Biology subjects

Sacks, M. S.

Publications and source records attributed to Sacks, M. S..

8 recordsLinked to original sources

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

CARDIAX-NNFE - A Cardiac Mechanics SciML Framework

One goal of Scientific Machine Learning (SciML) is to advance traditional scientific computing frameworks with modern machine learning tools. This includes extending established methods, such as the finite element method, with cardiac function applications due to their complexity and need for very rapid execution times for real time clinical use. In this work, we present an advanced form of the Neural Network Finite Element (NNFE) method specialized for cardiac simulations, termed CARDIAX-NNFE. The NNFE method learns the parameter-to-displacement field map by training over the residual of the hyperelastic material PDE, using the domain represented by finite elements. The implementation is developed in Python using JAX to leverage its automatic differentiation, highly parallel GPU, and JIT-compilation capabilities. To demonstrate CARDIAX-NNFE effectiveness, we trained full cardiac pressure-volume responses using a simplified heart model, spanning the entire cardiac physiological functional range. Results indicated the ability to simulate a family of pressure-volume solutions with average nodal positional error of 0.023 mm and maximal error of 0.054 mm, with a single complete PV loop evaluated in 0.002 seconds. The CARDIAX-NNFE software platform thus provides for a robust platform for cardiac functional simulations. Moreover, it provides the structure for residual-based SciML methods, which can apply to a variety of physics-based biomedical problems that require high execution speed for clinical applications.

bioengineering↗

bioRxiv2026

3D Microscale Mechanical Simulations of Hydrogel Coated Electrospun Meshes

Electrospun fiber meshes have long served as biomaterials in a wide range of biomedical applications due to their functional similarities to extracellular matrix and highly tunable properties. Altering the mechanical behaviors of individual fibers and their microarchitecture (e.g.; diameter, crimp, orientation, density) can in principle be used to control bulk level behaviors. Moreover, electrospun meshes are often combined with softer coatings and hydrogels to control surface interactions with body tissues. Yet, fully optimizing their behaviors for specific applications remains an elusive target due to a continued lack of understanding of the micromechanical mechanisms and their relation to bulk mechanical behaviors. Our goal herein was to understand how actual nanoCT-generated 3D microfiber geometry can be used to predict bulk mechanical properties of hydrogel-mesh composites. Electrospun polyurethane meshes were fabricated with a random fiber orientation and coated with a PEG-based hydrogel. The fiber-hydrogel composite was then imaged with a nanoCT scanner at a voxel resolution of 180 nm. From these images, custom Python programs were written to segment, refine, and tesselate a high-resolution finite element of the fiber mesh and hydrogel volumes into a single integrated bi-material finite element model. The resulting mesh was used to run simulations of the planar biaxial mechanical tests used to characterize the bulk mechanical behaviors. Our framework thus enabled systematic investigations of both the macroscopic bulk mechanical response of the overall fiber mesh and the microscopic localized mechanical response of fibers under various stages of loading. The resultant simulations were accurate and predictive of the bulk mechanical responses. It is interesting to note that the fiber-hydrogel composite material experienced the largest stresses within the fiber phase and the largest strains within the hydrogel. This key result underscores that while the previous analytical model assumed local affine deformations, at the microscale this assumption does not hold. We also found very different effective fiber stress-strain responses in each model. It is likely these differences are due to the substantial heterogeneous non-affine local deformations present in the actual fiber-hydrogel composite. This finding further reveals the need for more rigorous approaches to better understand how electrospun-based materials function in order to improve their use in modern medical devices and implants.

bioengineering↗

bioRxiv2025

3D Contractile and Remodeling Behaviors of Functionally Normal and Prolapsed Human Mitral Valve Interstitial Cells

Mitral valve prolapse (MVP) can lead to heart failure, arrhythmia, and death. The only treatments available for MVP are replacement or repair; alternative therapies remain elusive due to lack of knowledge of the underlying pathological processes. The goal of the present study was thus to explore how MVP affects human mitral valve interstitial cell (hMVICs) extracellular matrix (ECM) remodeling and basal contractility characteristics. Isolated MVP and physiologically normal hMVICs were embedded in poly(ethylene) glycolbased hydrogels containing fluorescent fiducial markers and 3D traction force microscopy via inverse modeling was employed to determine the local change in hMVIC hydrogels due to enzymatic degradation and collagen deposition. Results indicated pronounced hydrogel softening occurred generally further from the hMVICs, whereas stiffening occurred in close proximity to hMVICs due to collagen deposition as verified by collagen-staining. MVP hMVICs induced greater hydrogel stiffening and less degradation than normal hMVICs. Interestingly, even though MVP hMVICs had higher basal contractile displacements, their corresponding traction forces and hydrogel strain energy densities were significantly lower than those of normal hMVICs. These findings elucidate, for the first time, that MVP hMVICs have significantly altered biophysical contractile and ECM remodeling behaviors compared to normal hMVICs. Simple SummaryWhen a mitral heart valve gets thick, stiffened, and degraded, it can flip backwards (prolapse), causing blood to flow the wrong way. This can cause heart failure, arrhythmia, or even death. The only treatment for mitral valve prolapse (MVP) is surgery. To pave the way for a medication, this study aimed to understand how cells that maintain the mitral valve, mitral valve interstitial cells (MVICs), act on their surrounding tissue. The mechanical properties of the MVICs were tested, including how much they contract and how much they pull on their surroundings. Also, the mechanical properties that the MVICs place on their surroundings were tested, like how much they stiffen and degrade the tissue and how much energy is stored in the tissue as the MVICs contract. Compared to normal MVICs, we found that MVP MVICs stiffen their surroundings more and degrade their surroundings less. We also found that even though MVP MVICs contract more than normal MVICs, the energy that they place on their surroundings is less than that of normal MVICs, indicating that MVP MVICs are less mechanically effective. This is the first time that this ineffectiveness has been seen and may be key to targeting MVP with future medications.

cell biology↗

bioRxiv2025

A New Computational Inverse Modeling Approach for Cellular Traction Force Microscopy that Accounts for Hydrogel Compressibility

We have recently documented significant compressible behaviors in hydrogels implemented in 3D traction force microscopy (TFM). Therefore, here we have developed a new computational pipeline that accounts for this observation. Additionally, the new method accurately recovers large ranges and spatial heterogeneity of hydrogel moduli induced by cellular remodeling associated with enhanced extracellular matrix secretion and MMP-degradation. The algorithm sought best fit of the 3D displacement field with a multi-stage approach, wherein the Tikhonov regularization parameter in L-BFGS was progressively lowered. Forward simulations were performed in FEniCS, with gradients computed with FEniCS-adjoint and MOOLA to weight degrees of freedom according to hydrogel volume affected. Once developed, we conducted a series of synthetic test cases applying actual cell geometries, experimentally-matched compressibility, and realistic displacements with experimental noise levels. Employing an incompressible material model resulted in predicted moduli with over 415% mean relative error and predicted strain energies 5-fold greater than the prescribed values. Moreover, errors in predicted traction forces were amplified by a factor of 10. Thus, accounting for hydrogel compressibility was critical for accurate hydrogel moduli and strain energy recovery. To demonstrate the utility of our approach, we applied it to TFM data of human mitral valve interstitial cells embedded in PEG hydrogels with pre-altered moduli of 54 Pa. We determined that J [isin] [0.45, 1.66] and local hydrogel moduli exhibited large variations, 3.6 Pa to 2.4 MPa. This study underscores the need for correct handling of hydrogel compressibility for accurate estimation of local hydrogel moduli and traction forces.

bioengineering↗

bioRxiv2025

Multicellularity, Culture Duration, and Hydrogel Stiffness Guide Induced Pluripotent Stem Cell-Derived Endothelial Progenitor Cell Contractility

Human induced pluripotent stem cells (hiPSCs) offer immense potential for tissue engineering, yet poor vascularization remains a significant hurdle. Understanding how hiPSC-derived endothelial progenitor cells (hiPSC-EPs) form networks is essential for therapeutic progress. This study investigates extracellular matrix (ECM) remodeling and cellular contractility during the early self-assembly of hiPSC-EPs within 3D hyaluronic acid-based hydrogels. By tracking microsphere displacements before and after cytochalasin-D treatment, we quantified contractile forces in single cells and clusters at days 4 and 7. We then applied a novel inverse modeling approach using a compressible material model to determine spatially varying changes in hydrogel modulus caused by enzymatic degradation and ECM deposition. Our findings reveal that basal contractility and remodeling are nonlinearly influenced by multicellularity, culture duration, and initial stiffness. Increased hydrogel stiffness, paired with synergistic rises in strain energy, resulted in high traction forces in longer culture times. These results provide critical mechanical insights into hiPSC-EP self-assembly, advancing our ability to engineer functional vascular networks.

bioengineering↗

bioRxiv2025

Matrix Stiffness Regulates Mechanotransduction and Vascular Network Formation of hiPSC-Derived Endothelial Progenitors Encapsulated in 3D Hydrogels

The mechanical properties of the extracellular matrix (ECM), particularly stiffness, regulate endothelial progenitor responses during vascular development, yet their behavior in physiologically compliant matrices (<1 kPa) remains underexplored. Using norbornene-modified hyaluronic acid (NorHA) hydrogels with tunable stiffness (190-884 Pa), we investigated how hydrogel stiffness influences cell morphology, endothelial maturation, mechanotransduction, and microvascular network formation in human induced pluripotent stem cell-derived endothelial progenitors (hiPSC-EPs). Our findings reveal a stiffness-dependent tradeoff between mechanotransduction and vascular network formation. At intermediate stiffness (551 Pa), cells exhibited the greatest increase in endothelial marker CD31 expression and Yes-associated protein (YAP)/ transcriptional coactivator with PDZ-binding motif (TAZ) nuclear translocation, indicating enhanced mechanotransduction and endothelial maturation. However, this did not translate to superior plexus formation. Instead, the most compliant matrix (190 Pa) supported greater vascular connectivity, characterized by longer branches ([~]0.03/volume vs. 0.015 at 551 Pa) and enhanced actin remodeling. 3D cell contraction measurements revealed a 15.6-fold higher basal displacement in compliant hydrogels, suggesting that cell-generated forces and matrix deformability collectively drive vascular morphogenesis. Unlike prior studies focusing on pathological stiffness ranges (>10 kPa), our results emphasize that vascularization is not solely driven by the most mechanotransductive environment but rather by a balance of compliance, contractility, and cell-induced remodeling. These findings underscore the need to design hydrogels that provide sufficient mechanotransduction for endothelial maturation while maintaining compliance to support dynamic vascular morphogenesis. This work provides a mechanically tuned framework for optimizing microenvironments to balance endothelial differentiation and vascular network formation in tissue engineering and regenerative medicine.

bioengineering↗

bioRxiv2019

Mitral valve leaflet response to ischemic mitral regurgitation: From gene expression to tissue remodeling

AimsIschemic mitral regurgitation is frequently observed following myocardial infarction and is associated with higher mortality and poor clinical prognosis if left untreated. Accumulating evidence suggests that mitral valve leaflets actively remodel post-myocardial infarction, yet the cellular mechanisms underlying these responses and how this affects tissue function remain largely unknown. We sought to elucidate mitral valve remodeling post myocardial infarction at the tissue, cellular, and transcriptomic levels. Methods and ResultsThe mechanical behavior of ovine mitral valve leaflets pre- and 8 weeks post- myocardial infarction reveal a significant decrease in radial direction extensibility, which essentially eliminated the mechanical anisotropy typically observed in healthy mitral valves. Quantitative histology and ultrastructural assessment by transmission electron microscopy revealed altered leaflet composition and architecture at 8 weeks post-myocardial infarction. Assessment of the mitral valve interstitial cell nuclear aspect ratio, a metric of cellular deformation, revealed that they were on average rounder following myocardial infarction. RNA sequencing indicated that YAP-induced genes were elevated at 4 weeks post-myocardial infarction and genes related to extracellular matrix organization were some of the most downregulated in sheep with IMR compared to sheep without ischemic mitral regurgitation at 4 weeks post-myocardial infarction. Additionally, RNA sequencing revealed the possible recruitment of immune cells in this remodeling process due to the drastic elevation of CXCL9 and CLEC10A. ConclusionsOur multiscale assessment revealed significant mechanical and microstructural changes due to myocardial infarction. RNA sequencing provided a baseline for global gene expression changes in response to myocardial infarction with and without ischemic mitral regurgitation and suggests YAP-induced mechanotransduction, altered expression of extracellular matrix-related genes, and recruitment of immune cells as mechanisms contributing to altered mitral valve biomechanics post-myocardial infarction.

bioengineering↗