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

基本信息

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
项目类别：
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

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

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项目摘要

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.

在过去的二十年中，糖尿病设备技术的显着进展已经实现。这些小说技术改善了对每日注射的血糖控制，从而降低了遇到的可能性糖尿病并发症。胰岛素输注泵组可提供剂量灵活性和增强的临床功效减少HBA1C和严重降血糖事件的术语。尽管有这些技术进步胰岛素输送系统，当前最佳实践套装通常限制为三天。当前面临的挑战延长皮下胰岛素给药组和输液泵的寿命涉及不可靠通过皮肤病理发展的胰岛素功效。目前，所有商用胰岛素配方包含胰岛素酚类防腐剂（IPP），称为赋形剂，是双边剑。尽管它们提供胰岛素蛋白稳定性，不育和延长胰岛素保质期，但我们的实验室最近有了表明这些是细胞毒性的，诱导炎症和继发性纤维化。随后，我们在鼠中的数据猪模型表明，接近灌注前IPP的去除可显着降低输注部位炎症同时保持蛋白质功能。因此，增加输注的两个主要障碍磨损时间是IPP的介毒性和透皮套管诱导的组织损伤，这两者都是炎症驱动的。成熟的肥大细胞（MC）位于皮肤组织中。因此，MC是第一个皮肤损伤中的响应者，是皮肤一旦皮肤策划炎症反应的关键因素违反了。因此，我们的中心假设得到了我们已发表和初步数据的支持累积的IPP和透皮注射和输液设备会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MC 与巨噬细胞（MQ）相互作用，我们进一步假设增加MC脱粒会促进M1 表型导致嗜中性粒细胞和MQ的吞噬作用胰岛素摄取/降解，从而改变了血液葡萄糖控制。因此，我们的总体目标首先是确定MC激活的发生方式，其次是在与IPP相关的同时，对产生的组织反应（炎症和纤维化级联反应）的贡献输注期持续时间的浓度和组成。我们将在三个中检验我们的假设具体目的：1）确定IPP诱导的MC激活和胰岛素降解，2）采用新型转基因鼠标模型（CRE/LOXP）确定IPP和设备MC的机制和介体诱导的炎症和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，该提议的成功完成可能会导致当前糖尿病管理实践将实现提高胰岛素输注寿命的目标设备，最重要的是，维持可用于未来复发胰岛素管理的组织部位。