Aptamer Coatings for Improved Host Response of Biomedical Implants

用于改善生物医学植入物宿主反应的适体涂层

• 批准号: 7611156
• 负责人: Ralph Ballerstadt
• 金额: $ 12.22万
• 依托单位: BIOTEX, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611156
• 关键词: Acids; Acute; Address; Adhesions; Affinity; Amino Acid Sequence; Animal Model; Antibodies; Binding; Biological; Biological Assay; Blood Coagulation Factor; Cardiovascular system; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Surface Receptors; Cells; Cellulose; Chemicals; Chemistry; Classification; Collagen; Communication; DNA; DNA Modification Process; Development; Devices; Diabetes Mellitus; Drug Delivery Systems; Endothelial Cells; Engineering; Equilibrium; Euthanasia; Evolution; Extracellular Matrix; Extracellular Matrix Proteins; Fiber; Fibrinogen; Fibronectins; Fluorescence Polarization; Fluorescent Antibody Technique; Foreign Bodies; Future; Histopathology; Housing; Human; Immobilization; Immobilized Cells; Immune response; Implant; In Vitro; Inflammatory; Integrins; Intercellular Fluid; Laminin; Lead; Libraries; Ligands; Marketing; Membrane; Methodology; Modeling; Natural regeneration; Nucleic Acids; Oligonucleotides; Orthopedics; Peptides; Phase; Prevention; Production; Property; Protein Binding; Proteins; Protocols documentation; Randomized; Rattus; Reaction; Research; Research Personnel; Serum; Signal Transduction; Single-Stranded DNA; Site; Skin Tissue; Specificity; Stents; Structure; Surface; Technology; Therapeutic; Tissue Engineering; Tissues; Uncertainty; Vascularization; Vitronectin; Wound Healing; amino group; angiogenesis; aptamer; base; biomaterial compatibility; capsule; cell growth; cost; extracellular; glucose monitor; glucose sensor; holistic approach; implant coating; implantable device; implantation; implanted sensor; improved; in vivo; new technology; novel; nuclease; prospective; public health relevance; response; sensor; synthetic construct; tissue reconstruction

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.

描述（由申请人提供）：目前提高植入物可接受性的重点是设计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，这种控制可能最终导致植入物具有长期操作功能。为了成功地开发这样的材料，已经采取了两种策略：第一，通过开发非粘附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到粘附性涂层上来增强植入物/细胞相互作用。另一种方法集中于在细胞外基质中发现的一类细胞粘附蛋白，其含有结合特定细胞表面受体（例如整联蛋白）的三个氨基酸序列ArgGlyAsp（RGD）。该I期研究的重点是研究一种新的概念，通过利用适体来改善任何长期植入物的生物相容性，从而大大改善植入物和间质液（ISF）之间的沟通。我们的新技术的前提是在植入物和细胞外基质（ECM）组织之间的界面处提供多重和冗余的主动相互作用，用于有效的植入物“包埋”，以最小化急性炎症反应，加速组织重建，并减轻纤维化囊形成。为了完成这一任务，我们将鉴定适体，即从随机文库中选择的短序列寡核酸，其结合细胞外基质（ECM）的各种靶分子。在第一阶段，我们将通过选择对ECM中发现的四种主要蛋白质具有特异性的适体进行概念验证研究，然后将已识别的适体配体固定到模型植入物（BioTex葡萄糖传感器已在开发中）的表面。然后，我们将在几周内在小动物模型中研究适体涂层植入物的宿主反应。BioTex的研究人员相信，这种新的整体方法，如果成功的话，将适用于广泛的植入物，以改善和扩展其体内功能。公共卫生相关性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、辅助和矫形器械以及治疗药物输送等应用。所有这些生物医学植入物应用的共同点是需要稳定、主动的植入物界面，其导致组织基质重塑以减轻异物反应。该项目的重点是开发一种可用于大量植入物和植入物类型的化学物质，以增强其功能或延长其在体内的存活时间。这将通过鉴定和利用一种新的适体来实现，所述适体是选自大的随机文库的高亲和力、高选择性的核酸配体，其涂覆到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）之间提供多个和冗余的附着点。由于植入物应用的多样性，这种技术的市场很难估计，但毫无疑问达到数十亿美元。