PhD, University of Cincinnati, 2016, Engineering and Applied Science: Biomedical Engineering

Tendon injuries are common, debilitating, and often difficult to treat. Reattaching ruptured tendons to their bony insertions has been a fundamental challenge in orthopaedics for decades, yet effective solutions that restore normal fibrocartilaginous enthesis architecture and mechanical function are still lacking. In our tissue engineering laboratory, we believe that the developmental signals governing tendon differentiation and patterning can be strategically reintroduced and/or manipulated during adult tendon repair in order to achieve better functional outcomes. In recent years, Indian hedgehog (Ihh) signaling has emerged as a key regulator of enthesis differentiation, growth, and mineralization. Given Ihh's importance during development, the overall objective of this dissertation was to examine the role of hedgehog signaling in mature tendons and evaluate the potential therapeutic effects of recombinant Ihh during enthesis healing. In aim 1, we developed and biomechanically characterized a new murine model of patellar tendon (PT) enthesis injury. Unlike the larger animal models that have been traditionally used for studies of tendon-to-bone healing, the murine model provides us the opportunity to conduct both basic and translational tissue engineering studies in transgenic strains relatively quickly and at low cost. In aim 2, we defined the natural patterns of endogenous hedgehog signaling in the mature murine PT. We found that hedgehog signaling remained active in the unmineralized entheseal fibrocartilage even in 46 week old mice, thereby suggesting a role for Ihh in enthesis homeostasis throughout life. Prominent hedgehog signaling activity was also seen in regions of tendon undergoing fibrocartilaginous metaplasia. This observation, coupled with our finding that direct stimulation of cultured tenocytes with Ihh caused the cells to adopt a more chondrocytic phenotype, suggests that hedgehog signaling may regulate fibrocartilage formation in tendons. In ai (open full item for complete abstract)

Committee: Jason Shearn Ph.D. (Committee Chair); Keith Kenter M.D. (Committee Member); David Butler Ph.D. (Committee Member); Rulang Jiang Ph.D. (Committee Member) Subjects: Biomedical Research

MS, University of Cincinnati, 2002, Engineering : Aerospace Engineering

Previous work performed in Noyes-Giannetras Laboratory has shown that mechanical alignment of undifferentiated mesenchymal stem cells about a suture causes alignment of cells and contraction of constructs in culture in a form that is suitable for implantation for tendon repair. With preliminary proof of concept, it is now our goal to fine-tune this procedure to determine the various factors that will lead to the highest quality tissue from a biomechanical standpoint and the fastest cell proliferation rates in culture. The basis for this step assumes that natural in-vivo conditions are optimal for in-vitro culture and that if we can simulate in-vivo forces or strains for a variety of activities we can precondition the implant and cells to the signals they will receive after surgery. However, these in-vivo force patterns are generally not known for a tissue for different activities and likely vary from tendon to tendon. Knowing tendon and ligament forces during normal activities is important in order to understand the levels of in-vivo forces the constructs will be expected to bear once implanted. While researchers have to date failed to develop tissue-engineered replacements that match the ultimate mechanical properties of normal tissues, it is conceivable that less stringent design requirements based on normal activity forces (rather than ultimate or failure properties) may be sufficient for functional efficacy. The purpose of this research study was to determine the in-vivo force-time patterns acting on the rabbit patellar tendon and Achilles tendon models for two speeds of activity and for two inclinations of activity. In addition, we sought to determine the failure properties of these tissues so as to compute safety factors (i.e. ratios of failure tissue force to in-vivo operating force). This data will provide design parameters for preparing tissue engineered implants containing mesenchymal stem cells (MSCs) that will more effectively repair surgical defects in (open full item for complete abstract)

Committee: Dr. David L. Butler (Advisor) Subjects:

Master of Science in Engineering, University of Akron, 2013, Biomedical Engineering

Patellar instability is a major problem among young individuals. Chronic patellar instability termed as patellar dislocation occurs mainly due to the reduction in the medial restraining forces for the patella, excessive Q-angle, patella alta and trochlear dysplasia. It causes a tear of the medial patellofemoral ligament (MPFL) in the majority of instances. The MPFL is the main passive stabilizer preventing patellar instability and accounts for 50-60 % of the total restraining forces. Reconstruction of the torn MPFL is a surgical option performed in chronic cases to improve patellofemoral biomechanics and to provide better stability at the knee. Finite element analysis (FEA) makes it possible to simulate the surgical technique of reconstruction of the MPFL, observe the effects on the articular cartilage structures and determine the patellofemoral kinematics, which is not possible with in vivo imaging analysis. In the present study, subject specific computational (finite element) models were built in ABAQUS based on the 3D anatomical geometry of the patellofemoral joint from pre–op MRI scans. The femur and patella were modeled as rigid structures with quadrilateral elements. Patellofemoral articular cartilage was modeled as isotropic elastic structures with hexahedral elements. The quadriceps muscle group, patellar tendon and the MPFL graft were represented using linear tension-only springs. The quadriceps muscle force was calculated from the foot load that the patient was able to withstand at a particular flexion angle during the MRI scan. The MPFL reconstruction surgery was simulated by modeling the ligament with uniaxial connector elements and material properties representing the graft material. FE simulations with appropriate boundary and loading conditions showed that the lateral translation was restricted with a MPFL graft. Validation of these FE models was done by comparing the results with the kinematics obtained from an analysis based on MRI scans take (open full item for complete abstract)

Committee: John Elias Dr (Advisor); Marnie Saunders Dr (Advisor); Mary Verstraete Dr (Committee Member) Subjects: Biomechanics; Biomedical Engineering; Biomedical Research; Engineering

PhD, University of Cincinnati, 2011, Engineering and Applied Science: Biomedical Engineering

Tendon and ligament tears and ruptures remain common and significant musculoskeletal injuries. Repairing these injuries continues to be a prominent challenge in orthopaedics and sports medicine. Despite advances in surgical techniques and procedures, traditional repair techniques maintain a high incidence of re-rupture. This has led some researchers to consider using tissue engineered constructs (TECs). Previous studies in our laboratory have demonstrated that TEC stiffness at the time of surgery is positively correlated with repair tissue stiffness 12 weeks post-surgery. This correlation provided the rationale for implanting a soft tissue patellar tendon autograft (PTA) to repair a central-third defect in the rabbit patellar tendon (PT). The PTA was significantly stiffer than previous TECs and matched the stiffness of the normal central-third PT. Accordingly, we expected a significant improvement in repair tissue biomechanics relative to both natural healing (NH) and TEC repair. At 12 weeks, treatment with PTA improved repair tissue stiffness relative to NH. However, PTA and NH tissues did not differ in maximum force, modulus or maximum stress. Additionally, neither repair group regenerated normal zonal insertion sites. To enhance integration at the tendon-to-bone insertion site, PTA repairs were 1) given up to 26 weeks to recover and 2) augmented at the patellar and tibial insertions with mesenchymal stem cell (MSC)-collagen gel biologic augmentations (BAs). The role of the native cell population in PTA healing was also tested by de-cellularizing the PTA at surgery. We found that osteotendinous integration improved with recovery time for both de-cellularized PTA (dcPTA) and PTA repairs. However, biomechanical properties were only affected by recovery time for dcPTA repairs. Despite the changes in biomechanical properties demonstrated by dcPTA repairs, biomechanical properties did not vary between dcPTA and PTA repairs at any time point. We also found that MSC-co (open full item for complete abstract)

Committee: Jason Shearn PhD (Committee Chair); Keith Kenter MD (Committee Member); David Butler PhD (Committee Member) Subjects: Biomedical Research

PhD, University of Cincinnati, 2005, Engineering : Biomedical Engineering

The objective of this study was to test the governing hypothesis that implanting mesenchymal stem cell (MSC)-seeded collagen gel and collagen sponge scaffolds into surgically induced rabbit patellar tendon (PT) defects will improve the repair tissues'structural and material properties as well as histological appearance. We evaluated the effects of MSC-construct seeding concentration and collagen concentration on the in vivo repair quality after defect injury to the rabbit patellar tendon.In addition, we investigated the effects of adding a collagen sponge scaffold andmechanical stimulation using a silicone dish system on the in vivo repair of the rabbit patellar tendon. The effects of those treatments were assessed using biomechanical and immunohistochemical assays at 12 weeks post surgery. No significant differences were found in the biomechanical properties of the cellgel repairs with different MCS and collagen concentrations. The maximum force and linear stiffness for these repairs was 30% of normal central PT and no ectopic bone was found in any repair site. In a subsequent study, different collagen scaffolds (fibers, films,and sponges) were evaluated in vitro. We found that constructs prepared with cells,collagen gel and collagen sponge exhibited the greatest cell viability, penetration and mechanical integrity after 14 days in culture. In an attempt to increase the stiffness of the repairs, a type I collagen sponge was incorporated into the cell-gel constructs. The cell gel-sponge repairs averaged 75% of the normal tendon linear stiffness and 60% of the normal tendon maximum force. In the next study, cell-gel-sponge constructs were mechanically stimulated and used for rabbit PT repair. Linear stiffness and linear modulus for the stimulated repairs averaged 80% and 40% of normal PT values, respectively. In the last study, cell-sponge constructs (using a different collagen sponge)were mechanically stimulated and used for rabbit PT repair. Linear stiffness and li (open full item for complete abstract)

Committee: Dr. David Butler (Advisor) Subjects: Engineering, Biomedical