Veranstaltungsprogramm

Total artificial hearts (TAH) are used as a temporary treatment for severe biventricular heart failure. However, long-term cardiac replacement is hampered by limited durability and complication rates, which may be attributable to the modus operandi of state-of-the-art pumping systems. The aim of this study was to assess the feasibility of a novel valveless pumping principle for a durable pulsatile TAH (ShuttlePump).

With a rotating and linearly shuttling piston within a cylindrical housing with 2 in- and outlets, the pump features only one single moving part and delivers pulsatile flow to both systemic and pulmonary circulation. The pump and actuation system were designed iteratively based on analytical and in silico methods, utilizing computational fluid dynamics (CFD) and finite elements method (FEM). Pump characteristics were evaluated experimentally in a mock circulation loop mimicking the cardiovascular system, while hemocompatibility related parameters were calculated numerically. Further, we retrospectively assessed the anatomical compatibility of the ShuttlePump using virtual implantation techniques within 3D-reconstructed anatomies of adult heart failure patients.

Pump characteristics cover the entire required operating range for a TAH (2.5 -9 L/min at 50 - 160 mmHg arterial pressures) at stroke frequencies of 1.5 - 5 Hz while balancing left and right atrial pressures. The FEM analysis showed a mean overall copper loss of 8.84 W. Normalized index of hemolysis was lower than in state-of-the-art rotary blood pumps and 95% of the pumps blood volume was exchanged after 1.42 s, indicating a good washout behaviour. The local blood temperature rise did not exceed 2 K. Virtual fitting results showed good anatomical compatibility of the ShuttlePump: Successful virtual implantation was achieved in 9/11 patients. However, in 2 patients, pump interaction with the thoracic cage was observed and considered unsuccessful virtual implantation. A strong correlation observed between the measured anatomical parameters and the ShuttlePump volume exceeding pericardium highlights the importance of these measurements apart from body surface area.

This study indicates feasibility of a novel pumping system for a TAH with numerical and experimental results as well as virtual implantations, substantiating further development of the ShuttlePump.

Introduction
Infective endocarditis poses an increasingly prevalent, often fatal complication frequently associated with severe SARS-CoV-2 infections. Currently used annuloplasty rings for surgical valve repair do not offer antibacterial features, therefore leaving systemic antibiosis as the only additional treatment. In this study we aimed to develop a fully absorbable magnesium (Mg)-based annuloplasty ring covered with silver nanoparticle (AgNP)-loaded polycaprolactone (PCL) providing potent antibacterial activity. Initially, in-vitro and in-vivo biocompatibility, mechanical and degradation studies of the Mg alloy ZX00 and the AgNP-PCL coverage were performed. Finally, long-term functionality of the annuloplasty rings is being assessed in a sheep model.

Methods
In-vitro biocompatibility, inflammatory, degradation and hemocompatibility assays were performed. Human umbilical vein endothelial, human foreskin fibroblasts and macrophages were utilized. ZX00 was implanted (as a rod) subcutaneously in rats (5 months follow-up) for histopathological, degradational (μCT), immunohistochemistry, inflammatory (qPCR) and mechanical bending assessments. Electrospun AgNP-PCL was tested for antibacterial activity using two endocarditis pathogens. To ensure implant functionality, cardiopulmonary bypass surgery was performed to implant the rings in sheep hearts (n=5, 1 year follow-up). Diastolic and systolic heart function (echocardiography) and blood chemistry were assessed.

Results
Ultimate iin-vitro and in-vivo biocompatibility of ZX00 and AgNP-PCL and antibacterial activity of AgNP-PCL were demonstrated. Implants degraded homogeneously. Rings were implanted successfully in a sheep model with no implant failure. Follow-up for one year is ongoing. Echocardiography shows preserved mitral valve function. Blood chemistry outcomes were positive.

Conclusion
This newly developed, antibacterial annuloplasty ring could be a promising new option in operative care of endocarditis.

Introduction: Cardiac patches support damaged myocardial tissue post-myocardial infarction (MI), aiding in mechanical strength, growth factor supply, and conduction bridging. Designing mechanically anisotropic cardiac patches with auxetic microstructures that expand perpendicular to applied forces, mimicking myocardial tissue behavior, can enhance mechanical properties suitable for implantation in the anisotropic myocardium. Herein, we fabricated auxetic cardiac patches from synthetic polymers to be functionalized with composite hydrogels for implantation after MI.

Methods: Micropatterned polycaprolactone (PCL) and thermoplastic polyurethane (TPU) scaffolds were fabricated using a 3D bioplotter with a custom printing protocol, allowing precise control over printhead movement. Mechanical properties were assessed under dynamic loading using unidirectional, quasistatic tensile tests conducted with a rheometer equipped with a custom-designed clamp system. Biocompatibility was evaluated with human umbilical vein endothelial cells (HUVECs) cultured on the scaffolds, assessed via XTT assays, live/dead staining, and SEM microscopy at 24, 48, and 72 hours. Hemocompatibility was investigated through hemolysis and clot formation assays. Inflammatory responses were studied by analyzing the expression of pro-inflammatory and anti-inflammatory markers (CD80, CCR7, IL-1a, and TNF-a) in macrophages using PCR. In a pilot ex vivo study using a Langendorff isolated heart system, patch applicability and effects on cardiac function in rabbit and rat hearts were assessed.

Results: The optimized fabrication process produced uniform PCL and TPU scaffolds with controlled pore sizes and anisotropic stiffness ratios. Rheometer testing confirmed auxetic behavior, demonstrating strain expansion perpendicular to applied forces. Tensile tests indicated ultimate strain values (7-20%) similar to physiological myocardial ranges (15-22%). HUVEC biocompatibility assays confirmed good cell viability and proliferation across all time points. The patches showed a low hemolysis rate, indicating good hemocompatibility. Immunomodulatory effects were observed with a significant reduction in inflammatory gene expression after one week. In ex vivo testing, the auxetic behavior and stiffness of the patches were adjusted to match the anisotropic ratio of the model organ, with patch application via minimal sutures demonstrating efficient attachment without impairing epicardial tissue movement. The Langendorff system dynamic tests showed that auxetic patches modulated cardiac function and have the potential for adaptability across different organ sizes.

Conclusion: High-resolution 3D printing of auxetic, mechanically tunable patches demonstrated promising attachment for functional outcomes in pilot ex vivo studies. This approach offers a scalable platform for delivering molecules that support myocardial regeneration and epicardial conductivity, with potential applications in human myocardial repair.

Introduction:

Following myocardial infarction a 3D-printed cardiac patch can provide mechanical support to the infarcted area of the myocardium. Additionally, suitable constructs can offer a platform for tissue regeneration. [1]

However, most 3D-printed constructs have a hydrophobic surface, which limits cellular adhesion, affecting tissue regeneration on a cardiac patch. To overcome this limitation, the human placenta chorion extracellular matrix (hpcECM) can be used as a hydrogel surface coating to modulate cell adhesion, viability and inflammatory behavior, promoting factors crucial for tissue regeneration. [2]

Materials and Methods:

The polymer polycaprolactone (PCL) was used to print porous patches. Subsequently, the porous constructs were coated using different hpcECM concentrations (uncoated PCL, 0.02% and 0.2% hpcECM-PCL). To evaluate the surface coating, a fibronectin-antibody staining, wettability as well as nano-mechanic measurements were performed. Human umbilical vein endothelial cells (HUVEC), human foreskin fibroblasts (HFF), undifferentiated as well as retinoic acid differentiated H9c2 cells, and endothelial progenitor cells (EPC) were employed to evaluate cell viability, attachment, and activation using XTT assays, live-dead assays, and electron microscopy. An initial cell attachment assay was performed to evaluate cellular attachment after 30 minutes. Immunological behavior was examined using PCR to assess pro- and anti-inflammatory gene expression in human macrophages. Hemocompatibility was tested through hemolysis and blood clot formation assays. The in-vitro experiments were carried out from early time points up to one week.

Results:

Increasing the concentration of hpcECM on porous PCL constructs significantly enhanced initial cell attachment after 30 minutes. Cell viability improved in HUVECs, HFFs, and differentiated H9c2 cells, as demonstrated by XTT and live-dead assays. Coated constructs exhibited greater cell attachment and activation of EPCs compared to uncoated PCL constructs. PCR analysis showed a slight upregulation of pro-inflammatory markers at 72 hours, followed by a strong expression of the anti-inflammatory cytokine IL-10 after one week. Hemocompatibility was confirmed across all tested groups.

Conclusion:

HpcECM demonstrated strong potential as a surface coating on porous PCL construct to support the attachment and activation of cardiac-related cells, outperforming the already existing surface coating fibronectin in-vitro. This enhancement could improve the functionality of cardiac patches, promoting cardiomyocyte regeneration in-vivo.

References:

[1] Wang Z, Wang L, Li T, et al. Theranostics. 2021;11(16):7948-7969. 2021 doi:10.7150/thno.61621

[2] Hinderer S, Layland SL, Schenke-Layland K. Adv Drug Deliv Rev. 2016;97:260-269. doi:10.1016/j.addr.2015.11.019

Background:

Aortic stenosis (AS) leads to restricted blood flow from the left ventricle (LV), causing chronic pressure overload, ventricular remodeling, and potentially heart failure. Surgical aortic valve replacement (SAVR) can reverse this remodeling, facilitating physiological and structural adaptation of the heart. This study aimed to investigate sex-dependent differences in reverse remodeling following SAVR through echocardiographic assessment of cardiac structure and function, along with the analysis of circulating biomarkers related to cardiac damage, myocardial stretch, inflammatory status, kidney filtration, and liver metabolism. Additionally, heart failure, cardiomyopathy, and quality of life questionnaires were evaluated.

Methods:

The study involved 108 adult patients with AS and/or regurgitation scheduled for elective SAVR, with detailed data collected from 90 patients. We evaluate different lab parameter, echocardiography, clinic and quality of life at four timepoints to analyze the reverse remodeling after aortic valve replacement. Exclusion criteria included prior myocardial infarction, endocarditis, need for bypass surgery, electrophysiological device implantation, resuscitation, glomerular filtration rate (GFR) below 60 mL/min/1.73 m², or oncologic malignancies.

Results:

All patients survived SAVR, with a significant reduction in maximal aortic blood flow velocity (Vmax) in both sexes within 4-6 days post-operation. Measurements of interventricular septal (IVS) and LV posterior wall width revealed that female patients, despite having greater initial hypertrophy, experienced faster reverse remodeling compared to males. Left ventricular ejection fraction (LVEF) increased in both sexes after SAVR, including responders, non-responders, and those with preserved LVEF prior to surgery. Sex-dependent differences were observed in the levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) during the remodeling process. SAVR significantly improved New York Heart Association (NYHA) heart failure and Canadian Cardiovascular Society (CCS) angina classifications in both sexes, although women had higher initial NYHA scores. Enrichment analysis of circulating mRNAs from pre- to post-operative states and from post-operative to 6 months follow-up showed overrepresentation of pathways related to matrisome, fibroblast activation, cell-cell contact, and immune response. Unbiased principal component analysis revealed a clear distinction between male and female transcriptomic profiles during reverse remodeling.

Conclusion:

SAVR effectively restored blood flow from the LV to the aorta, promoted reverse remodeling, and improved heart failure (NYHA) and angina (CCS) classifications in both sexes. Postoperative improvements in physical activity were associated with weight loss and better mental health. Echocardiographic parameters and biomarker analysis demonstrated significant sex differences in the extent and dynamics of reverse remodeling, with women undergoing SAVR at an older age and with more advanced hypertrophy. Women were also more prone to kidney failure due to prolonged exposure to pressure overload. Comprehensive analysis of cardiac structure, blood biomarkers, and myocardial wall dynamics may help identify non-responders earlier and optimize subsequent interventions.

Operating conditions (flow rate, pressure head, pump speed) affect hemocompatibility in rotary blood pumps (RBPs). Previously, experiments with constant operating conditions revealed a higher normalised index of hemolysis (NIH) at low flow rates. In patients, however, the pump flow rate through the ventricular assist device changes dynamically with the remaining natural cardiac cycle, resulting in off-design operation (low/high flow rates) for more than 50% of the cardiac cycle and the effect on hemocompatibility is so far not known. Thus, the aim of this study was to investigate the effect of realistic pulsatile boundary conditions on the hemocompatibility of RBPs employing novel and validated in-silico and in-vitro setups.

To investigate these realistic conditions, pulsatile blood experiments were performed using the HeartMate 3 (HM3, Abbott Inc, Chicago, USA) in a novel hybrid mock circulatory loop with citrated human blood from hemochromatosis patients. Three pulsatile conditions (high-, low- and no residual cardiac function) were investigated for two pump speed settings (normal: 5400rpm, 4.3L/min and low: 4800rpm, 2.5L/min), respectively. The change in plasma-free hemoglobin (dfHb30min) and NIH were assessed to describe blood damage. Additionally, high molecular weight (HMW) von Willebrand Factor (vWF) multimer degradation was assessed using immunoblotting. Measured flow rate curves were used as boundary conditions for accompanying dynamic computational fluid dynamics (CFD) simulations at a typical pump speed (5400 rpm). Hemocompatibility was assessed numerically by calculating dfHb, NIH and several parameters including blood volume exposed to shear stresses above thresholds associated with different kinds of blood damage.

Experimentally, there was no significant difference of dfHb_30min (p>0.388), NIH (p>0.382) and HMW vWF multimers degradation (p>0.364) between the three conditions, but differences of these parameters were observed between the normal- and low speed settings. These trends in blood trauma were well captured in the CFD results, however, a new computational strategy was required: To calculate NIH numerically, dfHb generated over one cardiac cycle needs to be divided by the averaged flow rate over a cardiac cycle rather than the instantaneous flow rate values. CFD parameters point towards slightly compromised hemocompatibility at high pulsatility.

Hemocompatibility of the HM3 is not significantly affected by different pulsatile conditions with periodic high/low flow or even backflows through the pump in in-vitro evaluation, but rather by the operating condition in terms of mean flow rate and pump speed. With the novel CFD approach, trends in hemocompatibility observed in-vitro were replicated in-silico. These results contribute to a detailed understanding of hemocompatibility of blood pumps and the identification of safe operating conditions for RBPs, which may improve clinical outcomes.

Introduction: Perivascular adipose tissue (PVAT) plays an important role in the maintainance of vascular homeostasis. Therefore, the formation of a functional PVAT around vascular grafts after implantation is a major contributor to long-term graft survival. However, the role of cell communication via extracellular vesicles (EVs) from the PVAT with other vascular cells during the graft healing process remains unclear. Therefore, the current study aims to investigate the role of PVAT-EVs on endothelial cell properties and angiogenesis. Materials and Methods: Autologous vessels, expanded polytetrafluorethylene (ePTFE), and thermoplastic polyurethane (TPU)/ TPU-urea (TPUU) grafts were implanted into the abdominal aorta of Sprague Dawley rats for one week. After graft retrieval, cells were isolated from the respective PVATs. EVs were isolated from early passage cells and their angiogenic potential was assessed via morphology and protein expression as well as 3D sprouting assays. In addition, the expression of healing-related miRNAs was assessed. Results: Stimulation with PVAT-EVs from TPU/TPUU implants led to an increase in endothelial cell size. Angiogenesis assays showed a reduced angiogenic potential of PVAT-EVs derived from ePTFE implants. In addition, miRNA expression showed a more pro-inflammatory phenotype of ePTFE PVAT-EVs compared to autologous vessel and TPUU grafts. Discussion: The unsatisfactory clinical performance of ePTFE small-diameter vascular grafts (SDVGs) is associated with limited endothelialization and vascular ingrowth into the graft wall. The current study suggests that EV-mediated cell communication in ePTFE PVAT contributes to these limitations. Additional experiments will help to further investigate EV function during the healing process of newly developed SDVGs.