Tissue Engineering Cornea Replacements

描述(申请人提供)：角膜损伤导致严重的视力损失，仅次于白内障。角膜置换术是一项正在发展中的技术，由于疾病(如疱疹感染)、LASIK并发症、遗传性问题(如Fuchs病)以及相关手术的并发症(如白内障)，许多患者正在成为一种必需品。目前用于角膜移植的策略主要是使用合成材料或致敏材料。虽然这些策略部分有效，但缺点是它们可能会刺激宿主免疫反应，导致组织排斥反应，或者带来从不健康的捐赠者器官转移疾病的风险。越来越多的矫正眼科手术使角膜不适合移植，进一步减少了可接受的过敏原供应，使这些并发症更加严重。迫切需要开发一种人类角膜替代物来缓解这些缺点，这也是拟议计划的目标。这个假说是，丝蛋白-生物材料板层系统与角膜特异性细胞相结合，可以通过生物工程来匹配体内的角膜特性，并满足功能要求。拟议的系统将利用丝绸的新材料和生物特性，包括引导细胞和细胞外基质沉积的表面微图案、缓慢降解、生物兼容性、光学透明度和机械耐用性，以处理、缝合和耐受眼压。一种能够缓慢降解以替代宿主天然组织的角膜组织系统将为角膜移植技术带来重大的新进展。与角膜干细胞相结合，我们预计首先在2D中优化细胞-丝素相互作用，然后以3D板层结构的形式进行优化。随后将对这些角膜组织系统(机械、光学)的性能进行功能评估，并对手术方法和宿主整合进行优化。拟议计划的结果将是体外优化人类角膜置换和体内实用价值的评估。研究团队拥有支持计划计划所需的材料、细胞和系统研究背景，在我们的R21计划期间收集的数据为拟议研究的所有方面提供了支持文件。我们解决这一需求的方法是独一无二的，并提供了新的方法来满足日益增长的角膜置换需求。体外来源的成功开发将改善目前的短缺，并为患者提供急需的替代方案。 与公共卫生相关：角膜疾病是导致全世界广泛视力丧失的原因，仅次于白内障。目前有许多来源可用于角膜置换，包括致敏材料和合成材料。然而，这些选择中的每一种都存在问题，包括疾病传播、植入后的炎症反应以及可能导致组织排斥或装置故障的不良材料性能。对矫正手术的日益增长的需求加剧了这些担忧，这种手术使得潜在的捐赠者的角膜不适合移植。因此，迫切需要开发新的角膜替换设备，该设备提供所需的材料和生物学特性来解决上述限制，同时还提供一种集成策略，允许该设备被患者的天然组织替换。

DESCRIPTION (provided by applicant): Corneal damage causes significant vision loss, second only to cataracts. Corneal replacement is a developing technology that is becoming a necessity for many patients due to disease (e.g., herpes infection), complications from LASIK, hereditary problems (e.g., Fuch's disease) and complications from related surgeries (e.g., cataracts). Current strategies employed for corneal grafting primarily make use of synthetic or allergenic materials. While these strategies are partially effective, the downside is that they can stimulate host immune responses resulting in tissue rejection or carry the risk of transferring diseases from unhealthy donor organs. These complications are compounded by the growing use of corrective eye surgery which renders corneas unsuitable for grafting, further reducing the availability of acceptable allergenic supplies. The development of a human cornea replacement that alleviates these shortcomings is urgently needed and this is the goal of the proposed program. The hypothesis is that silk protein-biomaterial lamellar systems coupled with cornea- specific cells can be bioengineered to match in vivo corneal properties and meet functional requirements. The proposed system will exploit the novel material and biological features of silk, including surface micropatterning to guide cells and extracellular matrix deposition, slow degradation, biocompatibility, optical transparency and mechanical durability for handling, suturing and tolerating ocular pressures. A cornea tissue system that slowly degrades to allow for host native tissue replacement would offer a significant and novel advancement in corneal transplantation technology. In combination with corneal derived stem cells, we anticipate optimizing cell-silk interactions first in 2D and then as 3D lamellar structures. Functional assessments of the performance of these cornea tissue systems (mechanical, optical) will follow as will optimization of surgical methods and host integration. The outcome of the proposed program will be the in vitro optimization of human cornea replacements and in vivo assessments of utility. The research team has the required background with the materials, cells and systems of study to support the program plans, and the data collected during our R21 program provides supporting documentation for all aspects of the proposed study. Our approach to addressing this need is unique and offers novel methodology to meet the ever-growing demands for corneal replacements. Successful development of an in vitro source will ameliorate the current shortages and provide a much-needed alternative for patients. PUBLIC HEALTH RELEVANCE: Corneal diseases are responsible for extensive vision loss throughout the world, second only to cataracts. A number of sources are currently available for cornea replacement and include allergenic and synthetic materials. However, each of these options has problems, including disease transmission; inflammatory responses post implantation and poor material performance that may result in tissue rejection or device failure. These concerns are compounded by the growing demand for corrective surgery which renders would-be donor corneas unsuitable for grafting. Thus, a crucial need exists to develop new cornea replacement devices that provide the required material and biological properties to address the above limitations, while also offering an integration strategy that allows the device to be replaced by the patients' native tissues.