Intra-articular fractures (IAFs) often lead to poor outcomes, despite surgeons’ best efforts at reconstructing the fractured articular surface. The objective of articular fracture reduction is to improve joint congruity thereby lower articular contact pressure and minimize the risk of post-traumatic osteoarthritis (PTOA). Surgical fracture reductions performed using less invasive approaches (i.e., percutaneously) rely heavily upon C-arm fluoroscopy to judge articular surface congruity. Based on varied outcomes, it appears that the use of 2D imaging alone for this purpose may prove inadequate. Despite this, there has been little investigation into novel metrics for assessment of reduction quality. This work first explores seven methods for assessment of reduction quality (3 2D, 3 3D, and one biomechanical). The results indicate that metrics which take 3D measurement or joint biomechanics into account when characterizing reduction quality are more strongly correlated with PTOA development. A computer assisted surgery system, which provides up-to-date 3D fracture geometry and contact stress distributions intra-operatively, was developed. Its utility was explored in a series of ten cadaveric tibial plafond fracture reductions, where contact stresses and contact areas were compared in surgeries with vs. without biomechanical guidance. The use of biomechanical guidance caused an increase in surgical time and fluoroscopy usage (39% and 17%, respectively). However, it facilitated decreases in the mean and maximum contact stress by 0.7 and 1.5 MPa, respectively. Contact areas engaged at known deleterious levels (contact stress > 4.5 MPa) were also 44% lower in cases which used guidance. The findings of this work suggest that enhanced visualization of a fracture intra-operatively may facilitate improved long-term outcomes. Further development and study of this system is warranted.

Traumatic injuries lead to articular cartilage lesion formation and result in the development of osteoarthritis. Recent research suggests that the early stage of mechanical injuries involve cell death (apoptosis and necrosis) and inflammation. In this thesis, we focus on building mathematical models to investigate the biological mechanism involving chondrocyte death and inflammatory responses in the process of cartilage degeneration. Chapter 1 describes the structure of articular cartilage, the process of carti- lage degeneration, and reviews of existing mathematical models. Chapter 2 presents a delay-diffusion-reaction model of cartilage lesion formation under cyclic loading. Computational methods were used to simulate the impact of varying loading stresses and erythropoietin levels. The model is parameterized with experimental results, and is therefore clinically relevant. Due to numerical limitations using delay differential equations, a new model is presented using tools for population dynamics. Chapter 3 presents an age and space-structured model of articular cartilage lesion formation un- der a single blunt impact. Age structure is introduced to represent the time delay in cytokine synthesis and cell transition. Numerical simulations produce similar tempo- ral and spatial patterns to our experimental data. In chapter 4, we extend our model under the cyclic loading setting. Chapter 5 builds a spatio-temporal model adapted from the former models, and investigates the distribution of model parameters using experimental data and statistical methods. Chapter 6 concludes.

Research in the biomedical sciences is incredibly diverse and often involves the interaction of specialists in a variety of fields. In particular, quantitative, mathematical, and computational methods are increasingly playing significant roles in studying problems arising in biomedical science. This is particularly exciting for mathematical modeling as the complexity of biological systems poses new challenges to modelers and leads to interesting mathematical problems. On the other hand mathematical modeling can provide considerable insight to laboratory and clinical researchers. In this thesis we develop mathematical representations for three biological processes that are of current interest in biomedical science. A deeper understanding of these processes is desirable not only from the standpoint of basic science, but also because of the connections these processes have with certain diseases. The processes we consider are collective cell motility, bone remodeling, and injury response in articular cartilage. Our goals are to develop mathematical representations of these processes that can provide a conceptual framework for understanding the processes at a fundamental level, that make rigorous the intuition biological researchers have developed about these processes, and that help to translate theoretical and experimental work into information that can be used in clinical settings where the primary concern is in treating diseases associated with the process.

Highly comminuted intra-articular fractures are complex and difficult injuries to treat. Once emergent care is rendered, the definitive treatment objective is to restore the original anatomy while minimizing surgically induced trauma. Operations that use limited or percutaneous approaches help preserve tissue vitality, but reduced visibility makes reconstruction more difficult. A pre-operative plan of how comminuted fragments would best be re-positioned to restore anatomy helps in executing a successful reduction. The objective of this work was to create new virtual fracture reconstruction technologies that would deliver that information for a clinical series of severe intra-articular fractures. As a step toward clinical application, algorithmic development benefits from the availability of more precise and controlled data. Therefore, this work first developed 3D puzzle solving methods in a surrogate platform not confounded by various in vivo complexities. Typical tibial plafond fracture fragmentation/dispersal patterns were generated with five identical replicas of human distal tibia anatomy that were machined from blocks of high-density polyetherurethane foam (bone fragmentation surrogate). Replicas were fractured using an instrumented drop tower and pre- and post-fracture geometries were obtained using laser scans and CT. A semi-automatic virtual reconstruction computer program aligned fragment native surfaces to a pre-fracture template. After effective reconstruction algorithms were created for the surrogate tibias, the next aim was to develop new algorithms that would accommodate confounding biologic factors and puzzle solve clinical fracture cases. First, a novel image analysis technique was developed to segment bone geometries from pre- and post-surgical reduction CT scans using a modified 3D watershed segmentation algorithm. Next, 3D puzzle solving algorithms were advanced to obtain fracture reconstructions in a series of highly comminuted tibial plafond fracture cases. Each tibia was methodically reconstructed by matching fragment native (periosteal and articular) surfaces to an intact template that was created from a mirror image of the healthy contralateral limb. Virtual reconstructions obtained for ten tibial plafond fracture cases had average alignment errors of 0.39±0.5 mm. These novel 3D puzzle solving methods are a significant advancement toward improving treatment by providing a powerful new tool for planning the surgical reconstruction of comminuted articular fractures.

While mechanical loading is essential for articular cartilage homeostasis, it also plays a central role in the etiology of osteoarthritis. The mechanotransduction events underlying these dual effects, however, remain unclear. Previously, we have shown that lethal amounts of reactive oxygen species (ROS) were liberated from mitochondrial complex 1 in response to a mechanical insult. The sensitivity of this response to an actin polymerase inhibitor, cytochalasin B, indicated a link between ROS release and cytoskeletal distortion caused by excessive compressive strain. It did not, however, rule out the possibility that ROS may also mediate the beneficial effects of normal stresses that induce lower tissue strains required for proper homeostasis. If this possibility is true, one would expect the amount of ROS released in loaded cartilage to be positively correlated with the level of strain, and ROS should only reach lethal levels under super-physiological deformations. To test this hypothesis, full cartilage tissue strains were measured in cartilage explants subjected to static normal stresses of 0, 0.1, 0.25, 0.5, and1.0 MPa. After compression, the percentage of ROS-producing cells was measured using the oxidation-sensitive fluorescent probe, dihydroethidium, and confocal microscopy. In support of our theory, the percentage of fluorescing cells increased linearly with increasing strains (0-75%, r2 = 0.8, p < 0.05). Additionally, hydrostatic stress, which causes minimal tissue strain, induced minimal ROS release. In terms of cell viability, cartilage explants compressed with strains >40% experienced substantial cell death, while explants with strains

Articular cartilage is a complex soft tissue covering the end of moving bones in joints which provide pressure load distribution over the joint surface and smooth lubrication with little friction for establishing movement. Articular cartilage has an intrinsically limited capacity for self-repair when injured due to the lack of nerve and blood supply. Considered that injured cartilage is left untreated, it is likely to undergo progressive cartilage degeneration without pain which may lead to posttraumatic osteoarthritis. Therefore functional and physiologic restoration of injured cartilage back to a normal condition has long been in demand, yet current available repairing methods in clinics have met with limited success. Mechanically applied loads to articular cartilage is necessary for chondrocytes, cartilage cells, since they are responsible for cartilage matrix turnover by synthesizing extracellular matrix (ECM) molecules in response to bio- chemical and mechanical changes in ECM. Ultrasound has emerged as an anabolic stimulator over the past few decades and a number of studies have proven that ultrasound therapy is beneficial for cartilage repair by synthesizing cartilage ECM components such as type II collagen and proteoglycan. Ultrasound therapy has also proven its potential for the attenuation of progressive cartilage degradation and induction of chondrogenic differentiation of mesenchymal stem cells. The use of ultrasound as an anabolic stimulator would be valuable with respect to cartilage repair since ultrasound as a form of mechanical energy can be non-invasively transferred into a human body. However, understanding the underlying mechanisms has been slow and the mechanisms have been roughly classified into thermal and non-thermal effects. Biologically detailed underlying mechanisms have not been sufficiently studied. That might be the reason why the application of ultrasound as a therapeutic tool has been limitedly available in clinics. In this study, mechanism involved biophysical effects of low intensity ultrasound has been studied for cartilage regeneration. First of all, the effect of ultrasound therapy as a mechanical stimulator on chondrogenic progenitor cell homing toward injured sites in cartilage was investigated with underlying biologic mechanisms. And the feasibility of ultrasound therapy for reactive oxygen species production mediated cartilage energy modulation was evaluated. There have been extensive preclinical studies about the effects of microbubble mediated ultrasound therapy on the targeted drugs or gene delivery into tissues of interest. Mechanical shock waves are released during ultrasound mediated microbubble destruction and the waves facilitate drug delivery into target tissues through transient blood vessel disruption. However, the clinical use of this technique has been limited through vascular system. In this study, the effects of microbubble mediated low intensity ultrasound therapy on directly delivered mechanical shock waves and controlled drug release were investigated. In conclusion, low intensity ultrasound therapy accelerates the homing of chondrogeic progenitor cells toward injured sites in cartilage via triggering mechanotransductive cell signaling pathways. This may result in speed up the return to normal cellularity and cartilage integrity by accelerating cartilage matrix repair. Low intensity ultrasound therapy was investigated as an energy modulator for chondrocytes via reactive oxygen species production in articular cartilage; however, little effects of ultrasound therapy driven cartilage energy modulation were found. The strong relationship between microbubbles mediated low intensity ultrasound therapy and the controlled release of drugs and mechanical shock waves was found. This strongly suggests that low intensity ultrasound therapy can play a role as a non-invasive controller for the release of drugs and lethal shock waves upon request.

Osteoarthritis (OA) is the most common type of arthritis, a disease in which inflammation and stiffness of the joints occur. This debilitating disease of the joints currently reigns as the most prevalent among the world's populations. Of particular interest to our group is the study of the biomechanical factors relating to knee OA. Studies have shown that knee OA is related to multiple biomechanical factors, all of which are complexly interrelated. These factors have been seen to produce varied effects on the structures of the knee. This work examines validation of a computational model implementing discrete element analysis, and discusses the potential for large-scale, subject-specific modeling of the knee. In particular, contact stress can be estimated using this technique, and these estimates can potentially be related to OA onset in subjects.

[Truncated abstract] Autologous Chondrocyte Implantation (ACI) has shown early clinical success as a repair procedure to address focal articular cartilage defects in the knee, and involves isolating and culturing a patient's own chondrocytes in vitro and re-implantation of those cells into the cartilage defect. Over time, repair tissue can develop and remodel into hyaline-like cartilage. A progressive partial weight bearing (PWB) program becomes the critical factor in applying protection and progressive stimulation of the implanted cells, to promote best chondrocyte differentiation and development, without overloading the graft. The aim of this thesis was to investigate whether patients could replicate this theoretical load bearing model to possibly render the best quality tissue development. In addition, this proposed external load progression is only a means to loading the articular surface. Several factors, including those that may result from pathology, have the potential to influence gait patterns, and therefore, articular loading. The association between increasing external loads (ground reaction forces - GRF) and knee joint kinetics during partial and full weight bearing gait was, therefore, investigated in the ACI patient group, as was the contribution of other gait variables to these knee joint kinetics which may be modified by the clinician. Finally, current weight bearing (WB) protocols have been based on early ACI surgical techniques. With advancement in the surgical procedure and ongoing clinical experience, we employed a randomised controlled clinical trial to assess the effectiveness of an 'accelerated' load bearing program, compared with the traditionally 'conservative' post-operative protocol. ... Although similar spatio-temporal, knee kinematic and external loading parameters were observed between the traditional and accelerated rehabilitation groups, the accelerated group was 'more comparable' to the controls in their external knee adduction and flexion moments, where the traditional group had lower knee moments. Knee moments greatly affect knee articular loading, and large adduction moments have been related to poor clinical outcomes after surgery. Therefore, the return of normal levels may be ideal for graft stimulation, however, may overload the immature chondrocytes. Acceleration of the intensive rehabilitation program will enable the patient to return to normal activities earlier, whilst reducing time and expenses associated with the rehabilitative process, and may enhance long-term tissue development. However, continued follow-up is required to determine if there are any detrimental effects that may emerge as a result of the accelerated load bearing program, and assess the recovery of normal gait patterns and whether longer term graft outcomes are affected by the recovery time course of normal gait function, and/or abnormal loading mechanics in gait. Furthermore, analysis at all levels of PWB is needed to identify a more complete set of variables attributing to the magnitude of external knee joint kinetics and, therefore, knee articular loading, while the influence muscle activation patterns may have on articular loading needs to be investigated. This becomes critical when you consider loads experienced by the articular surface throughout the early post-operative period following ACI may be important to short- and long-term graft development.

Thesis (M.S.) -- Mississippi State University. Department of Agricultural and Biological Engineering. / Title from title screen. Includes bibliographical references.

This thesis demonstrated the effects of exogenous stimuli on engineered articular cartilage constructs and elucidated mechanisms underlying the responses to these agents. In particular, a series of studies detailed the effects of chondroitinase-ABC (C-ABC), hyaluronic acid (HA), and TGF-β1 on the biochemical and biomechanical properties of self-assembled articular cartilage. Work with C-ABC showed that this catabolic agent can be employed to improve the tensile properties of constructs. When constructs were cultured for 6 weeks, treating with C-ABC at 2 weeks enhanced the tensile stiffness. Furthermore, treating at 2 and 4 weeks synergistically increased tensile properties and allowed compressive stiffness to recover to control levels. Another study showed that combining C-ABC and TGF-β1 synergistically enhanced the biochemical and biomechanical properties of neotissue. Microarray analysis demonstrated that TGF-β1 increased MAPK signaling in self-assembled neocartilage whereas C-ABC had minimal effects on gene expression. SEM analysis showed that C-ABC increased collagen fibril diameter and fibril density, indicating that C-ABC potentially acts via a biophysical mechanism. Constructs treated with C-ABC and TGF-β1 also showed stability and maturation in vivo , exhibiting a tensile stiffness of 3.15±0.47 MPa compared to a pre-implantation stiffness of 1.95±0.62 MPa. To assess the response to HA application, studies were conducted to optimize HA administration and examine its effects in conjunction with TGF-β1. Applying HA increased the compressive stiffness 1-fold and increased GAG content by 35%, with these improvements depending on HA molecular weight, application commencement time, and concentration. Microarray and PCR analyses showed that HA also influenced genetic signaling, up-regulating multiple genes associated with the TGF-β1 pathway. In addition to genetic effects, the enhanced GAG retention due to HA treatment could increase the fixed charge density of the matrix and thereby increase resistance to compressive loading. Additive effects were observed when HA was applied in conjunction with TGF-β1, with the combined treatment increasing compressive stiffness and GAG content by 150% and 65%, respectively. In general, results demonstrated mechanisms underlying C-ABC, HA, and TGF-β1 treatments and showed how these agents can be applied to improve cartilage regeneration efforts.