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Infusion device optimization by addressing root causes of the inflammatory response

Award Number: R01DK129681
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/20/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Infusion device optimization by addressing root causes of the inflammatory response - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $502,660 )
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/28/2026	NON-COMPETING CONTINUATION	$502,660
														Subtotal = $502,660

Issue Date FY: 2025 ( Subtotal = $510,643 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/9/2025	NON-COMPETING CONTINUATION	$459,580
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/13/2025	NON-COMPETING CONTINUATION	$51,063
														Subtotal = $510,643

Issue Date FY: 2024 ( Subtotal = $536,774 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/20/2024	NON-COMPETING CONTINUATION	$33,549
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/5/2024	NON-COMPETING CONTINUATION	$503,225
														Subtotal = $536,774

Issue Date FY: 2023 ( Subtotal = $557,693 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/28/2023	NON-COMPETING CONTINUATION	$557,693
														Subtotal = $557,693

Issue Date FY: 2022 ( Subtotal = $535,597 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/21/2022	NEW	$535,597
														Subtotal = $535,597

Grand Total All Awards = $2,643,367

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Infusion device optimization by addressing root causes of the inflammatory response

Award Number: R01DK129681

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/20/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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