Infusion device optimization by addressing root causes of the inflammatory response

通过解决炎症反应的根本原因来优化输注装置

• 批准号: 10612439
• 负责人: Ulrike Klueh
• 金额: $ 55.77万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-20 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612439
• 关键词: Abdomen; Achievement; Address; Advanced Development; Affect; Air; American; Arachidonic Acids; Biological; Blood Glucose; Body Surface Area; Buttocks; Cannulas; Cell Communication; Cell Degranulation; Cell Line; Cells; Characteristics; Cicatrix; Complications of Diabetes Mellitus; Connective Tissue; Cre-LoxP; Cresol; Cutaneous; Data; Dermal; Devices; Diabetes Mellitus; Disease; Dose; Enzyme Inhibition; Epidemic; Epidermis; Event; Excipients; Excision; Fibrosis; Formulation; Future; Genes; Glycosylated hemoglobin A; Goals; Health Expenditures; Human; Hypoglycemia; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Infusion Pumps; Infusion procedures; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Leukocytes; Life; Longevity; MCL1 gene; Macrophage; Mediator; Methodology; Molecular; Mus; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Persons; Phagocytosis; Pharmaceutical Preparations; Pharmaceutical Solutions; Phenols; Phenotype; Phosphotransferases; Practice Management; Preventive therapy; Probability; Proteins; Public Health; Publishing; Puncture procedure; Reaction; Recurrence; Research Project Grants; Role; Rotation; Site; Skin; Skin Tissue; Skin injury; Sterility; Subcutaneous Tissue; System; Technology; Testing; Time; Tissues; Toxic effect; Transgenic Mice; absorption; arm; blood glucose regulation; chemokine; clinical efficacy; clinically relevant; cytokine; cytotoxic; cytotoxicity; diabetes management; diabetes mellitus therapy; euglycemia; first responder; flexibility; glycemic control; improved; in vivo; injection/infusion; innovation; insight; insulin mediators; manufacture; mast cell; mouse model; neutrophil; new technology; novel; pediatric patients; pharmacokinetics and pharmacodynamics; porcine model; practice setting; pre-clinical; preservation; prevent; recruit; skin irritation; skin organogenesis; subcutaneous; tissue injury; uptake

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.

过去二十年，糖尿病设备技术取得了重大进展。这些小说 技术改善了日常注射的血糖控制，从而降低了发生这种情况的可能性 糖尿病并发症。胰岛素输注泵套件提供剂量灵活性并增强临床疗效 降低 HbA1c 和严重低血糖事件。尽管有这些技术进步 对于胰岛素输送系统，目前的最佳实践套件佩戴时间通常限于三天。当前的挑战 延长皮下胰岛素给药装置和输液泵的使用寿命涉及不可靠的 通过皮肤病理的发展来发挥胰岛素的功效。目前，所有市售胰岛素 制剂中含有胰岛素酚类防腐剂（IPP），被称为赋形剂，是一把双刃剑。 虽然它们提供胰岛素蛋白稳定性、无菌性并延长胰岛素保质期，但我们的实验室最近 研究表明，这些物质具有细胞毒性，会诱发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，邻近输注前 IPP 去除可显着减少输注部位 炎症同时保持蛋白质功能。由此可见，增加输液器的两大障碍 佩戴时间是 IPP 的化学毒性和透皮插管引起的组织损伤，两者 是炎症驱动的。成熟的肥大细胞（MC）存在于皮肤组织中。因此，MC是第一批 皮肤损伤的反应者，并且是皮肤损伤后协调炎症反应的关键因素 违反了。因此，我们的中心假设（得到我们已发表的初步数据的支持）是： 累积的 IPP 以及透皮注射和输注装置会因以下原因导致局部皮肤刺激： 肥大细胞激活和随后的白细胞募集，从而引发炎症级联反应。作为主持人 与巨噬细胞 (MQ) 相互作用，我们进一步假设增加 MC 脱颗粒会促进 M1 表型导致嗜中性粒细胞和 MQ 吞噬胰岛素摄取/降解，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 激活如何发生，其次， 与 IPP 相关时对所产生的组织反应（炎症和纤维化级联）的贡献 输注期间的浓度和成分。我们将分三步检验我们的假设 具体目标：1) 确定 IPP 诱导的 MC 激活和胰岛素降解，2) 采用新型转基因 小鼠模型 (Cre/loxP) 以确定 IPP 和设备 MC 诱导的机制和介质 炎症，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改变当前的 糖尿病管理实践将实现延长胰岛素输注寿命的目标 设备，最重要的是，维持可用于未来反复胰岛素给药的组织部位。