Thesis (M.S.)--Ohio State University, 2008. / Title from first page of PDF file. Includes bibliographical references (p. 75-100).

Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2007. / Committee Chair: Barbara, Boyan; Committee Member: Hanjoong Jo; Committee Member: Zvi, Schwartz.

Thesis (M.S.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains xi, 86 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 59-62).

Thesis (Ph. D.)--University of Missouri--Columbia, 2004. / Typescript. Vita. Includes bibliographical references. Also issued on the Internet.

Thesis (Ph. D.)--University of Missouri--Columbia, 2004. / "July 2004." Typescript. Vita. Includes bibliographical references. Also issued on the Internet.

Thesis (M.S.)--University of Delaware, 2007. / Principal faculty advisors: George R. Dodge and Mary C. Farach-Carson, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (Ph. D.)--Bioengineering, Georgia Institute of Technology, 2006. / Harish Radhakrishna, Committee Member ; Christopher Jacobs, Committee Member ; Andres Garcia, Committee Member ; Marc E. Levenston, Committee Chair ; Barbara Boyan, Committee Member.

Young patients diagnosed with post-traumatic osteoarthritis (PTOA) face significant hurdles to restoring pain-free joint function. While surgical interventions exist for replacing damaged cartilage, few are able to offer complete replacement of the articular surface with a bearing material that maintains the longevity and mechanical properties of native articular cartilage necessary to prevent the need for costly and painful revision procedures. Osteochondral allograft technology has begun to address this need by allowing surgeons to resurface constrained small to medium articular defects with live tissue-bank-sourced cartilage tissue explants. A primary limitation surgeons face when choosing osteochondral allotransplantation to treat large articular surface deficits is the scarcity of high-quality live explant tissue with sufficient congruence to fully restore the biomechanical function in the affected joint. This dissertation asserts that augmentation of native tissues donated to tissue banks is a promising strategy for providing more physiologically appropriate tissue replacements for patients with PTOA, providing significant symptomatic relief and allowing young patients to delay or prevent invasive total joint arthroplasty treatments.This dissertation aims to improve treatment modalities for this patient population by developing a surgical technique that enables adaptive reshaping of the articular surface of donor osteochondral tissue explants. The driving hypothesis of this dissertation is that osteochondral allografts that conform better to the opposing articular surface result in better clinical outcomes than those with lesser congruence with the native joint. The corollary hypothesis is that better conformity may be achieved by providing some measure of bending flexibility to the allograft, using streamlined tissue processing procedures to cut grooves in the bony substrate. To address these needs, we first developed, implemented, and validated the technology for milling grooves on the back of large human and canine osteochondral allografts. This resulted in the development of a process for milling grooves in patellar osteochondral samples using a computer-numerically controlled 3-axis milling machine. Sample-specific spatial information was captured within machining fixtures to generate machining paths. The curvature of human and canine osteochondral allografts was captured using a laser scanning system to fit B-Spline surfaces and generate articular curvature maps for the modified allografts. We hypothesize that due to the surface modification enabled by the bending method, bendable osteochondral allografts may provide better curvature matching for patella transplants in the patellofemoral joint. We used a cadaveric knee joint model to investigate patellofemoral joint congruence for unbent and bendable osteochondral allografts at various flexion angles. Shell and bendable allografts were machined from donor human patellae and inserted into the patellofemoral joint space of five knee joints, creating 25 femur-patella osteochondral allograft pairings. Patellofemoral joints with either shell or bendable allografts were loaded at 15-degree increments from 15 to 90 degrees flexion, and the resultant patellofemoral joint contact area was measured and compared against the native patellofemoral contact areas. On average, no significant difference in contact area was found between native patellofemoral joints and OCAs or BOCAs, indicating that both types of allografts restored native congruence. This result aligned with prior computational models of the behavior of bendable and shell allografts in the patellofemoral joint. This finding suggests that future investigations of the benefits of BOCA for allografting other joints could be initiated using computational methods, as the results of the current study suggest that the computational predictions may remain valid under the right set of conditions. Clinical studies of outcomes of osteochondral tissue transplantation indicate that maintenance of donor chondrocyte viability is crucial for the long-term success of the transplanted tissue. In order to assure that CNC machined allografts maintained appropriate chondrocyte viability and tissue sterility, we created a sterile environment for CNC milling of fresh canine patellar osteochondral allografts and quantified allograft chondrocyte viability for up to two weeks post-milling. Following machining and extended culture, bending of the allografts produced neither fracture of the samples nor resulted in loss of chondrocyte viability when compared to non-grooved controls. Therefore, these results provide basic scientific support for the clinical use of bendable osteochondral allografts. Having developed a method of bendable allografts and verifying the tissue viability and sterility, in addition to simulating joint contact in the cadaveric model, we ran a study to assess the performance of bendable osteochondral allografts and shell allografts in the contralateral stifle joints of purpose-bred dogs. This animal model was used to measure the clinical outcomes of bendable osteochondral allografts transplantation following in-vivo loading. Functional clinical outcomes were collected, including force mat kinematics, lameness scoring, range of motion, and pain scoring. At the termination of the study, allograft tissue and synovial fluid from the joint were recovered to assess the sterility, chondrocyte viability, chondrocyte morphology, and bony integration of the allograft. The allografts showed no signs of infection or rejection, and the CNC-machined shell allografts performed well in the joint. Unfortunately, the grooves machined for the bendable allograft patellae were more appropriate in width for the human patella. The removal of excess bony tissue destabilized the bendable allografts and led to fractures and fissures in the tissue. Based on the fissuring and fragmentation mode of failure noted in the canine BOCAs, the size and number of the machined grooves must be optimized for preclinical testing so the potential advantages of bendable OCAs can be realized without compromising their integrity and osteointegration during healing. Bulk mechanical properties and failure thresholds dependent on the width of allograft grooves must be established to reduce the risk of post-transplantation failure. Ongoing work aims to establish safe geometrically-based machining criteria and determine load-to-failure thresholds for osteochondral allografts to improve tissue integrity and functional viability post-transplantation. This aim will be addressed by loading canine bendable allografts with variable groove widths to assess the threshold for mechanical failure against simulated femoral trochlea. The aim of this study is to define allograft bulk mechanical properties and failure thresholds for producing bendable osteochondral allografts. The final chapter of this dissertation aims to assess the impact of sustained mechanical loading on the fluid exchange between the interfibrillar and extrafibrillar space in native articular cartilage, as the fluid load support in articular cartilage is crucial to the maintenance of the low coefficient of friction within the tissue. In our study, we developed a technique to measure water extruded from the interfibrillar space in articular cartilage by applying static compression to unconfined tissue. Preliminary results indicate that the loading and pressurization of the articular tissue can potentially make previously trapped interfibrillar water content more accessible

published_or_final_version / abstract / Biochemistry / Doctoral / Doctor of Philosophy

Osteoarthritis, a degenerative joint disease that affects nearly 30 million Americans, is characterized by lesions of articular cartilage that often lead to severe pain and loss of joint function. The current economic burden of osteoarthritis is estimated to be approximately $190 billion, and with the prevalence of arthritis expected to rise due to the aging population, the associated costs are forecasted to increase. Debilitating osteoarthritis is managed clinically by the surgical implantation of a cartilage graft or cartilage cells to replace the damaged tissue; however, current repair methods often result in poor long-term outcomes due to inadequate integration of the graft with host cartilage and bone. Thus, there is a significant clinical need for approaches that enable functional connection of grafting devices to the host tissue. To address this challenge, the strategy described in this thesis is a versatile, cup-shaped fibrous scaffold system designed to promote the simultaneous integration of the cartilage graft with both the host cartilage and subchondral bone. This thesis is guided by the hypotheses that 1) graft integration with native cartilage can be strengthened by inducing chondrocyte migration to the graft-cartilage junction through chemotactic factor release from the walls of the cup, and 2) graft integration with host bone and the formation of calcified cartilage can be facilitated by pre-incorporation of calcium phosphate nanoparticles in the base of the cup. To test these hypotheses, a microfiber-based integration cup was designed with degradable, polymer-based walls that release insulin-like growth factor-1, which is well-established for inducing chondrocyte migration, and a base consisting of polymer with calcium deficient apatite nanoparticles. In the first aim of this thesis, the dose of insulin-like growth factor-1 in the cup walls was optimized to enhance the migration of cells from surrounding cartilage into the scaffold, and this design was tested in vitro to ensure that the scaffold supports chondrocyte viability, growth, and biosynthesis of a cartilage-like matrix. In the second aim of this thesis, the composition and dose of calcium phosphate in the base of the cup was optimized to support chondrocyte growth and the production of calcified cartilage-like tissue. Subsequently, in the third aim, the independently developed walls and base were joined into a scaffold that was tested in vitro and in vivo, using a simulated full thickness defect model, to examine its potential for clinical translation. Results from these studies demonstrate that the cup system can be implemented with autologous tissue and cell-based grafting strategies as well as with tissue engineered hydrogel grafts to promote integration with host tissue. Moreover, these investigations have yielded new insights into both chemical and structural parameters that direct chondrocyte migration and calcified cartilage formation. In summary, this thesis describes the design and optimization of a novel, multi-functional device for improving integration of cartilage grafts with host tissues. The impact of the studies in this thesis extends beyond cartilage integration, as the interface scaffold design criteria elucidated here are readily applicable to the formation of interfaces between other grafts and host tissues.