lumped-parameter-finite-element-modeling-heart-failure-with-preserved

Lumped-Parameter and Finite Element Modeling of Heart Failure with Preserved Ejection Fraction

Scientific efforts in the field of computational modeling of cardiovascular diseases have largely focused on heart failure with reduced ejection fraction ...

Massachusetts Institute of Technology

Harvard/Massachusetts Institute of Technology

A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinical translation. We developed a multifunctional, catheter-based technology with no implantable rigid components that functions by unfolding an adhesive-loaded elastic patch and deploying a double-balloon design to stabilize and apply pressure to the patch against the tissue defect site. The device uses a fiber-optic system and reflective metallic coating to uniformly disperse ultraviolet light for adhesive activation. Using this device, we demonstrate closure on the distal side of a defect in porcine abdominal wall, stomach, and heart tissue ex vivo. The catheter was further evaluated as a potential tool for tissue closure in vivo in rat heart and abdomen and as a perventricular tool for closure of a challenging cardiac septal defect in a large animal (porcine) model. Patches attached to the heart and abdominal wall with the device showed similar inflammatory response as sutures, with 100% small animal survival, indicating safety. In the large animal model, a ventricular septal defect in a beating heart was reduced to <1.6 mm. This new therapeutic platform has utility in a range of clinical scenarios that warrant minimally invasive and atraumatic repair of hard-to-reach defects. 

A light-reflecting balloon catheter for atraumatic tissue defect repair.

Soft robotic devices have significant potential for medical device applications that warrant safe synergistic interaction with humans. This article describes the optimization of an implantable soft robotic system for heart failure whereby soft actuators wrapped around the ventricles are programmed to contract and relax in synchrony with the beating heart. Elastic elements integrated into the soft actuators provide recoiling function so as to aid refilling during the diastolic phase of the cardiac cycle. Improved synchronization with the biological system is achieved by incorporating the native ventricular pressure into the control system to trigger assistance and synchronize the device with the heart. A three-state electro-pneumatic valve configuration allows the actuators to contract at different rates to vary contraction patterns. An in vivo study was performed to test three hypotheses relating to mechanical coupling and temporal synchronization of the actuators and heart. First, that adhesion of the actuators to the ventricles improves cardiac output. Second, that there is a contraction-relaxation ratio of the actuators which generates optimal cardiac output. Third, that the rate of actuator contraction is a factor in cardiac output.

An Implantable Extracardiac Soft Robotic Device for the Failing Heart: Mechanical Coupling and Synchronization.

Efficient coupling of soft robotic cardiac assist devices to the external surface of the heart is crucial to augment cardiac function and represents a hurdle to translation of this technology. In this work, we compare various fixation strategies for local and global coupling of a direct cardiac compression sleeve to the heart. For basal fixation, we find that a sutured Velcro band adheres the strongest to the epicardium. Next, we demonstrate that a mesh-based sleeve coupled to the myocardium improves function in an acute porcine heart failure model. Then, we analyze the biological integration of global interface material candidates (medical mesh and silicone) in a healthy and infarcted murine model and show that a mesh interface yields superior mechanical coupling via pull-off force, histology, and microcomputed tomography. These results can inform the design of a therapeutic approach where a mesh-based soft robotic DCC is implanted, allowed to biologically integrate with the epicardium, and actuated for active assistance at a later timepoint. This strategy may result in more efficient coupling of extracardiac sleeves to heart tissue, and lead to increased augmentation of heart function in end-stage heart failure patients.

Towards Alternative Approaches for Coupling of a Soft Robotic Sleeve to the Heart.

The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development and application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. The pre-clinical use of the therapeutic epicardial reservoir as a research model may enable insights into regenerative cardiac therapy, and assist the development of experimental therapies towards clinical use.

Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir.

The mechanical reinforcement of the ventricular wall after a myocardial infarction has been shown to modulate and attenuate negative remodeling that can lead to heart failure. Strategies include wraps, meshes, cardiac patches, or fluid-filled bladders. Here, we review the literature describing these strategies in the two broad categories of global restraint and local reinforcement. We further subdivide the global restraint category into biventricular and univentricular support. We discuss efforts to optimize devices in each of these categories, particularly in the last five years. These include adding functionality, biomimicry, and adjustability. We also discuss computational models of these strategies, and how they can be used to predict the reduction of stresses in the heart muscle wall. We discuss the range of timing of intervention that has been reported. Finally, we give a perspective on how novel fabrication technologies, imaging techniques, and computational models could potentially enhance these therapeutic strategies.

Optimizing Epicardial Restraint and Reinforcement Following Myocardial Infarction: Moving Towards Localized, Biomimetic, and Multitherapeutic Options.

Delivery of therapeutic-laden biomaterials to the epicardial surface of the heart presents a promising method of treating a variety of diseased conditions by offering targeted, localized release with limited systemic recirculation and enhanced myocardial tissue uptake. A vast range of biomaterials and therapeutic agents using this approach been investigated. However, the fundamental factors that govern transport of the drug molecules from the biomaterials to the tissue are not well understood. Here, the transport of a drug analog from a biomaterial reservoir to the epicardial surface is characterized using experimental techniques and microscale modeling. Using the experimentally determined parameters, a multiscale model of transport is developed. The model is then used to study the effect of important design parameters such as loading conditions, biomaterial geometry, and orientation relative to the cardiac fibers on drug delivery to the myocardium. The simulations highlight the significance of the cardiac fiber anisotropy as a crucial factor in governing drug distribution on the epicardial surface and limiting factor for penetration into the myocardium. The multiscale model can be useful for rapid iteration of different device concepts and for determination of designs for epicardial drug delivery that may be optimal and most promising for the ultimate therapeutic goal.

Multiscale Experimental and Computational Modeling Approaches to Characterize Therapy Delivery to the Heart from an Implantable Epicardial Biomaterial Reservoir.

Two dry surfaces can instantly adhere upon contact with each other through intermolecular forces such as hydrogen bonds, electrostatic interactions and van der Waals interactions. However, such instant adhesion is challenging when wet surfaces such as body tissues are involved, because water separates the molecules of the two surfaces, preventing interactions. Although tissue adhesives have potential advantages over suturing or stapling, existing liquid or hydrogel tissue adhesives suffer from several limitations: weak bonding, low biological compatibility, poor mechanical match with tissues, and slow adhesion formation. Here we propose an alternative tissue adhesive in the form of a dry double-sided tape (DST) made from a combination of a biopolymer (gelatin or chitosan) and crosslinked poly(acrylic acid) grafted with N-hydrosuccinimide ester. The adhesion mechanism of this DST relies on the removal of interfacial water from the tissue surface, resulting in fast temporary crosslinking to the surface. Subsequent covalent crosslinking with amine groups on the tissue surface further improves the adhesion stability and strength of the DST. In vitro mouse, in vivo rat and ex vivo porcine models show that the DST can achieve strong adhesion between diverse wet dynamic tissues and engineering solids within five seconds. The DST may be useful as a tissue adhesive and sealant, and in adhering wearable and implantable devices to wet tissues.

Dry double-sided tape for adhesion of wet tissues and devices.

Regenerative medicine approaches, specifically stem cell technologies, have demonstrated significant potential to treat a diverse array of pathologies. However, such approaches have resulted in a modest clinical benefit, which may be attributed to poor cell retention/survival at the disease site. A delivery system that facilitates regional and repeated delivery to target tissues can provide enhanced clinical efficacy of cell therapies when localized delivery of high doses of cells is required. In this study, a new regenerative reservoir platform (Regenervoir) is described for use in large animal models, with relevance to cardiac, abdominal, and soft tissue pathologies. Regenervoir incorporates multiple novel design features essential for clinical translation, with a focus on scalability, mechanism of delivery, fixation to target tissue, and filling/refilling with a therapeutic cargo, and is demonstrated in an array of clinical applications that are easily translated to human studies. Regenervoir consists of a porous reservoir fabricated from a single material, a flexible thermoplastic polymer, capable of delivering cargo via fill lines to target tissues. A radiopaque shear thinning hydrogel can be delivered to the therapy reservoir and multiple fixation methods (laparoscopic tacks and cyanoacrylate bioadhesive) can be used to secure Regenervoir to target tissues through a minimally invasive approach.

Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models.

Minimally Invasive Delivery of Tissue Engineered Heart Valves to the Pulmonary Annulus.

Reliable functions of bioelectronic devices require conformal, stable and conductive interfaces with biological tissues. Integrating bioelectronic devices with tissues usually relies on physical attachment or surgical suturing; however, these methods face challenges such as non-conformal contact, unstable fixation, tissue damage, and/or scar formation. Here, we report an electrical bioadhesive (e-bioadhesive) interface, based on a thin layer of a graphene nanocomposite, that can provide rapid (adhesion formation within 5 s), robust (interfacial toughness >400 J m) and on-demand detachable integration of bioelectronic devices on diverse wet dynamic tissues. The electrical conductivity (>2.6 S m) of the e-bioadhesive interface further allows bidirectional bioelectronic communications. We demonstrate biocompatibility, applicability, mechanical and electrical stability, and recording and stimulation functionalities of the e-bioadhesive interface based on ex vivo porcine and in vivo rat models. These findings offer a promising strategy to improve tissue-device integration and enhance the performance of biointegrated electronic devices.

Electrical bioadhesive interface for bioelectronics.

The complex motion of the beating heart is accomplished by the spatial arrangement of contracting cardiomyocytes with varying orientation across the transmural layers, which is difficult to imitate in organic or synthetic models. High-fidelity testing of intracardiac devices requires anthropomorphic, dynamic cardiac models that represent this complex motion while maintaining the intricate anatomical structures inside the heart. In this work, we introduce a biorobotic hybrid heart that preserves organic intracardiac structures and mimics cardiac motion by replicating the cardiac myofiber architecture of the left ventricle. The heart model is composed of organic endocardial tissue from a preserved explanted heart with intact intracardiac structures and an active synthetic myocardium that drives the motion of the heart. Inspired by the helical ventricular myocardial band theory, we used diffusion tensor magnetic resonance imaging and tractography of an unraveled organic myocardial band to guide the design of individual soft robotic actuators in a synthetic myocardial band. The active soft tissue mimic was adhered to the organic endocardial tissue in a helical fashion using a custom-designed adhesive to form a flexible, conformable, and watertight organosynthetic interface. The resulting biorobotic hybrid heart simulates the contractile motion of the native heart, compared with in vivo and in silico heart models. In summary, we demonstrate a unique approach fabricating a biomimetic heart model with faithful representation of cardiac motion and endocardial tissue anatomy. These innovations represent important advances toward the unmet need for a high-fidelity in vitro cardiac simulator for preclinical testing of intracardiac devices.

An organosynthetic dynamic heart model with enhanced biomimicry guided by cardiac diffusion tensor imaging.

Catheters gain arrays of sensors and actuators.

The performance of indwelling medical devices that depend on an interface with soft tissue is plagued by complex, unpredictable foreign body responses. Such devices-including breast implants, biosensors, and drug delivery devices-are often subject to a collection of biological host responses, including fibrosis, which can impair device functionality. This work describes a milliscale dynamic soft reservoir (DSR) that actively modulates the biomechanics of the biotic-abiotic interface by altering strain, fluid flow, and cellular activity in the peri-implant tissue. We performed cyclical actuation of the DSR in a preclinical rodent model. Evaluation of the resulting host response showed a significant reduction in fibrous capsule thickness ( = 0.0005) in the actuated DSR compared with non-actuated controls, whereas the collagen density and orientation were not changed. We also show a significant reduction in myofibroblasts ( = 0.0036) in the actuated group and propose that actuation-mediated strain reduces differentiation and proliferation of myofibroblasts and therefore extracellular matrix production. Computational models quantified the effect of actuation on the reservoir and surrounding fluid. By adding a porous membrane and a therapy reservoir to the DSR, we demonstrate that, with actuation, we could (i) increase transport of a therapy analog and (ii) enhance pharmacokinetics and time to functional effect of an inotropic agent. The dynamic reservoirs presented here may act as a versatile tool to further understand, and ultimately to ameliorate, the host response to implantable biomaterials.

Article	Year
A light-reflecting balloon catheter for atraumatic tissue defect repair. Science translational medicine\| PubMed ID: 26400910	2015
An Implantable Extracardiac Soft Robotic Device for the Failing Heart: Mechanical Coupling and Synchronization. Soft robotics\| PubMed ID: 29182083	2017
Towards Alternative Approaches for Coupling of a Soft Robotic Sleeve to the Heart. Annals of biomedical engineering\| PubMed ID: 29766347	2018
Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir. Nature biomedical engineering\| PubMed ID: 31011199	2018
Optimizing Epicardial Restraint and Reinforcement Following Myocardial Infarction: Moving Towards Localized, Biomimetic, and Multitherapeutic Options. Biomimetics (Basel, Switzerland)\| PubMed ID: 31105193	2019
Multiscale Experimental and Computational Modeling Approaches to Characterize Therapy Delivery to the Heart from an Implantable Epicardial Biomaterial Reservoir. Advanced healthcare materials\| PubMed ID: 31322319	2019
Dry double-sided tape for adhesion of wet tissues and devices. Nature\| PubMed ID: 31666696	2019
Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models. Advanced healthcare materials\| PubMed ID: 32339411	2020
Minimally Invasive Delivery of Tissue Engineered Heart Valves to the Pulmonary Annulus. JACC. Basic to translational science\| PubMed ID: 32876644	2020
Electrical bioadhesive interface for bioelectronics. Nature materials\| PubMed ID: 32989277	2021
An organosynthetic dynamic heart model with enhanced biomimicry guided by cardiac diffusion tensor imaging. Science robotics\| PubMed ID: 33022595	2020
Catheters gain arrays of sensors and actuators. Nature biomedical engineering\| PubMed ID: 33093667	2020
An actuatable soft reservoir modulates host foreign body response. Science robotics\| PubMed ID: 33137787	2019

Ellen T. Roche

Biography

JoVE Journal Publications

Other Publications