TML - Research
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, diabetes, ophthalmology, and wound healing.
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.
Characterize mechanotransduction signaling pathways in dysfunctional endothelial cells experiencing different disturbed 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.
Develop prognostic indicators of atherosclerotic plaque progression to advanced phenotypes. 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.
Engineer mechanotherapies as a regenerative medicine approach to treat endothelial cell dysfunction in advanced atherosclerotic plaques. Endothelial cell dysfunction is modulated by disturbed arterial mechanics, which is a key step in the initiation and progression of atherosclerotic plaques. Our laboratory is developing techniques to deliver a therapeutic mechanical stimulus to dysfunctional endothelial cells and examine its efficacy as both a treatment for advanced plaques and preventative for plaque progression.
Diabetes dramatically increases the risk of coronary artery disease (caused by the development of atherosclerosis) by 2-4 fold and diabetics are threefold more likely to die from a heart attack. This is due to the higher coronary plaque burden and higher prevalence of advanced plaques, including thin cap fibroatheroma (the plaque type most vulnerable to rupture), in diabetics compared to non-diabetics. The main consequence of diabetes is hyperglycemia, which is the primary clinical indicator used for diagnosis; long-term glycemic control remains the best predictor of cardiovascular disease in both types of diabetes.
Characterize how hyperglycemia interacts with disturbed blood flow to alter mechanotransduction signaling in dysfunctional endothelial cells and promote advanced atherosclerotic plaques. Although it is known that diabetes promotes atherosclerosis, the precise mechanism remains to be determined. Our laboratory is exploring how hyperglycemia effects endothelial cell sensing of blood flow and whether it exacerbates the pro-atherogenic phenotype that leads to the development of advanced plaques.
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).
Build a growth model to assess lens capsule-IOL interactions over time after cataract surgery and aid in the design of novel IOLs. 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.