Department of Biomedical Engineering

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3D Reconstruction of Coronary Artery Vascular Smooth Muscle Cells.
(PLOS, 2016) Luo, Tong; Chen, Huan; Kassab, Ghassan S.; Department of Biomedical Engineering, Purdue School of Engineering and Technology, IUPUI
Aims: The 3D geometry of individual vascular smooth muscle cells (VSMCs), which are essential for understanding the mechanical function of blood vessels, are currently not available. This paper introduces a new 3D segmentation algorithm to determine VSMC morphology and orientation. Methods and Results: A total of 112 VSMCs from six porcine coronary arteries were used in the analysis. A 3D semi-automatic segmentation method was developed to reconstruct individual VSMCs from cell clumps as well as to extract the 3D geometry of VSMCs. A new edge blocking model was introduced to recognize cell boundary while an edge growing was developed for optimal interpolation and edge verification. The proposed methods were designed based on Region of Interest (ROI) selected by user and interactive responses of limited key edges. Enhanced cell boundary features were used to construct the cell’s initial boundary for further edge growing. A unified framework of morphological parameters (dimensions and orientations) was proposed for the 3D volume data. Virtual phantom was designed to validate the tilt angle measurements, while other parameters extracted from 3D segmentations were compared with manual measurements to assess the accuracy of the algorithm. The length, width and thickness of VSMCs were 62.9±14.9μm, 4.6±0.6μm and 6.2±1.8μm (mean±SD). In longitudinal-circumferential plane of blood vessel, VSMCs align off the circumferential direction with two mean angles of -19.4±9.3° and 10.9±4.7°, while an out-of-plane angle (i.e., radial tilt angle) was found to be 8±7.6° with median as 5.7°. Conclusions: A 3D segmentation algorithm was developed to reconstruct individual VSMCs of blood vessel walls based on optical image stacks. The results were validated by a virtual phantom and manual measurement. The obtained 3D geometries can be utilized in mathematical models and leads a better understanding of vascular mechanical properties and function.
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 Technology
Raloxifene (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.
Accurate and representative decoding of the neural drive to muscles in humans with multi-channel intramuscular thin-film electrodes
(Wiley, 2015-09-01) Muceli, Silvia; Poppendieck, Wigand; Negro, Francesco; Yoshida, Ken; Hoffmann, Klaus P.; Butler, Jane E.; Gandevia, Simon C.; Farina, Dario; Department of Biomedical Engineering, School of Engineering and Technology
Intramuscular electrodes developed over the past 80 years can record the concurrent activity of only a few motor units active during a muscle contraction. We designed, produced and tested a novel multi-channel intramuscular wire electrode that allows in vivo concurrent recordings of a substantially greater number of motor units than with conventional methods. The electrode has been extensively tested in deep and superficial human muscles. The performed tests indicate the applicability of the proposed technology in a variety of conditions. The electrode represents an important novel technology that opens new avenues in the study of the neural control of muscles in humans. We describe the design, fabrication and testing of a novel multi-channel thin-film electrode for detection of the output of motoneurones in vivo and in humans, through muscle signals. The structure includes a linear array of 16 detection sites that can sample intramuscular electromyographic activity from the entire muscle cross-section. The structure was tested in two superficial muscles (the abductor digiti minimi (ADM) and the tibialis anterior (TA)) and a deep muscle (the genioglossus (GG)) during contractions at various forces. Moreover, surface electromyogram (EMG) signals were concurrently detected from the TA muscle with a grid of 64 electrodes. Surface and intramuscular signals were decomposed into the constituent motor unit (MU) action potential trains. With the intramuscular electrode, up to 31 MUs were identified from the ADM muscle during an isometric contraction at 15% of the maximal force (MVC) and 50 MUs were identified for a 30% MVC contraction of TA. The new electrode detects different sources from a surface EMG system, as only one MU spike train was found to be common in the decomposition of the intramuscular and surface signals acquired from the TA. The system also allowed access to the GG muscle, which cannot be analysed with surface EMG, with successful identification of MU activity. With respect to classic detection systems, the presented thin-film structure enables recording from large populations of active MUs of deep and superficial muscles and thus can provide a faithful representation of the neural drive sent to a muscle.
An afferent explanation for sexual dimorphism in the aortic baroreflex of rat
(American Physiological Society (APS), 2014-09-15) Santa Cruz Chavez, Grace C.; Li, Bai-Yan; Glazebrook, Patricia A.; Kunze, Diana L.; Schild, John H.; Department of Biomedical Engineering, Purdue School of Engineering and Technology, IUPUI
Sex differences in baroreflex (BRx) function are well documented. Hormones likely contribute to this dimorphism, but many functional aspects remain unresolved. Our lab has been investigating a subset of vagal sensory neurons that constitute nearly 50% of the total population of myelinated aortic baroreceptors (BR) in female rats but less than 2% in male rats. Termed “Ah,” this unique phenotype has many of the nonoverlapping electrophysiological properties and chemical sensitivities of both myelinated A-type and unmyelinated C-type BR afferents. In this study, we utilize three distinct experimental protocols to determine if Ah-type barosensory afferents underlie, at least in part, the sex-related differences in BRx function. Electron microscopy of the aortic depressor nerve (ADN) revealed that female rats have less myelin (P < 0.03) and a smaller fiber cross-sectional area (P < 0.05) per BR fiber than male rats. Electrical stimulation of the ADN evoked compound action potentials and nerve conduction profiles that were markedly different (P < 0.01, n = 7 females and n = 9 males). Selective activation of ADN myelinated fibers evoked a BRx-mediated depressor response that was 3–7 times greater in female (n = 16) than in male (n = 17) rats. Interestingly, the most striking hemodynamic difference was functionally dependent upon the rate of myelinated barosensory fiber activation. Only 5–10 Hz of stimulation evoked a rapid, 20- to 30-mmHg reduction in arterial pressure of female rats, whereas rates of 50 Hz or higher were required to elicit a comparable depressor response from male rats. Collectively, our experimental results are suggestive of an alternative myelinated baroreceptor afferent pathway in females that may account for, at least in part, the noted sex-related differences in autonomic control of cardiovascular function.
Applications of atomic force microscopy for the assessment of nanoscale morphological and mechanical properties of bone
(2012-01) Wallace, Joseph M.
Scanning probe microscopy (SPM) has been in use for 30 years, and the form of SPM known as atomic force microscopy (AFM) has been around for 25 of those years. AFM has been used to produce high resolution images of a variety of samples ranging from DNA to carbon nanotubes. Type I collagen and many collagen-based tissues (including dentin, tendon, cartilage, skin, fascia, vocal cords, and cornea) have been studied with AFM, but comparatively few studies of bone have been undertaken. The purpose of this review is to introduce the general principles of AFM operation, demonstrate what AFM has been used for in bone research, and discuss the new directions that this technique can take the study of bone at the nanoscale.
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 Technology
Bone 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.
Biaxial deformation of collagen and elastin fibers in coronary adventitia
(American Physiological Society (APS), 2013-12-01) Chen, Huan; Slipchenko, Mikhail N.; Liu, Yi; Zhao, Xuefeng; Cheng, Ji-Xin; Lanir, Yoram; Kassab, Ghassan S.; Department of Biomedical Engineering, Purdue School of Engineering and Technology, IUPUI
The microstructural deformation-mechanical loading relation of the blood vessel wall is essential for understanding the overall mechanical behavior of vascular tissue in health and disease. We employed simultaneous mechanical loading-imaging to quantify in situ deformation of individual collagen and elastin fibers on unstained fresh porcine coronary adventitia under a combination of vessel inflation and axial extension loading. Specifically, the specimens were imaged under biaxial loads to study microscopic deformation-loading behavior of fibers in conjunction with morphometric measurements at the zero-stress state. Collagen fibers largely orientate in the longitudinal direction, while elastin fibers have major orientation parallel to collagen, but with additional orientation angles in each sublayer of the adventitia. With an increase of biaxial load, collagen fibers were uniformly stretched to the loading direction, while elastin fibers gradually formed a network in sublayers, which strongly depended on the initial arrangement. The waviness of collagen decreased more rapidly at a circumferential stretch ratio of λθ = 1.0 than at λθ = 1.5, while most collagen became straightened at λθ = 1.8. These microscopic deformations imply that the longitudinally stiffer adventitia is a direct result of initial fiber alignment, and the overall mechanical behavior of the tissue is highly dependent on the corresponding microscopic deformation of fibers. The microstructural deformation-loading relation will serve as a foundation for micromechanical models of the vessel wall.
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 Technology
Introduction: 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.
Board 3: CLEAR Scholars in Engineering: Academic, Career, and Leadership Development to Help Students with Financial Challenges Achieve their Full Academic Potential
(ASEE, 2018) Alfrey, Karen D.; Biomedical Engineering, School of Engineering and Technology
Funded by a National Science Foundation S-STEM grant, the CLEAR Scholars in Engineering program provides financial support, mentoring, and leadership and career development to undergraduate students with demonstrated potential to succeed in engineering, but who face significant financial challenges, possibly in combination with other barriers to meeting their full potential, such as being a first-generation college student or a member of an underrepresented group. In addition to scholarship support, CLEAR Scholars are provided with an intentional set of activities that promotes student retention, achievement, and persistence to graduation through: (a) Community-building through a cohort model; (b) Leadership and career development; (c) Engagement with industry; (d) Advising through mentoring; and (e) Resources for academic success (hence the acronym CLEAR). The ultimate goal of this project is to produce engineering graduates with lower student loan indebtedness and greater preparation for post-degree roles. After five years, 13 out of 14 students who participated in the program so far successfully completed an engineering degree; and of those graduates, 12 out of 13 remain in a STEM field either in an industry or academic job or in a post-baccalaureate educational program. We have found that participants in the program have been significantly more likely than average to pursue an industrial or research internship as an undergraduate, contributing both to retention in their chosen fields and post-graduation success.
Bone cell-independent benefits of raloxifene on the skeleton: A novel mechanism for improving bone material properties
(2014) Gallant, Maxime A.; Brown, Drew M.; Hammond, Max; Wallace, Joseph M.; Du, Jiang; Deymier-Black, Alix C.; Almer, Jonathan D.; Stock, Stuart R.; Allen, Matthew R.; Burr, David B.
Raloxifene is an FDA approved agent used to treat bone loss and decrease fracture risk. In clinical trials and animal studies, raloxifene reduces fracture risk and improves bone mechanical properties, but the mechanisms of action remain unclear because these benefits occur largely independent of changes to bone mass. Using a novel experimental approach, machined bone beams, both from mature male canine and human male donors, were depleted of living cells and then exposed to raloxifene ex vivo. Our data show that ex vivo exposure of non-viable bone to raloxifene improves intrinsic toughness, both in canine and human cortical bone beams tested by 4-point bending. These effects are cell-independent and appear to be mediated by an increase in matrix bound water, assessed using basic gravimetric weighing and sophisticated ultrashort echo time magnetic resonance imaging. The hydroxyl groups (-OH) on raloxifene were shown to be important in both the water and toughness increases. Wide and small angle x-ray scattering patterns during 4-pt bending show that raloxifene alters the transfer of load between the collagen matrix and the mineral crystals, placing lower strains on the mineral, and allowing greater overall deformation prior to failure. Collectively, these findings provide a possible mechanistic explanation for the therapeutic effect of raloxifene and more importantly identify a cell-independent mechanism that can be utilized for novel pharmacological approaches for enhancing bone strength.

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