Comparative Bioactivities of Chemically Modified Fucoidan and λ-Carrageenan toward Cells Encapsulated in Covalently Cross-Linked Hydrogels.

The sulfated marine polysaccharides, fucoidan and λ-carrageenan, are known to possess anti-inflammatory, immunomodulatory, and cellular protective properties. Although they hold considerable promise for tissue engineering constructs, their covalent cross-linking in hydrogels and comparative bioactivities to cells are absent from the literature. Thus, fucoidan and λ-carrageenan were modified with methacrylate groups and were covalently cross-linked with the synthetic polymer poly(vinyl alcohol)-methacrylate (PVA-MA) to form 20 wt % biosynthetic hydrogels. Identical degrees of methacrylation were confirmed by 1H NMR, and covalent conjugation was determined by using a colorimetric 1,9-dimethyl-methylene blue (DMMB) assay. Pancreatic beta cells were encapsulated in the hydrogels, followed by culturing in the 3D environment for a prolonged period of 32 days and evaluation of the cellular functionality by live/dead, adenosine 5'-triphosphate (ATP) level, and insulin secretion. The results confirmed that fucoidan and λ-carrageenan exhibited ∼12% methacrylate substitution, which generated hydrogels with stable conjugation of the polysaccharides with PVA-MA. The cells encapsulated in the PVA-fucoidan hydrogels demonstrated consistently high ATP levels over the culture period. Furthermore, only cells in the PVA-fucoidan hydrogels retained glucose responsiveness, demonstrating comparatively higher insulin secretion in response to glucose. In contrast, cells in the PVA-λ-carrageenan and the PVA control hydrogels lost all glucose responsiveness. The present work confirms the superior effects of chemically modified fucoidan over λ-carrageenan on pancreatic beta cell survival and function in covalently cross-linked hydrogels, thereby illustrating the importance of differential polysaccharide structural features on their biological effects.

Simulating impaired left ventricular-arterial coupling in aging and disease: a systematic review.

Aortic stenosis, hypertension, and left ventricular hypertrophy often coexist in the elderly, causing a detrimental mismatch in coupling between the heart and vasculature known as ventricular-vascular (VA) coupling. Impaired left VA coupling, a critical aspect of cardiovascular dysfunction in aging and disease, poses significant challenges for optimal cardiovascular performance. This systematic review aims to assess the impact of simulating and studying this coupling through computational models. By conducting a comprehensive analysis of 34 relevant articles obtained from esteemed databases such as Web of Science, Scopus, and PubMed until July 14, 2022, we explore various modeling techniques and simulation approaches employed to unravel the complex mechanisms underlying this impairment. Our review highlights the essential role of computational models in providing detailed insights beyond clinical observations, enabling a deeper understanding of the cardiovascular system. By elucidating the existing models of the heart (3D, 2D, and 0D), cardiac valves, and blood vessels (3D, 1D, and 0D), as well as discussing mechanical boundary conditions, model parameterization and validation, coupling approaches, computer resources and diverse applications, we establish a comprehensive overview of the field. The descriptions as well as the pros and cons on the choices of different dimensionality in heart, valve, and circulation are provided. Crucially, we emphasize the significance of evaluating heart-vessel interaction in pathological conditions and propose future research directions, such as the development of fully coupled personalized multidimensional models, integration of deep learning techniques, and comprehensive assessment of confounding effects on biomarkers.

Neural activity of retinal ganglion cells under continuous, dynamically-modulated high frequency electrical stimulation.

Objective.Current retinal prosthetics are limited in their ability to precisely control firing patterns of functionally distinct retinal ganglion cell (RGC) types. The aim of this study was to characterise RGC responses to continuous, kilohertz-frequency-varying stimulation to assess its utility in controlling RGC activity.Approach.We usedin vitropatch-clamp experiments to assess electrically-evoked ON and OFF RGC responses to frequency-varying pulse train sequences. In each sequence, the stimulation amplitude was kept constant while the stimulation frequency (0.5-10 kHz) was changed every 40 ms, in either a linearly increasing, linearly decreasing or randomised manner. The stimulation amplitude across sequences was increased from 10 to 300µA.Main results.We found that continuous stimulation without rest periods caused complex and irreproducible stimulus-response relationships, primarily due to strong stimulus-induced response adaptation and influence of the preceding stimulus frequency on the response to a subsequent stimulus. In addition, ON and OFF populations showed different sensitivities to continuous, frequency-varying pulse trains, with OFF cells generally exhibiting more dependency on frequency changes within a sequence. Finally, the ability to maintain spiking behaviour to continuous stimulation in RGCs significantly reduced over longer stimulation durations irrespective of the frequency order.Significance.This study represents an important step in advancing and understanding the utility of continuous frequency modulation in controlling functionally distinct RGCs. Our results indicate that continuous, kHz-frequency-varying stimulation sequences provide very limited control of RGC firing patterns due to inter-dependency between adjacent frequencies and generally, different RGC types do not display different frequency preferences under such stimulation conditions. For future stimulation strategies using kHz frequencies, careful consideration must be given to design appropriate pauses in stimulation, stimulation frequency order and the length of continuous stimulation duration.

Modulating functionally-distinct vagus nerve fibers using microelectrodes and kilohertz frequency electrical stimulation.

Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα- and Aß-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B- and C-) indicated a stronger dependency.Clinical Relevance- Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects.

The direct influence of retinal degeneration on electrical stimulation efficacy: Significant implications for retinal prostheses.

Photoreceptor loss and inner retinal network remodeling severely impacts the ability of retinal prosthetic devices to create artificial vision. We developed a computational model of a degenerating retina based on rodent data and tested its response to retinal electrical stimulation. This model includes detailed network connectivity and diverse neural intrinsic properties, capable of exploring how the degenerated retina influences the performance of electrical stimulation during the degeneration process. Our model suggests the possibility of quantitatively modulating retinal ON and OFF pathways between phase II and III of retinal degeneration without requiring any differences between ON and OFF RGC intrinsic cellular properties. The model also provided insights about how remodeling events influence stage-dependent differential electrical responses of ON and OFF pathways.Clinical Relevance-This data-driven model can guide future development of retinal prostheses and stimulation strategies that may benefit patients at different stages of retinal disease progression, particularly in the early and mid-stages, thus increasing their global acceptance.

Cells-in-Touch: 3D Printing in Reconstruction and Modelling of Microscopic Biological Geometries for Education and Future Research Applications.

Additive manufacturing (3D printing) and computer-aided design (CAD) still have limited uptake in biomedical and bioengineering research and education, despite the significant potential of these technologies. The utility of organ-scale 3D-printed models of living structures is widely appreciated, while the workflows for microscopy data translation into tactile accessible replicas are not well developed yet. Here, we demonstrate an accessible and reproducible CAD-based methodology for generating 3D-printed scalable models of human cells cultured in vitro and imaged using conventional scanning confocal microscopy with fused deposition modeling (FDM) 3D printing. We termed this technology CiTo-3DP (Cells-in-Touch for 3D Printing). As a proof-of-concept, we created dismountable CiTo-3DP models of human epithelial, mesenchymal, and neural cells by using selectively stained nuclei and cytoskeletal components. We also provide educational and research context for the presented cellular models. In the future, the CiTo-3DP approach can be adapted to different imaging and 3D printing modalities and comprehensively present various cell types, subcellular structures, and extracellular matrices. The resulting CAD and 3D printed models could be used for a broad spectrum of education and research applications.

Repeatability of brain phase-based magnetic resonance electric properties tomography methods and effect of compressed SENSE and RF shimming.

Magnetic resonance electrical properties tomography (MREPT) is an emerging imaging modality to noninvasively measure tissue conductivity and permittivity. Implementation of MREPT in the clinic requires repeatable measurements at a short scan time and an appropriate protocol. The aim of this study was to investigate the repeatability of conductivity measurements using phase-based MREPT and the effects of compressed SENSE (CS), and RF shimming on the precision of conductivity measurements. Conductivity measurements using turbo spin echo (TSE) and three-dimensional balanced fast field echo (bFFE) with CS factors were repeatable. Conductivity measurement using bFFE phase showed smaller mean and variance that those measured by TSE. The conductivity measurements using bFFE showed minimal deviation with CS factors up to 8, with deviation increasing at CS factors > 8. Subcortical structures produced less consistent measurements than cortical parcellations at higher CS factors. RF shimming using full slice coverage 2D dual refocusing echo acquisition mode (DREAM) and full coverage 3D dual TR approaches further improved measurement precision. BFFE is a more optimal sequence than TSE for phase-based MREPT in brain. Depending on the area of the brain being measured, the scan can be safely accelerated with compressed SENSE without sacrifice of precision, offering the potential to employ MREPT in clinical research and applications. RF shimming with better field mapping further improves precision of the conductivity measures.

Simulating the impact of photoreceptor loss and inner retinal network changes on electrical activity of the retina.

Objective.A major reason for poor visual outcomes provided by existing retinal prostheses is the limited knowledge of the impact of photoreceptor loss on retinal remodelling and its subsequent impact on neural responses to electrical stimulation. Computational network models of the neural retina assist in the understanding of normal retinal function but can be also useful for investigating diseased retinal responses to electrical stimulation.Approach.We developed and validated a biophysically detailed discrete neuronal network model of the retina in the software package NEURON. The model includes rod and cone photoreceptors, ON and OFF bipolar cell pathways, amacrine and horizontal cells and finally, ON and OFF retinal ganglion cells with detailed network connectivity and neural intrinsic properties. By accurately controlling the network parameters, we simulated the impact of varying levels of degeneration on retinal electrical function.Main results.Our model was able to reproduce characteristic monophasic and biphasic oscillatory patterns seen in ON and OFF neurons during retinal degeneration (RD). Oscillatory activity occurred at 3 Hz with partial photoreceptor loss and at 6 Hz when all photoreceptor input to the retina was removed. Oscillations were found to gradually weaken, then disappear when synapses and gap junctions were destroyed in the inner retina. Without requiring any changes to intrinsic cellular properties of individual inner retinal neurons, our results suggest that changes in connectivity alone were sufficient to give rise to neural oscillations during photoreceptor degeneration, and significant network connectivity destruction in the inner retina terminated the oscillations.Significance.Our results provide a platform for further understanding physiological retinal changes with progressive photoreceptor and inner RD. Furthermore, our model can be used to guide future stimulation strategies for retinal prostheses to benefit patients at different stages of disease progression, particularly in the early and mid-stages of RD.

Slotted Monopole Patch Antenna for Microwave-Based Head Imaging Applications.

A modified monopole patch antenna for microwave-based hemorrhagic or ischemic stroke recognition is presented in this article. The designed antenna is fabricated on a cost-effective FR-4 lossy material with a 0.02 loss tangent and 4.4 dielectric constant. Its overall dimensions are 0.32 λ × 0.28 λ × 0.007 λ, where λ is the lower bandwidth 1.3 GHz frequency wavelength. An inset feeding approach is utilized to feed the antenna to reduce the input impedance (z = voltage/current). A total bandwidth (below -10 dB) of 2.4 GHz (1.3-3.7 GHz) is achieved with an effective peak gain of over 6 dBi and an efficiency of over 90%. A time-domain analysis confirms that the antenna produces minimal signal distortion. Simulated and experimental findings share a lot of similarities. Brain tissue is penetrated by the antenna to a satisfactory degree, while still exhibiting a safe specific absorption rate (SAR). The maximum SAR value measured for the head model is constrained to be equal to or below 0.1409 W/kg over the entire usable frequency band. Evaluation of theoretical and experimental evidence indicates the intended antenna is appropriate for Microwave Imaging (MWI) applications.

kHz-frequency electrical stimulation selectively activates small, unmyelinated vagus afferents.

BACKGROUND: Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise over 80% of fibers in the vagus and form the sensory arc of autonomic reflexes of the gut, lungs, heart and vessels and the immune system. Selective bioelectronic activation of C-afferents could be used to mechanistically study and treat diseases of peripheral organs in which vagal reflexes are involved, but it has not been achieved. METHODS: We stimulated the vagus in rats and mice using trains of kHz-frequency stimuli. Stimulation effects were assessed using neuronal c-Fos expression, physiological and nerve fiber responses, optogenetic and computational methods. RESULTS: Intermittent kHz stimulation for 30 min activates specific motor and, preferentially, sensory vagus neurons in the brainstem. At sufficiently high frequencies (>5 kHz) and at intensities within a specific range (7-10 times activation threshold, T, in rats; 15-25 × T in mice), C-afferents are activated, whereas larger, A- and B-fibers, are blocked. This was determined by measuring fiber-specific acute physiological responses to kHz stimulus trains, and by assessing fiber excitability around kHz stimulus trains through compound action potentials evoked by probing pulses. Aspects of selective activation of C-afferents are explained in computational models of nerve fibers by how fiber size and myelin shape the response of sodium channels to kHz-frequency stimuli. CONCLUSION: kHz stimulation is a neuromodulation strategy to robustly and selectively activate vagal C-afferents implicated in physiological homeostasis and disease, over larger vagal fibers.

Fluid structure computational model of simulating mitral valve motion in a contracting left ventricle.

BACKGROUND: Fluid structure interaction simulations h hold promise in studying normal and abnormal cardiac function, including the effect of fluid dynamics on mitral valve (MV) leaflet motion. The goal of this study was to develop a 3D fluid structure interaction computational model to simulate bileaflet MV when interacting with blood motion in left ventricle (LV). METHODS: The model consists of ideal geometric-shaped MV leaflets and the LV, with MV dimensions based on human anatomical measurements. An experimentally-based hyperelastic isotropic material was used to model the mechanical behaviour of the MV leaflets, with chordae tendineae and papillary muscle tips also incorporated. LV myocardial tissue was prescribed using a transverse isotropic hyperelastic formulation. Incompressible Navier-Stokes fluid formulations were used to govern the blood motion, and the Arbitrary Lagrangian Eulerian (ALE) method was employed to determine the mesh deformation of the fluid and solid domains due to trans-valvular pressure on MV boundaries and the resulting leaflet movement. RESULTS: The LV-MV generic model was able to reproduce physiological MV leaflet opening and closing profiles resulting from the time-varying atrial and ventricular pressures, as well as simulating normal and prolapsed MV states. Additionally, the model was able to simulate blood flow patterns after insertion of a prosthetic MV with and without left ventricular outflow tract flow obstruction. In the MV-LV normal model, the regurgitant blood flow fraction was 10.1 %, with no abnormality in cardiac function according to the mitral regurgitation severity grades reported by the American Society of Echocardiography. CONCLUSION: Our simulation approach provides insights into intraventricular fluid dynamics in a contracting LV with normal and prolapsed MV function, as well as aiding in the understanding of possible complications after transcatheter MV implantation prior to clinical trials.

A varying-radius cable equation for the modelling of impulse propagation in excitable fibres.

In this study, we present a varying-radius cable equation for nerve fibres taking into account the varying diameter along the neuronal segments. Finite element neuronal models utilising the classical (fixed-radius) and varying-radius cable formulations were compared using simple and realistic morphologies under intra- and extracellular electrical stimulation protocols. We found that the use of the classical cable equation to model intracellular neural electrical stimulation exhibited an error of 17% in a passive resistive cable model with abrupt change in radius from 1 to 2 µm, when compared to the known analytical solution and varying-radius cable formulation. This error was observed to increase substantially using more realistic neuron morphologies and branching structures. In the case of extracellular stimulation however, the difference between the classical and varying-radius formulations was less pronounced, but we expect this difference will increase under more complex stimulation paradigms such as high-frequency stimulation. We conclude that for computational neuroscience applications, it is essential to use the varying-radius cable equation for accurate prediction of neuronal responses under electrical stimulation.

An artificial intelligence powered platform for auto-analyses of spine alignment irrespective of image quality with prospective validation.

BACKGROUND: Assessment of spine alignment is crucial in the management of scoliosis, but current auto-analysis of spine alignment suffers from low accuracy. We aim to develop and validate a hybrid model named SpineHRNet+, which integrates artificial intelligence (AI) and rule-based methods to improve auto-alignment reliability and interpretability. METHODS: From December 2019 to November 2020, 1,542 consecutive patients with scoliosis attending two local scoliosis clinics (The Duchess of Kent Children's Hospital at Sandy Bay in Hong Kong; Queen Mary Hospital in Pok Fu Lam on Hong Kong Island) were recruited. The biplanar radiographs of each patient were collected with our medical machine EOS™. The collected radiographs were recaptured using smartphones or screenshots, with deidentified images securely stored. Manually labelled landmarks and alignment parameters by a spine surgeon were considered as ground truth (GT). The data were split 8:2 to train and internally test SpineHRNet+, respectively. This was followed by a prospective validation on another 337 patients. Quantitative analyses of landmark predictions were conducted, and reliabilities of auto-alignment were assessed using linear regression and Bland-Altman plots. Deformity severity and sagittal abnormality classifications were evaluated by confusion matrices. FINDINGS: SpineHRNet+ achieved accurate landmark detection with mean Euclidean distance errors of 2·78 and 5·52 pixels on posteroanterior and lateral radiographs, respectively. The mean angle errors between predictions and GT were 3·18° and 6·32° coronally and sagittally. All predicted alignments were strongly correlated with GT (p < 0·001, R2 > 0·97), with minimal overall difference visualised via Bland-Altman plots. For curve detections, 95·7% sensitivity and 88·1% specificity was achieved, and for severity classification, 88·6-90·8% sensitivity was obtained. For sagittal abnormalities, greater than 85·2-88·9% specificity and sensitivity were achieved. INTERPRETATION: The auto-analysis provided by SpineHRNet+ was reliable and continuous and it might offer the potential to assist clinical work and facilitate large-scale clinical studies. FUNDING: RGC Research Impact Fund (R5017-18F), Innovation and Technology Fund (ITS/404/18), and the AOSpine East Asia Fund (AOSEA(R)2019-06).

An integrated fluid-structure interaction and thrombosis model for type B aortic dissection.

False lumen thrombosis (FLT) in type B aortic dissection has been associated with the progression of dissection and treatment outcome. Existing computational models mostly assume rigid wall behavior which ignores the effect of flap motion on flow and thrombus formation within the FL. In this study, we have combined a fully coupled fluid-structure interaction (FSI) approach with a shear-driven thrombosis model described by a series of convection-diffusion reaction equations. The integrated FSI-thrombosis model has been applied to an idealized dissection geometry to investigate the interaction between vessel wall motion and growing thrombus. Our simulation results show that wall compliance and flap motion can influence the progression of FLT. The main difference between the rigid and FSI models is the continuous development of vortices near the tears caused by drastic flap motion up to 4.45 mm. Flap-induced high shear stress and shear rates around tears help to transport activated platelets further to the neighboring region, thus speeding up thrombus formation during the accelerated phase in the FSI models. Reducing flap mobility by increasing the Young's modulus of the flap slows down the thrombus growth. Compared to the rigid model, the predicted thrombus volume is 25% larger using the FSI-thrombosis model with a relatively mobile flap. Furthermore, our FSI-thrombosis model can capture the gradual effect of thrombus growth on the flow field, leading to flow obstruction in the FL, increased blood viscosity and reduced flap motion. This model is a step closer toward simulating realistic thrombus growth in aortic dissection, by taking into account the effect of intimal flap and vessel wall motion.

Multiphysics Computational Modelling of the Cardiac Ventricles.

Development of cardiac multiphysics models has progressed significantly over the decades and simulations combining multiple physics interactions have become increasingly common. In this review, we summarise the progress in this field focusing on various approaches of integrating ventricular structures. electrophysiological properties, myocardial mechanics, as well as incorporating blood hemodynamics and the circulatory system. Common coupling approaches are discussed and compared, including the advantages and shortcomings of each. Currently used strategies for patient-specific implementations are highlighted and potential future improvements considered.

Selective myelinated nerve fiber stimulation via temporal interfering electric fields.

We have investigated selective electrical stimulation of myelinated nerve fibers using a computational model of temporal interfering (TI) fields. The model consists of two groups of electrodes placed on the outer bundle surface, each group stimulated at a different frequency. We manipulated the stimulus waveform, magnitude and frequency of short-duration stimuli (70ms), and investigated fiber-specific stimulus-elicited compound action potentials. Results show that under 100Hz & 200Hz TI stimulation with 0.6mA total current shared by the electrodes, continuous action potentials were generated in deeper nerve fibers, and that the firing region was steerable by changing individual electrode currents. This study provides a promising platform for non-invasive nerve bundle stimulation by TI fields.

Effects of modifying the electrode placement and pulse width on cognitive side effects with unilateral ECT: A pilot randomised controlled study with computational modelling.

BACKGROUND: The electrode placement and pulse width for electroconvulsive therapy (ECT) are important treatment parameters associated with ECT related retrograde memory side-effects. Modification of these parameters with right unilateral (RUL) ECT may have utility for further reducing these side-effects. OBJECTIVE: This study explored use of the frontoparietal (FP) placement for reducing retrograde memory side effects with ECT. We hypothesised that superior retrograde memory outcomes would occur with FP compared to temporoparietal (TP) placement and with ultrabrief (UB: 0.3 ms) compared to brief pulse (BP: 1.0 ms) width ECT. METHODS: In this randomised cross-over, double-blinded study, participants received a single treatment of BP TP, BP FP, UB TP and UB FP ECT. Neuropsychological testing was conducted prior to and immediately following each treatment. Computational modelling was conducted to explore associations between E-fields in regions-of-interest associated with memory. RESULTS: Nine participants completed the study. The FP placement was not superior to TP for retrograde memory outcomes. For both electrode placements UB pulse width was associated with significantly better visual retrograde memory compared to BP (p < .05). With TP ECT, higher E-fields in regions-of-interest were significantly associated with greater visual retrograde memory side-effects (hippocampi: r = -0.77, p = .04; inferior frontal gyri: r = -0.92, p < .01; middle frontal gyri: r = -0.84, p = .02). CONCLUSIONS: Modification of pulse-width had greater effects than electrode placement for reducing retrograde memory side-effects with RUL ECT. Preliminary findings suggested that higher E-fields may be associated with greater cognitive side-effects with ECT.

The role of regional myocardial topography post-myocardial infarction on infarct extension.

Infarct extension involves necrosis of healthy myocardium in the border zone (BZ), progressively enlarging the infarct zone (IZ) and recruiting the remote zone (RZ) into the BZ, eventually leading to heart failure. The mechanisms underlying infarct extension remain unclear, but myocyte stretching has been suggested as the most likely cause. Using human patient-specific left-ventricular (LV) numerical simulations established from cardiac magnetic resonance imaging (MRI) of myocardial infarction (MI) patients, the correlation between infarct extension and regional mechanics abnormality was investigated by analysing the fibre stress-strain loops (FSSLs). FSSL abnormality was characterised using the directional regional external work (DREW) index, which measures FSSL area and loop direction. Sensitivity studies were also performed to investigate the effect of infarct stiffness on regional myocardial mechanics and potential for infarct extension. We found that infarct extension was correlated to severely abnormal FSSL in the form of counter-clockwise loop at the RZ close to the infarct, as indicated by negative DREW values. In regions demonstrating negative DREW values, we observed substantial fibre stretching in the isovolumic relaxation (IVR) phase accompanied by a reduced rate of systolic shortening. Such stretching in IVR phase in part of the RZ was due to its inability to withstand the high LV pressure that was still present and possibly caused by regional myocardial stiffness inhomogeneity. Further analysis revealed that the occurrence of severely abnormal FSSL due to IVR fibre stretching near the RZ-BZ boundary was due to a large amount of surrounding infarcted tissue, or an excessively stiff IZ.