Scholarly Works, Biomedical Engineering and Mechanics

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Effects of a low-cost prosthetic knee on amputee gait over uneven and even terrains
Aviles, Jessica; Castleberry, Julia; Madigan, Michael L. (Wolters Kluwer Health, 2024-11-05)
Limited data are available related to using a low-cost prosthetic knee while walking. To address this gap, this study compared the performance of a low-cost prosthetic knee with 2 more advanced prosthetic knees while walking on even and uneven terrains. Two adult subjects with above-knee amputations completed walking trials using a low-cost prosthetic knee (ReMotion knee) and their personal prosthetic knees (Ottobock 3R60 Pro mechanical knee and Ossur Rheo microprocessor knee) over even and uneven terrains. Several measures of gait performance were obtained including step size, stability, energy expenditure, as well as user perception of ReMotion workload and performance during gait. Effects of the ReMotion knee were different between the mechanical and microprocessor knee user. In addition, subjects perceived the positive aspects associated with the ReMotion knee to be its lightweight feature and their perceived increased in stability during walking while both subjects disliked the inability of the ReMotion knee to adjust to preferred walking speeds. This study provided an understanding of low-cost prosthetic technology among lower-limb amputees compared to prosthetic technology with more technologically advanced assistance. These findings may help guide future low-cost prosthetic knee design considerations for use on various terrains.
Approximate Bayesian Techniques for Statistical Model Selection and Quantifying Model Uncertainty-Application to a Gait Study
Franck, Christopher T.; Arena, Sara L.; Madigan, Michael L. (Springer, 2022-08-20)
Frequently, biomedical researchers need to choose between multiple candidate statistical models. Several techniques exist to facilitate statistical model selection including adjusted R2, hypothesis testing and p-values, and information criteria among others. One particularly useful approach that has been slow to permeate the biomedical literature is the notion of posterior model probabilities. A major advantage of posterior model probabilities is that they quantify uncertainty in model selection by providing a direct, probabilistic comparison among competing models as to which is the “true” model that generated the observed data. Additionally, posterior model probabilities can be used to compute posterior inclusion probabilities which quantify the probability that individual predictors in a model are associated with the outcome in the context of all models considered given the observed data. Posterior model probabilities are typically derived from Bayesian statistical approaches which require specialized training to implement, but in this paper we describe an easy-to-compute version of posterior model probabilities and inclusion probabilities that rely on the readily-available Bayesian information criterion. We illustrate the utility of posterior model probabilities and inclusion probabilities by re-analyzing data from a published gait study investigating factors that predict required coefficient of friction between the shoe sole and floor while walking.
Head kinematics of human subjects during laboratory-induced ladder falls to the ground
Ferro, Gabrielle M.; Rowson, Steven; Madigan, Michael L. (Pergamon-Elsevier, 2024-08-20)
Introduction: Fall-induced traumatic brain injury (TBI) is considered one of the most serious occupational injuries in construction. Given the frequency of falls from ladders, knowledge of head kinematics during ladder falls to the ground may help inform any potential improvement to construction safety helmet design and improve their protection against head injury. Therefore, the goal of this descriptive study was to measure head kinematics during laboratory-induced ladder falls to the ground. Method: Eighteen young adults wearing a hockey helmet simulated construction tasks that challenged their balance while standing on stepladders and an extension ladder with their feet at heights up to 1.8 m above padding covering the ground. Falls onto the padding occurred spontaneously or were induced by an investigator nudging the ladder to simulate ladder movement resulting from the ground shifting. Optoelectronic motion capture was used to capture head kinematics up to the instant immediately before head impact. Results: Of 115 total falls, 15 involved head impact with the padding and were analyzed. Head impact during all 15 of these falls occurred on the back of the head. Immediately before impact with the padding, head vertical velocity ranged from 0.42 to 3.88 m/s and head angular velocity about a medial–lateral axis ranged from 60.1 to 1215.5 deg/s. Conclusions: These data can be used with computer simulations or headform impact testing to estimate true head impact kinematics, or to inform future versions of construction safety helmet testing standards. Practical applications: This is the first study we are aware of to capture head kinematics of human subjects during ladder falls to the ground. These results have the potential to inform future versions of construction safety helmet testing standards and contribute to improved helmet design for protection against fall-induced head injury.
Effect of processing parameters and thermal history on microstructure evolution and functional properties in laser powder bed fusion of 316L
Deshmukh, Kaustubh; Riensche, Alex; Bevans, Ben; Lane, Ryan J.; Snyder, Kyle; Halliday, Harold (Scott); Williams, Christopher B.; Mirzaeifar, Reza; Rao, Prahalada (Elsevier, 2024-07-03)
In this paper, we explain and quantify the causal effect of processing parameters and part-scale thermal history on the evolution of microstructure and mechanical properties in the laser powder bed fusion additive manufacturing of Stainless Steel 316L components. While previous works have correlated the processing parameters to flaw formation, microstructures evolved, and properties, a missing link is the understanding of the effect of thermal history. Accordingly, tensile test coupons were manufactured under varying processing conditions, and their microstructure-related attributes, e.g., grain morphology, size and texture; porosity; and microhardness were characterized. Additionally, the yield and tensile strengths of the samples were measured using digital image correlation. An experimentally validated computational model was used to predict the thermal history of each sample. The temperature gradients and sub-surface cooling rates ascertained from the model predictions were correlated with the experimentally characterized microstructure and mechanical properties. By elucidating the fundamental process-thermal-structure–property relationship, this work establishes the foundation for future physics-based prediction of microstructure and functional properties in laser powder bed fusion.
Reverse social contagion as a mechanism for regulating mass behaviors in highly integrated social systems
Porfiri, Maurizio; De Lellis, Pietro; Aung, Eighdi; Meneses, Santiago; Abaid, Nicole; Waters, Jane S.; Garnier, Simon (Oxford University Press, 2024-06-26)
Mass behavior is the rapid adoption of similar conduct by all group members, with potentially catastrophic outcomes such as mass panic. Yet, these negative consequences are rare in integrated social systems such as social insect colonies, thanks to mechanisms of social regulation. Here, we test the hypothesis that behavioral deactivation between active individuals is a powerful social regulator that reduces energetic spending in groups. Borrowing from scaling theories for human settlements and using behavioral data on harvester ants, we derive ties between the hypermetric scaling of the interaction network and the hypometric scaling of activity levels, both relative to the colony size. We use elements of economics theory and metabolic measurements collected with the behavioral data to link activity and metabolic scalings with group size. Our results support the idea that metabolic scaling across social systems is the product of different balances between their social regulation mechanisms.
Learning from Experience: A Faculty-Led Collaborative Inquiry Exploring Embedded Communication Skills Across Engineering Curricula
Biviano, Angelo; Branscome, Caroline; Burgoyne, Christine Bala; Carper, Kathleen; Iorio, Josh; Scarff, Kelly; Taylor, Ashley R.; Arena, Sara (ASEE Conferences, 2024-06-23)
This evidence-based practice paper describes a collaborative inquiry process to explore a critical question for engineering faculty: what are practical strategies for leveraging evidence-based practices to embed communication skills across core engineering curricula? Within engineering education, there is a growing consensus that communication skills are essential for engineering graduates. For example, the Accreditation Board for Engineering and Technology (ABET) distinctly highlights communication skills as a required student learning outcome for accreditation of engineering programs in ABET Criterion 3.3.: an ability to communicate effectively with a range of audiences. Numerous studies exploring engineers’ school-to-work transition suggest that communication is one of the most important skill sets for engineering practice according to both recent graduates (Passow, 2012) and industry (Male et. al, 2010). As the Engineer of 2020 Report concisely noted, “good engineering will require good communication” (National Academy of Engineering, 2004, p. 56). Despite the engineering education community’s shared vision for ensuring engineering graduates can communicate effectively, few practical examples exist to illuminate how faculty can leverage evidence-based practices to integrate communication skills into their existing technical curricula. Therefore, the purpose of this paper is to share seven practical case-based examples of strategies implemented in a spectrum of engineering disciplines and learning environments to support faculty in integrating communication skills into existing engineering curriculum. We first describe our collaborative inquiry process to create a “systematic structure for learning from experience” (Yorks & Kasl, 2002, p. 3). Our learning from experience is rooted in the reflections of faculty representing seven engineering departments who teach communication skills across a diverse range of engineering curricular contexts (e.g., course size, course level, technical subject, etc.) Next, we provide seven case studies of evidence-based strategies-in-action across this range of learning contexts, including both undergraduate and graduate education. For example, one case study discusses the integration of a community-focused debate project in a mining engineering undergraduate course to build students’ communications skills in rhetorical situation analysis while another study in a construction engineering management department attends to aspects of diversity and inclusion by promoting a writing process that begins with visual design. These case studies provide rich context for the learning environment and the implementation of the evidence-based practice, with the ultimate goal of supporting faculty in drawing connections to their own teaching strategies. Finally, we conclude by situating the case studies in the broader engineering education literature and sharing reflections for lessons learned on integration of communication instruction across existing engineering curricula.
First-In-DOg HISTotripsy for Intracranial Tumors Trial: The FIDOHIST Study
Vezza, Christina; Ruger, Lauren; Langman, Maya; Vickers, Elliana; Prada, Francesco; Sukovich, Jonathan; Hall, Timothy; Xu, Zhen; Parker, Rell L.; Vlaisavljevich, Eli; Rossmeisl, John H. (SAGE Publications, 2024-10-17)
Objective: Brain tumors represent some of the most treatment refractory cancers, and there is a clinical need for additional treatments for these tumors. Domesticated dogs are the only other mammalian species which commonly develop spontaneous brain tumors, making them an ideal model for investigating novel therapies. Histotripsy is a non-thermal ultrasonic ablation method that emulsifies tissue through acoustic cavitation. The primary objectives of this prospective study were to assess the feasibility and safety of histotripsy to ablate naturally occurring canine brain tumors. Secondary endpoints included characterization of magnetic resonance imaging (MRI) responses to histotripsy treatment, and exploratory immunogenomic tumor response analyses. Methods: The study design utilized a treat and resect paradigm, where tumors were approached using craniotomy, partially ablated with histotripsy delivered through the cranial defect, imaged with MRI, and then resected. Dogs were evaluated with clinical, brain MRI, immunopathologic, and genomic examinations before treatment, intraoperatively, and 1, 14, and 42 days post-treatment. Here we report the results of the three dogs with meningiomas, all of which were treated with a custom eight element 1 MHz histotripsy transducer at a pulse repetition frequency of 100 Hz and a treatment dosage of 400 pulses/point. Results: Histotripsy was successfully delivered to all dogs, resulting in histopathologic evidence of ablations that were sharply demarcated from untreated tumor, with measured treatments approximating planned volumes in 2/3 dogs. One dog experienced an adverse event consisting of transient cerebral edema that was possibly attributable to histotripsy. Histotripsy ablations could be grossly visualized and identified on MRI, with features consistent with hemorrhage and necrosis. Significant expression or upregulation of the damage associated molecular pattern HMGB1, cytokine-cytokine receptor interaction, and NF-κb signaling pathways were observed in histotripsy treated tumors. Conclusion: Ablation of canine meningiomas with histotripsy through an open cranial window was feasible and clinically well tolerated.
Durotaxis and extracellular matrix degradation promote clustering of cancer cells
Potomkin, Mykhailo; Kim, Oleg V.; Klymenko, Yuliya; Alber, Mark; Aronson, Igor S. (Elsevier, 2025-01-24)
Early stages of metastasis depend on the collective behavior of cancer cells and their interaction 23 with the extracellular matrix (ECM). Cancer cell clusters are known to exhibit higher metastatic 24 potential than single cells. To explore clustering dynamics, we developed a calibrated computa- 25 tional model describing how motile cancer cells biochemically and biomechanically interact with 26 the ECM during the initial invasion phase, including ECM degradation and mechanical remod- 27 eling. The model reveals that cluster formation time, size, and shape are influenced by ECM 28 degradation rates and cellular responsiveness to external stresses (durotaxis). The results align 29 with experimental observations, demonstrating distinct cell trajectories and cluster morphologies 30 shaped by biomechanical parameters. These simulations provide valuable insights into cancer 31 invasion dynamics and may suggest potential therapeutic strategies targeting early-stage inva- 32 sive cells.
Cancer detection in dogs using rapid Raman molecular urinalysis
Robertson, John L.; Dervisis, Nikolaos G.; Rossmeisl, John H. Jr.; Nightengale, Marlie; Fields, Daniel; Dedrick, Cameron; Ngo, Lacey; Issa, Amr Sayed; Guruli, Georgi; Orlando, Giuseppe; Senger, Ryan S. (Frontiers, 2024-02-07)
Introduction: The presence of cancer in dogs was detected by Raman spectroscopy of urine samples and chemometric analysis of spectroscopic data. The procedure created a multimolecular spectral fingerprint with hundreds of features related directly to the chemical composition of the urine specimen. These were then used to detect the broad presence of cancer in dog urine as well as the specific presence of lymphoma, urothelial carcinoma, osteosarcoma, and mast cell tumor. Methods: Urine samples were collected via voiding, cystocentesis, or catheterization from 89 dogs with no history or evidence of neoplastic disease, 100 dogs diagnosed with cancer, and 16 dogs diagnosed with non-neoplastic urinary tract or renal disease. Raman spectra were obtained of the unprocessed bulk liquid urine samples and were analyzed by ISREA, principal component analysis (PCA), and discriminant analysis of principal components (DAPC) were applied using the Rametrix®Toolbox software. Results and discussion: The procedure identified a spectral fingerprint for cancer in canine urine, resulting in a urine screening test with 92.7% overall accuracy for a cancer vs. cancer-free designation. The urine screen performed with 94.0% sensitivity, 90.5% specificity, 94.5% positive predictive value (PPV), 89.6% negative predictive value (NPV), 9.9 positive likelihood ratio (LR+), and 0.067 negative likelihood ratio (LR-). Raman bands responsible for discerning cancer were extracted from the analysis and biomolecular associations were obtained. The urine screen was more effective in distinguishing urothelial carcinoma from the other cancers mentioned above. Detection and classification of cancer in dogs using a simple, non-invasive, rapid urine screen (as compared to liquid biopsies using peripheral blood samples) is a critical advancement in case management and treatment, especially in breeds predisposed to specific types of cancer.
Reinforcement learning processes as forecasters of depression remission
Bansal, Vansh; McCurry, Katherine L.; Lisinski, Jonathan; Kim, Dong-Youl; Goyal, Shivani; Wang, John M.; Lee, Jacob; Brown, Vanessa M.; LaConte, Stephen M.; Casas, Brooks; Chiu, Pearl H. (Elsevier, 2024-09-11)
Background: Aspects of reinforcement learning have been associated with specific depression symptoms and may inform the course of depressive illness. Methods: We applied support vector machines to investigate whether blood‑oxygen-level dependent (BOLD) responses linked with neural prediction error (nPE) and neural expected value (nEV) from a probabilistic learning task could forecast depression remission. We investigated whether predictions were moderated by treatment use or symptoms. Participants included 55 individuals (n = 39 female) with a depression diagnosis at baseline; 36 of these individuals completed standard cognitive behavioral therapy and 19 were followed during naturalistic course of illness. All participants were assessed for depression diagnosis at a follow-up visit. Results: Both nPE and nEV classifiers forecasted remission significantly better than null classifiers. The nEV classifier performed significantly better than the nPE classifier. We found no main or interaction effects of treatment status on nPE or nEV accuracy. We found a significant interaction between nPE-forecasted remission status and anhedonia, but not for negative affect or anxious arousal, when controlling for nEV-forecasted remission status. Limitations: Our sample size, while comparable to that of other studies, limits options for maximizing and evaluating model performance. We addressed this with two standard methods for optimizing model performance (90:10 train and test scheme and bootstrapped sampling). Conclusions: Results support nEV and nPE as relevant biobehavioral signals for understanding depression outcome independent of treatment status, with nEV being stronger than nPE as a predictor of remission. Reinforcement learning variables may be useful components of an individualized medicine framework for depression healthcare.
Stabilizing milk-derived extracellular vesicles (mEVs) through lyophilization: a novel trehalose and tryptophan formulation for maintaining structure and Bioactivity during long-term storage
Dogan, Alan B.; Marsh, Spencer R.; Tschetter, Rachel J.; Beard, Claire E.; Amin, Md R.; Jourdan, L. Jane; Gourdie, Robert G. (2025-01-13)
Extracellular vesicles (EVs) are widely investigated for their implications in cell-cell signaling, immune modulation, disease pathogenesis, cancer, regenerative medicine, and as a potential drug delivery vector. However, maintaining integrity and bioactivity of EVs between Good Manufacturing Practice separation/filtration and end-user application remains a consistent bottleneck towards commercialization. Milk-derived extracellular vesicles (mEVs), separated from bovine milk, could provide a relatively low-cost, scalable platform for large-scale mEV production; however, the reliance on cold supply chain for storage remains a logistical and financial burden for biologics that are unstable at room temperature. Herein, we aim to characterize and engineer a freeze-dried, mEV formulation that can be stored at room temperature without sacrificing structure/bioactivity and can be reconstituted before delivery. In addition to undertaking established mEV assays of structure and function on our preparations, we introduce a novel, efficient, high throughput assay of mEV bioactivity based on Electric Cell Substrate Impedance Sensing (ECIS) in Human dermal fibroblast monolayers. By adding appropriate excipients, such as trehalose and tryptophan, we describe a protective formulation that preserves mEV bioactivity during long-term, room temperature storage. Our identification of the efficacy of tryptophan as a novel additive to mEV lyophilization solutions could represent a significant advancement in stabilizing small extracellular vesicles outside of cold storage conditions.
Gradient descent optimization of acoustic holograms for transcranial focused ultrasound
Sallam, Ahmed; Cengiz, Ceren; Pewekar, Mihir; Hoffmann, Eric; Legon, Wynn; Vlaisavljevich, Eli; Shahab, Shima (AIP Publishing, 2024-10-08)
Acoustic holographic lenses, also known as acoustic holograms, can change the phase of a transmitted wavefront in order to shape and construct complex ultrasound pressure fields, often for focusing the acoustic energy on a target region. These lenses have been proposed for transcranial focused ultrasound (tFUS) to create diffraction-limited focal zones that target specific brain regions while compensating for skull aberration. Holograms are currently designed using time-reversal approaches in full-wave time-domain numerical simulations. Such simulations need time-consuming computations, which severely limits the adoption of iterative optimization strategies. In the time-reversal method, the number and distribution of virtual sources can significantly influence the final sound field. Because of the computational constraints, predicting these effects and determining the optimal arrangement is challenging. This study introduces an efficient method for designing acoustic holograms using a volumetric holographic technique to generate focused fields inside the skull. The proposed method combines a modified mixed-domain method for ultrasonic propagation with a gradient descent iterative optimization algorithm. The findings are further validated in underwater experiments with a realistic 3D-printed skull phantom. This approach enables substantially faster holographic computation than previously reported techniques. The iterative process uses explicitly defined loss functions to bias the ultrasound field’s optimization parameters to specific desired characteristics, such as axial resolution, transversal resolution, coverage, and focal region uniformity, while eliminating the uncertainty associated with virtual sources in time-reversal techniques. The proposed techniques enable more rapid hologram computation and more flexibility in tailoring ultrasound fields for specific therapeutic requirements.
Quantitative ultrasound assessment of fatty infiltration of the rotator cuff muscles using backscatter coefficient
Toto-Brocchi, Marco; Wu, Yuanshan; Jerban, Saeed; Han, Aiguo; Andre, Michael; Shah, Sameer B.; Chang, Eric Y. (2024-10-22)
Background: To prospectively evaluate ultrasound backscatter coefficients (BSCs) of the supraspinatus and infraspinatus muscles and compare with Goutallier classification on magnetic resonance imaging (MRI). Methods: Fifty-six participants had shoulder MRI exams and ultrasound exams of the supraspinatus and infraspinatus muscles. Goutallier MRI grades were determined and BSCs were measured. Group means were compared and the strength of relationships between the measures were determined. Using binarized Goutallier groups (0–2 versus 3–4), areas under the receiver operating characteristic curves (AUROCs) were calculated. The nearest integer cutoff value was determined using Youden’s index. Results: BSC values were significantly different among most Goutallier grades for the supraspinatus and infraspinatus muscles (both p < 0.001). Strong correlations were found between the BSC values and Goutallier grades for the supraspinatus (τb = 0.72, p < 0.001) and infraspinatus (τb = 0.79, p < 0.001) muscles. BSC showed excellent performance for classification of the binarized groups (0–2 versus 3–4) for both supraspinatus (AUROC = 0.98, p < 0.0001) and infraspinatus (AUROC = 0.98, p < 0.0001) muscles. Using a cutoff BSC value of −17 dB, sensitivity, specificity, and accuracy for severe fatty infiltration were 87.0%, 90.0%, and 87.5% for the supraspinatus muscle, and 93.6%, 87.5%, and 92.7% for the infraspinatus muscle. Conclusion: BSC can be applied to the rotator cuff muscles for assessment of fatty infiltration. For both the supraspinatus and infraspinatus muscles, BSC values significantly increased with higher Goutallier grades and showed strong performance in distinguishing low versus high Goutallier grades. Relevance statement: Fatty infiltration of the rotator cuff muscles can be quantified using BSC values, which are higher with increasing Goutallier grades. Key Points Ultrasound BSC measurements are reliable for the quantification of muscle fatty infiltration. BCS values increased with higher Goutallier MRI grades. BCS values demonstrated high performance for distinguishing muscle fatty infiltration groups.
Detection, Isolation and Quantification of Myocardial Infarct with Four Different Histological Staining Techniques
Wu, Xiaobo; Meier, Linnea; Liu, Tom X.; Toldo, Stefano; Poelzing, Steven; Gourdie, Robert G. (MDPI, 2024-10-18)
Background/Objectives: The precise quantification of myocardial infarction is crucial for evaluating therapeutic strategies. We developed a robust, color-based semi-automatic algorithm capable of infarct region detection, isolation and quantification with four different histological staining techniques, and of the isolation and quantification of diffuse fibrosis in the heart. Methods: Our method is developed based on the color difference in the infarct and non-infarct regions after histological staining. Mouse cardiac tissues stained with Masson’s trichrome (MTS), hematoxylin and eosin (H&E), 2,3,5-Triphenyltetrazolium chloride and picrosirius red were included to demonstrate the performance of our method. Results: We demonstrate that our algorithm can effectively identify and produce a clear visualization of infarct tissue in the four staining techniques. Notably, the infarct region on an H&E-stained tissue section can be clearly visualized after processing. The MATLAB-based program we developed holds promise for infarct quantification. Additionally, our program can isolate and quantify diffuse fibrotic elements from an MTS-stained cardiac section, which suggests the algorithm’s potential for evaluating pathological cardiac fibrosis in diseased cardiac tissues. Conclusions: We demonstrate that this color-based algorithm is capable of accurately identifying, isolating and quantifying cardiac infarct regions with different staining techniques, as well as diffuse and patchy fibrosis in MTS-stained cardiac tissues.
Investigation of High Frequency Irreversible Electroporation for Canine Spontaneous Primary Lung Tumor Ablation
Hay, Alayna N.; Aycock, Kenneth N.; Lorenzo, Melvin F.; David, Kailee; Coutermarsh-Ott, Sheryl; Salameh, Zaid; Campelo, Sabrina N.; Arroyo, Julio P.; Ciepluch, Brittany; Daniel, Gregory; Davalos, Rafael V.; Tuohy, Joanne (MDPI, 2024-09-07)
In this study, the feasibility of treating canine primary lung tumors with high-frequency irreversible electroporation (H-FIRE) was investigated as a novel lung cancer treatment option. H-FIRE is a minimally invasive tissue ablation modality that delivers bipolar pulsed electric fields to targeted cells, generating nanopores in cell membranes and rendering targeted cells nonviable. In the current study, canine patients (n = 5) with primary lung tumors underwent H-FIRE treatment with an applied voltage of 2250 V using a 2-5-2 µs H-FIRE waveform to achieve partial tumor ablation prior to the surgical resection of the primary tumor. Surgically resected tumor samples were evaluated histologically for tumor ablation, and with immunohistochemical (IHC) staining to identify cell death (activated caspase-3) and macrophages (IBA-1, CD206, and iNOS). Changes in immunity and inflammatory gene signatures were also evaluated in tumor samples. H-FIRE ablation was evident by the microscopic observation of discrete foci of acute hemorrhage and necrosis, and in a subset of tumors (n = 2), we observed a greater intensity of cleaved caspase-3 staining in tumor cells within treated tumor regions compared to adjacent untreated tumor tissue. At the study evaluation timepoint of 2 h post H-FIRE, we observed differential gene expression changes in the genes IDO1, IL6, TNF, CD209, and FOXP3 in treated tumor regions relative to paired untreated tumor regions. Additionally, we preliminarily evaluated the technical feasibility of delivering H-FIRE percutaneously under CT guidance to canine lung tumor patients (n = 2). Overall, H-FIRE treatment was well tolerated with no adverse clinical events, and our results suggest H-FIRE potentially altered the tumor immune microenvironment.
The connexin 43 carboxyl terminal mimetic peptide αCT1 prompts differentiation of a collagen scar matrix in humans resembling unwounded skin
Montgomery, Jade; Richardson, William J.; Marsh, Spencer; Rhett, J. Matthew; Bustos, Francis; Degen, Katherine; Ghatnekar, Gautam S.; Grek, Christina L.; Jourdan, L. Jane; Holmes, Jeffrey W.; Gourdie, Robert G. (Wiley, 2021-07-10)
Phase II clinical trials have reported that acute treatment of surgical skin wounds with the therapeutic peptide alpha Connexin Carboxy-Terminus 1 (αCT1) improves cutaneous scar appearance by 47% 9-month postsurgery. While Cx43 and ZO-1 have been identified as molecular targets of αCT1, the mode-of-action of the peptide in scar mitigation at cellular and tissue levels remains to be further characterized. Scar histoarchitecture in αCT1 and vehicle-control treated skin wounds within the same patient were compared using biopsies from a Phase I clinical trial at 29-day postwounding. The sole effect on scar structure of a range of epidermal and dermal variables examined was that αCT1-treated scars had less alignment of collagen fibers relative to control wounds—a characteristic that resembles unwounded skin. The with-in subject effect of αCT1 on scar collagen order observed in Phase I testing in humans was recapitulated in Sprague–Dawley rats and the IAF hairless guinea pig. Transient increase in histologic collagen density in response to αCT1 was also observed in both animal models. Mouse NIH 3T3 fibroblasts and primary human dermal fibroblasts treated with αCT1 in vitro showed more rapid closure in scratch wound assays, with individual cells showing decreased directionality in movement. An agent-based computational model parameterized with fibroblast motility data predicted collagen alignments in simulated scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D collagen matrix postwounding that is similar to unwounded skin—changes that correlate with long-term improvement in scar appearance.
Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts
Teng, Allen C. T.; Gu, Liyang; Di Paola, Michelle; Lakin, Robert; Williams, Zachary J.; Au, Aaron; Chen, Wenliang; Callaghan, Neal; Zadeh, Farigol Hakem; Zhou, Yu-Qing; Fatah, Meena; Chatterjee, Diptendu; Jourdan, L. Jane; Liu, Jack; Simmons, Craig A.; Kislinger, Thomas; Yip, Christopher M.; Backx, Peter H.; Gourdie, Robert G.; Hamilton, Robert M.; Gramolini, Anthony O. (Nature Portfolio, 2022-10-18)
The intercalated disc (ICD) is a unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigate the functional and cellular effects of Tmem65 reductions on the myocardium in a mouse model by injecting CD1 mouse pups (3–7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA, which reduces Tmem65 expression by 90% in mouse ventricles compared to scrambled shRNA injection. Tmem65 knockdown (KD) results in increased mortality which is accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection and progression to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts display depressed hemodynamics as measured echocardiographically as well as slowed conduction in optical recording accompanied by prolonged PR intervals and QRS duration in electrocardiograms. Immunoprecipitation and super-resolution microscopy demonstrate a physical interaction between Tmem65 and sodium channel β subunit (β1) in mouse hearts and this interaction appears to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na+ currents but did show reduced Ca2+ and K+ currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.
Epigenomic tomography for probing spatially defined chromatin state in the brain
Liu, Zhengzhi; Deng, Chengyu; Zhou, Zirui; Ya, Xiao; Jiang, Shan; Zhu, Bohan; Naler, Lynette B.; Jia, Xiaoting; Yao, Danfeng (Daphne); Lu, Chang (Cell Press, 2024-03-25)
Spatially resolved epigenomic profiling is critical for understanding biology in the mammalian brain. Singlecell spatial epigenomic assays were developed recently for this purpose, but they remain costly and labor intensive for examining brain tissues across substantial dimensions and surveying a collection of brain samples. Here, we demonstrate an approach, epigenomic tomography, that maps spatial epigenomes of mouse brain at the scale of centimeters. We individually profiled neuronal and glial fractions of mouse neocortex slices with 0.5 mm thickness. Tri-methylation of histone 3 at lysine 27 (H3K27me3) or acetylation of histone 3 at lysine 27 (H3K27ac) features across these slices were grouped into clusters based on their spatial variation patterns to form epigenomic brain maps. As a proof of principle, our approach reveals striking dynamics in the frontal cortex due to kainic-acid-induced seizure, linked with transmembrane ion transporters, exocytosis of synaptic vesicles, and secretion of neurotransmitters. Epigenomic tomography provides a powerful and cost-effective tool for characterizing brain disorders based on the spatial epigenome.
Correlating tire traction performance on snow with measured parameters of ASTM F1805 using regression analysis
Shenvi, Mohit Nitin; Sandu, Corina; Untaroiu, Costin D.; Pierce, Eric (Elsevier, 2023-09)
Winter tires sold in North America are often tested using the ASTM F1805 testing process to determine if they can be labeled with the ‘mountain snowflake’ symbol which indicates better performance for snow usage. The standard dictates the requirements for testing and necessary track preparation methodologies. In addition, the requirements of the standard dictate the range of three major conditions for tests to be carried out, namely the CTI penetration measurement, the snow temperature, and the ambient temperature. However, these parameters cannot be directly used in the simulation stage of snow modeling for better evaluation of prototypes. It is well-known that snow properties depend on a wide variety of parameters, making the creation of an accurate and robust snow material model, and, consequently, applying a simulation-based approach for tire design, difficult. This work focuses on the analysis of a dataset of five winter seasons of a 14-in. Standard Reference Test Tire on snow used to benchmark the performance of a potential winter tire. The blinded data measured at Smithers Winter Test Center were used in the analysis to train regression models for predicting the traction coefficient and evaluating the extent to which the measured parameters affect the variation in the traction coefficient. This study utilized twenty-six different modeling approaches and implementation of principal component analysis. The findings of this study highlight the relative importance of the compression and shear characteristics of the snow on the traction of the tire. It was found that regression methods based on Gaussian processes were better at predicting the traction coefficient. The study also highlights the importance of utilizing a single physical tire as the reference tire for benchmarking according to the ASTM F1805.
Leveraging an Open-Access Digital Design Notebook for Graduate Biomedical Engineering Education in Nigeria
Casserly, Padraic; Dare, Ademola; Onuh, Joy; Baah, Williams; Taylor, Ashley R. (Springer, 2024-03-15)
Amidst the dual challenges of an eight-month university closure from nationwide public university strikes in Nigeria and the lingering impacts of the Covid-19 pandemic, we needed to innovate the delivery of BME graduate curriculum to ensure graduate students continued to progress in their studies. To ensure BME graduate students were engaging in team-based, clinician-identified engineering design challenges, we developed a digital design notebook (DDN) using Google Sites as an open-access, collaborative tool for scaffolding and documenting the engineering design process. Student design teams remotely uploaded digital content documenting their project work onto scaffolded DDNs created by program instructors. DDNs were purposefully designed to shepherd students through the design process such that each phase of the design process corresponded to an editable "page" of the DDN. Video lectures, learning resources, assignments, and other program information were embedded into the DDN for students to access throughout their design challenge. Project mentors and program instructors remotely monitored and assessed students' work using the DDN. At the end of the design challenge, students effectively created an e-portfolio which showcased the work they conducted to build a biomedical prototype. Designing and implementing the DDN builds on previous research which demonstrates that "structured" design notebooks can be used as effective tools in engineering design and design thinking education. Our work also leverages educational frameworks for infusing engineering design into existing graduate biomedical engineering curriculum in Nigeria.

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