Scholarly Works, School of Biomedical Engineering and Sciences

Permanent URI for this collection

https://hdl.handle.net/10919/23275

Research articles, presentations, and other scholarship

Browse

Now showing 1 - 20 of 149

Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction
Adams, William P.; Raisch, Tristan B.; Zhao, Yajun; Davalos, Rafael V.; Barrett, Sarah; King, D. Ryan; Bain, Chandra B.; Colucci-Chang, Katrina; Blair, Grace A.; Hanlon, Alexandra L.; Lozano, Alicia; Veeraraghavan, Rengasayee; Wan, Xiaoping; Deschenes, Isabelle; Smyth, James W.; Hoeker, Gregory S.; Gourdie, Robert G.; Poelzing, Steven (Lippincott Williams & Wilkins, 2023-09-29)
BACKGROUND: Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces. METHODS: Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. RESULTS: CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran 70 kDa; albumin or dextran 2 MDa; dextran 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. CONCLUSIONS: Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.
On-chip phased interdigital metamaterials enable versatile manipulation of surface acoustic waves, microfluids, and micro/nano-objects
Li, Jiali; Bo, Luyu; Li, Teng; Shen, Liang; Qiu, Chongpeng; Du, Yingshan; Yang, Shujie; Tian, Zhenhua (Springer Nature, 2025-12-08)
Surface acoustic waves (SAWs) offer great potential for quantum information processing, optomechanics, acoustofludics, and acoustic tweezers. However, existing SAW chips lack the ability to control SAWs in a manner similar to current metamaterials, which can achieve versatile subwavelength-resolution manipulation of bulk acoustic waves. This study presents on-chip phased interdigital metamaterials (PIMs) featuring customized interdigital electrodes whose geometries are encoded with deep-subwavelength-resolution phase profiles, enabling versatile transformation of SAWs and manipulation of fluids and micro/nano-objects. Our on-chip PIMs can transform forward SAWs into waves with desired wavefronts and energy patterns, such as SAWs propagating in a specified direction, a SAW jet with energy confined in a wavelength, and twin jets. They also enable “diode-like” SAW transmission, allowing for routing the information carried by SAWs along a forward pathway while blocking backward communication. Additionally, SAWs generated by PIMs exhibit unique energy patterns, allowing for versatile active control of fluid streaming and micro/nano-object distributions.
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.
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.
Airborne Acoustic Vortex End Effector-Based Contactless, Multi-Mode, Programmable Control of Object Surfing
Li, Teng; Li, Jiali; Bo, Luyu; Brooks, Michael R.; Du, Yingshan; Cai, Bowen; Pei, Zhe; Shen, Liang; Sun, Chuangchuang; Cheng, Jiangtao; Pan, Y. Albert; Tian, Zhenhua (Wiley, 2024-09-01)
Tweezers based on optical, electric, magnetic, and acoustic fields have shown great potential for contactless object manipulation. However, current tweezers designed for manipulating millimeter-sized objects such as droplets, particles, and small animals exhibit limitations in translation resolution, range, and path complexity. Here, a novel acoustic vortex tweezers system is introduced, which leverages a unique airborne acoustic vortex end effector integrated with a three-degree-of-freedom (DoF) linear motion stage, for enabling contactless, multi-mode, programmable manipulation of millimeter-sized objects. The acoustic vortex end effector utilizes a cascaded circular acoustic array, which is portable and battery-powered, to generate an acoustic vortex with a ring-shaped energy pattern. The vortex applies acoustic radiation forces to trap and spin an object at its center, simultaneously protecting this object by repelling other materials away with its high-energy ring. Moreover, The vortex tweezers system facilitates contactless, multi-mode, programmable object surfing, as demonstrated in experiments involving trapping, repelling, and spinning particles, translating particles along complex paths, guiding particles around barriers, translating and rotating droplets containing zebrafish larvae, and merging droplets. With these capabilities, It is anticipated that the tweezers system will become a valuable tool for the automated, contactless handling of droplets, particles, and bio-samples in biomedical and biochemical research. A novel acoustic vortex tweezers system is reported, which leverages a unique acoustic vortex end effector based on a portable, battery-powered, cascaded circular acoustic array. The system enables contactless, multi-mode, programmable object surfing, as demonstrated in experiments involving trapping, repelling, and spinning particles, translating particles along complex paths, guiding particles around barriers, and translating and rotating droplets containing zebrafish larvae. image
Photoacoustic imaging for non-invasive assessment of biomarkers of intestinal injury in experimental necrotizing enterocolitis
Weis, Jared A.; Rauh, Jessica L.; Ellison, Maryssa A.; Cruz-Diaz, Nildris; Yamaleyeva, Liliya M.; Welch, Cherrie D.; Zeller, Kristen A.; Weis, Victoria G. (Springernature, 2025-01-01)
BackgroundNecrotizing enterocolitis (NEC) is an often-lethal disease of the premature infant intestinal tract, exacerbated by significant diagnostic difficulties. In NEC, the intestine exhibits hypoperfusion and dysmotility, contributing to disease pathogenesis. However, these features cannot be accurately and quantitively assessed with current imaging modalities. We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model.MethodsIn this first-in-disease application, we evaluated NEC using PAI to assess intestinal health biomarkers in an experimental model of NEC. NEC was induced in neonatal rats from birth to 4-days. Healthy breastfed (BF) and NEC rat pups were imaged at 2- and 4-days.ResultsIntestinal tissue oxygen saturation was measured with PAI, and NEC pups showed significant decreases at 2- and 4-days. Ultrasound and PAI cine recordings were used to capture intestinal peristalsis and contrast agent transit within the intestine. Intestinal motility, assessed using computational intestinal deformation analysis, demonstrated significant reductions in both early and established NEC. NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay.ConclusionThis preclinical study presents PAI as an emerging diagnostic imaging modality for intestinal disease assessment in premature infants.ImpactNecrotizing enterocolitis (NEC) is a devastating intestinal disease affecting premature infants with significant mortality.NEC presents significant clinical diagnostic difficulties, with limited diagnostic confidence complicating timely and effective interventional efforts.This study is an important foundational first-in-disease preclinical study that establishes the utility for PAI to detect changes in intestinal tissue oxygenation and intestinal motility with NEC disease induction and progression.This study demonstrates the feasibility and exceptional promise for the use of PAI to non-invasively assess oxygenation and motility in the healthy and diseased infant intestine.
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.
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.
Integrative Constraint-Based Modeling and Proteomics Uncover Astrocytic Metabolic Adaptations to the Post-TBI Microenvironment
Wilson, Kelsey A.; Talty, Caiti-Erin; Parker, Brian C.; VandeVord, Pamela J. (MDPI, 2025-07-04)
Traumatic brain injury (TBI) is a major neurological condition affecting millions of individuals each year. Mild TBI (mTBI) manifests differently, with some individuals experiencing persistent, debilitating symptoms while others recover more rapidly. Despite its classification as “mild,” mTBI leads to both short- and long-term neurological effects, many of which occur due to functional changes in the brain. TBI-induced environmental changes within the brain play a critical role in shaping these functional outcomes. The importance of astrocytes in maintaining central nervous system (CNS) homeostasis has been increasingly recognized for their pivotal role in the brain’s response to TBI. Previous studies showed significant TBI-associated metabolic dysregulations. Therefore, we sought to analyze how astrocytes might adapt to persistent metabolic stressors in the post-injury microenvironment and identify injury-induced shifts occurring in vivo that may contribute to chronic metabolic dysfunction. We used an astrocyte-specific genome-scale metabolic model that allowed for the input of biologically relevant uptake rates corresponding to healthy astrocytes to analyze how the activity of metabolic pathways differed in hypoxic and acidic conditions. Additionally, these fluxes were integrated with mass spectrometry-based proteomics from male Sprague-Dawley rats subjected to mTBI to identify chronic adaptive neural responses post-injury. Comparison of modeled metabolic fluxes and experimental proteomic data demonstrated remarkable alignment, with both predicting significant changes in key metabolic processes including glycolysis, oxidative phosphorylation, the TCA cycle, and the Pentose Phosphate Pathway. These overlapping signatures may represent core survival strategies, offering insight into metabolic priorities and potentially serving as biomarkers of injury adaptation or recovery capacity.
Effects of exercise-induced low back pain on intrinsic trunk stiffness and paraspinal muscle reflexes
Miller, Emily M.; Bazrgari, Babak; Nussbaum, Maury A.; Madigan, Michael L. (Elsevier, 2012-11-23)
The purpose of this study was to (1) compare trunk neuromuscular behavior between individuals with no history of low back pain (LBP) and individuals who experience exercise-induced LBP (eiLBP) when pain free, and (2) investigate changes in trunk neuromuscular behavior with eiLBP. Seventeen young adult males participated including eight reporting recurrent, acute eiLBP and nine control participants reporting no history of LBP. Intrinsic trunk stiffness and paraspinal muscle reflex delay were determined in both groups using sudden trunk flexion position perturbations 1-2 days following exercise when the eiLBP participants were experiencing an episode of LBP (termed post-exercise) and 4-5 days following exercise when eiLBP had subsided (termed post-recovery). Post-recovery, when the eiLBP group was experiencing minimal LBP, trunk stiffness was 26% higher in the eiLBP group compared to the control group (p=0.033) and reflex delay was not different (p=0.969) between groups. Trunk stiffness did not change (p=0.826) within the eiLBP group from post-exercise to post-recovery, but decreased 22% within the control group (p=0.002). Reflex delay decreased 11% within the eiLBP group from post-exercise to post-recovery (p=0.013), and increased 15% within the control group (p=0.006). Although the neuromuscular mechanisms associated with eiLBP and chronic LBP may differ, these results suggest that previously-reported differences in trunk neuromuscular behavior between individuals with chronic LBP and healthy controls reflect a combination of inherent differences in neuromuscular behavior between these individuals as well as changes in neuromuscular behavior elicited by pain.
Effects of Manual Material Handling Workload on Measures of Fall Risk
Allin, Leigh J.; Madigan, Michael L. (Taylor & Francis, 2020-12-15)
OCCUPATIONAL APPLICATIONS: We found, contrary to expectations, that performing a fatiguing simulated heavy manual material handling (MMH) task did not adversely affect the risk of trip-induced falls when compared to a less-fatiguing light MMH task. However, when considering these MMH tasks together rather than in comparison, our results provide evidence for adverse effects of fatigue on both gait and the ability to recover balance after tripping. The current results provide additional evidence that physical fatigue increases fall risk, start to clarify the mechanisms by which this increase occurs, and can help in developing and evaluating fall prevention strategies targeting these mechanisms.
Burst sine wave electroporation (B-SWE) for expansive blood–brain barrier disruption and controlled non-thermal tissue ablation for neurological disease
Campelo, Sabrina N.; Salameh, Zaid S.; Arroyo, Julio P.; May, James L.; Altreuter, Sara O.; Hinckley, Jonathan; Davalos, Rafael V.; Rossmeisl, John H. Jr. (AIP Publishing, 2024-05-30)
The blood–brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE’s transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond.
Improving Assessment in Kidney Transplantation by Multitask General Path Model
Lan, Qing; Chen, Xiaoyu; Li, Murong; Robertson, John; Lei, Yong; Jin, Ran (2023)
Kidney transplantation helps end-stage patients regain health and quality-of-life. The decisions for matching donor kidneys and recipients affect success of transplantation. However, current kidney matching decision procedures do not consider viability loss during preservation. The objective here is to forecast heterogeneous kidney viability, based on historical datasets to support kidney matching decision-making. Six recently procured porcine kidneys were used to conduct viability assessment experiments to validate the proposed multitask general path model. The model forecasts kidney viability by transferring knowledge from learning the commonality of all kidneys and the heterogeneity of each kidney. The proposed model provides exactly accurate kidney viability forecasting results compared to the state-of-the-art models including a multitask learning model, a general path model, and a general linear model. The proposed model provides satisfactory kidney viability forecasting accuracy because it quantifies the degradation information from trajectory of a viability loss path. It transfers knowledge of common effects from all kidneys and identifies individual effects of each kidney. This method can be readily extended to other decision-making scenarios in kidney transplantation to improve overall assessment performance. For example, analytical generalizations gained by modeling have been validated based on needle biopsy data targeting the improvement of tissue extraction accuracy. The proposed model applied in multiple kidney assessment processes in transplantation can potentially reduce the kidney discard rate by providing effective kidney matching decisions. Thus, the increased kidney utilization rate will benefit more patients and prolong their lives.
Trunk postural control during unstable sitting among individuals with and without low back pain: A systematic review with an individual participant data meta-analysis
Alshehri, Mansour A.; Alzahrani, Hosam; van den Hoorn, Wolbert; Klyne, David M.; Vette, Albert H.; Hendershot, Brad D.; Roberts, Brad W. R.; Larivière, Christian; Barbado, David; Vera-Garcia, Francisco J.; van Dieen, Jaap H.; Cholewicki, Jacek; Nussbaum, Maury A.; Madigan, Michael L.; Reeves, Norman Peter; Silfies, Sheri P.; Brown, Stephen H. M.; Hodges, Paul W. (Public Library of Science, 2024-01-24)
Introduction Sitting on an unstable surface is a common paradigm to investigate trunk postural control among individuals with low back pain (LBP), by minimizing the influence lower extremities on balance control. Outcomes of many small studies are inconsistent (e.g., some find differences between groups while others do not), potentially due to confounding factors such as age, sex, body mass index [BMI], or clinical presentations. We conducted a systematic review with an individual participant data (IPD) meta-analysis to investigate whether trunk postural control differs between those with and without LBP, and whether the difference between groups is impacted by vision and potential confounding factors. Methods We completed this review according to PRISMA-IPD guidelines. The literature was screened (up to 7th September 2023) from five electronic databases: MEDLINE, CINAHL, Embase, Scopus, and Web of Science Core Collection. Outcome measures were extracted that describe unstable seat movements, specifically centre of pressure or seat angle. Our main analyses included: 1) a two-stage IPD meta-analysis to assess the difference between groups and their interaction with age, sex, BMI, and vision on trunk postural control; 2) and a two-stage IPD meta-regression to determine the effects of LBP clinical features (pain intensity, disability, pain catastrophizing, and fear-avoidance beliefs) on trunk postural control. Results Forty studies (1,821 participants) were included for the descriptive analysis and 24 studies (1,050 participants) were included for the IPD analysis. IPD meta-analyses revealed three main findings: (a) trunk postural control was worse (higher root mean square displacement [RMSdispl], range, and long-term diffusion; lower mean power frequency) among individuals with than without LBP; (b) trunk postural control deteriorated more (higher RMSdispl, shortand long-term diffusion) among individuals with than without LBP when vision was removed; and (c) older age and higher BMI had greater adverse impacts on trunk postural control (higher short-term diffusion; longer time and distance coordinates of the critical point) among individuals with than without LBP. IPD meta-regressions indicated no associations between the limited LBP clinical features that could be considered and trunk postural control. Conclusion Trunk postural control appears to be inferior among individuals with LBP, which was indicated by increased seat movements and some evidence of trunk stiffening. These findings are likely explained by delayed or less accurate corrective responses.
Engineered live bacteria as disease detection and diagnosis tools
Tanniche, Imen; Behkam, Bahareh (2023-10-24)
Sensitive and minimally invasive medical diagnostics are essential to the early detection of diseases, monitoring their progression and response to treatment. Engineered bacteria as live sensors are being developed as a new class of biosensors for sensitive, robust, noninvasive, and in situ detection of disease onset at low cost. Akin to microrobotic systems, a combination of simple genetic rules, basic logic gates, and complex synthetic bioengineering principles are used to program bacterial vectors as living machines for detecting biomarkers of diseases, some of which cannot be detected with other sensing technologies. Bacterial whole-cell biosensors (BWCBs) can have wide-ranging functions from detection only, to detection and recording, to closed-loop detection-regulated treatment. In this review article, we first summarize the unique benefits of bacteria as living sensors. We then describe the different bacteria-based diagnosis approaches and provide examples of diagnosing various diseases and disorders. We also discuss the use of bacteria as imaging vectors for disease detection and image-guided surgery. We conclude by highlighting current challenges and opportunities for further exploration toward clinical translation of these bacteria-based systems.
Development of a Synthetic, Injectable Hydrogel to Capture Residual Glioblastoma and Glioblastoma Stem-Like Cells with CXCL12-Mediated Chemotaxis
Khan, Zerin Mahzabin; Munson, Jennifer M.; Long, Timothy E.; Vlaisavljevich, Eli; Verbridge, Scott S. (Wiley, 2023-06)
Glioblastoma (GBM), characterized by high infiltrative capacity, is the most common and deadly type of primary brain tumor in adults. GBM cells, including therapy-resistant glioblastoma stem-like cells (GSCs), invade the healthy brain parenchyma to form secondary tumors even after patients undergo surgical resection and chemoradiotherapy. New techniques are therefore urgently needed to eradicate these residual tumor cells. A thiol-Michael addition injectable hydrogel for compatibility with GBM therapy is previously characterized and optimized. This study aims to develop the hydrogel further to capture GBM/GSCs through CXCL12-mediated chemotaxis. The release kinetics of hydrogel payloads are investigated, migration and invasion assays in response to chemoattractants are performed, and the GBM-hydrogel interactions in vitro are studied. With a novel dual-layer hydrogel platform, it is demonstrated that CXCL12 released from the synthetic hydrogel can induce the migration of U251 GBM cells and GSCs from the extracellular matrix microenvironment and promote invasion into the synthetic hydrogel via amoeboid migration. The survival of GBM cells entrapped deep into the synthetic hydrogel is limited, while live cells near the surface reinforce the hydrogel through fibronectin deposition. This synthetic hydrogel, therefore, demonstrates a promising method to attract and capture migratory GBM cells and GSCs responsive to CXCL12 chemotaxis.
Characterization and structure-property relationships of an injectable thiol-Michael addition hydrogel toward compatibility with glioblastoma therapy
Khan, Zerin Mahzabin; Wilts, Emily; Vlaisavljevich, Eli; Long, Timothy E.; Verbridge, Scott S. (Elsevier, 2022-05-01)
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer and although patients undergo surgery and chemoradiotherapy, residual cancer cells still migrate to healthy brain tissue and lead to tumor relapse after treatment. New therapeutic strategies are therefore urgently needed to better mitigate this tumor recurrence. To address this need, we envision after surgical removal of the tumor, implantable biomaterials in the resection cavity can treat or collect residual GBM cells for their subsequent eradication. To this end, we systematically characterized a poly(ethylene glycol)-based injectable hydrogel crosslinked via a thiol-Michael addition reaction by tuning its hydration level and aqueous NaHCO3 concentration. The physical and chemical properties of the different formulations were investigated by assessing the strength and stability of the polymer networks and their swelling behavior. The hydrogel biocompatibility was assessed by performing in vitro cytotoxicity assays, immunoassays, and immunocytochemistry to monitor the reactivity of astrocytes cultured on the hydrogel surface over time. These characterization studies revealed key structure-property relationships. Furthermore, the results indicated hydrogels synthesized with 0.175 M NaHCO3 and 50 wt% water content swelled the least, possessed a storage modulus that can withstand high intracranial pressures while avoiding a mechanical mismatch, had a sufficiently crosslinked polymer network, and did not degrade rapidly. This formulation was not cytotoxic to astrocytes and produced minimal immunogenic responses in vitro. These properties suggest this hydrogel formulation is the most optimal for implantation in the resection cavity and compatible toward GBM therapy. Statement of significance: Survival times for glioblastoma patients have not improved significantly over the last several decades, as cancer cells remain after conventional therapies and form secondary tumors. We characterized a biodegradable, injectable hydrogel to reveal structure-property relationships that can be tuned to conform the hydrogel toward glioblastoma therapy. Nine formulations were systematically characterized to optimize the hydrogel based on physical, chemical, and biological compatibility with the glioblastoma microenvironment. This hydrogel can potentially be used for adjuvant therapy to glioblastoma treatment, such as by providing a source of molecular release for therapeutic agents, which will be investigated in future work. The optimized formulation will be developed further to capture and eradicate glioblastoma cells with chemical and physical stimuli in future research.
Electroresponsive Hydrogels for Therapeutic Applications in the Brain
Khan, Zerin Mahzabin; Wilts, Emily; Vlaisavljevich, Eli; Long, Timothy E.; Verbridge, Scott S. (Wiley, 2021-12-01)
Electroresponsive hydrogels possess a conducting material component and respond to electric stimulation through reversible absorption and expulsion of water. The high level of hydration, soft elastomeric compliance, biocompatibility, and enhanced electrochemical properties render these hydrogels suitable for implantation in the brain to enhance the transmission of neural electric signals and ion transport. This review provides an overview of critical electroresponsive hydrogel properties for augmenting electric stimulation in the brain. A background on electric stimulation in the brain through electroresponsive hydrogels is provided. Common conducting materials and general techniques to integrate them into hydrogels are briefly discussed. This review focuses on and summarizes advances in electric stimulation of electroconductive hydrogels for therapeutic applications in the brain, such as for controlling delivery of drugs, directing neural stem cell differentiation and neurogenesis, improving neural biosensor capabilities, and enhancing neural electrode-tissue interfaces. The key challenges in each of these applications are discussed and recommendations for future research are also provided.
In-Season Concussion Symptom Reporting in Male and Female Collegiate Rugby Athletes
Kieffer, Emily E.; Brolinson, Per Gunnar; Maerlender, Arthur C.; Smith, Eric P.; Rowson, Steven (2021-11-01)
Symptom inventories are generally only collected after a suspected concussion, but regular in-season monitoring may allude to clinical symptoms associated with repetitive subconcussive impacts and potential undiagnosed concussions. Despite sex-specific differences in symptom presentation and outcome of concussion, no return-to-play protocol takes sex into account. The objective of this study was to monitor a cohort of contact-sport athletes and compare the frequency and severity of in-season concussion-like symptom reporting between sexes. Graded symptom checklists from 144 female and 104 male athlete-seasons were administered weekly to quantify the effect of subconcussive impacts on frequency and severity of in-season symptom reporting. In-season, mean symptom severity score (SSS) (p = 0.026, mean difference of 1.8), mean number of symptoms (p = 0.044, mean difference of 0.9), max SSS (p < 0.001, mean difference of 19.2), and max number of symptoms (p < 0.001, mean difference of 6.8) were higher in the females. The females' survey results showed differences between elevated and concussed SSS (p < 0.005, mean difference of 28.1) and number of symptoms reported (p = 0.001, mean difference of 6.6). The males did not have a difference in SSS (p = 0.97, mean difference of 1.12) nor in number of symptoms (p = 0.35, mean difference of 1.96) from elevated to concussed athletes. Rugby players report concussion-like symptoms in the absence of a diagnosed concussion in-season. Female athletes reported elevated symptom frequencies with greater severities than the males, but both sexes reported considerable levels throughout the season.
Harnessing Tissue Engineering Tools to Interrogate Host-Microbiota Crosstalk in Cancer
Udayasuryan, Barath; Nguyen, Tam T. D.; Slade, Daniel J.; Verbridge, Scott S. (Cell Press, 2020-12-18)
Recent studies have begun to highlight the diverse and tumor-specific microbiomes across multiple cancer types. We believe this work raises the important question of whether the classical “Hallmarks of Cancer” should be expanded to include tumor microbiomes. To answer this question, the causal relationships and co-evolution of these microbiotic tumor ecosystems must be better understood. Because host-microbe interactions should be studied in a physiologically relevant context, animal models have been preferred. Yet these models are often poor mimics of human tumors and are difficult to interrogate at high spatiotemporal resolution. We believe that in vitro tissue engineered platforms could provide a powerful alternative approach that combines the high-resolution of in vitro studies with a high degree of physiological relevance. This review will focus on tissue engineered approaches to study host-microbe interactions and to establish their role as an emerging hallmark of cancer with potential as a therapeutic target.

Browse

Recent Submissions