理提示中提供。该过程的失调或延迟会导致慢性非愈合伤口，雾霾形成和视觉妥协。常规的医学和手术治疗有时不足以产生最佳结果。迫切需要改善角膜伤口的治疗方法。因此，提出了一种新型，多功能和可推广的工程方法，以促进有利的角膜伤口愈合结果。通过利用蛋白质偶联化学，界面科学和纳米糖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。与传统的局部治疗与治疗剂的角膜伤口相比，将细胞活性因子直接整合到角膜伤口床中可以实现明显较少的化合物，这种方法可提供细胞毒性的可能性较低，具有更大的安全余量，并且在治疗计划执行方面的成本节省大量成本。可生物降解的材料将用于获得角膜伤口中细胞活性因子持久性的时间控制。将细胞活性因子（S）直接整合到角膜伤口中，将最大程度地减少由于长期存在的持续的细胞活性因子信号传导而产生的有害作用的可能性。抗菌因子（如白银和人B-德防御素-3）是一种天然存在的宿主肽，将用于测试新的主张，即它们直接整合到角膜伤口中可以提供抗菌活性而不会损害愈合。该提案的总体目的是确定如何利用新颖的界面材料工程方法来从根本上改变角膜伤口床的表面化学和生物物理特征，以促进有利的愈合结果。在假设1中，将使用带有纳米 - 毛发珠的聚电解质多层（PEM）将抗菌化合物和细胞活性因子整合到角膜伤口床中。令人兴奋的初步数据已经记录了通过冲压将功能化PEM转移到伤口床中的可行性，并表明PEM中的亚微米珠有效地转移到软材料（例如角膜伤口床）中。通过优化PEM和珠材料的生物降解，可以实现抗菌和细胞活性因子的瞬态居住在角膜伤口床中。在掺入珠子和/或PEM之后，将研究银和B-德法素3的动力学，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，在保留其生物活性的同时，在各种模型表面上共价固定细胞活性因子的能力。首先，将确定各种与角膜细胞一起使用的各种蛋白质连接化学的安全性。然后，将确定细胞活性因子EGF的最佳连锁化学，以及将EGF固定到角膜伤口床上的最佳过程。最后，将共价固定的EGF的功效与传统的EGF局部处理进行比较。如果成功，这笔赠款的结果将对人类和动物角膜伤口的管理产生巨大影响。