<p dir="ltr"><a href="" target="_blank">Almost every case of cervical cancer in the United States is medically preventable with vaccination and proper screening, yet many Americans are insufficiently screened. Over 12 thousand American women suffered from cervical cancer in 2018</a>¹ causing 4 thousand deaths, with over a third in women who had never received a routine screening test².</p><p dir="ltr">New, sensitive testing techniques for cervical cancer screening are facilitating HPV testing without evaluating the cells collected in the sample by eye. This opens the door to new, accessible methods of screening such as rapid testing in clinic and at home, self-sampling, and mail-in testing. As cervical cancer morbidity and mortality is largely a result of healthcare inequities, these methods may have a significant impact on cervical cancer outcomes.</p><p dir="ltr">The goal of this project is to create a proof-of-concept, sample-to-answer rapid test to be used for cervical cancer screening in Indiana outpatient clinics. We began the project by conducting interviews and a survey to explore Indiana clinician perspectives on cervical screening methods such as self-sampling, rapid testing, and home-based screening. Clinicians preferred in-clinic testing with same-visit results, in the hopes that face-to-face explanation of results and scheduling follow-up care in person would improve patient retention for these important follow-up tests. To create such a test, we augmented an isothermal nucleic acid amplification method that copies 13 of the 14 high-risk human papillomavirus (hrHPV) types with an endogenous b-globin sample control and a simple colorimetric lateral flow strip (LFS) readout. When tested with HPV 16 the assay achieved a limit of detection of 1000 HPV copies per reaction, which would detect endocervical samples deemed ‘sufficient’ by clinical guidelines. It also performs in endocervical cells using methods and equipment that could be implemented in an outpatient clinic. The final test accepts swabs or brushes of endocervical cells, lyses them in 5 minutes, copies the target DNA and a sample adequacy control, and delivers the readout within 40 minutes on an LFS readout. Future directions for this assay include soliciting feedback from clinicians and other stakeholders about the prototype developed, adapting the assay to interferents of clinical endocervical samples, and adding probes for other HPV types, such as HPV 18 and eventually the other hrHPV types.</p>

<p>  </p> <p>Understanding the mechanical properties of peripheral nerves is essential for chronically implanted device design. The work in this thesis aimed to understand the relationship between local deformation responses to global strain changes in peripheral nerves. A custom-built mechanical testing rig and sample holder enabled an improved cyclical uniaxial tensile testing environment on rabbit sciatic nerves (N=5). A speckle was placed on the surface of the nerve and recorded with a microscope camera to track local deformations. The development of a semi-automated digital image processing algorithm systematically measured local speckle dimension and nerve diameter changes. Combined with the measured force response, local and global strain values constructed a stress-strain relationship and corresponding elastic modulus. Preliminary exploration of models such as Fung and 2-Term Mooney-Rivlin confirmed the hyperelastic nature of the nerve. The results of strain analysis show that, on average, local strain levels were approximately five times smaller than globally measured strains; however, the relationship was dependent on global strain magnitude. Elastic modulus values corresponding to ~9% global strains were 2.070 ± 1.020 MPa globally and 10.15 ± 4 MPa locally. Elastic modulus values corresponding to ~6% global strains were 0.173 ± 0.091 MPa globally and 1.030 ± 0.532 MPa locally.   </p>

<p>  </p> <p>With the recent advancement of computation and imaging technology, Image-based computational fluid dynamics (ICFD) has emerged as a great non-invasive capability to study biomedical flows. These modern technologies increase the potential of computation-aided diagnostics and therapeutics in a patient-specific environment. I studied three components of this image-based computational fluid dynamics process in this work.</p> <p>To ensure accurate medical assessment, realistic computational analysis is needed, for which patient-specific image segmentation of the diseased vessel is of paramount importance. In this work, image segmentation of several human arteries, veins, capillaries, and organs was conducted to use them for further hemodynamic simulations. To accomplish these, several open-source and commercial software packages were implemented. </p> <p>This study incorporates a new computational platform, called <em>InVascular</em>, to quantify the 4D velocity field in image-based pulsatile flows using the Volumetric Lattice Boltzmann Method (VLBM). We also conducted several parametric studies on an idealized case of a 3-D pipe with the dimensions of a human renal artery. We investigated the relationship between stenosis severity and Resistive index (RI). We also explored how pulsatile parameters like heart rate or pulsatile pressure gradient affect RI.</p> <p>As the process of ICFD analysis is based on imaging and other hemodynamic data, it is often time-consuming due to the extensive data processing time. For clinicians to make fast medical decisions regarding their patients, we need rapid and accurate ICFD results. To achieve that, we also developed surrogate models to show the potential of supervised machine learning methods in constructing efficient and precise surrogate models for Hagen-Poiseuille and Womersley flows.</p>

This thesis proposes an algorithm that determine the geometry of 3D-printed, custom-designed spring element bands made of thermoplastic elastomer (TPE) for use in a wearable orthotic device to aid in the physical therapy of a human hand exhibiting spasticity after stroke. Each finger of the hand is modeled as a mechanical system consisting of a triple-rod pendulum with nonlinear stiffness at each joint and forces applied at the attachment point of each flexor muscle. The system is assumed quasi-static, which leads to a torque balance between the flexor tendons in the hand, joint stiffness and the design force applied to the fingertip by the 3D-printed spring element. To better understand material properties of the spring element’s material, several tests are performed on TPE specimens printed with different infill geometries, including tensile tests and cyclic loading tests. The data and stress-strain curves for each geometry type are presented, which yield a nonlinear relationship between stress and strain as well as apparent hysteresis. Polynomial curves are used to fit the data, which allows for the band geometry to be designed. A hypothetical hand is presented along with how input measurements might be taken for the algorithm. The inputs are entered into the algorithm, and the geometry of the bands for each finger are generated. Results are discussed, and future work is noted, providing a means for the design of a customized orthotic device.

The current clinical management of abdominal aortic aneurysm (AAA) disease is based on measuring the aneurysm maximum diameter to decide when timely intervention can be recommended to a patient. However, other parameters may also play a role in causing or predisposing the AAA to either an early or delayed rupture relative to its size. Therefore, patient-specific assessment of rupture risk based on physical principles such as individualized biomechanics can be conducive to the development of a vascular tool with translational potential. To that end, the present doctoral research materialized into a framework for image based patient-specific vascular biomechanics assessment. A robust generalized approach is described herein for image-based volume mesh generation of complex multidomain bifurcated vascular trees with the capability of incorporating regionally varying wall thickness. The developed framework is assessed for geometrical accuracy, mesh quality, and optimal computational performance. The relative influence of the shape and the constitutive wall material property on the AAA wall mechanics was explored. This study resulted in statistically insignificant differences in peak wall stress among 28 AAA geometries of similar maximum diameter (in the 50 – 55 mm range) when modeled with five different hyperelastic isotropic constitutive equations. Relative influence of regionally varying vs. uniform wall thickness distribution on the AAA wall mechanics was also assessed to find statistically significant differences in spatial maxima of wall stresses, strains, and strain energy densities among the same 28 AAA geometries modeled with patient-specific non-uniform wall thickness and two uniform wall thickness assumptions. Finally, the feasibility of estimating in vivo wall strains from individual clinical images was evaluated. Such study resulted in a framework for in vivo 3D strain distributions based on ECG gated, unenhanced, dynamic magnetic resonance images acquired for 20 phases in the cardiac cycle. Future efforts should be focused on further development of the framework for in vivo estimation of regionally varying hyperelastic, anisotropic constitutive material models with active mechanics components and the integration of such framework with an open source finite element solver with the goal of increasing the translational potential of these tools for individualized prediction of AAA rupture risk in the clinic.

This thesis presents a new mechanical design for an exoskeleton actuator to power the sagittal plane motion in the human hip. The device uses a DC motor to drive a Scotch yoke mechanism and series elasticity to take advantage of the cyclic nature of human gait and to reduce the maximum power and control requirements of the exoskeleton. The Scotch yoke actuator creates a position-dependent transmission that varies between 4:1 and infinity, with the peak transmission ratio aligned to the peak torque periods of the human gait cycle. Simulation results show that both the peak and average motor torque can be reduced using this mechanism, potentially allowing a less powerful motor to be used. Furthermore, the motor never needs to reverse direction even when the hip joint does. Preliminary testing shows the exoskeleton can provide an assistive torque and is capable of accurate position tracking at speeds covering the range of human walking. This thesis provides a detailed analysis of how the dynamic nature of human walking can be leveraged, how the hip actuator was designed, and shows how the exoskeleton performed during preliminary human trials.

Neuronal membrane disruption and mechanoporation are nanoscale damage mechanisms that critically affect brain cell viability during traumatic brain injury (TBI). These nanoscale cellular impairments are elusive in experiments and necessitate in silico approaches such as molecular dynamics (MD) simulations. Implementing MD, this research aims to investigate the effects of different key factors related to membrane deformation and damage, including force field resolutions, lipid compositions, and loading conditions. To examine the impact of force field resolution, MD deformation simulations were conducted on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) lipid bilayer membranes, using all-atom (AA), united-atom (UA), and coarse-grained Martini (CG-M) force fields. The mechanical responses of the three models progressively changed based on the coarse-graining level. The coarser systems exhibited lower yield stresses and failure strains, and higher mechanoporation damage. To study the influence of lipid components, tensile deformation was applied on seven lipid bilayers, each of which contained a different lipid type commonly found in human brain membrane. Larger headgroup structure, greater degree of unsaturation, and tail-length asymmetry decreased lipid packing, increased the area per lipid (APL), and decreased the failure strain of membrane. Lastly, the deformation behavior of a complex multicomponent MD bilayer (realistically representing human neuronal plasma membrane) under different strain rates and strain states was inspected. The yield stress increased with increasing strain rates and more equibiaxial strain states. Meanwhile, lower strain rates resulted in fewer but larger pores, as well as lower strain and APL at failure. Besides, more equibiaxial strain states exhibited more and larger pores, and lower failure strain. Similar failure APL was obtained regardless of strain states, suggesting that the membrane failed when reaching a critical APL value. In addition, the inclusion of cholesterol was shown to decrease the critical APL. The strain-state dependence results were then used to update the Membrane Failure Limit Diagram (MFLD) that indicates the planar strains for potential membrane failure. Overall, the study provides a non-invasive approach that aids in the current understanding of nanoscale neuronal damage dynamics and essential aspects affecting membrane mechanical responses, and furthermore lays the groundwork for future studies on brain injury biomechanics under various TBI scenarios.

<p dir="ltr">The brain is a dynamic tissue that is passively driven by a combination of the cardiac cycle, respiration, and slow wave oscillations. The function of the brain relies on its ability to maintain a normal homeostatic balance between its mechanical environment and metabolic demands, which can be greatly altered in the cases of neurodegeneration or traumatic brain injury. It has been a challenge in the field to quantify the dynamics of the tissue and cerebrospinal fluid flow in human subjects on a patient-specific basis over the many spatial and temporal scales that it relies upon. Non-invasive imaging tools like structural, functional, and dynamic MRI sequences provide modern researchers with an unprecedented view into the human brain. Our work leverages these sequences by developing novel, open-source pipelines to 1) quantify the biomechanical environment of the brain tissue over 133 functional brain regions, and 2) estimate real-time cerebrospinal fluid velocity from flow artifacts on functional MRI by employing breathing regimens to enhance fluid motion. These pipelines provide a comprehensive view of the macroscale tissue and fluid motion in a given patient. Additionally, we sought to understand how the transmission of macroscale forces, in the context of traumatic brain injury, contribute to neuronal damage by 3) developing a digital twin to simulate 30-200 g-force loading of 2D neuronal cultures and observing the morphological and electrophysiological consequences of these impacts in vitro by our collaborators. Taken together, we believe these works are a steppingstone that will enable future researchers to deeply understand the mechanical contributions that underly clinical neurological outcomes and perhaps lead to the development of earlier diagnostics, which is of dire need in the case of neurodegenerative diseases.</p>

This paper describes the design, manufacturing, and testing of a novel controllable hypoxic incubator with fully functional oxygen gas control and temperature control in a humid environment. On the current market, a majority of the few hypoxic incubators use pre-mixed gas that does not offer precise control over gas concentration. The objective for this project was to create a chamber that allows the user to set the O2 concentration to varying set points of % O2 while maintaining the chamber at a constant body temperature, CO2 level, humidity, and sterility. To start the project, multiple concepts were developed for the chamber design and the control system. These concepts were compared against developed engineering specs and were evaluated amongst the team and sponsor. From there, a detailed CAD model was developed and utilized to design the structure and was used as a guide for manufacturing. The control system was prototyped on breadboards via Arduino. This breadboard testing served as the map to solder perf boards, which are utilized as the final structure for the control system. Once all parts were sourced, machined, and assembled for the final chamber and the control system, these subassemblies were integrated together with a regulated gas system via various tubing. The integrated final design underwent a variety of testing to validate the incubator design and control system. Testing was performed throughout the course of this project: material testing, gas leak testing, cell test, temperature control test, and gas control system optimization; however, the most important of these tests were those relating to the environmental control of the incubator. These tests confirmed whether the incubator design was functional as a practical incubator. Testing confirmed that O2 and temperature control maintained in spec over a short and long period of time while maintaining a humid environment. CO2 control optimization had more complications than the O2 hypoxia system. During testing CO2 concentration would typically overshoot the set point, likely due to a lack of precise control over the gas flow. CO2 variability was reduced due to optimization in the code, but not fully mitigated. Future iterations of this chamber could improve upon the CO2 control and streamline the user interface.

<p>Subcutaneous injection through devices such as autoinjectors is a preferred delivery method for wide array of pharmaceuticals such as monoclonal antibodies. Needle insertion during drug delivery involves large deformation, damage, and fracture of the skin tissue and affects drug transport and uptake. Yet, our understanding of needle insertion biomechanics is limited, but is crucially important to create autoinjectors that lead to the least amount of pain, penetrate the skin to a desired depth, produce small lesions that minimize back flow of drug, and operate robustly even given the variability in the skin mechanics among individuals. Computational models of needle insertion lends itself as an excellent avenue for studying the biomechanics of injector- skin interactions and for proposing better device designs. This work is focused on introducing a comprehensive computational modeling framework for optimizing needle insertion by autoinjector devices, while addressing limitations in experimental data and constitutive modeling of damage and fracture mechanisms in skin</p>