Infusion device optimization by addressing root causes of the inflammatory response

在过去的二十年中，糖尿病器械技术取得了重大进展。这些新颖 技术改善了每日注射的血糖控制，从而降低了遇到 糖尿病并发症胰岛素输注泵套件提供给药灵活性和增强的临床疗效， 降低HbA 1c和重度低血糖事件。尽管这些技术进步， 对于胰岛素输送系统，目前最佳实践的装置佩戴通常限于三天。目前受到的挑战 延长皮下胰岛素给药装置和输注泵的使用寿命涉及不可靠的 胰岛素的功效通过皮肤病理学的发展。目前，所有市售胰岛素 制剂含有胰岛素酚类防腐剂（IPP），称为赋形剂，是一把双刃剑。 虽然它们提供胰岛素蛋白质稳定性、无菌性和延长胰岛素保质期，但我们的实验室最近 显示这些是细胞毒性，诱导炎症和继发性纤维化。随后，我们在小鼠中的数据 和猪模型表明，在输注前去除IPP显著减少了输注部位 炎症，同时保持蛋白质功能。因此，增加输液器的两大障碍 磨损时间是IPP的化学毒性和经皮插管诱导的组织损伤，两者都 是由炎症驱动的成熟的肥大细胞（MC）存在于皮肤组织中。因此，MC是第一批 在皮肤损伤的反应，并在协调炎症反应的关键贡献者，一旦皮肤是 被攻破了因此，我们的中心假设，由我们公布的和初步的数据支持，是， 累积的IPP和经皮注射和输注装置会导致局部皮肤刺激， 肥大细胞活化和随后的白细胞募集，从而启动炎症级联反应。为MC 与巨噬细胞（MQ）相互作用，我们进一步假设增加MC脱粒促进M1 表型导致中性粒细胞吞噬胰岛素摄取/降解& MQ，从而改变血液 血糖控制因此，我们的总体目标是，首先，确定MC激活是如何发生的，其次， 导致组织反应（炎症和纤维化级联反应）的贡献，同时将IPP 在输注期的持续时间内的浓度和组成。我们将在三个方面来检验我们的假设 具体目的：1）确定IPP诱导的MC活化和胰岛素降解，2）使用新的转基因 小鼠模型（Cre/loxP），以确定IPP和器械MC诱导的机制和介质 炎症，和3）在临床前胰岛素输注泵治疗期间保持长期组织完整性 猪模型最终，该提案的成功完成可能会导致改变当前的 实现延长胰岛素输注寿命目标的糖尿病管理实践 设备，最重要的是，维持组织部位可用于未来的反复胰岛素给药。

Significant progress in diabetes device technology has been realized over the past two decades. These novel technologies improve glycemic control over daily injections thus reducing the probability of encountering diabetic complications. Insulin infusion pump sets provide dosing flexibility and enhanced clinical efficacy in terms of reducing HbA1c and severe hypoglycemic events. Despite these technological improvements in insulin delivery systems, current best-practice set wear is typically limited to three days. Current challenges to extending the lifespan of subcutaneous insulin administration sets and infusion pumps involve unreliable insulin efficacy through the development of skin pathologies. Currently, all commercially available insulin formulations contain insulin phenolic preservatives (IPP) known as excipients that are a double edge sword. While they provide insulin protein stability, sterility and prolong insulin shelf life, our laboratory has recently shown that these are cytotoxic, induce inflammation and secondary fibrosis. Subsequently, our data in murine and porcine models demonstrated that proximate pre-infusion IPP removal significantly reduces infusion site inflammation while maintaining protein functionality. Thus, the two major obstacles to increased infusion set wear time are the chemotoxicity of the IPP and the transdermal cannula induced tissue injury, both of which are inflammation driven. Mature mast cells (MC) reside in cutaneous tissue. Thus, MC are one of the first responder in skin injury and are key contributors in orchestrating the inflammatory response once the skin is breached. Therefore, our central hypothesis, supported by our published and preliminary data, is that accumulative IPP and the transdermal injection and infusion devices contribute to local skin irritation due to mast cell activation and subsequent leukocyte recruitment, thus initiating the inflammatory cascade. As MC interact with macrophages (MQ) we further hypothesize that increased MC degranulation promotes M1 phenotype leading to phagocytosis insulin uptake/degradation by neutrophils & MQ and thus altering blood glucose control. Therefore, our overall goals are, first, to determine how MC activation occurs, and, second, the contribution to the resulting tissue reactions (inflammation and fibrotic cascades) while correlating IPP concentration and composition for the duration of the infusion period. We will test our hypothesis in three specific aims: 1) determine IPP induced MC activation and insulin degradation, 2) employ novel transgenic mouse models (Cre/loxP) to determine the mechanisms and mediators of IPP and device MC induced inflammation, and 3) preserve long-term tissue integrity during insulin infusion pump therapy in a pre-clinical porcine model. Ultimately, the successful accomplishment of this proposal could result in transforming current diabetes management practices that would achieve the goals of increasing the lifespan of insulin infusion devices and most importantly, sustaining a tissue site available for future recurrent insulin administrations.