A pneumatic reconfigurable socket for transtibial amputees.

Many transtibial amputees rate the fit between their residual limb and prosthetic socket as the most critical factor in satisfaction with using their prosthesis. This study aims to address the issue of prosthetic socket fit by reconfiguring the socket shape at the interface of the residual limb and socket. The proposed reconfigurable socket shifts pressure from sensitive areas and compensates for residual limb volume fluctuations, the most important factors in determining a good socket fit. Computed tomography scan images are employed to create the phantom limb of an amputee and to manufacture the reconfigurable socket. The performance of the reconfigurable socket was evaluated both experimentally and numerically using finite element modelling. The study showed that the reconfigurable socket can reduce interface pressure at targeted areas by up to 61%.

Large volume subcutaneous delivery using multi-orifice jet injection.

Needle-free jet injection is an alternative drug delivery technique that uses the liquid drug itself to penetrate through the skin. This technology is not only a promising alternative to hypodermic needles but also has the potential to replace intravenous delivery with rapid, needle-free subcutaneous delivery for large-volume treatments. In this work we propose a parallelised, 'multi-orifice' approach to overcome the volume constraints of subcutaneous tissue. We present a prototype multi-orifice nozzle with up to seven orifices and use this nozzle to perform injections into samples of ex vivo porcine tissue. These injections demonstrated the rapid (<0.15 s) delivery of up to 2 mL into the tissue using both three and seven orifices. Delivery success (measured as the percentage of fluid deposited in the tissue relative to the total volume that left the device) was very similar when using three versus seven injection orifices. A computational fluid dynamic model of multi-orifice jet injection is also presented. This model predicts that jet production is largely unaffected as the spacing between orifices is changed from 3 mm to 48 mm. This finding is supported by measurements of the speed, volume, and shape of the jets produced by the prototype nozzle that showed very similar jets were produced through all seven orifices. These findings demonstrate the feasibility of multi-orifice jet injection for needle-free delivery of large volumes. This promising technique has the potential to improve patient experience and reduce healthcare costs in large volume parenteral delivery applications.

Measurement and Analysis of In Vivo Gastroduodenal Slow Wave Patterns Using Anatomically-Specific Cradles and Electrodes.

OBJECTIVE: Bioelectrical 'slow waves' regulate gastrointestinal contractions. We aimed to confirm whether the pyloric sphincter demarcates slow waves in the intact stomach and duodenum. METHODS: We developed and validated novel anatomically-specific electrode cradles and analysis techniques which enable high-resolution slow wave mapping across the in vivo gastroduodenal junction. Cradles housed flexible-printed-circuit and custom cradle-specific electrode arrays during acute porcine experiments (N = 9; 44.92 kg ± 8.49 kg) and maintained electrode contact with the gastroduodenal serosa. Simultaneous gastric and duodenal slow waves were filtered independently after determining suitable organ-specific filters. Validated algorithms calculated slow wave propagation patterns and quantitative descriptions. RESULTS: Butterworth filters, with cut-off frequencies (0.0167 - 2) Hz and (0.167 - 3.33) Hz, were optimal filters for gastric and intestinal slow wave signals, respectively. Antral slow waves had a frequency of (2.76 ± 0.37) cpm, velocity of (4.83 ± 0.21) mm·s-1, and amplitude of (1.13 ± 0.24) mV, before terminating at the quiescent pylorus that was (46.54 ± 5.73) mm wide. Duodenal slow waves had a frequency of (18.13 ± 0.56) cpm, velocity of (11.66 ± 1.36) mm·s-1, amplitude of (0.32 ± 0.03) mV, and originated from a pacemaker region (7.24 ± 4.70) mm distal to the quiescent zone. CONCLUSION: Novel engineering methods enable measurement of in vivo electrical activity across the gastroduodenal junction and provide qualitative and quantitative definitions of slow wave activity. SIGNIFICANCE: The pylorus is a clinical target for a range of gastrointestinal motility disorders and this work may inform diagnostic and treatment practices.

Measuring and Modelling the Effect of Inorganic Phosphate on Cross-bridge Mechanics in Human Cardiac Muscle.

Many common chronic diseases operate at the intersection of metabolic and cardiovascular dysfunction. In order to model the effects of these diseases and investigate underlying causes we are developing a cardiomyocyte model which incorporates both the mechanics and metabolic factors that underlie work done by the heart. In this paper we present the first experimental results from our study measuring mechanical properties in human cardiac trabeculae, including the effect of inorganic phosphate (Pi) on the complex modulus at 37 °C. Extending our previous mathematical model, we have developed a computationally efficient model of cardiac cross-bridge mechanics which is sensitive to changes in cellular Pi. This extended model was parameterised with human cardiac complex modulus data. It captured the changes to cardiac mechanics following an increase in Pi concentration that we measured experimentally, including a reduced elastic modulus and a right-shift in frequency. The human cardiac trabecula we studied had a low sensitivity to Pi compared to what has been previously reported in mammalian cardiac tissue, which suggests that the muscle may have cellular compensatory mechanisms to cope with elevated Pi levels. This study demonstrates the feasibility of our experimental-modelling pipeline for future investigation of mechanical and metabolic effects in the diseased human heart.Clinical Relevance- This study presents the first measurement of the effect of Pi on the stiffness frequency response of human cardiac tissue and extends an experimental-modelling framework appropriate for investigating effects of disease on the human heart.

Rotatable Orifice for Needle-Free Jet Injection.

This research explores a new development in orifice technology for needle-free jet injection. The premise lies in the ability to control the angle at which the drug is delivered into the tissue to increase the lateral dispersion of the drug. Towards this aim, a spherical orifice that can rotate to adjust the injection angle is explored. This work tests the design and feasibility of the spherical orifice, its housing, and the orifice seats. The results show that the most successful way to create a fluid seal within the housing was to use an o-ring to create a fluid seal at the inlet side of the sphere and an extended brass seat on the outlet side of the sphere. This allowed jet speeds up to approximately 123 m/s through a 0.2 mm orifice machined into 9.5 mm diameter brass sphere. Jet speeds large enough to penetrate porcine tissue were reached at jet angles of 0° to 50° relative to the base of the injector. Although the jets successfully penetrated the tissue, the amount of fluid delivered varied depending on the injection angle. With a shallow angle injection, the fluid retention rate (the percentage of the ejected fluid from the injector which the tissue sample retained) was on average 44%. When the spherical orifice was at its maximum angle, the injection achieved an average fluid retention rate of 22%. At its widest angle, lateral dispersion of the drug also increased by approximately 40%, in comparison to conventional needles and traditional perpendicular jet injection. In summary, a spherical orifice needle-free injection system successfully produced high-speed jets and delivered liquid into porcine tissue at injection angles from 0° to 50°, demonstrating the feasibility of this technique that offers unique advantages over typical orifice plates and conventional needles.Clinical Relevance-A rotatable nozzle can be used to control the angle of needle-free drug delivery.

Measurement of Blood Dilution during Lancet-Free Blood Sampling.

In this paper, we report on a fluorescent and colorimetric system for measuring the dilution of capillary blood released by a needle-free jet injector. Jet injection uses a high-speed liquid jet to penetrate tissue, and in the process can release capillary blood that can be collected for performing blood tests. In this way, blood sampling can be performed without the use of a lancet. However, any injectate that mixes with the collected blood dilutes the sample and may significantly impact subsequent analyses. By adding the fluorescent marker indocyanine green to the injected liquid, the fraction of injectate mixed into the collected blood can be measured. The incorporation of colorimetry allows our system to also correct for the impact of hematocrit on fluorescence. The results from this system show that it can determine the dilution of blood that has been diluted by up to 10 %, the upper limit of dilution typically observed in lancet-free blood sampling via jet injection.Clinical Relevance- Blood samples can be collected by jet injection without significant dilution, avoiding the need for lancing.

An Instrument for High-throughput Testing of Heart Tissue In Vitro.

Cardiac trabeculae are small samples of heart muscle tissue that can be dissected and studied in vitro to better understand the underlying physiology of cardiac muscle. However, instruments for such experimentation often (1) involve delicate mounting of the muscle, (2) constrain investigations to one muscle at a time and, thus, (3) cannot retain the muscle in the same experimental configuration for post-experimental assessment including imaging analysis. Here, we present a novel device that allows trabeculae to be secured by a visible-light photo-initiated hydrogel, manipulated via a force sensor, and stimulated while being imaged. We use our robust, accurate image registration techniques to measure cantilever and gel deformation during trabecula contraction and thereby provide a measure of trabecula force production during twitches. A variety of experiments can then be conducted, with the potential for the trabecula to be fixed in place using hydrogel for further post-experiment analysis, as well as longitudinal evaluation. The device has multiple wells making it amenable to high-throughput testing.Clinical Relevance- These methods may allow longitudinal and high-throughput studies of cardiac tissue samples in health and disease.

Methods for assessing cardiac myofilament calcium sensitivity.

Myofilament calcium (Ca2+) sensitivity is one of several mechanisms by which force production of cardiac muscle is modulated to meet the ever-changing demands placed on the heart. Compromised Ca2+ sensitivity is associated with pathologies, which makes it a parameter of interest for researchers. Ca2+ Sensitivity is the ratio of the association and dissociation rates between troponin C (TnC) and Ca2+. As it is not currently possible to measure these rates in tissue preparations directly, methods have been developed to infer myofilament sensitivity, typically using some combination of force and Ca2+ measurements. The current gold-standard approach constructs a steady-state force-Ca2+ relation by exposing permeabilised muscle samples to a range of Ca2+ concentrations and uses the half-maximal concentration as a proxy for sensitivity. While a valuable method for steady-state investigations, the permeabilisation process makes the method unsuitable when examining dynamic, i.e., twitch-to-twitch, changes in myofilament sensitivity. The ability of the heart to transiently adapt to changes in load is an important consideration when evaluating the impact of disease states. Alternative methods have been proffered, including force-Ca2+ phase loops, potassium contracture, hybrid experimental-modelling and conformation-based fluorophore approaches. This review provides an overview of the mechanisms underlying myofilament Ca2+ sensitivity, summarises existing methods, and explores, with modelling, whether any of them are suited to investigating dynamic changes in sensitivity. We conclude that a method that equips researchers to investigate the transient change of myofilament Ca2+ sensitivity is still needed. We propose that such a method will involve simultaneous measurements of cytosolic Ca2+ and TnC activation in actively twitching muscle and a biophysical model to interpret these data.

Resolving an inconsistency in the estimation of the energy for excitation of cardiac muscle contraction.

In the excitation of muscle contraction, calcium ions interact with transmembrane transporters. This process is accompanied by energy consumption and heat liberation. To quantify this activation energy or heat in the heart or cardiac muscle, two non-pharmacological approaches can be used. In one approach using the "pressure-volume area" concept, the same estimate of activation energy is obtained regardless of the mode of contraction (either isovolumic/isometric or ejecting/shortening). In the other approach, an accurate estimate of activation energy is obtained only when the muscle contracts isometrically. If the contraction involves muscle shortening, then an additional component of heat associated with shortening is liberated, over and above that of activation. The present study thus examines the reconcilability of the two approaches by performing experiments on isolated muscles measuring contractile force and heat output. A framework was devised from the experimental data to allow us to replicate several mechanoenergetics results gleaned from the literature. From these replications, we conclude that the choice of initial muscle length (or ventricular volume) underlies the divergence of the two approaches in the estimation of activation energy when the mode of contraction involves shortening (ejection). At low initial muscle lengths, the heat of shortening is relatively small, which can lead to the misconception that activation energy is contraction mode independent. In fact, because cardiac muscle liberates heat of shortening when allowed to shorten, estimation of activation heat must be performed only under isometric (isovolumic) contractions. We thus recommend caution when estimating activation energy using the "pressure-volume area" concept.

Isolated cardiac muscle contracting against a real-time model of systemic and pulmonary cardiovascular loads.

Isolated cardiac tissues allow a direct assessment of cardiac muscle function and enable precise control of experimental loading conditions. However, current experimental methods do not expose isolated tissues to the same contraction pattern and cardiovascular loads naturally experienced by the heart. In this study, we implement a computational model of systemic-pulmonary impedance that is solved in real time and imposed on contracting isolated rat muscle tissues. This systemic-pulmonary model represents the cardiovascular system as a lumped-parameter, closed-loop circuit. The tissues performed force-length work-loop contractions where the model output informed both the shortening and restretch phases of each work-loop. We compared the muscle mechanics and energetics associated with work-loops driven by the systemic-pulmonary model with that of a model-based loading method that only accounts for shortening. We obtained results that show simultaneous changes of afterload and preload or end-diastolic length of the muscle, as compared with the static, user-defined preload as in the conventional loading method. This feature allows assessment of muscle work output, heat output, and efficiency of contraction as functions of end-diastolic length. The results reveal the behavior of cardiac muscle as a pump source to achieve load-dependent work and efficiency outputs over a wider range of loads. This study offers potential applications of the model to investigate cardiac muscle response to hemodynamic coupling between systemic and pulmonary circulations in an in vitro setting.NEW & NOTEWORTHY We present the use of a "closed-loop" model of systemic and pulmonary circulations to apply, for the first time, real-time model-calculated preload and afterload to isolated cardiac muscle preparations. This method extends current experimental protocols where only afterload has been considered. The extension to include preload provides the opportunity to investigate ventricular muscle response to hemodynamic coupling and as a pump source across a wider range of cardiovascular loads.

Non-contact quantification of aortic stenosis and mitral regurgitation using carotid waveforms from skin displacements.

Objective. Early diagnosis of heart problems is essential for improving patient prognosis.Approach. We created a non-contact imaging system that calculates the vessel-induced deformation of the skin to estimate the carotid artery pressure displacement waveforms. We present a clinical study of the system in patients (n= 27) with no underlying condition, aortic stenosis (AS), or mitral regurgitation (MR).Main results. Displacement waveforms were compared to aortic catheter pressures in the same patients. The morphologies of the pressure and displacement waveforms were found to be similar, and pulse wave analysis metrics, such as our modified reflection indices (RI) and waveform duration proportions, showed no significant differences. Compared with the control group, AS patients displayed a greater proportion of time to peak (p= 0.026 andp= 0.047 for catheter and displacement, respectively), whereas augmentation index (AIx)was greater for the displacement waveform only (p= 0.030). The modified RI for MR (p= 0.047 andp= 0.004 for catheter and displacement, respectively) was lower than in the controls. AS and MR were also significantly different for the proportion of time to peak (p= 0.018 for the catheter measurements), RI (p= 0.045 andp= 0.002 for the catheter and displacement, respectively), and AIx (p= 0.005 for the displacement waveform).Significance. These findings demonstrate the ability of our system to provide insights into cardiac conditions and support further development as a diagnostic/telehealth-based screening tool.

Vacuum-Assisted Needle-Free Capillary Blood Sampling.

BACKGROUND: Poor glycemic management persists among people practicing insulin therapy in relation to type 1 and 2 diabetes despite a clear relationship with negative health outcomes. Skin penetration by jet injection has recently been shown as a viable method for inducing blood release from fingertips. This study examines the use of vacuum to enhance the volume of blood released and quantifies any dilution of the collected blood. METHODS: A single-blind crossover study involving 15 participants, each receiving four different interventions, was conducted wherein each participant served as their own control. Each participant experienced fingertip lancing and fingertip jet injection, both with and without applied vacuum. Participants were divided into three equal groups to explore different vacuum pressures. RESULTS: This study found that glucose concentration in blood collected under vacuum following jet injection and lancing were equivalent. We found that applying a 40 kPa vacuum following jet injection produced a 35-fold increase in the collected volume. We determined the limited extent to which the injectate dilutes blood collected following jet injection. The mean dilution of blood collected by jet injection was 5.5%. We show that jet injection is as acceptable to patients as lancing, while being equally suited for conducting glucose measurements. CONCLUSIONS: Vacuum significantly enhances the volume of capillary blood released from the fingertip without any difference in pain. The blood collected by jet injection with vacuum is equivalent to that from lancing for glucose measurement purposes.

Minimally invasive capillary blood sampling methods.

INTRODUCTION: Whole blood samples, including arterial, venous, and capillary blood, are regularly used for disease diagnosis and monitoring. The global Covid-19 pandemic has highlighted the need for a more resilient screening capacity. Minimally invasive sampling techniques, such as capillary blood sampling, are routinely used for point of care testing in the home healthcare setting and clinical settings such as the Intensive Care Unit with less pain and wounding than conventional venepuncture. AREAS COVERED: In this manuscript, we aim to provide a overview of state-of-the-art of techniques for obtaining samples of capillary blood. We first review both established and novel methods for releasing blood from capillaries in the skin. Next, we provide a comparison of different capillary blood sampling methods based on their mechanism, testing site, puncture size, cost, wound geometry, healing, and perceptions of pain. Finally, we overview established and new methods for enhancing capillary blood collection. EXPERT OPINION: We expect that microneedles will prove to be a preferred option for paediatric blood collection. The ability of microneedles to collect a capillary blood sample without pain will improve paediatric healthcare outcomes. Jet injection may prove to be a useful method for facilitating both blood collection and drug delivery.

Hydrogen bonding dissipating hydrogels: The influence of network structure design on structure-property relationships.

Hydrogels made with semi-interpenetrating networks of the oligomerized polyphenol tannic acid, and poly(acrylamide), exhibit high stiffness and toughness. However, the structure property relationships that give rise to enhanced mechanical properties is not well understood. Herein, we systematically investigate the hydrogels using small angle X-ray scattering and small and Ultra-small angle neutron scattering within a wide length scale range (1 nm to 20 µm), polarized optical microscopy, and rheology. Small angle X-ray and neutron scattering reveal the presence of micron sized hydrogen bonded clusters in the hydrogels. Breaking of hydrogen bonded clusters above a critical solution temperature was clearly observed in the small angle neutron scattering data. Polarized optical microscopy show enhanced anisotropy for the gels with oligomerized tannic acid incorporated - when compared to gels with monomeric tannic acid. Rheological studies at varying temperatures nicely corroborate the structural changes observed at high temperatures and reveal a self-healing behavior of the gels. The knowledge gained from this study will aid in rational design of hydrogels for biomedical applications.

Jet-Induced Blood Release From Human Fingertips: A Single-Blind, Randomized, Crossover Trial.

BACKGROUND: Lancet pricks are often poorly received by individuals with diabetes; jet injection may allow lancet-free blood sampling. We examine whether the technique of jet injection can release sufficient blood from the fingertip to enable measurement of blood glucose concentration. In addition, we assess the effect of jet shape and cross-sectional area on fluid release, blood dilution, and perceived pain. METHODS: A randomized, single-blind, crossover study was conducted on 20 healthy volunteers who received interventions on four fingertips: a lancet prick, and jet injection of a small quantity of saline solution through three differently shaped and sized nozzles. Released fluid volume, blood concentration, and glucose concentration were assessed immediately after the intervention. Pain perception and duration, and any skin reactions, were evaluated both immediately and 24 hours after the intervention. RESULTS: Jet injection released sufficient blood from the fingertip to conduct a glucose measurement. A slot-shaped nozzle released the most blood, although less than a lancet, with slightly higher pain. The blood glucose levels estimated from the extracted fluid showed a mean absolute percentage error of 25%. There was no consistent evidence that a jet injection leads to different skin reactions at the intervention site relative to a lancet prick. CONCLUSIONS: Fingertip penetration by jet injection can release a volume of fluid sufficient for blood glucose measurement. Jet injection with a slot-shaped nozzle and/or a nozzle with larger outlet area helps to release more fluid. This technique may enable blood sampling, glucose concentration measurement, and insulin delivery to be performed in a single device.

Analysis of metabolite and strain effects on cardiac cross-bridge dynamics using model linearisation techniques.

Multi-scale models of cardiac energetics are becoming crucial in better understanding the prevalent chronic diseases operating at the intersection of metabolic and cardiovascular dysfunction. Computationally efficient models of cardiac cross-bridge kinetics that are sensitive to changes in metabolite concentrations are necessary to simulate the effects of disease-induced changes in cellular metabolic state on cardiac mechanics across disparate spatial scales. While these models do currently exist, deeper analysis of how the modelling of metabolite effects and the assignment of strain dependence within the cross-bridge cycle affect the properties of the model is required. In this study, model linearisation techniques were used to simulate and interrogate the complex modulus of an ODE-based model of cross-bridge kinetics. Active complex moduli were measured from permeabilised rat cardiac trabeculae under five different metabolite conditions with varying ATP and Pi concentrations. Sensitivity to metabolites was incorporated into an existing three-state cross-bridge model using either a direct dependence or a rapid equilibrium approach. Combining the two metabolite binding methods with all possible locations of strain dependence within the cross-bridge cycle produced 64 permutations of the cross-bridge model. Using linear model analysis, these models were systematically explored to determine the effects of metabolite binding and their interaction with strain dependence on the frequency response of cardiac muscle. The results showed that the experimentally observed effects of ATP and Pi concentrations on the cardiac complex modulus could be attributed to their regulation of cross-bridge detachment rates. Analysis of the cross-bridge models revealed a mechanistic basis for the biochemical schemes which place Pi release following cross-bridge formation and ATP binding prior to cross-bridge detachment. In addition, placing strain dependence on the reverse rate of the cross-bridge power stroke produced the model which most closely matched the experimental data. From these analyses, a well-justified metabolite-sensitive model of rat cardiac cross-bridge kinetics is presented which is suitable for parameterisation with other data sets and integration with multi-scale cardiac models.

Uncovering cross-bridge properties that underlie the cardiac active complex modulus using model linearisation techniques.

The properties underlying cardiac cross-bridge kinetics can be characterised by a muscle's active complex modulus. While the complex modulus can be described by a series of linear transfer functions, the biophysical mechanisms underlying these components are represented inconsistently among existing cross-bridge models. To address this, we examined the properties commonly implemented in cross-bridge models using model linearisation techniques and assessed their contributions to the complex modulus. From this analysis, we developed a biophysical model of cross-bridge kinetics that captures the three components of the active complex modulus: (1) the elastic modulus at low frequencies that arises from allowing the proportion of cross-bridges in the post-power stroke state to increase with sarcomere length, (2) the increase in elastic modulus at high frequencies that arises from the dependence of cross-bridge strain on sarcomere velocity, and (3) the negative viscous modulus which signifies the production of work by cross-bridges arises from either a sarcomere length or strain dependence, or both, on the rate of change of cross-bridge proportion in the post-power stroke state. While a model that includes all these features can theoretically reproduce the cardiac complex modulus, analysis of their transfer functions reveals that the relative contributions of these components are often not taken into account. As a result, the negative viscous component that signifies work production is not visible because the complex modulus is dominated by the effects of sarcomere velocity on cross-bridge strain.

Anatomically-Specific, 3D-Printed Cradles Enable In Vivo Mapping of the Bioelectrical Activation across the Gastroduodenal Junction.

Rhythmic bioelectrical 'slow waves' are a key regulatory mechanism underpinning digestion. The pyloric sphincter separates the independent slow wave and contractile behavior of the stomach and small intestine, while also regulating gastric emptying. In this study, we develop and validate anatomically-specific electrode cradles and analysis techniques in pigs, to map in vivo slow wave activation across this critical pylorus region for the first time. 3D printed electrode cradles were developed from reconstructions of magnetic resonance images, to accurately capture anatomical geometry. A low-pass Savitzky-Golay filter with an equivalent cut-off frequency of ~2 Hz was chosen as the optimal filter for analysis of both gastric and intestinal slow waves. Slow waves in the terminal antrum occurred with a frequency of (2.81±0.55) cycles per minute (cpm), velocity of (5.04 ± 0.29) mm s-1, and amplitude of (1.38±0.37) mV, before terminating at a zone of quiescence at the pylorus that was (41.22±7.4)nm wide. The proximal duodenal pacemaker initiated slow waves at a frequency of (18.1±0.80) cpm, velocity of (11.3±2.4) mm s-1, and amplitude of (0.376±0.027) mV. This work enables quantitative definitions of numerous physiological features of the in vivo pylorus region, including the electrically quiescent zone and duodenal pacemaker location. Clinical Relevance- This work establishes a novel method for in vivo measurement of bioelectrical slow wave activity of the pyloric region, which is a key target for physiological investigation and clinical intervention. In the future, the methods developed here may inform diagnosis and/or treatment of functional gastrointestinal disorders.

A novel modular modeling approach for understanding different electromechanics between left and right heart in rat.

While ion channels and transporters involved in excitation-contraction coupling have been linked and constructed as comprehensive computational models, validation of whether each individual component of a model can be reused has not been previously attempted. Here we address this issue while using a novel modular modeling approach to investigate the underlying mechanism for the differences between left ventricle (LV) and right ventricle (RV). Our model was developed from modules constructed using the module assembly principles of the CellML model markup language. The components of three existing separate models of cardiac function were disassembled as to create smaller modules, validated individually, and then the component parts were combined into a new integrative model of a rat ventricular myocyte. The model was implemented in OpenCOR using the CellML standard in order to ensure reproducibility. Simulated action potential (AP), Ca2+ transient, and tension were in close agreement with our experimental measurements: LV AP showed a prolonged duration and a more prominent plateau compared with RV AP; Ca2+ transient showed prolonged duration and slow decay in LV compared to RV; the peak value and relaxation of tension were larger and slower, respectively, in LV compared to RV. Our novel approach of module-based mathematical modeling has established that the ionic mechanisms underlying the APs and Ca2+ handling play a role in the variation in force production between ventricles. This simulation process also provides a useful way to reuse and elaborate upon existing models in order to develop a new model.