Mechanobiology of ocular hypertension and optic nerve degeneration in glaucoma
Glaucoma is the leading cause of irreversible blindness in the world. The elevated intraocular pressure characteristic of many cases of glaucoma is attributable to increased resistance to aqueous humor outflow. However, the cause of this increased flow resistance and its primary location eluded investigators for over 140 years. We have previously shown that increased stiffness of Schlemm’s Canal (SC) endothelium and its underneath substrate, the juxtacanalicular tissue (JCT), is central to the elevated outflow resistance and intraocular pressure in human glaucomatous eyes. Nonetheless, the underlying processes for this etiology are still unknown or poorly understood.
We aim to investigate the mechanisms in charge for altered mechanobiology of SC endothelium and their prospects for developing new therapeutics and regenerative approaches for the disease. A representative example of these efforts is that we have shown targeted delivery of nanoparticles, which contain cytoskeletal disrupting agents to soften the SC endothelium, can significantly reduce the intraocular pressure in mouse, suggesting that targeting the SC mechanobiology could be a promising avenue for creating new drugs for glaucoma.
Nuclear mechanobiology and mechanotransduction
Cells and tissues in living organisms are continually exposed to mechanical stimuli. Transmission of these extracellular forces and mechanical clues to the cell nucleus, referred to as mechanotransduction, plays a significant role in normal physiological phenomena such as cell function, migration, and tissue regeneration as well as pathological conditions like cancer metastasis, neurodegeneration, and fibrosis.
We aim to understand how engagements between the extracellular matrix, cell cytoskeleton, and nucleoskeleton are involved in mechanotransduction and regulation of cell behavior. For example, we have shown that the four filamentous lamins isoforms (lamins A, C, B1, and B2), which are central elements of nucleoskeleteon, differentially engage with F-actin and vimentin cytoskeletal systems to regulate cell mechanics, contractility, and migratory behavior. Unveiling these processes is crucial for understanding the pathology of lamin-associated diseases such as cancer, progeria, dilated cardiomyopathy, and muscular dystrophies.
3D bioelectronic interfaces for multifunctional organ/organoid on chip systems
Progress in stem cell biology and tissue engineering has facilitated the engineering of submillimeter to centimeter scale spheroids, organoids, and tissues for studying human development and disease states. The emergence of these 3D multicellular biological systems calls for technologies that allow investigation of their behavior with modalities of interest ranging from electrophysiology and force measurements to thermal or chemical sensing and stimulation. Nonetheless, current technologies in neuroscience and mechanobiology have limitations in providing such modalities. For instance, existing microelectrode arrays have major setbacks due to their planar, rigid, and 2D geometries that limit their interaction with a 3D neural tissue to their basal contact regions with the arrays. Similarly, present approaches for characterizing contractility in engineered muscle tissues rely on optical measurement of their motion against a deformable structure, such as elastomeric pillars, which suffer from uncertainties in beam geometry, material constitutive properties, or imaging limitations.
We focus on developing new classes of soft bioelectronic interfaces that can integrate with biological tissues and provide continuous objective readouts of interest. Our current interest is focused on developing flexible 3D devices for electrophysiology and muscle contractility measurements in an engineered on-chip neuromuscular system to study ALS. These advanced sensor-integrated biosystems can be utilized for basic science studies of neural and muscular systems as well as efforts towards developing regenerative engineering and personalized medicine strategies for neuromuscular disorders, neurodegenerative diseases, and muscular dystrophies.
Engineered implantable electronics for tissue regeneration and therapy
Cardiac diseases are still a leading cause of death worldwide despite significant advances in cardiovascular devices and medicine. A major challenge in patients who suffer ischemic myocardial infarction is limited capacity of adult human heart for regeneration, which results in replacement of the lost cardiomyocytes (CMs) by fibrotic scar tissues and later progression to heart failure. While whole heart transplantation remains a viable option for patients with terminal stage heart failure, the high incidence of myocardial infarction and shortage of organ impose a significant limitation and call for development of novel effective methods for regeneration and repair of the injured myocardium. Stem cell-based therapies such as engineered cardiac patches (CPs) that morphologically and functionally resemble myocardium have recently emerged as a potential solution for cardiac regeneration.
Despite major advances in creating stem cell derived CMs, patches, and their positive effect on improving cardiac function, studies show that CM maturation and lethal arrhythmic complications due to low electrical or mechanical integration between the CP and host myocardium remain as big challenges. To address these bottlenecks, we’re focused on developing ultrathin stretchable electronic cardiac patches that integrate with iPSC derived human cardiomyocytes and vascular endothelial cells for both in vitro and in vivo applications. These patches will have modalities for electrical stimulation and recording, and strain sensing for cardiac contraction measurements. Our ultimate goal is to create implantable electronic patches that can be wirelessly monitored for electrophysiological activity and modulation.