Scholarly Works, Biomedical Engineering and Mechanics

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Spatial Intracranial Pressure Fields Driven by Blast Overpressure in Rats
Norris, Carly; Murphy, Susan F.; Talty, Caiti-Erin; VandeVord, Pamela J. (Springer, 2024-10-01)
Free-field blast exposure imparts a complex, dynamic response within brain tissue that can trigger a cascade of lasting neurological deficits. Full body mechanical and physiological factors are known to influence the body's adaptation to this seemingly instantaneous insult, making it difficult to accurately pinpoint the brain injury mechanisms. This study examined the intracranial pressure (ICP) profile characteristics in a rat model as a function of blast overpressure magnitude and brain location. Metrics such as peak rate of change of pressure, peak pressure, rise time, and ICP frequency response were found to vary spatially throughout the brain, independent of blast magnitude, emphasizing unique spatial pressure fields as a primary biomechanical component to blast injury. This work discusses the ICP characteristics and considerations for finite element models, in vitro models, and translational in vivo models to improve understanding of biomechanics during primary blast exposure.
Scale modeling of thermo-structural fire tests of multi-orientation wood laminates
Gangi, Michael J.; Lattimer, Brian Y.; Case, Scott W. (Springer, 2024-07-01)
The stacking sequence of laminated wood significantly impacts the composite mechanical behavior of the material, especially when scaling down thermo-mechanical tests on plywood. In previous research, we developed a scaling methodology for thermo-structural tests on samples with similar cross sections, however this paper focused on testing plywood samples with different stacking sequences between the scales. Plywood samples at 1/2 -scale and 1/4 -scale were subjected to combined bending and thermal loading, with the loading scaled to have the same initial static bending stresses. While the 1/4 -scale 4-layer [0 degrees/90 degrees]s laminate and the 1/2 -scale 8-layer [0 degrees/90 degrees/90 degrees/0 degrees]s laminate had an equal number of 0 degrees and 90 degrees layers, as the char front progresses, the sections behave differently. Thus, modeling becomes essential to extrapolating the data from the smaller 1/4 -scale test to predict the behavior of the larger 1/2 -scale test. Reduced cross-sectional area models (RCAM) incorporating classical laminated plate theory were used to predict the mechanical response of the composite samples as the char front increased. Three methods were proposed for calibrating the RCAM models: Fourier number scaling, from detailed kinetics-based pyrolysis GPyro models, and fitting to data from fire exposure thermal response tests. The models calibrated with the experimental char measurements produced the most accurate predictions. The experimental char models validated to predict the behavior of the 1/4 -scale tests within 2.5%, were then able to predict the 1/2 -scale test behavior within 4.5%.
Gait asymmetry persists following unilateral and bilateral total ankle arthroplasty
Carpentier, Stephanie H.; Barylak, Martin; Arena, Sara L.; Queen, Robin M. (Wiley, 2024-11-01)
Total ankle arthroplasty (TAA) improves gait symmetry in patients with unilateral end-stage ankle arthritis but has not been studied in patients undergoing bilateral TAA (B-TAA), and few studies compare TAA patients to control subjects. The purpose of this study was to compare gait symmetry in U-TAA and B-TAA patients and healthy controls. Using prospective databases, 19 unilateral and 19 bilateral ankle arthritis patients undergoing TAA were matched to 19 control subjects by age, sex, and BMI. The Normalized Symmetry Index (NSI) was determined for joint mechanics and ground reaction forces (GRF) during walking trials at a single visit for controls and preoperatively and 1 to 2 years postoperatively for TAA patients. Data was analyzed using linear mixed-effects models to determine differences among time points and cohorts at a significance of alpha = 0.05. Following surgery, B-TAA and U-TAA experienced improved peak plantarflexion moment symmetry (p = 0.017) but remained less symmetric than controls. B-TAA patients had more symmetry than U-TAA patients during peak weight acceptance GRF (p = 0.002), while U-TAA patients had greater peak dorsiflexion symmetry than B-TAA patients. TAA patients demonstrated more asymmetry compared to control subjects for all outcome measures. There was no significant impact of TAA on gait symmetry for GRF or peak ankle angles, and neither U-TAA nor B-TAA was consistently associated with higher gait symmetry. These results indicate that TAA improves symmetry during peak plantarflexion moment, and that significant gait asymmetry persists for B-TAA and U-TAA patients compared to healthy participants.
Instrumented Mouthguard Decoupling Affects Measured Head Kinematic Accuracy
Gellner, Ryan A.; Begonia, Mark T.; Wood, Matthew; Rockwell, Lewis; Geiman, Taylor; Jung, Caitlyn; Rowson, Steven (Springer, 2024-10-01)
Many recent studies have used boil-and-bite style instrumented mouthguards to measure head kinematics during impact in sports. Instrumented mouthguards promise greater accuracy than their predecessors because of their superior ability to couple directly to the skull. These mouthguards have been validated in the lab and on the field, but little is known about the effects of decoupling during impact. Decoupling can occur for various reasons, such as poor initial fit, wear-and-tear, or excessive impact forces. To understand how decoupling influences measured kinematic error, we fit a boil-and-bite instrumented mouthguard to a 3D-printed dentition mounted to a National Operating Committee on Standards for Athletic Equipment (NOCSAE) headform. We also instrumented the headform with linear accelerometers and angular rate sensors at its center of gravity (CG). We performed a series of pendulum impact tests, varying impactor face and impact direction. We measured linear acceleration and angular velocity, and we calculated angular acceleration from the mouthguard and the headform CG. We created decoupling conditions by varying the gap between the lower jaw and the bottom face of the mouthguard. We tested three gap conditions: 0 mm (control), 1.6 mm, and 4.8 mm. Mouthguard measurements were transformed to the CG and compared to the reference measurements. We found that gap condition, impact duration, and impact direction significantly influenced mouthguard measurement error. Error was higher for larger gaps and in frontal (front and front boss) conditions. Higher errors were also found in padded conditions, but the mouthguards did not collect all rigid impacts due to inherent limitations. We present characteristic decoupling time history curves for each kinematic measurement. Exemplary frequency spectra indicating characteristic decoupling frequencies are also described. Researchers using boil-and-bite instrumented mouthguards should be aware of their limitations when interpreting results and should seek to address decoupling through advanced post-processing techniques when possible.
On-Field Evaluation of Mouthpiece-and-Helmet-Mounted Sensor Data from Head Kinematics in Football
Holcomb, Ty D.; Marks, Madison E.; Pritchard, N. Stewart; Miller, Logan E.; Rowson, Steven; Bullock, Garrett S.; Urban, Jillian E.; Stitzel, Joel D. (Springer, 2024-10-01)
Purpose Wearable sensors are used to measure head impact exposure in sports. The Head Impact Telemetry (HIT) System is a helmet-mounted system that has been commonly utilized to measure head impacts in American football. Advancements in sensor technology have fueled the development of alternative sensor methods such as instrumented mouthguards. The objective of this study was to compare peak magnitude measured from high school football athletes dually instrumented with the HIT System and a mouthpiece-based sensor system. Methods Data was collected at all contact practices and competitions over a single season of spring football. Recorded events were observed and identified on video and paired using event timestamps. Paired events were further stratified by removing mouthpiece events with peak resultant linear acceleration below 10 g and events with contact to the facemask or body of athletes. Results A total of 133 paired events were analyzed in the results. There was a median difference (mouthpiece subtracted from HIT System) in peak resultant linear and rotational acceleration for concurrently measured events of 7.3 g and 189 rad/s(2). Greater magnitude events resulted in larger kinematic differences between sensors and a Bland Altman analysis found a mean bias of 8.8 g and 104 rad/s(2), respectively. Conclusion If the mouthpiece-based sensor is considered close to truth, the results of this study are consistent with previous HIT System validation studies indicating low error on average but high scatter across individual events. Future researchers should be mindful of sensor limitations when comparing results collected using varying sensor technologies.
Development of an Injectable Hydrogel for Histotripsy Ablation Toward Future Glioblastoma Therapy Applications
Khan, Zerin Mahzabin; Zhang, Junru; Gannon, Jessica; Johnson, Blake N.; Verbridge, Scott S.; Vlaisavljevich, Eli (Springer, 2024-12-01)
Glioblastoma (GBM) is the most common and malignant type of primary brain tumor. Even after surgery and chemoradiotherapy, residual GBM cells can infiltrate the healthy brain parenchyma to form secondary tumors. To mitigate GBM recurrence, we recently developed an injectable hydrogel that can be crosslinked in the resection cavity to attract, collect, and ablate residual GBM cells. We previously optimized a thiol-Michael addition hydrogel for physical, chemical, and biological compatibility with the GBM microenvironment and demonstrated CXCL12-mediated chemotaxis can attract and entrap GBM cells into this hydrogel. In this study, we synthesize hydrogels under conditions mimicking GBM resection cavities and assess feasibility of histotripsy to ablate hydrogel-encapsulated cells. The results showed the hydrogel synthesis was bio-orthogonal, not shear-thinning, and can be scaled up for injection into GBM resection mimics invitro. Experiments also demonstrated ultrasound imaging can distinguish the synthetic hydrogel from healthy porcine brain tissue. Finally, a 500 kHz transducer applied focused ultrasound treatment to the synthetic hydrogels, with results demonstrating precise histotripsy bubble clouds could be sustained in order to uniformly ablate red blood cells encapsulated by the hydrogel for homogeneous, mechanical fractionation of the entrapped cells. Overall, this hydrogel is a promising platform for biomaterials-based GBM treatment.
Parameter Identification of Soil Material Model for Soil Compaction Under Tire Loading: Laboratory vs. In-Situ Cone Penetrometer Test Data
Shokanbi, Akeem; Jasoliya, Dhruvin; Untaroiu, Costin D. (MDPI, 2025-10-15)
Accurate numerical simulations of soil-tire interactions are essential for optimizing agricultural machinery to minimize soil compaction and enhance crop yield. This study developed and compared two approaches for identifying and validating parameters of a LS-Dyna soil model. The laboratory-based approach derives parameters from triaxial, consolidation, and cone penetrometer tests (CPT), while the optimization-based method refines them using in-situ CPT data via LS-OPT to better capture field variability. Simulations employing Multi-Material Arbitrary Lagrangian–Eulerian (MM-ALE), Smoothed Particle Hydrodynamics (SPH), and Hybrid-SPH methods demonstrate that Hybrid-SPH achieves the optimal balance of accuracy (2% error post-optimization) and efficiency (14-h runtime vs. 22 h for SPH). Optimized parameters improve soil–tire interaction predictions, including net traction and tire sinkage across slip ratios from −10% to 30% (e.g., sinkage of 12.5 mm vs. 11.1 mm experimental at 30% slip, with overall mean-absolute percentage error (MAPE) reduced to 3.5% for sinkage and 4.2% for traction) and rut profiles, outperforming lab-derived values. This framework highlights the value of field-calibrated optimization for sustainable agriculture, offering a cost-effective alternative to field trials for designing low-compaction equipment and reducing yield losses from soil degradation. While sandy loam soil at 0.4% moisture content was used in this study, future extensions to different soil types with varied moisture are recommended.
Characterization of an Advanced Blast Simulator for Investigation of Large Scale Blast Traumatic Brain Injury Studies
Nelson, Allison J.; Ritzel, David; Showalter, Noah; Boppe, Danny; Riegel, Andy; VandeVord, Pamela J. (Springer, 2025-01-01)
Blast traumatic brain injury (bTBI) is a prominent military health concern. The pervasiveness and long-term impacts of this injury highlight the need for investigation of the physiological outcomes of bTBI. Preclinical models allow for the evaluation of behavioral and neuropathological sequelae associated with bTBI. Studies have implemented rodent models to investigate bTBI due to the relative small size and low cost; however, a large animal model with similar neuroanatomical structure to humans is essential for clinical translation. Small blast simulators are used to induce bTBI in rodents, but a large animal model demands a larger device. This study describes a large advanced blast simulator (ABS4) that is a gas-detonation-driven system consisting of 5 sections totaling 40 ft in length with a cross-section of 4 x 4 ft at the test section. It is highly suitable for large animals and human surrogate investigations. This work characterized the ABS4 in preparation of large-scale bTBI testing. An array of tests were conducted with target overpressures in the test section ranging from 10 to 50 psi, and the pressure-time profiles clearly illustrate the essential characteristics of a free-field blast wave, specifically a sharp peak pressure and a defined negative phase. Multiple blast tests conducted at the same target pressure produced very similar pressure profiles, exhibiting the reproducibility of the ABS4 system. With its extensive range of pressures and substantial size, the ABS4 will permit military-relevant translational blast testing.
Implicit Solvent with Explicit Ions Generalized Born Model in Molecular Dynamics: Application to DNA
Kolesnikov, Egor S.; Xiong, Yeyue; Onufriev, Alexey V. (American Chemical Society, 2024-09-16)
The ion atmosphere surrounding highly charged biomolecules, such as nucleic acids, is crucial for their dynamics, structure, and interactions. Here, we develop an approach for the explicit treatment of ions within an implicit solvent framework suitable for atomistic simulations of biomolecules. The proposed implicit solvent/explicit ions model, GBION, is based on a modified generalized Born (GB) model; it includes separate, modified GB terms for solute-ion and ion-ion interactions. The model is implemented in the AMBER package (version 24), and its performance is thoroughly investigated in atomistic molecular dynamics (MD) simulations of double-stranded DNA on a microsecond time scale. The aggregate characteristics of monovalent (Na+ and K+) and trivalent (Cobalt Hexammine, CoHex(3+)) counterion distributions around double-stranded DNA predicted by the model are in reasonable agreement with the experiment (where available), all-atom explicit water MD simulations, and the expectation from the Manning condensation theory. The radial distributions of monovalent cations around DNA are reasonably close to the ones obtained using the explicit water model: expressed in units of energy, the maximum deviations of local ion concentrations from the explicit solvent reference are within 1 k(B)T, comparable to the corresponding deviations expected between different established explicit water models. The proposed GBION model is able to simulate DNA fragments in a large volume of solvent with explicit ions with little additional computational overhead compared with the fully implicit GB treatment of ions. Ions simulated using the developed model explore conformational space at least 2 orders of magnitude faster than in the explicit solvent. These advantages allowed us to observe and explore an unexpected "stacking" mode of DNA condensation in the presence of trivalent counterions (CoHex(3+)) that was revealed by recent experiments.
Ultrasound-Guided Mechanical High-Intensity Focused Ultrasound (Histotripsy) Through an Acoustically Permeable Polyolefin-Based Cranioplasty Device
Ruger, Lauren; Langman, Maya; Farrell, Renata; Rossmeisl, John H. Jr.; Prada, Francesco; Vlaisavljevich, Eli (IEEE, 2024-10-01)
Histotripsy is a non-thermal focused ultrasound therapy in development for the non-invasive ablation of cancerous tumors. Intracranial histotripsy has been limited by significant pressure attenuation through the skull, requiring large, complex array transducers to overcome this effect. Objective: Recently, a biocompatible, polyolefin-based cranioplasty device was developed to allow ultrasound (US) transmission into the intracranial space with minimal distortion. In this study, we investigated the in vitro feasibility of applying US-guided histotripsy procedures across the prosthesis. Methods: Pressure waveforms and beam profiles were collected for single- and multi-element histotripsy transducers. Then, high-speed optical images of the bubble cloud with and without the prosthesis were collected in water and tissue-mimicking agarose gel phantoms. Finally, red blood cell (RBC) tissue phantom and excised brain tissue experiments were completed to test the ablative efficacy across the prosthesis. Results: Single element tests revealed increased pressure loss with increasing transducer frequency and increasing transducer-to-prosthesis angle. Array transducer measurements at 1 MHz showed average pressure losses of >50% across the prosthesis. Aberration correction recovered up to 18% of the pressure lost, and high-speed optical imaging in water, agarose gels, and RBC phantoms demonstrated that histotripsy bubble clouds could be generated across the prosthesis at pulse repetition frequencies of 50-500 Hz. Histologic analysis revealed a complete breakdown of brain tissue treated across the prosthesis. Conclusion & Significance: Overall, the results of this study demonstrate that the cranial prosthesis may be used as an acoustic window through which intracranial histotripsy can be applied under US guidance without the need for large transcranial array transducers.
How Shell Add-On Products Influence Varsity Football Helmet Performance
Stark, Nicole; Begonia, Mark T.; Jung, Caitlyn; Rowson, Steven (Springer, 2024-11-01)
Purpose: The study purpose was to investigate the laboratory-based performance of three commercially available shell add-on products under varsity-level impact conditions. Methods: Pendulum impact tests were conducted at multiple locations (front, front boss, rear, side) and speeds (3.1, 4.9, 6.4 m/s) using two helmet models. Tests were performed with a single add-on configuration for baseline comparisons and a double add-on configuration to simulate collisions with both players wearing shell add-ons. A linear mixed-effect model was used to evaluate peak linear acceleration (PLA), peak rotational acceleration (PRA), and concussion risk, which was calculated from a bivariate injury risk function, based on shell add-on and test configuration. Results: All shell add-ons decreased peak head kinematics and injury risk compared to controls, with the Guardian NXT producing the largest reductions (PLA: 7.9%, PRA: 14.1%, Risk: 34.1%) compared to the SAFR Helmet Cover (PLA: 4.5%, PRA: 9.3%, Risk: 24.7%) and Guardian XT (PLA: 3.2%, PRA: 5.0%, Risk: 15.5%). The same trend was observed in the double add-on test configuration. However, the Guardian NXT (PLA: 17.1%; PRA: 11.5%; Risk: 62.8%) and SAFR Helmet Cover (PLA: 12.2%; PRA: 9.1%; Risk: 52.2%) produced larger reductions in peak head kinematics and injury risk than the Guardian XT (PLA: 5.7%, PRA: 2.2%, Risk: 21.8%). Conclusion: In laboratory-based assessments that simulated varsity-level impact conditions, the Guardian NXT was associated with larger reductions in PLA, PRA, and injury risk compared to the SAFR Helmet Cover and Guardian XT. Although shell add-ons can enhance head protection, helmet model selection should be prioritized.
Mild traumatic brain injury gives rise to chronic depression-like behavior and associated alterations in glutamatergic protein expression
Talty, Caiti-Erin; Murphy, Susan; VandeVord, Pamela J. (Pergamon-Elsevier, 2024-11-12)
Mild traumatic brain injury (mTBI) is known to result in chronic somatic, cognitive, and emotional symptoms. Depression is commonly reported among individuals suffering from persistent concussion symptoms; however, the underlying mechanisms are not understood. The glutamatergic system has recently been linked with mTBI and depression due to reports of similar changes in expression of glutamatergic proteins. Using a closed-head controlled cortical impact (cCCI) model in adult male rats (n = 8/group), this study investigated the emergence of self-care deficits and changes in social interaction behaviors at four, eight and twelve weeks post-injury. Western blotting was used to assess associated changes in expression of glutamate transporters and N-methyl-Daspartate (NMDA) receptor subunits at twelve weeks. Splash test results revealed deficits in self-care behaviors beginning at eight weeks, which continued through twelve weeks in the injury group. Injured animals also exhibited decreased preference for social novelty at four weeks and loss of desire for social interaction as a whole by twelve weeks. GluN1 was increased in injured animals compared to shams in the frontal cortex and amygdala, while decreased GLT-1 was observed in the hippocampus. Linear regression was performed to evaluate relationships between behavioral and molecular variables; the results suggested that injury affects these relationships in a region-dependent manner. Together, these results suggest that the development of chronic depression-like behavior was associated with changes in glutamatergic protein expression. Deeper investigations into how injury influences glutamatergic synaptic protein expression are needed, as this has the potential to affect circuit-level neurotransmission that drives depression-like behavior following mTBI.
Regulation of craving for real-time fMRI neurofeedback based on individual classification
Kim, Dong-Youl; Lisinski, Jonathan; Caton, Matthew; Casas, Brooks; LaConte, Stephen M.; Chiu, Pearl H. (Royal Society, 2024-10-21)
In previous real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) studies on smoking craving, the focus has been on within-region activity or between-region connectivity, neglecting the potential predictive utility of broader network activity. Moreover, there is debate over the use and relative predictive power of individual-specific and group-level classifiers. This study aims to further advance rtfMRI-NF for substance use disorders by using whole-brain rtfMRI-NF to assess smoking craving-related brain patterns, evaluate the performance of group-level or individual-level classification (n = 31) and evaluate the performance of an optimized classifier across repeated NF runs. Using real-time individual-level classifiers derived from whole-brain support vector machines, we found that classification accuracy between crave and no-crave conditions and between repeated NF runs increased across repeated runs at both individual and group levels. In addition, individual-level accuracy was significantly greater than group-level accuracy, highlighting the potential increased utility of an individually trained whole-brain classifier for volitional control over brain patterns to regulate smoking craving. This study provides evidence supporting the feasibility of using whole-brain rtfMRI-NF to modulate smoking craving-related brain responses and the potential for learning individual strategies through optimization across repeated feedback runs.This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.
Demonstration of chemotherapeutic-mediated changes in meningeal lymphatics in vitro, ex vivo, and in vivo
Roberts, L. Monet; Hammel, Jennifer H.; Peng, Jin; Cunningham, Jessica J.; Schumaecker, Sophia; Davis, Skylar; Azar, Francesca; Alkaid Feng, Tzu-Yu; Wang, Maosen; Rutkowski, Melanie; Munson, Jennifer M. (Nature Research, 2025-10-13)
Systemic chemotherapy often affects cells beyond the tumor, raising concerns about their impact on peripheral tissues, including the central nervous system (CNS). The meningeal lymphatics drain cerebrospinal fluid from the CNS to the deep cervical lymph nodes, assisting in immunosurveillance and linking theCNSto the periphery. They have been implicated in a number of brain-related disorders with disruption exacerbating cognitive deficits. However, in vivo, distinguishing between direct and indirect effects of systemic chemotherapy on the meningeal lymphatics remains highly challenging, making it difficult to isolate specific impact on the CNS. To address this, we present two models we have developed that allow the examination of cellular and tissue-level changes to study the effects of systemic chemotherapy on the meningeal lymphatics. Our in vitro tissue engineered model representative of a meningeal lymphatic vessel lumen shows cell disruption, while our ex vivo model culturing mouse meningeal layers probes structural changes in a controlled setting. Finally, we correlate functional outcomes with observed changes in vivo and show that systemic taxane chemotherapy leads to morphological changes in the meningeal lymphatics, a trend of reduced flow through the brain, and impaired cognition, emphasizing the need for further study of off-target impacts in the CNS and the value of multi-model approaches.
Nanotechnology for immuno-oncology
Grippin, Adam J.; Lee, DaeYong; Parkes, Eileen E.; Jiang, Wen; Kim, Betty Y. S. (Nature Portfolio, 2025-08-01)
Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.
Comparing efficiency of patent production between US institutions using a hybrid NIH-USPTO dataset
DiSanto, Rocco M.; Van Dyke, Mark; Barker, Michael J.; Gourdie, Robert G. (Nature Portfolio, 2023-08)
A database that links patents to NIH awards enables evaluation of key milestones along the research translation pathway.
Development and characterization of the mode-of-action of inhibitory and agonist peptides targeting the voltage-gated sodium channel SCN1B beta-subunit
Williams, Zachary J.; Alvarez-Laviada, Anita; Hoagland, Daniel; Jourdan, L. Jane; Poelzing, Steven; Gorelik, Julia; Gourdie, Robert G. (Elsevier, 2024-09)
Cardiac arrhythmia treatment is a clinical challenge necessitating safer and more effective therapies. Recent studies have highlighted the role of the perinexus, an intercalated disc nanodomain enriched in voltage-gated sodium channels including both Nav1.5 and β1 subunits, adjacent to gap junctions. These findings offer insights into action potential conduction in the heart. A 19-amino acid SCN1B (β1/β1B) mimetic peptide, βadp1, disrupts VGSC beta subunit-mediated adhesion in cardiac perinexii, inducing arrhythmogenic changes. We aimed to explore βadp1's mechanism and develop novel SCN1B mimetic peptides affecting β1-mediated adhesion. Using patch clamp assays in neonatal rat cardiomyocytes and electric cell substrate impedance sensing (ECIS) in β1-expressing cells, we observed βadp1 maintained inhibitory effects for up to 5 h. A shorter peptide (LQLEED) based on the carboxyl-terminus of βadp1 mimicked this inhibitory effect, while dimeric peptides containing repeated LQLEED sequences paradoxically promoted intercellular adhesion over longer time courses. Moreover, we found a link between these peptides and β1-regulated intramembrane proteolysis (RIP) - a signaling pathway effecting gene transcription including that of VGSC subunits. βadp1 increased RIP continuously over 48 h, while dimeric agonists acutely boosted RIP for up to 6 h. In the presence of DAPT, an RIP inhibitor, βadp1's effects on ECIS-measured intercellular adhesion was reduced, suggesting a relationship between RIP and the peptide's inhibitory action. In conclusion, novel SCN1B (β1/β1B) mimetic peptides are reported with the potential to modulate intercellular VGSC β1-mediated adhesion, potentially through β1 RIP. These findings suggest a path towards the development of anti-arrhythmic drugs targeting the perinexus.
Acute adenoviral infection elicits an arrhythmogenic substrate prior to myocarditis
Padget, Rachel L.; Zeitz, Michael J.; Blair, Grace A.; Wu, Xiaobo; North, Michael D.; Tanenbaum, Mira T.; Stanley, Kari E.; Phillips, Chelsea M.; King, D. Ryan; Lamouille, Samy; Gourdie, Robert G.; Hoeker, Gregory S.; Swanger, Sharon A.; Poelzing, Steven; Smyth, James W. (American Heart Association, 2024-03-29)
BACKGROUND: Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate before significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species specificity, models of infection are lacking, and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse adenovirus type-3 was previously reported as cardiotropic, yet it has not been utilized to understand the mechanisms of cardiac infection and pathology. METHODS: We have developed mouse adenovirus type-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart before an appreciable immune response or gross cardiomyopathy. RESULTS: Optical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43^Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43^Ser368 are protected against mouse adenovirus type-3–induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of mouse adenovirus type-3–infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased IK1 and IKs current density. Turning to human systems, we find human adenovirus type-5 increases phosphorylation of Cx43^Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes, indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. CONCLUSIONS: Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.
Milk extracellular vesicles: A burgeoning new presence in nutraceuticals and drug delivery
Marsh, Spencer R.; Beard, Claire E.; Gourdie, Robert G. (Wiley, 2025-05-01)
Mammalian milk, a multifaceted developmental biofluid, has attracted new attention due to its diverse constituents and their implications for health and disease. Among these constituents, extracellular vesicles (EVs) have emerged as focal points of investigation. EVs, including exosomes and small EVs, have demonstrated biological activity in preclinical studies—including reports of enhancement of cognition and neural complexity, promotion of gastrointestinal development, barrier function and microbiome richness, the bolstering of immune response, and facilitation of musculoskeletal maturation in neonates. The richness of milk as a source of EVs is noteworthy, with hundreds of milliliters (at >10¹² EVs/mL) of nanovesicles extractable from a single liter of milk (>10¹⁴ EVs/starting liter of milk). Techniques such as tangential flow filtration hold promise for scalable production, potentially extending to thousands of liters. Together with the scale and increasing sophistication of the dairy industry, the abundance of EVs in milk underscores their commercial potential in various nutraceutical applications. Beyond natural bioactivity, milk EVs (mEVs) present intriguing possibilities as orally deliverable, non-immunogenic pharmaceutical carriers, with burgeoning interest in their utilization for heart disease and cancer chemotherapy and as vectors for gene-editing modules such as CrispR. This review synthesizes current knowledge on mEV biogenesis, characterization, isolation methodologies, and cargo contents. Moreover, it delves into the therapeutic potential of mEVs, both as inherently bioactive nanovesicles and as versatile platforms for drug delivery. As efforts progress toward large-scale implementation, rigorous attention to safe, industrial-scale production and robust assay development will be pivotal in harnessing the translational promise of small EVs from milk.
Tumor-derived extracellular vesicles disrupt the blood-brain barrier endothelium following high-frequency irreversible electroporation
Murphy, Kelsey R.; Aycock, Kenneth N.; Marsh, Spencer; Hay, Alayna N.; Athanasiadi, Ilektra; Bracha, Shay; Chang, Christine; Gourdie, Robert G.; Davalos, Rafael V.; Rossmeisl, John H. Jr.; Dervisis, Nikolaos G. (Nature Portfolio, 2024-11-18)
High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood–brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), disrupt the BBB endothelium. Monolayers of bEnd.3 cerebral endothelial cells were exposed to supernatants of H-FIRE or radiation (RT)-treated LL/2 and F98 cancer cells. Endothelial cell response was evaluated microscopically and via flow cytometry for apoptosis. sTDEV were isolated following H-FIRE and RT, characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy, and applied to a Transwell BBB endothelium model to quantify permeability changes. Supernatants of H-FIRE-treated tumor cells, but not supernatants of sham- or RT-treated cells, disrupted endothelial cell monolayer integrity while maintaining viability. sTDEV released by glioma cells treated with 3000 V/cm H-FIRE increased permeability of the BBB endothelium model compared to sTDEV released after lower H-FIRE doses and RT. NTA revealed significantly decreased sTDEV release after the 3000 V/cm H-FIRE dose. Our results demonstrate that sTDEV increase permeability of the BBB endothelium after H-FIRE ablation in vitro. sTDEV-mediated mechanisms of BBB disruption may be exploited for drug delivery to infiltrative margins following H-FIRE ablation.

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