Collage of images of students working from the Pedrigi Research Lab

Overview

Research in the Translational Mechanobiology Lab (TML) employs techniques in biomechanics, cell and molecular biology, histology, imaging, regenerative medicine, and tissue engineering to explore the influence of biomechanical (and biochemical) stimuli in modulating normal and pathological cell behaviors. The goal is to translate an understanding of mechanobiological mechanisms of disease to create new therapies, develop prognostic indicators of disease progression, and improve the design of implantable medical devices. The primary applications of the work are in cardiovascular medicine, ophthalmology, and wound healing.



Atherosclerosis

Atherosclerosis is a chronic inflammatory disease that manifests as plaques composed of a lipid-rich necrotic core and immune cells within the intima of the artery wall. Plaque rupture exposes the highly thrombogenic necrotic core to the bloodstream, leading to platelet activation, thrombosis, and artery occlusion. This event is the most common trigger of heart attack and stroke, which are leading causes of morbidity and mortality in the United States. An interesting feature of atherosclerosis is that plaques develop in regions of arteries experiencing disturbed blood flow. This observation suggests that specific biomechanical signatures play a principal role in atherogenesis by promoting a dysfunctional endothelium—the cell type that sits at the interface between the bloodstream and vessel wall.



A historical section portion from a mouse aorta with overlapping nuclear (DAPI; blue), KLF2 (red), and elastin (green) stainings. KLF2 is a principal atheroprotective transcription factor in endothelial cells that is activated under normal flow conditions.
A histological section from a mouse aorta with overlapping nuclear (DAPI; blue), KLF2 (red), and elastin (green) stainings. KLF2 is a principal atheroprotective transcription factor in endothelial cells that is activated under normal flow conditions.

Characterizing mechanotransduction signaling pathways in endothelial cells under normal and atherogenic arterial mechanical environments

The precise environmental cues that promote advanced plaque development, particularly those vulnerable to rupture, remain unknown. Our laboratory explores how different biomechanical signatures (stemming from disturbed vessel wall stretch and blood flow) activate mechanotransduction signaling in dysfunctional endothelial cells to promote the development of advanced plaques. The goal is to identify novel pharmaceutical targets of patho-mechanotransduction in atherosclerosis.

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Engineering mechanotherapies as a regenerative medicine approach to treat endothelial cell dysfunction in advanced atherosclerotic plaques

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Assessing the efficacy of nanoparticles as both a diagnostic and therapeutic for advanced plaques

Mouse carotid artery from micro-CT imaging, instrumented with a cuff that disturbs blood flow and promotes the development of advanced plaques. Vessels are computationally opened and layed flat to look at the distribution of shear and endothelial signaling (KLF2).
Mouse carotid artery from micro-CT imaging, instrumented with a cuff that disturbs blood flow and promotes the development of advanced plaques. Vessels are computationally opened and layed flat to look at the distribution of shear and endothelial cell signaling (KLF2).

Developing prognostic indicators of plaque progression

Several studies, including from our group, have quantified a relationship between local blood flow disturbances and the development of specific plaque types in both patients and experimental animal models. Our laboratory is working to synthesize these data within a computational framework to predict plaque progression. This framework includes the development of novel mechanical biomarkers and the use of techniques in statistical pattern recognition and machine learning.

Cataract Surgery

Cataract surgery is the most common corrective procedure in the aged population and post-surgical capsule fibrosis is the most common complication. During surgery, the cloudy lens fibers are removed through a permanent hole placed in the lens capsule and replaced with an artificial intraocular lens (IOL). This procedure permanently alters the biomechanical environment of the lens capsule, which promotes the fibrotic response that is mediated by the inhabiting lens epithelial cells. The severity of capsule fibrosis depends on IOL design and current IOLs lack the ability to accommodate (i.e., change focus from distant to near objects).



Finite element model of the post-surgical lens capsule with implanted prosthetic intraocular lens (IOL).
Finite element model of the post-surgical lens capsule with implanted prosthetic intraocular lens (IOL). The model is coupled to a growth and remodeling framework that is driven by altered mechanics to predict IOL efficacy over time after cataract surgery.

Building growth models of the lens capsule to predict prosthetic intraocular lens efficacy over time after cataract surgery

An obstacle in the design of IOLs, particularly those with an accommodative feature, is the dramatic remodeling of the lens capsule that occurs after cataract surgery due to the fibrotic response of the inhabiting lens epithelial cells. Our laboratory is working on computational tools to aid in predicting lens capsule-IOL interactions and thus IOL efficacy over time after cataract surgery. The approach employs finite element analysis and growth modeling techniques.