Scholarly Works, Biomedical Engineering and Mechanics

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New focus on cardiac voltage-gated sodium channel β1 and β1B: Novel targets for treating and understanding arrhythmias?
Williams, Zachary J.; Payne, Laura Beth; Wu, Xiaobo; Gourdie, Robert G. (Elsevier, 2025-01)
Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by 2 classes of membrane-spanning subunit: an α-subunit (pore forming) and 2 β-subunits (non–pore forming). NaV1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including NaV1.6, being present. There are 4 β-subunits (β1–β4) encoded by 4 genes (SCN1B–SCN4B), each of which is expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the β-subunit extracellular amino-terminal domain facilitates adhesive interactions in intercalated discs and that its carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway, with a carboxyl-terminal peptide generated by β1 RIP trafficked to the nucleus and altering transcription of various genes, including NaV1.5. In addition to β1, the Scn1b gene encodes for an alternative splice variant, β1B, which contains an identical extracellular adhesion domain to β1 but has a unique carboxyl-terminus. Although β1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with NaV1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known of the 2 β-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate β1 and β1B may be attractive targets for novel antiarrhythmic therapeutics.
Gap junctional and ephaptic coupling in cardiac electrical propagation: homocellular and heterocellular perspectives
Wu, Xiaobo; Payne, Laura Beth; Gourdie, Robert G. (Wiley, 2025-05-31)
Electrical communication in the heart is crucial for maintaining normal cardiac function. Traditionally, gap junctional coupling between cardiomyocytes has been accepted as the primary mechanism governing electrical propagation in the heart. However, numerous studies have demonstrated that gap junctions are also present between different cell types in heterocellular structures and disruption of such gap junctional coupling can be associated with cardiac dysfunction. In addition to gap junctional coupling, ephaptic coupling has been proposed as another mechanism for electrical communication between cardiomyocytes. Reducing ephaptic coupling has been shown to have negative impacts on cardiac conduction. While the existence of ephaptic coupling between different types of cardiac cell is under investigation, a recent study suggests that ephaptic coupling at heterocellular contacts between cardiomyocytes and fibroblasts may provide a proarrhythmic substrate in cardiac disease. In this review, we examine the current literature on electrical communication in the heart, including gap junctional and ephaptic coupling in homocellular and heterocellular contexts. Further, we offer a perspective on gaps in knowledge and opportunities for further advancing our understanding of electrical coupling mechanisms in action potential propagation in the heart. (Figure presented.).
Comparison of conjunctival pedicle flap to corneal fixation strength achieved by Tisseel® fibrin glue, ethyl cyanoacrylate adhesive, ReSure® hydrogel sealant, and conventional suturing with 8-0 VICRYL® ophthalmic suture
VerHulst, Elodie M.; Galarza, Roxanne M. Rodriguez; Herring, Ian P.; Ramos, Renata Velloso; Kemper, Andrew R. (Wiley, 2025-03-01)
Objective To determine and compare the fixation strength of conjunctival pedicle flaps to cornea achieved via conventional ophthalmic suture and three different adhesive compounds. Animals Studied Ex vivo porcine globes. Procedures Following a 6 mm wide 500-micron-restricted depth lamellar keratectomy, conjunctival pedicle flaps were secured to the keratectomy site with either 8-0 VICRYL (R) suture or one of three adhesive products, including Tisseel (R) bioadhesive, ReSure (R) synthetic adhesive, or ethyl cyanoacrylate adhesive (n = 10 per surgical group). Adhesive application protocol varied by product based upon adhesive biocompatibility. Corneoconjunctival tissues were then harvested, clamped in a tensile testing device, and loaded at a rate of 1 mm/s under video surveillance until the point of failure. Peak load was determined for each test and used to compare fixation strength between samples. Results Forty conjunctival flaps were performed, with 6 omitted from evaluation due to dehiscence prior to tensile testing. Of the 34 flaps analyzed, 10 were secured with suture, 10 with cyanoacrylate, 8 with ReSure (R), and 6 with Tisseel (R). Flaps secured with suture withstood significantly higher applied tensile force compared with cyanoacrylate (p = .02474), ReSure (R) (p = .00000), and Tisseel (R) (p = .00002). Flaps secured with cyanoacrylate withstood significantly greater force than those secured with ReSure (R) and Tisseel (R) (p = .01194 and 0.01798, respectively). There was no significant difference in fixation strength between ReSure (R) and Tisseel (R) glue (p = .95675). Conclusions Conjunctival pedicle flap fixation using 8-0 VICRYL (R) suture fixation was able to withstand significantly greater maximum tensile force compared to ReSure (R), Tisseel (R), or cyanoacrylate adhesives. Fixation strength achieved with cyanoacrylate adhesive was significantly greater than that achieved with ReSure (R) or Tisseel (R).
Characterizing Natural Frequencies of the Hybrid III and NOCSAE Headforms
Dingelstedt, Kristin J.; Rowson, Steven (Springer, 2024-10-01)
The vibrational characteristics of the Hybrid III and NOCSAE headforms are not well understood. It is hypothesized that they may perform differently in certain loading environments due to their structural differences; their frequency responses may differ depending on the impact characteristics. Short-duration impacts excite a wider range of headform frequencies than longer-duration (padded) impacts. While headforms generally perform similarly during padded head impacts where resonant frequencies are avoided, excitation of resonant frequencies during short-duration impacts can result in differences in kinematic measurements between headforms for the matched impacts. This study aimed to identify the natural frequencies of each headform through experimental modal analysis techniques. An impulse hammer was used to excite various locations on both the Hybrid III and NOCSAE headforms. The resulting frequency response functions were analyzed to determine the first natural frequencies. The average first natural frequency of the NOCSAE headform was 812 Hz. The Hybrid III headform did not exhibit any natural frequencies below 1000 Hz. Comparisons of our results with previous studies of the human head suggest that the NOCSAE headform's vibrational response aligns more closely with that of the human head, as it exhibits lower natural frequencies. This insight is particularly relevant for assessing head injury risk in short-duration impact scenarios, where resonant frequencies can influence the injury outcome.
Bilayer surrogate brain response under various blast loading conditions
Norris, Carly; Arnold, B.; Wilkes, Jessica M.; Squibb, Carson; Nelson, Allison J.; Schwenker, Hannah; Mesisca, Jenna K.; Vossenberg, A.; Vandevord, Pamela J. (Springer, 2024-08-01)
Variations in the experimental constraints applied within blast simulations can result in dramatically different measured biomechanical responses. Ultimately, this limits the comparison of data between research groups and leads to further inquisitions about the "correct" biomechanics experienced in blast environments. A novel bilayer surrogate brain was exposed to blast waves generated from advanced blast simulators (ABSs) where detonation source, boundary conditions, and ABS geometry were varied. The surrogate was comprised of Sylgard 527 (1:1) as a gray matter simulant and Sylgard 527 (1:1.2) as a white matter simulant. The intracranial pressure response of this surrogate brain was measured in the frontal region under primary blast loading while suspended in a polyurethane spherical shell with 5 mm thickness and filled with water to represent the cerebrospinal fluid. Outcomes of this work discuss considerations for future experimental designs and aim to address sources of variability confounding interpretation of biomechanical responses.
High-Frequency Irreversible Electroporation Alters Proteomic Profiles and Tropism of Small Tumor-Derived Extracellular Vesicles to Promote Immune Cell Infiltration
Murphy, Kelsey R.; Aycock, Kenneth N.; Marsh, Spencer; Yang, Liping; Hinckley, Jonathan; Selmek, Aubrie; Gourdie, Robert G.; Bracha, Shay; Davalos, Rafael V.; Rossmeisl, John H.; Dervisis, Nikolaos G. (MDPI, 2025-11-13)
High-frequency irreversible electroporation (H-FIRE) is a nonthermal tumor ablation technique that disrupts the blood–brain barrier (BBB) in a focal and reversible manner. However, the mechanisms underlying this disruption remain poorly understood, particularly the role of small tumor-derived extracellular vesicles (sTDEVs) released from ablated tumor cells. In this study, we investigate the proteomic and functional alterations of sTDEVs released from F98 glioma and LL/2 Lewis lung carcinoma cells following H-FIRE ablation. Mass spectrometry analysis revealed 108 unique proteins in sTDEVs derived from ablative doses of H-FIRE, which are capable of disrupting the BBB in an in vitro model. Proteomic analysis of TDEVs highlights key changes in pathways related to integrin signaling, Platelet-derived growth factor receptor (PDGFR) signaling, and ubiquitination, which may underline their interactions with brain endothelial cells. These “disruptive” sTDEVs exhibit enhanced tropism for cerebral endothelial cells both in vitro and in vivo, where they persist in the brain longer than sTDEVs released after non-ablative H-FIRE doses. Notably, when introduced into a healthy Fischer rat model, disruptive sTDEVs are associated with increased recruitment of Iba1+ immune cells, suggesting a potential role in modulating post-ablation immune responses. However, despite their altered protein composition, these vesicles do not directly increase BBB permeability in vivo. This study is the first to demonstrate that electroporation-based tumor ablation significantly alters the composition and functionality of tumor-derived extracellular vesicles, potentially influencing the tumor microenvironment post-ablation. These findings have important implications for developing multimodal treatment strategies that combine H-FIRE with systemic therapies to enhance efficacy while managing the peritumoral microenvironment.
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.

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