The knee joint plays an essential role in the human musculoskeletal system. It has evolved to withstand extreme loading conditions, while providing almost frictionless joint movement. However, its performance may be disrupted by disease, anatomical deformities, soft tissue imbalance or injury. Knee disorders are often puzzling, and accurate diagnosis may be challenging. Current evaluation approach is usually limited to a detailed interview with the patient, careful physical examination and radiographic imaging. The X-ray screening may reveal bone degeneration, but does not carry sufficient information of the soft tissue conditions. More advanced imaging tools such as MRI or CT are available, but expensive, time consuming and can be used only under static conditions. Moreover, due to limited resolution the radiographic techniques cannot reveal early stage arthritis. The arthroscopy is often the only reliable option, however due to its semi-invasive nature, it cannot be considered as a practical diagnostic tool. Therefore, the motivation for this work was to combine three scientific methods to provide a comprehensive, non-invasive evaluation tool bringing insight into the in vivo, dynamic conditions of the knee joint and articular cartilage degeneration. Electromyography and inverse dynamics were employed to independently determine the forces present in several muscles spanning the knee joint. Though both methods have certain limitations, the current work demonstrates how the use of these two methods concurrently enhances the biomechanical analysis of the knee joint conditions, especially the performance of the extensor mechanism. The kinetic analysis was performed for 12 TKA, 4 healthy individuals in advanced age and 4 young subjects. Several differences in the knee biomechanics were found between the three groups, identifying age-related and post-operative decrease in the extensor mechanism efficiency, explaining the increased effort of performing everyday activities experienced by the elderly and TKA subjects. The concept of using accelerometers to assess the cartilage degeneration has been proven based on a group of 23 subjects with non-symptomatic knees and 52 patients suffering from knee arthritis. Very high success (96.2%) of pattern classification obtained in this work clearly demonstrates that vibroarthrography is a promising, non-invasive and low-cost technique offering screening capabilities.

The efficient treatment of cancer with chemotherapy is challenged by the limited penetration of drugs into the tumor. Nanoparticles (10 – 100 nanometers) have emerged as a logical choice to specifically deliver chemotherapeutics to tumors, however, their transport into the tumor is also impeded owing to their bigger size compared to free drug moieties. Currently, monolayer cell cultures, as models for drug testing, cannot recapitulate the structural and functional complexity of in-vivo tumors. Furthermore, strategies to improve drug distribution in tumor tissues are also required. In this study, we hypothesized that hyperthermia (43°C) will improve the distribution of silica nanoparticles in three-dimensional multicellular tumor spheroids. Tumor spheroids mimic the functional and histomorphological complexity of in-vivo avascular tumors and are therefore valuable tools to study drug distribution. Ovarian cancer (Skov3) and uterine sarcoma (MES-SA/Dx5) spheroids were generated using the liquid overlay method. The growth ratio and cytotoxicity assays showed that the application of adjuvant hyperthermia with Doxorubicin (DOX) did not yield higher cell killing compared to DOX therapy alone. These results illustrated the role of spheroids in resistance to heat and DOX. In order to study the cellular uptake kinetics of nanoparticles under hyperthermia conditions, the experimental measurements of silica nanoparticle uptake by cells were fitted using a novel inverse estimation method based on Bayesian estimation. This was coupled with advection reaction transport to model nanoparticle transport in spheroids. The model predicted an increase in Area Under the Curve (AUC) and penetration distance (W1/2) that were validated with in-vitro experiments in spheroids. Based on these observations, a novel multifunctional theranostic nanoparticle probe was created for generating highly localized hyperthermia by encapsulating a Near Infrared (NIR) dye, IR820 (for imaging and hyperthermia) and DOX in Organically modified silica nanoparticles (Ormosil). Pegylated Ormosil nanoparticles had an average diameter of 58.2±3.1 nm, zeta potential of -6.9 ± 0.1 mV and high colloidal stability in physiological buffers. Exposure of the IR820 within the nanoparticles to NIR laser led to the generation of hyperthermia as well as release of DOX which translated to higher cell killing in Skov3 cells, deeper penetration of DOX into spheroids and complete destruction of the spheroids. In-vivo bio-distribution studies showed higher fluorescence from organs and increased plasma elimination life of IR820 compared to free IR820. However, possible aggregation of particles on laser exposure and accumulation in lungs still remain a concern.

Lymph is primarily composed of fluid and proteins from the blood circulatory system that drain into the space surrounding cells, interstitial space. From the interstitial space, the fluid enters and circulates in the lymphatic system until it is delivered into the venous system. In contrast to the blood circulatory system, the lymphatic system lacks a central pumping organ dictating the predominant driving pressure and velocity of lymph. Transport of lymph via capillaries, pre-collecting and collecting lymphatic vessels relies on the synergy between pressure gradients, local tissue motion, valves and lymphatic vessel contractility. The direction of lymph transport is regulated by bicuspid valves distributed throughout pre-collecting and collecting lymphatic vessels. Effective transport of lymph into the venous system is of prime importance. Disruption of lymph transport, because of impaired lymphatic function, reduced numbers of vessels or valvular insufficiencies can have severe health consequences, including lymphedema for which current clinical therapies are not curative. The lymphatic valves are usually bicuspid, however, congenital malformations in the valve such as single leaflet valve formation and arrested lymphatic valve development are observed and can cause lymphedema. Here we employ 4-week-old mice to study the effects of valves and malformed valves on lymph transport shedding light into some of the potentially underlying consequences of lymphedema. Polyethylene glycol (PEG) coated latex particles were injected into the inguinal lymph node of anesthetized mice. Particle displacement measurements through efferent lymphatic vessels yielded velocity, wall shear stress, vorticity and strain of the efferent lymph flow field carrying lymph from subdermal inguinal lymph nodes. Lymphatic vessel endothelial Prox1 green fluorescent protein (GFP) marker enabled the detection of lymphatic vessel walls and valves. Flow field, flow velocity, flow rate, velocity profiles, wall shear stress, vorticity and strain values were compared in regions downstream of normal and malformed valves in two wild type mice. A Clec2-deficient mouse, which experiences lymphatic development defects and is used as a lymphedema model, was employed to further elucidate the lymphatic valves on transport. The absence of centralized pumping yields highly variable lymphatic flow cycles varying from one to fifteen seconds. The presence of lymphatic valves introduces boundary conditions that yield spatial and temporal flow gradients increasing the degree of complexity of lymph transport. The valves dictate the trajectory of the particles and promote the formation of recirculation zones. Even in the presence of valves, lymph flow commonly reverses. Congenital defects like a single leaflet valve lowers the lymph flow efficiency and promotes higher wall shear stress regions. Furthermore, the absence of functional valves in the Clec2-deficient mouse not displaying lymphedema yielded lymph flow lacking the pulsatility that characterizes normal lymphatic flow.

Osteoarthritis is one of the most common causes of disability in adults in America. It is a progressive and degenerative disease where the articular cartilage is broken down and lost from the surfaces of bones causing chronic pain and swelling in the joints, and currently has no cure. The most commonly osteoarthritis starts from a focal lesion on the cartilage surface, which will expand on the surface and downwards through the thickness of the tissue. The current gold standard for correcting cartilage focal lesions is the osteochondral autograft/allograft transplantation (OAT), which replaces the defect with a fresh osteochondral graft. The main limiting factor for using the OAT comes from the limited number of autograft and allografts that are available for implantation. To address the concern of graft availability, this study will look at the development of a porcine osteochondral xenograft (OCXG). The first aim of this research is to establish a decellularization protocol that will remove the antigens and cellular debris, which are the leading causes of graft rejection when implanting animal tissue in humans. The second aim of this study is restoring the mechanical strength of the OCXG that was lost during the decellularization process through crosslinking the tissue using genipin and epigallocatechin gallate (EGCG). The third aim is comparing the performance of the complete crosslinked OCXG at different degrees of crosslinking in a long-term goat animal model. The final aim is an alternative way to correct focal lesions through the development of an injectable collagen stabilizing treatment with genipin and punicalagin that will slow or stop the growth of a lesion and prevent osteoarthritis.

An ongoing debate concerning Neandertal ecology is whether or not they utilized long range weaponry. The anteroposteriorly expanded cross-section of Neandertal humeri have led some to argue they thrusted their weapons, while the rounder cross-section of Late Upper Paleolithic modern human humeri suggests they threw their weapons. We test the hypothesis that Neandertal humeri were built to resist strains engendered by thrusting rather than throwing using finite element models of one Neandertal, one Early Upper Paleolithic (EUP) human and three recent human humeri, representing a range of cross-sectional shapes and sizes. Electromyography and kinematic data and articulated skeletons were used to determine muscle force magnitudes and directions during three positions of spear throwing and three positions of spear thrusting. Maximum von Mises strains were determined at the 35% and 50% cross-sections of all models. During throwing and thrusting, von Mises strains produced by the Neandertal humerus fell roughly within or below those produced by the modern human humeri. The EUP humerus performed similarly to the Neandertal, but slightly poorer during spear thrusting. This implies the Neandertal and EUP human humeri were just as well adapted at resisting strains during throwing as recent humans and just as well or worse adapted at resisting strains during thrusting as recent humans. We also did not find any correlation between strains and biomechanical metrics used to measure humeral adaptation in throwing and thrusting (retroversion angle, Imax/Imin, J). These results failed to support our hypothesis and suggest they were capable of using long distance weaponry.

The humerus of a racing horse Thoroughbred is highly susceptible to stress fractures at a characteristic location as a result of cyclic loading. The propensity of a Thoroughbred to exhibit humeral fracture has made equines useful models in the epidemiology of stress fractures. In this study, a racing Thoroughbred humerus was simulated during training using a 3D finite element model in conjunction with a bone remodeling algorithm. Nine muscle forces and two contact forces were applied to the 3-dimensional finite element model, which contains four separate load cases representing fore-stance, mid-stance, aft-stance, and standing. Four different training programs were incorporated into the model, which represent Baseline Layup and Long Layup training programs along with two newly implemented programs for racing, which have an absence of a layup period, last a period of 24 weeks, and a race once every four weeks. Muscle and contact forces were rescaled for all load cases to simulate dirt, turf, and synthetic track surfaces. Bone porosity, damage, and BMU activation frequency were examined at the stress fracture site and compared with a control location called the caudal diaphysis. It was found that race programs exhibited similar remodeling patterns between each other. Damage at the stress fracture site and caudal diaphysis was reduced during all training programs for the turf and synthetic track surfaces with respect to the dirt track surface. Key findings also included changes in bone remodeling at the stress fracture site and caudal diaphysis as a result of turf and synthetic track surfaces. This model can serve as a framework for further studies in human or equine athletes who are susceptible to stress fractures.

Transcatheter aortic heart valve replacement (TAVR) is a procedure to replace a failing aortic valve and is becoming the new standard of care for patients that are not candidates for open-heart surgery [2]. However, this minimally invasive technique has shown to cause ischemic brain lesions, or “silent infarcts”, in 90% of TAVR patients, which can increase the patient’s risk for stroke by two to four times in future years [3]. Claret Medical Inc., a medical device company, has developed a cerebral protection system that filters and captures embolic debris released during endovascular procedures, such as TAVR. This thesis utilized CT scans from Claret Medical to create a physical construct of the aortic arch to experimentally validate a theoretical computer model through flow visualization. The hypothesis was that the empirical model can accurately mimic the fluid dynamic properties of the aortic arch in order validate an in silico model using the finite elements program COMSOL MultiPhysics® Modeling Software. The physical model was created from a patient CT scan of the aortic arch using additive manufacturing (3D printing) and polymer casting, resulting in the shape of the aortic arch within a transparent, silicone material. Fluid was pumped through the model to visualize and quantify the velocity of the fluid within the aortic arch. COMSOL MultiPhysics® was used to model the aortic arch and obtain velocity measurements, which were statistically compared to the velocity measurements from the physical model. There was no significant difference between the values of the physical model and the computer model, confirming the hypothesis. Overall, this study successfully used CT scans to create an anatomically accurate physical model that was validated by a computer model using a novel technique of flow visualization. As TAVR and similar procedures continue to develop, the need for experimental evaluation and visualization of devices will continue to grow, making this project relevant to many companies in the medical device industry.

Osteoarthritis (OA) is a degenerative condition of articular cartilage that affects more than 25 million people in the US. Joint injuries, like anterior cruciate ligament (ACL) tears, can lead to OA due to a change in articular cartilage loading. Gait analysis combined with knee joint finite element modeling (FEM) has been used to predict the articular cartilage loading. To predict the change of articular cartilage loading during gait due to various ACL injuries, a tibiofemoral FEM was developed from magnetic resonance images (MRIs) of a 33 year male, with no prior history of knee injuries. The FEM was validated for maximum contact pressure and anterior tibial translation using cadaver knee studies. The FEM was used to model gait of knees with an intact ACL, anteromedial (AM) bundle injury, posterolateral (PL) bundle injury, complete ACL injury, AM deficiency, PL deficiency, complete ACL rupture, as well as a bone-patellar tendon-bone (BPTB) graft. Generally, the predicted maximum contact pressure and contact area increased for all the ACL injuries when compared to intact ACLs. While an increase in maximum contact pressure and contact area is an indication of an increased risk of the development of OA, the percent of increase was typically small suggesting that walking is a safe activity for individuals with ACL injuries.

OBJECTIVE The purpose of this study was to determine how kinematic, big data can be evaluated using computational, comprehensive analysis of movement parameters in a diverse population. METHODS Retrospective data was collected, cleaned, and reviewed for further analysis of biomechanical movement in an active population using 3D collinear resistance loads. The active sample of the population involved in the study ranged from age 7 to 82 years old and respectively identified as active in 13 different sports. Moreover, a series of exercises were conducted by each participant across multiple sessions. Exercises were measured and recorded based on 6 distinct biometric movement parameters: explosiveness, velocity, power, deceleration, braking, consistency, endurance, and range of motion. Analysis and data visualization portrayed how 3D collinear resistance load impacted specific muscles and performance metrics. RESULTS The model with the highest accuracy rate was Naive Bayes and Fast Large Margin at 58.3% for future predictions considering impact for specific muscles, movement parameters, and performance metric data. The data visualization involved a proof-of-concept human-computer interface and presented each component in relation to one another within the active population database, movement parameters, and performance metrics. DISCUSSION Understanding the findings regarding 3D collinear resistance sets a precedence for future development for the active population and research in the sports analytics field. Additionally, the visual proof of concept interface promotes future development for a diverse, active population.

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.