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  ADENOSINE PRECONDITIONING OF HUMAN ISLETS FOR PROTECTION AGAINST HYPOXIA INJURY

  (Wake Forest University, 2026) Ritchey, Thomas Brett

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  Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β-cells, which leads to a lifelong need for exogenous insulin. Pancreatic islet transplantation is a promising approach for β-cell replacement, but many transplanted islets are lost soon after implantation due to hypoxia, inflammation, and ischemia-reperfusion injury. Human islets are especially vulnerable to hypoxic stress because they have high metabolic demands and limited antioxidant defenses. Reducing metabolic activity before hypoxia may help improve islet survival during transplantation. This study examined how adenosine affects human islet viability, insulin metabolism, and resistance to hypoxia-reperfusion injury. Human islets were treated with adenosine at 10 µM and 1 mM. After treatment, viability, insulin content, and glucose-stimulated insulin secretion (GSIS) were measured. Adenosine treatment significantly reduced total insulin content but maintained islet viability and glucose responsiveness. Time-course experiments showed that this metabolic suppression was reversible after adenosine was removed, with insulin content and secretion recovering over several days. In a hypoxia-reperfusion model, 24-hour adenosine preconditioning improved islet survival and preserved glucose-stimulated insulin secretion after 48 hours of hypoxia. Islets exposed to hypoxia without preconditioning lost both viability and functional responsiveness. Principal component analysis (PCA) was used to examine the relationships among viability, SI, RI, and insulin content. The analysis showed that insulin content and viability were the main sources of variation, while the functional indices formed a secondary axis related to glucose responsiveness. Together, these results demonstrate that adenosine induces a reversible reduction in metabolic activity that protects human islets from hypoxia-induced injury. Adenosine preconditioning therefore represents a simple and potentially translatable strategy to improve islet survival in β-cell replacement therapies.

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  DEVELOPMENT OF A BIODEGRADABLE ANTIMICROBIAL DRESSING FOR SECOND DEGREE BURNS AFFECTING THE RETICULAR DERMIS

  (Wake Forest University, 2026) Campbell, Darnell Rashard

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  ABSTRACTDevelopment of a Biodegradable Antimicrobial Dressing for Second Degree Burns Affecting the Reticular Dermis. Second-degree burns are the most common type of burn injury worldwide. The leading cause of complications in these wounds is bacterial infection, particularly by Staphylococcus aureus (S. aureus), a pathogen found on healthy skin that can rapidly colonize the wound bed. Once established, these bacteria form biofilms; structured communities encased in a protective matrix, that makes them resist treatment and host defenses. Standard topical treatments, such as silver sulfadiazine or Plurogel secured by secondary dressings, often fail to prevent biofilm formation and require painful, repeated mechanical removal that disrupts new tissue growth. To address these limitations, this dissertation developed a biodegradable, burn wound dressing. Poly(1,8-octanediol-co-citrate) (POC) was selected as the scaffold material due to its safe antimicrobial degradants, mechanical tunability, and ability to be removed via gentle washing, thereby reducing the pain associated with mechanical dressing changes. This scaffold was infused with hydrogels we derived from probiotic Escherichia coli Nissle 1917 (EcN) to deliver bacteriocins, antimicrobial peptides produced by EcN that inhibit competing microbes. Two formulations were developed: a "Sterile EcN Hydrogel" sterilized by irradiation to remove bacterial presence, and an "EcN Live Gel" preserving probiotic viability. Results established 50 mg/mL as the optimal hydrogel concentration. The Sterile EcN Hydrogel functioned as a superior standalone biofilm deterrent, achieving a 96% biofilm deterrence against S. aureus, while the EcN Live Gel-POC composite achieved a 5-log reduction in colony-forming units. The POC scaffold was engineered with a 2-hour secondary crosslinking to match the reticular dermis, utilizing hydrolysis-mediated citrate release to create an antimicrobial acidic microenvironment. The final composite achieved a 99.9% reduction of colony-forming units in bacterial burden in vitro, validating the POC-EcN system as a superior, resorbable alternative to the current standard of care.

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  METHAMPHETAMINE EXACERBATES FENTANYL SELF-ADMINISTRATION AND WORSENS MESOLIMBIC DOPAMINE DEFICITS

  (Wake Forest University, 2026) Dawes, Monica

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  ABSTRACTMETHAMPHETAMINE EXACERBATES FENTANYL SELF-ADMINISTRATION AND WORSENS MESOLIMBIC DOPAMINE DEFICITS Recent trends in opioid use suggest that the United States is ensnared in the ‘fourth wave’ of the opioid epidemic, characterized by increasing use of synthetic opioids, primarily fentanyl (FENT), and increased prevalence of co-use with psychomotor stimulants, particularly methamphetamine (METH). While there has been substantial research on opioid use disorder (OUD), most preclinical studies have focused on the use of opioids in isolation, which does not represent reality for many people with OUD, as the majority of this population co-uses multiple substances. Little is known about the behavioral and neurobiological consequences of combined FENT and METH use, despite the increasing prevalence of this deadly combination. Therefore, I sought to determine how the addition of METH to FENT alters behavioral responding across multiple self-administration protocols. As hypothesized, we demonstrated that combined FENT+METH exhibited increased reinforcing efficacy under progressive ratio self-administration protocols. Under fixed ratio 1 (FR1) schedules of reinforcement, we showed that the addition of METH to FENT disrupted the ability of animals to dose-dependently titrate their responding to FENT, suggestive of more hazardous self-administration behavior, particularly in males. Further, we found that, under extinction protocols, FENT+METH males displayed perseverative responding. Through this project we developed a novel ‘bout’ analysis program in collaboration with the laboratory of Dr. Jeffery Weiner. This analysis method led to the identification of a unique and consistent pattern of FENT+METH intake, characterized by single responses made at regular intervals, that appears to be conserved between sexes and across self-administration paradigms. This pattern is striking in contrast to the ‘bout’- like response patterns of animals self-administering either FENT or METH alone. We also examined the effects of FENT+METH on the mesolimbic dopamine (DA) system following acute and chronic drug exposure. Assessment of DA terminal function in the NAc core with fast scan cyclic voltammetry following chronic exposure to FENT+METH indicated that, even at subthreshold doses of FENT and METH, the combination of these substances results in hypodopaminergia (hypoDA). Further, examinations of extracellular DA levels in the nucleus accumbens (NAc) with in vivo microdialysis suggests that acute exposure to FENT+METH produced supra-additive increases in extracellular DA. The results of this work suggest that the combination of FENT and METH represents a distinctly hazardous form of substance use with increased vulnerability for ‘risky’ behaviors and worsened allostatic changes to the mesolimbic DA system.

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  Translational Biomechanics: Measurement Validity and Applied Movement Assessment in Sport

  (Wake Forest University, 2026) Carter, William

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  This thesis examines how accessible biomechanical tools can support movement assessment in clinical and sport settings by addressing two applied problems: evaluating the performance of smartphone-based markerless motion capture and identifying biomechanics of youth football tackling associated with safer, higher-quality technique. In the first study, lower extremity joint angle measurements from a smartphone-based markerless motion capture system were compared with a gold standard marker-based motion capture system during bilateral and single-leg squat tasks. Hip and knee flexion demonstrated convergence and good to excellent reliability, while ankle dorsiflexion showed weaker agreement. These findings support the potential clinical utility of smartphone-based systems for movement screening, particularly for physically larger joint ranges; smaller joint ranges require cautious interpretation. In the second study, 84 tackles from 14 youth football athletes were analyzed using two-dimensional video-based biomechanical measures synchronized with head kinematic data from instrumented mouthpieces. Tackling technique was highly variable, but the most interpretable trends emerged at impact, where more upright head and trunk posture was more likely to be found in tackles with higher performance scores and lower head kinematic magnitudes. Together, these studies highlight the translational value of biomechanical assessment tools for improving movement evaluation, informing coaching and rehabilitation, and advancing athlete safety in real-world settings.

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  Neurocognition and Behavior as a Determinant of Head Impact Exposure in Youth Football Athletes

  (Wake Forest University, 2026) Moessbauer, Marjorie Wren

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  ABSTRACTRepetitive head impacts (RHIs) have been associated with potential long-term neurological consequences, raising concerns about athlete safety in contact sports. Youth football athletes are exposed to RHIs with considerable variability in exposure across individuals. While prior research has focused on physical and environmental contributors to head impact exposure (HIE), less is known about the role of neurocognitive factors and their behavioral manifestations. This thesis examines the relationship between pre-season neurocognitive profiles, focusing particularly on behaviors of impulsivity and attention, and in-season head impact exposure in youth football. Across two studies, athletes underwent pre-season cognitive testing and were instrumented to quantify head impacts throughout a competitive season. The first study investigated how impulsivity relates to observable on-field behaviors, demonstrating that highly impulsive athletes exhibit more frequent maladaptive behaviors during competition. The second study evaluated associations between neurocognitive profiles and head impact kinematics, finding that exposure patterns differ by session type and cognitive profile, although differences in impact magnitude were not observed. Overall, these findings suggest that neurocognitive characteristics may contribute to variability in both behavior and head impact exposure. This work highlights the importance of incorporating behavioral and cognitive factors into strategies aimed at improving safety in youth football.

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