Improving Host Response to Implantable Glucose Sensors via Nitric Oxide Release

描述(申请人提供)：美国约有2400万成人和儿童患有1,000,000例糖尿病，每年新诊断的病例为160万例。2型糖尿病是最常见的疾病形式，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，这种疾病最常在儿童、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，每年至少需要1095根手指。由于针棒的费用、疼痛和不便，许多糖尿病患者没有遵循维持健康血糖水平所必需的严格监测时间表。连续血糖监测系统为代谢控制提供了一种替代的、实时的方法。然而，由于人体对皮下埋植剂的不良反应，连续血糖监测仪的可靠性和临床应用受到限制。目前关于一氧化氮在消炎、防止瘢痕组织形成和增加新血管形成方面的作用的科学知识表明，一氧化氮释放表面可能会创造最佳的组织环境，以提高连续血糖监测仪的准确性。该项目的目的是利用Novan公司专有的一氧化氮释放纳米颗粒技术(Nitricil(Tm))创建一种一氧化氮释放装置涂层，以减少植入皮下葡萄糖传感器时发生的异物反应。通过这两年的第一阶段SBIR，公司的目标是：1)在兔动物模型中评估氮氧化物涂层铂丝对异物的响应，作为一氧化氮浓度和释放动力学的函数；2)使用Aim 1的优化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/或线性度损失10%作为合格/不合格标准来评估传感器响应；3)证明一氧化氮释放涂层和基于酶的传感器功能随时间的稳定性。在第一阶段里程碑完成后，Novan将探索扩大传感器浸渍涂层程序的规模，将涂层应用于企业合作伙伴提供的商业设备，根据ISO-10993和食品和药物管理局指南评估成品葡萄糖传感器的生物兼容性，并在猪动物模型中进行Nitricil(Tm)涂层葡萄糖传感器的概念验证测试，以确定与血糖水平的平均绝对百分比偏差。 与公共卫生相关：大约2400万美国人患有糖尿病，每年造成近2000亿美元的经济损失。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。连续血糖监测系统为新陈代谢控制提供了一种实时方法，并已向“闭环系统”迈进了一大步。然而，由于人体对皮下植入的反应不佳，连续血糖监测仪的可靠性和临床应用受到限制。这个第一阶段项目的目标是创造一种一氧化氮释放装置涂层，以减少植入皮下葡萄糖传感器时发生的异物反应，并提高这些装置的准确性。

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. PUBLIC HEALTH RELEVANCE: Approximately 24 million Americans have Diabetes Mellitus (diabetes) at an annual economic cost of nearly $200 billion. Type 1 diabetics living with this disease must frequently monitor their blood glucose levels to prevent deleterious bouts of hyper- or hypoglycemia. Continuous glucose monitoring systems provide a real time method for metabolic control and have made significant strides toward a "closed-loop" system. However, the reliability and resulting clinical utility of continuous glucose monitors is limited due the body's poor response to subcutaneous implants. The goal of this Phase I project is to create a nitric oxide-releasing device coating to reduce the foreign body response that occurs upon implantation of subcutaneous glucose sensors and improve the accuracy of these devices.