There is a fascinating two-fold paradox in dissecting the response to endovascular intervention that speaks to the tension between clinical and preclinical environments. While the clinic motivates examination of mechanisms of vascular repair it cannot be the venue to examine this biology given the extreme uncontrolled variability of the human condition. The number of variables that can change between different people and arterial segments for an individual challenge person-to-person comparison. The animal model can provide the means and tools with which to change specific forces in a controlled manner, one at a time but the response of the intact healthy animal is not the response of the diseased human. The healthy animal artery compensates for aberrancies imposed by suboptimal intervention to restore homeostasis, and it is difficult to impose permanent disruptions in the animal. Intact compensatory mechanisms restore near-healthy state making the native artery less-than-ideal environment to study device biology. Inducing disease in the animal reintroduces uncontrolled variability and in a manner not necessarily synonymous with the human condition. Thus, we must acknowledge that there will forever be a disparity between the diseased human and intact animal. And yet, herein lays the opportunity. Rather than claiming that the one (animal) can ever mimic the other (human), we embrace the difference and examine the nature of the difference to define how compensation and its impairment affects endovascular interventions. The fundamental hypothesis that drives this work is that one must consider the environment AND the intervention, not either alone. Analogous to how pharmacokinetics (what drugs do to the body) are affected by pharmacodynamics (what the body does to the drug), we examine how what devices do to blood vessels is influenced by what vessels do to devices. We will identify the dominant forms of vascular compensation (elastic vessel recoil, intimal hyperplasia) in clinical trial data and how they are impaired with lesions. Comparing actual with virtual angioplasty (developed in last funding period) we will track actual with predicted effects over a range of possible interventions. Our international network of collaborators will make available the largest and most refined clinical trials images from patients providing access to and scope of disease over a full range of lesions, interventions and outcomes. Then using animal models of disease (also developed with NIH support) where we can control not only lesion morphology but geographic/geometric aberrations as well, we will define how lesion morphology drives the compensation to specific types of geometric aberrations and then the late biologic response. Finally, we will come full circle comparing animal and human to understand when the one converges on the other. We leverage past funding and emerging innovation to create new means of developing and examining emerging endovascular technology, establish new perspectives on pathology of vascular repair, and understand better when animal models might recapitulate human biomechanical and biological variability.

Public Health Relevance

We have brought together an international collaborative network of clinician-scientists dedicated to understanding vascular repair and the response to endovascular devices. Leveraging past NIH funding, data from large clinical trials and emerging innovation in devices on the one hand and animal models on the other, we create new means of developing and examining emerging endovascular technology, establish new perspectives on pathology of vascular repair, and understand better when animal models might recapitulate human biomechanical and biological variability.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049039-23
Application #
9497796
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Okita, Richard T
Project Start
1994-08-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
23
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Sch Allied Health Professions
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
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