Improving Host Response to Implantable Glucose Sensors via Nitric Oxide Release

描述（由申请人提供）：美国约有2400万成人和儿童患有糖尿病（糖尿病），每年诊断出160万新病例。2型糖尿病是最常见的糖尿病，占全球糖尿病患者的90%以上。其余5%至10%的糖尿病患者患有更严重的1型糖尿病，这种糖尿病最常在儿童、青少年或年轻人中被诊断出来，其特征是身体无法产生胰岛素。患有这种疾病的1型糖尿病患者必须经常监测他们的血糖水平，以防止有害的高血糖或低血糖发作。2010年美国糖尿病协会指南建议每天测试三次或更多次，每年至少有1,095次手指针刺。由于针刺的成本、疼痛和不便，许多糖尿病患者不遵守维持健康血糖水平所必需的严格监测时间表。连续葡萄糖监测系统为代谢控制提供了一种替代的实时方法。然而，由于人体对皮下植入物的不良反应，连续葡萄糖监测仪的可靠性和由此产生的临床效用受到限制。目前关于一氧化氮在减少炎症、防止瘢痕组织形成和增加新血管形成中的作用的科学知识表明，释放一氧化氮的表面可以创造最佳的组织环境，以提高连续葡萄糖监测仪的准确性。本项目的目的是使用Novan专有的一氧化氮释放纳米颗粒技术（Nitricil（tm））创建一氧化氮释放器械涂层，以减少皮下葡萄糖传感器植入后发生的异物反应。在这两年中，第一阶段SBIR公司的目标是：1）在兔动物模型中评价Nitricil（tm）涂层铂丝的异物反应，作为一氧化氮浓度和释放动力学的函数; 2）使用Aim 1中优化的Nitricil（TM）涂层制造四层酶葡萄糖传感器，并使用灵敏度、响应时间、和/或线性作为通过/失败标准;和3）证明在最终灭菌的传感器上一氧化氮释放涂层和酶基传感器功能两者随时间的稳定性。在完成第一阶段的里程碑后，Novan将探索扩大探头浸涂程序，将涂层应用于公司合作伙伴提供的市售器械，根据ISO-10993和FDA指南评价成品葡萄糖探头的生物相容性，并对Nitricil（TM）进行概念验证测试-在猪动物模型中使用经涂覆的葡萄糖传感器，以建立与血糖水平的平均绝对百分比偏差。

DESCRIPTION (provided by applicant): Approximately 24 million adults and children in the United States have 1 Diabetes Mellitus (diabetes) and 1.6 million new cases are diagnosed each year. Type 2 is the most common form of the disease accounting for over 90% of the diabetics worldwide. The remaining 5 to 10% of diabetics are plagued with the more serious Type 1 condition which is most often diagnosed in children, adolescents or young adults and is characterized by the body's inability to produce insulin. Type 1 diabetics living with this disease must frequently monitor their blood glucose levels to prevent deleterious bouts of hyper- or hypoglycemia. The 2010 American Diabetes Association guidelines recommend testing three or more times a day which results in a minimum of 1,095 finger sticks per year. Because of the cost, pain, and inconvenience of needle sticks, many diabetics do not follow the rigorous monitoring schedule necessary for maintaining healthy blood glucose levels. Continuous glucose monitoring systems provide an alternative, real-time method for metabolic control. However, the reliability and resulting clinical utility of continuous glucose monitors is limited due the body's adverse response to subcutaneous implants. Current scientific knowledge regarding nitric oxide's role in reducing inflammation, preventing scar tissue formation, and increasing new blood vessel formation suggests that nitric oxide-releasing surfaces may create an optimal tissue environment to improve the accuracy of continuous glucose monitors. The purpose of this project is to create a nitric oxide-releasing device coating, using Novan's proprietary nitric oxide-releasing nanoparticle technology (Nitricil(tm)), to reduce the foreign body response that occurs upon implantation of subcutaneous glucose sensors. Through this two year, Phase I SBIR the Company aims to: 1) evaluate the foreign body response of Nitricil(tm) coated platinum wires in a rabbit animal model as a function of nitric oxide concentration and release kinetics; 2) fabricate four layer enzymatic glucose sensors using the optimized Nitricil(tm) coating from Aim 1 and evaluate sensor response using a <10% loss in sensitivity, response time, and/or linearity as pass/fail criteria; and 3) demonstrate the stability of both the nitric oxide-releasing coating and the enzyme-based sensor function on terminally sterilized sensors over time. Following the completion of Phase I milestones, Novan will explore the scale up of sensor dip-coating procedures, apply the coating to commercially available devices provided by a corporate partner, evaluate the biocompatibility of finished glucose sensors according to ISO-10993 and FDA guidelines, and conduct proof-of-concept testing of the Nitricil(tm)- coated glucose sensor in porcine animal models to establish mean absolute percent deviation from blood glucose levels.