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:
- 金额:$ 55.77万
- 依托单位:
- 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:
- 关键词:AbdomenAchievementAddressAdvanced DevelopmentAffectAirAmericanArachidonic AcidsBiologicalBlood GlucoseBody Surface AreaButtocksCannulasCell CommunicationCell DegranulationCell LineCellsCharacteristicsCicatrixComplications of Diabetes MellitusConnective TissueCre-LoxPCresolCutaneousDataDermalDevicesDiabetes MellitusDiseaseDoseEnzyme InhibitionEpidemicEpidermisEventExcipientsExcisionFibrosisFormulationFutureGenesGlycosylated hemoglobin AGoalsHealth ExpendituresHumanHypoglycemiaIn VitroIncidenceInflammationInflammatoryInflammatory ResponseInfusion PumpsInfusion proceduresInjectionsInsulinInsulin-Dependent Diabetes MellitusKnowledgeLaboratoriesLeukocytesLifeLongevityMCL1 geneMacrophageMediatorMethodologyMolecularMusPathologyPathway interactionsPatientsPeptide HydrolasesPersonsPhagocytosisPharmaceutical PreparationsPharmaceutical SolutionsPhenolsPhenotypePhosphotransferasesPractice ManagementPreventive therapyProbabilityProteinsPublic HealthPublishingPuncture procedureReactionRecurrenceResearch Project GrantsRoleRotationSiteSkinSkin TissueSkin injurySterilitySubcutaneous TissueSystemTechnologyTestingTimeTissuesToxic effectTransgenic Miceabsorptionarmblood glucose regulationchemokineclinical efficacyclinically relevantcytokinecytotoxiccytotoxicitydiabetes managementdiabetes mellitus therapyeuglycemiafirst responderflexibilityglycemic controlimprovedin vivoinjection/infusioninnovationinsightinsulin mediatorsmanufacturemast cellmouse modelneutrophilnew technologynovelpediatric patientspharmacokinetics and pharmacodynamicsporcine modelpractice settingpre-clinicalpreservationpreventrecruitskin irritationskin organogenesissubcutaneoustissue injuryuptake
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,糖尿病设备技术取得了重大进展。这些小说
项目成果
期刊论文数量(0)
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Ulrike Klueh其他文献
Ulrike Klueh的其他文献
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{{ truncateString('Ulrike Klueh', 18)}}的其他基金
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:
10443241 - 财政年份:2022
- 资助金额:
$ 55.77万 - 项目类别:
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