Browsing by Author "Biomedical Engineering, School of Engineering and Technology"
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Item 6'-Methoxy Raloxifene-analog enhances mouse bone properties with reduced estrogen receptor binding(Elsevier, 2020-01-17) Powell, Katherine M.; Brown, Alexa P.; Skaggs, Cayla G.; Pulliam, Alexis N.; Berman, Alycia G.; Deosthale, Padmini; Plotkin, Lilian I.; Allen, Matthew R.; Williams, David R.; Wallace, Joseph M.; Biomedical Engineering, School of Engineering and TechnologyRaloxifene (RAL) is an FDA-approved drug used to treat osteoporosis in postmenopausal women. RAL suppresses bone loss primarily through its role as a selective estrogen receptor modulator (SERM). This hormonal estrogen therapy promotes unintended side effects, such as hot flashes and increased thrombosis risk, and prevents the drug from being used in some patient populations at-risk for fracture, including children with bone disorders. It has recently been demonstrated that RAL can have significant positive effects on overall bone mechanical properties by binding to collagen and increasing bone tissue hydration in a cell-independent manner. A Raloxifene-Analog (RAL-A) was synthesized by replacing the 6-hydroxyl substituent with 6-methoxy in effort to reduce the compound's binding affinity for estrogen receptors (ER) while maintaining its collagen-binding ability. It was hypothesized that RAL-A would improve the mechanical integrity of bone in a manner similar to RAL, but with reduced estrogen receptor binding. Molecular assessment showed that while RAL-A did reduce ER binding, downstream ER signaling was not completely abolished. In-vitro, RAL-A performed similarly to RAL and had an identical concentration threshold on osteocyte cell proliferation, differentiation, and function. To assess treatment effect in-vivo, wildtype (WT) and heterozygous (OIM+/-) female mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL or RAL-A from 8 weeks to 16 weeks of age. There was an untreated control group for each genotype as well. Bone microarchitecture was assessed using microCT, and mechanical behavior was assessed using 3-point bending. Results indicate that both compounds produced analogous gains in tibial trabecular and cortical microarchitecture. While WT mechanical properties were not drastically altered with either treatment, OIM+/- mechanical properties were significantly enhanced, most notably, in post-yield properties including bone toughness. This proof-of-concept study shows promising results and warrants the exploration of additional analog iterations to further reduce ER binding and improve fracture resistance.Item Accurate simulation of cuff electrode stimulation predicting in-vivo strength-duration thresholds(Wiley, 2022) Lazorchak, Nathaniel; Horn, M. Ryne; Muzquiz, M. Ivette; Mintch, Landan M.; Yoshida, Ken; Biomedical Engineering, School of Engineering and TechnologyBackground: In-silico experiments used to optimize and inform how peripheral nerve based electrode designs perform hold the promise of greatly reducing the guesswork with new designs as well as the number of animals used to identify and prove promising designs. Given adequate realism, in-silico experiments offer the promise of identifying putative mechanisms that further inform exploration of novel stimulation and recording techniques and their interactions with bioelectric phenomena. However, despite using validated nerve fiber models, when applied to the more complex case of an implanted extracellular electrode, the in-silico experiments often do not compare quantitatively with the results of experiments conducted in in-vivo experiments. This suggests that the accuracy/realism of the environment and the lamination of the nerve bundle plays an important role in this discrepancy. This paper describes the sensitivity of in-silico models to the electrical parameter estimates and volume conductor type used. Methods: In-vivo work was performed on rat vagus nerves (N = 2) to characterize the strength-duration curve for various peaks identified in a compound nerve action potential (CAP) measured via a needle electrode. The vagus nerve has several distinct populations of nerve fiber calibers and types. Recruitment of a fiber caliber/type generates distinct peaks that can be identified, and whose conduction delay correlates to a conduction velocity. Peaks were identified by their recruitment thresholds and associated to their conduction velocities by the conduction delays of their peaks. An in-silico analog of the in-vivo experiment was constructed and experiments were run at the two extreme volume conductor cases: (1) The nerve in-saline, and (2) the nerve in-air. The specifically targeted electrical parameters were extraneural environment (in-air versus saline submersion), the resistivity (ρ) of the epineurium and perineurium, and the relative permittivity (εr ) of those same tissues. A time varying finite element method (FEM) model of the potential distribution vs time was quantified and projected onto a modified McIntyre, Richardson, and Grill (MRG), myelinated spinal nerve, active fiber model in NEURON to identify the threshold of activation as a function of stimulus pulse amplitude versus pulse width versus fiber diameter. The in-silico results were then compared to the in-vivo results. Results: The finite element method simulations spanned two macro environments: in-saline and in-air. For these environments, the resistivities for low and high frequencies as well as two different permittivity cases were used. Between these 8 cases unique cases it was found that the most accurate combination of those variables was the in-air environment for low-frequency resistivity (ρ0 ) and ex-vivo a measured permittivity (εr,measured ) from unpublished ex-vivo experiments in canine vagal nerve, achieving a high degree of convergence (r2 = 0.96). As the in-vivo work was conducted in in-air, the in-air boundary condition test case was convergent with the in-silico results. Conclusions: The results of this investigation suggest that increasing realism in simulations begets more accurate predictions. Of particular importance are (ρ) and extraneural environment, with reactive electrical parameters becoming important for input waveforms with energy in higher frequencies.Item Anticancer Peptides Derived from Aldolase A and Induced Tumor-Suppressing Cells Inhibit Pancreatic Ductal Adenocarcinoma Cells(MDPI, 2023-10-11) Cui, Changpeng; Huo, Qingji; Xiong, Xue; Li, Kexin; Fishel, Melissa L.; Li, Baiyan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyPDAC (pancreatic ductal adenocarcinoma) is a highly aggressive malignant tumor. We have previously developed induced tumor-suppressing cells (iTSCs) that secrete a group of tumor-suppressing proteins. Here, we examined a unique procedure to identify anticancer peptides (ACPs), using trypsin-digested iTSCs-derived protein fragments. Among the 10 ACP candidates, P04 (IGEHTPSALAIMENANVLAR) presented the most efficient anti-PDAC activities. P04 was derived from aldolase A (ALDOA), a glycolytic enzyme. Extracellular ALDOA, as well as P04, was predicted to interact with epidermal growth factor receptor (EGFR), and P04 downregulated oncoproteins such as Snail and Src. Importantly, P04 has no inhibitory effect on mesenchymal stem cells (MSCs). We also generated iTSCs by overexpressing ALDOA in MSCs and peripheral blood mononuclear cells (PBMCs). iTSC-derived conditioned medium (CM) inhibited the progression of PDAC cells as well as PDAC tissue fragments. The inhibitory effect of P04 was additive to that of CM and chemotherapeutic drugs such as 5-Flu and gemcitabine. Notably, applying mechanical vibration to PBMCs elevated ALDOA and converted PBMCs into iTSCs. Collectively, this study presented a unique procedure for selecting anticancer P04 from ALDOA in an iTSCs-derived proteome for the treatment of PDAC.Item Anticancer peptides from induced tumor-suppressing cells for inhibiting osteosarcoma cells(e-Century, 2023-09-15) Cui, Chang-Peng; Huo, Qing-Ji; Xiong, Xue; Li, Ke-Xin; Ma, Peng; Qiang, Gui-Fen; Pandya, Pankita H.; Saadatzadeh, Mohammad R.; Vishehsaraei, Khadijeh Bijangi; Kacena, Melissa A.; Aryal, Uma K.; Pollok, Karen E.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyOsteosarcoma (OS) is the most frequent primary bone cancer, which is mainly suffered by children and young adults. While the current surgical treatment combined with chemotherapy is effective for the early stage of OS, advanced OS preferentially metastasizes to the lung and is difficult to treat. Here, we examined the efficacy of ten anti-OS peptide candidates from a trypsin-digested conditioned medium that was derived from the secretome of induced tumor-suppressing cells (iTSCs). Using OS cell lines, the antitumor capabilities of the peptide candidates were evaluated by assaying the alterations in metabolic activities, proliferation, motility, and invasion of OS cells. Among ten candidates, peptide P05 (ADDGRPFPQVIK), a fragment of aldolase A (ALDOA), presented the most potent OS-suppressing capabilities. Its efficacy was additive with standard-of-care chemotherapeutic agents such as cisplatin and doxorubicin, and it downregulated oncoproteins such as epidermal growth factor receptor (EGFR), Snail, and Src in OS cells. Interestingly, P05 did not present inhibitory effects on non-OS skeletal cells such as mesenchymal stem cells and osteoblast cells. Collectively, this study demonstrated that iTSC-derived secretomes may provide a source for identifying anticancer peptides, and P05 may warrant further evaluations for the treatment of OS.Item Assessing monocyte phenotype in poly(γ-glutamic acid) hydrogels formed by orthogonal thiol–norbornene chemistry(IOP, 2021-07) Kim, Min Hee; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and TechnologyHydrogels with tunable properties are highly desirable in tissue engineering applications as they can serve as artificial extracellular matrix to control cellular fate processes, including adhesion, migration, differentiation, and other phenotypic changes via matrix induced mechanotransduction. Poly(γ-glutamic acid) (PGA) is an natural anionic polypeptide that has excellent biocompatibility, biodegradability, and water solubility. Moreover, the abundant carboxylic acids on PGA can be readily modified to introduce additional functionality or facilitate chemical crosslinking. PGA and its derivatives have been widely used in tissue engineering applications. However, no prior work has explored orthogonal crosslinking of PGA hydrogels by thiol-norbornene (NB) chemistry. In this study, we report the synthesis and orthogonal crosslinking of PGA-norbornene (PGANB) hydrogels. PGANB was synthesized by standard carbodiimide chemistry and crosslinked into hydrogels via either photopolymerization or enzymatic reaction. Moduli of PGA hydrogels were readily tuned by controlling thiol-NB crosslinking conditions or stoichiometric ratio of functional groups. Orthogonally crosslinked PGA hydrogels were used to evaluate the influence of mechanical cues of hydrogel substrate on the phenotype of naïve human monocytes and M0 macrophages in 3D culture.Item Attraction and Compaction of Migratory Breast Cancer Cells by Bone Matrix Proteins through Tumor-Osteocyte Interactions(Nature Publishing Group, 2018-04-03) Chen, Andy; Wang, Luqi; Liu, Shengzhi; Wang, Yue; Liu, Yunlong; Wang, Mu; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyBone is a frequent site of metastasis from breast cancer. To understand the potential role of osteocytes in bone metastasis, we investigated tumor-osteocyte interactions using two cell lines derived from the MDA-MB-231 breast cancer cells, primary breast cancer cells, and MLO-A5/MLO-Y4 osteocyte cells. When three-dimensional (3D) tumor spheroids were grown with osteocyte spheroids, tumor spheroids fused with osteocyte spheroids and shrank. This size reduction was also observed when tumor spheroids were exposed to conditioned medium isolated from osteocyte cells. Mass spectrometry-based analysis predicted that several bone matrix proteins (e.g., collagen, biglycan) in conditioned medium could be responsible for tumor shrinkage. The osteocyte-driven shrinkage was mimicked by type I collagen, the most abundant organic component in bone, but not by hydroxyapatite, a major inorganic component in bone. RNA and protein expression analysis revealed that tumor-osteocyte interactions downregulated Snail, a transcription factor involved in epithelial-to-mesenchymal transition (EMT). An agarose bead assay showed that bone matrix proteins act as a tumor attractant. Collectively, the study herein demonstrates that osteocytes attract and compact migratory breast cancer cells through bone matrix proteins, suppress tumor migration, by Snail downregulation, and promote subsequent metastatic colonization.Item Author Correction: Inhibitory effects of dopamine receptor D1 agonist on mammary tumor and bone metastasis(Springer Nature, 2022-11-03) Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai‑Yan; Matsuura, Nariaki; Koizumi, Masahiko; Yin, Yukun; Gan, Liangying; Xu, Aihua; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyThis corrects the article "Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis" in volume 7, 45686. doi: 10.1038/srep45686Item The baroreflex afferent pathway plays a critical role in H2S-mediated autonomic control of blood pressure regulation under physiological and hypertensive conditions(Springer Nature, 2021) Li, Ying; Feng, Yan; Liu, Li; Li, Xue; Li, Xin-yu; Sun, Xun; Li, Ke-xin; Zha, Rong-rong; Wang, Hong-dan; Zhang, Meng-di; Fan, Xiong-xiong; Wu, Di; Fan, Yao; Zhang, Hao-cheng; Qiao, Guo-fen; Li, Bai-yan; Biomedical Engineering, School of Engineering and TechnologyHydrogen sulfide (H2S), which is closely related to various cardiovascular disorders, lowers blood pressure (BP), but whether this action is mediated via the modification of baroreflex afferent function has not been elucidated. Therefore, the current study aimed to investigate the role of the baroreflex afferent pathway in H2S-mediated autonomic control of BP regulation. The results showed that baroreflex sensitivity (BRS) was increased by acute intravenous NaHS (a H2S donor) administration to renovascular hypertensive (RVH) and control rats. Molecular expression data also showed that the expression levels of critical enzymes related to H2S were aberrantly downregulated in the nodose ganglion (NG) and nucleus tractus solitarius (NTS) in RVH rats. A clear reduction in BP by the microinjection of NaHS or L-cysteine into the NG was confirmed in both RVH and control rats, and a less dramatic effect was observed in model rats. Furthermore, the beneficial effects of NaHS administered by chronic intraperitoneal infusion on dysregulated systolic blood pressure (SBP), cardiac parameters, and BRS were verified in RVH rats. Moreover, the increase in BRS was attributed to activation and upregulation of the ATP-sensitive potassium (KATP) channels Kir6.2 and SUR1, which are functionally expressed in the NG and NTS. In summary, H2S plays a crucial role in the autonomic control of BP regulation by improving baroreflex afferent function due at least in part to increased KATP channel expression in the baroreflex afferent pathway under physiological and hypertensive conditions.Item Biomedical Engineering Students Gain Design Knowledge and Report Increased Confidence When Continually Challenged with Integrated Design Projects(ASEE, 2020-06) Higbee, Steven; Miller, Sharon; Biomedical Engineering, School of Engineering and TechnologyIntroduction: The undergraduate biomedical engineering (BME) curriculum should prepare students to confidently approach complex problems, as graduates will enter the workforce in an environment of rising healthcare costs, decreasing average life expectancy, and significant socioeconomic disparities in health outcomes. With this landscape, solutions to contemporary problems will require innovative thinking and groundbreaking medical technologies, suggesting that the future of BME will be increasingly design-oriented. Undergraduate BME curricula generally include laboratory and project components aimed at preparing students for senior capstone; however, students may begin capstone without the knowledge, skills, and confidence required for engineering design success. With these shortcomings in mind, we vertically integrated design experiences in our undergraduate BME curriculum and evaluated student design performance throughout. Methods: Four engineering design project assignments were developed and integrated into sophomore- and junior-level BME laboratory courses, establishing a continuous design thread spanning the four years of the undergraduate BME curriculum. Through the sequence of projects, student teams worked to design (1) fracture fixation devices, (2) electromyogram-controlled motor assemblies, (3) compact spectrophotometers, and (4) programmable drug dosing devices. We developed a common instructional Design Module, organized around an adapted version of the FDA waterfall diagram, and used it in each course to build student understanding of the BME design process. By emphasizing different portions of the waterfall diagram in each course and varying student deliverables, we implemented a stepwise approach to building student design confidence. The set of design projects also intentionally target a multitude of skills relevant to design, including computer-aided design (CAD), computational modeling, iteration, prototyping, programming (LabVIEW and Python), hardware-software integration, and technical communication. A mixed methods approach was employed to assess student knowledge, confidence, and achievement in design. A pre-/post-quiz (8 questions worth 10 points total) was used to assess student knowledge of design concepts and their application toward medical device design. Students self-reported their design confidence levels prior to the first design project and after each design project, and focus groups were held after design projects to assess student design confidence going forward. Students also rated how worthwhile and enjoyable they found each project using a reflection grid and reflected on the integration of prior coursework into their design projects. Finally, student design reports were scored by instructors using a rubric influenced by AAC&U VALUE Rubrics and the Informed Design Teaching and Learning Matrix. Students also self-reported design mastery via survey, and these responses were correlated to scores from the instructor rubric. Results: Students engaged in 200-level and 300-level projects demonstrated knowledge gains of the BME design process after one project (p < 0.0001) and further knowledge gains after a second project (not statistically significant). In particular, students gained knowledge related to the waterfall diagram, design requirements and constraints, and verification and validation (p < 0.005 for each). In their reflections, students demonstrate cognizance of prior coursework knowledge that they have integrated into their designs, adding to the sought-after sense of curricular connectedness. After the completion of each project, students self-reported significant confidence gains in four major areas (p < 0.05 for each): (1) design process and approach, (2) working with hardware, (3) working with software and interfacing with hardware, and (4) communicating results. Focus group responses support the observed quantitative improvements in student design confidence. Finally, instructor scoring of student design reports indicates that design achievement and ability to communicate design improve as students progress through the curriculum; however, student self-assessment of design mastery does not correlate strongly with instructor scores. Discussion: Active learning in undergraduate classrooms has been shown to improve performance, motivation, and communication skills among engineering students. By implementing and assessing hands-on engineering design project assignments at the sophomore and junior levels, we have improved student design knowledge, confidence, and achievement prior to capstone design. Future work will address limitations of student self-reporting of confidence levels and will investigate changes in the quality of capstone projects that could result from better prepared students.Item Biomimetic stiffening of cell-laden hydrogels via sequential thiol-ene and hydrazone click reactions(Elsevier, 2021) Chang, Chun-Yi; Johnson, Hunter C.; Babb, Olivia; Fishel, Melissa L.; Lin, Chien-Chi; Biomedical Engineering, School of Engineering and TechnologyHydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that has received little attention in the development of dynamic hydrogels. In this contribution, we present a gelatin-based cell-laden hydrogel system capable of being dynamically stiffened while accumulating HA, a key glycosaminoglycans (GAG) increasingly deposited by stromal cells during tumor progression. Central to this strategy is the synthesis of a dually-modified gelatin macromer – gelatin-norbornene-carbohydrazide (GelNB-CH), which is susceptible to both thiol-norbornene photopolymerization and hydrazone click chemistry. We demonstrate that the crosslinking density of cell-laden thiol-norbornene hydrogels can be dynamically tuned via simple incubation with aldehyde-bearing macromers (e.g., oxidized dextran (oDex) or oHA). The GelNB-CH hydrogel system is highly cytocompatible, as demonstrated by in situ encapsulation of pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF). The unique dynamic stiffening scheme provides a platform to study tandem accumulation of HA and elevation in matrix stiffness in the pancreatic tumor microenvironment.