Master of Science in Engineering, University of Akron, 2019, Biomedical Engineering

Wound healing is a challenge not specific to a particular demographic. It affects all areas of the world and is the result of many different disease types and scenarios. There is a vast array of sources for disease initiation in wound healing and the field currently lacks simple and effective solutions for remedying the ailment. Oxygen is an essential component required in many of the biochemical processes occurring during the wound healing process and many chronic wounds lack oxygen resulting in wounds that do not heal or heal too slowly. A wound healing hydrogel, methacrylated fluorinated (Ali15) chitosan (MAC) also known as MAC(Ali15)F, was developed and characterized in an attempt to enhance local oxygen concentrations in oxygen-deficient skin. More specifically, this chitosan-based hydrogel used Schiff base nucleophilic substitution to attach perfluorocarbons (PFCs), which are known for their ability to capture oxygen from the surrounding atmosphere. Material characterization studies showed the MAC(Ali15)F hydrogel's ability to release oxygen, to sustain lysozyme concentrations of 1000 U/mL, and to retain the ability after degradation to sequester oxygen. The MAC(Ali15)F hydrogel showed evidence of biocompatibility when exposed to human dermal fibroblasts and in rodent studies. In vitro studies established that the hydrogels encouraged cell proliferation. In vivo studies indicated that the wounds being treated with hydrogels were able to progressively heal in a moist environment. Preliminary studies show that the hydrogels have the potential to provide specific levels of oxygen to the wound site while simultaneously providing moisture for wounds in a portable and customizable bandage size.

Committee: Nic Leipzig Ph.D. (Advisor); Brian Davis Ph.D. (Committee Member); Judith Fulton Ph.D. (Committee Member); Rebecca Kuntz-Willits Ph.D. (Committee Member) Subjects: Biomedical Engineering; Chemical Engineering

Doctor of Philosophy, The Ohio State University, 2019, Vision Science

Purpose. Half of the nearly 500 million diabetic patients globally will develop degenerative corneal changes, termed diabetic keratopathy, during the course of their disease, leading to sight-threatening scarring. Dogs are a naturally occurring model of insulin-dependent diabetes and develop ocular surface changes with disease; however, corneal fragility and delayed wound healing are not observed clinically in the dog. Due to the consistently increasing prevalence and estimated costs to treat diabetic keratopathy, there has been a growing effort to identify novel therapies to minimize discomfort and sight-threatening scarring. Topical insulin has been shown to reduce wound area and restore corneal sensitivity in diabetic rats and promote cellular proliferation. Both the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1-R) stimulate cell signaling events through activation of a receptor tyrosine kinase (RTK), although different cellular pathways can be initiated due to the different properties of each receptor. Additionally, the two RTKs can each contribute two subunits to yield a hybrid receptor (Hybrid-R). RTK expression within ocular tissue has been evaluated in humans and rodents. The purpose of this study was to assess in vitro cytotoxicity with insulin treatment and suggest a mechanism by which improved wound healing occurs by characterizing RTK and induced kinase expression within the PI3K-Akt pathway in both human and canine corneal cells. Methods. Lactate dehydrogenase (LDH) assays were performed to assess for cytotoxicity. In vitro scratch tests were used to evaluate wound healing outcomes under variable glucose conditions in the presence or absence of human recombinant insulin. Fluorescent cellular glucose uptake and protein and DNA synthesis assays were performed to characterize the effect of insulin on glucose transport dynamics and protein and DNA synthesis, respectively. Protein co-immunoprecipitation, RT-PCR, and immunohistoche (open full item for complete abstract)

Committee: Heather Chandler PhD (Advisor); Andrew Hartwick OD, PhD (Committee Member); Timothy Plageman PhD (Committee Member); Amit Sharma PhD (Committee Member) Subjects: Biomedical Research; Cellular Biology; Molecular Biology; Ophthalmology

Master of Science in Biological Sciences, Youngstown State University, 2012, Department of Biological Sciences and Chemistry

Although new surgical techniques and technologies have attempted to combat the occurrence of hernias, patients continue to suffer from hernias following abdominal surgeries. Regenerative therapy, including the use of bone marrow derived-mesenchymal stromal cells (MSCs) or platelet-rich plasma (PRP), offers a new avenue to reducing the problem of hernias seen in post-operative patients. In this study, midline laparotomies were performed on Lewis rats. The incision was repaired with CollaTape or Allomax mesh with or without the addition of MSCs and/or PRP. At 4 and 8 weeks postoperative, abdominal fascia was excised (n=7 per group). The current study attempted to detect collagen type I (COLI) with immunohistochemistry (IHC) in paraffin-embedded sections from CollaTape supplemented abdominal walls. IHC was unsuccessful at identifying COLI. Future studies may require the identification of new antibodies that are effective in paraffin-embedded tissues. Collagen amount and organization, and myocyte degeneration of healed abdominal walls repaired with AlloMax were compared using Trichrome stained slides. AlloMax, with the addition of MSCs, resulted in decreased collagen production when compared to AlloMax with PRP. However, abdominal wall repaired with AlloMax, PRP and MSCs had a greater positive correlation between collagen organization and amount than uninjured abdominal wall. MSCs ability to suppress immune response may be deleterious to abdominal wound healing when combined with Allomax surgical mesh. Although the use of MSCs did not improve collagen redistribution in a healing abdominal wound in this study, the research presented here may lead to future discoveries involving MSC supplemented wound repair.

Committee: Diana Fagan Ph.D. (Advisor); Johanna Krontiris-Litowitz Ph.D. (Committee Member); Mark Womble Ph.D. (Committee Member) Subjects: Alternative Medicine; Biomedical Research; Histology; Surgery

Doctor of Philosophy, The Ohio State University, 2007, Oral Biology

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis resulting in increased serum glucocorticoids (GCs); GCs are used clinically for their potent anti-inflammatory actions. Thus, because the stress-induced increase in GC is anti-inflammatory, stress predictably suppresses the inflammatory phase of wound healing and slows closure of cutaneous wounds. Previous studies from this laboratory suggest that the steroid hormone dehydroepiandrosterone (DHEA) and its metabolites androstenediol (AED) and androstenetriol (AET) counter-regulate the immune-suppressive functions of GCs. Thus we hypothesized that pharmacological treatment of animals with AED would diminish the health adverse effects of elevated GCs. It is further hypothesized that by counterbalancing the GC-mediated transcriptional regulation of cytokine gene expression through interactions with the transcriptional activator NF-κB, AED will restore inflammation and improve wound healing in stressed animals. A murine model of cutaneous wound healing was used. Male CD-1 mice underwent daily cycles of restraint stress (RST), which began three days prior to wounding. Animals were treated with AED at 3 timepoints, while control animals received vehicle treatment. Photoplanimetry was utilized to assess healing kinetics of the wounds. Wounds were harvested at various times and processed for real time PCR analysis, or the TransAM™ assay. The results show that RST delayed wound closure and altered the kinetics of inflammatory gene expression compared to control animals and did so by modulating NF-κB activation. Treatment with AED prevented the anti-inflammatory effects of RST and augmented NF-κB driven gene expression above control levels. Preliminary data suggest the effects of AED are manifest at the level of transcription initiation complex formation, and future studies will test this hypothesis. In conclusion, the data indicate that AED may be a viable pharmacological approach to functionally antagonize the eff (open full item for complete abstract)

Committee: David Padgett (Advisor) Subjects:

Master of Science, The Ohio State University, 2008, Graduate School

Committee: Not Provided (Other) Subjects:

Master of Science, The Ohio State University, 1969, Graduate School

Committee: Not Provided (Other) Subjects:

Doctor of Philosophy, The Ohio State University, 2024, Biophysics

Extracellular Vesicles (EVs) have gained attention for their role in healthy and pathophysiological processes, including cell death, inflammation, angiogenesis, and cancer progression. EVs are released by cells and play a crucial role in cell-to-cell communication as they can contain active biomolecules such as proteins, lipids, mRNAs, and microRNAs. Due to their inherent characteristics like high cargo protection, endosomal escape, biocompatibility, and stability in bodily fluids, EVs are considered the next-generation drug delivery system. Moreover, EVs can be engineered (eEVs) to modify cargo payloads to target specific diseases. This thesis focuses on engineering extracellular vesicles with multiple molecular cargos to assess their therapeutic potential in conditions such as skin ischemia, Neurofibromatosis type 1, and peripheral nervous system disorders. The first chapter covers biogenesis, cargo selection, and methods for engineering extracellular vesicles. The second chapter concentrates on engineering vasculogenic EVs loaded with the transcription factors Etv2, Fli1, and Foxc2 to induce direct reprogramming of human dermal fibroblasts into endothelial cells in vitro and in vivo. The therapeutic effect of the vasculogenic eEVs was evaluated in an in vivo wound injury mouse model. The results showed a significant positive impact by promoting wound closure, increased vascularization, and enhanced blood perfusion in the injured area. The next two chapters are dedicated to developing eEVs loaded with a healthy version of the gene NF1 to treat the autosomal disorder Neurofibromatosis type 1 for human subjects and genetically engineered mouse models, in chapters three and four, respectively. Chapter Five focuses on the efficient delivery of eEVs in the central and peripheral nervous system via a retrograde injection into the sciatic nerve. This approach can potentially assess the delivery of molecular payloads using eEVs to treat various conditions, including neuro (open full item for complete abstract)

Committee: Natalia Higuita-Castro (Advisor); Devina Purmessur (Committee Member); Heather Powell (Committee Member); Daniel Gallego-Perez (Committee Member) Subjects: Biomedical Engineering; Biophysics

Master of Science, The Ohio State University, 2023, Dentistry

Introduction: E-cigarettes are small, battery-powered devices that deliver a mixture of nicotine, propylene glycol, glycerol, and flavoring agents as aerosols. These devices are being used by ex-smokers, current cigarette smokers, and previous nonsmokers. Previous studies in our laboratory and others have demonstrated that e-cigarette use is associated with high pro-inflammatory response, hypokeratinization of oral epithelium, and increased cytotoxicity, suggesting that these devices can increase the risk for poor postoperative healing outcomes. Objective: The study was aimed to assess oral wound healing in orally and systemically healthy e-cigarette users. Methods: A parallel-arm, prospective clinical study was conducted. 8 subjects using e-cigarettes and 8 age- and gender-matched non-vapers were recruited. Punch biopsy wounds of 5 mm of diameter were created bilaterally in the palatal mucosa opposite to the 2nd premolar. Pre-wounding palatal mucosal swabs were also collected for metabolomics profiling of the microbiome at all time points. Subjects were followed up at 1, 2, 4, 7, 14 and 21 days post-operatively, and 3 mm punch biopsies of the healing wounds were collected from the right and left palate at 1- and 3- weeks respectively. Biopsies were subjected to immunohistochemistry to quantify the levels of vimentin, keratin and filaggrin. Results: Statistically significant differences in overall healing were observed between control and test groups, between visits, as well as different trends shown by the groups over the visits. Significant differences were observed between groups and between visits in terms of bleeding and swelling, while only significant differences between visits were seen for epithelialization and redness. Pain perception and difficulty to obtain hemostasis were more observed in the test group. Pathway analysis between week 1 and 3 revealed that carbohydrate and lipid metabolism was significantly higher in e-cigarette users while synthesis (open full item for complete abstract)

Committee: Purnima Kumar (Committee Member); Binnaz Leblebicioglu (Advisor); Yi-Chu Wu (Committee Member) Subjects: Dentistry; Health Sciences

Doctor of Philosophy, The Ohio State University, 2022, Biomedical Engineering

The standard of care for treating full-thickness burns, split-thickness autografting, is an effective but limited method of treatment for burns that cover a large total body surface area (TBSA). Due to the low availability of donor sites, time to closure becomes extended, increasing possibility of infection and pathological scarring. Tissue engineering strategies, such as cultured epithelial autografts (CEAs) and cultured skin substitutes (CCS), utilize a small amount of donor tissue and isolates cells from these biopsies for in vitro expansion and tissue development. Although these treatments are life saving, they require extensive time for production, increasing time to application. As the probability for hypertrophic scarring increases as the time to healing increases, rapid wound closure is needed to promote optimal aesthetic and functional outcomes for burn survivors. To develop methods for rapid skin regeneration, a replacement for the extracellular matrix (ECM) must be fabricated. As the natural ECM is comprised of collagen fibrils and fibers that range from nanometers to several microns in diameter, the process of electrospinning is often used to create these scaffolds as it allows for the adjustment of scaffold properties on a micro- and macroscopic level. Choice of parameters, including but not limited to the solvent, voltage, and source of collagen, can be modified to obtain desired scaffold properties. With a functional ECM that can be seeded with dermal fibroblasts to recreate the dermis, a method to rapidly deliver autologous cells to the wound and promore epidermal regeneration is needed. Standard laboratory methods to isolate primary human keratinocytes are labor intensive and require an extensive enzymatic treatment to dissociate the epidermis from the dermis. To investigate the potential of cells harvested using a rapid isolation method, surgical discard tissue was processed using two methods of cellular isolation. Cells were isolated using e (open full item for complete abstract)

Committee: Heather Powell (Advisor); Daniel Gallego-Perez (Committee Member); Katelyn Swindle-Reilly (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, University of Akron, 0, Polymer Science

When the skin is compromised through injury, the onset of wound healing is initiated by signaling the surrounding cells to the wound site. Medical interventions may be required to prevent exacerbating wounds. One type of products are cellular matrices which is bioactive but expensive. The other types are synthetic acellular wound dressing which is inexpensive but bioinert. These two types of products are locating at two ends of the spectrum. As a result, there is an unmet need for bioactive but cost-effect materials for wound healing. In this dissertation, we aim at creating bio-active synthetic materials to from two directions, one is to enhance cell migration the other one is to modulate immune responses. First, we hypothesize that RGD-conjugated polymer could enhance the migration of fibroblast. The methodology of designing 3D-printed porous scaffolds post-functionalized with tripeptide RGD on the surface was established. In vitro, the migration rate of human dermal fibroblasts was increased from 12% to 35% as the RGD concentration increases. In vivo, slightly increased granulation tissue formation was observed for wounds treated with RGD functionalized scaffolds. In the second part, we hypothesized that polyesters with different functional groups could provide guidelines in designing synthetic skin grafts to prevent undesired immune responses. In vitro, pro-inflammatory cytokines (IL-1β) were measured by qPCR when seeding macrophages on polymer films and showed distinct immune profiles. This provided information on what functional groups may elicit early inflammation when implantation.

Committee: Abraham Joy (Advisor); James Eagan (Committee Chair); Christine McDonald (Committee Member); Nic Leipzig (Committee Member); Mesfin Tsige (Committee Member) Subjects: Biomedical Research; Polymer Chemistry

Master of Science, The Ohio State University, 2022, Dentistry

Objectives: This study aimed to determine the clinical and patient-centered outcomes during the healing of standardized buccal gingiva wounds and assess the effect of gingival phenotype (thin or thick) on such outcomes. Materials & Methods: A case-control clinical trial was conducted; periodontally and systemically healthy non-smoker volunteers were recruited, based on determination of thick or thin periodontal phenotype. Standardized circular buccal gingival wounds (3 mm diameter, 1 mm depth) were created between the maxillary right premolars, using a single-use biopsy punch. Clinical outcomes were recorded at postoperative days 3, 7, and 14, using the Pippi modification of the Landry Healing Index and the peroxide test to evaluate wound epithelialization. Additionally, patient-centered outcomes were assessed using custom and OHIP-14 questionnaires at pre-treatment, and postoperative days 3 (D3), 7 (D7), and 14 (D14). Statistical analyses were performed to determine inter-group differences and correlations between parameters. Results: Twenty-six volunteers (aged 24-36 years old; 12 males, 14 females; 13 thick, 13 thin, age- and sex-matched groups) completed the study protocol. The mean(±sd) Healing Score Index was 4.0±0, 5.7±0.5, and 6.8±0.4 at D3, D7, and D14, respectively, for the thick group; corresponding values for the thin group were 4.0±0.4, 5.7±0.6, and 6.8±0.4, with no significant difference between groups. No wound was epithelialized on D3 (H2O2 test). On D7 and D14, 69.2% and 100% of thick group wounds were ii epithelialized; corresponding frequencies for thin group were 61.5% and 92.3%. Clinically assessed wound closure (H2O2 test) results were consistent with the photographic image analysis results for wound area, which also showed no inter-group differences. Image analysis showed that by day 14 over 95% of the original wound area was closed in both groups. Postoperative mean OHIP-14 scores on D3 were 14.5±1.05 and 14.8±1.24 for thick and thin g (open full item for complete abstract)

Committee: Dimitris N. Tatakis (Advisor); David L. Hall (Committee Member); Binnaz Leblebicioglu (Committee Member) Subjects: Dentistry

Doctor of Philosophy, University of Akron, 2022, Chemical Engineering

In the United States alone, there are more than 6.5 million patients suffering from chronic wounds forcing a cost of around $25 billion per year to healthcare market. Persistent infection in diabetic wounds is a primary cause of wound healing failure and increases the likelihood of non-traumatic limb amputations. Heavy wound bacterial burden in diabetic wounds and their chronicity requires multiple clinical strategies to be applied simultaneously. Previous research has shown benefits of using supplemental oxygen to improve the diabetic wound healing processes, through hyperbaric oxygen therapy and oxygen-delivering wound dressings. Moreover, oxygen can enhance inherent anti-infective mechanisms by upregulating the formation of reactive oxygen species. However, for a highly infected wound, supplemental oxygen alone may not be adequate to control infection. Thus, antibacterial agents still need to be used to achieve satisfactory outcomes. Oxygen is also able to synergistically enhance the antibacterial functions of some antibiotics leading to reduced infection. Therefore, I aimed to develop a dual-functioning oxygenating and antibacterial wound healing platform to combine the wound healing and anti-infective advantages of oxygen and an effective antiseptic agent, in a single hydrogel wound dressing based. I created these dressings using fluorinated methacrylamide chitosan hydrogels (MACF), with excellent oxygen absorption characteristics, as well as an effective antiseptic agent called polyhexamethylene biguanide (PHMB). The overall hypotheses of this study were first. Synergistic oxygenating MACF-PHMB dressings can improve natural mechanisms against wound infection by upregulating neutrophil antimicrobial activity in vitro, and second. providing localized oxygen through MACF hydrogels along with the incorporated antiseptic agent, PHMB, can promote wound healing and infection control in diabetic mouse models with infected wounds, to create a synergistic oxygena (open full item for complete abstract)

Committee: Nic Leipzig (Advisor); Abraham Joy (Committee Member); Lu-Kwang Ju (Committee Member); Bi-Min Newby (Committee Member); Hazel Barton (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Engineering

Doctor of Philosophy, University of Akron, 2022, Chemistry

Methanotrophic bacteria absorb methane and oxidize it as their sole source of carbon and energy. Almost all methanotrophic bacteria contain an extensive network of Intracytoplasmic membrane (ICM). The ICMs contain particulate methane monooxygenase (pMMO), which is the initial enzyme in the metabolism of methane. Due to the accumulation of high lipid content in the form of ICM and the formation of polyhydroxybutyrate (PHB), there is a growing interest in utilizing these bacteria to convert the ICM and PHB to biofuel. Structural aspects of the ICM have been characterized by transmission electron microscopy. However, the dynamics and functional role of ICMs remain elusive. A rapid fluorescence microscopy method to visualize ICMs in situ using lipophilic dyes was developed in Chapter III. The extent to which ICM formation occurs in cells depends on the concentration of copper. The ICM formation was visualized and quantified in type I methanotroph Methylotuvimicrobium alcaliphilum (comb. Nov. 20Z) by tracking the bulk copper conversion spectroscopically and by live single-cell confocal imaging. Both methods showed a lag phase prior to the increase in ICM amounts over time. During the ICM formation, there was a significant amount of cell to cell heterogeneity. Further, rapid in-vivo quantification of the PHB method was developed to determine the conditions that enhance the PHB accumulation in methanotrophs. A rapid and cost-effective single cell PHB analysis through fluorescence microscopy by staining via Nile Blue A (NBA) in type II methanotroph Methylocystis sp. Rockwell was described in Chapter IV. NBA stained both the outer membrane of the cell and individual granules of PHB, distinctly but not the ICMs. The ICMs in Methylocystis. sp. Rockwell resides peripheral to the inner membrane whereas PHB is present in the cytoplasmic region. Methylocystis sp. Rockwell accumulated PHB when grown in ammonium mineral slats (AMS) medium, regardless of nitrogen or carbon stress. PH (open full item for complete abstract)

Committee: Adam Smith (Advisor); Sailaja Paruchuri (Committee Member); Nic Leipzig (Committee Member); Chrys Wesdemiotis (Committee Member); Yi Pang (Committee Member) Subjects: Biology; Chemistry

Master of Science in Biological Sciences, Youngstown State University, 2021, Department of Biological Sciences and Chemistry

The calcaneal (Achilles) tendon is capable of handling tremendous tensile loads during locomotion. However, cases of Achilles tendon ruptures have increased in recent years, requiring long healing times. Repaired tendons are more prone to re-rupture after healing, which may negatively impact patient quality of life. Thus, there exists a need for new methods of treatment aimed to improve and accelerate tendon healing. We studied the effect a combination of collagen, platelet-rich plasma (PRP), and mesenchymal stromal cells (MSC) on healing a complete Achilles tendon rupture in a Lewis rat model. The PRP was produced from rat blood collected during exsanguination procedures. MSCs from rat bone marrow met the criteria to be considered stem cells in a rat model, as they were seen to be plastic adherent and capable of tri-lineage differentiation. Rupture was surgically simulated by a full-thickness transection of the tendon, followed by surgical repair. All treatments included a strip of CollaTapeTM wrapped around the repair, acting as a vehicle for the biologics prior to closure of the wound. A single, 100µL subcutaneous injection of MSCs, PRP, or both were administered adjacent to the incision and assigned 1- or 2-week recovery periods before harvesting the operated and unoperated tendons. We observed promising trends which show an increase in gene expression activity in the treated tendons and differences in the expression of Col1a1 and Col3a1 which align with our predicted response to the treatments. However, due to contamination of the GAPDH RT-PCR results, the collagen analysis results remain inconclusive. The biomechanical properties of the tendons were determined using force-extension analysis. When normalized as a percent of the unoperated tendon, a significant improvement was seen in the strain at failure and in ultimate tensile strength after only one week of recovery in the rats who received any biological treatments used in this study, when compared to a sur (open full item for complete abstract)

Committee: Diana Fagan PhD (Advisor); Gary Walker PhD (Committee Member); Carmen Panaitof PhD (Committee Member) Subjects: Biology; Biomechanics; Biomedical Research; Physiology; Surgery

Doctor of Philosophy, Case Western Reserve University, 2022, Biomedical Engineering

Challenges in the effective treatment of chronic wounds place a significant financial strain on the overall healthcare system of the United States. For the Veterans Heath Administration (VHA), the high incidence of wounds incurs significant costs due to the need for repeated out-patient visits, frequent hospital admissions, and long periods of bedrest. The continued high incidence rate of chronic wounds in Veterans coupled with an increase in healthcare spending per capita indicates that there remains an unmet technological and clinical need for effective therapies. Non-invasive smart biomedical devices have the potential to bridge this clinical gap by providing clinically-relevant data facilitating monitoring of chronic wounds throughout the healing process. Novel epidermal electronics leveraging stretchable and flexible substrates and dry electrodes enable biomedical devices to conform to the irregular topography of the body for long-term, clinically relevant durations. This work sought to develop a wearable electroceutical device, herein referred to as exciflex, for the site-specific repair of chronic wounds via the delivery of a controllable electroceutical therapy to the ischemic wound environment. The first aim of this thesis involved the fabrication and characterization of two novel biomaterials: Flexatrode elastomeric conductive nanocomposites and AFTIDerm an absorbent, flexible, transparent, and inexpensive substrate. These materials have initial application for integration into exciflex, with the potential of platform technology utility as stand-alone components as flexible electrodes and substrates for wearable bioelectronic applications. The structure-property relationship, electro-mechanical characteristics, thermal, and biological properties of these materials were investigated and characterized leveraging clinical specifications. The second aim of this thesis involved design and microfabrication of the multi-material exciflex substrate, integrat (open full item for complete abstract)

Committee: Kath Bogie (Advisor); Christian Zorman (Advisor); Celeste Alfes (Committee Member); Colin Drummond (Advisor); Sam Senyo (Committee Chair) Subjects: Biomedical Engineering; Biomedical Research; Electrical Engineering; Materials Science; Nanotechnology; Polymer Chemistry; Polymers

Doctor of Philosophy, The Ohio State University, 2021, Biomedical Sciences

Tissue engineered scaffolds and regenerative medicine-based therapeutics hold great potential for a growing patient population in need of alternative tissue replacements. The initial work of this dissertation is on efforts to improve the translational capability of tissue engineered vascular grafts (TEVGs) to the clinic. A challenge in translating our group's TEVGs, as well as is seen with other tissue engineered scaffolds, is balancing the host response where an appropriate amount of healthy neotissue is created and remodeled overtime replacing the biodegradable scaffold and avoiding complications such as graft thrombosis and stenosis. Approaches to optimize tissue engineered scaffolds for use in patients often focuses on material alterations, cell seeding, bioreactor growth, or drug/small molecule co-administration. Seeding our TEVGs with bone-marrow derived nucleated cells has proven to be an effective approach to minimize graft occlusion and alter neotissue development; however, the exact mechanism underlying this remains unclear. The initial focus of this dissertation sought to elucidate what effect interleukin-10, an anti-inflammatory cytokine, had on graft patency and neotissue development from cells seeded onto TEVGs, from the host TEVG recipient, and from a recombinant protein drug delivery. This work demonstrated interleukin-10 from the host was critical in maintaining TEVG patency. Another promising approach optimizing a thrombosis and stenosis resistant TEVG has been our group's investigations into a novel wound healing modulator known as the lysosomal trafficking (LYST) protein. The protein, encoded by the LYST gene, is poorly understood with much of existing information coming from observations into disease states and cellular dysfunction that occurs in presence of a LYST gene mutation. A notable cellular finding is the perniculear clustering of enlarged lysosomes in mutant LYST cells due to defects in lysosomal fusion/fission. We serendipitously (open full item for complete abstract)

Committee: Christopher Breuer (Advisor); Ginny Bumgardner (Committee Member); Ryan Roberts (Committee Member); David Dean (Committee Member) Subjects: Biomedical Engineering; Cellular Biology; Experiments; Histology; Immunology; Medicine

Doctor of Philosophy (PhD), Wright State University, 2021, Biomedical Sciences PhD

Carbon Nanotubes (CNTs) have beneficial properties for cell scaffolding, which has translated into effective growth of bone, muscle, and cardiac cells. However, loose carbon nanotubes can cause in vivo toxicity. To reduce this risk, our team has developed biomimetic scaffolds with multiscale hierarchy where carpet-like CNT arrays are covalently bonded to larger biocompatible substrates. In this study, we have tested such scaffolds in two distinct types of biomedical applications involving glioblastoma and keratinocyte cells. The growth of glioblastoma (GBM) cells on our CNT-coated biomimetic scaffolds was evaluated to check their suitability as a potential chemotherapy-loaded implant for GBM patient treatment. We utilized CNT carpets on flat carbon fiber cloths and porous carbon foams and identified differing effects on cell growth by altering the surface features, such as hydrophilicity. Synthesized CNT-coating is naturally superhydrophobic and prevents GBM cell growth initially, but over time cell proliferation increases to normal levels. When the CNT surface was modified to be hydrophilic, GBM cells followed a normal growth curve. These findings support the feasibility of developing a CNT-coated chemotherapy-loaded implant for post-surgical resection in GBM patients. Keratinocyte cell growth on CNT-coated carbon fiber cloth was investigated to assess its compatibility as a skin graft material for wound healing applications. Due to its covalently linked structure, biocompatibility, functionalizable topological features, and extensive surface area, CNTs could provide a suitable surface for skin cell proliferation. CNTs can also provide directionality, which can be important for supporting scaffolds used in wound healing applications. This project aimed to determine whether the use of CNTs attached to carbon scaffolds are capable of sustaining keratinocyte growth for future development of novel skin graft development. Studies demonstrated biocompatibility for (open full item for complete abstract)

Committee: Sharmila M. Mukhopadhyay Ph.D. (Advisor); Courtney E.W. Sulentic Ph.D. (Committee Member); David R. Cool Ph.D. (Committee Member); Saber Hussain Ph.D. (Committee Member); David R. Ladle Ph.D. (Committee Member); Tyler Nelson Ph.D. (Other) Subjects: Biomedical Engineering; Biomedical Research; Nanotechnology

Doctor of Philosophy, University of Akron, 2021, Polymer Science

Wound dressings play a pivotal role in providing favorable wound healing outcomes. Active dressings which incorporate bioactive agents such as anti-inflammatory drugs, antimicrobial compounds or peptides and proteins can help to alleviate patient pain and reduce healing times. This is especially true for diabetic ulcers, which are wounds that are stuck in the inflammatory stage of wound healing and are often associated with bacterial infection. This work describes the development of wound dressings capable of improving healing outcomes. To do so, a series of functional polyesters derived from a modular N-substituted diol monomer platform were synthesized. Wound dressings comprising these polyesters were fabricated using the 3D printing and electrospinning techniques. Dyes serving as model drug compounds were released from electrospun dressings to show the ability of these dressings to deliver drugs. The two fabrication techniques were used to create dressings comprised of varying polyester compositions. An in vivo acute wound rat model showed that despite their varying compositions and thread sizes, none of them were detrimental to normal healing processes. Electrospun dressings showed broad spectrum antimicrobial activity in an acute infected wound mouse model when an antimicrobial poly(ester urethane) was incorporated. Finally, 3D printed scaffolds were conjugated with peptides capable of recruiting keratinocytes and fibroblasts in an attempt to improve healing outcomes in an acute wound rat model. These studies seek to guide future researchers in the design and implementation of active wound dressings, especially by showing the utility of functionality within those dressing systems.

Committee: Abraham Joy (Advisor); Chrinstine McDonald (Advisor); Toshikazu Miyoshi (Committee Chair); Chunming Liu (Committee Member); Nic Leipzig (Committee Member) Subjects: Animals; Biochemistry; Biomedical Engineering; Biomedical Research; Chemistry; Experiments; Histology; Materials Science; Microbiology; Molecules; Organic Chemistry; Plastics; Polymer Chemistry; Polymers

Master of Science, University of Toledo, 2020, Bioengineering

A common complication of diabetes mellitus is diabetic ulcers, which are the leading cause of lower extremity amputations. Inefficient angiogenesis causes diabetic wounds to remain open , putting the wound at risk for bacterial infection. Wound dressings are constantly being studied to discover a more cost effective and biologically interactive treatment. Borate bioactive glasses are a viable option for soft tissue repair treatments due to their ability of fast degradation, rapid ion release, and ability to initiate the cellular facilitation of growth factors. A cobalt-borate bioactive glass series termed as the CGK glass series was specifically designed to meet the need of diminished angiogenesis in diabetic wounds. Glasses were synthesized via air quenching method and were ground to a particle size below 10µm. Glass characterization through XRD confirmed amorphous structure, while DTA confirmed glass transition temperature. MAS-NMR was utilized to determine the fraction of trigonal borates in comparison to tetrahedral borates contributing to the bioactivity of the glass. It confirmed that the CGK bioactive glass series has a higher amount of trigonal borate than tetrahedral borate groups indicating that the CGK glass is reactive in aqueous solution . FTIR was utilized to access structural vibrations occurring in the CGK glass series and confirmed di-borate and metaborate structures within the glass network. To access angiogenic potential, preliminary studies such as the CAM assay and ICP techniques were employed. It can be concluded that, the CGK glass is not only a bioactive glass series but has a high potential as treatment for Diabetic wounds.

Committee: Aisling Coughlan (Committee Chair); Kelly Marbaugh (Committee Member); Patricia Relue (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, The Ohio State University, 2020, Nursing

Background: Chronic venous leg ulcers (CVLUs) are debilitating wounds affecting nearly 9.7 million people worldwide, mainly older adults. Novel treatment approaches are needed because the incidence of CVLUs is rising and standard topical therapies are often ineffective. Chronic systemic and local inflammation are involved in the pathobiology of CVLUs. Potential targets for adjunct oral therapies include leptin and adiponectin, two hormones in systemic circulation involved in inflammation regulation. Higher leptin to adiponectin ratios (LARs) are associated with more inflammation. Some studies have shown that supplementing diets with marine omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has beneficial effects on LARs, however the collective findings are inconclusive. Thus, the primary purpose of this secondary analysis of data from a randomized clinical trial (RCT), was to determine effects of EPA+DHA supplementation on LARs in older adults with CVLUs. Methods: The parent study evaluated the effects of EPA+DHA (3.0 g/d) versus placebo on lipid mediators of inflammation and CVLU healing at 0, 4, and 8 weeks (n = 40). While leptin and adiponectin were not the primary outcomes variables in the parent study, plasma levels were quantified at the three study time points for 32 participants. Therefore, for this dissertation study, statistical methods were used to analyze the existing leptin and adiponectin data to determine effects of daily oral EPA+DHA supplementation iii versus placebo on circulating levels of leptin, adiponectin, and LARs, and to evaluate associations between leptin, adiponectin, LARs, biomarkers of inflammation (proinflammatory cytokines), and percent of wound healing. Results: On average, participants (n = 32) were white (62.5%), obese (BMI: M = 41.5), older (age: M = 61.3), males (62.5%) with a history of cardiovascular disease. There were no differences in sociodemographic data between the two gro (open full item for complete abstract)

Committee: Jodi McDaniel (Committee Chair); Shannon Gillespie (Committee Member); Tonya Orchard (Committee Member); Alai Tan (Committee Member) Subjects: Nursing