Project Details
Description
ABSTRACT
While being an increasingly used option of reconstruction for severe defects arising from trauma and/or burn
injuries, VCA remains limited in use due to the complex ethical calculus of a treatment that improves life quality
dramatically, but at the cost of the side effects of long-term immunosuppression. In the longer term the most
promising approach is the induction of tolerance by mixed chimerism by bone-marrow co-transplantation. In the
shorter term, new strategies for monitoring immunosuppression to enable timely interventions, and reducing
immunogenicity of VCAs are necessary for making this treatment more accessible to patients in need. The
objective of this application is to develop a functional preservation platform that enables creating engineered
VCA grafts by exogenous administration of genetically-modified cells, their preservation in a clinically practicable
protocol, and testing the efficacy in reducing immunogenicity in rodent models of rejection and tolerance
induction. Biosensor cells will be genetically engineered with a transcription factor response element as a gene
promoter to serve as a theranostic, simultaneously driving the secretion of blood-based biomarker and a
therapeutic protein to attenuate a rejection response. We will combine this with our perfusion-based supercooled
preservation technologies to enable both engraftment of cells and to provide a time-window that makes the
utilization of engineered grafts viable in clinical time frames. This objective has been formulated based on our
prior work and preliminary results, where we have shown successful engineering of cells with required response
characteristics, development of an ex vivo rat limb perfusion system that can serve as a platform for engrafting
these cell biosensors into vascular grafts prior to transplant, and demonstrating that transducted cells can remain
viable in vivo for up to 4 months. The proposed work would lead to a smart-graft technology that can sensitively
measure local tissue signaling would enable practical monitoring and diagnosis of acute rejection episodes, can
transform care of transplant patients since compliance issues in medication would be dramatically reduced, and
will likely increase the overall efficacy and therefore reduce graft rejections. In the longer term, the preservation
methods developed here could also be enabling for tolerance induction in VCA transplants, and therefore allow
for their wide-spread use which is not possible currently.
Status | Active |
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Effective start/end date | 7/1/21 → 3/31/25 |
Funding
- National Institute of Biomedical Imaging and Bioengineering: $459,128.00
- National Institute of Biomedical Imaging and Bioengineering: $449,944.00
- National Institute of Biomedical Imaging and Bioengineering: $459,128.00
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