Phillip M. Trusty

Long-term toughness of photopolymerizable (meth)acrylate networks in aqueous environments

Photopolymerizable (meth)acrylate networks are potentially advantageous biomaterials due to their ability to be formed in situ, their fast synthesis rates and their tailorable material properties. The objective of this study was to evaluate how immersion time in phosphate-buffered saline (PBS) affects the toughness of photopolymerizable methyl acrylate (MA)-co-methyl methacrylate-co-poly(ethylene glycol) dimethacrylate networks containing various concentrations of MA. Stress-strain behavior was determined by performing tensile strain to failure testing after soaking in PBS for different periods (1 day up to 9 months). In tandem, differential scanning calorimetry and PBS content measurements were undertaken at each time point in order to determine whether time-dependent changes in toughness were related to changes in T(g) or PBS absorption. The effect of immersion time on network toughness was shown to be dependent upon composition in a manner related to the viscoelastic state of the polymer upon initial immersion in PBS. The results demonstrate that tough acrylate-based materials may not maintain their toughness after several months in PBS. In addition, decreasing the PBS content by changing the network hydrophobicity resulted in better toughness maintenance after 9 months. The results provide a possible means to toughen various amorphous acrylate-based implant materials that are being explored for load-bearing biomedical applications, beyond the systems considered in this work.

Can time-averaged flow boundary conditions be used to meet the clinical timeline for Fontan surgical planning?

Cardiovascular simulations have great potential as a clinical tool for planning and evaluating patient-specific treatment strategies for those suffering from congenital heart diseases, specifically Fontan patients. However, several bottlenecks have delayed wider deployment of the simulations for clinical use; the main obstacle is simulation cost. Currently, time-averaged clinical flow measurements are utilized as numerical boundary conditions (BCs) in order to reduce the computational power and time needed to offer surgical planning within a clinical time frame. Nevertheless, pulsatile blood flow is observed in vivo, and its significant impact on numerical simulations has been demonstrated. Therefore, it is imperative to carry out a comprehensive study analyzing the sensitivity of using time-averaged BCs. In this study, sensitivity is evaluated based on the discrepancies between hemodynamic metrics calculated using time-averaged and pulsatile BCs; smaller discrepancies indicate less sensitivity. The current study incorporates a comparison between 3D patient-specific CFD simulations using both the time-averaged and pulsatile BCs for 101 Fontan patients. The sensitivity analysis involves two clinically important hemodynamic metrics: hepatic flow distribution (HFD) and indexed power loss (iPL). Paired demographic group comparisons revealed that HFD sensitivity is significantly different between single and bilateral superior vena cava cohorts but no other demographic discrepancies were observed for HFD or iPL. Multivariate regression analyses show that the best predictors for sensitivity involve flow pulsatilities, time-averaged flow rates, and geometric characteristics of the Fontan connection. These predictors provide patient-specific guidelines to determine the effectiveness of analyzing patient-specific surgical options with time-averaged BCs within a clinical time frame.

Fontan Surgical Planning: Previous Accomplishments, Current Challenges, and Future Directions

The ultimate goal of Fontan surgical planning is to provide additional insights into the clinical decision-making process. In its current state, surgical planning offers an accurate hemodynamic assessment of the pre-operative condition, provides anatomical constraints for potential surgical options, and produces decent post-operative predictions if boundary conditions are similar enough between the pre-operative and post-operative states. Moving forward, validation with post-operative data is a necessary step in order to assess the accuracy of surgical planning and determine which methodological improvements are needed. Future efforts to automate the surgical planning process will reduce the individual expertise needed and encourage use in the clinic by clinicians. As post-operative physiologic predictions improve, Fontan surgical planning will become an more effective tool to accurately model patient-specific hemodynamics.

In Vitro Examination of the HeartWare CircuLite Ventricular Assist Device in the Fontan Connection.

The failing Fontan physiology may benefit from ventricular assist device (VAD) mechanical circulatory support, although a subpulmonary VAD placed at the Fontan connection has never successfully supported the Fontan circulation long term. The HeartWare CircuLite continuous flow VAD was examined for Fontan circulatory support in an in vitro mock circulation. The VAD was tested in three different scenarios: VAD in parallel, baffle restricted VAD in parallel, and VAD in series. Successful support was defined as simultaneous decrease in inferior vena cava (IVC) pressure of 5 mm Hg or more and an increase in cardiac output (CO) to 4.25 L/min or greater. The VAD in parallel scenario resulted in a CO decrease to 3.46 L/min and 2.22 mm Hg decrease in IVC pressure. The baffle restricted VAD in parallel scenario resulted in a CO increase to 3.9 L/min increase in CO and 20.5 mm Hg decrease in IVC pressure (at 90% restriction). The VAD in series scenario resulted in a CO of 1.75 L/min and 5.9 mm Hg decrease in IVC pressure. We successfully modeled chronic failing Fontan physiology using patient-specific hemodynamic and anatomic data. Although unsuccessful in supporting Fontan patients as defined here, the HeartWare CircuLite VAD demonstrates the possibility to reduce Fontan pressure and increase CO with a VAD in the Fontan connection. This study provides insight into pump performance and design issues when attempting to support Fontan circulation. Refinements in VAD design with specific parameters to help support this patient population is the subject of our future work.

Impact of hemodynamics and fluid energetics on liver fibrosis after Fontan operation

Objective: The staged Fontan procedure has shown promising short‐term outcomes in patients with single ventricles. However, Fontan‐associated liver disease is a marked problem as patients age. The purpose of this study is to investigate the relationship between hemodynamics and liver fibrosis in patients undergoing the Fontan. Methods: A total of 33 patients undergoing the Fontan with liver fibrosis were included in this study. Cardiac magnetic resonance and phase‐contrast cardiac magnetic resonance data, as well as catheterization measurements and liver biopsies, were obtained for each patient. Computational fluid dynamic simulations were performed to quantify total cavopulmonary connection hemodynamics using patient‐specific anatomies and blood flow waveforms reconstructed from cardiac magnetic resonance data. Collagen deposition (as a measure of liver fibrosis) was quantified by digital image analysis of Sirius Red stained slides. Statistical analyses were performed to investigate potential relationships between liver fibrosis and Fontan hemodynamics. Results: Liver fibrosis was found to be related to global metrics (inferior vena cava flow, ventricle power output) rather than to local total cavopulmonary connection hemodynamics and efficiency. Indexed inferior vena cava flow showed a significant, positive correlation with liver fibrosis (rho = 0.624, P < .001). Upper and lower Sirius Red tertile comparisons showed a significant difference in indexed inferior vena cava flow (P = .008). Conclusions: Significant increases in inferior vena cava flow consistent with fibrosis induced arterialization and ventricular power output suggest a burden being placed on the single ventricle from liver fibrosis. Local total cavopulmonary connection flow dynamics do not seem to influence the degree of fibrosis. Favorable total cavopulmonary connection hemodynamics may not be enough to overcome the power shortage and elevated venous pressures inherent to a Fontan circulation.

Using a Novel In Vitro Fontan Model and Condition-Specific Real-Time MRI Data to Examine Hemodynamic Effects of Respiration and Exercise

Several studies exist modeling the Fontan connection to understand its hemodynamic ties to patient outcomes (Chopski in: Experimental and Computational Assessment of Mechanical Circulatory Assistance of a Patient-Specific Fontan Vessel Configuration. Dissertation, 2013; Khiabani et al. in J Biomech 45:2376–2381, 2012; Taylor and Figueroa in Annu Rev Biomed 11:109–134, 2009; Vukicevic et al. in ASAIO J 59:253–260, 2013). The most patient-accurate of these studies include flexible, patient-specific total cavopulmonary connections. This study improves Fontan hemodynamic modeling by validating Fontan model flexibility against a patient-specific bulk compliance value, and employing real-time phase contrast magnetic resonance flow data. The improved model was employed to acquire velocity field information under breath-held, free-breathing, and exercise conditions to investigate the effect of these conditions on clinically important Fontan hemodynamic metrics including power loss and viscous dissipation rate. The velocity data, obtained by stereoscopic particle image velocimetry, was visualized for qualitative three-dimensional flow field comparisons between the conditions. Key hemodynamic metrics were calculated from the velocity data and used to quantitatively compare the flow conditions. The data shows a multi-factorial and extremely patient-specific nature to Fontan hemodynamics.

Exercise capacity in the Bidirectional Glenn physiology: Coupling cardiac index, ventricular function and oxygen extraction ratio

In Bi-directional Glenn (BDG) physiology, the superior systemic circulation and pulmonary circulation are in series. Consequently, only blood from the superior vena cava is oxygenated in the lungs. Oxygenated blood then travels to the ventricle where it is mixed with blood returning from the lower body. Therefore, incremental changes in oxygen extraction ratio (OER) could compromise exercise tolerance. In this study, the effect of exercise on the hemodynamic and ventricular performance of BDG physiology was investigated using clinical patient data as inputs for a lumped parameter model coupled with oxygenation equations. Changes in cardiac index, Qp/Qs, systemic pressure, oxygen extraction ratio and ventricular/vascular coupling ratio were calculated for three different exercise levels. The patient cohort (n=29) was sub-grouped by age and pulmonary vascular resistance (PVR) at rest. It was observed that the changes in exercise tolerance are significant in both comparisons, but most significant when sub-grouped by PVR at rest. Results showed that patients over 2 years old with high PVR are above or close to the upper tolerable limit of OER (0.32) at baseline. Patients with high PVR at rest had very poor exercise tolerance while patients with low PVR at rest could tolerate low exercise conditions. In general, ventricular function of SV patients is too poor to increase CI and fulfill exercise requirements. The presented mathematical model provides a framework to estimate the hemodynamic performance of BDG patients at different exercise levels according to patient specific data.

The Effect of Respiration-Driven Flow Waveforms on Hemodynamic Metrics Used in Fontan Surgical Planning

OBJECTIVE Poor total cavopulmonary connection (TCPC) hemodynamics have been hypothesized to be associated with long-term complications in Fontan patients. Image-based Fontan surgical planning has shown great potential as a clinical tool because it can pre-operatively evaluate patient-specific hemodynamics. Current surgical planning paradigms commonly utilize cardiac-gated phase contrast magnetic resonance (MR) imaging to acquire vessel flows. These acquisitions are often taken under breath-held (BH) conditions and ignore the effect of respiration on blood flow waveforms. This study investigates the effect of respiration-driven flow waveforms on patient-specific hemodynamics using real-time MR acquisitions. METHODS Patient-specific TCPCs were reconstructed from cardiovascular MR images. Real-time phase contrast MR images were acquired under both free-breathing (FB) and breath-held conditions for 9 patients. Numerical simulations were employed to assess flow structures and hemodynamics used in Fontan surgical planning including hepatic flow distribution (HFD) and indexed power loss (iPL), which were then compared between FB and BH conditions. RESULTS Differences in TCPC flow structures between FB and BH conditions were observed throughout the respiratory cycle. However, the average differences (BH - FB values for each patient, which are then averaged) in iPL and HFD between these conditions were 0.002 ± 0.011 (p = 0.40) and 1 ± 3% (p = 0.28), respectively, indicating no significant difference in clinically important hemodynamic metrics. CONCLUSIONS Respiration affects blood flow waveforms and flow structures, but might not significantly influence the values of iPL or HFD. Therefore, breath-held MR acquisition can be adequate for Fontan surgical planning when focusing on iPL and HFD.

Imaging insights from the bifurcated Y-graft Fontan procedure

Results From August, 2010 to July, 2015, 45 children (median age 3.6 years, range 1.5 18.9 years) have undergone a Y-graft Fontan. In all 45 patients, echocardiography was unable to visualize the Y-arm connections to the branch PA’s. Thirty-nine patients underwent CMR a median of 9 days after Fontan (range 4-295 days), and 6 patients with pacemakers underwent CTA. Early in the experience, time resolved contrast enhanced magnetic resonance angiogram (CEMRA) provided the best spatial resolution for baffle evaluation (Figure 1a). In late 2013, our CMR protocol changed to include a blood pool Gadolinium contrast agent, Gadofosveset Trisodium. Subsequently, postcontrast, 3D, respiratory navigated, inversion recovery gradient echo imaging (3D IR GRE) provided superior spatial resolution for the final 19 children (Figure 1b). In one patient, thrombosis in the baffle was found. In 40 patients, some degree of stenosis was found in a Fontan baffle or branch PA, though most were mild (n = 27). Among those with moderate or severe stenosis, most occurred in the central PA, between the insertion of the bidirectional Glenn (BDG) and a Y-arm (n = 7). Phase contrast imaging and the time resolved CEMRA provided insights into Fontan hemodynamics. In 14 patients, inferior systemic venous return was affected by the BDG position and angulation, with competitive flow in either the left or right Y-arm resulting in asymmetric inferior systemic venous return to the branch PA’s (Figure 2). This finding was more pronounced in patients with central PA stenosis.