Clinical Focus


  • Thoracic and Cardiac Surgery

Academic Appointments


Professional Education


  • Residency: Stanford University Dept of Cardiothoracic Surgery (2023) CA
  • Internship: Stanford University Dept of General Surgery (2015) CA
  • Medical Education: University of Michigan Medical School (2014) MI
  • Post-Doctoral Research Fellow, Stanford University Department of Cardiothoracic Surgery
  • Residency, Stanford University Medical Center, Cardiothoracic Surgery
  • Internship, Stanford University Medical Center, Cardiothoracic Surgery (2015)
  • MD, University of Michigan Medical School (2014)
  • BBA, University of Michigan Ross School of Business (2009)

All Publications


  • Trimmed central venous catheters do not increase endothelial injury in an ovine model. The journal of vascular access Wang, H., Williams, K. M., Elde, S., Bulterys, P. L., Thakore, A. D., Lucian, H. J., Farry, J. M., Mullis, D. M., Zhu, Y., Paulsen, M. J., Woo, Y. J. 2023: 11297298231153716

    Abstract

    Central venous catheters (CVCs) are often trimmed during heart transplantation and pediatric cardiac surgery. However, the risk of endothelial injury caused by the cut tip of the CVC has not been evaluated. We hypothesized that there is no difference in the degree of endothelial injury associated with trimmed CVCs versus standard untrimmed CVCs.In four adult male sheep, the left external jugular vein was exposed in three segments, one designated for an untouched control group, one for the trimmed CVC group, and one for the untrimmed CVC group. Trimmed and untrimmed CVC tips were rotated circumferentially within their respective segments to abrade the lumen of the vein. The vein samples were explanted, and two representative sections from each sample were analyzed using hematoxylin and eosin (H&E) staining, as well as with immunohistochemistry against CD31, von Willebrand factor (vWF), endothelial nitric oxide synthase (eNOS), and caveolin. Higher immunohistochemical stain distributions and intensities are associated with normal health and function of the venous endothelium. Data are presented as counts with percentages or as means with standard error.H&E staining revealed no evidence of endothelial injury in 6/8 (75%) samples from the untouched control group, and no injury in 4/8 (50%) samples from both the trimmed and untrimmed CVC groups (p = 0.504). In all remaining samples from each group, only mild endothelial injury was observed. Immunohistochemical analysis comparing trimmed CVCs versus untrimmed CVCs revealed no difference in the percentage of endothelial cells staining positive for CD31 (57.5% ± 7.2% vs 55.0% ± 9.2%, p = 0.982), vWF (73.8% ± 8.0% vs 62.5% ± 9.6%, p = 0.579), eNOS (66.3% ± 4.2% vs 63.8% ± 7.5%, p = 0.962), and caveolin (53.8% ± 5.0% vs 51.3% ± 4.4%, p = 0.922). There were no significant differences between the groups in the distributions of stain intensity for CD31, vWF, eNOS, and caveolin.Trimmed CVCs do not increase endothelial injury compared to standard untrimmed CVCs.

    View details for DOI 10.1177/11297298231153716

    View details for PubMedID 36765464

  • Force Profiles of Single Ventricle Atrioventricular Leaflets in Response to Annular Dilation and Leaflet Tethering. Seminars in thoracic and cardiovascular surgery Kidambi, S., Moye, S. C., Lee, J., Cowles, T. H., Strong, E. B., Wilkerson, R., Paulsen, M. J., Woo, Y. J., Ma, M. R. 2022

    Abstract

    We sought to understand how leaflet forces change in response to annular dilation and leaflet tethering in single ventricle physiology. Explanted fetal bovine tricuspid valves were sutured onto image-derived annuli and ventricular mounts. Control valves (CV) were secured to a size-matched HLHS-type annulus and compared to: 1) normal tricuspid valves (NTV) secured to a size-matched saddle-shaped annulus, 2) HLHS-type annulus with leaflet tethering (LT), 3) HLHS-type annulus with annular dilation (DIL), or 5) a combined disease model with both dilation and tethering (DIS). The specimens were tested in a systemic heart simulator at various SVPs. Leaflet forces were measured using optical strain sensors sutured to each leaflet edge. Average force in the anterior leaflet was 43.2% lower in CV compared to NTV (p<0.001). LT resulted in a 6.6% increase in average forces on the anterior leaflet (p=0.04), 10.7% increase on the posterior leaflet (p=0.03), and 14.1% increase on the septal leaflet (p<0.001). In DIL, average septal leaflet forces increased relative to the control valves by 42.2% (p=0.01). In DIS, average leaflet forces increased by 54.8% in the anterior leaflet (p<0.001), 37.6% in the posterior leaflet (p=0.03), and 79.9% in the septal leaflet (p<0.001). The anterior leaflet experiences the highest forces in the normal tricuspid annulus under SVP conditions. Annular dilation resulted in an increase in forces on the septal leaflet and leaflet tethering resulted in an increase in forces across all 3 leaflets. Annular dilation and leaflet tethering combined resulted in the largest increase in leaflet forces across all 3 leaflets.

    View details for DOI 10.1053/j.semtcvs.2022.09.012

    View details for PubMedID 36455710

  • DynaRing: A Patient-Specific Mitral Annuloplasty Ring With Selective Stiffness Segments. Journal of medical devices Frishman, S., Kight, A., Pirozzi, I., Maddineni, S., Imbrie-Moore, A. M., Karachiwalla, Z., Paulsen, M. J., Kaiser, A. D., Woo, Y. J., Cutkosky, M. R. 2022; 16 (3): 031009

    Abstract

    Annuloplasty ring choice and design are critical to the long-term efficacy of mitral valve (MV) repair. DynaRing is a selectively compliant annuloplasty ring composed of varying stiffness elastomer segments, a shape-set nitinol core, and a cross diameter filament. The ring provides sufficient stiffness to stabilize a diseased annulus while allowing physiological annular dynamics. Moreover, adjusting elastomer properties provides a mechanism for effectively tuning key MV metrics to specific patients. We evaluate the ring embedded in porcine valves with an ex-vivo left heart simulator and perform a 150 million cycle fatigue test via a custom oscillatory system. We present a patient-specific design approach for determining ring parameters using a finite element model optimization and patient MRI data. Ex-vivo experiment results demonstrate that motion of DynaRing closely matches literature values for healthy annuli. Findings from the patient-specific optimization establish DynaRing's ability to adjust the anterior-posterior and intercommissural diameters and saddle height by up to 8.8%, 5.6%, 19.8%, respectively, and match a wide range of patient data.

    View details for DOI 10.1115/1.4054445

    View details for PubMedID 35646225

  • FDA Emergency Use Authorization-Approved Novel Coronavirus Disease 2019, Pressure-Regulated, Mechanical Ventilator Splitter That Enables Differential Compliance Multiplexing. ASAIO journal (American Society for Artificial Internal Organs : 1992) Paulsen, M. J., Zhu, Y., Park, M. H., Imbrie-Moore, A. M., Baker, S., Walter Edmonston, D., Dawson, T., Ly, E., Martin Bell, S., Tran, N. A., Jung, J., Cedarleaf-Pavy, J., Sridhar, K. R., Venkataraman, V., Woo, Y. J. 2022

    Abstract

    Infection with the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may cause viral pneumonia and acute respiratory distress syndrome (ARDS). Treatment of ARDS often requires mechanical ventilation and may take weeks for resolution. In areas with a large outbreaks, there may be shortages of ventilators available. While rudimentary methods for ventilator splitting have been described, given the range of independent ventilatory settings required for each patient, this solution is suboptimal. Here, we describe a device that can split a ventilator among up to four patients while allowing for individualized settings. The device has been validated in vitro and in vivo.

    View details for DOI 10.1097/MAT.0000000000001756

    View details for PubMedID 35667305

  • Ex vivo biomechanical analysis of flexible versus rigid annuloplasty rings in mitral valves using a novel annular dilation system. BMC cardiovascular disorders Zhu, Y., Imbrie-Moore, A. M., Wilkerson, R. J., Paulsen, M. J., Park, M. H., Woo, Y. J. 2022; 22 (1): 73

    Abstract

    BACKGROUND: Mitral annuloplasty rings restore annular dimensions to increase leaflet coaptation, serving a fundamental component in mitral valve repair. However, biomechanical evaluations of annuloplasty rings are lacking. We aim to biomechanically analyze flexible and rigid annuloplasty rings using an ex vivo mitral annular dilation model.METHODS: Juvenile porcine mitral valves (n=4) with intercommissural distance of 28mm were dilated to intercommissural distances of 40mm using a 3D-printed dilator and were sewn to an elastic mount. Fiber bragg grating sensors were anchored to native chordae to measure chordal forces. The valves were repaired using size 28 rigid and flexible annuloplasty rings in a random order. Hemodynamic data, echocardiography, and chordal force measurements were collected.RESULTS: Mitral annular dilation resulted in decreased leaflet coaptation height and increased mitral regurgitation fraction. Both the flexible and rigid annuloplasty rings effectively increased leaflet coaptation height compared to that post dilation. Rigid ring annuloplasty repair significantly decreased the mitral regurgitation fraction. Flexible annuloplasty ring repair reduced the chordal rate of change of force (7.1±4.4N/s versus 8.6±5.9N/s, p=0.02) and peak force (0.6±0.5N versus 0.7±0.6N, p=0.01) compared to that from post dilation. Rigid annuloplasty ring repair was associated with higher chordal rate of change of force (9.8±5.8N/s, p=0.0001) and peak force (0.7±0.5N, p=0.01) compared to that after flexible ring annuloplasty repair.CONCLUSIONS: Both rigid and flexible annuloplasty rings are effective in increasing mitral leaflet coaptation height. Although the rigid annuloplasty ring was associated with slightly higher chordal stress compared to that of the flexible annuloplasty ring, it was more effective in mitral regurgitation reduction. This study may help direct the design of an optimal annuloplasty ring to further improve patient outcomes.

    View details for DOI 10.1186/s12872-022-02515-x

    View details for PubMedID 35219298

  • A Novel Device for Intraoperative Direct Visualization of a Pressurized Root in Aortic Valve Repair. The Annals of thoracic surgery Zhu, Y., Imbrie-Moore, A. M., Paulsen, M. J., Park, M. H., Tran, N. A., Woo, Y. J. 2022

    Abstract

    PURPOSE: One major challenge in generating reproducible aortic valve (AV) repair results is the inability to assess AV morphology under physiologic pressure. A transparent intraoperative aortic valve visualization device was designed and manufactured.DESCRIPTION: This device is comprised of an open proximal end, a cantilevered edge to allow attachment of the device to the aorta or graft, a distal viewing surface, and two side ports for fluid delivery and air removal.EVALUATION: The performance of the device was evaluated ex vivo using normal porcine AV in situ (n=3), AV after valve-sparing aortic root replacement (VSARR, n=3), and porcine pulmonary valve in Ross procedure (n=3), and in 3 patients who underwent VSARR. AV morphology was clearly visualized using the device in all experiments. In human, the use of this device successfully illustrated cusp prolapse after the initial VSARR and effectively guided additional cusp repair.CONCLUSIONS: This device successfully allows for direct visual assessment of the AV apparatus under physiologic pressure. The use of this device can potentially increase the adoptability of AV repair in clinical practice.

    View details for DOI 10.1016/j.athoracsur.2022.02.013

    View details for PubMedID 35216987

  • Biomechanical engineering analysis of an acute papillary muscle rupture disease model using an innovative 3D-printed left heart simulator. Interactive cardiovascular and thoracic surgery Marin-Cuartas, M., Zhu, Y., Imbrie-Moore, A. M., Park, M. H., Wilkerson, R. J., Leipzig, M., Pandya, P. K., Paulsen, M. J., Borger, M. A., Woo, Y. J. 1800

    Abstract

    OBJECTIVES: The severity of acute papillary muscle (PM) rupture varies according to the extent and site of the rupture. However, the haemodynamic effects of different rupture variations are still poorly understood. Using a novel ex vivo model, we sought to study acute PM rupture to improve clinical management.METHODS: Using porcine mitral valves (n=32) mounted within an ex vivo left heart simulator, PM rupture was simulated. The mitral valve was divided into quadrants for analysis according to the PM heads. Acute PM rupture was simulated by incrementally cutting from 1/3 to the total number of chordae arising from 1 PM head of interest. Haemodynamic parameters were measured.RESULTS: Rupture >2/3 of the chordae from 1 given PM head or regurgitation fraction >60% led to markedly deteriorated haemodynamics. Rupture at the anterolateral PM had a stronger negative effect on haemodynamics than rupture at the posteromedial PM. Rupture occurring at the anterior head of the anterolateral PM led to more marked haemodynamic instability than rupture occurring at the other PM heads.CONCLUSIONS: The haemodynamic effects of acute PM rupture vary considerably according to the site and extent of the rupture. Rupture of ≤2/3 of chordae from 1 PM head or rupture at the posteromedial PM lead to less marked haemodynamics effects, suggesting a higher likelihood of tolerating surgery. Rupture at the anterolateral PM, specifically the anterior head, rupture of >2/3 of chordae from 1 PM head or regurgitation fraction >60% led to marked haemodynamic instability, suggesting the potential benefit from bridging strategies prior to surgery.

    View details for DOI 10.1093/icvts/ivab373

    View details for PubMedID 35022737

  • Natural cardiac regeneration conserves native biaxial left ventricular biomechanics after myocardial infarction in neonatal rats. Journal of the mechanical behavior of biomedical materials Wang, H., Wisneski, A., Imbrie-Moore, A. M., Paulsen, M. J., Wang, Z., Xuan, Y., Lopez Hernandez, H., Hironaka, C. E., Lucian, H. J., Shin, H. S., Anilkumar, S., Thakore, A. D., Farry, J. M., Eskandari, A., Williams, K. M., Grady, F., Wu, M. A., Jung, J., Stapleton, L. M., Steele, A. N., Zhu, Y., Woo, Y. J. 1800; 126: 105074

    Abstract

    After myocardial infarction (MI), adult mammals exhibit scar formation, adverse left ventricular (LV) remodeling, LV stiffening, and impaired contractility, ultimately resulting in heart failure. Neonatal mammals, however, are capable of natural heart regeneration after MI. We hypothesized that neonatal cardiac regeneration conserves native biaxial LV mechanics after MI. Wistar rat neonates (1 day old, n=46) and adults (8-10 weeks old, n=20) underwent sham surgery or permanent left anterior descending coronary artery ligation. At 6 weeks after neonatal MI, Masson's trichrome staining revealed negligible fibrosis. Echocardiography for the neonatal MI (n=15) and sham rats (n=14) revealed no differences in LV wall thickness or chamber diameter, and both groups had normal ejection fraction (72.7% vs 77.5%, respectively, p=0.1946). Biaxial tensile testing revealed similar stress-strain curves along both the circumferential and longitudinal axes across a full range of physiologic stresses and strains. The circumferential modulus (267.9kPa vs 274.2kPa, p=0.7847), longitudinal modulus (269.3kPa vs 277.1kPa, p=0.7435), and maximum shear stress (3.30kPa vs 3.95kPa, p=0.5418) did not differ significantly between the neonatal MI and sham groups, respectively. In contrast, transmural scars were observed at 4 weeks after adult MI. Adult MI hearts (n=7) exhibited profound LV wall thinning (p<0.0001), chamber dilation (p=0.0246), and LV dysfunction (ejection fraction 45.4% vs 79.7%, p<0.0001) compared to adult sham hearts (n=7). Adult MI hearts were significantly stiffer than adult sham hearts in both the circumferential (321.5kPa vs 180.0kPa, p=0.0111) and longitudinal axes (315.4kPa vs 172.3kPa, p=0.0173), and also exhibited greater maximum shear stress (14.87kPa vs 3.23kPa, p=0.0162). Our study is the first to show that native biaxial LV mechanics are conserved after neonatal heart regeneration following MI, thus adding biomechanical support for the therapeutic potential of cardiac regeneration in the treatment of ischemic heart disease.

    View details for DOI 10.1016/j.jmbbm.2022.105074

    View details for PubMedID 35030471

  • Electrophysiologic Conservation of Epicardial Conduction Dynamics After Myocardial Infarction and Natural Heart Regeneration in Newborn Piglets. Frontiers in cardiovascular medicine Wang, H., Pong, T., Obafemi, O. O., Lucian, H. J., Aparicio-Valenzuela, J., Tran, N. A., Mullis, D. M., Elde, S., Tada, Y., Baker, S. W., Wang, C. Y., Cyr, K. J., Paulsen, M. J., Zhu, Y., Lee, A. M., Woo, Y. J. 2022; 9: 829546

    Abstract

    Newborn mammals, including piglets, exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). The electrophysiologic properties of this naturally regenerated myocardium have not been examined. We hypothesized that epicardial conduction is preserved after P1 MI in piglets. Yorkshire-Landrace piglets underwent left anterior descending coronary artery ligation at age P1 (n = 6) or P7 (n = 7), After 7 weeks, cardiac magnetic resonance imaging was performed with late gadolinium enhancement for analysis of fibrosis. Epicardial conduction mapping was performed using custom 3D-printed high-resolution mapping arrays. Age- and weight-matched healthy pigs served as controls (n = 6). At the study endpoint, left ventricular (LV) ejection fraction was similar for controls and P1 pigs (46.4 ± 3.0% vs. 40.3 ± 4.9%, p = 0.132), but significantly depressed for P7 pigs (30.2 ± 6.6%, p < 0.001 vs. control). The percentage of LV myocardial volume consisting of fibrotic scar was 1.0 ± 0.4% in controls, 9.9 ± 4.4% in P1 pigs (p = 0.002 vs. control), and 17.3 ± 4.6% in P7 pigs (p < 0.001 vs. control, p = 0.007 vs. P1). Isochrone activation maps and apex activation time were similar between controls and P1 pigs (9.4 ± 1.6 vs. 7.8 ± 0.9 ms, p = 0.649), but significantly prolonged in P7 pigs (21.3 ± 5.1 ms, p < 0.001 vs. control, p < 0.001 vs. P1). Conduction velocity was similar between controls and P1 pigs (1.0 ± 0.2 vs. 1.1 ± 0.4 mm/ms, p = 0.852), but slower in P7 pigs (0.7 ± 0.2 mm/ms, p = 0.129 vs. control, p = 0.052 vs. P1). Overall, our data suggest that epicardial conduction dynamics are conserved in the setting of natural heart regeneration in piglets after P1 MI.

    View details for DOI 10.3389/fcvm.2022.829546

    View details for PubMedID 35355973

  • Biomechanical engineering comparison of four leaflet repair techniques for mitral regurgitation using a novel 3-dimensional-printed left heart simulator JTCVS TECHNIQUES Paulsen, M. J., Cuartas, M., Imbrie-Moore, A., Wang, H., Wilkerson, R., Farry, J., Zhu, Y., Ma, M., MacArthur, J. W., Woo, Y. 2021; 10: 244-251
  • Biomechanical engineering comparison of four leaflet repair techniques for mitral regurgitation using a novel 3-dimensional-printed left heart simulator. JTCVS techniques Paulsen, M. J., Cuartas, M. M., Imbrie-Moore, A., Wang, H., Wilkerson, R., Farry, J., Zhu, Y., Ma, M., MacArthur, J. W., Woo, Y. J. 2021; 10: 244-251

    Abstract

    Mitral valve repair is the gold standard treatment for degenerative mitral regurgitation; however, a multitude of repair techniques exist with little quantitative data comparing these approaches. Using a novel ex vivo model, we sought to evaluate biomechanical differences between repair techniques.Using porcine mitral valves mounted within a custom 3-dimensional-printed left heart simulator, we induced mitral regurgitation using an isolated P2 prolapse model by cutting primary chordae. Next, we repaired the valves in series using the edge-to-edge technique, neochordoplasty, nonresectional remodeling, and classic leaflet resection. Hemodynamic data and chordae forces were measured and analyzed using an incomplete counterbalanced repeated measures design with the healthy pre-prolapse valve as a control.With the exception of the edge-to-edge technique, all repair methods effectively corrected mitral regurgitation, returning regurgitant fraction to baseline levels (baseline 11.9% ± 3.7%, edge-to-edge 22.5% ± 6.9%, nonresectional remodeling 12.3% ± 3.0%, neochordal 13.4% ± 4.8%, resection 14.7% ± 5.5%, P < 0.01). Forces on the primary chordae were minimized using the neochordal and nonresectional techniques whereas the edge-to-edge and resectional techniques resulted in significantly elevated primary forces. Secondary chordae forces also followed this pattern, with edge-to-edge repair generating significantly higher secondary forces and leaflet resection trending higher than the nonresectional and neochord repairs.Although multiple methods of degenerative mitral valve repair are used clinically, their biomechanical properties vary significantly. Nonresectional techniques, including leaflet remodeling and neochordal techniques, appear to result in lower chordal forces in this ex vivo technical engineering model.

    View details for DOI 10.1016/j.xjtc.2021.09.040

    View details for PubMedID 34977730

    View details for PubMedCentralID PMC8691825

  • Videographic conceptual dynamic representation of bicuspid aortic valve anatomic configurations and structural inter-relationships. JTCVS techniques Woo, Y. J., Paulsen, M. J., de Kerchove, L., Zhu, Y. 2021; 9: 44-45

    View details for DOI 10.1016/j.xjtc.2021.06.019

    View details for PubMedID 34647056

  • From hardware store to hospital: a COVID-19-inspired, cost-effective, open-source, in vivo-validated ventilator for use in resource-scarce regions. Bio-design and manufacturing Park, M. H., Zhu, Y., Wang, H., Tran, N. A., Jung, J., Paulsen, M. J., Imbrie-Moore, A. M., Baker, S., Wilkerson, R., Marin-Cuartas, M., Mullis, D. M., Woo, Y. J. 2021: 1-8

    Abstract

    Resource-scarce regions with serious COVID-19 outbreaks do not have enough ventilators to support critically ill patients, and these shortages are especially devastating in developing countries. To help alleviate this strain, we have designed and tested the accessible low-barrier in vivo-validated economical ventilator (ALIVE Vent), a COVID-19-inspired, cost-effective, open-source, in vivo-validated solution made from commercially available components. The ALIVE Vent operates using compressed oxygen and air to drive inspiration, while two solenoid valves ensure one-way flow and precise cycle timing. The device was functionally tested and profiled using a variable resistance and compliance artificial lung and validated in anesthetized large animals. Our functional test results revealed its effective operation under a wide variety of ventilation conditions defined by the American Association of Respiratory Care guidelines for ventilator stockpiling. The large animal test showed that our ventilator performed similarly if not better than a standard ventilator in maintaining optimal ventilation status. The FiO2, respiratory rate, inspiratory to expiratory time ratio, positive-end expiratory pressure, and peak inspiratory pressure were successfully maintained within normal, clinically validated ranges, and the animals were recovered without any complications. In regions with limited access to ventilators, the ALIVE Vent can help alleviate shortages, and we have ensured that all used materials are publicly available. While this pandemic has elucidated enormous global inequalities in healthcare, innovative, cost-effective solutions aimed at reducing socio-economic barriers, such as the ALIVE Vent, can help enable access to prompt healthcare and life saving technology on a global scale and beyond COVID-19.Supplementary Information: The online version contains supplementary material available at 10.1007/s42242-021-00164-1.

    View details for DOI 10.1007/s42242-021-00164-1

    View details for PubMedID 34567825

  • A neonatal leporine model of age-dependent natural heart regeneration after myocardial infarction. The Journal of thoracic and cardiovascular surgery Wang, H., Hironaka, C. E., Mullis, D. M., Lucian, H. J., Shin, H. S., Tran, N. A., Thakore, A. D., Anilkumar, S., Wu, M. A., Paulsen, M. J., Zhu, Y., Baker, S. W., Woo, Y. J. 2021

    Abstract

    OBJECTIVES: Neonatal rodents and piglets naturally regenerate the injured heart after myocardial infarction. We hypothesized that neonatal rabbits also exhibit natural heart regeneration after myocardial infarction.METHODS: New Zealand white rabbit kits underwent sham surgery or left coronary ligation on postnatal day 1 (n=94), postnatal day 4 (n=11), or postnatal day 7 (n=52). Hearts were explanted 1day postsurgery to confirm ischemic injury, at 1week postsurgery to assess cardiomyocyte proliferation, and at 3weeks postsurgery to assess left ventricular ejection fraction and scar size. Data are presented as mean±standard deviation.RESULTS: Size of ischemic injury as a percentage of left ventricular area was similar after myocardial infarction on postnatal day 1 versus on postnatal day 7 (42.3%±5.4% vs 42.3%±4.7%, P=.9984). Echocardiography confirmed severely reduced ejection fraction at 1day after postnatal day 1 myocardial infarction (33.7%±5.3% vs 65.2%±5.5% for postnatal day 1 sham, P=.0001), but no difference at 3weeks after postnatal day 1 myocardial infarction (56.0%±4.0% vs 58.0%±3.3% for postnatal day 1 sham, P=.2198). Ejection fraction failed to recover after postnatal day 4 myocardial infarction (49.2%±1.8% vs 58.5%±5.8% for postnatal day 4 sham, P=.0109) and postnatal day 7 myocardial infarction (39.0%±7.8% vs 60.2%±5.0% for postnatal day 7 sham, P<.0001). At 3weeks after infarction, fibrotic scar represented 5.3%±1.9%, 14.3%±4.9%, and 25.4%±13.3% of the left ventricle area in the postnatal day 1, postnatal day 4, and postnatal day 7 groups, respectively. An increased proportion of peri-infarct cardiomyocytes expressed Ki67 (15.9%±1.8% vs 10.2%±0.8%, P=.0039) and aurora B kinase (4.0%±0.9% vs 1.5%±0.6%, P=.0088) after postnatal day 1 myocardial infarction compared with sham, but no increase was observed after postnatal day 7 myocardial infarction.CONCLUSIONS: A neonatal leporine myocardial infarction model reveals that newborn rabbits are capable of age-dependent natural heart regeneration.

    View details for DOI 10.1016/j.jtcvs.2021.08.013

    View details for PubMedID 34649718

  • Heart Valve Biomechanics: The Frontiers of Modeling Modalities and the Expansive Capabilities of Ex Vivo Heart Simulation. Frontiers in cardiovascular medicine Park, M. H., Zhu, Y., Imbrie-Moore, A. M., Wang, H., Marin-Cuartas, M., Paulsen, M. J., Woo, Y. J. 2021; 8: 673689

    Abstract

    The field of heart valve biomechanics is a rapidly expanding, highly clinically relevant area of research. While most valvular pathologies are rooted in biomechanical changes, the technologies for studying these pathologies and identifying treatments have largely been limited. Nonetheless, significant advancements are underway to better understand the biomechanics of heart valves, pathologies, and interventional therapeutics, and these advancements have largely been driven by crucial in silico, ex vivo, and in vivo modeling technologies. These modalities represent cutting-edge abilities for generating novel insights regarding native, disease, and repair physiologies, and each has unique advantages and limitations for advancing study in this field. In particular, novel ex vivo modeling technologies represent an especially promising class of translatable research that leverages the advantages from both in silico and in vivo modeling to provide deep quantitative and qualitative insights on valvular biomechanics. The frontiers of this work are being discovered by innovative research groups that have used creative, interdisciplinary approaches toward recapitulating in vivo physiology, changing the landscape of clinical understanding and practice for cardiovascular surgery and medicine.

    View details for DOI 10.3389/fcvm.2021.673689

    View details for PubMedID 34307492

  • Electrophysiologic Conservation of Epicardial Conduction Dynamics After Myocardial Infarction in Newborn Piglets Wang, H., Pong, T., Lucian, H., Aparicio-Valenzuela, J., Tada, Y., Sakhamuri, S., Baker, S. W., Tran, N. A., Paulsen, M. J., Zhu, Y., Lee, A. M., Woo, Y. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Economic Analysis and Long-Term Follow-Up of Distant Referral for Degenerative Mitral Valve Repair. The Annals of thoracic surgery Brescia, A. A., Paulsen, M. J., Watt, T. M., Rosenbloom, L. M., Wisniewski, A. M., Li, J., Wang, G., Likosky, D. S., Hopp, W. J., Bolling, S. F., Michigan Mitral Research Group (MMRG) 2020

    Abstract

    BACKGROUND: Despite the superiority of mitral valve repair (MVr) over replacement for degenerative disease, repair rates vary widely across centers. Traveling to a Mitral Reference Center (MRC) is one way to increase the odds of MVr. This study assessed the economic value (quality/cost) and long-term outcomes of distant referral to a MRC.METHODS: Among 746 mitral surgery patients between January 2011-June 2013, low-risk patients with ejection fraction>40% undergoing isolated degenerative MVr were identified and included 26 out-of-state (DISTANT) and 104 in-state patients (LOCAL). Short- and long-term outcomes and institutional financial data (including travel expenses) were used to compare groups. National average and MRC-specific MVr rates, clinical outcomes, and marginal value of quality-adjusted life years collected from STS database and Medicare estimates were used to perform a nationally-representative cost-benefit analysis for distant referral.RESULTS: Age, ejection fraction, operative time, blood transfusions, and annuloplasty ring size did not differ between groups. Median charges were $76,022 for LOCAL and $74,171 for DISTANT (p=0.35), while median payments (including travel expenses) were $57,795 for LOCAL and $58,477 for DISTANT (p=0.70). Short- and long-term outcomes were similar between groups and median follow-up was 7.1 years. Estimated 5-year survival was 97% (96% for LOCAL and 100% for DISTANT; p=0.24). Cost-benefit analysis showed a net benefit through distant referral to a MRC ranging from $436-$6,078 to the payor and $22,163-$30,067 to the patient, combining for an estimated $22,599-$32,528 societal benefit.CONCLUSIONS: These data suggest that distant referral to a MRC is achievable and reasonable.

    View details for DOI 10.1016/j.athoracsur.2020.05.114

    View details for PubMedID 32693045

  • Ex Vivo Analysis of a Porcine Bicuspid Aortic Valve and Aneurysm Disease Model. The Annals of thoracic surgery Zhu, Y., Imbrie-Moore, A. M., Park, M. H., Paulsen, M. J., Wang, H., MacArthur, J. W., Woo, Y. J. 2020

    Abstract

    We identified an extremely rare congenital porcine type 0 lateral bicuspid aortic valve (BAV) from a fresh porcine heart. Using a 3D-printed ex vivo left heart simulator, we analyzed valvular hemodynamics at baseline, in an aortic aneurysm disease model, and after valve-sparing root replacement (VSRR). We showed that BAV regurgitation due to aortic aneurysm can be successfully repaired without significant hemodynamic impairment with the VSRR technique in an individualized approach. Our results provide direct hemodynamic evidence supporting the use of VSRR for patients with BAV regurgitation.

    View details for DOI 10.1016/j.athoracsur.2020.05.086

    View details for PubMedID 32663472

  • Novel bicuspid aortic valve model with aortic regurgitation for hemodynamic status analysis using an exvivo simulator. The Journal of thoracic and cardiovascular surgery Zhu, Y., Imbrie-Moore, A. M., Paulsen, M. J., Priromprintr, B., Wang, H., Lucian, H. J., Farry, J. M., Woo, Y. J. 2020

    Abstract

    OBJECTIVE: The objective was to design and evaluate a clinically relevant, novel exvivo bicuspid aortic valve model that mimics the most common human phenotype with associated aortic regurgitation.METHODS: Three bovine aortic valves were mounted asymmetrically in a previously validated 3-dimensional-printed left heart simulator. The non-right commissure and the non-left commissure were both shifted slightly toward the left-right commissure, and the left and right coronary cusps were sewn together. The left-right commissure was then detached and reimplanted 10mm lower than its native height. Free margin shortening was used for valve repair. Hemodynamic status, high-speed videography, and echocardiography data were collected before and after the repair.RESULTS: The bicuspid aortic valve model was successfully produced and repaired. High-speed videography confirmed prolapse of the fused cusp of the baseline bicuspid aortic valve models in diastole. Hemodynamic and pressure data confirmed accurate simulation of diseased conditions with aortic regurgitation and the subsequent repair. Regurgitant fraction postrepair was significantly reduced compared with that at baseline (14.5 ± 4.4% vs 28.6%±3.4%; P=.037). There was no change in peak velocity, peak gradient, or mean gradient across the valve pre- versus postrepair: 293.3±18.3cm/sec versus 325.3±58.2cm/sec (P=.29), 34.3±4.2mm Hg versus 43.3±15.4mm Hg (P=.30), and 11±1mm Hg versus 9.3±2.5mm Hg (P=.34), respectively.CONCLUSIONS: An exvivo bicuspid aortic valve model was designed that recapitulated the most common human phenotype with aortic regurgitation. These valves were successfully repaired, validating its potential for evaluating valve hemodynamics and optimizing surgical repair for bicuspid aortic valves.

    View details for DOI 10.1016/j.jtcvs.2020.06.028

    View details for PubMedID 32747120

  • Safety of photosynthetic Synechococcus elongatus for in vivo cyanobacteria-mammalian symbiotic therapeutics. Microbial biotechnology Williams, K. M., Wang, H., Paulsen, M. J., Thakore, A. D., Rieck, M., Lucian, H. J., Grady, F., Hironaka, C. E., Chien, A. J., Farry, J. M., Shin, H. S., Jaatinen, K. J., Eskandari, A., Stapleton, L. M., Steele, A. N., Cohen, J. E., Woo, Y. J. 2020

    Abstract

    The cyanobacterium Synechococcus elongatus (SE) has been shown to rescue ischaemic heart muscle after myocardial infarction by photosynthetic oxygen production. Here, we investigated SE toxicity and hypothesized that systemic SE exposure does not elicit a significant immune response in rats. Wistar rats intravenously received SE (n=12), sterile saline (n=12) or E. coli lipopolysaccharide (LPS, n=4), and a subset (8 SE, 8 saline) received a repeat injection 4weeks later. At baseline, 4h, 24h, 48h, 8days and 4weeks after injection, clinical assessments, blood cultures, blood counts, lymphocyte phenotypes, liver function tests, proinflammatory cytokines and immunoglobulins were assessed. Across all metrics, SE rats responded comparably to saline controls, displaying no clinically significant immune response. As expected, LPS rats exhibited severe immunological responses. Systemic SE administration does not induce sepsis or toxicity in rats, thereby supporting the safety of cyanobacteria-mammalian symbiotic therapeutics using this organism.

    View details for DOI 10.1111/1751-7915.13596

    View details for PubMedID 32476224

  • Multiaxial Lenticular Stress-Strain Relationship of Native Myocardium is Preserved by Infarct-Induced Natural Heart Regeneration in Neonatal Mice. Scientific reports Wang, H., Bennett-Kennett, R., Paulsen, M. J., Hironaka, C. E., Thakore, A. D., Farry, J. M., Eskandari, A., Lucian, H. J., Shin, H. S., Wu, M. A., Imbrie-Moore, A. M., Steele, A. N., Stapleton, L. M., Zhu, Y., Dauskardt, R. H., Woo, Y. J. 2020; 10 (1): 7319

    Abstract

    Neonatal mice exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). Cardiac biomechanics intricately affect long-term heart function, but whether regenerated cardiac muscle is biomechanically similar to native myocardium remains unknown. We hypothesized that neonatal heart regeneration preserves native left ventricular (LV) biomechanical properties after MI. C57BL/6J mice underwent sham surgery or left anterior descending coronary artery ligation at age P1 or P7. Echocardiography performed 4 weeks post-MI showed that P1 MI and sham mice (n=22, each) had similar LV wall thickness, diameter, and ejection fraction (59.6% vs 60.7%, p=0.6514). Compared to P7 shams (n=20), P7 MI mice (n=20) had significant LV wall thinning, chamber enlargement, and depressed ejection fraction (32.6% vs 61.8%, p<0.0001). Afterward, the LV was explanted and pressurized ex vivo, and the multiaxial lenticular stress-strain relationship was tracked. While LV tissue modulus for P1 MI and sham mice were similar (341.9 kPa vs 363.4 kPa, p=0.6140), the modulus for P7 MI mice was significantly greater than that for P7 shams (691.6 kPa vs 429.2 kPa, p=0.0194). We conclude that, in neonatal mice, regenerated LV muscle has similar biomechanical properties as native LV myocardium.

    View details for DOI 10.1038/s41598-020-63324-w

    View details for PubMedID 32355240

  • A novel cross-species model of Barlow's disease to biomechanically analyze repair techniques in an exvivo left heart simulator. The Journal of thoracic and cardiovascular surgery Imbrie-Moore, A. M., Paulsen, M. J., Zhu, Y., Wang, H., Lucian, H. J., Farry, J. M., MacArthur, J. W., Ma, M., Woo, Y. J. 2020

    Abstract

    OBJECTIVE: Barlow's disease remains challenging to repair, given the complex valvular morphology and lack of quantitative data to compare techniques. Although there have been recent strides in exvivo evaluation of cardiac mechanics, to our knowledge, there is no disease model that accurately simulates the morphology and pathophysiology of Barlow's disease. The purpose of this study was to design such a model.METHODS: To simulate Barlow's disease, a cross-species exvivo model was developed. Bovine mitral valves (n=4) were sewn into a porcine annulus mount to create excess leaflet tissue and elongated chordae. A heart simulator generated physiologic conditions while hemodynamic data, high-speed videography, and chordal force measurements were collected. The regurgitant valves were repaired using nonresectional repair techniques such as neochord placement.RESULTS: The model successfully imitated the complexities of Barlow's disease, including redundant, billowing bileaflet tissues with notable regurgitation. After repair, hemodynamic data confirmed reduction of mitral leakage volume (25.9±2.9 vs 2.1±1.8mL, P<.001) and strain gauge analysis revealed lower primary chordae forces (0.51±0.17 vs 0.10±0.05N, P<.001). In addition, the maximum rate of change of force was significantly lower postrepair for both primary (30.80±11.38 vs 8.59±4.83N/s, P<.001) and secondary chordae (33.52±10.59 vs 19.07±7.00N/s, P=.006).CONCLUSIONS: This study provides insight into the biomechanics of Barlow's disease, including sharply fluctuating force profiles experienced by elongated chordae prerepair, as well as restoration of primary chordae forces postrepair. Our disease model facilitates further in-depth analyses to optimize the repair of Barlow's disease.

    View details for DOI 10.1016/j.jtcvs.2020.01.086

    View details for PubMedID 32249088

  • A novel 3D-Printed preferential posterior mitral annular dilation device delineates regurgitation onset threshold in an ex vivo heart simulator. Medical engineering & physics Imbrie-Moore, A. M., Paullin, C. C., Paulsen, M. J., Grady, F., Wang, H., Hironaka, C. E., Farry, J. M., Lucian, H. J., Woo, Y. J. 2020

    Abstract

    Mitral regurgitation (MR) due to annular dilation occurs in a variety of mitral valve diseases and is observed in many patients with heart failure due to mitral regurgitation. To understand the biomechanics of MR and ultimately design an optimized annuloplasty ring, a representative disease model with asymmetric dilation of the mitral annulus is needed. This work shows the design and implementation of a 3D-printed valve dilation device to preferentially dilate the posterior mitral valve annulus. Porcine mitral valves (n=3) were sewn into the device and mounted within a left heart simulator that generates physiologic pressures and flows through the valves, while chordal forces were measured. The valves were incrementally dilated, inducing MR, while hemodynamic and force data were collected. Flow analysis demonstrated that MR increased linearly with respect to percent annular dilation when dilation was greater than a 25.6% dilation threshold (p<0.01). Pre-threshold, dilation did not cause significant increases in regurgitant fraction. Forces on the chordae tendineae increased as dilation increased prior to the identified threshold (p < 0.01); post-threshold, the MR resulted in highly variable forces. Ultimately, this novel dilation device can be used to more accurately model a wide range of MR disease states and their corresponding repair techniques using ex vivo experimentation. In particular, this annular dilation device provides the means to investigate the design and optimization of novel annuloplasty rings.

    View details for DOI 10.1016/j.medengphy.2020.01.005

    View details for PubMedID 32008935

  • Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model. Cells Wang, H., Paulsen, M. J., Hironaka, C. E., Shin, H. S., Farry, J. M., Thakore, A. D., Jung, J., Lucian, H. J., Eskandari, A., Anilkumar, S., Wu, M. A., Cabatu, M. C., Steele, A. N., Stapleton, L. M., Zhu, Y., Woo, Y. J. 2020; 9 (1)

    Abstract

    Newborn mice and piglets exhibit natural heart regeneration after myocardial infarction (MI). Discovering other mammals with this ability would provide evidence that neonatal cardiac regeneration after MI may be a conserved phenotype, which if activated in adults could open new options for treating ischemic cardiomyopathy in humans. Here, we hypothesized that newborn rats undergo natural heart regeneration after MI. Using a neonatal rat MI model, we performed left anterior descending coronary artery ligation or sham surgery in one-day-old rats under hypothermic circulatory arrest (n = 74). Operative survival was 97.3%. At 1 day post-surgery, rats in the MI group exhibited significantly reduced ejection fraction (EF) compared to shams (87.1% vs. 53.0%, p < 0.0001). At 3 weeks post-surgery, rats in the sham and MI groups demonstrated no difference in EF (71.1% vs. 69.2%, respectively, p = 0.2511), left ventricular wall thickness (p = 0.9458), or chamber diameter (p = 0.7801). Masson's trichome and picrosirius red staining revealed minimal collagen scar after MI. Increased numbers of cardiomyocytes positive for 5-ethynyl-2'-deoxyuridine (p = 0.0072), Ki-67 (p = 0.0340), and aurora B kinase (p = 0.0430) were observed within the peri-infarct region after MI, indicating ischemia-induced cardiomyocyte proliferation. Overall, we present a neonatal rat MI model and demonstrate that newborn rats are capable of endogenous neocardiomyogenesis after MI.

    View details for DOI 10.3390/cells9010229

    View details for PubMedID 31963369

  • Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model. Cytokine Steele, A. N., Paulsen, M. J., Wang, H. n., Stapleton, L. M., Lucian, H. J., Eskandari, A. n., Hironaka, C. E., Farry, J. M., Baker, S. W., Thakore, A. D., Jaatinen, K. J., Tada, Y. n., Hollander, M. J., Williams, K. M., Seymour, A. J., Totherow, K. P., Yu, A. C., Cochran, J. R., Appel, E. A., Woo, Y. J. 2020; 127: 154974

    Abstract

    Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1α (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.

    View details for DOI 10.1016/j.cyto.2019.154974

    View details for PubMedID 31978642

  • SELECTIVELY COMPLIANT ANNULOPLASTY RING TO ENABLE ANNULAR DYNAMICS IN MITRAL VALVE REPAIR EVALUATED BY IN-VITRO STEREOVISION Frishman, S., Imbrie-Moore, A. M., Cutkosky, M. R., Kight, A., Pirozzi, I., Paulsen, M. J., Woo, J. Y., Am Soc Mech Eng AMER SOC MECHANICAL ENGINEERS. 2020
  • Artificial papillary muscle device for off-pump transapical mitral valve repair. The Journal of thoracic and cardiovascular surgery Imbrie-Moore, A. M., Zhu, Y. n., Park, M. H., Paulsen, M. J., Wang, H. n., Woo, Y. J. 2020

    Abstract

    New transapical minimally invasive artificial chordae implantation devices are a promising alternative to traditional open-heart repair, with the potential for decreased postoperative morbidity and reduced recovery time. However, these devices can place increased stress on the artificial chordae. We designed an artificial papillary muscle to alleviate artificial chordae stresses and thus increase repair durability.The artificial papillary muscle device is a narrow elastic column with an inner core that can be implanted during the minimally invasive transapical procedure via the same ventricular incision site. The device was 3-dimensionally printed in biocompatible silicone for this study. To test efficacy, porcine mitral valves (n = 6) were mounted in a heart simulator, and isolated regurgitation was induced. Each valve was repaired with a polytetrafluoroethylene suture with apical anchoring followed by artificial papillary muscle anchoring. In each case, a high-resolution Fiber Bragg Grating sensor recorded forces on the suture.Hemodynamic data confirmed that both repairs-with and without the artificial papillary muscle device-were successful in eliminating mitral regurgitation. Both the peak artificial chordae force and the rate of change of force at the onset of systole were significantly lower with the device compared with apical anchoring without the device (P < .001 and P < .001, respectively).Our novel artificial papillary muscle could integrate with minimally invasive repairs to shorten the artificial chordae and behave as an elastic damper, thus reducing sharp increases in force. With our device, we have the potential to improve the durability of off-pump transapical mitral valve repair procedures.

    View details for DOI 10.1016/j.jtcvs.2020.11.105

    View details for PubMedID 33451843

  • Biomimetic six-axis robots replicate human cardiac papillary muscle motion: pioneering the next generation of biomechanical heart simulator technology. Journal of the Royal Society, Interface Imbrie-Moore, A. M., Park, M. H., Paulsen, M. J., Sellke, M. n., Kulkami, R. n., Wang, H. n., Zhu, Y. n., Farry, J. M., Bourdillon, A. T., Callinan, C. n., Lucian, H. J., Hironaka, C. E., Deschamps, D. n., Joseph Woo, Y. n. 2020; 17 (173): 20200614

    Abstract

    Papillary muscles serve as attachment points for chordae tendineae which anchor and position mitral valve leaflets for proper coaptation. As the ventricle contracts, the papillary muscles translate and rotate, impacting chordae and leaflet kinematics; this motion can be significantly affected in a diseased heart. In ex vivo heart simulation, an explanted valve is subjected to physiologic conditions and can be adapted to mimic a disease state, thus providing a valuable tool to quantitatively analyse biomechanics and optimize surgical valve repair. However, without the inclusion of papillary muscle motion, current simulators are limited in their ability to accurately replicate cardiac biomechanics. We developed and implemented image-guided papillary muscle (IPM) robots to mimic the precise motion of papillary muscles. The IPM robotic system was designed with six degrees of freedom to fully capture the native motion. Mathematical analysis was used to avoid singularity conditions, and a supercomputing cluster enabled the calculation of the system's reachable workspace. The IPM robots were implemented in our heart simulator with motion prescribed by high-resolution human computed tomography images, revealing that papillary muscle motion significantly impacts the chordae force profile. Our IPM robotic system represents a significant advancement for ex vivo simulation, enabling more reliable cardiac simulations and repair optimizations.

    View details for DOI 10.1098/rsif.2020.0614

    View details for PubMedID 33259750

  • A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model. Journal of cardiovascular development and disease Cohen, J. E., Goldstone, A. B., Wang, H. n., Purcell, B. P., Shudo, Y. n., MacArthur, J. W., Steele, A. N., Paulsen, M. J., Edwards, B. B., Aribeana, C. N., Cheung, N. C., Burdick, J. A., Woo, Y. J. 2020; 7 (4)

    Abstract

    The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy's potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure-volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure-volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.

    View details for DOI 10.3390/jcdd7040053

    View details for PubMedID 33212844

  • Comprehensive Ex Vivo Comparison of 5 Clinically Used Conduit Configurations for Valve-Sparing Aortic Root Replacement Using a 3-Dimensional-Printed Heart Simulator. Circulation Paulsen, M. J., Imbrie-Moore, A. M., Baiocchi, M. n., Wang, H. n., Hironaka, C. E., Lucian, H. J., Farry, J. M., Thakore, A. D., Zhu, Y. n., Ma, M. n., MacArthur, J. W., Woo, Y. J. 2020; 142 (14): 1361–73

    Abstract

    Many graft configurations are clinically used for valve-sparing aortic root replacement, some specifically focused on recapitulating neosinus geometry. However, the specific impact of such neosinuses on valvular and root biomechanics and the potential influence on long-term durability are unknown.Using a custom 3-dimenstional-printed heart simulator with porcine aortic roots (n=5), the anticommissural plication, Stanford modification, straight graft (SG), Uni-Graft, and Valsalva graft configurations were tested in series using an incomplete counterbalanced measures design, with the native root as a control, to mitigate ordering effects. Hemodynamic and videometric data were analyzed using linear models with conduit as the fixed effect of interest and valve as a fixed nuisance effect with post hoc pairwise testing using Tukey's correction.Hemodynamics were clinically similar between grafts and control aortic roots. Regurgitant fraction varied between grafts, with SG and Uni-Graft groups having the lowest regurgitant fractions and anticommissural plication having the highest. Root distensibility was significantly lower in SG versus both control roots and all other grafts aside from the Stanford modification (P≤0.01 for each). All grafts except SG had significantly higher cusp opening velocities versus native roots (P<0.01 for each). Relative cusp opening forces were similar between SG, Uni-Graft, and control groups, whereas anticommissural plication, Stanford modification, and Valsalva grafts had significantly higher opening forces versus controls (P<0.01). Cusp closing velocities were similar between native roots and the SG group, and were significantly lower than observed in the other conduits (P≤0.01 for each). Only SG and Uni-Graft groups experienced relative cusp closing forces approaching that of the native root, whereas relative forces were >5-fold higher in the anticommissural plication, Stanford modification, and Valsalva graft groups.In this ex vivo modeling system, clinically used valve-sparing aortic root replacement conduit configurations have comparable hemodynamics but differ in biomechanical performance, with the straight graft most closely recapitulating native aortic root biomechanics.

    View details for DOI 10.1161/CIRCULATIONAHA.120.046612

    View details for PubMedID 33017215

  • Quadrupling the N95 Supply during the COVID-19 Crisis with an Innovative 3D-Printed Mask Adaptor. Healthcare (Basel, Switzerland) Imbrie-Moore, A. M., Park, M. H., Zhu, Y. n., Paulsen, M. J., Wang, H. n., Woo, Y. J. 2020; 8 (3)

    Abstract

    The need for personal protective equipment during the COVID-19 pandemic is far outstripping our ability to manufacture and distribute these supplies to hospitals. In particular, the medical N95 mask shortage is resulting in healthcare providers reusing masks or utilizing masks with filtration properties that do not meet medical N95 standards. We developed a solution for immediate use: a mask adaptor, outfitted with a quarter section of an N95 respirator that maintains the N95 seal standard, thereby quadrupling the N95 supply. A variety of designs were 3D-printed and optimized based on the following criteria: seal efficacy, filter surface area and N95 respirator multiplicity. The final design is reusable and features a 3D-printed soft silicone base as well as a rigid 3D-printed cartridge to seal one-quarter of a 3M 1860 N95 mask. Our mask passed the computerized N95 fit test for six individuals. All files are publicly available with this publication. Our design can provide immediate support for healthcare professionals in dire need of medical N95 masks by extending the current supply by a factor of four.

    View details for DOI 10.3390/healthcare8030225

    View details for PubMedID 32717841

  • A Novel Aortic Regurgitation Model from Cusp Prolapse with Hemodynamic Validation Using an Ex Vivo Left Heart Simulator. Journal of cardiovascular translational research Zhu, Y. n., Imbrie-Moore, A. M., Paulsen, M. J., Priromprintr, B. n., Park, M. H., Wang, H. n., Lucian, H. J., Farry, J. M., Woo, Y. J. 2020

    Abstract

    Although ex vivo simulation is a valuable tool for surgical optimization, a disease model that mimics human aortic regurgitation (AR) from cusp prolapse is needed to accurately examine valve biomechanics. To simulate AR, four porcine aortic valves were explanted, and the commissure between the two largest leaflets was detached and re-implanted 5 mm lower to induce cusp prolapse. Four additional valves were tested in their native state as controls. All valves were tested in a heart simulator while hemodynamics, high-speed videography, and echocardiography data were collected. Our AR model successfully reproduced cusp prolapse with significant increase in regurgitant volume compared with that of the controls (23.2 ± 8.9 versus 2.8 ± 1.6 ml, p = 0.017). Hemodynamics data confirmed the simulation of physiologic disease conditions. Echocardiography and color flow mapping demonstrated the presence of mild to moderate eccentric regurgitation in our AR model. This novel AR model has enormous potential in the evaluation of valve biomechanics and surgical repair techniques. Graphical Abstract.

    View details for DOI 10.1007/s12265-020-10038-z

    View details for PubMedID 32495264

  • In Vivo Validation of Restored Chordal Biomechanics After Mitral Ring Annuloplasty in a Rare Ovine Case of Natural Chronic Functional Mitral Regurgitation. Journal of cardiovascular development and disease Wang, H. n., Paulsen, M. J., Imbrie-Moore, A. M., Tada, Y. n., Bergamasco, H. n., Baker, S. W., Shudo, Y. n., Ma, M. n., Woo, J. Y. 2020; 7 (2)

    Abstract

    Mitral valve chordae tendineae forces are elevated in the setting of mitral regurgitation (MR). Ring annuloplasty is an essential component of surgical repair for MR, but whether chordal forces are reduced after mitral annuloplasty has never been validated in vivo. Here, we present an extremely rare ovine case of natural, severe chronic functional MR, in which we used force-sensing fiber Bragg grating neochordae to directly measure chordal forces in the baseline setting of severe MR, as well as after successful mitral ring annuloplasty repair. Overall, our report is the first to confirm in vivo that mitral ring annuloplasty reduces elevated chordae tendineae forces associated with chronic functional MR.

    View details for DOI 10.3390/jcdd7020017

    View details for PubMedID 32429298

  • Mitral chordae tendineae force profile characterization using a posterior ventricular anchoring neochordal repair model for mitral regurgitation in a three-dimensional-printed ex vivo left heart simulator. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery Paulsen, M. J., Imbrie-Moore, A. M., Wang, H., Bae, J. H., Hironaka, C. E., Farry, J. M., Lucian, H. J., Thakore, A. D., MacArthur, J. W., Cutkosky, M. R., Woo, Y. J. 2019

    Abstract

    OBJECTIVES: Posterior ventricular anchoring neochordal (PVAN) repair is a non-resectional technique for correcting mitral regurgitation (MR) due to posterior leaflet prolapse, utilizing a single suture anchored in the myocardium behind the leaflet. This technique has demonstrated clinical efficacy, although a theoretical limitation is stability of the anchoring suture. We hypothesize that the PVAN suture positions the leaflet for coaptation, after which forces are distributed evenly with low repair suture forces.METHODS: Porcine mitral valves were mounted in a 3-dimensional-printed heart simulator and chordal forces, haemodynamics and echocardiography were collected at baseline, after inducing MR by severing chordae, and after PVAN repair. Repair suture forces were measured with a force-sensing post positioned to mimic in vivo suture placement. Forces required to pull the myocardial suture free were also determined.RESULTS: Relative primary and secondary chordae forces on both leaflets were elevated during prolapse (P<0.05). PVAN repair eliminated MR in all valves and normalized chordae forces to baseline levels on anterior primary (0.37±0.23 to 0.22±0.09 N, P<0.05), posterior primary (0.62±0.37 to 0.14±0.05 N, P=0.001), anterior secondary (1.48±0.52 to 0.85±0.43 N, P<0.001) and posterior secondary chordae (1.42±0.69 to 0.59±0.17 N, P=0.005). Repair suture forces were minimal, even compared to normal primary chordae forces (0.08±0.04 vs 0.19±0.08 N, P=0.002), and were 90 times smaller than maximum forces tolerated by the myocardium (0.08±0.04 vs 6.9±1.3 N, P<0.001).DISCUSSION: PVAN repair eliminates MR by positioning the posterior leaflet for coaptation, distributing forces throughout the valve. Given extremely low measured forces, the strength of the repair suture and the myocardium is not a limitation.

    View details for DOI 10.1093/ejcts/ezz258

    View details for PubMedID 31638697

  • Custom Patient-Specific Three-Dimensional Printed Mitral Valve Models for Pre-Operative Patient Education Enhance Patient Satisfaction and Understanding JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME Hung, K. S., Paulsen, M. J., Wang, H., Hironaka, C., Woo, Y. 2019; 13 (3)

    View details for DOI 10.1115/1.4043737

    View details for Web of Science ID 000483046800013

  • Neonatal Heart Regeneration Preserves Native Ventricular Biomechanical Properties After Myocardial Infarction Wang, H., Bennett-Kennett, R., Paulsen, M. J., Hironaka, C. E., Thakore, A. D., Farry, J. M., Eskandari, A., Lucian, H. J., Wu, M. A., Imbrie-Moore, A., Steele, A. N., Stapleton, L. M., Dauskardt, R. H., Woo, Y. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Bioengineered analog of stromal cell-derived factor 1 alpha preserves the biaxial mechanical properties of native myocardium after infarction JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS Wang, H., Wisneski, A., Paulsen, M. J., Imbrie-Moore, A., Wang, Z., Xuan, Y., Hernandez, H., Lucian, H. J., Eskandari, A., Thakore, A. D., Parry, J. M., Hironaka, C. E., von Bornstaedt, D., Steele, A. N., Stapleton, L. M., Williams, K. M., Wu, M. A., MacArthur, J. W., Woo, Y. 2019; 96: 165–71
  • Modeling conduit choice for valve-sparing aortic root replacement on biomechanics with a 3-dimensional-printed heart simulator JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Paulsen, M. J., Kasinpila, P., Imbrie-Moore, A. M., Wang, H., Hironaka, C. E., Koyano, T. K., Fong, R., Chiu, P., Goldstone, A. B., Steele, A. N., Stapleton, L. M., Ma, M., Woo, Y. 2019; 158 (2): 392–403
  • Ex Vivo Biomechanical Study of Apical Versus Papillary Neochord Anchoring for Mitral Regurgitation Imbrie-Moore, A. M., Paulsen, M. J., Thakore, A. D., Wang, H., Hironaka, C. E., Lucian, H. J., Farry, J. M., Edwards, B. B., Bae, J., Cutkosky, M. R., Woo, Y. ELSEVIER SCIENCE INC. 2019: 90–97
  • A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering ADVANCED HEALTHCARE MATERIALS Steele, A. N., Stapleton, L. M., Farry, J. M., Lucian, H. J., Paulsen, M. J., Eskandari, A., Hironaka, C. E., Thakore, A. D., Wang, H., Yu, A. C., Chan, D., Appel, E. A., Woo, Y. 2019; 8 (5)
  • Ex vivo biomechanical study of apical versus papillary neochord anchoring for mitral regurgitation. The Annals of thoracic surgery Imbrie-Moore, A. M., Paulsen, M. J., Thakore, A. D., Wang, H., Hironaka, C. E., Lucian, H. J., Farry, J. M., Edwards, B. B., Bae, J. H., Cutkosky, M. R., Woo, Y. J. 2019

    Abstract

    BACKGROUND: Neochordoplasty is an important repair technique, though optimal anchoring position is unknown. While typically anchored at papillary muscles, new percutaneous devices anchor the chordae at or near the ventricular apex, which may have an effect on chordal forces and the long-term durability of the repair.METHODS: Porcine mitral valves (n=6) were mounted in a left heart simulator that generates physiological pressure and flow through the valves while chordal forces were measured using Fiber Bragg Grating strain gauge sensors. Isolated mitral regurgitation was induced by cutting P2 primary chordae and the regurgitant valve was repaired using PTFE neochord with apical anchoring, followed by papillary muscle fixation for comparison. In both cases, the neochord was anchored to a customized force-sensing post positioned to mimic the relevant in vivo placement.RESULTS: Echocardiographic and hemodynamic data confirmed that the repairs restored physiologic hemodynamics. Forces on the chordae and neochord were lower for papillary fixation than the apical (p=0.003). Additionally, the maximum rate of change of force was higher for the chordae and neochord for apical fixation when compared to papillary (p=0.028).CONCLUSIONS: Apical point of anchoring results in higher forces on the chordae and neochord stitch as well as an increased rate of loading on the neochord when compared to the papillary muscle fixation. These results suggest the papillary fixation repair may have superior durability.

    View details for PubMedID 30836099

  • A Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration CELL Das, S., Goldstone, A. B., Wang, H., Farry, J., D'Amato, G., Paulsen, M. J., Eskandari, A., Hironaka, C. E., Phansalkar, R., Sharma, B., Rhee, S., Shamskhou, E., Agalliu, D., Perez, V., Woo, Y., Red-Horse, K. 2019; 176 (5): 1128-+
  • A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering. Advanced healthcare materials Steele, A. N., Stapleton, L. M., Farry, J. M., Lucian, H. J., Paulsen, M. J., Eskandari, A., Hironaka, C. E., Thakore, A. D., Wang, H., Yu, A. C., Chan, D., Appel, E. A., Woo, Y. J. 2019: e1801147

    Abstract

    Hydrogels have emerged as a diverse class of biomaterials offering a broad range of biomedical applications. Specifically, injectable hydrogels are advantageous for minimally invasive delivery of various therapeutics and have great potential to treat a number of diseases. However, most current injectable hydrogels are limited by difficult and time-consuming fabrication techniques and are unable to be delivered through long, narrow catheters, preventing extensive clinical translation. Here, the development of an easily-scaled, catheter-injectable hydrogel utilizing a polymer-nanoparticle crosslinking mechanism is reported, which exhibits notable shear-thinning and self-healing behavior. Gelation of the hydrogel occurs immediately upon mixing the biochemically modified hyaluronic acid polymer with biodegradable nanoparticles and can be easily injected through a high-gauge syringe due to the dynamic nature of the strong, yet reversible crosslinks. Furthermore, the ability to deliver this novel hydrogel through a long, narrow, physiologically-relevant catheter affixed with a 28-G needle is highlighted, with hydrogel mechanics unchanged after delivery. Due to the composition of the gel, it is demonstrated that therapeutics can be differentially released with distinct elution profiles, allowing precise control over drug delivery. Finally, the cell-signaling and biocompatibility properties of this innovative hydrogel are demonstrated, revealing its wide range of therapeutic applications.

    View details for PubMedID 30714355

  • A Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration. Cell Das, S., Goldstone, A. B., Wang, H., Farry, J., D'Amato, G., Paulsen, M. J., Eskandari, A., Hironaka, C. E., Phansalkar, R., Sharma, B., Rhee, S., Shamskhou, E. A., Agalliu, D., de Jesus Perez, V., Woo, Y. J., Red-Horse, K. 2019

    Abstract

    Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.

    View details for PubMedID 30686582

  • Use of a supramolecular polymeric hydrogel as an effective post-operative pericardial adhesion barrier. Nature biomedical engineering Stapleton, L. M., Steele, A. N., Wang, H. n., Lopez Hernandez, H. n., Yu, A. C., Paulsen, M. J., Smith, A. A., Roth, G. A., Thakore, A. D., Lucian, H. J., Totherow, K. P., Baker, S. W., Tada, Y. n., Farry, J. M., Eskandari, A. n., Hironaka, C. E., Jaatinen, K. J., Williams, K. M., Bergamasco, H. n., Marschel, C. n., Chadwick, B. n., Grady, F. n., Ma, M. n., Appel, E. A., Woo, Y. J. 2019; 3 (8): 611–20

    Abstract

    Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.

    View details for DOI 10.1038/s41551-019-0442-z

    View details for PubMedID 31391596

  • Development and ex vivo validation of novel force-sensing neochordae for measuring chordae tendineae tension in the mitral valve apparatus using optical fibers with embedded Bragg gratings. Journal of biomechanical engineering Paulsen, M. J., Bae, J. H., Imbrie-Moore, A. n., Wang, H. n., Hironaka, C. n., Farry, J. M., Lucian, H. n., Thakore, A. n., Cutkosky, M. R., Woo, Y. J. 2019

    Abstract

    Few technologies exist that can provide quantitative data on forces within the mitral valve apparatus. Marker-based strain measurements can be performed, but chordal geometry and restricted optical access are limitations. Foil-based strain sensors have been described and work well, but the sensor footprint limits the number of chordae that can be measured. We instead utilized Fiber Bragg Grating (FBG) sensors-optical strain gauges made of 125µm diameter silica fibers- to overcome some limitations of previous methods of measuring chordae tendineae forces. Using FBG sensors, we created a force-sensing neochord that mimics the natural shape and movement of native chordae. FBG sensors reflect a specific wavelength of light depending on the spatial period of gratings. When force is applied, the gratings move relative to one another, shifting the wavelength of reflected light. This shift is directly proportional to force applied. The FBG sensors were housed in a protective sheath fashioned from a 0.025" flat coil, and attached to the chordae using polytetrafluoroethylene suture. The function of the force-sensing neochordae was validated in a 3D-printed left heart simulator, which demonstrated that FBG sensors provide highly sensitive force measurements of mitral valve chordae at a temporal resolution of 1000 Hz. As ventricular pressures increased, such as in hypertension, chordae forces also increased. Overall, FBG sensors are a viable, durable, and high-fidelity sensing technology that can be effectively used to measure mitral valve chordae forces and overcome some limitations of other such technologies.

    View details for DOI 10.1115/1.4044142

    View details for PubMedID 31253992

  • Bioengineered analog of stromal cell-derived factor 1α preserves the biaxial mechanical properties of native myocardium after infarction. Journal of the mechanical behavior of biomedical materials Wang, H. n., Wisneski, A. n., Paulsen, M. J., Imbrie-Moore, A. n., Wang, Z. n., Xuan, Y. n., Hernandez, H. L., Lucian, H. J., Eskandari, A. n., Thakore, A. D., Farry, J. M., Hironaka, C. E., von Bornstaedt, D. n., Steele, A. N., Stapleton, L. M., Williams, K. M., Wu, M. A., MacArthur, J. W., Woo, Y. J. 2019; 96: 165–71

    Abstract

    Adverse remodeling of the left ventricle (LV) after myocardial infarction (MI) results in abnormal tissue biomechanics and impaired cardiac function, often leading to heart failure. We hypothesized that intramyocardial delivery of engineered stromal cell-derived factor 1α analog (ESA), our previously-developed supra-efficient pro-angiogenic chemokine, preserves biaxial LV mechanical properties after MI. Male Wistar rats (n = 45) underwent sham surgery (n = 15) or permanent left anterior descending coronary artery ligation. Rats sustaining MI were randomized for intramyocardial injections of either saline (100 μL, n = 15) or ESA (6 μg/kg, n = 15), delivered at four standardized borderzone sites. After 4 weeks, echocardiography was performed, and the hearts were explanted. Tensile testing of the anterolateral LV wall was performed using a displacement-controlled biaxial load frame, and modulus was determined after constitutive modeling. At 4 weeks post-MI, compared to saline controls, ESA-treated hearts had greater wall thickness (1.68 ± 0.05 mm vs 1.42 ± 0.08 mm, p = 0.008), smaller end-diastolic LV internal dimension (6.88 ± 0.29 mm vs 7.69 ± 0.22 mm, p = 0.044), and improved ejection fraction (62.8 ± 3.0% vs 49.4 ± 4.5%, p = 0.014). Histologic analysis revealed significantly reduced infarct size for ESA-treated hearts compared to saline controls (29.4 ± 2.9% vs 41.6 ± 3.1%, p = 0.021). Infarcted hearts treated with ESA exhibited decreased modulus compared to those treated with saline in both the circumferential (211.5 ± 6.9 kPa vs 264.3 ± 12.5 kPa, p = 0.001) and longitudinal axes (194.5 ± 6.5 kPa vs 258.1 ± 14.4 kPa, p < 0.001). In both principal directions, ESA-treated infarcted hearts possessed similar tissue compliance as sham non-infarcted hearts. Overall, intramyocardial ESA therapy improves post-MI ventricular remodeling and function, reduces infarct size, and preserves native LV biaxial mechanical properties.

    View details for PubMedID 31035067

  • Modeling conduit choice for valve-sparing aortic root replacement on biomechanics with a 3-dimensional-printed heart simulator. The Journal of thoracic and cardiovascular surgery Paulsen, M. J., Kasinpila, P., Imbrie-Moore, A. M., Wang, H., Hironaka, C. E., Koyano, T. K., Fong, R., Chiu, P., Goldstone, A. B., Steele, A. N., Stapleton, L. M., Ma, M., Woo, Y. J. 2018

    Abstract

    OBJECTIVE: The optimal conduit for valve-sparing aortic root replacement is still debated, with several conduit variations available, ranging from straight tubular grafts to Valsalva grafts. Benefits of neosinus reconstruction include enhanced flow profiles and improved hemodynamics. Curiously, however, some clinical data suggest that straight grafts may have greater long-term durability. In this study, we hypothesized that straight tubular grafts may help maintain the native cylindrical position of the aortic valve commissures radially, resulting in preserved leaflet coaptation, reduced stresses, and potentially improved valve performance.METHODS: Using 3D printing, a left heart simulator with a valve-sparing root replacement model and a physiologic coronary circulation was constructed. Aortic valves were dissected from fresh porcine hearts and reimplanted into either straight tubular grafts (n=6) or Valsalva grafts (n=6). Conduits were mounted into the heart simulator and hemodynamic, echocardiographic, and high-speed videometric data were collected.RESULTS: Hemodynamic parameters and coronary blood flow were similar between straight and Valsalva grafts, although the former were associated with lower regurgitant fractions, less peak intercommissural radial separation, preserved leaflet coaptation, decreased leaflet velocities, and lower relative leaflet forces compared with Valsalva grafts.CONCLUSIONS: Valsalva grafts and straight grafts perform equally well in terms of gross hemodyanics and coronary blood flow. Interestingly, however, the biomechanics of these 2 conduits differ considerably, with straight grafts providing increased radial commissural stability and leaflet coaptation. Further investigation into how these parameters influence clinical outcomes is warranted.

    View details for PubMedID 30745047

  • Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets CIRCULATION von Bornstadt, D., Wang, H., Paulsen, M. J., Goldstone, A. B., Eskandari, A., Thakore, A., Stapleton, L., Steele, A. N., Truong, V. N., Jaatinen, K., Hironaka, C., Woo, Y. 2018; 138 (19): 2130–44
  • A Novel, Shear-Thinning and Rapidly Self-Healing Polymer Nanoparticle Hydrogel Diminishes Post-Operative Adhesions in Rodent and Ovine Models of Cardiac Adhesion Formation Stapleton, L. M., Steele, A. N., Wang, H. N., Paulsen, M. J., Hernandez, H. L., Lucian, H. J., Smith, A. A., Yu, A. C., Thakore, A. D., Eskandari, A., Farry, J. M., Williams, K. N., Hironaka, C. N., Totherow, K. P., Jaatinen, K. J., Appel, E. A., Woo, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Experimental Insights Into Transapical Neochordplasty: A Quantitative Examination of Neochord Placement Using an Ex Vivo Left Heart Simulator Imbrie-Moore, A. M., Paulsen, M. J., Bae, J. H., Farry, J. M., Wang, H., Hironaka, C. E., Edwards, B. B., Thakore, A. D., Lucien, H. J., Deschamps, D. M., Kulkarni, R., Cutkosky, M. R., Won, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Computationally-Engineered Analog of Stromal Cell-Derived Factor 1[alpha] Preserves the Mechanical Properties of Infarcted Myocardium Under Planar Biaxial Tension Wang, H., Wisneski, A., Paulsen, M. J., Wang, Z., Hernandez, L., Xuan, Y., von Bornstaedt, D., Steele, A. N., Stapleton, L. M., Lucian, H. J., Anahita, E., Thakore, A. D., Farry, J. M., Hironaka, C. E., Williams, K. M., Wu, M., MacArthur, J. W., Woo, Y. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • A 3D Printed Ex Vivo Left Heart Simulator Quantifies and Validates Posterior Ventricular Anchoring Neochordoplasty Paulsen, M. J., Bae, J., Imbrie-Moore, A. M., Wang, H., Farry, J. M., Lin, M. A., Hironaka, C. E., Lucian, H. J., Edwards, B. B., Thankore, A. D., MacArthur, J. W., Steele, A. N., Stapleton, L., Williams, K. M., Deschamps, D., Kulkarni, R., Cutkosky, M. R., Woo, Y. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Development and Ex Vivo Validation of Novel Force-Sensing Neo-Tendons for Measuring Chordae Tendineae Tension in the Mitral Valve Apparatus Using Optical Fibers With Embedded Bragg Gratings Paulsen, M. J., Bae, J., Imbrie-Moore, A. M., Wang, H., Hironaka, C. E., Lucian, H. J., Edwards, B. B., Farry, J. M., Deschamps, D., Kulkarni, R., Thakore, A. D., Williams, K. M., Cutkosky, M. R., Woo, Y. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets. Circulation von Bornstädt, D., Wang, H., Paulsen, M. J., Goldstone, A. B., Eskandari, A., Thakore, A., Stapleton, L., Steele, A. N., Truong, V. N., Jaatinen, K., Hironaka, C., Woo, Y. J. 2018; 138 (19): 2130-2144

    Abstract

    Cardiovascular bypass grafting is an essential treatment for complex cases of atherosclerotic disease. Because the availability of autologous arterial and venous conduits is patient-limited, self-assembled cell-only grafts have been developed to serve as functional conduits with off-the-shelf availability. The unacceptably long production time required to generate these conduits, however, currently limits their clinical utility. Here, we introduce a novel technique to significantly accelerate the production process of self-assembled engineered vascular conduits.Human aortic smooth muscle cells and skin fibroblasts were used to construct bilevel cell sheets. Cell sheets were wrapped around a 22.5-gauge Angiocath needle to form tubular vessel constructs. A thin, flexible membrane of clinically approved biodegradable tissue glue (Dermabond Advanced) served as a temporary, external scaffold, allowing immediate perfusion and endothelialization of the vessel construct in a bioreactor. Subsequently, the matured vascular conduits were used as femoral artery interposition grafts in rats (n=20). Burst pressure, vasoreactivity, flow dynamics, perfusion, graft patency, and histological structure were assessed.Compared with engineered vascular conduits formed without external stabilization, glue membrane-stabilized conduits reached maturity in the bioreactor in one-fifth the time. After only 2 weeks of perfusion, the matured conduits exhibited flow dynamics similar to that of control arteries, as well as physiological responses to vasoconstricting and vasodilating drugs. The matured conduits had burst pressures exceeding 500 mm Hg and had sufficient mechanical stability for surgical anastomoses. The patency rate of implanted conduits at 8 weeks was 100%, with flow rate and hind-limb perfusion similar to those of sham controls. Grafts explanted after 8 weeks showed a histological structure resembling that of typical arteries, including intima, media, adventitia, and internal and external elastic membrane layers.Our technique reduces the production time of self-assembled, cell sheet-derived engineered vascular conduits to 2 weeks, thereby permitting their use as bypass grafts within the clinical time window for elective cardiovascular surgery. Furthermore, our method uses only clinically approved materials and can be adapted to various cell sources, simplifying the path toward future clinical translation.

    View details for DOI 10.1161/CIRCULATIONAHA.118.035231

    View details for PubMedID 30474423

    View details for PubMedCentralID PMC6261325

  • SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Goldstone, A. B., Burnett, C. E., Cohen, J. E., Paulsen, M. J., Eskandari, A., Edwards, B. E., Ingason, A. B., Steele, A. N., Patel, J. B., MacArthur, J. W., Shizuru, J. A., Woo, Y. 2018; 11 (4): 274–84
  • Angiogenesis precedes cardiomyocyte migration in regenerating mammalian hearts JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Ingason, A. B., Goldstone, A. B., Paulsen, M. J., Thakore, A. D., Truong, V. N., Edwards, B. B., Eskandari, A., Bollig, T., Steele, A. N., Woo, Y. 2018; 155 (3): 1118-+

    Abstract

    Although the mammalian heart's ability to fully regenerate is debated, its potential to extensively repair itself is gaining support. We hypothesized that heart regeneration relies on rapid angiogenesis to support myocardial regrowth and sought to characterize the timeline for angiogenesis and cell proliferation in regeneration.One-day-old CD-1 mice (P1, N = 60) underwent apical resection or sham surgery. Hearts were explanted at serial time points from 0 to 30 days postresection and analyzed with immunohistochemistry to visualize vessel ingrowth and cardiomyocyte migration into the resected region. Proliferating cells were labeled with 5-ethynyl-2'-deoxyuridine injections 12 hours before explant. 5-Ethynyl-2'-deoxyuridine-positive cells were counted in both the apex and remote areas of the heart. Masson's trichrome was used to assess fibrosis.By 30 days postresection, hearts regenerated with minimal fibrosis. Compared with sham surgery, apical resection stimulated a significant increase in proliferation of preexisting cardiomyocytes between 3 and 11 days after injury. Capillary migration into the apical thrombus was detected as early as 2 days postresection, with development of mature arteries by 5 days postresection. New vessels became perfused by 5 days postresection as evidenced by lectin injection. Vessel density and diameter significantly increased within the resected area over 21 days, and vessel ingrowth always preceded cardiomyocyte migration, with coalignment of most migrating cardiomyocytes with ingrowing vessels.Endothelial cells migrate into the apical thrombus early after resection, develop into functional arteries, and precede cardiomyocyte ingrowth during mammalian heart regeneration. This endogenous neonatal response emphasizes the importance of expeditious angiogenesis required for neomyogenesis.

    View details for PubMedID 29452461

  • SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells. Journal of cardiovascular translational research Goldstone, A. B., Burnett, C. E., Cohen, J. E., Paulsen, M. J., Eskandari, A., Edwards, B. E., Ingason, A. B., Steele, A. N., Patel, J. B., MacArthur, J. W., Shizuru, J. A., Woo, Y. J. 2018

    Abstract

    Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.

    View details for PubMedID 29468554

  • An innovative biologic system for photon-powered myocardium in the ischemic heart. Science advances Cohen, J. E., Goldstone, A. B., Paulsen, M. J., Shudo, Y. n., Steele, A. N., Edwards, B. B., Patel, J. B., MacArthur, J. W., Hopkins, M. S., Burnett, C. E., Jaatinen, K. J., Thakore, A. D., Farry, J. M., Truong, V. N., Bourdillon, A. T., Stapleton, L. M., Eskandari, A. n., Fairman, A. S., Hiesinger, W. n., Esipova, T. V., Patrick, W. L., Ji, K. n., Shizuru, J. A., Woo, Y. J. 2017; 3 (6): e1603078

    Abstract

    Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.

    View details for PubMedID 28630913

  • Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction, microvascular dysfunction, and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy. Cardiovascular diabetology Kawamura, M. n., Paulsen, M. J., Goldstone, A. B., Shudo, Y. n., Wang, H. n., Steele, A. N., Stapleton, L. M., Edwards, B. B., Eskandari, A. n., Truong, V. N., Jaatinen, K. J., Ingason, A. B., Miyagawa, S. n., Sawa, Y. n., Woo, Y. J. 2017; 16 (1): 142

    Abstract

    Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM.Primary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle).SMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group.Treatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.

    View details for PubMedID 29096622