Détails sur le projet
Description
PROJECT SUMMARY/ABSTRACT
Despite the global need, there is no heart valve replacement with long-term durability or growth potential. Such
need is most critical for pediatric patients born with congenital heart defects, as continued growth and remodeling
of the implanted valve is essential for avoiding multiple surgeries, which are the current standard of care. Living
allogenic valve transplantation (LAVT) has recently been introduced as a means of delivering a valve
replacement with physiologic growth and self-repair mechanisms. Nevertheless, LAVT suffers from limitations
regarding i) availability, ii) ex vivo viability, iii) the cost, time and resource constraints related to minimizing tissue
ischemic time, and iv) immunogenicity. What remains lacking is a living valvular allograft that can be transplanted
off-the-shelf. Therefore, this project seeks to develop a strategy for the preservation of living valvular allografts
for at least 3 weeks ex vivo. The central hypothesis is that environmental control of the key factors inducing
valve degradation, combined with biomimetic physical stimuli, will enable maintenance of valve viability,
microarchitecture, and function. To inform the design of this storage strategy, pathologic processes in failed
cryopreserved homografts (the historic gold-standard) will be characterized (Aim 1). The rationale is that the
mechanisms underlying failure of currently-available homografts will serve as the blueprint for developing a
storage technique capable of overcoming these same adverse outcomes (Aim 2). Patterns of cell infiltration and
cell phenotype, pathologic shifts in the extracellular matrix, and immunologic rejection will be investigated. Aim
2 will be carried out in integrated fashion with Aim 1. Aims 2.1 and 2.2 identify the temperature and biochemical
cues required to preserve valvular allograft physiology ex vivo, respectively. Aim 2.3 will be executed in parallel,
and focuses on development of a bioreactor which continuously exposes valvular allografts to open/close cycles
at a physiologic rate. Taken together, the project’s success would enable ex vivo valve preservation, significantly
enhancing the clinical availability and logistic-ease of LAVT. The living nature of these tissues is particularly
relevant to the pediatric field, where it is imperative that implanted grafts grow with the patient. Furthermore, this
study has focus on the environmental elements required to maintain valvular homeostasis. This offers unique
insights in valve tissue physiology, and how the absence of key bio-instructive factors can contribute to valvular
disease. This study will be carried out as a collaborative effort between the labs of Dr. Gordana Vunjak-Novakovic
(University Professor at Columbia) and Dr. David Kalfa (Congenital Heart Surgeon and Director of the Pediatric
Heart Valve Center at Columbia), both located on the Columbia University Medical Center Campus. The
proposed fellowship applies tools of cell and tissue engineering towards developing living-tissue valve
replacements for clinical use, synergizing translational research with clinical experience. The labs collectively
bring expertise in cardiac valve engineering, tissue engineering, stem cells, valve physiology, and cardiothoracic
surgery – synergizing these skills towards developing a living valve replacement for young patients.
Statut | Actif |
---|---|
Date de début/de fin réelle | 9/30/24 → 9/30/25 |
Keywords
- Pediatría, perinaltología y salud infantil
Empreinte numérique
Explorer les sujets de recherche abordés dans ce projet. Ces étiquettes sont créées en fonction des prix/bourses sous-jacents. Ensemble, ils forment une empreinte numérique unique.