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Role of Macrophages on Tissue Remodeling Following Cochlear Implantation

Award Number: R01DC018488
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Role of Macrophages on Tissue Remodeling Following Cochlear Implantation - Project Summary Cochlear implant (CI) electrode arrays are made of platinum (Pt) wires and contacts encased in polydimethylsiloxane (PDMS, silicone) housing. These materials provide mechanical stability and flexibility critical to the long-term function of the device. However, they also induce a foreign body response and fibrosis that have detrimental effects. For example, the fibrotic capsule that eventually encases all CI electrode arrays leads to increased impedances and signal broadening which decreases the effectiveness of the device. Further, intracochlear fibrosis is implicated in the loss of acoustic hearing that can occur months to years after implantation. As candidacy for CI is rapidly expanding, including many patients with significant residual hearing, there is an urgent need to understand the fundamental processes that lead to intracochlear fibrosis. Macrophages are recognized as key, central regulators of the foreign body response to biomaterials in other tissues and our preliminary data demonstrate vigorous macrophage recruitment following implantation of CIs. We hypothesize CI biomaterials activate macrophages leading to the recruitment of fibroblasts and fibrosis/encapsulation of the biomaterials and that electrical stimulation modulates this macrophage response dependent on the stimulus level and timing of onset. In Aim 1, in vitro culture models are used to explore the differential effect of PDMS and Pt on macrophage recruitment, activation, and regulation of cochlear fibroblast proliferative and synthetic functions. Aim 1 also investigates the temporal and spatial activation and recruitment of macrophages following cochlear implantation using a reporter mouse model. Aim 2 examines the role of macrophages in fibrosis/neo-ossification following cochlear implantation. First, we test the requirement of macrophages for intracochlear fibrosis following CI using a mouse line that allows conditional and selective depletion of macrophages. Next, implanted mice are treated with a specific CSF1R inhibitor to deplete macrophages as a preclinical translational model. Finally, a CX3CR1 null mouse is used to determine the effect of fractalkine signaling on post-CI fibrosis. Aim 3 determines the effects of varying levels of electrical stimulation and effects of timing of electrical stimulation onset on macrophage recruitment and intracochlear fibrosis. The proposed work provides a rigorous investigation of the effects that specific biomaterials, insertion trauma, and electrical stimulation exert on macrophage responses and the regulation of the fibrosis in the cochlea. The long-term impact of the work is to identify specific, effective, and durable strategies to limit fibrosis following CI or other injuries to the cochlea.


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 = $578,210 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	001	6	2/27/2026	COMPETING CONTINUATION	$578,210
2026	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	002	5	4/17/2026	NON-COMPETING CONTINUATION	$0
2026	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	000	5	2/23/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $578,210

Issue Date FY: 2024 ( Subtotal = $397,707 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	000	5	5/31/2024	NON-COMPETING CONTINUATION	$397,707
														Subtotal = $397,707

Issue Date FY: 2023 ( Subtotal = $399,056 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	000	4	6/1/2023	NON-COMPETING CONTINUATION	$399,056
														Subtotal = $399,056

Issue Date FY: 2022 ( Subtotal = $610,916 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	000	2	5/17/2022	SUPPLEMENT FOR EXPANSION	$209,579
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	001	3	6/14/2022	NON-COMPETING CONTINUATION	$401,337
														Subtotal = $610,916

Issue Date FY: 2021 ( Subtotal = $415,362 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	000	2	5/18/2021	NON-COMPETING CONTINUATION	$415,362
														Subtotal = $415,362

Issue Date FY: 2020 ( Subtotal = $434,565 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Research Related to Deafness and Communication Disorders	000	1	7/2/2020	NEW	$434,565
														Subtotal = $434,565

Grand Total All Awards = $2,835,816

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Role of Macrophages on Tissue Remodeling Following Cochlear Implantation

Award Number: R01DC018488

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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