Biomedical Engineering and Bioengineering Commons^™

Pet Imaging Of Early Therapeutic Response In Solid Tumors, Stephanie J. Blocker

Wayne State University Dissertations

An important pillar of precision medicine for oncology is the ability to identify patients who respond to treatment early into their therapy. Positron emission tomography (PET) allows physicians and researchers to measure changes in tumor behavior prior to noticeable differences in morphology.

Objective: Determine the utility of multiple tracers for PET in assessing early changes in tumor activity that result from treatment.

Methods: Two tracers for PET were studied. 64Cu-labeled liposomes were used to assess changes in liposome delivery two solid colon tumors early into treatment with bevacizumab (Bev). 18F-FMAU thymidine analog (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine), was utilized to detect early response to …

Finite Element Simulation And Additive Manufacturing Of Stiffness-Matched Niti Fixation Hardware For Mandibular Reconstruction Surgery, Ahmadreza Jahadakbar, Narges Shayesteh Moghaddam, Amirhesam Amerinatanzi, David Dean, Haluk E. Karaca, Mohammad Elahinia

Mechanical Engineering Faculty Publications

Process parameters and post-processing heat treatment techniques have been developed to produce both shape memory and superelastic NiTi using Additive Manufacturing. By introducing engineered porosity, the stiffness of NiTi can be tuned to the level closely matching cortical bone. Using additively manufactured porous superelastic NiTi, we have proposed the use of patient-specific, stiffness-matched fixation hardware, for mandible skeletal reconstructive surgery. Currently, Ti-6Al-4V is the most commonly used material for skeletal fixation devices. Although this material offers more than sufficient strength for immobilization during the bone healing process, the high stiffness of Ti-6Al-4V implants can cause stress shielding. In this paper, …

Raman Spectroscopy Detects Distant Invasive Brain Cancer Cells Centimeters Beyond Mri Capability In Humans, Michael Jermyn, Joannie Desroches, Jeanne Mercier, Karl St-Arnaud

Dartmouth Scholarship

Surgical treatment of brain cancer is limited by the inability of current imaging capabilities such as magnetic resonance imaging (MRI) to detect the entirety of this locally invasive cancer. This results in residual cancer cells remaining following surgery, leading to recurrence and death. We demonstrate that intraoperative Raman spectroscopy can detect invasive cancer cells centimeters beyond pathological T1-contrast-enhanced and T2-weighted MRI signals. This intraoperative optical guide can be used to detect invasive cancer cells and minimize post-surgical cancer burden. The detection of distant invasive cancer cells beyond MRI signal has the potential to increase the effectiveness of surgery and directly …

Long-Term Biocompatibility, Imaging Appearance And Tissue Effects Associated With Delivery Of A Novel Radiopaque Embolization Bead For Image-Guided Therapy, Karun Sharma, Zainab Bascal, Hugh Kilpatrick, Koorosh Ashrafi, Sean L. Willis, Matthew R. Dreher, Andrew L. Lewis

Pediatrics Faculty Publications

The objective of this study was to undertake a comprehensive long-term biocompatibility and imaging assessment of a new intrinsically radiopaque bead (LC Bead LUMI™) for use in transarterial embolization. The sterilized device and its extracts were subjected to the raft of ISO10993 biocompatibility tests that demonstrated safety with respect to cytotoxicity, mutagenicity, blood contact, irritation, sensitization, systemic toxicity and tissue reaction. Intra-arterial administration was performed in a swine model of hepatic arterial embolization in which 0.22–1 mL of sedimented bead volume was administered to the targeted lobe(s) of the liver. The beads could be visualized during the embolization procedure with …

A Fourier Description Of Covariance, And Separation Of Simultaneously Encoded Slices With In-Plane Acceleration In Fmri, Mary C. Kociuba

Dissertations (1934 -)

Functional magnetic resonance imaging (fMRI) studies aim to identify localized neural regions associated with a cognitive task performed by the subject. An indirect measure of the brain activity is the blood oxygenation level dependent (BOLD) signal fluctuations observed within the complex-valued spatial frequencies measured over time. The standard practice in fMRI is to discard the phase information after image reconstruction, even with evidence of biological task-related change in the phase time-series. In the first aim of this dissertation, a complex-valued time-series covariance is derived as a linear combination of second order temporal Fourier frequency coefficients. As opposed to magnitude-only analysis, …

An Interactive Videogame Designed To Improve Respiratory Navigator Efficiency In Children Undergoing Cardiovascular Magnetic Resonance, Sean M. Hamlet, Christopher M. Haggerty, Jonathan D. Suever, Gregory J. Wehner, Jonathan D. Grabau, Kristin N. Andres, Moriel H. Vandsburger, David K. Powell, Vincent L. Sorrell, Brandon K. Fornwalt

Saha Cardiovascular Research Center Faculty Publications

Background: Advanced cardiovascular magnetic resonance (CMR) acquisitions often require long scan durations that necessitate respiratory navigator gating. The tradeoff of navigator gating is reduced scan efficiency, particularly when the patient’s breathing patterns are inconsistent, as is commonly seen in children. We hypothesized that engaging pediatric participants with a navigator-controlled videogame to help control breathing patterns would improve navigator efficiency and maintain image quality.

Methods: We developed custom software that processed the Siemens respiratory navigator image in real-time during CMR and represented diaphragm position using a cartoon avatar, which was projected to the participant in the scanner as visual feedback. The …

Imaging Right Ventricular Function To Predict Outcome In Pulmonary Arterial Hypertension, Alessandro Bellofiore, Melanie Brewis, Rebecca Vanderpool, Naomi Chesler, Martin Johnson, Robert Naeije, Andrew Peacock

Faculty Publications

Right ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation.MethodsWe measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV–arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or …

Microdose Fluorescence Imaging Of Aby-029 On An Operating Microscope Adapted By Custom Illumination And Imaging Modules, Jonathan T. Elliott, Alisha V. Dsouza, Kayla Marra, Brian W. Pogue, David Roberts, Keith Paulsen

Dartmouth Scholarship

Fluorescence guided surgery has the potential to positively impact surgical oncology; current operating microscopes and stand-alone imaging systems are too insensitive or too cumbersome to maximally take advantage of new tumor-specific agents developed through the microdose pathway. To this end, a custom-built illumination and imaging module enabling picomolar-sensitive near-infrared fluorescence imaging on a commercial operating microscope is described. The limits of detection and system specifications are characterized, and in vivo efficacy of the system in detecting ABY-029 is evaluated in a rat orthotopic glioma model following microdose injections, showing the suitability of the device for microdose phase 0 clinical trials.

Application Of Bioinstrumentation In Developing A Pressure Suit For Suborbital Flight, Pedro Llanos, Erik Seedhouse

Publications

This presentation features Embry-Riddle Aeronautical University's U-2 pressure suit. Built to be light and cost-effective, this suit is comfortable, comes in multiple sizes, operates in pressures up to 5 PSID, has an active airflow-based cooling system, and features bio-instrumentation to measure heart rate, breathing rate, skin temperature and other vitals.

Diffuse Optical Measurements Of Head And Neck Tumor Hemodynamics For Early Prediction Of Chemoradiation Therapy Outcomes, Lixin Dong, Mahesh Kudrimoti, Daniel Irwin, Li Chen, Sameera Kumar, Yu Shang, Chong Huang, Ellis L. Johnson, Scott D. Stevens, Brent J. Shelton, Guoqiang Yu

Biomedical Engineering Faculty Publications

This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n = 29) and incomplete response (IR) (n = 18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 …

Nanobubbles Provide Theranostic Relief To Cancer Hypoxia, Christopher M. Long, Pushpak N. Bhandari, Joseph Irudayaraj

The Summer Undergraduate Research Fellowship (SURF) Symposium

Hypoxia is a common motif among tumors, contributing to metastasis, angiogenesis, cellular epigenetic abnormality, and resistance to cancer therapy. Hypoxia also plays a pivotal role in oncological studies, where it can be used as a principal target for new anti-cancer therapeutic methods. Oxygen nanobubbles were designed in an effort to target the hypoxic tumor regions, thus interrupting the hypoxia-inducible factor-1α (HIF-1α) regulatory pathway and inhibiting tumor progression. At less than 100nm, oxygen nanobubbles act as a vehicle for site-specific oxygen delivery, while also serving as an ultrasound contrast agent for advanced imaging purposes. Through in vitro and in vivo studies, …

Characterization Of Left-Ventricular Thrombus Formation Using High Frequency Ultrasound, Kelsey A. Bullens, Arvin H. Soepriatna, Pavlos P. Vlachos, Craig J. Goergen

The Summer Undergraduate Research Fellowship (SURF) Symposium

Heart failure is a leading cause of death in the United States, and cardiac thrombus, a common morbidity associated with heart failure, significantly increases a patient’s risk of embolic events. The objective of this project is to characterize left-ventricular (LV) thrombus development using high frequency ultrasound imaging in a murine model. C57BL/6J wild-type mice (n=6) were injected intraperitoneally with iron dextran five times a week for six weeks to increase oxidative stress in the heart. Granulocyte-colony stimulating factor (G-CSF) was subcutaneously injected daily during the second week to initiate stem cell migration and stimulate endothelial cell activation, thus increasing the …

Three-Dimensional Printing And Nanotechnology For Enhanced Implantable Materials, Karthik Kumar Tappa

Doctoral Dissertations

Orthopedic and oro-maxillofacial implants have revolutionized treatment of bone diseases and fractures. Currently available metallic implants have been in clinical use for more than 40 years and have proved medically efficacious. However, several drawbacks remain, such as excessive stiffness, accumulation of metal ions in surrounding tissue, growth restriction, required removal/revision surgery, inability to carry drugs, and susceptibility to infection. The need for additional revision surgery increases financial costs and prolongs recovery time for patients. These metallic implants are bulk manufactured and often do not meet patient's requirements. A surgeon must machine (cut, weld, trim or drill holes) them in order …

Portable, Parallel 9-Wavelength Near-Infrared Spectral Tomography (Nirst) System For Efficient Characterization Of Breast Cancer Within The Clinical Oncology Infusion Suite, Yan Zhao, Brian W. Pogue, Steffen J. Haider, Jiang Gui, Roberta Diflorio-Alexander, Keith Paulsen, Shudong Jiang

Dartmouth Scholarship

A portable near-infrared spectral tomography (NIRST) system was developed with simultaneous frequency domain (FD) and continuous-wave (CW) optical measurements for efficient characterization of breast cancer in a clinical oncology setting. Simultaneous FD and CW recordings were implemented to speed up acquisition to 3 minutes for all 9 wavelengths, spanning a range from 661nm to 1064nm. An adjustable interface was designed to fit various breast sizes and shapes. Spatial images of oxy- and deoxy-hemoglobin, water, lipid, and scattering components were reconstructed using a 2D FEM approach. The system was tested on a group of 10 normal subjects, who were examined bilaterally …

Using Mathematical Modeling To Unmask The Concealed Nature Of Long Qt-3 Syndrome, Steven Poelzing, Amara Greer-Short, Seth H. Weinberg

Biology and Medicine Through Mathematics Conference

No abstract provided.

Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez

Biology: Student Scholarship & Creative Works

ABSTRACT: The HIV-1 pandemic continues to thrive due to ineffective HIV-1 vaccines. Historically, the world’s most infectious diseases, such as polio and smallpox, have been eradicated or have come close to eradication due to the advent of effective vaccines. Highly active antiretroviral therapy is able to delay the onset of AIDS but can neither rid the body of HIV-1 proviral DNA nor prevent further transmission. A prophylactic vaccine that prevents the various mechanisms HIV-1 has to evade and attack our immune system is needed to end the HIV-1 pandemic. Recent advances in engineered nuclease systems, like the CRISPR/Cas9 system, have …

Cardiac Remodeling And Dysfunction In Childhood Obesity: A Cardiovascular Magnetic Resonance Study, Linyuan Jing, Cassi M. Binkley, Jonathan D. Suever, Nivedita Umasankar, Christopher M. Haggerty, Jennifer Rich, Christopher D. Nevius, Gregory J. Wehner, Sean M. Hamlet, David K. Powell, Aurelia Radulescu, H. Lester Kirchner, Frederick H. Epstein, Brandon K. Fornwalt

Pediatrics Faculty Publications

Background: Obesity affects nearly one in five children and is associated with increased risk of premature death. Obesity-related heart disease contributes to premature death. We aimed to use cardiovascular magnetic resonance (CMR) to comprehensively characterize the changes in cardiac geometry and function in obese children.

Methods and results: Forty-one obese/overweight (age 12 ± 3 years, 56 % female) and 29 healthy weight children (age 14 ± 3 years, 41 % female) underwent CMR, including both standard cine imaging and displacement encoded imaging, for a complete assessment of left ventricular (LV) structure and function. After adjusting for age, LV mass index …

Micellular Electrokinetic Chromatography For Studying Amyloid Beta Oligomer Membrane Affinity, Andrew Bryson

Biomedical Engineering Undergraduate Honors Theses

Amyloid Beta (Aβ) was the major focus of this study. It is a peptide that is present in the brain with a high tendency to self-aggregate. When this protein aggregates, it forms oligomers and protofibrils which in turn are deposited as senile plaques in the brain. The reason for the concern with these plaques is their association with the neurological disorder Alzheimer’s disease. It has been found that the most dangerous oligomers are formed in a portion of the plasma membrane known as lipid rafts. The purpose of this study was to understand how micelles affect the aggregation properties of …

Diffusion Modeling And Device Development For Peritoneal Membrane Oxygenation, Liana Hatoum

Department of Mechanical and Materials Engineering: Dissertations, Theses, and Student Research

Acute respiratory distress syndrome (ARDS) is a pulmonary disease that causes hypoxemia and respiratory failure. The mortality rate for ARDS ranges between 27% and 45%. Current treatments including mechanical ventilation and extracorporeal membrane oxygenation (ECMO) are often associated with high risk complications including barotrauma, infection, thrombosis, and hemorrhage. Alternative pulmonary support techniques are needed to improve the survival rate of patients suffering from ARDS. Previous studies introducing pure O₂ gas, perfluorocarbons and red blood cells into the intraperitoneal (IP) cavity have reported no effect or only a mild increase in oxygenation. Here we report peritoneal membrane oxygenation (PMO) using …

Pulmonary Primary Blast Injuries, Moe Uddin

Honors Scholar Theses

Primary underwater explosions are particularly dangerous because of the water properties relative to air, and the resulting pathologies presents difficulty in determining their etiologies. The whole body is affected by the blast wave and the survivor is considered a trauma patient. The exact mechanism of injury is not well understood. In the literature, there are inconsistencies between the explosive and the resulting outcome of the experimental animals. Primary lung blast injuries is the leading cause of mortality in underwater explosions and this explores the different pathologies, symptoms, and treatments that are currently available.

The Connectivity Domain: Analyzing Resting State Fmri Data Using Feature-Based Data-Driven And Model-Based Methods, Armin Iraji, Vince D. Calhoun, Natalie M. Wiseman, Esmaeil Davoodi-Bojd, Mohammad R. N. Avanaki, Zhifeng Kou

Biomedical Engineering Faculty Research Publications

Spontaneous fluctuations of resting state functional MRI (rsfMRI) have been widely used to understand the macro-connectome of the human brain. However, these fluctuations are not synchronized among subjects, which leads to limitations and makes utilization of first-level model-based methods challenging. Considering this limitation of rsfMRI data in the time domain, we propose to transfer the spatiotemporal information of the rsfMRI data to another domain, the connectivity domain, in which each value represents the same effect across subjects. Using a set of seed networks and a connectivity index to calculate the functional connectivity for each seed network, we transform data into …

Influence Of The 3d Microenvironment On Glioblastoma Migration And Drug Response, Ruth Marisol Herrera Perez

Open Access Dissertations

Glioblastoma (GBM) is a highly invasive brain cancer characterized by poor prognosis. Despite significant efforts by the basic and clinical research community our understanding of GBM progression and recurrence has been incremental. Improvements in therapeutic response have been dismal, and GBM continues to be the deadliest tumor of the central nervous system, with patient average survival rate of 12 months. Synergistic relationships that the tumor cells establish with the brain microenvironment have been proven fundamental for successful tumor progression and maintenance. Yet, many in vitro GBM studies are performed in formats that fail to recapitulate the most essential component of …

Exploring Oculomotor Trends In Collegiate Athletes, Brett Whorley, Julie A. Honaker

UCARE: Research Products

Collaborative efforts to improve athlete safety without significantly hindering the rules of the games aim to develop a novel system to better measure and diagnose concussions. Provided that common signs of concussions include blurred vision, distant gaze, and dizziness, the Dizziness and Balance Disorders Lab at UNL believes that the simple oculomotor exam studied in this project may be applied to this procedure. Within the broader goal to better understand the causes, signs, symptoms, and prognosis of concussions, researchers desired to further investigate the results of this oculomotor test. The aim was to identify and interpret correlations between collegiate athlete …

Mri Signal Intensity Differentiation Of Brainstem Encephalitis Induced By Enterovirus 71: A Classification Approach For Acute And Convalescence Stages, Hongwu Zeng, Wenxian Huang, Feiqiu Wen, Yonker Wang, Yungen Gan, Weibin Zeng, Ranran Chen, Yanxia He, Zaiyi Liu, Changhong Liang, Kelvin K. L. Wong

Radiology Faculty Publications

Background: The objective of this study is to assess standardized histograms of signal intensities of T1 signal and T2 signal on sagittal view without enhancement during (1) acute stage, and (2) convalescence stage of pediatric patients with Enterovirus 71 related brainstem encephalitis (BE), and with respect to (3) healthy normal.

Methods: Our subjects were hospitalized between March 2010 and October 2012, and underwent pre- and post-contrast MRI studies. The research question to be answered is whether the comparison of the MRI image intensity histograms and relevant statistical quantification can add new knowledge to the diagnosis of BE patients. So, both …

Human Igg1 Antibodies Suppress Angiogenesis In A Target-Independent Manner, Sasha Bogdanovich, Younghee Kim, Takeshi Mizutani, Reo Yasuma, Laura Tudisco, Valeria Cicatiello, Ana Bastos-Carvalho, Nagaraj Kerur, Yoshio Hirano, Judit Z. Baffi, Valeria Tarallo, Shengjian Li, Tetsuhiro Yasuma, Parthasarathy Arpitha, Benjamin James Fowler, Charles B. Wright, Ivana Apicella, Adelaide Greco, Arturo Brunetti, Menotti Ruvo, Annamaria Sandomenico, Miho Nozaki, Ryo Ijima, Hiroki Kaneko, Yuichiro Ogura, Hiroko Terasaki, Balamurali K. Ambati, Jeanette H. W. Leusen, Wallace Y. Langdon, Michael R. Clark, Bradley D. Gelfand, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Publications

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type …

Effect Of Twisted Fiber Anisotropy In Cardiac Tissue On Ablation With Pulsed Electric Fields, Fei Xie, Christian W. Zemlin

Bioelectrics Publications

Background: Ablation of cardiac tissue with pulsed electric fields is a promising alternative to current thermal ablation methods, and it critically depends on the electric field distribution in the heart.

Methods: We developed a model that incorporates the twisted anisotropy of cardiac tissue and computed the electric field distribution in the tissue. We also performed experiments in rabbit ventricles to validate our model. We find that the model agrees well with the experimentally determined ablation volume if we assume that all tissue that is exposed to a field greater than 3 kV/cm is ablated. In our numerical analysis, we considered …

Toward Magnetic Resonance Only Treatment Planning: Distortion Mitigation And Image-Guided Radiation Therapy Validation, Ryan Glen Price

Wayne State University Dissertations

While MR-only treatment planning has shown promise, there are still several well-known challenges that are currently limiting widespread clinical implementation.

Firstly, MR images are affected by both patient-induced and system-level geometric distortions that can significantly degrade treatment planning accuracy. . In addition, the availability of comprehensive distortion analysis software is currently limited. Also while many groups have been working toward a synthetic CT solution, further study is needed on the implementation of synCTs as the reference datasets for linac-based image-guided radiation therapy (IGRT) to help determine their robustness in an MR-only workflow.

A 36×43×2 cm3 phantom with 255 known landmarks …

A Microfluidic-Based Tactile Sensor For Palpating Mice Tumor Tissues, Yichao Yang, Garett Johnson, Dean Krusienski, Siqi Guo, Cheng Lin, Zhili Hao

Mechanical & Aerospace Engineering Faculty Publications

In light of the need of tissue palpation for Robotics-assisted Minimally Invasive Surgery (RMIS), this paper presents a microfluidic-based tactile sensor for palpating mice tissues for tumor localization. The core of the sensor is a 3x3 sensing-plate/transducer array built into a single polydimethylsiloxane (PDMS) microstructure, with a transducer spacing of 3.75mmx1.5mm. Mounted on a robot, the sensor is pressed against a tissue region with a pre-defined indentation depth pattern, and consequently the stiffness distribution across the tissue region translates to the deflection distribution of the sensing-plate array and is captured by the transducer array underneath as resistance changes. Thus, the …

Development And Application Of Gadolinium Free Cardiac Magnetic Resonance Fibrosis Imaging For Multiscale Study Of Heart Failure In Patients With End Stage Renal Disease, Tori A. Stromp

Theses and Dissertations--Physiology

Cardiac magnetic resonance (CMR) is a powerful tool to noninvasively image ventricular fibrosis. Late gadolinium enhancement (LGE) CMR identifies focal and, with T1 mapping, diffuse fibrosis. Despite prevalent cardiac fibrosis and heart failure, patients with end stage renal disease (ESRD) are excluded from LGE. Absence of a suitable diagnostic has limited the understanding of heart failure and obstructed development of therapies in the setting of ESRD. A quantitative, gadolinium free fibrosis detection method could overcome this critical barrier, propelling the advancement of diagnostic, monitoring, and therapy options. This project describes the development of a gadolinium free CMR technique and application …

Radio-Frequency Plasma Polymerized Biodegradable Carrier For In Vivo Release Of Cis-Platinum, Sudhir Bhatt, Fatemeh Valamanesh, Jerome Pulpytel, Rea Lo Dico, Aliby Baiyukha, Iman Al-Dybiat, Marc Pocard, Farzaneh Arefi-Khonsari, Massoud Mirshahi

Bioelectrics Publications

A low pressure plasma process based on plasma deposition has been used to develop a drug delivery strategy. In this study, a drug delivery system based on different layers of plasma co-polymerized Poly ε-caprolactone-Polyethylene glycol (PCL-PEG) co-polymers was deposited on biocompatible substrates. Cis-platinum (118 μgm/cm²) was used as an anti-cancer drug and incorporated for local delivery of the chemotherapeutic agent. The co-polymer layers and their interaction with cancer cells were analyzed by scanning electron microscopy. Our study showed that the plasma-PCL-PEG coated cellophane membranes, in which the drug, was included did not modify the flexibility and appearance of …