# Immunology of xenogeneic extracellular matrix scaffolds for heart valve tissue engineering

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $397,500

## Abstract

ABSTRACT:
American Heart Association estimates a 2.5% prevalence of valvular heart disease in the US, requiring over
100,000 valve replacements annually. Current replacement heart valves are far from ideal, leading the NHLBI
cardiac surgery working group to recommend increased support for heart valve biomaterial research. Although
glutaraldehyde fixed xenogeneic tissue valves (e.g., bovine pericardium (BP)) improve short-term survival,
chronic graft-specific immune responses persist, resulting in long-term biomaterial damage, calcification and
ultimately failure (~2-10 yr depending on age at implantation). Indeed, NHLBI xenotransplantation working group
noted that biomaterial antigenicity represents the primary translational barrier to expanding the use of xenogeneic
tissues in clinical practice. Unfixed BP in which human-relevant antigens are eliminated has potential to serve as
an immunologically-acceptable extracellular matrix (ECM) scaffold for heart valve bioprostheses. However,
identifying human-relevant BP antigens and facilitating their removal from candidate ECM scaffolds represent
critical translational barriers for development of such biomaterials. We hypothesize that elimination of human-
relevant antigens can be achieved by employing targeted antigen solubilization steps during BP ECM scaffold
production. This proposal seeks to define primary BP antigens responsible for initiating graft-specific immune
responses in human patients (Aim 1, Phase 1), quantify removal (Aim 1, Phase 2) and target elimination of such
human-relevant antigens from BP ECM scaffolds (Aim 1, Phase 3). Unfixed ECM scaffolds that avoid destructive
graft-specific adaptive immune responses have potential to modulate constructive pro-regenerative recipient
innate immune responses. Our group has previously demonstrated that retention of native tissue ECM niche in
BP scaffolds is critical to promoting pro-regenerative in vivo recipient responses. However, extent to which
exposure of natural matricryptic sites can further enhance pro-regenerative innate immune polarization towards
intact BP ECM scaffolds remains unknown. We hypothesize that ECM niche and matricryptic signal exposure are
critical factors in modulating human macrophage polarization and ultimate in vivo scaffold fate. This proposal
aims to determine mechanisms (i.e., ECM niche component and macrophage receptor) by which differing
sources of matricryptic signal exposure modulate human macrophage polarization (Aim 2, Phase 1) and combine
optimal levels of each matricryptic exposure source toward maximizing pro-regenerative polarization (Aim 2,
Phase 2). Aim 1 and 2 factors identified as having potential to positively modulate in vivo scaffold fate in humans
will be validated using an in vivo ovine heart valve replacement model (Aim 3). Completion of this proposal will
provide mechanistic insights into human-relevant antigens responsible for initiating graft-specific immune
response towards current clinicall...

## Key facts

- **NIH application ID:** 10199250
- **Project number:** 1R01HL153098-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Leigh Gareth Griffiths
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199250

## Citation

> US National Institutes of Health, RePORTER application 10199250, Immunology of xenogeneic extracellular matrix scaffolds for heart valve tissue engineering (1R01HL153098-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10199250. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*