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.

在过去的二十年中，糖尿病设备技术取得了重大进展。这些小说