Biology subjects

Rausch, M. K.

Publications and source records attributed to Rausch, M. K..

At least 19 recordsLinked to original sources

bioRxiv2026

Effect of Clover versus Zipping on Annular Geometry and Dynamics in Tricuspid Edge-to-Edge Repair

Introduction: Transcatheter edge-to-edge repair effectively reduces tricuspid regurgitation (TR), with some patients showing an additional 'annuloplasty effect'. Methods: Ten adult sheep underwent pulmonary artery banding to induce right ventricular failure and functional TR. Six weeks later, sonomicrometry crystals were implanted around the tricuspid annulus (TA). Two Abbott XTW clips were then placed using either a Zipping (n=5) or Clover (n=5) configuration. Echocardiographic and sonomicrometry data were collected before and after clip implantation to assess TA geometry and function. Results: The model produced right ventricular dilation, dysfunction, and moderate-to-severe functional TR. In all animals, leaflet approximation with two clips significantly reduced TR severity (3.6+/-0.5 to 1.3+/-1.1; p=0.01) and septal-lateral annular diameter (29.2+/-2.2 to 26.7+/-2.9 mm; p=0.01). However, a significant reduction in septal-lateral annular diameter occurred only with the Clover technique (30+/-2 to 27+/-1 mm; p=0.001). Conclusions: Both techniques reduced TR, but only the Clover configuration produced an acute annuloplasty effect by selectively decreasing septal-lateral annular diameter.

bioengineering↗

bioRxiv2026

No Strings Attached: Predicting Tricuspid Valve Deformation Without In Vivo Chordal Geometry

Predictive biomechanical models of the tricuspid valve require accurate representation of the chordae tendineae, yet subject-specific chordal geometry is difficult to reconstruct from non-invasive imaging. Here, we adopt a framework for generating functionally equivalent synthetic chordae without prior knowledge of in vivo chordal attachments. To this end, we first adapt an anatomy-informed hyperelastic shape-matching method that establishes correspondence between end-diastolic and end-systolic leaflet configurations using chordal-mimicking forces, a rigid contact template, and a Gaussian-smoothed locally corrective pressure field. We then generate synthetic chordal insertion sites using zone-based rejection sampling and calibrate the unloaded length of each chord by combining reaction forces with the chordal stress-stretch relationship. The framework was evaluated using Texas TriValve 1.1, a high-fidelity finite element model of a human tricuspid valve validated against beating-heart echocardiography. We found that shape matching reproduced the target end-systolic geometry with a mean inter-surface distance of 0.29 {+/-} 0.35 mm. Moreover, synthetic chordal insertions faithfully reproduce end-systolic leaflet deformations. We subsequently examined synthetic chordal configurations containing 202, 225, and 450 insertions, informed by measurements from eight explanted human tricuspid valves. Here, increasing insertion number reduced mean inter-surface distance from 0.63 {+/-} 0.52 mm to 0.49 {+/-} 0.44 mm and reduced contact area errors from 3.52% to 0.59%. Across all configurations, mean maximum principal stretch errors in leaflet belly regions remained below 2.4%, while areal strain errors ranged from 0.34% to 10.01%. These results demonstrate that anatomically informed shape matching coupled with stress-based chordal calibration can reproduce tricuspid valve closure without explicit subject-specific chordal geometry. This framework provides a foundation for generating synthetic subvalvular anatomy for future imaging-derived, predictive tricuspid valve models.

bioengineering↗

bioRxiv2026

Sex-Specific Remodeling Phenotypes of the Tricuspid Valve Leaflets in an Ovine Model of Functional Tricuspid Regurgitation

BackgroundModerate to severe tricuspid regurgitation (TR) affects approximately 1.6 million Americans, yet more than 90% of patients with significant TR remain untreated. Women exhibit higher TR prevalence and more rapid disease progression than men, but the valve-intrinsic mechanisms underlying these sex disparities remain unclear. We hypothesized that sex and circulating testosterone influence tricuspid leaflet remodeling during right-sided pressure overload. MethodsFemale, castrated male (C-Male), and non-castrated male (NC-Male) adult Dorset sheep (n = 45) underwent pulmonary artery banding (PAB) and were followed for 13 {+/-} 1.5 weeks. Tricuspid leaflets were evaluated using morphometry, 3D profilometry, biaxial mechanical testing, histology, and bulk RNA sequencing. Sex-stratified differential gene expression was performed, and pathway enrichment of key biological processes were compared between sexes. ResultsPAB produced a uniform hemodynamic stimulus and equivalent moderate-to-severe TR across sex groups. Despite similar TR burden, leaflet remodeling diverged substantially by sex and castration status. C-Males developed the broadest remodeling phenotype, characterized by diffuse multi-leaflet growth, thickening, increased nuclei count, and low-strain stiffening. Females demonstrated more restricted leaflet and region-specific structural and cellular changes, along with circumferential low-strain stiffening. NC-Males exhibited preferential septal remodeling characterized by growth, thickening, increased nuclei count, and radial high-strain stiffening. Transcriptomic analysis revealed that females upregulated a focused matricellular remodeling program enriched for extracellular space organization (67 DEGs; FDR=0.025), whereas C-Males activated coordinated extracellular matrix and apoptosis-regulatory programs (388 DEGs; FDR=0.009). In contrast, NC-Males exhibited broad transcriptional response (406 DEGs) without significant pathway enrichment. ConclusionsTricuspid leaflet maladaptation during pressure overload is sex-dependent and testosterone-sensitive, involving distinct structural, mechanical, and transcriptional remodeling programs. These findings identify sex and testosterone status as previously under-recognized modulators of tricuspid valve remodeling and may help explain clinical sex disparities in TR progression. NOVELTY AND SIGNIFICANCE What is known?O_LIPulmonary hypertension and right ventricular pressure overload are linked to tricuspid leaflet remodeling through leaflet thickening, enlargement, and altered mechanical properties. C_LIO_LISex and sex-steroid hormones regulate fibrosis and extracellular matrix remodeling in cardiovascular tissues, but their role in tricuspid leaflet remodeling remains poorly understood. C_LI What new information does this article contribute?O_LISex and circulating testosterone status influence the magnitude, spatial distribution, biomechanical behavior, and transcriptional organization of tricuspid leaflet remodeling during pressure overload. C_LIO_LIFemales, castrated males, and non-castrated males develop distinct remodeling programs characterized by focused matricellular remodeling, coordinated extracellular matrix/apoptosis signaling, and diffuse transcriptional activation, respectively. C_LIO_LIThese findings identify sex and hormonal status as biological regulators of tricuspid valve maladaptation during functional tricuspid regurgitation. C_LI SummarySex differences in tricuspid regurgitation progression are recognized clinically, yet the mechanobiological basis underlying these disparities remains poorly understood. Using a controlled ovine model of pressure overload-induced secondary tricuspid regurgitation, we demonstrated that tricuspid leaflet maladaptation is a sex-specific and testosterone-sensitive process spanning structural, mechanical, and transcriptional scales. Under comparable hemodynamic overload, all animals developed significant tricuspid regurgitation, but leaflet remodeling patterns diverged substantially across sexes. Castrated male sheep exhibited the broadest maladaptive phenotype, characterized by diffuse multi-leaflet growth and thickening, increased low-stretch stiffness, and coordinated extracellular matrix and apoptosis-regulatory transcriptional programs. Female sheep developed more spatially restricted remodeling accompanied by a focused matricellular and extracellular matrix secretory response, whereas non-castrated male sheep demonstrated selective leaflet remodeling with broad, but less coordinated, transcriptional activation. Different remodeling patterns emerged in females and castrated males despite comparable testosterone levels, suggesting that testosterone depletion alone does not fully explain these tricuspid valve remodeling phenotypes. These findings establish sex and testosterone status as previously underrecognized biological regulators of tricuspid leaflet maladaptation and support the emerging view that valve leaflets are active, mechanobiologically responsive, participants in functional tricuspid regurgitation progression.

bioengineering↗

bioRxiv2026

Flow alters fibrin molecular and network structure and decreases binding of fibrinolytic enzymes

Thrombolysis with tissue Plasminogen Activator (tPA), approved for treating acute ischemic stroke (AIS) within 3-4.5 h of symptom onset, converts Plasminogen (Plg) to Plasmin to degrade fibrin, while fibrin also enhances Plg activation by binding to both tPA and Plg. Therefore, in this study, we investigated whether arterial-like flow, characteristic of AIS, alters fibrin structure and susceptibility to fibrinolysis. Using a newly developed platform for quantitative imaging and spectroscopy, we found that flow generates denser fibrin networks with reduced molecular transport despite reduced protofibril packing within fibrin fibers. Raman spectroscopy revealed an -helix-to-{beta}-sheet transition, accompanied by reduced Plg and tPA binding, although the reduction in tPA binding emerged only after prolonged flow exposure. Consistently, multi-scale molecular dynamics simulations showed that the Plg binding site destabilized at lower forces than the primary tPA binding site. Together, these multi-scale findings help explain the limited efficacy and narrow therapeutic window of thrombolysis.

biophysics↗

bioRxiv2026

The Mechanical and Biological Evolution of Pressure Ulcer Formation and Healing in Mice

Pressure ulcers arise from sustained mechanical loading that impairs perfusion and damages skin tissues, yet the coupled mechanical and biological mechanisms of their formation and healing remain poorly characterized. We addressed this gap using a mouse model in which dorsal skin underwent 72 hours of magnet-induced ischemia followed by reperfusion, with tissue collected at 0, 3, 6, and 9 days and compared with baseline controls. From each mouse, we obtained paired samples from pressure ulcer and remote control (non-loaded) sites, mapped thickness by tissue profilometry, and performed equibiaxial testing with full-field digital image correlation and inverse finite element analysis to estimate regional material parameters. In parallel, we quantified CD31+ vasculature, F4/80+ macrophages, collagen content, and key cytokines. Pressure ulcer sites were compressed and thinner at Day 0, developed ulcers by Day 3, and continued to remodel through Day 9. Mechanical tests revealed heterogeneous strain fields with elevated deformation along ulcer borders, while remote control tissue deformed more homogeneously. These mechanical changes evolved alongside dynamic vessel and macrophage repopulation, increased collagen content at early time points, and cytokine upregulation within pressure ulcer tissue. Collectively, our data define the spatiotemporal co-evolution of tissue geometry, mechanics, collagen remodeling, and inflammation in pressure ulcers and provide a quantitative foundation for predictive mechanobiological models.

bioengineering↗

bioRxiv2026

The Tricuspid Valve Maladapts in a Pulmonary Hypertension Rat Model

Tricuspid valve regurgitation is a frequent valve lesion and, if severe, an independent predictor of mortality. In most patients, the valve itself has historically been considered intact. Yet, we have previously shown that the valve may not be an innocent bystander. In multiple sheep models, we have shown that the tricuspid valve thickens and stiffens. This remodeling may contribute to valve disease. Our goal is to extend our investigation of tricuspid valve remodeling to a rodent model, potentially opening scientific opportunity and enabling scaling our studies. To this end, we used pulmonary artery banding (PAB) in male rats to induce pressure overload and right ventricular remodeling. After excising the tricuspid valve, we quantified anterior leaflet morphology, mapped anterior leaflet thickness using optical coherence tomography, and evaluated anterior leaflet belly mechanics using a custom bulge testing system. Compared with SHAM controls, PAB increased anterior leaflet area. Moreover, anterior leaflets in PAB animals exhibited region-specific thickening, with the largest increases near the annulus. Finally, anterior leaflets in PAB animals were significantly less compliant. However, leaflet stiffening stemmed from aforementioned thickening, i.e., structural stiffening, not constitutive stiffening. Our findings demonstrate that we can reliably quantify leaflet area, thickness, and stiffness in the minuscule tricuspid valves of rats. We also show that tricuspid valve remodeling is not ovine-specific, but also affects the tricuspid valves of rats. Together, our findings support our hypothesis that tricuspid valves are not innocent bystanders in regurgitation, and that rats may serve as a scalable model system for future investigations. NEW & NOTEWORTHYUsing a rat pulmonary artery banding model of pulmonary hypertension, we show that chronic right ventricular pressure overload induces leaflet enlargement and region-specific thickness remodeling of the tricuspid valve. Although structural mechanical metrics change under pressure loading, normalization by thickness reveals that geometric remodeling rather than intrinsic material stiffening predominates. These findings highlight leaflet structural (mal)adaptation as a potential contributor to functional tricuspid regurgitation and underscore the importance of considering leaflet geometry in therapeutic strategies.

physiology↗

bioRxiv2026

MRI-Based Blood Clot Phenotyping: An In Vitro Study

Background and PurposeNeurointerventional outcomes depend on clot composition and may be influenced by clot contraction. Thus, a priori identification of clot composition and contraction could inform procedural strategies and improve outcomes. The goal of our work is to conduct an in vitro test to determine whether MRI can reliably predict both clot composition and contractile state. Materials and MethodsTo this end, we prepared blood clots spanning clinically observed compositions (0-80% red blood cells (RBCs)) in both contracted and uncontracted states. Contraction was controlled by coagulating blood with or without thrombin. We imaged these clots using quantitative, clinical, and investigational MRI sequences. Using these data, we then determined whether MRI signal intensities, quantitative parameters, and radiomic features capturing intensity and texture patterns can (i) predict clot hematocrit and (ii) classify clots by composition (RBC-rich vs. fibrin-rich) and contraction state. ResultsQuantitative MRI parameters (T1, T2, ADC) decreased with increasing hematocrit (R2 = 0.56-0.85, p < 0.001), while signal intensities from clinical sequences showed weaker correlations (R2 = 0.46-0.62, p < 0.001). Radiomic models predicted hematocrit with performance comparable to MRI parameters. When applied to classification, radiomic features accurately discriminated RBC-versus fibrin-rich clots, with AUCs exceeding 0.90 across nearly all sequences. In contrast, classification of contraction state showed greater variability in AUCs across sequences but remained high for quantitative T1 and T2 values (AUCs up to 0.88). Trends were consistent across clots coagulated with and without thrombin. Pooling features across sequences did not outperform the best individual sequence for either regression or classification. ConclusionsWe demonstrate that MRI-based radiomic analysis quantitatively characterizes clot composition and contraction in vitro. These findings support the feasibility of using MRI for pre-interventional clot phenotyping, with potential to inform thrombolytic and mechanical thrombectomy strategies. Thus, in vivo studies validating these results are warranted.

bioengineering↗

bioRxiv2026

Transcatheter Edge-to-Edge Repair Increases Annular Forces in In Vitro Whole Heart Preparations

BackgroundTricuspid transcatheter edge-to-edge repair (TEER) can induce an acute annuloplasty effect. While this has a therapeutic benefit, the mechanisms driving the reduction in annular size remain unclear. ObjectivesWe quantify the annular force induced by TEER in vitro in whole porcine heart preparations. We explore the impact of clipping different leaflet pairs on the TEER-induced annular forces. MethodsWe performed 49 interventions in 13 porcine hearts using a MitraClip XT. The clip was implanted between either the anterior-septal (AS), anterior-posterior (AP), or posterior-septal (SP) leaflet pairs. We also considered two-clip interventions between the combination of the AS-AP, AS-PS, or AP-PS leaflet pairs. For each intervention, we measured the right ventricular pressure, transvalvular flow rate, and force at eight locations around the annulus. ResultsTEER induced significant inward-pulling forces on the annulus. The maximum force was induced following an AS-PS two-clip intervention. A single AS clip induced the largest force among the one-clip interventions. Furthermore, the AP and AS-AP interventions induced the smallest annular forces. ConclusionsThe magnitude of the TEER-induced force depends on the intervention and number of clips implanted.

bioengineering↗

bioRxiv2025

Understanding the Mechanisms Behind the Annuloplasty Effect in Tricuspid Valve TEER: A Computational Study

BackgroundAn annuloplasty effect has been observed following tricuspid transcatheter edge-to-edge repair (TEER) and has been shown to have a therapeutic benefit. However, the mechanisms underlying the annuloplasty effect remain unknown. ObjectivesWe investigate the impact of TEER-induced annular forces on the annuloplasty effect. Additionally, we explored the impact of clip size, clip orientation, leaflet pair, and leaflet site on TEER-induced annular forces. MethodsWe simulated 36 TEER repairs in finite element models of three human tricuspid valves. We used either a NTW or XTW TriClip. The clip was placed between either the anterior-septal or anterior-posterior leaflet pairs, in either the central or near-annulus site. For each scenario, we quantified the reduction in annular area, septal-lateral (SL) diameter, and anterior-posterior (AP) diameter. We also report the total annular force, orientation of maximum annular force, total papillary muscle force, leaflet stress, and coaptation area ratio following TEER. ResultsTEER induced annular forces, which strongly predicted the annuloplasty effect as measured by reduction in annular area and SL diameter. The maximum annular force aligned with the orientation of the clip. Furthermore, XTW clips induced more annular force and leaflet stress than NTW clips. A central anterior-posterior site induced more force than a near-annulus anterior-posterior site, but showed no difference from an anterior-septal pair. ConclusionsTEER procedural parameters, such as clip size and site, strongly influence the magnitude of induced annular forces, which, in turn, correlate with the degree of annuloplasty effect.

bioengineering↗

bioRxiv2025

In vitro blood clot mechanical properties depend on fibrinogen and white blood cell subtypes in addition to hematocrit

BackgroundUnderstanding the role of blood composition in clot mechanics may provide critical cues toward their diagnosis and treatment. To this end, we previously showed that sex and standard blood composition measures explain some variability in clot mechanics, but much remains unaccounted for. Ours and others studies ignored the roles of fibrinogen and white blood cell (WBC) subtypes, which is surprising given their physiological importance. ObjectiveTo develop a more complete understanding of what determines clots mechanical properties, we now study the role of previously untested factors, namely fibrinogen levels and WBC subtypes, in addition to sex and standard blood composition measures. MethodsWe drew blood from healthy young adults and prepared in vitro clot samples. Using pure shear and mode-I fracture tests, we measured clots stiffness, fracture toughness, strength, and work to rupture. We then used linear regressions to quantify how blood composition influences clot mechanical properties, reporting R2 to assess explanatory power. ResultsWe found that fibrinogen is the strongest predictor of clot mechanical properties, positively correlating with all four metrics and achieving the highest average R2. For example, fibrinogen accounts for 70% of the variation in stiffness and 78% in fracture toughness. Among WBC subtypes, neutrophils positively correlate with strength and work to rupture, whereas eosinophils negatively correlate with strength. ConclusionOur work shows that fibrinogen levels and WBC subtypes are previously untested but major determinants of in vitro clot mechanical properties. Future studies should connect these findings to in vivo clot behavior and clinical outcomes.

bioengineering↗

bioRxiv2025

Community Challenge towards Consensus on Characterization of Biological Tissue: C4Bios First Findings

This study investigates methodological variability across various expert laboratories worldwide, with regards to characterizing the mechanical properties of biological tissues. Two testing rounds were conducted on the specific use case of uniaxial tensile testing of porcine aorta. In the first round, 24 labs were invited to apply their established methods to assess inter-laboratory variability. This revealed significant methodological diversity and associated variability in the stress-stretch results, underscoring the necessity for a standardized approach. In the second round, a consensus protocol was collaboratively developed and adopted by 19 labs in an attempt to minimize variability. This involved standardized sample preparation and uniformity in testing protocol, including the use of a common cutting and thickness measurement tool. Despite protocol harmonization, significant variability persisted across labs, which could not be solely attributed to inherent biological differences in tissue samples. These results illustrate the challenges in unifying testing methods across different research settings, underlining the necessity for further refinement of testing practices. Enhancing consistency in biomechanical experiments is pivotal when comparing results across studies, as well as when using the resulting material properties for in silico simulations in medical research.

bioengineering↗

bioRxiv2025

The Tricuspid Valve is Transcriptionally Active During Prolonged Pressure Overload, Right-Sided Heart Failure, and Valve Regurgitation

BackgroundRight-sided heart failure (RHF), in the presence of tricuspid valve regurgitation (TR), can result from left-sided heart failure (LHF), pulmonary hypertension (PH), or heart malformations. The occurrence of RHF and TR represents a critical indicator of hospitalization rates and all-cause mortality. However, RHF has remained understudied, specifically with respect to the tricuspid valve, with few animal models to investigate the transformative processes and identify novel interventions. MethodsUsing the outbred sheep (Ovis aries) model of pulmonary artery banding (PAB) that induces RHF and TR, we generated three batches of ribosomal reduced RNA sequencing for 354 samples (NCBI SRA PRJNA1182691) containing right ventricle, left ventricle, each tricuspid valve leaflet, each mitral valve leaflet, and the pulmonary artery that represents both male and female sheep. The reads were assembled into a de novo sheep heart transcriptome for differential analysis. ResultsThe de novo sheep heart transcriptome enhanced transcript mapping of reads by 43-45% in the heart valves relative to the known sheep reference transcriptome. The identified transcripts produce validated tissue-specific pathways in ventricles (2,756 isoforms), pulmonary arteries (535 isoforms), and valves (1,215 isoforms), with transcript differences between the mitral and tricuspid valve involved in extracellular and endocrine signaling. The transcriptome also produced robust sex differences encoded by sex chromosomes and autosomes, highlighting epigenetic and sex hormone differences in the heart. Echocardiography and differential expression suggest that 8 weeks after PAB, the right ventricle has extensive morphological changes and known stress-induced lipid processing dysregulation. At 16-weeks post-PAB, tricuspid valve leaflets show the most significant transcriptional changes, with alterations in endocrine and immune pathway genes involved in cellular and extracellular remodeling. Genes within the tricuspid valve with differential expression and known human or mouse heart phenotypes include FLNA, LTBP4, VDR, CR2, PIGQ, CENPF, ACKR3, CR1, KLF2, and HIF3A. ConclusionsThis project highlights the complexity of heart valve tissues and their transcriptional activity in a sheep model of RHF. It suggests potential therapeutic interventions in heart valve remodeling in PAH, RHF, and TR. This work highlights the need for further human and model organism research into the dynamic valve cells and genes. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABS- Improved cardiac and valve specific transcriptome mapping through de novo transcriptome for clinically relevant ovine model. - Tricuspid valves show a sex dependent and active transcriptional response to pulmonary artery banding induced pulmonary hypertension and right sided heart failure. - Transcriptional phenotypes in ovine model mirror known human heart disease phenotypes. - Several transcripts identified with therapeutic potential for treating pressure overload conditions such as pulmonary hypertension. What Are the Clinical Implications?- Tricuspid valve remodeling due to pulmonary hypertension is accompanied by transcriptional alterations, and mechanical alterations alone may not be sufficient to address valve insufficiency. - Valve and ventricle sex specific gene expression changes following pulmonary hypertension indicate a potential role for hormonal influences and a need for personalized treatment strategies. - Improved patient outcomes for right heart failure, including diagnosis, early detection, and improved treatment strategies can be elucidated through the ovine model and supported through expanded interrogation of human tissues.

genomics↗

bioRxiv2025

Loading causes molecular damage in fibrin fibers

Blood clotting is the bodys natural reaction in wound healing and is also the cause of many pathologies. Fibrin - the main protein in the clotting process provides clots mechanical strength by forming a scaffold of complex fibrin fibers. Fibrin fibers exhibit high extensibility and primarily elastic properties under static loading, which differ from in vivo dynamic forces. In many biological materials, the mechanical response changes under repeated loading/unloading (cyclic loading). Using lateral force microscopy, we show fibrin fibers possess viscoelastic behavior and experience irreversible damage under cyclic loading. Cross-linking results in a more rigid structure with permanent damage occurring mostly at larger strains, which is corroborated by computational modeling of fibrin extension using a hyperelastic model. Molecular spectroscopy analysis with broadband coherent anti-Stokes Raman scattering spectroscopy in addition to molecular dynamic simulations allow identification of the source of damage, the unfolding pattern, and inter and intramolecular changes in fibrin. The results show partial recovery of proteins secondary and tertiary structures under load, providing deeper understanding of fibrins unique behavior in wound healing or pathologies like stroke and embolism.

biophysics↗

bioRxiv2024

Tricuspid valve maladaptation in sheep with biventricular heart failure: The posterior and septal leaflets

Tricuspid valve leaflets are dynamic tissues that can respond to altered biomechanical and hemodynamic loads. Each leaflet has unique structural and mechanical properties, leading to differential in vivo strains. We hypothesized that these intrinsic differences drive heterogeneous, disease-induced remodeling between the leaflets. Although we previously reported significant remodeling changes in the anterior leaflet, the responses among the other two leaflets have not been reported. Using a sheep model of biventricular heart failure, we compared the remodeling responses between all tricuspid leaflets. Our results show that the anterior leaflet underwent the most significant remodeling, while the septal and posterior leaflets exhibited similar but less pronounced changes. We found several between-leaflet differences in key structural and mechanical metrics that have been shown to contribute to valvular dysfunction. These findings underscore the need to consider leaflet-specific remodeling to fully understand tricuspid valve dysfunction and to develop targeted therapies for its treatment and more accurate computational models. STATEMENT OF SIGNIFICANCEOur study is significant as it advances our understanding of tricuspid valve remodeling by providing a comprehensive analysis of all three leaflets in a sheep model of biventricular heart failure. Unlike prior works that focused primarily on the anterior leaflet or generalized leaflet changes, we integrated morphological, histological, immunohistochemistry, biaxial mechanical testing, and two-photon microscopy to quantify differences between all three tricuspid valve leaflets (anterior, posterior, and septal) across multiple functional scales. This comprehensive approach highlights the unique remodeling response of each leaflet. Our findings offer critical insights for developing targeted therapeutic strategies and improving computational models of disease progression. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/613284v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1e8efaforg.highwire.dtl.DTLVardef@1cfee04org.highwire.dtl.DTLVardef@136956org.highwire.dtl.DTLVardef@68c488_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Polycaprolactone-based shape memory foams as self-fitting vaginal stents

There is an urgent critical need for a patient-forward vaginal stent that can prevent debilitating vaginal stenosis that occurs in up to 75% of patients who undergo pelvic radiation treatments and adolescent patients after vaginal reconstruction. To this end, we developed a self-fitting vaginal stent based on a shape-memory polymer (SMP) foam that can assume a secondary, compressed shape for ease of deployment. Upon insertion, the change in temperature and hydration initiates foam expansion to shape fit to the individual patient and restore the lumen of the stent to allow egress of vaginal secretions. To achieve rapid actuation at physiological temperature, we investigated the effect of architecture of two photocurable, polycaprolactone (PCL) macromers. Star-PCL-tetraacrylate displayed reduced melting temperature in the target range as compared to the linear-PCL-diacrylate. Emulsion-templating was then used to fabricate foams from 75:25 water-in-oil (W/O) emulsions that were subsequently annealed to yield high-porosity SMP foams. Upon axial shape memory testing, both foams displayed excellent shape fixity (90%); however, only the PCL star-foams displayed shape recovery ([~]84%) at 37{degrees}C to its permanent shape. A custom mold and curing system was then used to fabricate PCL star- foams into hollow, cylindrical stents. The stent was crimped to its temporary insertion shape (50% reduction in diameter, OD [~] 11 mm) with a custom radial crimper and displayed excellent shape fixity for deployment (> 95%) and shape recovery ([~] 100%). To screen vaginal stents, we developed a custom benchtop pelvic model that simulated vaginal anatomy, temperatures, and pressures with an associated computational model. A hysteroscope was used to visualize stent expansion and deformation via a scope port near the cervix of the benchtop model. A crimped SMP vaginal stent was deployed in the model and expanded to walls of the canal ([~]70% increase in cross-sectional area) in less than 5 minutes after irrigation with warm water. The vaginal stent demonstrated retention of vaginal caliber with less than 1% decrease in cross-sectional area under physiological pressure. Collectively, this work demonstrates the potential for SMP foams as self-fitting vaginal stents to prevent stenosis. Additionally, this work provides new open-source tools for the iterative design of other gynecological devices. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/577474v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1bc3162org.highwire.dtl.DTLVardef@4e5657org.highwire.dtl.DTLVardef@1069d33org.highwire.dtl.DTLVardef@13aa9da_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender

bioengineering↗

bioRxiv2023

Untangling the mechanisms of pulmonary hypertension-induced right ventricular stiffening in a large animal model

BackgroundPulmonary arterial hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) remodeling and stiffening; thus, impeding diastolic filling and ventricular function. Multiple mechanisms contribute to RV stiffening, including wall thickening, microstructural disorganization, and myocardial stiffening. The relative importance of each mechanism is unclear. Our objective is to use a large animal model as well as imaging, experimental, and computational approaches to untangle these mechanisms. MethodsWe induced PHT in eight sheep via pulmonary artery banding. After eight weeks, the hearts underwent anatomic and diffusion tensor MRI to characterize wall thickening and microstructural disorganization. Additionally, myocardial samples underwent histological and gene expression analyses to quantify compositional changes and mechanical testing to quantify myocardial stiffening. All findings were compared to 12 control animals. Finally, we used computational modeling to disentangle the relative importance of each stiffening mechanism. ResultsFirst, we found that the RVs of PHT animals thickened most at the base and the free wall. Additionally, we found that PHT induced excessive collagen synthesis and microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with excess collagen synthesis. Finally, our model of normalized RV pressure-volume relationships predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms. ConclusionsIn summary, we found that PHT induces wall thickening, microstructural disorganization, and myocardial stiffening. These remodeling mechanisms were both spatially and directionally dependent. Using modeling, we show that myocardial stiffness is the primary contributor to RV stiffening. Thus, myocardial stiffening may be an important predictor for PHT progression. Given the significant correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for non-invasively estimating myocardial stiffness and predicting PHT outcomes.

physiology↗

bioRxiv2023

Sex- and Age-dependent Skin Mechanics - A Detailed Look in Mice

Skin aging is of immense societal and, thus, scientific interest. Because mechanics play a critical role in skins function, a plethora of studies have investigated age-induced changes in skin mechanics. Nonetheless, much remains to be learned about the mechanics of aging skin. This is especially true when considering sex as a biological variable. In our work, we set out to answer some of these questions using mice as a model system. Specifically, we combined mechanical testing, histology, collagen assays, and two-photon microscopy to identify age- and sex-dependent changes in skin mechanics and to relate them to structural, microstructural, and compositional factors. Our work revealed that skin stiffness, thickness, and collagen content all decreased with age and were sex dependent. Interestingly, sex differences in stiffness were age induced. We hope our findings not only further our fundamental understanding of skin aging but also highlight both age and sex as important variables when conducting studies on skin mechanics.

biophysics↗

bioRxiv2023

Elasticity of Whole Blood Clots Measured via Volume Controlled Cavity Expansion

Measuring and understanding the mechanical properties of blood clots can provide insights into disease progression and the effectiveness of potential treatments. However, several limitations hinder the use of standard mechanical testing methods to measure the response of soft biological tissues, like blood clots. These tissues can be difficult to mount, and are inhomogeneous, irregular in shape, scarce, and valuable. To remedy this, we employ in this work Volume Controlled Cavity Expansion (VCCE), a technique that was recently developed, to measure local mechanical properties of soft materials in their natural environment. Through a highly controlled volume expansion of a water bubble at the tip of an injection needle, paired with simultaneous measurement of the resisting pressure, we obtain a local signature of whole blood clot mechanical response. Comparing this data with predictive theoretical models, we find that a 1-term Ogden model is sufficient to capture the nonlinear elastic response observed in our experiments and produces shear modulus values that are comparable to values reported in the literature. Moreover, we find that bovine whole blood stored at 4{degrees}C for greater than 2 days exhibits a statistically significant shift in the shear modulus from 2.53 {+/-} 0.44 kPa on day 2 (N = 13) to 1.23 {+/-} 0.18 kPa on day 3 (N = 14). In contrast to previously reported results, our samples did not exhibit viscoelastic rate sensitivity within strain rates ranging from 0.22 - 21.1 s-1. By surveying existing data on whole blood clots for comparison, we show that this technique provides highly repeatable and reliable results, hence we propose the more widespread adoption of VCCE as a path forward to building a better understanding of the mechanics of soft biological materials. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/528966v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1cf427borg.highwire.dtl.DTLVardef@15d7b7org.highwire.dtl.DTLVardef@53ab4org.highwire.dtl.DTLVardef@1513aee_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIVolume controlled cavity expansion overcomes common obstacles to testing biological samples C_LIO_LIWhole blood clot elasticity is well captured by the Ogden hyperelastic material model C_LIO_LIShear modulus strain-rate sensitivity was not observed in clots for moderate rates C_LI

bioengineering↗