A hyper-viscoelastic uniaxial characterization of collagenous embolus analogs in acute ischemic stroke.

PURPOSE: Acute ischemic stroke is a leading cause of death and morbidity worldwide. Despite advances in medical technology, nearly 30% of strokes result in incomplete vessel recanalization. Recent studies have demonstrated that clot composition correlates with success rates of mechanical thrombectomy procedures. To understand clot behavior during thrombectomy, which exerts considerable strains on thrombi, in vitro studies must characterize the rate-dependent high-strain behavior of embolus analogs (EAs) with different formation conditions, which can be used to fit models of hyper-viscoelasticity. METHODS: In this study, the effect of collagen infiltration as a carotid-induced collagen-rich thrombosis surrogate is considered as a contributor to embolus analog high-strain stiffness, when compared to 40% hematocrit EAs. RESULTS: EA high-strain stiffnesses, characterized on a uniaxial load frame, increase by an order of magnitude for collagenous clot analogs. Chandler loop analogs show high-strain stiffnesses and clot compositions commensurate with previous reports of stroke patient clots, and collagenous clots show significant increase in stiffness when compared to stroke patient clots. Finally, hyper-viscoelastic curve fitting demonstrates the asymmetry between tension and compression. Nonlinear, rate-dependent models that consider clot-stiffening behavior match the high strain stiffness of clots fairly well. Furthermore, we demonstrate that the stability of the elastic energy needs to be considered to obtain optimal curve fits for high-strain, rate dependent data. CONCLUSION: This study provides a framework for the development of dynamically formed EAs that mimic the mechanical and structural properties of in vivo clots and provides parameters for numerical simulation of clot behavior with hyper-viscoelastic models.

Characterizing thrombus adhesion strength on common cardiovascular device materials.

Thrombus formation in blood-contacting medical devices is a major concern in the medical device industry, limiting the clinical efficacy of these devices. Further, a locally formed clot within the device has the potential to detach from the surface, posing a risk of embolization. Clot embolization from blood-contacting cardiovascular devices can result in serious complications like acute ischemic stroke and myocardial infarction. Therefore, clot embolization associated with device-induced thrombosis can be life-threatening and requires an enhanced fundamental understanding of embolization characteristics to come up with advanced intervention strategies. Therefore, this work aims to investigate the adhesive characteristics of blood clots on common biocompatible materials used in various cardiovascular devices. This study focuses on characterizing the adhesion strength of blood clots on materials such as polytetrafluoroethylene (PTFE), polyurethane (PU), polyether ether ketone (PEEK), nitinol, and titanium, frequently used in medical devices. In addition, the effect of incubation time on clot adhesion is explored. Results from this work demonstrated strongest clot adhesion to titanium with 3 h of incubation resulting in 1.06 ± 0.20 kPa detachment stresses. The clot adhesion strength on titanium was 51.5% higher than PEEK, 35.9% higher than PTFE, 63.1% higher than PU, and 35.4% higher than nitinol. Further, adhesion strength increases with incubation time for all materials. The percentage increase in detachment stress over incubation time (ranging from 30 min to 3 h) for polymers ranged from at least 108.75% (PEEK), 140.74% (PU), to 151.61% (PTFE). Whereas, for metallic surfaces, the percentage rise ranged from 70.21% (nitinol) to 89.28% (titanium). Confocal fluorescence imaging of clot remnants on the material surfaces revealed a well-bounded platelet-fibrin network at the residual region, representing a comparatively higher adhesive region than the non-residual zone of the surface.

Current Approaches and Methods to Understand Acute Ischemic Stroke Treatment Using Aspiration Thrombectomy.

Acute ischemic stroke occurs when a blood clot occludes a cerebral artery. Mechanical interventions, primarily stent retrievers and aspiration thrombectomy, are used currently for removing the occluding clot and restoring blood flow. Aspiration involves using a long catheter to traverse the cerebral vasculature to reach the blood clot, followed by application of suction through the catheter bore. Aspiration is also used in conjunction with other techniques such as stent retrievers and balloon guide catheters. Despite the wide use of aspiration, our physical understanding of the process and the causes of the failure of aspiration to retrieve cerebral clots in certain scenarios is not well understood. Experimental and computational studies can help develop the capability to provide deeper insights into the procedure and enable development of new devices and more effective treatment methods. We recapitulate the aspiration-based thrombectomy techniques in clinical practice and provide a perspective of existing engineering methods for aspiration. We articulate the current knowledge gap in the understanding of aspiration and highlight possible directions for future engineering studies to bridge this gap, help clinical translation of engineering studies, and develop new patient-specific stroke therapy.

Fluid Dynamic Study of the Penn State Pediatric Total Artificial Heart.

Penn State University is developing a pediatric total artificial heart (TAH) as a bridge-to-transplant device that supports infants and small children with single ventricle anomalies or biventricular heart failure to address high waitlist mortality rates for pediatric patients with severe congenital heart disease (CHD). Two issues with mechanical circulatory support devices are thrombus formation and thromboembolic events. This in vitro study characterizes flow within Penn State's pediatric total artificial heart under physiological operating conditions. Particle image velocimetry (PIV) is used to quantify flow within the pump and to calculate wall shear rates (WSRs) along the internal pump surface to identify potential thrombogenic regions. Results show that the diastolic inflow jets produce sufficient wall shear rates to reduce thrombus deposition potential along the inlet side of the left and right pumps. The inlet jet transitions to rotational flow, which promotes wall washing along the apex of the pumps, prevents flow stasis, and aligns flow with the outlet valve prior to systolic ejection. However, inconsistent high wall shear rates near the pump apex cause increased thrombogenic potential. Strong systolic outflow jets produce high wall shear rates near the outlet valve to reduce thrombus deposition risk. The right pump, which has a modified outlet port angle to improve anatomical fit, produces lower wall shear rates and higher thrombus susceptibility potential (TSP) compared to the left pump. In summary, this study provides a fluid dynamic understanding of a new pediatric total artificial heart and indicates thrombus susceptibility is primarily confined to the apex, consistent with similar pulsatile heart pumps.

Influence of Hematocrit Level and Integrin αIIbßIII Function on vWF-Mediated Platelet Adhesion and Shear-Induced Platelet Aggregation in a Sudden Expansion.

Purpose: Shear-mediated thrombosis is a clinically relevant phenomenon that underlies excessive arterial thrombosis and device-induced thrombosis. Red blood cells are known to mechanically contribute to physiological hemostasis through margination of platelets and vWF, facilitating the unfurling of vWF multimers, and increasing the fraction of thrombus-contacting platelets. Shear also plays a role in this phenomenon, increasing both the degree of margination and the near-wall forces experienced by vWF and platelets leading to unfurling and activation. Despite this, the contribution of red blood cells in shear-induced platelet aggregation has not been fully investigated-specifically the effect of elevated hematocrit has not yet been demonstrated. Methods: Here, a microfluidic model of a sudden expansion is presented as a platform for investigating platelet adhesion at hematocrits ranging from 0 to 60% and shear rates ranging from 1000 to 10,000 s-1. The sudden expansion geometry models nonphysiological flow separation characteristic to mechanical circulatory support devices, and the validatory framework of the FDA benchmark nozzle. PDMS microchannels were fabricated and coated with human collagen. Platelets were fluorescently tagged, and blood was reconstituted at variable hematocrit prior to perfusion experiments. Integrin function of selected blood samples was inhibited by a blocking antibody, and platelet adhesion and aggregation over the course of perfusion was monitored. Results: Increasing shear rates at physiological and elevated hematocrit levels facilitate robust platelet adhesion and formation of large aggregates. Shear-induced platelet aggregation is demonstrated to be dependent on both αIIbßIII function and the presence of red blood cells. Inhibition of αIIbßIII results in an 86.4% reduction in overall platelet adhesion and an 85.7% reduction in thrombus size at 20-60% hematocrit. Hematocrit levels of 20% are inadequate for effective platelet margination and subsequent vWF tethering, resulting in notable decreases in platelet adhesion at 5000 and 10,000 s-1 compared to 40% and 60%. Inhibition of αIIbßIII triggered dramatic reductions in overall thrombus coverage and large aggregate formation. Stability of platelets tethered by vWF are demonstrated to be αIIbßIII-dependent, as adhesion of single platelets treated with A2A9, an anti-αIIbßIII blocking antibody, is transient and did not lead to sustained thrombus formation. Conclusions: This study highlights driving factors in vWF-mediated platelet adhesion that are relevant to clinical suppression of shear-induced thrombosis and in vitro assays of platelet adhesion. Primarily, increasing hematocrit promotes platelet margination, permitting shear-induced platelet aggregation through αIIbßIII-mediated adhesion at supraphysiological shear rates. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00796-0.

Numerical Study on the Impact of Central Venous Catheter Placement on Blood Flow in the Cavo-Atrial Junction.

An in silico study is performed to investigate fluid dynamic effects of central venous catheter (CVC) placement within patient-specific cavo-atrial junctions. Prior studies show the CVC infusing a liquid, but this study focuses on the placement without any liquid emerging from the CVC. A 7 or 15-French double-lumen CVC is placed virtually in two patient-specific models; the CVC tip location is altered to understand its effect on the venous flow field. Results show that the CVC impact is trivial on flow in the superior vena cava when the catheter-to-vein ratio ranges from 0.15 to 0.33. Results further demonstrate that when the CVC tip is directly in the right atrium, flow vortices in the right atrium result in elevated wall shear stress near the tip hole. A recirculation region characterizes a spatially variable flow field inside the CVC side hole. Furthermore, flow stagnation is present near the internal side hole corners but an elevated wall shear stress near the curvature of the side hole's exit. These results suggest that optimal CVC tip location is within the superior vena cava, so as to lower the potential for platelet activation due to elevated shear stresses and that CVC geometry and location depth in the central vein significantly influences the local CVC fluid dynamics. A thrombosis model also shows thrombus formation at the side hole and tip hole. After modifying the catheter design, the hemodynamics change, which alter thrombus formation. Future studies are warranted to study CVC design and placement location in an effort to minimize CVC-induced thrombosis incidence.

Venous Thromboembolism: Review of Clinical Challenges, Biology, Assessment, Treatment, and Modeling.

Venous thromboembolism (VTE) is a massive clinical challenge, annually affecting millions of patients globally. VTE is a particularly consequential pathology, as incidence is correlated with extremely common risk factors, and a large cohort of patients experience recurrent VTE after initial intervention. Altered hemodynamics, hypercoagulability, and damaged vascular tissue cause deep-vein thrombosis and pulmonary embolism, the two permutations of VTE. Venous valves have been identified as likely locations for initial blood clot formation, but the exact pathway by which thrombosis occurs in this environment is not entirely clear. Several risk factors are known to increase the likelihood of VTE, particularly those that increase inflammation and coagulability, increase venous resistance, and damage the endothelial lining. While these risk factors are useful as predictive tools, VTE diagnosis prior to presentation of outward symptoms is difficult, chiefly due to challenges in successfully imaging deep-vein thrombi. Clinically, VTE can be managed by anticoagulants or mechanical intervention. Recently, direct oral anticoagulants and catheter-directed thrombolysis have emerged as leading tools in resolution of venous thrombosis. While a satisfactory VTE model has yet to be developed, recent strides have been made in advancing in silico models of venous hemodynamics, hemorheology, fluid-structure interaction, and clot growth. These models are often guided by imaging-informed boundary conditions or inspired by benchtop animal models. These gaps in knowledge are critical targets to address necessary improvements in prediction and diagnosis, clinical management, and VTE experimental and computational models.

Clot embolization studies and computational framework for embolization in a canonical tube model.

Despite recent advances in the development of computational methods of modeling thrombosis, relatively little effort has been made in developing methods of modeling blood clot embolization. Such a model would provide substantially greater understanding of the mechanics of embolization, as in-vitro and in-vivo characterization of embolization is difficult. Here, a method of computationally simulating embolization is developed. Experiments are performed of blood clots formed in a polycarbonate tube, where phosphate-buffered saline is run through the tube at increasing flow rates until the clot embolizes. The experiments revealed embolization can be initiated by leading edge and trailing edge detachment or by non-uniform detachment. Stress-relaxation experiments are also performed to establish values of constitutive parameters for subsequent simulations. The embolization in the tube is reproduced in silico using a multiphase volume-of-fluid approach, where the clot is modeled as viscoelastic. By varying the constitutive parameters at the wall, embolization can be reproduced in-silico at varying flow rates, and a range of constitutive parameters fitting the experiments is reported. Here, the leading edge embolization is simulated at flow rates consistent with the experiments demonstrating excellent agreement in this specific behavior.

Effect of Hematocrit and Elevated Beat Rate on the 12cc Penn State Pediatric Ventricular Assist Device.

Congenital heart disease affects approximately 40,000 infants annually in the United States with 25% requiring invasive treatment. Due to limited number of donor hearts and treatment options available for children, pediatric ventricular assist devices (PVADs) are used as a bridge to transplant. The 12cc pneumatic Penn State PVAD is optimized to prevent platelet adhesion and thrombus formation at patient nominal conditions; however, children demonstrate variable blood hematocrit and elevated heart rates. Therefore, with pediatric patients exhibiting greater variability, particle image velocimetry is used to evaluate the PVAD with three non-Newtonian hematocrit blood analogs (20%, 40%, and 60%) and at two beat rates (75 and 120 bpm) to understand the device's performance. The flow fields demonstrate a strong inlet jet that transitions to a solid body rotation during diastole. During systole, the rotation dissipates and reorganizes into an outlet jet. This flow field is consistent across all hematocrits and beat rates but at a higher velocity magnitude during 120 bpm. There are also minor differences in flow field timing and surface washing due to hematocrit. Therefore, despite patient differences in hematocrit or required pumping output, thorough surface washing can be achieved in the PVAD by altering operating conditions, thus reducing platelet adhesion potential.

Modeling flow in an in vitro anatomical cerebrovascular model with experimental validation.

Acute ischemic stroke (AIS) is a leading cause of mortality that occurs when an embolus becomes lodged in the cerebral vasculature and obstructs blood flow in the brain. The severity of AIS is determined by the location and how extensively emboli become lodged, which are dictated in large part by the cerebral flow and the dynamics of embolus migration which are difficult to measure in vivo in AIS patients. Computational fluid dynamics (CFD) can be used to predict the patient-specific hemodynamics and embolus migration and lodging in the cerebral vasculature to better understand the underlying mechanics of AIS. To be relied upon, however, the computational simulations must be verified and validated. In this study, a realistic in vitro experimental model and a corresponding computational model of the cerebral vasculature are established that can be used to investigate flow and embolus migration and lodging in the brain. First, the in vitro anatomical model is described, including how the flow distribution in the model is tuned to match physiological measurements from the literature. Measurements of pressure and flow rate for both normal and stroke conditions were acquired and corresponding CFD simulations were performed and compared with the experiments to validate the flow predictions. Overall, the CFD simulations were in relatively close agreement with the experiments, to within ±7% of the mean experimental data with many of the CFD predictions within the uncertainty of the experimental measurement. This work provides an in vitro benchmark data set for flow in a realistic cerebrovascular model and is a first step towards validating a computational model of AIS.

Modeling Flow in an In Vitro Anatomical Cerebrovascular Model with Experimental Validation.

Acute ischemic stroke (AIS) is a leading cause of mortality that occurs when an embolus becomes lodged in the cerebral vasculature and obstructs blood flow in the brain. The severity of AIS is determined by the location and how extensively emboli become lodged, which are dictated in large part by the cerebral flow and the dynamics of embolus migration which are difficult to measure in vivo in AIS patients. Computational fluid dynamics (CFD) can be used to predict the patient-specific hemodynamics and embolus migration and lodging in the cerebral vasculature to better understand the underlying mechanics of AIS. To be relied upon, however, the computational simulations must be verified and validated. In this study, a realistic in vitro experimental model and a corresponding computational model of the cerebral vasculature are established that can be used to investigate flow and embolus migration and lodging in the brain. First, the in vitro anatomical model is described, including how the flow distribution in the model is tuned to match physiological measurements from the literature. Measurements of pressure and flow rate for both normal and stroke conditions were acquired and corresponding CFD simulations were performed and compared with the experiments to validate the flow predictions. Overall, the CFD simulations were in relatively close agreement with the experiments, to within ±7% of the mean experimental data with many of the CFD predictions within the uncertainty of the experimental measurement. This work provides an in vitro benchmark data set for flow in a realistic cerebrovascular model and is a first step towards validating a computational model of AIS.

Results of the Interlaboratory Computational Fluid Dynamics Study of the FDA Benchmark Blood Pump.

Computational fluid dynamics (CFD) is widely used to simulate blood-contacting medical devices. To be relied upon to inform high-risk decision making, however, model credibility should be demonstrated through validation. To provide robust data sets for validation, researchers at the FDA and collaborators developed two benchmark medical device flow models: a nozzle and a centrifugal blood pump. Experimental measurements of the flow fields and hemolysis were acquired using each model. Concurrently, separate open interlaboratory CFD studies were performed in which participants from around the world, who were blinded to the measurements, submitted CFD predictions of each benchmark model. In this study, we report the results of the interlaboratory CFD study of the FDA benchmark blood pump. We analyze the results of 24 CFD submissions using a wide range of different flow solvers, methods, and modeling parameters. To assess the accuracy of the CFD predictions, we compare the results with experimental measurements of three quantities of interest (pressure head, velocity field, and hemolysis) at different pump operating conditions. We also investigate the influence of different CFD methods and modeling choices used by the participants. Our analyses reveal that, while a number of CFD submissions accurately predicted the pump performance for individual cases, no single participant was able to accurately predict all quantities of interest across all conditions. Several participants accurately predicted the pressure head at all conditions and the velocity field in all but one or two cases. Only one of the eight participants who submitted hemolysis results accurately predicted absolute plasma free hemoglobin levels at a majority of the conditions, though most participants were successful at predicting relative hemolysis levels between conditions. Overall, this study highlights the need to validate CFD modeling of rotary blood pumps across the entire range of operating conditions and for all quantities of interest, as some operating conditions and regions (e.g., the pump diffuser) are more challenging to accurately predict than others. All quantities of interest should be validated because, as shown here, it is possible to accurately predict hemolysis despite having relatively inaccurate predictions of the flow field.

Computational analysis of effects of clot length on Acute ischemic stroke recanalization under different cyclic aspiration loading conditions.

Acute ischemic stroke, the second leading cause of death worldwide, results from occlusion of a cerebral artery by a blood clot. Application of cyclic aspiration using an aspiration catheter is a current therapy for the removal of lodged clots. In this study, we perform finite element simulations to analyze deformation of long clots, having length to radius ratio of 2-10, which corresponds to clot-length of 2.85-14.25 mm, under peak-to-peak cyclic aspiration pressures of 10-50 mmHg, and frequencies of 0.5, 1, and 2 Hz. Our computational system comprises of a nonlinear viscoelastic solid clot, a hyperelastic artery, and a nonlinear viscoelastic cohesive zone, the latter modeling the clot-artery interface. We observe that clots having length-to-radius ratio approximately greater than two separate from the inner arterial surface somewhere between the axial and distal ends, irrespective of the cyclic aspiration loading conditions. The stress distribution within the clot shows large tensile stresses in the clot interior, indicating the possibility of simultaneous fragmentation of the clot. Thus, this study shows us the various failure mechanisms simultaneously present in the clot during cyclic aspiration. Similarly, the stress distribution within the artery implies a possibility of endothelial damage to the arterial wall near the end where the aspiration pressure is applied. This framework provides a foundation for further investigation to clot fracture and adhesion characterization.

Performance of a Hydrogel Coated Nitinol with Oligonucleotide-Modified Nanoparticles Within Turbulent Conditions of Blood-Contacting Devices.

INTRODUCTION: Hydrogels offer a wide range of applications in the antithrombotic modification of biomedical devices. The functionalization of these hydrogels with potentially drug-laden nanoparticles in the context of deviceassociated turbulence is critically under-studied. Thus, the purpose of this study was to use a hydrogel-coating nitinol surface as a model to understand the functions of hydrogels and the capture of nanoparticles under clinically relevant flow conditions. METHODS: Nitinol was coated by an oligonucleotide (ON) functionalized hydrogel. Nanoparticles were functionalized with complementary oligonucleotides (CONs). The capture of CONfunctionalized nanoparticles by the ON-functionalized hydrogel surfaces was studied under both static and dynamic attachment conditions. Fluorescent-labelling of nanoparticles was utilized to assess capture efficacy and resistance to removal by device-relevant flow conditions. RESULTS: The specificity of the ON-CON bond was verified, exhibiting a dose-dependent attachment response. The hydrogel coating was resistant to stripping by flow, retaining >95% after exposure to one hour of turbulent flow. Attachment of nanoparticles to the hydrogel was higher in the static condition than under laminar flow (p < 0.01), but comparable to that of attachment under turbulent flow. Modified nitinol samples underwent one hour of flow treatment under both laminar and turbulent regimes and demonstrated decreased nanoparticle loss following static conjugation rather than turbulent conjugation (36.1% vs 53.8%, p < 0.05). There was no significant difference in nanoparticle functionalization by upstream injection between laminar and turbulent flow. CONCLUSION: The results demonstrate promising potential of hydrogelfunctionalized nitinol for capturing nanoparticles using nucleic acid hybridization. The hydrogel structure and ONCON bond integrity both demonstrated a resistance to mechanical damage and loss of biomolecular functionalization by exposure to turbulence. Further investigation is warranted to highlight drug delivery and antithrombogenic modification applications of nanoparticle-functionalized hydrogels.

The Accelerated Transcatheter Heart Valve Testing Environment: Loading, Motion, and Fluid Dynamics.

Transcatheter aortic valve replacements (TAVRs) are an increasingly common treatment for aortic valve disease due to their minimally invasive delivery. As TAVR designs require thinner leaflets to facilitate catheter-based delivery, they experience greater leaflet operational stresses and potentially greater durability issues than conventional surgical valves. Yet, our understanding of TAVR durability remains largely unexplored. Currently, preclinical TAVR durability is evaluated within an ISO:5840 compliant accelerated wear tester (AWT) up to a required 200 × 106 cycles, corresponding to approximately five years in vivo. While AWTs use high cycle frequencies (10-20 Hz) to achieve realistic timeframes, the resulting valve loading behaviors and fluid dynamics are not representative of the in vivo environment and thus may not accurately predict failure mechanisms. Despite the importance of fatigue and failure predictions for replacement heart valves, surprisingly, little quantitative information exists on the dynamic AWT environment. To better understand this environment, we examined frequency and diastolic period effects for the first time using high-speed enface imaging and particle image velocimetry to quantify valve motion and flow, respectively, using a Durapulse™ AWT at frequencies of 10, 15, and 20 Hz. Regardless of operating condition, no waveform achieved a physiologically relevant transvalvular loading pressure, despite having an ISO compliant geometric orifice area (GOA) and waveform. General fluid mechanics were consistent with in vivo but the AWT geometry developed secondary flow structures, which could impact mechanical loading. Therefore, the nonphysiologic loading and variability induced by changes in operating condition must be carefully regulated to ensure physiologically relevant fatigue.

Examining the universality of the hemolysis power law model from simulations of the FDA nozzle using calibrated model coefficients.

Computational fluid dynamics (CFD) is widely used to predict mechanical hemolysis in medical devices. The most popular hemolysis model is the stress-based power law model that is based on an empirical correlation between hemoglobin release from red blood cells (RBCs) and the magnitude of flow-induced stress and exposure time. Empirical coefficients are traditionally calibrated using data from experiments in simplified Couette-type blood-shearing devices with uniform-shear laminar flow and well-defined exposure times. Use of such idealized coefficients in simulations of real medical devices with complex hemodynamics is thought to be a primary reason for the historical inaccuracy of absolute hemolysis predictions using the power law model. Craven et al. (Biomech Model Mechanobiol 18:1005-1030, 2019) recently developed a CFD-based Kriging surrogate modeling approach for calibrating empirical coefficients in real devices that could potentially be used to more accurately predict absolute hemolysis. In this study, we use the FDA benchmark nozzle to investigate whether utilizing such calibrated coefficients improves the predictive accuracy of the standard Eulerian power law model. We first demonstrate the credibility of our CFD flow simulations by comparing with particle image velocimetry measurements. We then perform hemolysis simulations and compare the results with in vitro experiments. Importantly, the simulations use coefficients calibrated for the flow of a suspension of bovine RBCs through a small capillary tube, which is relatively comparable to the flow of bovine blood through the FDA nozzle. The results show that the CFD predictions of relative hemolysis in the FDA nozzle are reasonably accurate. The absolute predictions are, however, highly inaccurate with modified index of hemolysis values from CFD in error by roughly three orders of magnitude compared with the experiments, despite using calibrated model coefficients from a relatively similar geometry. We rigorously examine the reasons for the inaccuracy that include differences in the flow conditions in the hemolytic regions of each device and the lack of universality of the hemolysis power law model that is entirely empirical. Thus, while the capability to predict relative hemolysis is valuable for product development, further improvements are needed before the power law model can be relied upon to accurately predict the absolute hemolytic potential of a medical device.

Toward modeling thrombosis and thromboembolism in laminar and turbulent flow regimes.

Thrombosis and thromboembolism are deadly risk factors in blood-contacting biomedical devices, and in-silico models of thrombosis are attractive tools to understand the mechanics of these processes, though the simulation of thromboembolism remains underdeveloped. The purpose of this study is to modify an existing computational thrombosis model to allow for thromboembolism and to investigate the behavior of the modified model at a range of flow rates. The new and existing models are observed to lead to similar predictions of thrombosis in a canonical backward-facing step geometry across flow rates, and neither model predicts thrombosis in a turbulent flow. Simulations are performed by increasing flow rates in the case of a clot formed at lower flow to induce embolization. While embolization is observed, most of the clot breakdown is by shear rather than by breakup and subsequent transport of clotted material, and further work is required in the formulation and validation of embolization. This model provides a framework to further investigate thromboembolization.

Heparin-Peptide Nanogranules for Thrombosis-Actuated Anticoagulation.

Despite nearly a century of clinical use as a blood thinner, heparin's rapid serum clearance and potential to induce severe bleeding events continue to urge the development of more effective controlled delivery strategies. Subcutaneous depots that steadily release the anticoagulant into circulation represent a promising approach to reducing overdose frequency, sustaining therapeutic concentrations of heparin in plasma, and prolonging anticoagulant activity in a safe and effective manner. Subcutaneously deliverable heparin-peptide nanogranules that allow for long-lasting heparin bioavailability in the circulatory system, while enabling on-demand activation of heparin's anticoagulant effects in the thrombus microenvironment, are reported. Biophysical studies demonstrate this responsive behavior is due to the sequestration of heparin within self-assembling peptide nanofibrils and its mechanically actuated decoupling to elicit antithrombotic effects at the clotting site. In vivo studies show these unique properties converge to allow subcutaneous nanogranule depots to extend heparin serum concentrations for an order of magnitude longer than standard dosing regimens while enabling prolonged and controlled anticoagulant activity. This biohybrid delivery system demonstrates a potentially scalable platform for the development of safer, easier to administer, and more effective antithrombotic nanotechnologies.

Computational Investigation of Anastomosis Options of a Right-Heart Pump to Patient Specific Pulmonary Arteries.

Patients with Fontan circulation have increased risk of heart failure, but are not always candidates for heart transplant, leading to the development of the subpulmonic Penn State Fontan Circulation Assist Device. The aim of this study was to use patient-specific computational fluid dynamics simulations to evaluate anastomosis options for implanting this device. Simulations were performed of the pre-surgical anatomy as well as four surgical options: a T-junction and three Y-grafts. Cases were evaluated based on several fluid-dynamic quantities. The impact of imbalanced left-right pulmonary flow distribution was also investigated. Results showed that a 12-mm Y-graft was the most energy efficient. However, an 8-mm graft showed more favorable wall shear stress distribution, indicating lower risk of thrombosis and endothelial damage. The 8-mm Y-grafts also showed a more balanced pulmonary flow split, and lower residence time, also indicating lower thrombosis risk. The relative performance of the surgical options was largely unchanged whether or not the pulmonary vascular resistance remained imbalanced post-implantation.

Computational Modeling of the Penn State Fontan Circulation Assist Device.

To address the increasing number of failing Fontan patients, Penn State University and the Penn State Hershey Medical Center are developing a centrifugal blood pump for long-term mechanical support. Computational fluid dynamics (CFD) modeling of the Penn State Fontan Circulatory Assist Device (FCAD) was performed to understand hemodynamics within the pump and its potential for hemolysis and thrombosis. CFD velocity and pressure results were first validated against experimental data and found to be within the standard deviations of the velocities and within 5% of the pressures. Further simulations performed with a human blood model found that most of the fluid domain was subjected to low shear stress (<50 Pa), with areas of highest stress around the rotor blade tips that increased with pump flow rate and rotor speed (138-178 Pa). However, the stresses compared well to previous CFD studies of commercial blood pumps and remained mostly below common thresholds of hemolysis and platelet activation. Additionally, few regions of low shear rate were observed within the FCAD, signifying minimal potential for platelet adhesion. These results further emphasize the FCAD's potential that has been observed previously in experimental and animal studies.