Tunable Blood Shunt for Neonates With Complex Congenital Heart Defects

Despite advancements in procedures and patient care, mortality rates for neonatal recipients of the Norwood procedure, a palliation for single ventricle congenital malformations, remain high due to the use of a fixed-diameter blood shunt. In this study, a new geometrically tunable blood shunt was investigated to address limitations of the current treatment paradigm (e.g., Modified Blalock-Taussig Shunt) by allowing for controlled modulation of blood flow through the shunt to accommodate physiological changes due to the patient’s growth. First, mathematical and computational cardiovascular models were established to investigate the hemodynamic requirements of growing neonatal patients with shunts and to inform design criteria for shunt diameter changes. Then, two stages of prototyping were performed to design, build and test responsive hydrogel systems that facilitate tuning of the shunt diameter by adjusting the hydrogel’s degree of crosslinking. We examined two mechanisms to drive crosslinking: infusion of chemical crosslinking agents and near-UV photoinitiation. The growth model showed that 15–18% increases in shunt diameter were required to accommodate growing patients’ increasing blood flow; similarly, the computational models demonstrated that blood flow magnitudes were in agreement with previous reports. These target levels of diameter increases were achieved experimentally with model hydrogel systems. We also verified that the photocrosslinkable hydrogel, composed of methacrylated dextran, was contact-nonhemolytic. These results demonstrate proof-of-concept feasibility and reflect the first steps in the development of this novel blood shunt. A tunable shunt design offers a new methodology to rebalance blood flow in this vulnerable patient population during growth and development

IN VITRO MULTI-SCALE PATIENT-SPECIFIC MODELING OF HEMODYNAMICS IN STAGE 1 NORWOOD PALLIATION FOR THE TREATMENT OF SINGLE VENTRICLE HEART DISEASE

Hypoplastic left heart syndrome (HLHS) is a congenital heart defect in which the left ventricle is severely underdeveloped. The Norwood procedure is the first stage procedure to make an unrestrictive systemic blood flow and at the same time balance it with the pulmonary flow. This is done by constructing a neo-aorta using the pulmonary artery root and the autologous aorta, and then installing a shunt to the pulmonary artery. Variations of the Norwood surgery include the modified Blalock-Taussig (mBT) shunt, which diverts blood from the innominate artery to the pulmonary artery (PA), and the Right Ventricle Shunt (RVS), which diverts blood from the right ventricle to the PA. Recurrent neo-aortic coarctation (NAO) is a frequent complication of the Norwood procedure. It causes changes in circulation flow rate balances and hypertension in the aortic arch. Conventionally, the value of a coarctation index (CoI) is used in choosing interventions to treat NAO. Aortic arch morphology of Norwood patients is suspected to be a factor of hemodynamic response to NAO. This study aims to develop and validate an in vitro model of the Norwood circulation and to use it to better understand the hemodynamic impact of progressive coarctation severity in the Norwood patients with mBT and RVS shunts. Five patient-specific cases were selected, each case having a different aortic morphology. A multi-scale mock circulatory system (MCS) was developed to simulate patient-specific Norwood circulation. The MCS couples a lumped parameter network (LPN) model of the circulation with the 3D test section of the aorta and superior arteries. The system includes branches for the pulmonary, upper body, lower body and single ventricle. The MCS was set to patient specific conditions based on the clinical measurements. Flow rate and pressure measurements were made around the circulation model. The native arch anatomy of each patient was morphed to simulate coarctation by controlling the amount of narrowing of the aortic isthmus, while keeping the original patient-specific aortic geometry intact. Separate NAO models were created to provide for a range of CoI. Aortic pressure measurements were made to study pressure drop and recovery effects. In a further study, the MCS was modified to simulate the Norwood circulation with RVS. The NAO models were used to study coarctation effects. The MCS was validated against clinical measurements. The experimental measurements demonstrated that the time-based flow rate and pressure developed within the circulation recapitulated clinical measurements (0.72 \u3c R2 \u3c 0.95). The results showed good fidelity in replicating the mean values of the Norwood circulation at the patient-specific level (p \u3e 0.10). The system demonstrated the coarctation effects in the Norwood circulation with mBT. For all patient cases, the single ventricle power (SVP), mean pressure difference, and Qp/Qs increased noticeably when CoI \u3c 0.5 (p\u3c0.05). An increased SVP correlated with abnormal aortic arch morphology (dilated or tubular). Measurements from two of four cases studied showed that substituting the mBT with the RVS can relieve pulmonary overcirculation and improve the pulmonary to systemic flow balance (Qp/Qs). Using the RVS reduced SVP requirements by 74.5 mW on average. A tubular arch morphology was associated with a higher SVP with the RVS than those patients with a dilated arch. The study has shown that the hypothesis, “NAO may not need immediate surgical intervention at an early stage for some patients†was accepted. Aortic arch morphology does affect the hemodynamic response to NAO. Any morphological abnormality causes extra SVP. The RVS can relieve overcirculation and is associated with lower SVP level and SVP changes in some of the patients

Novel Applications of Cardiovascular Magnetic Resonance Imaging-Based Computational Fluid Dynamics Modeling in Pediatric Cardiovascular and Congenital Heart Disease

Cardiovascular diseases (CVDs) afflict many people across the world; thus, understanding the pathophysiology of CVD and the biomechanical forces which influence CVD progression is important in the development of optimal strategies to care for these patients. Over the last two decades, cardiac magnetic resonance (CMR) imaging has offered increasingly important insights into CVD. Computational fluid dynamics (CFD) modeling, a method of simulating the characteristics of flowing fluids, can be applied to the study of CVD through the collaboration of engineers and clinicians. This chapter aims to explore the current state of the CMR-derived CFD, as this technique pertains to both acquired CVD (i.e., atherosclerosis) and congenital heart disease (CHD)

In-Vitro and In-Silico Investigations of Alternative Surgical Techniques for Single Ventricular Disease

Single ventricle (SV) anomalies account for one-fourth of all cases of congenital Heart disease. The conventional second and third stage i.e. Comprehensive stage II and Fontan procedure of the existing three-staged surgical approach serving as a palliative treatment for this anomaly, entails multiple complications and achieves a survival rate of 50%. Hence, to reduce the morbidity and mortality rate associated with the second and third stages of the existing palliative procedure, the novel alternative techniques called “Hybrid Comprehensive Stage II” (HCSII), and a “Self-powered Fontan circulation” have been proposed. The goal of this research is to conduct in-vitro investigations to validate computational and clinical findings on these proposed novel surgical techniques. The research involves the development of a benchtop study of HCSII and self-powered Fontan circulation

Diagnostic and Therapeutic MEMS (Micro-Electro-Mechanical Systems) Devices for the Identification and Treatment of Human Disease

abstract: Early detection and treatment of disease is paramount for improving human health and wellness. Micro-scale devices promote new opportunities for the rapid, cost-effective, and accurate identification of altered biological states indicative of disease early-onset; these devices function at a scale more sensitive to numerous biological processes. The application of Micro-Electro-Mechanical Systems (MEMS) in biomedical settings has recently emerged and flourished over course of the last two decades, requiring a deep understanding of material biocompatibility, biosensing sensitively/selectively, biological constraints for artificial tissue/organ replacement, and the regulations in place to ensure device safety. Capitalizing on the inherent physical differences between cancerous and healthy cells, our ultra-thin silicone membrane enables earlier identification of bladder cancer—with a 70% recurrence rate. Building on this breakthrough, we have devised an array to multiplex this sample-analysis in real-time as well as expanding beyond bladder cancer. The introduction of new materials—with novel properties—to augment current and create innovative medical implants requires the careful analysis of material impact on cellular toxicity, mutagenicity, reactivity, and stability. Finally, the achievement of replacing defective biological systems with implanted artificial equivalents that must function within the same biological constraints, have consistent reliability, and ultimately show the promise of improving human health as demonstrated by our hydrogel check valve. The ongoing proliferation, expanding prevalence, and persistent improvement in MEMS devices through greater sensitivity, specificity, and integration with biological processes will undoubtedly bolster medical science with novel MEMS-based diagnostics and therapeutics.Dissertation/ThesisDoctoral Dissertation Electrical Engineering 201

Patient-specific design of the right ventricle to pulmonary artery conduit via computational analysis

Cardiovascular prostheses are routinely used in surgical procedures to address congenital malformations, for example establishing a pathway from the right ventricle to the pulmonary arteries (RV-PA) in pulmonary atresia and truncus arteriosus. Currently available options are fixed size and have limited durability. Hence, multiple re-operations are required to match the patients’ growth and address structural deterioration of the conduit. Moreover, the pre-set shape of these implants increases the complexity of operation to accommodate patient specific anatomy. The goal of the research group is to address these limitations by 3D printing geometrically customised implants with growth capacity. In this study, patient-specific geometrical models of the heart were constructed by segmenting MRI data of patients using Mimics inPrint 2.0. Computational Fluid Dynamics (CFD) analysis was performed, using ANSYS CFX, to design customised geometries with better haemodynamic performance. CFD simulations showed that customisation of a replacement RV-PA conduit can improve its performance. For instance, mechanical energy dissipation and wall shear stress can be significantly reduced. Finite Element modelling also allowed prediction of the suitable thickness of a synthetic material to replicate the behaviour of pulmonary artery wall under arterial pressures. Hence, eliminating costly and time-consuming experiments based on trial-and-error. In conclusion, it is shown that patient-specific design is feasible, and these designs are likely to improve the flow dynamics of the RV-PA connection. Modelling also provides information for optimisation of biomaterial. In time, 3D printing a customised implant may simplify replacement procedures and potentially reduce the number of operations required over a life time, bringing substantial improvements in quality of life to the patient

Application of engineering methodologies to address patient-specific clinical questions in congenital heart disease

The recent advances in medical imaging and in computer technologies have improved the prediction capabilities of biomechanical models. In order to replicate physiological, pathological or surgically corrected portions of the cardiovascular system, several engineering methodologies and their combinations can be adopted. Specifically, in this thesis, 3D reconstructions of patient-specific implanted devices and cardiovascular anatomies have been realised using both volumetric and biplanar visualisation methods, such as CT, MR, 4D-MR Flow and fluoroscopy. Finite Element techniques have been used to computationally deploy cardiovascular endoprosthesis, such as stents and percutaneous pulmonary valve devices, under patient-specific boundary conditions. To analyse pressure and velocity fields occurring in patient-specific vessel anatomies under patient-specific conditions, Lumped Parameter Networks and Computational Fluid Dynamics simulations have been employed. The above mentioned engineering tools have been here applied to address three clinical topics: 1 - Percutaneous pulmonary valve implantation (PPVI) Nowadays, more than 5,000 patients with pulmonary valve dysfunctions have been treated successfully with a percutaneous device, consisting in a bovine jugular venous valve sewn inside a balloon expandable stent. However, 25% of the treated patients experienced stent fracture. Using a novel methodological patient-specific approach that combines 3D reconstructions of the implanted stent from patients’ biplane fluoroscopy images and FE analyses, I carried out a risk stratification for stent fracture prediction. 2 - Transposition of the Great Arteries (TGA) Patients born with the congenital heart defect TGA need a surgical correction, which however, is associated with long term complications: the enlargement of the aortic root, and the development of a unilateral pulmonary stenosis. These may originate a complex hemodynamics that I tried to investigate by using patient-specific LPN and CFD models. 3 - Aortic Coarctation (CoA) Finally, combinations of FE and CFD-LPN models have been used to plan treatment in a patient with CoA and aberrant right subclavian

4D FLOW CMR in congenital heart disease

This thesis showed that the use of a cloud-based reconstruction applicationwith advanced eddy currents correction, integrated with interactiveimaging evaluation tools allowed for remote visualization and interpretationof 4D flow data and that was sufficient for gross visualizationof aortic valve regurgitation. Further, this thesis demonstrated that bulkflow and pulmonary regurgitation can be accurately quantified using 4Dflow imaging analyzed. Peak systolic velocity over the pulmonary valvemay be underestimated. However, the measurement of peak systolicvelocity can be optimized if measured at the level of highest velocity inthe pulmonary artery. Also correlated against invasive measurements (inan animal model), this thesis shows that aorta flow and pulmonary flowcan be accurately and simultaneously measured by 4D flow MRI.When applied in clinical practice, 4D flow has extra advantages, of beingable to visualize flow pattern, vorticity and to predict aortic growth. InASD patients it can measure shunt volume directly following the septumframe by frame. In Fontan patients in can visualize better than standardMRI the Fontan circuit and it can measure flow at multiple points alongthe Fontan circuit. We observed in our Fontan population that shunt lesionswere very common, most of the time via veno-venous collaterals.Further using advanced computations, we showed that WSS angle wasthe only independent predictor of aortic growth in BAV patients. We alsoshowed the feasibility of GLS analysis on 4D flow MRI and presented anintegrative approach in which flow and functional data are acquired inone sequence.From the technical point of view, 4D flow MRI has proved to complementthe traditional components of the standard cardiac MR exams, enablingin-depth insights into hemodynamics. At this moment it proved its addedvalue, but in most of the cases it is not able yet to replace the standardexam. This is still due to long scanning times and relatively longpost-processing times.<br/

4D FLOW CMR in congenital heart disease

This thesis showed that the use of a cloud-based reconstruction applicationwith advanced eddy currents correction, integrated with interactiveimaging evaluation tools allowed for remote visualization and interpretationof 4D flow data and that was sufficient for gross visualizationof aortic valve regurgitation. Further, this thesis demonstrated that bulkflow and pulmonary regurgitation can be accurately quantified using 4Dflow imaging analyzed. Peak systolic velocity over the pulmonary valvemay be underestimated. However, the measurement of peak systolicvelocity can be optimized if measured at the level of highest velocity inthe pulmonary artery. Also correlated against invasive measurements (inan animal model), this thesis shows that aorta flow and pulmonary flowcan be accurately and simultaneously measured by 4D flow MRI.When applied in clinical practice, 4D flow has extra advantages, of beingable to visualize flow pattern, vorticity and to predict aortic growth. InASD patients it can measure shunt volume directly following the septumframe by frame. In Fontan patients in can visualize better than standardMRI the Fontan circuit and it can measure flow at multiple points alongthe Fontan circuit. We observed in our Fontan population that shunt lesionswere very common, most of the time via veno-venous collaterals.Further using advanced computations, we showed that WSS angle wasthe only independent predictor of aortic growth in BAV patients. We alsoshowed the feasibility of GLS analysis on 4D flow MRI and presented anintegrative approach in which flow and functional data are acquired inone sequence.From the technical point of view, 4D flow MRI has proved to complementthe traditional components of the standard cardiac MR exams, enablingin-depth insights into hemodynamics. At this moment it proved its addedvalue, but in most of the cases it is not able yet to replace the standardexam. This is still due to long scanning times and relatively longpost-processing times.<br/