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Endothelial cells are constantly exposed to mechanical stimuli, of which mechanical stretch has shown various beneficial or deleterious effects depending on whether loads are within physiological or pathological levels, respectively. Vascular properties change with age, and on a cell-scale, senescence elicits changes in endothelial cell mechanical properties that together can impair its response to stretch. Here, high-rate uniaxial stretch experiments were performed to quantify and compare the stretch-induced damage of monolayers consisting of young, senescent, and aged endothelial populations. The aged and senescent phenotypes were more fragile to stretch-induced damage. Prominent damage was detected by immunofluorescence and scanning electron microscopy as intercellular and intracellular void formation. Damage increased proportionally to the applied level of deformation and, for the aged and senescent phenotype, induced significant detachment of cells at lower levels of stretch compared to the young counterpart. Based on the phenotypic difference in cell-substrate adhesion of senescent cells indicating more mature focal adhesions, a discrete network model of endothelial cells being stretched was developed. The model showed that the more affine deformation of senescent cells increased their intracellular energy, thus enhancing the tendency for cellular damage and impending detachment. Next to quantifying for the first-time critical levels of endothelial stretch, the present results indicate that young cells are more resilient to deformation and that the fragility of senescent cells may be associated with their stronger adhesion to the substrate., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Costanza Giampietro reports financial support was provided by Swiss National Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In vitro assessment is mandatory for artificial heart valve development. This study aims to investigate the effects of pulse duplicator features on valve responsiveness, conduct a sensitivity analysis across valve prosthesis types, and contribute on the development of versatile pulse duplicator systems able to perform reliable prosthetic aortic valve assessment under physiologic hemodynamic conditions., Methods: A reference pulse duplicator was established based on literature. Further optimization process led to new designs that underwent a parametric study, also involving different aortic valve prostheses. These designs were evaluated on criteria such as mean pressure differential and pulse pressure (assessed from high-fidelity pressure measurements), valve opening and closing behavior, flow, and regurgitation. Finally, the resulting optimized setup was tested under five different hemodynamic settings simulating a range of physiologic and pathologic conditions., Results: The results show that both, pulse duplicator design and valve type significantly influence aortic and ventricular pressure, flow, and valve kinematic response. The optimal design comprised key features such as a compliance chamber and restrictor for diastolic pressure maintenance and narrow pulse pressure. Additionally, an atrial reservoir was included to prevent atrial-aortic interference, and a bioprosthetic valve was used in mitral position to avoid delayed valve closing effects., Conclusion: This study showed that individual pulse duplicator features can have a significant effect on valve's responsiveness. The optimized versatile pulse duplicator replicated physiologic and pathologic aortic valve hemodynamic conditions, serving as a reliable characterization tool for assessing and optimizing aortic valve performance., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Endothelial cell physiology is governed by its unique microenvironment at the interface between blood and tissue. A major contributor to the endothelial biophysical environment is blood hydrostatic pressure, which in mechanical terms applies isotropic compressive stress on the cells. While other mechanical factors, such as shear stress and circumferential stretch, have been extensively studied, little is known about the role of hydrostatic pressure in the regulation of endothelial cell behavior. Here we show that hydrostatic pressure triggers partial and transient endothelial-to-mesenchymal transition in endothelial monolayers of different vascular beds. Values mimicking microvascular pressure environments promote proliferative and migratory behavior and impair barrier properties that are characteristic of a mesenchymal transition, resulting in increased sprouting angiogenesis in 3D organotypic model systems ex vivo and in vitro. Mechanistically, this response is linked to differential cadherin expression at the adherens junctions, and to an increased YAP expression, nuclear localization, and transcriptional activity. Inhibition of YAP transcriptional activity prevents pressure-induced sprouting angiogenesis. Together, this work establishes hydrostatic pressure as a key modulator of endothelial homeostasis and as a crucial component of the endothelial mechanical niche., (© 2024. The Author(s).)

Introduction: Along with recent advances in analytical technologies, tricarboxylic acid-cycle intermediates are increasingly identified as promising makers for cellular ischemia and mitochondrial dysfunction during hemorrhagic shock. For traumatized patients, the knowledge of the role of lipid oxidation substrates is sparse. In this study, we aimed to analyze the dynamics of systemic acylcarnitine (AcCa) release in a standardized polytrauma model with hemorrhagic shock., Methods: Fifty-two male pigs (50 ± 5 kg) were randomized into two groups: group isolated fracture was subject to a standardized femur shaft fracture, and group polytrauma was subject to a femur fracture, followed by blunt chest trauma, liver laceration, and a pressure-controlled hemorrhagic shock for 60 minutes. Resuscitation was performed with crystalloids. Fractures were stabilized by intramedullary nailing. Venous samples were collected at six time points (baseline, trauma, resuscitation, 2 hours, 4 hours, and 6 hours). Lipidomic analysis was performed via liquid chromatography coupled mass spectrometry. Measurements were collated with clinical markers and near-infrared spectrometry measurements of tissue perfusion. Longitudinal analyses were performed with linear mixed models, and Spearman's correlations were calculated. A p value of 0.05 was defined as threshold for statistical significance., Results: From a total of 303 distinct lipids, we identified two species of long-chain AcCas. Both showed a highly significant ( p < 0.001) twofold increase after hemorrhagic shock in group polytrauma that promptly normalized after resuscitation. This increase was associated with a significant decrease of the base excess ( p = 0.005), but recovery after resuscitation was faster. For both AcCas, there were significant correlations with decreased muscle tissue oxygen delivery ( p = 0.008, p = 0.003) and significant time-lagged correlations with the increase of creatine kinase ( p < 0.001, p < 0.001)., Conclusion: Our results point to plasma AcCas as a possible indicator for mitochondrial dysfunction and cellular ischemia in hemorrhagic shock. The more rapid normalization after resuscitation in comparison with acid base changes may warrant further investigation., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Objectives : A self-constructed valved pulmonary conduit made out of a de-cellularized porcine small intestinal submucosal extracellular matrix biological scaffold was tested in a chronic growing lamb model. Methods : The conduit was implanted in pulmonary valve position in 19 lambs. We monitored clinical, laboratory, and echocardiographic findings until 12 months after surgery. In two animals, euthanasia was planned at nine and twelve months. Pre-mortem chest computed tomography and post-mortem pathologic work up were performed. Data are presented as frequency and percentage, median and range, or mean and standard deviation. Results : Twelve (63.2%) animals survived the perioperative period. Three unexpected deaths occurred during the follow-up period: one due to aspiration pneumonia at 23 days after surgery, and two due to early and late infective endocarditis of the conduit at 18 and 256 days. In the two animals with planned scarification, the pre-mortem CT scan revealed mild or no calcification within the conduit or valve leaflets. In the echocardiographic examination at 12 months, peak and mean systolic pressure gradients across the conduit valve were 6.5 (3-21) mmHg and 3 (2-12) mmHg, while valve regurgitation was none (n = 2), trivial (n = 5), moderate (n = 1), or severe (n = 1). No clinical or laboratory signs of hemolysis were seen. After 12 months of follow-up, the animals' body weights had increased from 33 (27-38) kg to 53 (38-66) kg ( p = 0.010). Conclusions : Implantation of a valved pulmonary conduit in our growing lamb model was feasible. Infective endocarditis of the implanted valved conduit remained a significant complication.

Background: Automatic myocardial scar segmentation from late gadolinium enhancement (LGE) images using neural networks promises an alternative to time-consuming and observer-dependent semi-automatic approaches. However, alterations in data acquisition, reconstruction as well as post-processing may compromise network performance. The objective of the present work was to systematically assess network performance degradation due to a mismatch of point-spread function between training and testing data., Methods: Thirty-six high-resolution (0.7×0.7×2.0 mm 3 ) LGE k-space datasets were acquired post-mortem in porcine models of myocardial infarction. The in-plane point-spread function and hence in-plane resolution Δx was retrospectively degraded using k-space lowpass filtering, while field-of-view and matrix size were kept constant. Manual segmentation of the left ventricle (LV) and healthy remote myocardium was performed to quantify location and area (% of myocardium) of scar by thresholding (≥ SD5 above remote). Three standard U-Nets were trained on training resolutions Δx train = 0.7, 1.2 and 1.7 mm to predict endo- and epicardial borders of LV myocardium and scar. The scar prediction of the three networks for varying test resolutions (Δx test = 0.7 to 1.7 mm) was compared against the reference SD5 thresholding at 0.7 mm. Finally, a fourth network trained on a combination of resolutions (Δx train = 0.7 to 1.7 mm) was tested., Results: The prediction of relative scar areas showed the highest precision when the resolution of the test data was identical to or close to the resolution used during training. The median fractional scar errors and precisions (IQR) from networks trained and tested on the same resolution were 0.0 percentage points (p.p.) (1.24 - 1.45), and - 0.5 - 0.0 p.p. (2.00 - 3.25) for networks trained and tested on the most differing resolutions, respectively. Deploying the network trained on multiple resolutions resulted in reduced resolution dependency with median scar errors and IQRs of 0.0 p.p. (1.24 - 1.69) for all investigated test resolutions., Conclusion: A mismatch of the imaging point-spread function between training and test data can lead to degradation of scar segmentation when using current U-Net architectures as demonstrated on LGE porcine myocardial infarction data. Training networks on multi-resolution data can alleviate the resolution dependency., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Not applicable reports financial support was provided by Innosuisse Swiss Innovation Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Occult hypoperfusion describes the absence of sufficient microcirculation despite normal vital signs. It is known to be associated with prolonged elevation of serum lactate and later complications in severely injured patients. We hypothesized that changes in circulating lipids are related to responsiveness to resuscitation. The purpose of this study is investigating the relation between responsiveness to resuscitation and lipidomic course after poly trauma., Methods: Twenty-five male pigs were exposed a combined injury of blunt chest trauma, liver laceration, controlled haemorrhagic shock, and femoral shaft fracture. After 1 h, animals received resuscitation and fracture stabilization. Venous blood was taken regularly and 233 specific lipids were analysed. Animals were divided into two groups based on serum lactate level at the end point as an indicator of responsiveness to resuscitation (<2 mmol/L: responder group (R group), ≧2 mmol/L: occult hypoperfusion group (OH group))., Results: Eighteen animals met criteria for the R group, four animals for the OH group, and three animals died. Acylcarnitines showed a significant increase at 1 h compared to baseline in both groups. Six lipid subgroups showed a significant increase only in R group at 2 h. There was no significant change at other time points., Conclusions: Six lipid groups increased significantly only in the R group at 2 h, which may support the idea that they could serve as potential biomarkers to help us to detect the presence of occult hypoperfusion and insufficient resuscitation. We feel that further study is required to confirm the role and mechanism of lipid changes after trauma., (© 2022. The Author(s).)

Mechanical forces are of major importance in regulating vascular homeostasis by influencing endothelial cell behavior and functions. Adherens junctions are critical sites for mechanotransduction in endothelial cells. β-catenin, a component of adherens junctions and the canonical Wnt signaling pathway, plays a role in mechanoactivation. Evidence suggests that β-catenin is involved in flow sensing and responds to tensional forces, impacting junction dynamics. The mechanoregulation of β-catenin signaling is context-dependent, influenced by the type and duration of mechanical loads. In endothelial cells, β-catenin's nuclear translocation and signaling are influenced by shear stress and strain, affecting endothelial permeability. The study investigates how shear stress, strain, and surface topography impact adherens junction dynamics, regulate β-catenin localization, and influence endothelial barrier properties. Insight box Mechanical loads are potent regulators of endothelial functions through not completely elucidated mechanisms. Surface topography, wall shear stress and cyclic wall deformation contribute overlapping mechanical stimuli to which endothelial monolayer respond to adapt and maintain barrier functions. The use of custom developed flow chamber and bioreactor allows quantifying the response of mature human endothelial to well-defined wall shear stress and gradients of strain. Here, the mechanoregulation of β-catenin by substrate topography, wall shear stress, and cyclic stretch is analyzed and linked to the monolayer control of endothelial permeability., (© The Author(s) 2024. Published by Oxford University Press.)

Wireless medical sensors typically utilize electromagnetic coupling or ultrasound for energy transfer and sensor interrogation. Energy transfer and management is a complex aspect that often limits the applicability of implantable sensor systems. In this work, we report a new passive temperature sensing scheme based on an acoustic metamaterial made of silicon embedded in a polydimethylsiloxane matrix. Compared to other approaches, this concept is implemented without additional electrical components in situ or the need for a customized receiving unit. A standard ultrasonic transducer is used for this demonstration to directly excite and collect the reflected signal. The metamaterial resonates at a frequency close to a typical medical value (5 MHz) and exhibits a high-quality factor. Combining the design features of the metamaterial with the high-temperature sensitivity of the polydimethylsiloxane matrix, we achieve a temperature resolution of 30 mK. This value is below the current standard resolution required in infrared thermometry for monitoring postoperative complications (0.1 K). We fabricated, simulated, in vitro tested, and compared three acoustic sensor designs in the 29-43 °C (~302-316 K) temperature range. With this concept, we demonstrate how our passive metamaterial sensor can open the way toward new zero-power smart medical implant concepts based on acoustic interrogation., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2024.)

Microvascular obstruction (MVO) often occurs in ST-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI). Diagnosis and treatment of MVO lack appropriate and established procedures. This study focused on two major points by using an in vitro multiscale flow model, which comprised an aortic root model with physiological blood flow and a microfluidic model of the microcirculation with vessel diameters down to 50 μm. First, the influence of porcine microthrombi (MT), injected into the fluidic microchip, on perfusion was investigated. We found that only 43 % of all injected MT were fully occlusive. Second, it could also be shown that the maximal concentration of a dye (representing therapeutic agent) during intracoronary infusion could be increased on average by 58 % , when proximally occluding the coronary artery by a balloon during drug infusion. The obtained results and insights enhance the understanding of perfusion in MVO-affected microcirculation and could lead to improved treatment methods for MVO patients., Competing Interests: SF and RSS own stock and/or stock options in CorFlow Therapeutics AG. SF is an employee of CorFlow Therapeutics AG. SF, RSS and DO have a pending patent application for a microfluidic coronary circulation model. CorFlow Therapeutics AG partially funded the work of YR. YR, TS, MW, and NC and were provided free material (e.g., Occlusion‐infusion catheter) from CorFlow Therapeutics AG., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Objectives: Despite the success of coronary artery bypass graft (CABG) surgery using autologous saphenous vein grafts (SVGs), nearly 50% of patients experience vein graft disease within 10 years of surgery. One contributing factor to early vein graft disease is endothelial damage during short-term storage of SVGs in inappropriate solutions. Our aim was to evaluate the effects of a novel endothelial damage inhibitor (EDI) on SVGs from patients undergoing elective CABG surgery and on venous endothelial cells (VECs) derived from these SVGs., Methods: SVGs from 11 patients participating in an ongoing clinical registry (NCT02922088) were included in this study, and incubated with both full electrolyte solution (FES) or EDI for 1 h and then examined histologically. In 8 of 11 patients, VECs were isolated from untreated grafts, incubated with both FES and EDI for 2 h under hypothermic stress conditions and then analysed for activation of an inflammatory phenotype, cell damage and cytotoxicity, as well as endothelial integrity and barrier function., Results: The EDI was superior to FES in protecting the endothelium in SVGs (74 ± 8% versus 56 ± 8%, P < 0.001). Besides confirming that the EDI prevents apoptosis in SVG-derived VECs, we also showed that the EDI temporarily reduces adherens junctions in VECs while protecting focal adhesions compared to FES., Conclusions: The EDI protects the connectivity and function of the SVG endothelium. Our data suggest that the EDI can preserve focal adhesions in VECs during short-term storage after graft harvesting. This might explain the superiority of the EDI in maintaining most of the endothelium in venous CABG surgery conduits., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Mitral valve prolapse (MVP) is common among heart valve disease patients, causing severe mitral regurgitation (MR). Although complications such as cardiac arrhythmias and sudden cardiac death are rare, the high prevalence of the condition leads to a significant number of such events. Through next-generation gene sequencing approaches, predisposing genetic components have been shown to play a crucial role in the development of MVP. After the discovery of the X-linked inheritance of filamin A, autosomal inherited genes were identified. In addition, the study of sporadic MVP identified several genes, including DZIP1, TNS1, LMCD1, GLIS1, PTPRJ, FLYWCH, and MMP2. The early screening of these genetic predispositions may help to determine the patient population at risk for severe complications of MVP and impact the timing of reconstructive surgery. Surgical mitral valve repair is an effective treatment option for MVP, resulting in excellent short- and long-term outcomes. Repair rates in excess of 95% and low complication rates have been consistently reported for minimally invasive mitral valve repair performed in high-volume centers. We therefore conceptualize a potential preventive surgical strategy for the treatment of MVP in patients with genetic predisposition, which is currently not considered in guideline recommendations. Further genetic studies on MVP pathology and large prospective clinical trials will be required to support such an approach.

To facilitate pre-clinical animal and in-silico clinical trials for implantable pulmonary artery pressure sensors, understanding the respective species pulmonary arteries (PA) anatomy is important. Thus, morphological parameters describing PA of pigs and sheep, which are common animal models, were compared with humans. Retrospective computed tomography data of 41 domestic pigs (82.6 ± 18.8 kg), 14 sheep (49.1 ± 6.9 kg), and 49 patients (76.8 ± 18.2 kg) were used for reconstruction of the subject-specific PA anatomy. 3D surface geometries including main, left, and right PA as well as LPA and RPA side branches were manually reconstructed. Then, specific geometric parameters (length, diameters, taper, bifurcation angle, curvature, and cross-section enlargement) affecting device implantation and post-interventional device effect and efficacy were automatically calculated. For both animal models, significant differences to the human anatomy for most geometric parameters were found, even though the respective parameters' distributions also featured relevant overlap. Out of the two animal models, sheep seem to be better suitable for a preclinical study when considering only PA morphology. Reconstructed geometries are provided as open data for future studies. These findings support planning of preclinical studies and will help to evaluate the results of animal trials., (© 2023. The Author(s).)

Alternative engineering approaches have led the design of implants with controlled physical features to minimize adverse effects in biological tissues. Similar efforts have focused on optimizing the design features of percutaneous VAD drivelines with the aim to prevent infection, omitting however a thorough look on the implant-skin interactions that govern local tissue reactions. Here, we utilized an integrated approach for the biophysical modification of transdermal implants and their evaluation by chronic sheep implantation in comparison to the standard of care VAD drivelines. We developed a novel method for the transfer of breath topographical features on thin wires with modular size. We examined the impact of implant's diameter, surface topography, and chemistry on macroscopic, histological, and physical markers of inflammation, fibrosis, and mechanical adhesion. All implants demonstrated infection-free performance. The fibrotic response was enhanced by the increasing diameter of implants but not influenced by their surface properties. The implants of small diameter promoted mild inflammatory responses with improved mechanical adhesion and restricted epidermal downgrowth, in both silicone and polyurethane coated transdermal wires. On the contrary, the VAD drivelines with larger diameter triggered severe inflammatory reactions with frequent epidermal downgrowth. We validated these effects by quantifying the infiltration of macrophages and the level of vascularization in the fibrotic zone, highlighting the critical role of size reduction for the benign integration of transdermal implants with skin. This insight on how the biophysical properties of implants impact local tissue reactions could enable new solutions on the transdermal transmission of power, signal, and mass in a broad range of medical devices., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andreas Kourouklis, Xi Wu, Aldo Ferrari, and Edoardo Mazza have filed a patent (EP20208958.7) for protection of the technology described in the manuscript. All other authors have no interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)