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NIH grant 1K99HL183755-01A1: Immunomechanically Tuned Vascular Grafts to Mitigate Diabetic Inflammation
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: David R. Maestas. Award: $121285.
Start: 2026-09-05T00:00:00.
PROJECT SUMMARY
Cardiovascular disease (CVD) is the leading cause of death worldwide, with type 2 diabetes mellitus (T2D)
increasing the risk of mortality rises to 70%. Coronary artery bypass grafting (CABG) is a standard intervention
for severe CVD, yet nearly half of vein grafts fail within ten years. Additionally, women with T2D face higher
mortality risks and worse outcomes post-CABG than their male counterparts. While compliance-matched tissue
engineered vascular grafts (CM-TEVGs) can reduce biomechanical stress, T2D-driven inflammation and
advanced glycation end products (AGEs) impair vascular remodeling and graft patency. Further, the mechanisms
underlying sex-specific disruptions in TEVG remodeling in T2D remain unclear. This work seeks to design
immune modulatory (IM)CM-TEVGs to dampen T2D-driven inflammatory pathways that disrupt TEVG
remodeling and biocompatibility. With a diabetic-focused ex vivo 3D culture model and surgical implantation of
grafts into healthy and diabetic rats, we will investigate how T2D inflammation alters early vascular remodeling
in both sexes and attempt to steer it towards healthy repair.
Aim 1 will determine whether IMCM-TEVGs attenuate early inflammation in vivo in healthy rats. Graft loaded
with Interleukin (IL)-10 or IL-4 will be fabricated, validated for release and bioactivity, implanted for one week,
and evaluated by multiplex protein assays, targeted gene expression assays, 3D immunofluorescent imaging of
immune cells with two-photon microscopy, and validated with standard histology.
Aim 2 will develop a type 2 diabetes-specific, perfused 3D aorta-TEVG culture to model diabetic remodeling.
The system will incorporate high glucose, AGE stimulation, and explants from diabetic and lean rats, enabling
longitudinal label-free two-photon second harmonic generation imaging of collagen, stromal phenotyping, gene
expression, and collagen quantification.
Aim 3 (R00): Test targeted blockade of IL-6/TNFα and AGE-RAGE pathways using IMCM-TEVGs in diabetic
males and females. Remodeling will be mapped at 1- and 6-weeks by spatial transcriptomics, multiplex
proteomics, 3D immunofluorescent imaging, and collagen quantification, benchmarked against controls.
Expected impact: This project will utilize advanced vascular graft designs that integrate biomechanical
compliance with precise immunomodulation to assess sex-specific immune-stromal mechanisms in T2D.
Further, this project will deliver a scalable ex vivo platform to screen graft therapies alongside in vivo validation,
directly informing strategies to reduce graft failure in diabetic patients.document fetched 2026-09-13 02:46