Tissue Engineering Cornea Replacements

描述（由申请人提供）：角膜损伤导致严重的视力丧失，仅次于白内障。角膜置换是一种发展中的技术，由于疾病（例如，疱疹感染），LASIK的并发症，遗传问题（例如，Fuch病）和相关手术的并发症（例如，白内障）。目前用于角膜移植的策略主要利用合成或过敏性材料。虽然这些策略是部分有效的，但缺点是它们可能刺激宿主免疫反应，导致组织排斥或携带从不健康的供体器官转移疾病的风险。这些并发症由于越来越多地使用矫正眼科手术而变得复杂，矫正眼科手术使得角膜不适合移植，进一步减少了可接受的过敏源供应的可用性。迫切需要开发一种能够弥补这些缺点的人类角膜替代品，这是拟议计划的目标。假设丝蛋白-生物材料层状系统与角膜特异性细胞偶联，可以生物工程化以匹配体内角膜特性并满足功能要求。所提出的系统将利用丝的新材料和生物学特征，包括引导细胞和细胞外基质沉积的表面微图案化、缓慢降解、生物相容性、光学透明度和机械耐久性，用于处理、调节和耐受眼压。缓慢降解以允许宿主天然组织替代的角膜组织系统将在角膜移植技术中提供显著且新颖的进步。结合角膜来源的干细胞，我们预计首先在2D中优化细胞-丝的相互作用，然后作为3D层状结构。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。所提出的计划的结果将是体外优化的人类角膜替代品和体内评估的效用。研究团队拥有所需的材料、细胞和研究系统背景，以支持项目计划，在我们的R21项目期间收集的数据为拟议研究的各个方面提供了支持性文件。我们解决这一需求的方法是独特的，并提供了新的方法来满足不断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品。 公共卫生相关性：角膜疾病是全球范围内广泛的视力丧失的原因，仅次于白内障。目前有许多来源可用于角膜置换，包括过敏性和合成材料。然而，这些选择都存在问题，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设备故障的材料性能较差。这些担忧因矫正手术需求的增长而加剧，矫正手术使潜在的供体角膜不适合移植。因此，迫切需要开发新的角膜置换装置，其提供所需的材料和生物学特性以解决上述限制，同时还提供允许装置被患者的天然组织置换的整合策略。

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.