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.

在过去的二十年里，糖尿病设备技术取得了重大进展。这些小说 技术改善了对日常注射的血糖控制，从而降低了遇到 糖尿病并发症。胰岛素输注泵组提供给药灵活性和增强的临床疗效 降低HbA1c和严重低血糖事件的术语。尽管在技术上有了这些改进 胰岛素给药系统，目前的最佳实践套装佩戴通常限制为三天。当前面临的挑战 延长皮下胰岛素给药装置和输液泵的寿命涉及不可靠的问题 胰岛素通过皮肤病理的发展而发挥功效。目前，所有商用的胰岛素 配方中含有胰岛素酚类防腐剂(IPP)，称为赋形剂，是一把双刃剑。 在提供胰岛素蛋白质稳定性、无菌和延长胰岛素货架期的同时，我们的实验室最近 研究表明，这些都是细胞毒性的，会导致炎症和继发性纤维化。随后，我们在小鼠体内的数据 猪模型表明，输液前IPP的近似性清除显著减少了输液部位 炎症，同时维持蛋白质功能。因此，增加输液量的两大障碍 磨损时间是IPP的化学毒性和经皮插管引起的组织损伤，两者都是 是由炎症驱动的。成熟肥大细胞(MC)存在于皮肤组织中。因此，MC是第一批 在皮肤损伤中的反应者，是协调炎症反应的关键贡献者 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和经皮注射和输液装置会导致局部皮肤刺激，原因是 肥大细胞激活和随后的白细胞募集，从而启动炎症级联反应。作为MC 与巨噬细胞(MQ)的相互作用我们进一步假设MC脱颗粒增加促进M1 导致中性粒细胞吞噬/降解胰岛素的表型&MQ，从而改变血液 血糖控制。因此，我们的总体目标是，第一，确定MC激活是如何发生的，第二， 与IPP相关时对导致的组织反应(炎症和纤维性级联)的贡献 在输液期内的浓度和成分。我们将在三年内检验我们的假设 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 建立小鼠模型(Cre/loxP)以确定IPP和设备MC诱导的机制和介质 炎症，以及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。最终，这一提议的成功实现可能会导致当前的 将实现延长胰岛素输注寿命目标的糖尿病管理实践 最重要的是，维持一个组织部位，以供未来经常性的胰岛素给药。