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Extending the longevity of implantable biomedical devices by therapeutic regulation of the foreign body response

Award Number: R01AI197622
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Extending the longevity of implantable biomedical devices by therapeutic regulation of the foreign body response - While innovations in the engineering of biomaterials to support cell function and implant bioactivity have led to remarkable progress in regenerative medicine, the inevitable interaction of biomaterial surfaces with host biological systems remains a major obstacle to the success of biomedical implants. Implanted medical devices universally elicit a destructive, immune-mediated foreign body response (FBR) at the tissue-biomaterial interface, typified by the formation and accumulation of foreign body giant cells (FBGCs) via macrophage fusion. FBGCs secrete potent destructive mediators that promote tissue and implant destruction and device failure. However, interventions to prevent FBR and its detrimental effects are severely lacking, impeding the future of biomedical implants. We have shown that increased numbers of peri-implant FBGCs exacerbate the FBR and propose that regulating FBGC formation would be an effective approach for controlling the FBR. The transmembrane protein CD13 regulates diverse cellular processes and we have shown that mesh implants in CD13KO mice produce significantly more FBGCs with enhanced levels of secreted FBR mediators. In vitro induction of fusion in CD13KO myeloid progenitors results in hyperfusion, generating increased numbers of multinucleated FBGCs compared to WT cells, suggesting that CD13 regulates FBGC formation at the stage of cell fusion. Mechanistically, expression of fusogens is aberrantly sustained in CD13KO FBGCs due to defective ubiquitination and enhanced protein stability. Thus, CD13 acts as a brake to prevent uncontrolled myeloid cell fusion and may be a therapeutic target to control the FBR. We have characterized a panel of human CD13 mAbs that bind to distinct CD13 epitopes and determined that these mediate either CD13 gain- or loss-of-function; some reduce, while others promote CD13-dependent cell fusion and potentially be exploited therapeutically to specifically target cell fusion. To facilitate the clinical translation of our findings, we have generated ‘humanized’ mice, replacing mouse with human CD13, which express high levels of human CD13 and respond to fusion-regulatory human CD13 mAbs in vivo. Since the biomaterial parameters can impact the FBR, we will identify biomaterials that consistently induce FBGC formation and FBR in our mouse model. We will coat the implant with human CD13 mAbs, and determine the causal CD13+ cells by characterizing the FBR at the tissue/implant interface in inducible, global CD13KO and confirm the contribution of FBGCs to FBR (Aim 1). We will determine the optimal CD13 fusion-regulatory mAbs by epitope binning, generate additional fusion-blocker mAbs and test their therapeutic potential in vivo. Aim 2 will identify cell-specific molecular signatures, CD13-dependent mechanisms involved in FBGC fusion and FBR. Our animal models, primary mouse and human cells, CRISPR-engineered cell lines, CD13 gain- and loss-of-function human mAbs, in flow sorting, confocal microscopy, sc-RNA seq, and data mining of candidate gene will be used to address these questions.


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 = $572,890 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Allergy and Infectious Diseases Research	000	1	8/20/2026	NEW	$572,890
														Subtotal = $572,890

Grand Total All Awards = $572,890

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Extending the longevity of implantable biomedical devices by therapeutic regulation of the foreign body response

Award Number: R01AI197622

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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