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Open access publications by faculty, postdocs, and graduate students in the Department of Biomedical Engineering.
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Item A Dynamic Gradient Stiffness Material Platform to Manipulate Cardiac Fibroblasts' Spatio-Temporal Behavior(Advanced Functional Materials, 2024-04-05) Cao, Zheng; Clark, Andy T.; Vite, Alexia; Corbin, Elise A.After myocardial infarction, there exists a spatiotemporal variation of cardiac tissue stiffness across the infarcted border region outward to remote regions, influencing adverse remodeling and cardiac fibrosis, and this stiffness gradient changes over time. Here, a platform with dynamic, tunable, and reversible gradient stiffness can recapitulate in vitro the time-dependent stiffness range across the infarction border that occurs as part of the remodeling process is presented. This platform enables the observation of time-dependent interaction between cardiac fibroblasts and their mechanical microenvironment in a spatiotemporal manner. Specifically, the competition and cooperation of a chemical cue (antifibrotic drug) and mechanical cue (gradient softening) in tandem to attenuate the fibrotic responses of cardiac fibroblasts is examined. Applying a combined intervention showed either additive or antagonistic effects on fibrosis-related gene regulation compared to separate interventions of drug or softening. This work reveals the spatiotemporal variation of fibrotic response in cardiac fibroblasts as well as the complexity of antifibrotic drug dosing with stiffness changes and their combinatory effect on cardiac fibroblasts. This platform provides a unique in vitro tool to study disease progression mechanisms in a more clinically relevant microenvironment and also serves as a cost-effective model for potential therapeutic screening.Item Adaptive Functional Electrical Stimulation Delivers Stimulation Amplitudes Based on Real-Time Gait Biomechanics(Journal of Medical Devices, 2024-05-21) Donlin, Margo C.; Higginson, Jill S.Functional electrical stimulation (FES) is often used in poststroke gait rehabilitation to decrease foot drop and increase forward propulsion. However, not all stroke survivors experience clinically meaningful improvements in gait function following training with FES. The purpose of this work was to develop and validate a novel adaptive FES (AFES) system to improve dorsiflexor (DF) and plantarflexor (PF) stimulation timing and iteratively adjust the stimulation amplitude at each stride based on measured gait biomechanics. Stimulation timing was determined by a series of bilateral footswitches. Stimulation amplitude was calculated based on measured dorsiflexion angle and peak propulsive force, where increased foot drop and decreased paretic propulsion resulted in increased stimulation amplitudes. Ten individuals with chronic poststroke hemiparesis walked on an adaptive treadmill with adaptive FES for three 2-min trials. Stimulation was delivered at the correct time to the dorsiflexor muscles during 95% of strides while stimulation was delivered to the plantarflexor muscles at the correct time during 84% of strides. Stimulation amplitudes were correctly calculated and delivered for all except two strides out of nearly 3000. The adaptive FES system responds to real-time gait biomechanics as intended, and further individualization to subject-specific impairments and rehabilitation goals may lead to improved rehabilitation outcomes.Item Altered brain functional connectivity in the frontoparietal network following an ice hockey season(European Journal of Sport Science, 2022-05-08) DiFabio, Melissa S.; Smith, Daniel R.; Breedlove, Katherine M.; Pohlig, Ryan T.; Buckley, Thomas A.; Johnson, Curtis L.Sustaining sports-related head impacts has been reported to result in neurological changes that potentially lead to later-life neurological disease. Advanced neuroimaging techniques have been used to detect subtle neurological effects resulting from head impacts, even after a single competitive season. The current study used resting-state functional magnetic resonance imaging to assess changes in functional connectivity of the frontoparietal network, a brain network responsible for executive functioning, in collegiate club ice hockey players over one season. Each player was scanned before and after the season and wore accelerometers to measure head impacts at practices and home games throughout the season. We examined pre- to post-season differences in connectivity within the frontoparietal and default mode networks, as well as the relationship between the total number of head impacts sustained and changes in connectivity. We found a significant interaction between network region of interest and time point (p = .016), in which connectivity between the left and right posterior parietal cortex seed regions increased over the season (p < .01). Number of impacts had a significant effect on frontoparietal network connectivity, such that more impacts were related to greater connectivity differences over the season (p = .042). Overall, functional connectivity increased in ice hockey athletes over a season between regions involved in executive functioning, and sensory integration, in particular. Furthermore, those who sustained more impacts had the greatest changes in connectivity. Consistent with prior findings in resting-state sports-related head impact literature, these findings have been suggested to represent brain injury. Highlights: Functional connectivity of the frontoparietal network significantly increased between the pre- and post-season, which may be a compensatory mechanism driven by neural tissue injury caused by repetitive head impacts. Changes in frontoparietal network connectivity are related to head impact exposure, measured as the number of head impacts sustained in a single season. Functional connectivity of the default mode network did not change over an ice hockey season.Item Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer(Advanced Therapeutics, 2024-04-26) Dang, Megan N.; Suri, Sejal; Li, Kejian; Gomez Casas, Carolina; Stigliano, Gianna; Riley, Rachel S.; Scully, Mackenzie A.; Hoover, Elise C.; Aboeleneen, Sara B.; Kramarenko, George C.; Day, Emily S.The paucity of targeted therapies for triple-negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular β-catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis. To suppress Wnt signaling in TNBC cells, this work develops therapeutic nanoparticles (NPs) functionalized with FZD7 antibodies and β-catenin small interfering RNAs (siRNAs). The antibodies enable TNBC cell specific binding and inhibit Wnt signaling by locking FZD7 receptors in a ligand unresponsive state, while the siRNAs suppress β-catenin through RNA interference. Compared to NPs coated with antibodies or siRNAs individually, NPs coated with both agents more potently reduce the expression of several Wnt related genes in TNBC cells, leading to greater inhibition of cell proliferation, migration, and spheroid formation. In two murine models of metastatic TNBC, the dual antibody/siRNA nanocarriers outperformed controls in terms of inhibiting tumor growth, metastasis, and recurrence. These findings demonstrate suppressing Wnt signaling at both the receptor and mRNA levels via antibody/siRNA nanocarriers is a promising approach to combat TNBC.Item Antibody-nanoparticle conjugates to enhance the sensitivity of ELISA-based detection methods(Public Library of Science (PLOS), 2017-05-11) Billingsley, Margaret M.; Riley, Rachel S.; Day, Emily S.; Margaret M. Billingsley, Rachel S. Riley, Emily S. Day; Billingsley, Margaret M.; Riley, Rachel S.; Day, Emily S.Accurate antigen detection is imperative for clinicians to diagnose disease, assess treatment success, and predict patient prognosis. The most common technique used for the detection of disease-associated biomarkers is the enzyme linked immunosorbent assay (ELISA). In an ELISA, primary antibodies are incubated with biological samples containing the biomarker of interest. Then, detectible secondary antibodies conjugated with horseradish peroxidase (HRP) bind the primary antibodies. Upon addition of a color-changing substrate, the samples provide a colorimetric signal that directly correlates to the targeted biomarker concentration. While ELISAs are effective for analyzing samples with high biomarker content, they lack the sensitivity required to analyze samples with low antigen levels. We hypothesized that the sensitivity of ELISAs could be enhanced by replacing freely delivered primary antibodies with antibody-nanoparticle conjugates that provide excess binding sites for detectible secondary antibodies, ultimately leading to increased signal. Here, we investigated the use of nanoshells (NS) decorated with antibodies specific to epidermal growth factor receptor (EGFR) as a model system (EGFR-NS). We incubated one healthy and two breast cancer cell lines, each expressing different levels of EGFR, with EGFR-NS, untargeted NS, or unconjugated EGFR antibodies, as well as detectable secondary antibodies. We found that EGFR-NS consistently increased signal intensity relative to unconjugated EGFR antibodies, with a substantial 13-fold enhancement from cells expressing high levels of EGFR. Additionally, 40x more unconjugated antibodies were required to detect EGFR compared to those conjugated to NS. Our results demonstrate that antibody-nanoparticle conjugates lower the detection limit of traditional ELISAs and support further investigation of this strategy with other antibodies and nanoparticles. Owing to their enhanced sensitivity, we anticipate that nanoparticle-modified ELISAs can be used to detect low levels of biomarkers found in various diseases, such as cancers, tuberculosis, and rheumatoid arthritis, and may ultimately enable earlier diagnosis, better prognostication, and improved treatment monitoringItem Biomimetic Substrate to Probe Dynamic Interplay of Topography and Stiffness on Cardiac Fibroblast Activation(ACS Omega, 2023-02-14) Cao, Zheng; Ball, Jacob K.; Lateef, Ali H.; Virgile, Connor P.; Corbin, Elise A.Materials with the ability to change properties can expand the capabilities of in vitro models of biological processes and diseases as it has become increasingly clear that static, stiff materials with smooth surfaces fall short in recapitulating the in vivo cellular microenvironment. Here, we introduce a patterned material that can be rapidly stiffened and softened in situ in response to an external magnetic field through the addition of magnetic inclusions into a soft silicone elastomer with topographic surface patterning. This substrate can be used for cell culture to investigate short-term cellular responses to dynamic stiffening or softening and the interaction with topography that encourages cells to assume a specific morphology. We investigated short-term cellular responses to dynamic stiffening or softening in human ventricular cardiac fibroblasts. Our results indicate that the combination of dynamic changes in stiffness with and without topographic cues induces different effects on the alignment and activation or deactivation of myofibroblasts. Cells cultured on patterned substrates exhibited a more aligned morphology than cells cultured on flat material; moreover, cell alignment was not dependent on substrate stiffness. On a patterned substrate, there was no significant change in the number of activated myofibroblasts when the material was temporally stiffened, but temporal softening caused a significant decrease in myofibroblast activation (50% to 38%), indicating a competing interaction of these characteristics on cell behavior. This material provides a unique in vitro platform to observe the time-dependent dynamics of cells by better mimicking more complex behaviors and realistic microenvironments for investigating biological processes, such as the development of fibrosis.Item Can axial loading restore in vivo disc geometry, opening pressure, and T2 relaxation time?(JOR Spine, 2024-04-25) Newman, Harrah R.; Moore, Axel C.; Meadows, Kyle D.; Hilliard, Rachel L.; Boyes, Madeline S.; Vresilovic, Edward J.; Schaer, Thomas P.; Elliott, Dawn M.Background Cadaveric intervertebral discs are often studied for a variety of research questions, and outcomes are interpreted in the in vivo context. Unfortunately, the cadaveric disc does not inherently represent the LIVE condition, such that the disc structure (geometry), composition (T2 relaxation time), and mechanical function (opening pressure, OP) measured in the cadaver do not necessarily represent the in vivo disc. Methods We conducted serial evaluations in the Yucatan minipig of disc geometry, T2 relaxation time, and OP to quantify the changes that occur with progressive dissection and used axial loading to restore the in vivo condition. Results We found no difference in any parameter from LIVE to TORSO; thus, within 2 h of sacrifice, the TORSO disc can represent the LIVE condition. With serial dissection and sample preparation the disc height increased (SEGMENT height 18% higher than TORSO), OP decreased (POTTED was 67% lower than TORSO), and T2 time was unchanged. With axial loading, an imposed stress of 0.20–0.33 MPa returned the disc to in vivo, LIVE disc geometry and OP, although T2 time was decreased. There was a linear correlation between applied stress and OP, and this was conserved across multiple studies and species. Conclusion To restore the LIVE disc state in human studies or other animal models, we recommend measuring the OP/stress relationship and using this relationship to select the applied stress necessary to recover the in vivo condition.Item Cholesterol-substituted 3,4-ethylenedioxythiophene (EDOT-MA-cholesterol) and Poly(3,4-ethylenedioxythiophene) (PEDOT-MA-cholesterol)(Giant, 2023-05-23) Wu, Yuhang; Nagane, Samadhan S.; Baugh, Quintin; Lo, Chun-Yuan; Chhatre, Shrirang S.; Lee, Junghyun; Sitarik, Peter; Kayser, Laure V.; Martin, David C.Cholesterol is a rigid, crystalline, non-polar natural substance that exists in animal blood and cell membranes. Some of its derivatives are known to form ordered liquid crystalline mesophases under suitable conditions. In this work, we carefully examined the influence of cholesterol substitution on the characteristics of 3,4-ethylenedioxythiophene (EDOT-MA-cholesterol) and its corresponding polymer poly(3,4-ethylenedioxythiophene) (PEDOT-MA-cholesterol) synthesized by both chemical and electrochemical polymerization. We found evidence for an ordered lamellar (smectic-like) structure in the EDOT-MA-cholesterol monomer by differential scanning calorimetry (DSC), polarized optical microscopy (POM), and X-ray diffraction techniques. The ordered phase was observed to form on cooling from the isotropic melt at about 80 °C. Due to the insulating and bulky cholesterol side group on the EDOT monomer, we found that there was a maximum charge density for electrodeposition at ∼ 0.155 C.cm−2. A series of electrodepositions were performed from 0 to 0.155 C.cm−2 for probing the change of the charge transport with more charges used for the electrodeposition. We found that the impedance increased in the high-frequency range (above 104 Hz) and decreased in the low-frequency range (below 102 Hz). Three equivalent circuit models were proposed for fitting impedance data at different charge densities for a better understanding of the film growth process. The suppressed cyclic voltammogram (CV) of PEDOT-MA-cholesterol showed that the charge storage capability was essentially eliminated in the thickest films. The limited doping of the films was corroborated by their diminished electrochromic behavior, polaron-dominating absorption in UV-vis, overoxidized S 2p X-ray Photoelectron Spectroscopy (XPS) signal of electrodeposited films, and proton Nuclear Magnetic Resonance (1H NMR) of chemically polymerized samples. Dense film morphologies were confirmed by scanning electron microscopy (SEM). Grazing incident X-ray diffraction (GIWAXS) indicated the disrupted stacking of conjugated chains, which correlated with the decreased conductivity of the PEDOT-MA-cholesterol films. The measurement of the electrical conductivity gave a value of around 3.30 × 10−6 S.cm−1 which is about six orders of magnitude lower than has been seen in PEDOT (∼3 S.cm-1). Graphical abstract available at: https://doi.org/10.1016/j.giant.2023.100163Item Combination cancer imaging and phototherapy mediated by membrane-wrapped nanoparticles(International Journal of Hyperthermia, 2023-10-30) Aboeleneena, Sara B.; Scully, Mackenzie A.; Kramarenko, George C.; Day, Emily S.Cancer is a devastating health problem with inadequate treatment options. Many conventional treatments for solid-tumor cancers lack tumor specificity, which results in low efficacy and off-target damage to healthy tissues. Nanoparticle (NP)-mediated photothermal therapy (PTT) is a promising minimally invasive treatment for solid-tumor cancers that has entered clinical trials. Traditionally, NPs used for PTT are coated with passivating agents and/or targeting ligands, but alternative coatings are being explored to enhance tumor specific delivery. In particular, cell-derived membranes have emerged as promising coatings that improve the biointerfacing of photoactive NPs, which reduces their immune recognition, prolongs their systemic circulation and increases their tumor accumulation, allowing for more effective PTT. To maximize treatment success, membrane-wrapped nanoparticles (MWNPs) that enable dual tumor imaging and PTT are being explored. These multifunctional theranostic NPs can be used to enhance tumor detection and/or ensure a sufficient quantity of NPs that have arrived in the tumor prior to laser irradiation. This review summarizes the current state-of-the-art in engineering MWNPs for combination cancer imaging and PTT and discusses considerations for the path toward clinical translation.Item Connecting clinical, environmental, and genetic factors point to an essential role for vitamin A signaling in the pathogenesis of congenital diaphragmatic hernia(American Journal of Physiology - Lung Cellular and Molecular Physiology, 2023-04-01) Gilbert, Rachel M.; Gleghorn, and Jason P.Congenital diaphragmatic hernia (CDH) is a developmental disorder that results in incomplete diaphragm formation, pulmonary hypoplasia, and pulmonary hypertension. Although a variety of genes have been linked to its etiology, CDH is not a monogenetic disease, and the cause of the condition is still unclear in the vast majority of clinical cases. By comparing human clinical data and experimental rodent data from the literature, we present clear support demonstrating the importance of vitamin A (vitA) during the early window of pregnancy when the diaphragm and lung are forming. Alteration of vitA signaling via dietary and genetic perturbations can create diaphragmatic defects. Unfortunately, vitA deficiency is chronic among people of child-bearing age, and this early window of diaphragm development occurs before many might be aware of pregnancy. Furthermore, there is an increased demand for vitA during this critical period, which exacerbates the likelihood of deficiency. It would be beneficial for the field to further investigate the connections between maternal vitA and CDH incidence, with the goal of determining vitA status as a CDH risk factor. Regular clinical monitoring of vitA levels in child-bearing years is a tractable method by which CDH outcomes could be prevented or improved.Item Correlated noise in brain magnetic resonance elastography(Magnetic Resonance in Medicine, 2021-10-22) Hannum, Ariel J.; McIlvain, Grace; Sowinski, Damian; McGarry, Matthew D. J.; Johnson, Curtis L.Purpose: Magnetic resonance elastography (MRE) uses phase-contrast MRI to generate mechanical property maps of the in vivo brain through imaging of tissue deformation from induced mechanical vibration. The mechanical property estimation process in MRE can be susceptible to noise from physiological and mechanical sources encoded in the phase, which is expected to be highly correlated. This correlated noise has yet to be characterized in brain MRE, and its effects on mechanical property estimates computed using inversion algorithms are undetermined. Methods: To characterize the effects of signal noise in MRE, we conducted 3 experiments quantifying (1) physiomechanical sources of signal noise, (2) physiological noise because of cardiac-induced movement, and (3) impact of correlated noise on mechanical property estimates. We use a correlation length metric to estimate the extent that correlated signal persists in MRE images and demonstrate the effect of correlated noise on property estimates through simulations. Results: We found that both physiological noise and vibration noise were greater than image noise and were spatially correlated across all subjects. Added physiological and vibration noise to simulated data resulted in property maps with higher error than equivalent levels of Gaussian noise. Conclusion: Our work provides the foundation to understand contributors to brain MRE data quality and provides recommendations for future work to correct for signal noise in MRE.Item E-Selectin Targeted Gold Nanoshells to Inhibit Breast Cancer Cell Binding to Lung Endothelial Cells(ACS Applied Nano Material, 2023-01-27) Fereshteh, Z.; Dang, M. N.; Wenck, C.; Day, E. S.; Slater, J. H.Extravasation of circulating tumor cells (CTCs) from the vasculature is a key step in cancer metastasis. CTCs bind to cell adhesion molecules (CAMs) expressed by endothelial cells (ECs) for flow arrest prior to extravasation. While a number of EC-expressed CAMs have been implicated in facilitating CTC binding, this work investigated the efficacy of inhibiting cancer cell binding to human lung microvascular ECs via antibody blocking of E-selectin using antibody-functionalized gold nanoshells (NS). The antibody-functionalized gold NS were synthesized using both directional and non-directional antibody conjugation techniques with variations in synthesis parameters (linker length, amount of passivating agents, and ratio of antibodies to NS) to gain a better understanding of these properties on the resultant hydrodynamic diameter, zeta potential, and antibody loading density. We quantified the ability of E-selectin antibody-functionalized NS to bind human lung microvascular endothelial cells (HMVEC-Ls) under non-inflamed and inflamed (TNF-α) conditions to inhibit binding of triple-negative MDA-MB-231s. E-selectin-targeted NS prepared using non-directional conjugation had higher antibody loading than those prepared via directional conjugation, resulting in the conjugates having similar overall binding to HMVEC-Ls at a given antibody concentration. E-selectin-targeted NS reduced MDA-MB-231 binding to HMVEC-Ls by up to 41% as determined using an in vitro binding assay. These results provide useful insights into the characteristics of antibody-functionalized NS prepared under different conditions while also demonstrating proof of concept that these conjugates hold potential to inhibit CTC binding to ECs, a critical step in extravasation during metastasis.Item Foldable and Cytocompatible Sol-gel TiO2 Photonics(Nature Publishing Group, 2015-09-07) Li, Lan; Zhang, Ping; Wang, Wei-Ming; Lin, Hongtao; Zerdoum, Aidan B.; Geiger, Sarah J.; Liu, Yangchen; Xiao, Nicholas; Zou, Yi; Ogbuu, Okechukwu; Du, Qingyang; Jia, Xinqiao; Li, Jingjing; Hu, Juejun; Lan Li, Ping Zhang, Wei-Ming Wang, Hongtao Lin, Aidan B. Zerdoum, Sarah J. Geiger, Yangchen Liu, Nicholas Xiao, Yi Zou, Okechukwu Ogbuu, Qingyang Du, Xinqiao Jia, Jingjing Li & Juejun Hu; Li,Lan; Lin, Hongtao; Zerdoum, Aidan B; Geiger, Sarah J.; Liu, Yangchen; Xiao, Nicholas; Zou, Yi; Ogbuu, Okechukwu; Du, Qingyang; Jia, Xinqiao; Hu, JuejunIntegrated photonics provides a miniaturized and potentially implantable platform to manipulate and enhance the interactions between light and biological molecules or tissues in in-vitro and in-vivo settings, and is thus being increasingly adopted in a wide cross-section of biomedical applications ranging from disease diagnosis to optogenetic neuromodulation. However, the mechanical rigidity of substrates traditionally used for photonic integration is fundamentally incompatible with soft biological tissues. Cytotoxicity of materials and chemicals used in photonic device processing imposes another constraint towards these biophotonic applications. Here we present thin film TiO2 as a viable material for biocompatible and flexible integrated photonics. Amorphous TiO2 films were deposited using a low temperature (<250 °C) sol-gel process fully compatible with monolithic integration on plastic substrates. High-index-contrast flexible optical waveguides and resonators were fabricated using the sol-gel TiO2 material, and resonator quality factors up to 20,000 were measured. Following a multi-neutral-axis mechanical design, these devices exhibit remarkable mechanical flexibility, and can sustain repeated folding without compromising their optical performance. Finally, we validated the low cytotoxicity of the sol-gel TiO2 devices through in-vitro cell culture tests. These results demonstrate the potential of sol-gel TiO2 as a promising material platform for novel biophotonic devices.Item Fundamental limits of parasitoid-driven host population suppression: Implications for biological control(PLoS ONE, 2023-12-22) Singh, AbhyudaiParasitoid wasps are increasingly being used to control insect pest populations, where the pest is the host species parasitized by the wasp. Here we use the discrete-time formalism of the Nicholson-Bailey model to investigate a fundamental question—are there limits to parasitoid-driven suppression of the host population density while still ensuring a stable coexistence of both species? Our model formulation imposes an intrinsic self-limitation in the host’s growth resulting in a carrying capacity in the absence of the parasitoid. Different versions of the model are considered with parasitism occurring at a developmental stage that is before, during, or after the growth-limiting stage. For example, the host’s growth limitation may occur at its larval stage due to intraspecific competition, while the wasps attack either the host egg, larval or pupal stage. For slow-growing hosts, models with parasitism occurring at different life stages are identical in terms of their host suppression dynamics but have contrasting differences for fast-growing hosts. In the latter case, our analysis reveals that wasp parasitism occurring after host growth limitation yields the lowest pest population density conditioned on stable host-parasitoid coexistence. For ecologically relevant parameter regimes we estimate this host suppression to be roughly 10-20% of the parasitoid-free carrying capacity. We further expand the models to consider a fraction of hosts protected from parasitism (i.e., a host refuge). Our results show that for a given host reproduction rate there exists a critical value of protected host fraction beyond which, the system dynamics are stable even for high levels of parasitism that drive the host to arbitrary low population densities. In summary, our systematic analysis sheds key insights into the combined effects of density-dependence in host growth and parasitism refuge in stabilizing the host-parasitoid population dynamics with important implications for biological control.Item FZD7-Targeted Nanoparticles to Enhance Doxorubicin Treatment of Triple-Negative Breast Cancer(ACS Omega, 2024-03-16) Hoover, Elise C.; Ruggiero, Olivia M.; Swingler, Rachel N.; Day, Emily S.Doxorubicin (DOX) is a chemotherapy agent commonly used to treat triple-negative breast cancer (TNBC), but it has insufficient efficacy against the disease and considerable toxicity due to its off-target delivery. To improve the specificity of DOX for TNBC, we encapsulated it in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) coated with antibodies against Frizzled7 (FZD7), a receptor that is overexpressed on TNBC cells and which is a key activator of the Wnt signaling pathway. In vitro studies show that DOX encapsulation does not hinder its ability to localize to the nucleus in human TNBC cell cultures and that DOX delivered via NPs induces apoptosis and DNA damage via H2A.X phosphorylation to the same degree as freely delivered DOX. FZD7-targeted NPs delivering DOX caused significantly greater inhibition of metabolic activity and led to a smaller cell population following treatment when compared to freely delivered DOX or DOX-loaded NPs coated only with poly(ethylene glycol) (PEG). The FZD7 antibodies additionally provided significant levels of Wnt pathway inhibition, as demonstrated by an increase in β-catenin phosphorylation, indicative of β-catenin destruction and downregulation. These results show that FZD7-targeted platforms have great promise for improving the therapeutic window of otherwise toxic chemotherapies like DOX in TNBC and other cancers that display the overexpression of FZD7 receptors.Item Genome-wide screening reveals metabolic regulation of stop-codon readthrough by cyclic AMP(Nucleic Acids Research, 2023-09-06) Lyu, Zhihui; Villanueva, Patricia; O’Malley, Liam; Murphy, Parker; Augenstreich, Jacques; Briken, Volker; Singh, Abhyudai; Ling, JiqiangTranslational fidelity is critical for microbial fitness, survival and stress responses. Much remains unknown about the genetic and environmental control of translational fidelity and its single-cell heterogeneity. In this study, we used a high-throughput fluorescence-based assay to screen a knock-out library of Escherichia coli and identified over 20 genes critical for stop-codon readthrough. Most of these identified genes were not previously known to affect translational fidelity. Intriguingly, we show that several genes controlling metabolism, including cyaA and crp, enhance stop-codon readthrough. CyaA catalyzes the synthesis of cyclic adenosine monophosphate (cAMP). Combining RNA sequencing, metabolomics and biochemical analyses, we show that deleting cyaA impairs amino acid catabolism and production of ATP, thus repressing the transcription of rRNAs and tRNAs to decrease readthrough. Single-cell analyses further show that cAMP is a major driver of heterogeneity in stop-codon readthrough and rRNA expression. Our results highlight that carbon metabolism is tightly coupled with stop-codon readthrough. Graphical Abstract available at: https://doi.org/10.1093/nar/gkad725Item Growth factors and growth factor gene therapies for treating chronic wounds(Bioengineering and Translational Medicine, 2023-12-28) Mullin, James A.; Rahmani, Erfan; Kiick, Kristi L.; Sullivan, Millicent O.Chronic wounds are an unmet clinical need affecting millions of patients globally, and current standards of care fail to consistently promote complete wound closure and prevent recurrence. Disruptions in growth factor signaling, a hallmark of chronic wounds, have led researchers to pursue growth factor therapies as potential supplements to standards of care. Initial studies delivering growth factors in protein form showed promise, with a few formulations reaching clinical trials and one obtaining clinical approval. However, protein-form growth factors are limited by instability and off-target effects. Gene therapy offers an alternative approach to deliver growth factors to the chronic wound environment, but safety concerns surrounding gene therapy as well as efficacy challenges in the gene delivery process have prevented clinical translation. Current growth factor delivery and gene therapy approaches have primarily used single growth factor formulations, but recent efforts have aimed to develop multi-growth factor approaches that are better suited to address growth factor insufficiencies in the chronic wound environment, and these strategies have demonstrated improved efficacy in preclinical studies. This review provides an overview of chronic wound healing, emphasizing the need and potential for growth factor therapies. It includes a summary of current standards of care, recent advances in growth factor, cell-based, and gene therapy approaches, and future perspectives for multi-growth factor therapeutics. Translational Impact Statement Chronic wounds persist as a healthcare challenge despite extensive research on various treatments, including growth factors and gene therapies. Progress in translating these therapeutics to clinical use has been slow, with many growth factor approaches demonstrating promise in preclinical studies but providing limited benefits in clinical trials or clinical application. This review presents recent advances in growth factor therapies and growth factor gene therapies, discusses obstacles to regulatory approval, and offers perspectives on potential innovations for successful clinical translation.Item Imidazolium-Based Sulfonating Agent to Control the Degree of Sulfonation of Aromatic Polymers and Enable Plastics-to-Electronics Upgrading(JACS Au, 2024-07-03) Lo, Chun-Yuan; Koutsoukos, Kelsey P.; Nguyen, Dan My; Wu, Yuhang; Angel Trujillo, David Alejandro; Miller, Tabitha; Shrestha, Tulaja; Mackey, Ethan; Damani, Vidhika S.; Kanbur, Uddhav; Opila, Robert; Martin, David C.; Kaphan, David; Kayser, Laure V.The accumulation of plastic waste in the environment is a growing environmental, economic, and societal challenge. Plastic upgrading, the conversion of low-value polymers to high-value materials, could address this challenge. Among upgrading strategies, the sulfonation of aromatic polymers is a powerful approach to access high-value materials for a range of applications, such as ion-exchange resins and membranes, electronic materials, and pharmaceuticals. While many sulfonation methods have been reported, achieving high degrees of sulfonation while minimizing side reactions that lead to defects in the polymer chains remains challenging. Additionally, sulfonating agents are most often used in large excess, which prevents precise control over the degree of sulfonation of aromatic polymers and their functionality. Herein, we address these challenges using 1,3-disulfonic acid imidazolium chloride ([Dsim]Cl), a sulfonic acid-based ionic liquid, to sulfonate aromatic polymers and upgrade plastic waste to electronic materials. We show that stoichiometric [Dsim]Cl can effectively sulfonate model polystyrene up to 92% in high yields, with minimal defects and high regioselectivity for the para position. Owing to its high reactivity, the use of substoichiometric [Dsim]Cl uniquely allows for precise control over the degree of sulfonation of polystyrene. This approach is also applicable to a wide range of aromatic polymers, including waste plastic. To prove the utility of our approach, samples of poly(styrene sulfonate) (PSS), obtained from either partially sulfonated polystyrene or expanded polystyrene waste, are used as scaffolds for poly(3,4-ethylenedioxythiophene) (PEDOT) to form the ubiquitous conductive material PEDOT:PSS. PEDOT:PSS from plastic waste is subsequently integrated into organic electrochemical transistors (OECTs) or as a hole transport layer (HTL) in a hybrid solar cell and shows the same performance as commercial PEDOT:PSS. This imidazolium-mediated approach to precisely sulfonating aromatic polymers provides a pathway toward upgrading postconsumer plastic waste to high-value electronic materials.Item In vivo estimation of anisotropic mechanical properties of the gastrocnemius during functional loading with MR elastography(Physics in Medicine & Biology, 2023-02-06) Smith, Daniel R.; Caban-Rivera, Diego A.; Williams, L. Tyler; Van Houten, Elijah E. W.; Bayly, Phil V.; Paulsen, Keith D.; McGarry, Matthew D. J.; Johnson, Curtis L.Objective. In vivo imaging assessments of skeletal muscle structure and function allow for longitudinal quantification of tissue health. Magnetic resonance elastography (MRE) non-invasively quantifies tissue mechanical properties, allowing for evaluation of skeletal muscle biomechanics in response to loading, creating a better understanding of muscle functional health. Approach. In this study, we analyze the anisotropic mechanical response of calf muscles using MRE with a transversely isotropic, nonlinear inversion algorithm (TI-NLI) to investigate the role of muscle fiber stiffening under load. We estimate anisotropic material parameters including fiber shear stiffness (${\mu }_{1}$), substrate shear stiffness (${\mu }_{2}$), shear anisotropy ($\phi $), and tensile anisotropy ($\zeta $) of the gastrocnemius muscle in response to both passive and active tension. Main results. In passive tension, we found a significant increase in ${\mu }_{1},$ $\phi ,$ and $\zeta $ with increasing muscle length. While in active tension, we observed increasing ${\mu }_{2}$ and decreasing $\phi $ and $\zeta $ during active dorsiflexion and plantarflexion—indicating less anisotropy—with greater effects when the muscles act as agonist. Significance. The study demonstrates the ability of this anisotropic MRE method to capture the multifaceted mechanical response of skeletal muscle to tissue loading from muscle lengthening and contraction.Item Individual Muscle Force Estimation in the Human Forearm Using Multi-Muscle MR Elastography (MM-MRE)(IEEE Transactions on Biomedical Engineering, 2023-06-06) Smith, Daniel R.; Helm, Cody A.; Zonnino, Andrea; McGarry, Matthew D.J.; Johnson, Curtis L.; Sergi, FabrizioObjective: To establish the sensitivity of magnetic resonance elastography (MRE) to active muscle contraction in multiple muscles of the forearm. Methods: We combined MRE of forearm muscles with an MRI-compatible device, the MREbot, to simultaneously measure the mechanical properties of tissues in the forearm and the torque applied by the wrist joint during isometric tasks. We measured shear wave speed of thirteen forearm muscles via MRE in a series of contractile states and wrist postures and fit these outputs to a force estimation algorithm based on a musculoskeletal model. Results: Shear wave speed changed significantly upon several factors, including whether the muscle was recruited as an agonist or antagonist (p = 0.0019), torque amplitude (p = <0.0001), and wrist posture (p = 0.0002). Shear wave speed increased significantly during both agonist (p = <0.0001) and antagonist (p = 0.0448) contraction. Additionally, there was a greater increase in shear wave speed at greater levels of loading. The variations due to these factors indicate the sensitivity to functional loading of muscle. Under the assumption of a quadratic relationship between shear wave speed and muscle force, MRE measurements accounted for an average of 70% of the variance in the measured joint torque. Conclusion: This study shows the ability of MM-MRE to capture variations in individual muscle shear wave speed due to muscle activation and presents a method to estimate individual muscle force through MM-MRE derived measurements of shear wave speed. Significance: MM-MRE could be used to establish normal and abnormal muscle co-contraction patterns in muscles of the forearm controlling hand and wrist function.
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