Master of Science, University of Toledo, 2020, Mechanical Engineering

Synthetic bone cements have been used as organic graft substitutes for since the early 20th century for multiple surgical procedures including orthopedic and dental applications. Ceramic bone cement can primarily consist of phosphate, magnesium, and calcium which are all completely biocompatible and have exceptional properties for bone growth. However, a few main issues with phosphate-based cements includes their poor mechanical and physical qualities such as compressive strength, crack propagation, injectability, and cell culturing. This limits the uses of the cement to non-load bearing bone filler. The other issue is the potential for phase separation during injection in surgery. This causes the liquid component of the cement to be filter pressed through the powder component, and making the cement not set and deteriorate before bone regeneration. However, this would be unacceptable for clinical use. Recent studies have shown that these properties can be better developed through the incorporation additives like fiber reinforcements and retarders, increasing the liquid to powder ratio (LPR), decreasing the particle size, and selecting an efficient syringe. These strategies were used to improve the injectability of the both calcium phosphate cement (CPC) and magnesium phosphate cement (MPC) while maintain the mechanical and biological properties. In the first study the CPC's LPR was increased to 0.4, their powder particle sizes were decreased to less than 90 μm, and a suitable amount of citric acid was added as a retarder. Also, in some of the composition of CPC newberyite (NB), a reinforcement platelet particle, was added in different amounts to test the strength of the cement. In the second study MPC's LPR was increased to 0.4, their powder particle sizes were decreased to less than 45 μm, and a suitable amount of boric acid was added as a retarder. All components of both the CPC and MPC have good biological properties and many papers have shown that changing these (open full item for complete abstract)

Committee: Sarit Bhaduri (Committee Chair); Matthew Franchetti (Committee Member); Vijay Goel (Committee Member) Subjects: Biomedical Engineering

Doctor of Engineering, Cleveland State University, 2010, Fenn College of Engineering

The ultimate goal of this project is to develop a biodegradable and implantable scaffold with precise surface topographies that can provide osteoconductive stimuli to connective tissue progenitor cells (CTPs), and subsequently, enhance bone regeneration applications without the complications of autogenous cancellous bone grafts. This dissertation presents the modification of surface microtextures to provide osteoconductive stimuli to CTPs for bone regeneration applications. First, the effect of surface topography on cell proliferation and osteogenic differentiation was validated through experiments using surface post microtextures and CTPs. Post microtextures accelerated CTP growth behaviors compared to smooth polydimethylsiloxane (PDMS) and standard cell culture dishes. Second, soft lithographic techniques were used to develop PDMS post microtextures with varying geometry and arrangement. 10 um diameter post microtextures with various inter-spaces (5, 10, 20, and 40 um) and post heights (5, 10, 20, and 40 um) were developed, and cultured with CTPs to establish optimal and precise surface post microtextures that can provide CTPs with an osteoconductive environment. Cells on post microtextures with 10 um height and 10 um inter-space exhibited higher cell number than other micro-posts with different heights or inter-spaces, and smooth surfaces. The results demonstrate a significant response of CTPs to topography, and suggest a practical role for optimal post size on textured materials in modifying CTP behavior. Third, substrate stiffness of various PDMS formulations was analyzed to investigate the effects on morphology, proliferation, and osteogenic differentiation of CTPs. Stiffer PDMS substrates with surface microtextures provided an enhanced osteoconductive microenvironment to CTPs relative to softer PDMS substrates. Finally, soft lithography techniques were successfully applied to biodegradable materials, including cellulose acetate (CA) and poly lactic-co-glycoli (open full item for complete abstract)

Committee: Shuvo Roy (Committee Chair); Joanne Belovich (Committee Co-Chair); Aaron Fleischman (Committee Member); Nolan Holland (Committee Member); Ronald Midura (Committee Member) Subjects: Polymers

Doctor of Philosophy, The Ohio State University, 2018, Comparative and Veterinary Medicine

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving therapy both for malignant and non-malignant diseases. The success of allo-HSCTs, however, is limited by acute graft-versus-host disease (aGVHD), a frequent complication that remains a leading causes of non-relapse mortality following allo-HSCT. The pathogenesis of aGVHD involves donor T cells which target human leukocyte antigen mismatched host tissues, causing tissue injury through pro-inflammatory cytokine secretion and direct cytotoxicity. The morbidity and mortality associated with aGVHD pose a major barrier against the wider application of allo-HSCT as a curative modality. Thus, better understanding of aGVHD pathogenesis and novel therapeutics are needed. Modulation of T cell function, broadly, depends on control of gene expression. Two well-studied modes of modulating gene expression are noncoding RNAs and epigenetic modifications. Using unbiased approaches, we identified multiple microRNAs that are upregulated during aGVHD. We validated two of these, T-cell intrinsic miR-155 and serum miR-29a, due to their pivotal role in regulating the adaptive immune system. First, we investigate the molecular mechanisms by which miR-155 modulates T cell function in aGVHD. We identify that miR-155 expression in both donor CD8+ T cells and conventional CD4+ CD25- T cells is pivotal for aGVHD pathogenesis. Furthermore, we show that miR-155 strongly impacts alloreactive T cell expansion through proliferation and exhaustion as well as function by promoting a pro-inflammatory Th1 phenotype. Finally, we demonstrate that miR-155 expression in donor T cells regulates chemokine-dependent migration and infiltration into target organs. These findings provide novel insight into the role of miR-155 in regulating T cell function post-transplant and are convincing biological rationale to justify investigation of novel antagomiR-155 therapeutics to prevent or minimize aGVHD. Next, we strive to identify s (open full item for complete abstract)

Committee: Ramiro Garzon MD (Advisor); Michael Caligiuri MD (Committee Member); Renukaradhya Gourapura DVM, MS, PhD (Committee Member); M. Judith Radin DVM, PhD (Committee Member) Subjects: Immunology; Molecular Biology; Oncology

Doctor of Philosophy (Ph.D.), University of Dayton, 2013, Mechanical Engineering

The growing demand for superior materials that function as scaffolds for tissue repair and regeneration has served as a catalyst in medicine. The need for artificial or natural replacement or repair of organs, limbs and tissue presents an opportunity to deliver materials with superior biologics, architecture and mechanical properties. Current biomaterials utilized to repair damaged tissue or augment function commonly fail to meet the optimal combination of biomechanical and healing potential. Additionally, limited donor tissue availability and the increased cost of healthcare are driving factors for improving material processing and diagnostic assessment. Currently, metallic materials, such as titanium and stainless steel, function as implants and reinforcements. However, these materials are permanent and rigid and may inhibit natural healing of damaged tissue. Moreover, metallic implants corrode and fracture, causing repetitive injury and excess scar tissue formation. Conversely, polymer-based materials have shown promising results. A limited number of polymer biomaterials have been approved for scaffold and implant applications. Additionally, some polymers have the ability to degrade, an advantageous characteristic for biological applications. Nevertheless, most natural and synthetic biopolymers lack high strength and cannot be utilized as primary scaffolds in load bearing applications. The materials described earlier present shortcomings. The importance of the presented work is that it utilized mass producible materials, modified them for unique cellular environments and developed a computational model to predict cell behavior and facilitate future design endeavors. Specifically, the current analysis focused on preparing carbon-based scaffolds from monolithic, textile, composite, and nanoartifact derivatives. This work was the first to present an understanding between critical properties of carbon materials: crystallinity, orientation, surface (open full item for complete abstract)

Committee: Khalid Lafdi (Advisor); Robert Brockman (Committee Member); Wiebke Diestelkamp (Committee Member); Kevin Hallinan (Committee Member); Panagiotis Tsonis (Committee Member) Subjects: Biomedical Engineering; Materials Science; Mechanical Engineering; Medicine

Master of Science, The Ohio State University, 2009, Dentistry

Background: Alveolar ridge preservation (ARP) is a surgical technique designed to prevent naturally occurring post-extraction bone resorption.. The purpose of this study was to investigate clinical and histological healing outcomes following ARP performed on molar and premolar sites by using freeze-dried bone allograft (FDBA) together with a collagen membrane. Maxillary and mandibular sextants were compared for clinical and histological parameters. Methods: Inclusion criteria were single tooth extraction with intact mesial and distal adjacent teeth. Exclusion criteria were smokers, patients with ystemic health problems and acute infection. A stent was prepared from clear acrylic. Pre-operative clinical measurements included the amount of keratinized gingiva and clinical attachment level at tooth scheduled for extraction and at adjacent teeth were taken. The thickness of buccal and lingual plate, the length and diameter of the extracted tooth, buccal-lingual and mesial-distal defect size and, the distance from stent in place-occlusal plate to alveolar crest were measured. FDBA and collagen membrane were placed and flap was sutured. A re-entry surgery was performed following approximately 140 days healing period. Clinical measurements were repeated. A bone core was obtained and immediately frozen in liquid nitrogen. Frozen bone cores were analyzed with micro-CT scan for bone volume density and bone trabecular connectivity. Following micro-CT scan, cores were fixed in formalin, decalcified, embedded in paraffin and sectioned. Slides obtained from the mid-portion of the bone core were stained with trichrome and analyzed under light microscopy. Results: Twenty-one patients were completed the study. Following ARP, ridge height loss change was negligible (a loss of 0.4±0.3 mm in maxilla and a gain of 1.3±0.3 mm in mandible). However, average ridge width loss was 2.4±0.8 mm and 2.5±0.5 mm in maxilla and in mandible, respectively. In maxilla, initial CAL at mesial surface of (open full item for complete abstract)

Committee: Binnaz Leblebicioglu (Advisor); Dimitris Tatakis (Other); Suda Agarwal (Other); Do-Gyoon Kim (Other) Subjects: Dental Care

Doctor of Philosophy, The Ohio State University, 2006, Medical Science

Years of clinical and experimental evidence have shown that both the antigen-nonspecific innate immune system and the antigen-specific adaptive immune system can effectively eliminate malignant cells that remain after front-line therapy for cancer. Because the immune response to any given stimulus requires the coordinated activity of a large number of diverse cell types, elaborate communication networks have evolved that utilize direct cell-cell interactions as well as soluble growth factors, or cytokines, that can potentially travel great distances in the body. Knowledge of the mechanisms and effects of these cell-cell and cell-cytokine-cell interactions is of paramount importance as physicians and scientists advance the frontiers of cancer immunotherapy. Presented here is a series of studies that define roles for the cytokine interleukin 15 (IL-15) in acute graft versus host disease (GVHD) and graft rejection. Mediated by both the innate and adaptive immune systems, graft rejection and acute GVHD are the most common life threatening side effects of allogeneic bone marrow transplantation (BMT), a promising immunotherapeutic approach for aggressive and otherwise incurable hematopoietic malignancies. Also presented are studies evaluating a novel therapeutic antibody designed to interrupt the cell-cell signals that serve to prevent tumor cell lysis by natural killer (NK) cells, a critical part of the innate immune system. Together, these data unravel a small portion of the complex interactions between immune effector cells and malignant cells and provide justification for future basic and clinical immunotherapeutic studies.

Committee: Michael Caligiuri (Advisor) Subjects:

Master of Science in Engineering, University of Akron, 2006, Biomedical Engineering

The purpose of this study was to quantitatively determine the difference measured in the amount of bone growth when using two different types of bone grafts. Both grafts contained demineralized bone matrix, however the first graft, a control, utilized a hydrogel carrier, F-127. The second graft's carrier was a beta tricalcium phosphate putty made with the same hydrogel. The grafts were placed intramuscularly into the upper hind legs of 11 female, athymic rats. After a 28-day implantation period, the graft and immediately surrounding tissue was explanted, decalcified and embedded in JB-4. Slides were created and stained using toluidine blue to detect cartilage, osteoid, bone forming cells. This study concluded that there was no statistical difference seen in the quantitative measurement of new bone growth between the two grafts. The mean percentage of new bone growth was based upon the area of new bone over the total explant area. The results were 21% for the DBM with a hydrogel carrier and 22% for the DBM in a b-TCP putty carrier. The results warrant further study with the next animal model.

Committee: Glen Njus (Advisor) Subjects:

Master of Science, University of Akron, 2013, Polymer Science

Bone defects are considered one of the most significant problems in orthopedic surgery. Approximately 1.62 million surgical bone graft procedures were performed in the United States in 2005 and 672,000 fracture reductions in 2006. Although autograft, allograft and some synthetic bone graft materials such as bioceramics and biometallic-based scaffolds have been used successfully for bone defect repair, these materials are not ideal due to their limited supply, bioactivity and insufficient mechanical properties. In this study, we synthesized and characterized amino acid-based poly(ester urea)s for creating bioactive, load-bearing polymeric materials designed to restore function within critical-sized bone defects. Our preliminary data has shown that 1,6-hexanediol phenylalanine-based poly(ester urea)s possess mechanical properties nearly double that of poly(lactic acid) and potent osteoinductive activity. This thesis investigates the diol chain length in the polymer synthesis and its influence on the mechanical properties and in vitro biodegradation, which is the primary innovation of this work. The tunable diol chain length affords optimization of material modulus and in vitro biodegradation rate for the long bone defect repair. These novel biodegradable and non-toxic poly(ester urea)s offer a cost effective solution to the current technologies, the reinforcement of mechanical properties and aid in the healing process making them attractive alternatives to current treatments for bone defects.

Committee: Matthew Becker Dr. (Advisor); Abraham Joy Dr. (Committee Member) Subjects: Biomedical Engineering; Polymer Chemistry; Polymers