Local Mechanical Stress Research Articles

Impact of Externally Induced Local Mechanical Stress on Electrical Performance of Decananometer MOSFETs

Vertical, gigapascal-level mechanical stress (MS) is induced at different locations along the channel of 40-nm effective gate length planar CMOS field-effect transistor (FET) devices and electrical parameter variations are investigated. In both p-and n-channel devices, the threshold voltage, mobility, and ON-current are seen to change proportionally with the additional MS, while gate-induced drain-leakage current increases exponentially. A clear effect of the location of the applied force along the source–drain direction is observed on the transistor parameters. Simulations show that a mechanical load located closer to the FET source induces a stronger asymmetry between the source and drain stresses. This leads to asymmetric subband splitting/warping, which reduces the backscattering rate at the source, in line with theoretical predictions on the importance of the channel barrier near the source for current in quasi-ballistic transistors.

Low-intensity pulsed ultrasound/nanomechanical force generators enhance osteogenesis of BMSCs through microfilaments and TRPM7

BackgroundLow-intensity pulsed ultrasound (LIPUS) has been reported to accelerate fracture healing, but the mechanism is unclear and its efficacy needs to be further optimized. Ultrasound in combination with functionalized microbubbles has been shown to induce local shear forces and controllable mechanical stress in cells, amplifying the mechanical effects of LIPUS. Nanoscale lipid bubbles (nanobubbles) have high stability and good biosafety. However, the effect of LIPUS combined with functionalized nanobubbles on osteogenesis has rarely been studied.ResultsIn this study, we report cyclic arginine-glycine-aspartic acid-modified nanobubbles (cRGD-NBs), with a particle size of ~ 500 nm, able to actively target bone marrow mesenchymal stem cells (BMSCs) via integrin receptors. cRGD-NBs can act as nanomechanical force generators on the cell membrane, and further enhance the BMSCs osteogenesis and bone formation promoted by LIPUS. The polymerization of actin microfilaments and the mechanosensitive transient receptor potential melastatin 7 (TRPM7) ion channel play important roles in BMSCs osteogenesis promoted by LIPUS/cRGD-NBs. Moreover, the mutual regulation of TRPM7 and actin microfilaments promote the effect of LIPUS/cRGD-NBs. The extracellular Ca2 + influx, controlled partly by TRPM7, could participated in the effect of LIPUS/cRGD-NBs on BMSCs.ConclusionsThe nanomechanical force generators cRGD-NBs could promote osteogenesis of BMSCs and bone formation induced by LIPUS, through regulation TRPM7, actin cytoskeleton, and intracellular calcium oscillations. This study provides new directions for optimizing the efficacy of LIPUS for fracture healing, and a theoretical basis for the further application and development of LIPUS in clinical practice.

Remodeling of the Aged and Emphysematous Lungs: Roles of Microenvironmental Cues.

Aging is a slow process that affects all organs, and the lung is no exception. At the alveolar level, aging increases the airspace size with thicker and stiffer septal walls and straighter and thickened collagen and elastic fibers. This creates a microenvironment that interferes with the ability of cells in the parenchyma to maintain normal homeostasis and respond to injury. These changes also make the lung more susceptible to disease such as emphysema. Emphysema is characterized by slow but progressive remodeling of the deep alveolar regions that leads to airspace enlargement and increased but disorganized elastin and collagen deposition. This remodeling has been attributed to ongoing inflammation that involves inflammatory cells and the cytokines they produce. Cellular senescence, another consequence of aging, weakens the ability of cells to properly respond to injury, something that also occurs in emphysema. These factors conspire to make alveolar walls more prone to mechanical failure, which can set emphysema in motion by driving inflammation through immune stimulation by protein fragments. Both aging and emphysema are influenced by microenvironmental conditions such as local inflammation, chemical makeup, tissue stiffness, and mechanical stresses. Although aging and emphysema are not equivalent, they have the potential to influence each other in synergistic ways; aging sets up the conditions for emphysema to develop, while emphysema may accelerate cellular senescence and thus aging itself. This article focuses on the similarities and differences between the remodeled microenvironment of the aging and emphysematous lung, with special emphasis on the alveolar septal wall. © 2022 American Physiological Society. Compr Physiol 12:3559-3574, 2022.

Nanoscale Stress Localization Effects on the Radiation Susceptibility of GaN High‐Mobility Transistors

Nanoscale localized mechanical stress fields develop unavoidably in microelectronic devices due to structural and processing aspects. Their global average is too small to influence bandgap or mobility, but it is proposed that stress localization can influence defect nucleation sites under radiation. This is investigated on gallium nitride high‐electron‐mobility transistors (GaN HEMTs). Using transmission electron microscopy, we spatially resolved the stress field in the AlGaN layer for both pristine and 10 Mrad gamma‐irradiated HEMTs. The quantitative nanobeam electron diffraction and geometric phase analysis indicate that tensile stressed localizations experience higher radiation‐induced strain. This finding is explained by the tensile stress dependence of the carrier concentration and mobility in the AlGaN layer. Since gamma radiation damage is inflicted by high‐energy electrons only, localized regions of higher tensile stress in the AlGaN layer are expected to be more susceptible to gamma rays.

Recovery of LED Emission Power under the Exposure to γ-n-Pulse

The article presents results of the study of the effect of LED power modes based on AlGaAs heterostructures (short-circuit, open circuit, and active mode with the passage of operating current during irradiation) on the resistance to γ-n-pulse exposure. Reduction of LED emission power under the influence of γ-n-pulse occurs in two stages irrespective of irradiation power mode, with each stage characterized by its own regularity and its own factor. Built-in electric field of p-n-junction does not contribute significantly to the degradation of LED power when exposed to γ-n-pulse. At irradiation of LED in active power mode after exposure to γ-n-pulse (Fn ≤ 1.5·1012n/cm2, Dγ ≤ 20 Gy (Si)) a recovery of LED power by the value of ΔP is observed. Recovery of ΔP power leads to reduction of the damage factor at the first stage, to increase of the LED resistance, and to shift of the boundary between the stages to the area of higher neutron fluences. It is supposed, that the observed jump-like increase of ΔP radiation power under the influence of γ-n-pulse is caused by radiation-stimulated annealing of local mechanical stresses that is generated under the condition of passing of operating current through LED.

Mechanical Allosteric Couplings of Redox-Induced Conformational Changes in Respiratory Complex I.

We apply linear response theory to calculate mechanical allosteric couplings in respiratory complex I between the iron sulfur cluster N2, located in the catalytic cavity, and the membrane part of the enzyme, separated from it by more than 50 Å. According to our hypothesis, the redox reaction of ubiquinone in the catalytic cavity of the enzyme generates an unbalanced charge that via repulsion of the charged redox center N2 produces local mechanical stress that transmits into the membrane part of the enzyme where it induces proton pumping. Using coarse-grained simulations of the enzyme, we calculated mechanistic allosteric couplings that reveal the pathways of the mechanical transmission of the stress along the enzyme. The results shed light on the recent experimental studies where a stabilization of the enzyme with an introduced disulfide bridge resulted in the abolishing of proton pumping. Simulation of the disulfide bond action indicates a dramatic change of the mechanistic coupling pathways in line with experimental findings.

Abstract P1-08-20: In silico analysis of a novel mathematical model integrating in vitro and in vivo imaging data reveals driving mechanisms of breast cancer response to NAT for personalized tumor forecasting

Abstract The early assessment of neoadjuvant therapy (NAT) response in triple-negative breast cancer (TNBC) would enable a treating oncologist to adjust a therapeutic plan of a non-responding patient, and thereby enhance outcomes while preventing unnecessary toxicities. To address this challenge, we propose leveraging personalized, in silico forecasts of tumor response to therapeutic regimens via a mechanistic mathematical model calibrated with patient-specific longitudinal magnetic resonance imaging (MRI) data acquired early during NAT. Here, we focus on identifying the driving mechanisms involved in the model formulation through a global sensitivity analysis. Our model describes the dynamics of TNBC cell density as a combination of mobility, which is formulated as a diffusion process constrained by local tumor-induced mechanical stress, and net proliferation, which is represented with a logistic term. To model TNBC response to NAT drug combinations, we adjust the tumor cell proliferation rate with a recent pharmacodynamic model, MuSyC, which also accounts for synergy of potency and efficacy. Tumor cell density is estimated from diffusion-weighted MRI data, while tissue mechanical properties are defined from segmented contrast-enhanced T1-weighted MRI data. To model the heterogeneous intratumoral delivery of drugs, we use perfusion maps estimated from dynamic contrast-enhanced MRI data. NAT drug pharmacokinetics are approximated with a linear model, which reasonably represents their temporal decay during NAT. Sobol’s method is used for the global sensitivity analysis of the NAT response of two different tumors (one well-perfused and one poorly-perfused) on a 3D, tissue-scale domain. This allows us to assess the total effect (ST) of each model parameter on tumor volume and global cellularity. Here, we focus on two standard NAT regimens: doxorubicin plus cyclophosphamide, and paclitaxel plus carboplatin. The parameter space is constructed by integrating three approaches. First, we use prior patient-specific in silico estimates of tumor cell mobility and proliferation. Second, we experimentally constrain the parameters accounting for potential synergistic drug activity by using time-resolved, high-throughput, automated microscopy assays that capture drug-induced changes in proliferation rates of various TNBC lines (HCC1143, SUM149, MDAMB231, and MDAMB468; perfosfamide was used in lieu of the pro-drug cyclophosphamide). Third, we scale the resulting in vitro parameter ranges to be clinically-relevant through an in silico study with our mechanistic model. Our results show that out of the 15 model parameters considered in the sensitivity analysis only a minority exhibited a driving role (ST > 0.1) in representing the dynamics of TNBC response to NAT, namely: the baseline tumor cell proliferation rate along with the effect and ratio of peak concentration to EC50 of doxorubicin, paclitaxel, and carboplatin. The other parameters have a marginal effect and can thus be fixed to any value within the parameter space. We select these constant parameters such that they contribute to simplifying the model formulation, leading to a surrogate reduced model. We further show that the reduced and the original model produce distributions of tumor volume and global cellularity that are in remarkable agreement both qualitatively (Dice similarity coefficient > 0.90 and > 0.94, respectively) and parameter-wise (concordance correlation coefficient > 0.85 and > 0.89, respectively). Thus, we conclude that our reduced model constitutes a feasible surrogate for future clinical calibration-forecasting studies, thereby facilitating personalized NAT response forecasting with patient-specific imaging datasets acquired in vivo. Citation Format: Guillermo Lorenzo, Angela M. Jarrett, Christian T. Meyer, Darren R. Tyson, Vito Quaranta, Thomas E. Yankeelov. In silico analysis of a novel mathematical model integrating in vitro and in vivo imaging data reveals driving mechanisms of breast cancer response to NAT for personalized tumor forecasting [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-20.

Investigation of local internal stresses under conditions of uniaxial compression of a quartz single crystal

Based on the analysis of the time intervals between acoustic emission signals obtained in the process of uniaxial compression of a cylindrical sample of a quartz single crystal, local stresses were estimated. It is shown that a decrease in the ability of a material to monotonic stress relaxation with time can serve as a signal for the imminent breakdown of the material. Keywords: acoustic emission, kinetic concept of strength, local mechanical stresses.

Induced stress arising in crystalline silicon under exposure to ultra-short laser pulses of different duration in air and water

The silicon surface was modified in a single-pulse mode with femto-picosecond laser pulses (0.3 and 10 ps) in the near-IR range (1030 nm) during ablation in air and water. The resulting structures were studied using Raman microscopy. In the course of the study, it was found that nanocrystallites with a size of 7-8 nm appear at the crater boundary. Local mechanical stresses were found in the center of the crater, the sign of which depends on the applied energy density. The highest local compressive stresses arise in water in the subfilamentation mode at maximum energy densities. Keywords: silicon, Raman spectroscopy, ultrashort pulses, single-pulse ablation in air and liquid, local stresses.

Influence of the Characteristics of Multilayer Interference Antireflection Coatings Based on Nb, Si, and Al Oxides on the Laser-Induced Damage Threshold of ZnGeP2 Single Crystal

In this work, the effect of the defect structure and the parameters of antireflection interference coatings based on alternating layers of Nb2O5/Al2O3 and Nb2O5/SiO2 layers on the laser-induced damage threshold of ZGP crystals under the action of Ho:YAG laser radiation at a wavelength of 2.097 μm was determined. Coating deposition was carried out using the ion-beam sputtering method. The laser-induced damage threshold of the sample with a coating based on alternating layers Nb2O5 and SiO2 was W0d = 1.8 J/cm2. The laser-induced damage threshold of the coated sample based on alternating layers of Nb2O5 and Al2O3 was W0d = 2.35 J/cm2. It has been found that the presence of silicon conglomerates in an interference antireflection coating leads to a decrease in the laser-induced damage threshold of a nonlinear crystal due to local mechanical stresses and the scattering of incident laser radiation.

Structural and pathological changes in the enthesis are influenced by the muscle contraction type during exercise.

Mechanical stress is involved in the onset of sports-related enthesopathy. Although the amount of exercise undertaken is a recognized problem during disease onset, changes in muscle contraction type are also involved in the increase in mechanical stress during exercise. This study aimed to clarify the effects of increased mechanical stress associated with muscle contraction type and amount of exercise on enthesis. Twenty mice underwent treadmill exercise, and the muscle contraction type and overall load during exercise were adjusted by varying the angle and speed conditions. Histological analysis was used to the cross-sectional area of the muscle; area of the enthesis fibrocartilage (FC), and expression of inflammation-, degeneration-, and calcification-related factors in the FC area. In addition, the volume and structure of the bone and FC area were examined using microcomputer imaging. Molecular biological analysis was conducted to compare relative expression levels of inflammation and cytokine-related factors in tendons. The Overuse group, which increased the amount of exercise, showed no significant differences in parameters compared to the sedentary mice (Control group). The mice subjected to slow-speed downhill running (Misuse group) showed pathological changes compared to the Control and Overuse groups, despite the small amount of exercise. Thus, the enthesis FC area may be altered by local mechanical stress that would be increased by eccentric muscle contraction rather than by mechanical stress that increases with the overall amount of exercise. Clinical Significance: The muscle contraction type might be more involved in the onset of sports-related enthesopathy rather than the amount of exercise.

Tooth structure, mechanical properties, and diet specialization of Piranha and Pacu (Serrasalmidae): A comparative study

The relationship between diet, bite performance, and tooth structure is a topic of common interest for ecologists, biologists, materials scientists, and engineers. The highly specialized group of biters found in Serrasalmidae offers a unique opportunity to explore their functional diversity. Surprisingly, the piranha, whose teeth have a predominantly cutting function and whose main diet is soft flesh, is capable of exerting a greater bite force than a similarly sized pacu, who feeds on a hard durophagous diet. Herein, we expand our understanding of diet specialization in the Serrasalmidae family by investigating the influence of elemental composition and hierarchical structure on the local mechanical properties, stress distribution, and deformation mechanics of teeth from piranha (Pygocentrus nattereri) and pacu (Colossoma macropomum). Microscopic and spectroscopic analyses combined with nanoindentation and finite element simulations are used to probe the hierarchical features to uncover the structure-property relationships in piranha and pacu teeth. We show that the pacu teeth support a durophagous diet through its broad cusped-shaped teeth, thicker-irregular enameloid, interlocking interface of the dentin-enameloid junction, and increased hardness of the cuticle layer due to the larger concentrations of iron present. Comparatively, the piranha teeth are well suited for piercing due to their conical-shape which we report as having the greatest stiffness at the tip and evenly distributed enameloid. Statement of significanceThe hierarchical structure and local mechanical properties of the piranha and pacu teeth are characterized and related to their feeding habits. Finite element models of the anterior teeth are generated to map local stress distribution under compressive loading. Bioinspired designs from the DEJ interface are developed and 3D printed. The pacu teeth are hierarchically structured and have local mechanical properties more suitable to a durophagous diet than the piranha. The findings here can provide insight into the design and fabrication of layered materials with suture interfaces for applications that require compressive loading conditions.

Impact of silicon melt infiltration on the quality of cast crystalline silicon

Dislocation clusters are the most harmful defect in cast crystalline silicon, and it is very hard to determine the various dislocation origins. In this work, we design an experiment to investigate the impact of silicon melt infiltration on the crystal quality of cast crystalline silicon grown by different types of seeds. The results show that the infiltration of silicon melt at the ingot bottom will introduce more metal impurities, thus increasing the length of low minority carrier lifetime at the ingot bottom, which also proved by the numerical simulation of iron diffusion. Moreover, the solidified silicon melt would introduce local mechanical stress, which significantly increases the generation probability of defects in the mono-Si seeds and seed junctions, but not degrade the seeding quality of the poly-Si seeds. These results give a new insight to reduce dislocation origins for casting high-quality crystalline silicon ingots.

Electro-Chemo-Mechanical Failure in a High-Performance Solid Oxide Cell

Fuel electrode-supported solid oxide cells (FE-SOC) offer the possibility of low operation temperatures and / or high power density through the incorporation of a thin, supported electrolyte between two highly active electrodes. However, integrating fuel electrodes with an ionic conductor that is different from that of the electrolyte into FE-SOC remains a challenge due to the interdiffusion phenomena during co-sintering of the half-cell. As a result, most FE-SOC use cermet fuel electrodes made from Ni and stabilized zirconia.Here, we present a FE-SOC based on a Ni-Gd0.1Ce0.9O2- d (GDC) fuel electrode, a three-layer GDC / zirconia / GDC electrolyte and an La0.58Sr0.4CoO3- d (LSC) air electrode. The electrolyte is fabricated by co-sintering a thin, screen-printed layer of GDC with the fuel electrode and support. Subsequent electrolyte layers are deposited via physical vapor deposition (PVD), and the air electrode is fabricated via screen printing. The total electrolyte thickness is less than 5 µm, enabling an area-specific ohmic resistance < 10 mΩ cm² at 700 °C. A current density of 1.6 Acm-² is achieved at a cell voltage of 800 mV and a temperature of 700 °C, using 10% H2O/H2 as fuel and air as oxidant. This performance is about twice as high as that of a conventional Jülich cell using Ni-YSZ and LSCF electrodes and a 10 µm YSZ electrolyte under similar conditions. An electrolysis current of 2 A cm-² was achieved at a cell voltage of 1.11 V, at a temperature of 800 °C and using 50% H2O/H2 and air. The conventional Jülich cell requires a cell voltage above 1.25 V under similar conditions. Under these conditions, the new cell achieves a cell efficiency of 84 %, compared to 73 % for the conventional cell.However, running high electrolysis currents at temperatures below 750 °C resulted in catastrophic cell failure, visible as large voltage jumps in the I-V curve. In addition, a decreasing OCV value with decreasing temperature indicated damage to the cell before the catastrophic failure. Post-test analysis found a large number of cracks in the electrolyte, nucleating at the fuel electrode / electrolyte interface and running toward the air electrode. We show that the likely cause for this failure is the electrochemical reduction and subsequent chemical expansion of the doped ceria electrolyte layer, necessitating a detailed study of the local mechanical stresses in the cell during operation.

Sonotrodes for Ultrasonic Welding of Titanium/CFRP-Joints—Materials Selection and Design

Ultrasonic welding of titanium alloy Ti6Al4V to carbon fibre reinforced polymer (CFRP) at 20 kHz frequency requires suitable welding tools, so called sonotrodes. The basic function of ultrasonic welding sonotrodes is to oscillate with displacement amplitudes typically up to 50 µm at frequencies close to the eigenfrequency of the oscillation unit. Material properties, the geometry of the sonotrode, and the sonotrode tip topography together determine the longevity of the sonotrode. Durable sonotrodes for ultrasonic welding of high-strength joining partners, e.g., titanium alloys, have not been investigated so far. In this paper, finite element simulations were used to establish a suitable design assuring the oscillation of a longitudinal eigenmode at the operation frequency of the welding machine and to calculate local mechanical stresses. The primary aim of this work is to design a sonotrode that can be used to join high-strength materials such as Ti6Al4V by ultrasonic welding considering the longevity of the welding tools and high-strength joints. Material, sonotrode geometry, and sonotrode tip topography were designed and investigated experimentally to identify the most promising sonotrode design for continuous ultrasonic welding of Ti6AlV4 and CFRP. Eigenfrequency and modal shape were measured in order to examine the reliability of the calculations and to compare the performance of all investigated sonotrodes.

Thermo-Electrochemical-Mechanics Interactions on Thermal Safety in Li-Ion Cells

The thermal safety of lithium-ion batteries poses a serious concern towards using high power and energy-dense batteries for electric vehicles. The lithium-ion battery performance in a pouch cell format is greatly influenced by heterogeneity at different scales that translate to localized over-potentials, heat generation, plating severity, and mechanical stress. Such localized thermo-electrochemical-mechanics interactions can arise due to microstructural variability at mesoscale and cell architecture-induced heterogeneity (tab design) at a macro-scale. We use a microstructure resolved macro-scale (pouch cell) model to develop a fundamental understanding of the influence of heterogeneity on cell performance in terms of localized temperature rise, plating severity, and accelerated degradation under operational extremes. Finally, the effect of thermo-electrochemical interactions on localized lithium deposition is coupled to a thermal abuse model. The modeling capability elucidates the impact of plating heterogeneity on thermal runaway dynamics within a pouch cell operated under thermal abuse conditions.

Leaflet stress quantification of porcine vs bovine surgical bioprostheses: an in vitro study

Calcified aortic stenoses are among the most prevalent form of cardiovascular diseases in the industrialized countries. This progressive disease, with no effective medical therapy, ultimately requires aortic valve replacement – either a surgical or very recently transcatheter aortic valve implantation. Increase leaflet mechanical stress is one of the main determinants of the structural deterioration of bioprosthetic aortic valves. We applied a coupled in vitro/in silico method to compare the timing, magnitude, and regional distribution of leaflet mechanical stress in porcine versus pericardial bioprostheses (Mosaic and Trifecta). A double activation simulator was used for in vitro testing of a bioprosthesis with externally mounted pericardium (Abbott, Trifecta) and a bioprosthesis with internally mounted porcine valve (Medtronic, Mosaic). A non-contact system based on stereophotogammetry and digital image correlation (DIC) with high spatial and temporal resolution (2000 img/s) was used to visualize the valve leaflet motion and perform the three-dimensional analysis. A finite element model of the valve was developed, and the leaflet deformation obtained from the DIC analysis was applied to the finite element model calculate local leaflet mechanical stress throughout the cardiac cycle. The maximum leaflet stress was higher with the pericardial versus the porcine bioprosthesis (2.03 vs. 1.30 MPa) For both bioprostheses the highest values of leaflet stress occurred during diastole and were primarily observed in the upper leaflet edge near the commissures and to a lesser extent in the mid-portion of the leaflet body. In conclusion, the coupled in vitro/in silico method described in this study shows that the highest levels of leaflet stress occur in the regions of the commissures and mid-portion of the leaflet body. This method may have important insight with regard to bioprosthetic valve durability. Our results suggest that, compared to porcine bioprostheses, those with externally mounted pericardium have higher leaflet mechanical stress, which may translate into shorter durability.

Local fluid dynamics in patients with bifurcated coronary lesions undergoing percutaneous coronary interventions.

Although the coronary arteries are uniformly exposed to systemic cardiovascular risk factors, atherosclerosis development has a non-random distribution, which follows the local mechanical stresses including flow-related hemodynamic forces. Among these, wall shear stress plays an essential role and it represents the major flow-related factor affecting the distribution of atherosclerosis in coronary bifurcations. Furthermore, an emerging body of evidence suggests that hemodynamic factors such as low and oscillating wall shear stress may facilitate the development of in-stent restenosis and stent thrombosis after successful drug-eluting stent implantation. Drug-eluting stent implantation represents the gold standard for bifurcation interventions. In this specific setting of interventions on bifurcated lesions, the impact of fluid dynamics is expected to play a major role and constitutes substantial opportunity for future technical improvement. In the present review, available data is summarized regarding the role of local fluid dynamics in the clinical outcome of patients with bifurcated lesions.

A technique engineered for improving thermal conductive properties of polyamide-6 composites via hydroxylated boron nitride masterbatch-based melt blending

Thermal conductive and electrical insulating polymer composites are showing tremendous potential for modern electrical systems and electronic devices. Melt blending has been utilized as an effective technique to prepare thermal interface materials. However, during the process of melt-blending, strong π-π stacking and particle aggregation may be caused by thermal heating and local mechanical stress. Herein, ISP-PA6/BNNSs-OH (ISP-PN) composite has been fabricated by a masterbatch obtained via in-situ polymerization (ISP) and melt blending with polyamide-6 (PA6), with the incorporation of hydroxylated boron nitride nanosheets (BNNSs-OH). At the filler loading of 10 wt%, the through-plane thermal conductivity (TC) and Young's modulus of ISP-PN composites are respectively increased by 163% and 118%, compared to that of the neat PA6 resin. Prevailing over the matrix, the ISP-PN composites own volume electrical resistivity of ~5.11 × 1019 Ω cm. Meanwhile, the TC and mechanical properties of ISP-PN composites are 21.4% and 28.0% higher than the composites obtained by direct melt blending. The improved properties are attributed to the pre-disperse of filler through the masterbatch method. The PA6 chains were immobilized onto the BNNSs-OH by the condensation reaction, resulting in a sort of “chain-extender” and preventing the filler from re-aggregating during the process of melt-blending. This study pioneers a simple and versatile path to melt blending of thermally conductive polymer composites with good mechanical and electrical insulation properties in high-performance thermal management systems.

Abstract PS13-44: Identifying relevant parameters that characterize the early response to NAT in breast cancer patients using a novel personalized mechanistic model integrating in vitro and in vivo imaging data

Abstract The early determination of response to neoadjuvant therapy (NAT) in triple-negative breast cancer would enable the treating oncologist to adapt the therapeutic regimen of a non-responding patient (e.g., by changing dosage, dose schedule, prescribed drugs), and thereby improve treatment outcomes while avoiding unnecessary toxicities. To address this challenge, we propose to use personalized, in silico forecasts of tumor response to therapeutic regimens via a mechanistic mathematical model calibrated with patient-specific longitudinal multi-parametric magnetic resonance imaging (MRI) data acquired early in the course of NAT. Here, we extend our mechanistic model to include a new term describing the synergistic effects of NAT drug combinations and identify the driving parameters involved in its formulation by means of a sensitivity analysis. Our model describes tumor cell dynamics as a combination of proliferation, which is regulated by a logistic term, and mobility, which is described as a diffusion process constrained by the local tumor-induced mechanical stress. Tumor cell density is extracted from diffusion-weighted MRI data, while tissue mechanical properties are defined from segmented T1-weighted MRI data. We adjust the tumor proliferation rate in response to NAT drug combinations with a recent model of drug synergy, MuSyC, which accounts for distinct types of synergistic drug effects (synergy of potency vs. synergy of efficacy). We also consider the heterogeneous intratumoral delivery of drugs by means of perfusion maps estimated from dynamic contrast-enhanced MRI data. We use Sobol’s method for the sensitivity analysis of two different tumors - one well-perfused and one poorly-perfused. We simulate a four-cycle NAT protocol in which NAT drugs are delivered every 14 days, and assess the total effect (ST) of each parameter on the mean relative difference of tumor cell density with respect to a control simulation of tumor growth without NAT. Sensitivity analysis results directly depend on the definition of the parameter space, which we construct by combining two approaches. First, we experimentally constrain parameter ranges using time-resolved, high-throughput, automated microscopy assays to capture the changes in proliferation rates of various breast cancer lines (HCC1143, SUM149, MDAMB231, and MDAMB468) caused by two standard drug combinations: paclitaxel with carboplatin and doxorubicin with perfosfamide (metabolic derivative of the pro-drug cyclophosphamide), and fitting the MuSyC model to these data. Second, we scale the resulting in vitro parameter ranges to clinically-relevant in vivo ranges by running an in silico study with our mechanistic model of breast cancer growth and NAT response. Our results show that, out of the ten parameters involved in the synergy term, three have a dominant role in the dynamics of breast cancer during NAT (ST &amp;gt; 0.1): synergistic potency, the maximal change in tumor cell proliferation by the slowest decaying drug, and its concentration producing half of maximal effects. The other parameters have marginal (0.02 &amp;lt; ST &amp;lt; 0.1) to negligible effect (ST &amp;lt; 0.02). Ongoing studies are assessing the ability of our mechanistic model to forecast NAT response over a small patient cohort after patient-specific calibration of the driving parameters identified in the present study. Citation Format: Guillermo Lorenzo, Angela M. Jarrett, Christian T. Meyer, Darren R. Tyson, Vito Quaranta, Thomas E. Yankeelov. Identifying relevant parameters that characterize the early response to NAT in breast cancer patients using a novel personalized mechanistic model integrating in vitro and in vivo imaging data [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-44.