Fecobionics device for mapping colonic and anorectal neuromuscular function (NIH SPARC OT2)
The colon and anorectum have complex composition. Methods to study neuromuscular interactions and activity in health and gastrointestinal (GI) disease have been limited due to difficult access and lack of appropriate technologies. Many aspects of colonic mechanosensory physiology are still not well understood including the influence of enteric circuits and reflexes, and extrinsic nerve function in the various segments of the colon. The need for new technology and a better understanding of the neuromuscular function is substantial. A significant problem is a lack of physiologically-relevant and practical test for identifying the underlying mechanism(s). Hence, the overall objective is to validate a fully integrative dynamic tool that mimics feces transport in the lower GI tract. Accordingly, the following tasks are proposed: 1) Optimization of a wireless development of Fecobionics device and System for neuromuscular function studies of the colon. Milestone: Wireless device that can record during transport through colon and anorectum; 2) Conduct safety and performance studies in dogs (including IDE approval): Milestone: Studies that demonstrates safety and performance of the device under different neuromuscular conditions; and 3) Develop a validated mathematical model of the lower GI tract. Milestone: Geometric and functional mathematical model for colonic transport and defecation. The proposed technology (Fecobionics) is a simulated electronic feces that has the consistency and shape of normal stool. The measured variables in Fecobionics include multiple pressures, shape changes, velocity and orientation. Hence, it will be feasible to map and describe objectively (without disturbing the colonic transport and defecation processes) the transport characteristics and neuromuscular signatures during colonic transport and initial entry from the rectum into the relaxing anal canal. This unique device will provide new neuromuscular signatures of the lower GI tract under normal circumstances, and during intervention with enteric and peripheral nerve activity to enhance our understanding of physiological and pathophysiological mechanisms involved in the lower GI tract neuromuscular function. In line with SPARC mission, we intend to provide a new technology for lower GI testing, simulating normal stool transport and defecation with a bionics device. This technology will replace several current tests, because it provides an integrated frame work for assessing function and obviates the need for multiple tests of function. The central premise is that a novel and unique Fecobionics device that mimics natural lower GI transport will provide new mechanistic insights regarding colonic and anorectal physiology when compared to standard tests and facilitate development of new diagnostics for lower GI disorders. The significance is to address the major gaps in knowledge by developing a safe, low cost, less invasive, low risk, radiation-free device, and test its ability to provide new understanding of colonic neuromuscular and defecation function. This may later facilitate development of diagnostic and therapeutic tools that will reduce healthcare costs.
Roles of Ischemia and mechanical dyssynchrony in optimizing CRT responses (R01 HL134841)
Heart failure (HF) is a nationwide epidemic with over 6 million afflicted patients and 600,000 new patients diagnosed each year. Ischemic heart disease continues to be the leading cause of death in the United States. Over the past 16 years, cardiac resynchronization therapy (CRT) has been shown to increase LV performance, quality of life, and overall survival in a large number of (ischemic and non-ischemic) HF patients. Approximately 30% of patients, however, still do not improve after therapy (CRT non-responders) and the percentage of CRT non-responders have remained stable over the past decade. We believe that one of the critical barrier in improving CRT responder rate is the lack of an understanding of the interactions between ischemia and mechanical dyssynchrony. In this proposal, we seek to close this of understanding gap by using a multi-disciplinary approach that combines large-animal experiments and validated computational modeling. The overall goal of this proposal is to develop validated animal-specific biventricular computational models that couple cardiac electromechanics to a novel cardiac reversible remodeling (CRR) theory (i.e., CRR-EM models) to elucidate the long-term interactions between ischemia and mechanical dyssynchrony arising from left branch bundle block (LBBB), and how these interactions affect CRT. The following specific aims are constructed to accomplish this goal. First, we will establish the short term interactions between LBBB and ischemia, which both have implications on the regional oxygen supply-demand relation. Second, we will develop validated CRR-EM computational models using longitudinal data from animal models with varying severity of ischemia at different regions and mechanical dyssynchrony. Third, we will use the validated computational models to elucidate the long-term effects of CRT. The proposed approach and methodologies are innovative. More importantly, the completion of this project will significantly increase our understanding on the interactions between ischemia and mechanical dyssynchrony, and how these interactions can affect long-term CRT response. The findings of this project is translational and can serve as a foundation for future development of patient-specific methodologies to optimize CRT response.
Micro-Mechanical Role of Hypertension in Intimal Hyperplasia (R01 HL117990)
The roles of mechanical stresses and strains in hypertension and atherogenesis are well accepted. The objective of this proposal is to develop a validated micro-structural model of the entire vessel wall of coronary arteries in health and hypertension (as a mechanical stimulus for intimal hyperplasia, IH). The proposal involves in situ Multi-Photon Microscopy (MPM) that enables the 3-D depiction of elastin, collagen and smooth muscle cells (SMC) of the coronary artery under mechanical loading, experimental approach to quantify the layered structure of the wall, numerical algorithm that takes advantage of nonlinear mechanics, and modern computational capability to deal with the complex micro-structural geometry and boundary conditions. Accordingly, the Specific Aims are: 1) To develop a passive and active constitutive model for coronary arterial wall based on constituent ultrastructure (fibers and SMC); 2) To validate the full constitutive arterial wall model of Aim 1 using both passive and active data of (macroscopic) triaxial mechanical tests and in situ imaging of the microstructural deformation; and 3) To elucidate the mechanical role of hypertension on IH using the validated models of Aim 2 combined with finite element analysis and experimental validation. We have previously established the methods of triaxial mechanical testing (inflation, extension and twist), in situ micro-structure imaging, image processing and reconstruction, and developed a novel predictive micromechanics model of the adventitia. Here, we propose to extend these developments to the entire wall to provide a validated virtual vessel model that can be used to verify various hypotheses quantitatively (e.g., role of hypertension on IH). The success of the proposed microstructure-based computational framework will provide an accurate and reliable mathematical description of the structure-function relation of coronary arteries, and result in a new level of understanding for the mechanical response of the vessels. Furthermore, the extensive quantitative experimental data of the microstructures in health and hypertension (including IH) and their deformation will greatly enrich the understanding of the mechanical environment of the fibers and SMC and the remodeling process in atherogenesis.
Minimally Invasive Ventricular Polymeric Injection for Treatment of Heart Failure (R01 HL118627)
Heart failure (HF) is a worldwide epidemic that contributes considerably to the overall cost of health care in developed nations. The number of people afflicted with this complex disease is increasing at an alarming pace—a trend that is likely to continue for many years to come. The overall goal of our proposed research is to optimize a therapy for HF that involves percutaneous injection of a hydrogel (Algisyl-LVR) in the failing myocardium. Given the cardiovascular system’s complexity, a multi-disciplinary expertise across experimental and computational domains is required to fully investigate this novel HF therapy. The three specific aims include the following: First, we will validate mathematical (finite element) models of failing left ventricles that have been treated with Algisyl-LVR + coronary artery bypass grafting or Algisyl-LVR alone. The finite element models will have realistic 3D geometries based on magnetic resonance imaging and validated with in-vivo myocardial strain versus left and right ventricular pressure measurements. Additionally, ex-vivo 3D myofiber orientation and direct force measurements in skinned fiber preparations will be made. Second, we will use the validated finite element models and our method for automatically optimizing medical devices for treating HF to design the optimal Algisyl-LVR injection pattern and test it in swine with systolic HF. Lastly, we will deliver Algisyl-LVR percutaneously, using the optimal injection pattern determined in Aim 2, and test it in swine with systolic HF. The proposed approach and methodologies are innovative in simulation of animal-specific device therapy that holds very significant promise for treatment of the epidemic of HF.
Multi-Scale Laws of Myocardial Growth and Remodeling (U01 HL119578)
Heart failure (HF) is a worldwide epidemic that contributes considerably to the overall cost of health care in developed nations. The number of people afflicted with this complex disease is increasing at an alarming pace—a trend that is likely to continue for many years to come. The overall goals of our proposed research are to identify the mechanical culprits that dictate the bifurcation of the system from the stable healthy state into the instable state of HF and to determine the borderline between physiological/compensatory and pathophysiological/non-compensatory growth and remodeling (G&R). To address these goals, our research approach is to experimentally inform and validate multiscale laws of myocardial growth and remodeling (G&R) using three different clinically relevant large animal HF preparations in order to predict the propensity of patients with a myocardial infarction (MI) developing HF. Our specific Aim 1 is to elucidate a predictive validated multiscale law of myocardial G&R in eccentric hypertrophy associated with cardiac dilation. We hypothesize that a fiber-strain-based growth law can predict cardiac G&R in response to volume-overload, i.e., elevated myofiber strains stimulate concentric growth. Competing hypotheses based on stress-, strain rate-, and strain energy will be tested. Aim 2 is to validate a predictive multi-scale law of myocardial G&R in concentric hypertrophy associated with wall thickening. We hypothesize that a unified cross-fiber strain based growth law can predict cardiac G&R in response to pressure-overload. Similar competing hypotheses as in Aim 1 will be tested. In Aim 3, we will apply these G&R laws to predict the propensity for HF in ischemic heart disease based on specific mechanical indices of myocardial function. We hypothesize that there exists a threshold of a maximal rate of change of strain in reference to sarcomere length, above which compensatory G&R is not possible and the physiological negative feedback loop to maintain homeostasis gives way to a positive feedback loop that leads to progress remodeling and ultimate demise of the myocardium. Successful completion of this work will provide a fundamental understanding of the response of myocardium to mechanical stimuli that has substantial clinical relevance. Scientifically, this approach will provide the first ever validated and calibrated predictive micro-structural model of myocardial growth and remodeling that is fundamental to cardiology, tissue engineering, cardiac rehabilitation, and cardiac surgery. Clinically, we will provide a specific mechanical index to predict the propensity of HF in ischemic heart disease that may have a significant healthcare implication.
Coronary Blood Flow: Integrated Theory and Experiments (U01 HL118738)
Blood flow and rate of oxygen consumption are closely matched in vivo under normal conditions. Coronary flow is regulated through the combined action of metabolic, adrenergic, and mechanical (myogenic and shear) mechanisms. Since vascular mechanical processes are linked to the mechanics of cardiac contraction, understanding flow regulation requires a model that accounts for mechanics from the microvessel to the whole-organ level. Accordingly, the overall objective of this grant is to develop a validated multi-scale model of coronary autoregulation that accounts for the various major determinants of coronary flow regulation. To accomplish this goal, we set the following three Specific Aims: Aim 1: To construct a multi-scale mechanistic model of coronary flow regulation integrating cell-level models of endothelial and smooth-muscle function, single-vessel mechanics of coronary resistance arteries, autonomic function, network-level myocardiumcoronary vessel interaction and conducted metabolic response; Aim 2: To validate the ability of the model of Aim 1 to predict physiological dynamics observed in the awake exercising pig; and Aim 3: To use the models from Aim 1, refined by data from Aim 2 to understand the multiscale effects of stenosis on pulsatile flow in coronary arteries. We will test the hypothesis that the multiple parallel control mechanisms fail when coronary arteries become stenotic because they act out of sync and interfere. The model predictions will be compared to data from three complimentary protocols: (1) dynamic measurements of flow, pressure, and diameter in coronary arteries ranging from 50 m to the large epicardial vessels; (2) steady-state measurements of venous (coronary sinus) pO2 versus left-ventricular oxygen consumption in different exercise states; and (3) measurement of the dynamic reactive hyperemic response flow following acute transient occlusion of the left anterior descending coronary artery. Protocols will be conducted with and without specific pharmacological interventions to inhibit receptors and channels represented in the cell-level models. The validated model will be used to investigate critical questions, including: What is the principle mechanism coupling coronary blood flow to metabolism in vivo? How is high resting oxygen extraction functionally linked to the ability of the system to effectively respond to increased demand in exercise?
Mechano-transduction is the major focus in our research activities. We are trying to understand its role in coronary vascular biology and pathology, especially myogenic response to chemicals and physics. We also focus on gastrointestinal mechano-transduction to understand its role in motility, gut hormone, and nutrient ingestion.
Vascular Tissue Self-assembly
Vascular tissue self-assembly provides a possible solution for cardiovascular diseases. We are working on the critical topics on vascular self-assembly such as non-thrombogenic surface, vascular cell migration and growth, regulation of proliferation, genotype-phenotype conversion, hemodynamic regulation, etc. Our target is to assemble a functional blood vessel segment in vascular system.
Stent Models of Patient-Specific Bifurcation
The goal is to develop a stenting model of patient-specific bifurcation vessel based on actual bifurcation geometry. Balloon angioplasty (with applications to sizing) will be incorporated into the simulations. Solid mechanics will be strengthened as we focused mainly on the fluids aspect previously. We evaluate the impact of various bifurcation stenting techniques on vessel mechanics. The effects of stenting techniques, i.e., Culottes and T stenting will be simulated. These will be compared with effects of dedicated stent which scaffold the carina region of bifurcation. The above study will provide guidance for optimal interventional strategy for specific types of bifurcations.
Microvascular Remodeling in Aortic Stiffening-induced Hypertension
Hypertension (HTN) is one of the most common cardiovascular diseases. An increase in vascular stiffness is a primary component of HTN with broad implications on health care. Numerous epidemiological studies have reported that arterial stiffening is an independent predictor of cardiovascular (CV) outcomes such as myocardial infarction, stroke, and kidney disease. Some longitudinal studies have reported that arterial stiffness predicts an increase in systolic BP (SBP) and incidence of HTN. These observations indicate a correlation between aortic stiffening and the development of HTN in humans, but causality has yet to be demonstrated. Specifically, the hypothesis that aortic stiffening plays an essential role in the development of HTN has not been validated. This proposal focuses on this vital issue to elucidate the hemodynamic, cellular, and molecular changes that underlie the role of aortic stiffening in the etiology of HTN in small animal models. Accordingly, the general objective of this proposal is to understand the cause and effect relation between increased aortic stiffness and microvascular function including hemodynamics (pulse pressure, flow reversal, and peripheral resistance), oxidative stress, actin microfilament depolymerization and endothelial function. The central hypothesis is that aortic stiffness is an important determinant of the development and progression of HTN as it alters the microvasculature and peripheral resistance. Specifically, we ascertain that an increase in aortic stiffness increases pulse pressure (PP) causing local flow reversal and a decrease in wall shear stress (WSS). This, in turn, increases oxidative stress (through actin de-polymerization and Endothelin-1, ET-1) and results in compromised endothelial function. The endothelial dysfunction increases the tone or vasoconstriction of peripheral vessels which increases the total peripheral resistance (a landmark of HTN). This implies a positive feedback mechanism whereby the interplay between aortic stiffness and BP leads to the amplification of HTN.
Alzheimer’s Disease (AD) Animal Model
Alzheimer’s Disease (AD) affects more than 4.5 million elders in America, characterized by deposits of amyloid β plaques, neurofibrillary tangles, neuronal loss and neurovascular degeneration. At the capillary level, blood–brain barrier (BBB) dysfunction leads to the failure of neurotoxic amyloidβ clearance and accumulation of toxic blood-derived molecules (that is, thrombin and fibrin), which promotes increased deposition of basement membrane proteins and perivascular amyloid. The deposited proteins and amyloid obstruct capillary blood flow, subsequently resulting in synaptic and neuronal dysfunction. At the small intracerebral arteries level, hypercontractile small arteries dysregulate cerebral blood flow, accompanied by diminished amyloidβ clearance by the vascular smooth muscle cells (VSMCs), cerebral amyloid angiopathy cause micro bleeds and the loss of neurons. MiRNA have emerged as a powerful diagnostic tool and potential therapeutic targets for vascular diseases. The research focuses on elucidating the contribution of miRNAs on the cerebrovascular injury of AD, leading to a novel therapeutic strategy for AD treatment.
Early detection of Alzheimer (AD)
Current clinical treatments for AD are confined to drugs that temporarily ameliorate memory loss and behavioral aberrations. Early detection of AD will enhance the management of these patients prior to manifestations of symptomatic AD. A critical first step in developing early interventions for AD depends on the clear diagnosis. However, early detection and diagnosis of AD is daunting due to cost reasons, the impracticality for routine screening tools, and significant diagnostic error rate. The objective of this research is to develop early non-invasive diagnosis of AD.