Aptamer Coatings for Improved Host Response of Biomedical Implants

描述（由申请人提供）：目前提高植入物接受度的重点是设计能够主动控制材料表面与生物环境相互作用的材料。由于没有异物反应，这种控制最终可能导致植入物具有长期的操作功能。为了成功开发这种材料，研究人员采取了两种策略：第一，通过开发非粘性涂层来防止蛋白质粘附；第二，通过将细胞特异性配体固定在防污涂层上来增强植入物/细胞的相互作用。进一步的方法集中在一类细胞外基质中发现的细胞粘附蛋白，其中含有三个氨基酸序列ArgGlyAsp (RGD)，它与特定的细胞表面受体（例如整合素）结合。本I期研究的重点是研究一种新的概念，通过利用适体体大大改善种植体与间质液（ISF）之间的沟通，来改善任何长期种植体的生物相容性。我们的新技术的前提是在植入物和细胞外基质（ECM）组织之间的界面上提供多种和冗余的主动相互作用，以有效地“伪装”植入物，以最大限度地减少急性炎症反应，加速组织重建，并减轻纤维化胶囊的形成。为了完成这项任务，我们将鉴定适配体，从随机文库中选择与细胞外基质（ECM）的各种靶分子结合的短序列寡核苷酸。在第一阶段，我们将通过选择在ECM中发现的四种主要蛋白质的适配体来进行概念验证研究，然后将鉴定的适配体配体固定在模型植入物的表面（BioTex葡萄糖传感器已经在开发中）。然后，我们将在小动物模型中研究适体包被植入物的宿主反应数周。BioTex的研究人员相信，如果成功的话，这种新颖的整体方法将适用于大量的植入物，以改善和扩展其体内功能。目前迫切需要改善长期植入物的生物相容性，用于糖尿病血糖监测、心血管支架、辅助和矫形装置以及治疗性药物输送等应用。所有这些生物医学植入应用的共同点是需要一个稳定的、主动的植入界面，从而使组织基质被重塑以减轻异物反应。这个项目的重点是开发一种可以应用于大量植入物和植入物类型的化学物质，以增强它们的功能或延长它们在体内的存活时间。这将通过鉴定和利用一种新的适体来完成——从大型随机文库中选择的高亲和力、高选择性的核酸配体——涂覆在生物植入物的外部表面，这将在生物植入物和宿主组织的细胞外基质（ECM）之间提供多个冗余的附着点。由于植入应用的数量不同，这种技术的市场很难估计，但毫无疑问，其价值达数十亿美元。

DESCRIPTION (provided by applicant): Current focus in improving acceptance of implants is to engineer materials that proactively control the interaction of the material surface with the biological milieu. Such control could ultimately lead to implants with long-term operational functionality due to the absence of the foreign body response. To successfully develop such a material, two strategies have been pursued: first, prevention of protein adhesion by developing nonadhesive coatings, and, second, enhanced implant/cell-interaction by immobilizing cell-specific ligands onto the antifouling coating. A further approach is focused on a class of cell-adhesion proteins found in the extracellular matrix containing the three amino acid sequence ArgGlyAsp (RGD) which binds to particular cell surface receptors (e.g. integrins). The focus of this Phase I research is to study a novel concept for improving the biocompatibility of any long-term implant by utilizing aptamers to provide a greatly improved communication between implant and interstitial fluid (ISF). The premise of the our novel technology will be to provide a multiplicity and redundancy of proactive interactions at the interface between implant and extracellular matrix (ECM) tissue for effective implant "camouflaging", in order to minimize acute inflammatory reaction, accelerate tissue reconstruction, and mitigate fibrotic capsule formation. To accomplish this task, we will identify aptamers, short sequences of oligonucleic acid selected from random libraries that bind to a variety of target molecules of the Extracellular Matrix (ECM). In Phase I, we will perform a proof-of-concept study by selecting aptamers specific to four prominent proteins found in the ECM, followed by immobilization of the identified aptamer ligands to the surface of a model implant (the BioTex glucose sensor already under development). We will then study the host-response of the aptamer- coated implant in a small animal model over several weeks. BioTex researchers are confident that this novel holistic approach, if successful, will be applicable to a wide number of implants to improve and extend their in vivo functionality. PUBLIC HEALTH RELEVANCE There is an urgent need for improved biocompatibility of long-term implants for applications such as glucose-monitoring in diabetes, cardiovascular stents, assistive and orthopedic devices, as well as therapeutic drug-delivery. What is common to all these biomedical implant applications is the need for a stable, proactive implant interface which causes the tissue matrix to be remodeled to mitigate the foreign body response. This project focuses on development of a chemistry that could be applied for a large number of implants and implant types in order enhance their functionality or prolong their survival in the body. This will be accomplished through the identification and utilization of a novel aptamers - high-affinity, highly selective nucleic acid ligands selected from large random libraries - coated to the external bioimplant surface which will provide multiple and redundant attachment points between bioimplant and Extracellular Matrix (ECM) of host tissue. The market for such a technology is hard to estimate due to the diverse number of implant applications, but without any doubt amounts to several billion dollars.