This proposal aims to develop a novel and practical therapeutic platform to revascularize ischemic tissues. In peripheral artery disease (PAD), stenting and bypass fail to permanently relieve symptoms, and in 30% of cases, amputation must be performed. These patients exhibit mortality rates of 25% within a year of surgery and 60% within five years. Cases of critical limb ischemia (CLI), the most severe form of PAD, cost over $50,000 per patient per year, with direct billing of $25 billion per year in the U.S. Our lab has developed a novel approach in which a massive number of injectable microtissues (iMTs) with blood-vessel building blocks can be produced and gently harvested. In vitro, we demonstrated over a quarter billion cells can be easily coaxed into spheroids, and in vivo, we injected therapeutic quantities into wildtype and diseased mouse models. Our approach uses dissolvable alginate as a sacrificial material for microwells to generate microtissue reproducibly in a manner suited for mass production. In preliminary work, we have validated this approach by observing the self-organization of thousands of microtissues in vitro and in vivo, including rapid integration with the host's vascular network and re-perfusion. Instead of weeks, our results so far have shown that host re- vascularization and re-perfusion occurs within days. This R01 grant will allow us to automate the production of the microtissues, study the extent to which we can control the architecture of the ensuing in vivo vascular network, and most significantly, fully explore the therapeutic potential of this novel platform via a large, properly-powered number of treatment and control groups.

Public Health Relevance

Our proposal aims to revascularize and reperfuse ischemic tissues using a novel cell-based therapy strategy based on injectable microtissues. We aim to achieve re-perfusion within approximately a week after minimally invasive cell injection, validated via an established model of mouse hindlimb ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL141935-02
Application #
9654031
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lundberg, Martha
Project Start
2018-04-01
Project End
2022-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032