Jason Szafron

All Publications

• Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth ELIFE Nandadasa, S., Szafron, J. M., Pathak, V., Murtada, S., Kraft, C. M., O'Donnell, A., Norvik, C., Hughes, C., Caterson, B., Domowicz, M. S., Schwartz, N. B., Tran-Lundmark, K., Veigl, M., Sedwick, D., Philipson, E. H., Humphrey, J. D., Apte, S. S. 2020; 9

  Abstract

  The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by biomechanical observations and confirmed by computational analyses. This vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrate their opposing roles in umbilical vascular dimorphism, including effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that differential proteoglycan dynamics and inner layer buckling were positively selected during evolution.

  View details for DOI 10.7554/eLife.60683

  View details for Web of Science ID 000576789100001

  View details for PubMedID 32909945

  View details for PubMedCentralID PMC7529456

• Spontaneous reversal of stenosis in tissue-engineered vascular grafts. Science translational medicine Drews, J. D., Pepper, V. K., Best, C. A., Szafron, J. M., Cheatham, J. P., Yates, A. R., Hor, K. N., Zbinden, J. C., Chang, Y. C., Mirhaidari, G. J., Ramachandra, A. B., Miyamoto, S. n., Blum, K. M., Onwuka, E. A., Zakko, J. n., Kelly, J. n., Cheatham, S. L., King, N. n., Reinhardt, J. W., Sugiura, T. n., Miyachi, H. n., Matsuzaki, Y. n., Breuer, J. n., Heuer, E. D., West, T. A., Shoji, T. n., Berman, D. n., Boe, B. A., Asnes, J. n., Galantowicz, M. n., Matsumura, G. n., Hibino, N. n., Marsden, A. L., Pober, J. S., Humphrey, J. D., Shinoka, T. n., Breuer, C. K. 2020; 12 (537)

  Abstract

  We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.

  View details for DOI 10.1126/scitranslmed.aax6919

  View details for PubMedID 32238576

• Differential outcomes of venous and arterial tissue engineered vascular grafts highlight the importance of coupling long-term implantation studies with computational modeling ACTA BIOMATERIALIA Best, C. A., Szafron, J. M., Rocco, K. A., Zbinden, J., Dean, E. W., Maxfield, M. W., Kurobe, H., Tara, S., Bagi, P. S., Udelsman, B. V., Khosravi, R., Yi, T., Shinoka, T., Humphrey, J. D., Breuer, C. K. 2019; 94: 183-194

  Abstract

  Electrospinning is commonly used to generate polymeric scaffolds for tissue engineering. Using this approach, we developed a small-diameter tissue engineered vascular graft (TEVG) composed of poly-ε-caprolactone-co-l-lactic acid (PCLA) fibers and longitudinally assessed its performance within both the venous and arterial circulations of immunodeficient (SCID/bg) mice. Based on in vitro analysis demonstrating complete loss of graft strength by 12 weeks, we evaluated neovessel formation in vivo over 6-, 12- and 24-week periods. Mid-term observations indicated physiologic graft function, characterized by 100% patency and luminal matching with adjoining native vessel in both the venous and arterial circulations. An active and robust remodeling process was characterized by a confluent endothelial cell monolayer, macrophage infiltrate, and extracellular matrix deposition and remodeling. Long-term follow-up of venous TEVGs at 24 weeks revealed viable neovessel formation beyond graft degradation when implanted in this high flow, low-pressure environment. Arterial TEVGs experienced catastrophic graft failure due to aneurysmal dilatation and rupture after 14 weeks. Scaffold parameters such as porosity, fiber diameter, and degradation rate informed a previously described computational model of vascular growth and remodeling, and simulations predicted the gross differential performance of the venous and arterial TEVGs over the 24-week time course. Taken together, these results highlight the requirement for in vivo implantation studies to extend past the critical time period of polymer degradation, the importance of differential neotissue deposition relative to the mechanical (pressure) environment, and further support the utility of predictive modeling in the design, use, and evaluation of TEVGs in vivo. STATEMENT OF SIGNIFICANCE: Herein, we apply a biodegradable electrospun vascular graft to the arterial and venous circulations of the mouse and follow recipients beyond the point of polymer degradation. While venous implants formed viable neovessels, arterial grafts experienced catastrophic rupture due to aneurysmal dilation. We then inform a previously developed computational model of tissue engineered vascular graft growth and remodeling with parameters specific to the electrospun scaffolds utilized in this study. Remarkably, model simulations predict the differential performance of the venous and arterial constructs over 24 weeks. We conclude that computational simulations should inform the rational selection of scaffold parameters to fabricate tissue engineered vascular grafts that must be followed in vivo over time courses extending beyond polymer degradation.

  View details for DOI 10.1016/j.actbio.2019.05.063

  View details for Web of Science ID 000479020900015

  View details for PubMedID 31200116

  View details for PubMedCentralID PMC6819998

• Optimization of Tissue Engineered Vascular Graft Design Using Computational Modeling. Tissue engineering. Part C, Methods Szafron, J. M., B Ramachandra, A., Breuer, C. K., Marsden, A. L., Humphrey, J. D. 2019

  Abstract

  Tissue engineered vascular grafts hold great promise in many clinical applications, especially in pediatrics wherein growth potential is critical. A continuing challenge, however, is identification of optimal scaffold parameters for promoting favorable neovessel development. In particular, given the countless design parameters available, including those related to polymeric microstructure, material behavior, and degradation kinetics, the number of possible scaffold designs is almost limitless. Advances in computationally modeling the growth and remodeling of native blood vessels suggest that similar simulations could help reduce the search space for candidate scaffold designs in tissue engineering. Herein, we meld a computational model of in vivo neovessel formation with a surrogate management framework to identify optimal scaffold designs for use in the extra-cardiac Fontan circulation while comparing the utility of different objective functions. We show that evolving luminal radius and graft compliance can be matched to that of the native vein by the end of the simulation period with judicious combinations of scaffold parameters, though the inability to match these metrics at all times reveals constraints engendered by current materials. We emphasize further that there is yet a need to examine additional metrics, and combinations thereof, when seeking to optimize functionality and reduce the potential for adverse outcomes.

  View details for DOI 10.1089/ten.TEC.2019.0086

  View details for PubMedID 31218941

• Immuno-driven and Mechano-mediated Neotissue Formation in Tissue Engineered Vascular Grafts ANNALS OF BIOMEDICAL ENGINEERING Szafron, J. M., Khosravi, R., Reinhardt, J., Best, C. A., Bersi, M. R., Yi, T., Breuer, C. K., Humphrey, J. D. 2018; 46 (11): 1938-1950

  Abstract

  In vivo development of a neovessel from an implanted biodegradable polymeric scaffold depends on a delicate balance between polymer degradation and native matrix deposition. Studies in mice suggest that this balance is dictated by immuno-driven and mechanotransduction-mediated processes, with neotissue increasingly balancing the hemodynamically induced loads as the polymer degrades. Computational models of neovessel development can help delineate relative time-dependent contributions of the immunobiological and mechanobiological processes that determine graft success or failure. In this paper, we compare computational results informed by long-term studies of neovessel development in immuno-compromised and immuno-competent mice. Simulations suggest that an early exuberant inflammatory response can limit subsequent mechano-sensing by synthetic intramural cells and thereby attenuate the desired long-term mechano-mediated production of matrix. Simulations also highlight key inflammatory differences in the two mouse models, which allow grafts in the immuno-compromised mouse to better match the biomechanical properties of the native vessel. Finally, the predicted inflammatory time courses revealed critical periods of graft remodeling. We submit that computational modeling can help uncover mechanisms of observed neovessel development and improve the design of the scaffold or its clinical use.

  View details for DOI 10.1007/s10439-018-2086-7

  View details for Web of Science ID 000451768500019

  View details for PubMedID 29987541

  View details for PubMedCentralID PMC6279560

• A computational growth and remodeling framework for adaptive and maladaptive pulmonary arterial hemodynamics. Biomechanics and modeling in mechanobiology Szafron, J. M., Yang, W., Feinstein, J. A., Rabinovitch, M., Marsden, A. L. 2023

  Abstract

  Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step toward predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

  View details for DOI 10.1007/s10237-023-01744-z

  View details for PubMedID 37658985

• A Computational Growth and Remodeling Framework for Adaptive and Maladaptive Pulmonary Arterial Hemodynamics. bioRxiv : the preprint server for biology Szafron, J. M., Yang, W., Feinstein, J. A., Rabinovitch, M., Marsden, A. L. 2023

  Abstract

  Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step towards predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

  View details for DOI 10.1101/2023.04.20.537714

  View details for PubMedID 37131683

  View details for PubMedCentralID PMC10153237

• In vivo development of tissue engineered vascular grafts: a fluid-solid-growth model. Biomechanics and modeling in mechanobiology Latorre, M., Szafron, J. M., Ramachandra, A. B., Humphrey, J. D. 2022

  Abstract

  Methods of tissue engineering continue to advance, and multiple clinical trials are underway evaluating tissue engineered vascular grafts (TEVGs). Whereas initial concerns focused on suture retention and burst pressure, there is now a pressing need to design grafts to have optimal performance, including an ability to grow and remodel in response to changing hemodynamic loads. Toward this end, there is similarly a need for computational methods that can describe and predict the evolution of TEVG geometry, composition, and material properties while accounting for changes in hemodynamics. Although the ultimate goal is a fluid-solid-growth (FSG) model incorporating fully 3D growth and remodeling and 3D hemodynamics, lower fidelity models having high computational efficiency promise to play important roles, especially in the design of candidate grafts. We introduce here an efficient FSG model of in vivo development of a TEVG based on two simplifying concepts: mechanobiologically equilibrated growth and remodeling of the graft and an embedded control volume analysis of the hemodynamics. Illustrative simulations for a model Fontan conduit reveal the utility of this approach, which promises to be particularly useful in initial design considerations involving formal methods of optimization which otherwise add considerably to the computational expense.

  View details for DOI 10.1007/s10237-022-01562-9

  View details for PubMedID 35179675

• Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth. Communications medicine Blum, K. M., Zbinden, J. C., Ramachandra, A. B., Lindsey, S. E., Szafron, J. M., Reinhardt, J. W., Heitkemper, M., Best, C. A., Mirhaidari, G. J., Chang, Y., Ulziibayar, A., Kelly, J., Shah, K. V., Drews, J. D., Zakko, J., Miyamoto, S., Matsuzaki, Y., Iwaki, R., Ahmad, H., Daulton, R., Musgrave, D., Wiet, M. G., Heuer, E., Lawson, E., Schwarz, E., McDermott, M. R., Krishnamurthy, R., Krishnamurthy, R., Hor, K., Armstrong, A. K., Boe, B. A., Berman, D. P., Trask, A. J., Humphrey, J. D., Marsden, A. L., Shinoka, T., Breuer, C. K. 2022; 2: 3

  Abstract

  Background: Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity.Methods: Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models.Results: Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid-structure interaction simulations providing detailed hemodynamic and wall stress information.Conclusions: These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

  View details for DOI 10.1038/s43856-021-00063-7

  View details for PubMedID 35603301

• Publisher Correction: Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients. NPJ Regenerative medicine Schwarz, E. L., Kelly, J. M., Blum, K. M., Hor, K. N., Yates, A. R., Zbinden, J. C., Verma, A., Lindsey, S. E., Ramachandra, A. B., Szafron, J. M., Humphrey, J. D., Shin'oka, T., Marsden, A. L., Breuer, C. K. 2021; 6 (1): 47

  View details for DOI 10.1038/s41536-021-00157-9

  View details for PubMedID 34385470

• Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients. NPJ Regenerative medicine Schwarz, E. L., Kelly, J. M., Blum, K. M., Hor, K. N., Yates, A. R., Zbinden, J. C., Verma, A., Lindsey, S. E., Ramachandra, A. B., Szafron, J. M., Humphrey, J. D., Shin'oka, T., Marsden, A. L., Breuer, C. K. 2021; 6 (1): 38

  Abstract

  In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs in the treatment of congenital heart disease. We show two distinct phases of graft remodeling: an early phase distinguished by rapid changes in graft geometry and a second phase of sustained growth and decreased graft stiffness. Using clinically informed and patient-specific computational fluid dynamics (CFD) simulations, we demonstrate how changes to TEVG geometry, thickness, and stiffness affect patient hemodynamics. We show that metrics of patient hemodynamics remain within normal ranges despite clinically observed levels of graft narrowing. These insights strengthen the continued clinical evaluation of this technology while supporting recent indications that reversible graft narrowing can be well tolerated, thus suggesting caution before intervening clinically.

  View details for DOI 10.1038/s41536-021-00148-w

  View details for PubMedID 34294733

• From Uniaxial Testing of Isolated Layers to a Tri-Layered Arterial Wall: A Novel Constitutive Modelling Framework ANNALS OF BIOMEDICAL ENGINEERING Giudici, A., Khir, A. W., Szafron, J. M., Spronck, B. 2021

  Abstract

  Mechanical testing and constitutive modelling of isolated arterial layers yields insight into the individual layers' mechanical properties, but per se fails to recapitulate the in vivo loading state, neglecting layer-specific residual stresses. The aim of this study was to develop a testing/modelling framework that integrates layer-specific uniaxial testing data into a three-layered model of the arterial wall, thereby enabling study of layer-specific mechanics under realistic (patho)physiological conditions. Circumferentially and axially oriented strips of pig thoracic aortas (n = 10) were tested uniaxially. Individual arterial layers were then isolated from the wall, tested, and their mechanical behaviour modelled using a hyperelastic strain energy function. Subsequently, the three layers were computationally assembled into a single flat-walled sample, deformed into a cylindrical vessel, and subjected to physiological tension-inflation. At the in vivo axial stretch of 1.10 ± 0.03, average circumferential wall stress was 75 ± 9 kPa at 100 mmHg, which almost doubled to 138 ± 15 kPa at 160 mmHg. A ~ 200% stiffening of the adventitia over the 60 mmHg pressure increase shifted layer-specific load-bearing from the media (65 ± 10% → 61 ± 14%) to the adventitia (28 ± 9% → 32 ± 14%). Our approach provides valuable insight into the (patho)physiological mechanical roles of individual arterial layers at different loading states, and can be implemented conveniently using simple, inexpensive and widely available uniaxial testing equipment.

  View details for DOI 10.1007/s10439-021-02775-2

  View details for Web of Science ID 000657610800002

  View details for PubMedID 34081251

• Effects of Braiding Parameters on Tissue Engineered Vascular Graft Development ADVANCED HEALTHCARE MATERIALS Zbinden, J. C., Blum, K. M., Berman, A. G., Ramachandra, A. B., Szafron, J. M., Kerr, K. E., Anderson, J. L., Sangha, G. S., Earl, C. C., Nigh, N. R., Mirhaidari, G. M., Reinhardt, J. W., Chang, Y., Yi, T., Smalley, R., Gabriele, P. D., Harris, J. J., Humphrey, J. D., Goergen, C. J., Breuer, C. K. 2020; 9 (24): e2001093

  Abstract

  Tissue engineered vascular grafts (TEVGs) using scaffolds fabricated from braided poly(glycolic acid) (PGA) fibers coated with poly(glycerol sebacate) (PGS) are developed. The approach relies on in vivo tissue engineering by which neotissue forms solely within the body after a scaffold has been implanted. Herein, the impact of altering scaffold braid design and scaffold coating on neotissue formation is investigated. Several combinations of braiding parameters are manufactured and evaluated in a Beige mouse model in the infrarenal abdominal aorta. Animals are followed with 4D ultrasound analysis, and 12 week explanted vessels are evaluated for biaxial mechanical properties as well as histological composition. Results show that scaffold parameters (i.e., braiding angle, braiding density, and presence of a PGS coating) have interdependent effects on the resulting graft performance, namely, alteration of these parameters influences levels of inflammation, extracellular matrix production, graft dilation, neovessel distensibility, and overall survival. Coupling carefully designed in vivo experimentation with regression analysis, critical relationships between the scaffold design and the resulting neotissue that enable induction of favorable cellular and extracellular composition in a controlled manner are uncovered. Such an approach provides a potential for fabricating scaffolds with a broad range of features and the potential to manufacture optimized TEVGs.

  View details for DOI 10.1002/adhm.202001093

  View details for Web of Science ID 000577357800001

  View details for PubMedID 33063452

• Vascular adaptation in the presence of external support - A modeling study. Journal of the mechanical behavior of biomedical materials Ramachandra, A. B., Latorre, M., Szafron, J. M., Marsden, A. L., Humphrey, J. D. 2020; 110: 103943

  Abstract

  Vascular grafts have long been used to replace damaged or diseased vessels with considerable success, but a new approach is emerging where native vessels are merely supported, not replaced. Although external supports have been evaluated in diverse situations - ranging from aneurysmal disease to vein grafts or the Ross operation - optimal supports and procedures remain wanting. In this paper, we present a novel application of a growth and remodeling model well suited for parametrically exploring multiple designs of external supports while accounting for mechanobiological and immunobiological responses of the supported native vessel. These results suggest that a load bearing external support can reduce vessel thickening in response to pressure elevation. Results also suggest that the final adaptive state of the vessel depends on the structural stiffness of the support via a mechano-driven adaptation, although luminal encroachment may be a complication in the presence of chronic inflammation. Finally, the supported vessel can stiffen (structurally and materially) along circumferential and axial directions, which could have implications on overall hemodynamics and thus subsequent vascular remodeling. The proposed framework can provide valuable insights into vascular adaptation in the presence of external support, accelerate rational design, and aid translation of this emerging approach.

  View details for DOI 10.1016/j.jmbbm.2020.103943

  View details for PubMedID 32957235

• Electrospun Tissue-Engineered Arterial Graft Thickness Affects Long-Term Composition and Mechanics TISSUE ENGINEERING PART A Wu, Y., Szafron, J. M., Blum, K. M., Zbinden, J. C., Khosravi, R., Best, C. A., Reinhardt, J. W., Zeng, Q., Yi, T., Shinoka, T., Humphrey, J. D., Breuer, C. K., Wang, Y. 2021; 27 (9-10): 593-603

  Abstract

  Wall stress is often lower in tissue-engineered constructs than in comparable native tissues due to the use of stiff polymeric materials having thicker walls. In this work, we sought to design a murine arterial graft having a more favorable local mechanical environment for the infiltrating cells; we used electrospinning to enclose a compliant inner core of poly(glycerol sebacate) with a stiffer sheath of poly(caprolactone) to reduce the potential for rupture. Two scaffolds were designed that differed in the thickness of the core as previous computational simulations found that circumferential wall stresses could be increased in the core toward native values by increasing the ratio of the core:sheath. Our modified electrospinning protocols reduced swelling of the core upon implantation and eliminated residual stresses in the sheath, both of which had contributed to the occlusion of implanted grafts during pilot studies. For both designs, a subset of implanted grafts occluded due to thrombosis or ruptured due to suspected point defects in the sheath. However, there were design-based differences in collagen content and mechanical behavior during early remodeling of the patent samples, with the thinner-core scaffolds having more collagen and a stiffer behavior after 12 weeks of implantation than the thicker-core scaffolds. By 24 weeks, the thicker-core scaffolds also became stiff, with similar amounts of collagen but increased smooth muscle cell and elastin content. These data suggest that increasing wall stress toward native values may provide a more favorable environment for normal arterial constituents to form despite the overall stiffness of the construct remaining elevated due to the absolute increase in load-bearing constituents.

  View details for DOI 10.1089/ten.tea.2020.0166

  View details for Web of Science ID 000574697100001

  View details for PubMedID 32854586

  View details for PubMedCentralID PMC8126421

• Computer-Controlled Biaxial Bioreactor for Investigating Cell-Mediated Homeostasis in Tissue Equivalents JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Eichinger, J. F., Paukner, D., Szafron, J. M., Aydin, R. C., Humphrey, J. D., Cyron, C. J. 2020; 142 (7)

  Abstract

  Soft biological tissues consist of cells and extracellular matrix (ECM), a network of diverse proteins, glycoproteins, and glycosaminoglycans that surround the cells. The cells actively sense the surrounding ECM and regulate its mechanical state. Cell-seeded collagen or fibrin gels, so-called tissue equivalents, are simple but powerful model systems to study this phenomenon. Nevertheless, few quantitative studies document the stresses that cells establish and maintain in such gels; moreover, most prior data were collected via uniaxial experiments whereas soft tissues are mainly subject to multiaxial loading in vivo. To begin to close this gap between existing experimental data and in vivo conditions, we describe here a computer-controlled bioreactor that enables accurate measurements of the evolution of mechanical tension and deformation of tissue equivalents under well-controlled biaxial loads. This device allows diverse studies, including how cells establish a homeostatic state of biaxial stress and if they maintain it in response to mechanical perturbations. It similarly allows, for example, studies of the impact of cell and matrix density, exogenous growth factors and cytokines, and different types of loading conditions (uniaxial, strip-biaxial, and biaxial) on these processes. As illustrative results, we show that NIH/3T3 fibroblasts establish a homeostatic mechanical state that depends on cell density and collagen concentration. Following perturbations from this homeostatic state, the cells were able to recover biaxial loading similar to homeostatic. Depending on the precise loads, however, they were not always able to fully maintain that state.

  View details for DOI 10.1115/1.4046201

  View details for Web of Science ID 000550290400011

  View details for PubMedID 32005993

  View details for PubMedCentralID PMC7172870

• A computational bio-chemo-mechanical model of in vivo tissue-engineered vascular graft development INTEGRATIVE BIOLOGY Khosravi, R., Ramachandra, A. B., Szafron, J. M., Schiavazzi, D. E., Breuer, C. K., Humphrey, J. D. 2020; 12 (3): 47-63

  Abstract

  Stenosis is the primary complication of current tissue-engineered vascular grafts used in pediatric congenital cardiac surgery. Murine models provide considerable insight into the possible mechanisms underlying this situation, but they are not efficient for identifying optimal changes in scaffold design or therapeutic strategies to prevent narrowing. In contrast, computational modeling promises to enable time- and cost-efficient examinations of factors leading to narrowing. Whereas past models have been limited by their phenomenological basis, we present a new mechanistic model that integrates molecular- and cellular-driven immuno- and mechano-mediated contributions to in vivo neotissue development within implanted polymeric scaffolds. Model parameters are inferred directly from in vivo measurements for an inferior vena cava interposition graft model in the mouse that are augmented by data from the literature. By complementing Bayesian estimation with identifiability analysis and simplex optimization, we found optimal parameter values that match model outputs with experimental targets and quantify variability due to measurement uncertainty. Utility is illustrated by parametrically exploring possible graft narrowing as a function of scaffold pore size, macrophage activity, and the immunomodulatory cytokine transforming growth factor beta 1 (TGF-β1). The model captures salient temporal profiles of infiltrating immune and synthetic cells and associated secretion of cytokines, proteases, and matrix constituents throughout neovessel evolution, and parametric studies suggest that modulating scaffold immunogenicity with early immunomodulatory therapies may reduce graft narrowing without compromising compliance.

  View details for DOI 10.1093/intbio/zyaa004

  View details for Web of Science ID 000538786600001

  View details for PubMedID 32222759

  View details for PubMedCentralID PMC7155415

• Revealing the glass transition in shape memory polymers using Brillouin spectroscopy APPLIED PHYSICS LETTERS Steelman, Z. A., Weems, A. C., Traverso, A. J., Szafron, J. M., Maitland, D. J., Yakovlev, V. V. 2017; 111 (24): 241904

  Abstract

  Emerging medical devices which employ shape memory polymers (SMPs) require precise measurements of the glass transition temperature (Tg) to ensure highly controlled shape recovery kinetics. Conventional techniques like differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) have limitations that prevent utilization for certain devices, including limited accuracy and the need for sacrificial samples. In this report, we employ an approach based on Brillouin spectroscopy to probe the glass transition of SMPs rapidly, remotely, and nondestructively. Further, we compare the Tg obtained from Brillouin scattering with DMA- and DSC-measured Tg to demonstrate the accuracy of Brillouin scattering for this application. We conclude that Brillouin spectroscopy is an accurate technique for obtaining the glass transition temperature of SMPs, aligning closely with the most common laboratory standards while providing a rapid, remote, and nondestructive method for the analysis of unique polymeric medical devices.

  View details for DOI 10.1063/1.4999803

  View details for Web of Science ID 000418098900017

  View details for PubMedID 29282378

  View details for PubMedCentralID PMC5729035

• Stress Analysis-Driven Design of Bilayered Scaffolds for Tissue-Engineered Vascular Grafts JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Szafron, J. M., Breuer, C. K., Wang, Y., Humphrey, J. D. 2017; 139 (12)

  Abstract

  Continuing advances in the fabrication of scaffolds for tissue-engineered vascular grafts (TEVGs) are greatly expanding the scope of potential designs. Increasing recognition of the importance of local biomechanical cues for cell-mediated neotissue formation, neovessel growth, and subsequent remodeling is similarly influencing the design process. This study examines directly the potential effects of different combinations of key geometric and material properties of polymeric scaffolds on the initial mechanical state of an implanted graft into which cells are seeded or migrate. Toward this end, we developed a bilayered computational model that accounts for layer-specific thickness and stiffness as well as the potential to be residually stressed during fabrication or to swell during implantation. We found that, for realistic ranges of parameter values, the circumferential stress that would be presented to seeded or infiltrating cells is typically much lower than ideal, often by an order of magnitude. Indeed, accounting for layer-specific intrinsic swelling resulting from hydrophilicity or residual stresses not relieved via annealing revealed potentially large compressive stresses, which could lead to unintended cell phenotypes and associated maladaptive growth or, in extreme cases, graft failure. Metrics of global hemodynamics were also found to be inversely related to markers of a favorable local mechanobiological environment, suggesting a tradeoff in designs that seek mechanical homeostasis at a single scale. These findings highlight the importance of the initial mechanical state in tissue engineering scaffold design and the utility of computational modeling in reducing the experimental search space for future graft development and testing.

  View details for DOI 10.1115/1.4037856

  View details for Web of Science ID 000414346200008

  View details for PubMedID 28886204

  View details for PubMedCentralID PMC5676664

• Shape memory polymers with enhanced visibility for magnetic resonance- and X-ray imaging modalities ACTA BIOMATERIALIA Weems, A. C., Szafron, J. M., Easley, A. D., Herting, S., Smolen, J., Maitland, D. J. 2017; 54: 45-57

  Abstract

  Currently, monitoring of minimally invasive medical devices is performed using fluoroscopy. The risks associated with fluoroscopy, including increased risk of cancer, make this method especially unsuitable for pediatric device delivery and follow-up procedures. A more suitable method is magnetic resonance (MR) imaging, which makes use of harmless magnetic fields rather than ionizing radiation when imaging the patient; this method is safer for both the patient and the performing technicians. Unfortunately, there is a lack of research available on bulk polymeric materials to enhance MR-visibility for use in medical devices. Here we show the incorporation of both physical and chemical modifying agents for the enhancement of both MR and X-ray visibility. Through the incorporation of these additives, we are able to control shape recovery of the polymer without sacrificing the thermal transition temperatures or the mechanical properties. For long-term implantation, these MR-visible materials do not have altered degradation profiles, and the release of additives is well below significant thresholds for daily dosages of MR-visible compounds. We anticipate our materials to be a starting point for safer, MR-visible medical devices incorporating polymeric components.Shape memory polymers (SMPs) are polymeric materials with unique shape recovery abilities that are being considered for use in biomedical and medical device applications. This paper presents a methodology for the development of MR and X-ray visible SMPs using either a chemically loaded or physical loaded method during polymer synthesis. Such knowledge is imperative for the development and clinical application of SMPs for biomedical devices, specifically for minimally-invasive vascular occlusion treatments, and while there are studies pertaining to the visibility of polymeric particles, little work has been performed on the utility of biomaterials intended for medical devices and the impact of how adding multiple functionalities, such as imaging, may impact material safety and degradation.

  View details for DOI 10.1016/j.actbio.2017.02.045

  View details for Web of Science ID 000402342400004

  View details for PubMedID 28259837

  View details for PubMedCentralID PMC5811198

• Design and Characterization of an Endovascular Mechanical Thrombectomy Device JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME Szafron, J. M., Muschenborn, A. D., Maitland, D. J. 2014; 8 (2)

  View details for DOI 10.1115/1.4027010

  View details for Web of Science ID 000336045900011

• Porous media properties of reticulated shape memory polymer foams and mock embolic coils for aneurysm treatment BIOMEDICAL ENGINEERING ONLINE Muschenborn, A. D., Ortega, J. M., Szafron, J. M., Szafron, D. J., Maitland, D. J. 2013; 12: 103

  Abstract

  Shape memory polymer (SMP) foams are being investigated as an alternative aneurysm treatment method to embolic coils. The goal of both techniques is the reduction of blood flow into the aneurysm and the subsequent formation of a stable thrombus, which prevents future aneurysm rupture. The purpose of this study is to experimentally determine the parameters, permeability and form factor, which are related to the flow resistance imposed by both media when subjected to a pressure gradient.The porous media properties-permeability and form factor-of SMP foams and mock embolic coils (MECs) were measured with a pressure gradient method by means of an in vitro closed flow loop. We implemented the Forchheimer-Hazen-Dupuit-Darcy equation to calculate these properties. Mechanically-reticulated SMP foams were fabricated with average cell sizes of 0.7E-3 and 1.1E-3 m, while the MECs were arranged with volumetric packing densities of 11-28%.The permeability of the SMP foams was an order of magnitude lower than that of the MECs. The form factor differed by up to two orders of magnitude and was higher for the SMP foams in all cases. The maximum flow rate of all samples tested was within the inertial laminar flow regime, with Reynolds numbers ranging between 1 and 35.The SMP foams impose a greater resistance to fluid flow compared to MECs, which is a result of increased viscous and inertial losses. These results suggest that aneurysms treated with SMP foam will have flow conditions more favorable for blood stasis than those treated with embolic coils having packing densities ≤ 28%.

  View details for DOI 10.1186/1475-925X-12-103

  View details for Web of Science ID 000326629500001

  View details for PubMedID 24120254

  View details for PubMedCentralID PMC3853193