Research

The Cardiovascular Therapeutics (CV-PEUTICS LAB), formerly known as the TEMIM LAB’s primary research focus lies in the area of cell and engineered tissue mechanics with application in cardiovascular regenerative medicine. The CV-PEUTICS Lab, conducts both experimental and computational investigations in this area. A major goal of the lab is to develop functional valves with regenerative capacities (FVRC) using 1) porcine small intestinal submucosa (PSIS) substrates and 2) mechanically regulate stem cells for the FVRC application as well as for (3) broader application in cardiovascular regenerative medicine. Concurrently the CV-PEUTICS lab is also working towards the elucidation of mechanobiological cellular and molecular mechanisms that are involved in the etiology of valve diseases, particularly aortic valve calcification. Two specific projects in this area involve: (4) the delineation of flow conditions of the aortic valve that may serve to elucidate mechanosensitive pathways in vascular and valvular cells that lead to calcific aortic valve disease (CAVD), that in turn can be utilized for the development of an engineered CAVD tissue model system for drug discovery.  (5) Computational biomechanical models that can help elucidate sub-clinical thrombosis (and stroke) risks in patient-specific geometries after undergoing a trans-aortic valve replacement (TAVR) procedure.

The research in the CV-PEUTICS Lab has been supported by the AHA, the Miami Heart Research Institute, NSF, industry and academic funding sources.

The primary research themes in the CV-PEUTICS Lab currently are:

  • Tissue Engineered Heart Valves (TEHVs)

    TEHVs are conceptually appealing because they have the ability to grow with the young patient, thereby serving as a single-procedure and a permanent solution. Porcine tissues derived from the small intestine have shown promise for cardiovascular regenerative applications. Especially compelling is that we found that these acellular porcine small intestinal submucosa (PSIS) bioscaffolds have worked flawlessly for over a year thus far in humans, in pediatric patients who underwent compassionate care surgery at our clinical partner site at Joe DiMaggio’s Children’s hospital, Hollywood, FL.  To leverage this simple yet elegant approach, and after performing groundbreaking in vitro studies in our lab, we subsequently assessed the potential of PSIS to grow new valves for permanently treating critical congenital aortic valve disease in children. Currently, at an unprecedented level, we are in the midst of conducting a pilot study in a non-human primate model (Baboons) to determine how well the valve is received by the host, following which we will assess the in vivo tissue remodeling events – the study is currently being funded by the Florida Heart Research Institute and previously, by the American Heart Association (AHA).

    Representative publications from the CV-PEUTICS lab:

    • Gonzalez BA, Gonzalez MP, Scholl F, Bibevski S, Ladich E, Bibevski J, Morales P, Lopez J, Casares M, Brehier V, Hernandez L, Ramaswamy S: De Novo Valve Tissue Morphology Following Bioscaffold Mitral Valve Replacement in a Juvenile Non-Human Primate Model, Bioengineering (Basel) 2021, 8(7)-100.
    • Gonzalez BA, Perez-Nevarez M, Mirza A, Perez MG, Lin Y-M, Hsu C-PD, Caobi A, Raymond AD, Hernandez MG, Fernandez-Lima F, George F, Ramaswamy S: Physiologically-Relevant Fluid-Induced Oscillatory Shear Stress Stimulation of Mesenchymal Stem Cells Enhances the Engineered Valve Matrix Phenotype. Front. Cardiovasc. Med., 2020, May 19;7:69. doi: 10.3389/fcvm.2020.00069.
    • Gonzalez BA, Pour Issa E, Mankame OV, Bustillos J, Cuellar A, Rodriguez AJ, Scholl F, Bibevski S, Hernandez L, Brehier V, Casares M, Rivas K, Morales P, Lopez J, Wagner J, Bibevski J, Agarwal A, George F, Ramaswamy S: Porcine small intestinal submucosa mitral valve material responses support acute somatic growth. Tissue Eng Part A. 2020 May;26(9-10):475-489.
    • Ramaswamy S, Lordeus M, Mankame OV, Valdes-Cruz L, Bibevski S, Bell SM, Baez I, Scholl F. Hydrodynamic Assessment of Aortic Valves Prepared from Porcine Small Intestinal Submucosa. Cardiovasc Eng Technol. 2017, March; 8(1): 30-40.

  • Bioreactor technologies in cardiovascular medicine

    Our laboratory is motivated to also more broadly advance cardiovascular regenerative medical research and development because they are critically needed, and could serve several areas, including the treatment of heart valve disease, cardiac defects and damaged blood vessels. Prior to animal studies, in vitro culture of cells and tissue under bio-mimetic mechanical environments will promote functional de novo cardiovascular tissue development and their widespread use. These devices, known as bioreactors can optimize engineered tissue properties. Our laboratory has already conducted several research studies utilizing a novel Flow-Stretch-Flex (FSF) bioreactor.  Our customer discovery efforts have previously been funded by an NSF Innovation Corps (I-Corps) grant.  One product enabled via the utilization of the FSF bioreactor are injectable enhanced stem cell exosomes (IESCE), which will potentially accelerate healing and remodeling responses of any cardiovascular structure (heart, blood vessels, heart valve) damaged from disease. A second application lies in the tissue-level, mechanobiological evaluation of promising stem cell therapies (e.g. induced pluripotent stem cells) under cardiovascular-relevant states of cyclic flexure, cyclic stretch, pulsatile flow or any combination of these conditions.

    Representative publications from the CV-PEUTICS lab:

    • Williams A, Nasim S, Salinas M, Moshkforoush A, Tsoukias N, Ramaswamy S: A “sweet-spot” for fluid-induced oscillations in the conditioning of stem cell-based engineered heart valve tissues. J Biomech. 2017 Dec 8;65:40-48.
    • Salinas M, Rath S, Villegas A, Unnikrishnan V, Ramaswamy S. Relative Effects of Fluid Oscillations and Nutrient Transport in the In Vitro Growth of Valvular Tissues. Cardiovasc Eng Technol. 2016 Jun;7(2):170-81.
    • Rath S, Salinas M, Villegas A, Ramaswamy S. Differentiation and Distribution of Marrow Stem Cells in Flex-Flow Environments Demonstrate Support of the Valvular Phenotype.  PLOS ONE, 2015 Nov 4;10(11).
    • Ramaswamy S, Boronyak SM, Le T, Holmes A, Sotiropoulos F, Sacks MS. A novel bioreactor for mechanobiological studies of engineered heart valve tissue formation under pulmonary arterial physiological flow conditions. J Biomech Eng. 2014 Dec;136(12):121009.

  • Cell mechanobiology in cardiovascular pathology and regenerative medicine

    The current research objective of this project is to specifically test the hypothesis that an altered fluid shear stress distribution acting on aortic valvular endothelial cells (VEC) induces aortic valve narrowing or restenosis.  The end-goal of this work is to identify the molecular basis for disease (aortic valve dysfunction) as well as to facilitate enhanced cardiovascular tissue remodeling after exposure to different pulsatile flow profiles, including but not limited to oscillatory flow patterns.  On the other hand, in the context of regenerative medicine, a primary objective is to uncover the specific shear stress-regulating subcellular processes (again such as an oscillatory shear stress profile) that lead to gene expression that promotes healthy cardiovascular tissue remodeling.  Overall the proposed fluid-induced mechanobiological studies will provide fundamental insights on VEC-relevant flow-stimuli, VEC paracrine regulation on valvular interstitial cells (VIC), as well as the effects of these flow profiles on stem cells.

    Representative publications from the CV-PEUTICS lab:

    • Hsu C-PD, Hutcheson JD, Ramaswamy S: Oscillatory fluid-induced mechanobiology in heart valves with parallels to the vasculature.  Vascular Biology. 2020 2(1), R59-R71.
    • Castellanos G, Nasim S, Medina DA, Rath S, Ramaswamy S: Stem Cell cytoskeletal responses to pulsatile flow in heart valve tissue engineering studies. Cardiovasc. Med. 5:58. doi: 10.3389/fcvm.2018.00058, 2018.
    • Salinas M, Ramaswamy S. Computational simulations predict a key role for oscillatory fluid shear stress in de novo valvular tissue formation. J Biomech 2014 Nov 7;47(14):3517-23.
    • Ramaswamy S, Schornack PA, Smelko AG, Boronyak SM, Ivanova J, Mayer JE, Sacks MS: SPIO Labeling Efficiency and Subsequent MRI Tracking of Native Cell Populations Pertinent to Heart Valve Tissue Engineering Studies. NMR in Biomedicine, Vol. 25, 410-417, 2012.

  • Computational flow studies on valve tissue biomechanics for interventional planning

    We are developing highly-accurate predictive models to quantify the flow biomechanics in calcified heart valves. The goals here are to identify the most beneficial therapeutic for treatment, such as patient-pairinjg with a specific transaortic valve replacement (TAVR) system, as well as to collaborate with groups with emerging treatments for valve disease, in order to accurartely predict the hemodynamic improvements post valve treatment compared to pre-treatmemt, using our computational models.

    Representative publications from the CV-PEUTICS lab:

    • Tesfamariam MD, Mirza AM, Chaparro D, Ali AZ, Montalvan R, Saytashev I, Gonzalez BA, Barreto A, Ramella-Roman J, Hutcheson JD, Ramaswamy S: Elastin-Dependent Aortic Heart Valve Leaflet Curvature Changes During Cyclic Flexure. Bioengineering (Basel). 2019 May 7;6(2). pii: E39. doi: 10.3390/bioengineering6020039, 2019.
    • Williams A, Ramaswamy S: A comparison of the oscillatory shear index on the aortic valve-fibrosa with and without the presence of calcified deposits.  ProClinS Cardiology. 2019, August, Vol. 2, No. 1: 1-8.

  • iPSC-cardiomyocytes responses under flow, stretch and/or flexure conditions

    iPSC-cardiomyocytes responses under flow, stretch and/or flexure conditions:  The CV-PEUTICS lab is pleased to partner with the NSF’s funded Engineering Research Center (ERC) in cellular metamaterials (CELL-MET). The lead institution is Boston University. The overall end-goal of this project is to advance nano-bio-manufacturing methods that could lead to large-scale fabrication of functional heart tissue which could replace diseased or damaged muscle after a heart attack.