Engineering the Corneal Wound Bed to Promote Healing

设计角膜创面以促进愈合

• 批准号: 8450198
• 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
• 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/8450198
• 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; public health relevance; residence; submicron; wound

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(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人类患者中有600万至800万人失明。在所有这些情况下，伤口愈合是维持或恢复内环境平衡和确保最佳视觉结果的关键因素。角膜创面愈合是一个复杂的过程，细胞必须同时整合细胞外信号环境中细胞活性因子提供的多种信号以及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无法愈合的伤口、雾霾形成和视觉损害。传统的内科和外科治疗有时不足以产生最佳结果。眼下迫切需要改进治疗角膜创伤的方法。因此，提出了一种新颖的、通用的、可推广的工程方法，以促进良好的角膜创伤愈合效果。通过利用蛋白质偶联化学、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。与使用治疗剂的传统角膜伤口局部治疗相比，直接将细胞活性因子整合到角膜伤口床中能够使用显著较少的化合物，这种方法提供的细胞毒性可能性要低得多，具有更大的安全裕度，并在治疗计划的执行方面显著节省成本。可生物降解材料将被用来获得对细胞活性因子在角膜伤口中持续存在的时间控制。直接将细胞活性因子(S)整合到角膜伤口中将最大限度地减少长期存在的持续细胞活性因子信号所导致的有害影响的可能性。抗菌因子，如银和人类b-防御素-3，一种自然存在的宿主多肽，将被用来测试这一新的命题，即它们直接整合到角膜伤口中可以在不影响愈合的情况下提供抗菌活性。这项建议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伤口床的表面化学和生物物理特征，以促进良好的愈合结果。在假设1中，将利用负载纳米亚微米微珠的聚电解质多层膜(PEM)将抗菌化合物和细胞活性因子整合到角膜伤口床中。令人振奋的初步数据已经证明了通过冲压将功能化的PEM转移到伤口床的可行性，并表明PEM中的亚微米微珠是有效转移到软性材料(如角膜伤口床)所必需的。通过优化PEMS和微珠材料的生物降解性，可以实现抗菌和细胞活性因子整合到角膜伤口床上的瞬时停留。然后将研究银和b-防御素-3的动力学、抗菌活性和细胞毒性，然后将其掺入到微珠和/或PEM中。在假设2中，蛋白质连接化学将直接将抗微生物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，在不同的模型表面上能够共价固定细胞活性因子，同时保持它们的生物活性。首先，将确定用于角膜细胞的各种蛋白质连接化学物质的安全性。然后，将确定使细胞活性因子EGF能够调节或短暂停留的最佳连接化学以及将EGF固定到角膜伤口床的最佳工艺。最后，将共价固定化EGF的疗效与传统的EGF局部治疗进行比较。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重大影响。