Department of Biomedical Engineering Works

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    Recent advances in bio-orthogonal and dynamic crosslinking of biomimetic hydrogels
    (Royal Society of Chemistry, 2020-09-21) Arkenberg, Matthew R.; Nguyen, Han D.; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and Technology
    In recent years, dynamic, 'click' hydrogels have been applied in numerous biomedical applications. Owing to the mild, cytocompatible, and highly specific reaction kinetics, a multitude of orthogonal handles have been developed for fabricating dynamic hydrogels to facilitate '4D' cell culture. The high degree of tunability in crosslinking reactions of orthogonal 'click' chemistry has enabled a bottom-up approach to install specific biomimicry in an artificial extracellular matrix. In addition to click chemistry, highly specific enzymatic reactions are also increasingly used for network crosslinking and for spatiotemporal control of hydrogel properties. On the other hand, covalent adaptable chemistry has been used to recapitulate the viscoelastic component of biological tissues and for formulating self-healing and shear-thinning hydrogels. The common feature of these three classes of chemistry (i.e., orthogonal click chemistry, enzymatic reactions, and covalent adaptable chemistry) is that they can be carried out under ambient and aqueous conditions, a prerequisite for maintaining cell viability for in situ cell encapsulation and post-gelation modification of network properties. Due to their orthogonality, different chemistries can also be applied sequentially to provide additional biochemical and mechanical control to guide cell behavior. Herein, we review recent advances in the use of orthogonal click chemistry, enzymatic reactions, and covalent adaptable chemistry for the development of dynamically tunable and biomimetic hydrogels.
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    Mentor-focused Professional Development for Investigators Initiating Discipline-based Educational Research (DBER) in Biomedical Engineering
    (ASEE, 2021-07) Miller, Sharon; Higbee, Steven; Biomedical Engineering, School of Engineering and Technology
    Our work (NSF PFE: RIEF Award 1927150) initiates a discipline-based educational research study of student design self-efficacy in an undergraduate biomedical engineering (BME) program. A key component of this work focuses on our own professional development as engineering education researchers, which contributes to our abilities to undertake current and future engineering education studies. Our professional development goal is to establish and follow a mentoring plan that facilitates our development of engineering education research skills. We targeted three areas for learning and development as researchers: (1) social science research in design education, (2) mixed methods research, and (3) evidence-based teaching. To that end, we strategically invited engineering education research mentors to our team, deliberately structured our mentor conversations with literature readings to foster growth, and purposefully documented this process by continually responding to reflection questions in a professional development journal. Our approach to include our own professional development in our Research Initiation in Engineering Formation grant has proven instrumental in collecting data and in connecting us with the engineering education community.
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    Generation of the tumor-suppressive secretome from tumor cells
    (Ivyspring International, 2021-07-25) Liu, Shengzhi; Sun, Xun; Li, Kexin; Zha, Rongrong; Feng, Yan; Sano, Tomohiko; Dong, Chuanpeng; Liu, Yunlong; Aryal, Uma K.; Sudo, Akihiro; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Rationale: The progression of cancer cells depends on the soil and building an inhibitory soil might be a therapeutic option. We previously created tumor-suppressive secretomes by activating Wnt signaling in MSCs. Here, we examined whether the anti-tumor secretomes can be produced from tumor cells. Methods: Wnt signaling was activated in tumor cells by overexpressing β-catenin or administering BML284, a Wnt activator. Their conditioned medium (CM) was applied to cancer cells or tissues, and the effects of CM were evaluated. Tumor growth in the mammary fat pad and tibia in C57BL/6 female mice was also evaluated through μCT imaging and histology. Whole-genome proteomics analysis was conducted to determine and characterize novel tumor-suppressing proteins, which were enriched in CM. Results: The overexpression of β-catenin or the administration of BML284 generated tumor-suppressive secretomes from breast, prostate and pancreatic cancer cells. In the mouse model, β-catenin-overexpressing CM reduced tumor growth and tumor-driven bone destruction. This inhibition was also observed with BML284-treated CM. Besides p53 and Trail, proteomics analysis revealed that CM was enriched with enolase 1 (Eno1) and ubiquitin C (Ubc) that presented notable tumor-suppressing actions. Importantly, Eno1 immunoprecipitated CD44, a cell-surface adhesion receptor, and its silencing suppressed Eno1-driven tumor inhibition. A pan-cancer survival analysis revealed that the downregulation of MMP9, Runx2 and Snail by CM had a significant impact on survival outcomes (p < 0.00001). CM presented a selective inhibition of tumor cells compared to non-tumor cells, and it downregulated PD-L1, an immune escape modulator. Conclusions: The tumor-suppressive secretome can be generated from tumor cells, in which β-catenin presented two opposing roles, as an intracellular tumor promoter in tumor cells and a generator of extracellular tumor suppressor in CM. Eno1 was enriched in CM and its interaction with CD44 was involved in Eno1's anti-tumor action. Besides presenting a potential option for treating primary cancers and metastases, the result indicates that aggressive tumors may inhibit the growth of less aggressive tumors via tumor-suppressive secretomes.
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    Morphological and mechanical characterization of bone phenotypes in the Amish G610C murine model of osteogenesis imperfecta
    (PLOS, 2021-08-27) Kohler, Rachel; Tastad, Carli A.; Creecy, Amy; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and Technology
    Osteogenesis imperfecta (OI) is a hereditary bone disease where gene mutations affect Type I collagen formation resulting in osteopenia and increased fracture risk. There are several established mouse models of OI, but some are severe and result in spontaneous fractures or early animal death. The Amish Col1a2G610C/+ (G610C) mouse model is a newer, moderate OI model that is currently being used in a variety of intervention studies, with differing background strains, sexes, ages, and bone endpoints. This study is a comprehensive mechanical and architectural characterization of bone in G610C mice bred on a C57BL/6 inbred strain and will provide a baseline for future treatment studies. Male and female wild-type (WT) and G610C mice were euthanized at 10 and 16 weeks (n = 13-16). Harvested tibiae, femora, and L4 vertebrae were scanned via micro-computed tomography and analyzed for cortical and trabecular architectural properties. Femora and tibiae were then mechanically tested to failure. G610C mice had less bone but more highly mineralized cortical and trabecular tissue than their sex- and age-matched WT counterparts, with cortical cross-sectional area, thickness, and mineral density, and trabecular bone volume, mineral density, spacing, and number all differing significantly as a function of genotype (2 Way ANOVA with main effects of sex and genotype at each age). In addition, mechanical yield force, ultimate force, displacement, strain, and toughness were all significantly lower in G610C vs. WT, highlighting a brittle phenotype. This characterization demonstrates that despite being a moderate OI model, the Amish G610C mouse model maintains a distinctly brittle phenotype and is well-suited for use in future intervention studies.
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    Polyurethane coated with polyvinylpyrrolidones via triazole links for enhanced surface fouling resistance
    (Wiley, 2021-12) Wen, Xin; Almousa, Rashed; Na, Sungsoo; Anderson, Gregory G.; Xie, Dong; Biomedical Engineering, School of Engineering and Technology
    Surfaces with hydrophilic and antimicrobial properties are very attractive for cardiovascular device-associated applications. The aim of this study was to prepare and coat a hydrophilic polymer containing a functional group capable of forming triazole functionality onto the surface of polyurethane (PU). The modified surfaces were assessed with cell adhesion, bacterial adhesion and bacterial viability. Mouse fibroblast cells (NIH-3T3) and three bacterial species were used for assessment. The results showed that the modified surface not only exhibited a significant reduction in cell adhesion with a 25%–59% decrease to mouse fibroblast but also showed a significant reduction in bacterial attachment with 26%–67%, 24%–61% and 23%–57% decrease to Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, respectively, as compared with original PU. Furthermore, the polymer-modified surface exhibited a significant antibacterial function by inhibiting bacterial growth with reduction of 49%–84%, 44%–79% and 53%–79% to S. aureus, E. coli and P. aeruginosa, respectively, as compared with original PU. These results indicate that covalent polymer attachment enhanced the antibacterial and antifouling properties of the PU surface.
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    Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone
    (Springer Nature, 2021-07-06) Liu, Shengzhi; Wu, Di; Sun, Xun; Fan, Yao; Zha, Rongrong; Jalali, Aydin; Feng, Yan; Li, Kexin; Sano, Tomohiko; Vike, Nicole; Li, Fangjia; Rispoli, Joseph; Sudo, Akihiro; Liu, Jing; Robling, Alexander; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Osteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.
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    A Reversible Low Frequency Alternating Current Nerve Conduction Block Applied to Mammalian Autonomic Nerves
    (MDPI, 2021-07) Muzquiz, M. Ivette; Mintch, Landan; Horn, M. Ryne; Alhawwash, Awadh; Bashirullah, Rizwan; Carr, Michael; Schild, John H.; Yoshida, Ken; Biomedical Engineering, School of Engineering and Technology
    Electrical stimulation can be used to modulate activity within the nervous system in one of two modes: (1) Activation, where activity is added to the neural signalling pathways, or (2) Block, where activity in the nerve is reduced or eliminated. In principle, electrical nerve conduction block has many attractive properties compared to pharmaceutical or surgical interventions. These include reversibility, localization, and tunability for nerve caliber and type. However, methods to effect electrical nerve block are relatively new. Some methods can have associated drawbacks, such as the need for large currents, the production of irreversible chemical byproducts, and onset responses. These can lead to irreversible nerve damage or undesirable neural responses. In the present study we describe a novel low frequency alternating current blocking waveform (LFACb) and measure its efficacy to reversibly block the bradycardic effect elicited by vagal stimulation in anaesthetised rat model. The waveform is a sinusoidal, zero mean(charge balanced), current waveform presented at 1 Hz to bipolar electrodes. Standard pulse stimulation was delivered through Pt-Black coated PtIr bipolar hook electrodes to evoke bradycardia. The conditioning LFAC waveform was presented either through a set of CorTec® bipolar cuff electrodes with Amplicoat® coated Pt contacts, or a second set of Pt Black coated PtIr hook electrodes. The conditioning electrodes were placed caudal to the pulse stimulation hook electrodes. Block of bradycardic effect was assessed by quantifying changes in heart rate during the stimulation stages of LFAC alone, LFAC-and-vagal, and vagal alone. The LFAC achieved 86.2±11.1% and 84.3±4.6% block using hook (N = 7) and cuff (N = 5) electrodes, respectively, at current levels less than 110 µAp (current to peak). The potential across the LFAC delivering electrodes were continuously monitored to verify that the blocking effect was immediately reversed upon discontinuing the LFAC. Thus, LFACb produced a high degree of nerve block at current levels comparable to pulse stimulation amplitudes to activate nerves, resulting in a measurable functional change of a biomarker in the mammalian nervous system.
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    Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4
    (Springer Nature, 2021-05-24) Fan, Yao; Zha, Rongrong; Sano, Tomohiko; Zhao, Xinyu; Liu, Shengzhi; Woollam, Mark D.; Wu, Di; Sun, Xun; Li, Kexin; Egi, Motoki; Li, Fangjia; Minami, Kazumasa; Siegel, Amanda P.; Horiuchi, Takashi; Liu, Jing; Agarwal, Mangilal; Sudo, Akihiro; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.
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    In-vivo application of low frequency alternating currents on porcine cervical vagus nerve evokes reversible nerve conduction block
    (BMC, 2021-06-30) Muzquiz, Maria Ivette; Richardson, Lindsay; Vetter, Christian; Smolik, Macallister; Alhawwash, Awadh; Goodwill, Adam; Bashirullah, Rizwan; Carr, Michael; Yoshida, Ken; Biomedical Engineering, School of Engineering and Technology
    Background: This paper describes a method to reversibly block nerve conduction through direct application of a 1 Hz sinusoidal current waveform delivered through a bipolar nerve cuff electrode. This low frequency alternating current (LFAC) waveform was previously shown to reversibly block the effects of vagal pulse stimulation evoked bradycardia in-vivo in the anaesthetised rat model (Mintch et al. 2019). The present work measured the effectiveness of LFAC block on larger caliber myelinated vagal afferent fibers in human sized nerve bundles projecting to changes in breathing rate mediated by the Hering-Breuer (HB) reflex in anaesthetized domestic swine (n=5). Methods: Two bipolar cuff electrodes were implanted unilaterally to the left cervical vagus nerve, which was crushed caudal to the electrodes to eliminate cardiac effects. A tripolar recording cuff electrode was placed rostral to the bipolar stimulating electrodes on the same nerve to measure changes in the compound nerve action potentials (CNAP) elicited by the vagal pulse stimulation and conditioned by the LFAC waveform. Standard pulse stimulation was applied at a sufficient level to induce a reduction in breathing rate through the HB reflex. If unblocked, the HB reflex would cause breathing to slow down and potentially halt completely. Block was quantified by the ability of LFAC to reduce the effect of the HB reflex by monitoring the respiration rate during LFAC alone, LFAC and vagal stimulation, and vagal stimulation alone. Results: LFAC achieved 87.2 ±8.8% block (n=5) at current levels of 1.1 ±0.3 mAp (current to peak), which was well within the water window of the working electrode. CNAP showed changes that directly correlated to the effectiveness of LFAC block, which manifested itself as the slowing and amplitude reduction of components of the CNAP. Conclusion: These novel findings suggest that LFAC is a potential alternative or complementary method to other electrical blocking techniques in clinical applications.
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    Tumor Cell Secretomes in Response to Anti- and Pro-Tumorigenic Agents
    (MDPI, 2021) Liu, Sheng-Zhi; Sun, Xun; Li, Ke-Xin; Lin, Chien-Chi; Na, Sungsoo; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    Tumor cells regulate their progression not only by the factors within their cell bodies but also by the secretome they produce and secrete. While their secretome significantly alters the fate of tumor cells themselves, they also regulate the growth of surrounding cells including both companion cancer and non-cancer cells. Tumor cell secretome consists of varying molecules that have been reported mostly tumor-promotive. Furthermore, their pro-tumor capability is enhanced by the application of chemotherapeutic agents. However, multiple lines of emerging evidence suggest that the tumor cell secretome can be tumor-suppressive in response to paracrine and endocrine signaling. This review introduces both tumor-promotive and tumor-suppressive secretomes, focusing on multi-tasking proteins in the intracellular and extracellular domains. We describe tumorigenic signaling that governs the nature of the tumor cell secretome and discuss the possibility of inducing tumor-suppressive proteomes as a novel option for cancer treatment. We evaluated the counterintuitive procedure to generate tumor-suppressive proteomes from a unique type of tumor-modifying cells, which are named “induced tumor-suppressing cells” (iTSCs).