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Wallace H. Coulter Department of Biomedical Engineering

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Now showing 1 - 10 of 92
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    Enhancement of Ankle Fusion through FK506 Induced Osteogenesis
    (Georgia Institute of Technology, 2023-12-14) Huffman, Nicholas
    Ankle Arthrodesis is a common surgical procedure that typically involves the fusion of the tibia and talus of the patient. During surgery, the surgeon uses screws and plates to compress the bones together and cease plantar and dorsiflexion motion [1]. However, one of the main complications with the surgery is the non-union of bones. This can be due to loosening of the screws or failure to grow new bone in the joint space. Our team hypothesized that introducing an additional orthobiologic into the system would assist in bone formation and reducing non-union rates. In this study, we evaluated the effectiveness of osteogenic drugs to improve bone fusion within ankle arthrodesis. One such molecule we evaluated is FK506 (Tacrolimus), an FDA approved drug for treating organ transplant rejection. We implemented a cell culture model to test out the osteogenic potential of FK506. Bovine Marrow Derived Cells (MDCs) were cultured for 1-2 weeks and evaluated with Alizarin Red S Staining, Results were also tested with hMSCs. ALP Activity, and Gene Expression. We found that FK506 significantly affects Alizarin Red S staining within our MDCs. Additionally, we identified that rhPDGF-bb could be a potential adjuvant to FK506 treatment. Though future work will be needed to confirm the effects of rhPDGF-bb within an in vivo model. It was also noticed that there was significant variation associated with the MDC results between donors. We will look to answer those questions with flow cytometry in future experiments. Following those results, we tested our model within a rabbit ankle model to evaluate effectiveness.
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    Advancing the Clinical Realization of Pediatric Knee Exoskeletons and Gamified Rehabilitation for Crouch Gait
    (Georgia Institute of Technology, 2023-08-04) Dawson, Kendra Mirella
    Rehabilitation robotics offer valuable additions to traditional occupational therapies. Treatment of this type has predominantly focused on adult populations, however, through technological adaptations, they are now being increasingly integrated into pediatric rehabilitation settings [1]. In this thesis, both the rehabilitation protocol and exoskeleton design will be explored concerning pediatrics. The combination of visual biofeedback combined with robot assisted gait therapy has the potential to further improve results seen from robotic intervention alone [1]. An experiment was designed to be performed with pediatric subjects affected by cerebral palsy. This paper looks at the results from ably body testing. The subjects walk on a treadmill while wearing a bilateral powered knee exoskeleton and participating in a visual biofeedback game. The exoskeleton provides extension assistance for the first 40% of the gait cycle. A real-time avatar biofeedback game was designed to mimic the user’s trunk angle. The goal of the game is to keep the subjects engaged and encourage upright posture. The game displays an avatar that mimics the user’s trunk angle and a scoring system. Results showed improvement in gait posture. A review of the commercial exoskeleton field showed a lack of pediatric options. A pediatric knee exoskeleton that catered to the rehabilitation work setting was developed. The device was designed with specific goals in mind, focusing on factors like sizing, adjustment time, and user-friendliness. By prioritizing these aspects, the aim was to bridge the gap in the commercial field and create a rehabilitation tool that proves highly beneficial in clinical settings. Control of the exoskeleton was developed with the goal of improving upon previous designs in the EPIC lab. A graphic user interface was developed to enable the implementation of the device in clinical settings.
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    Immune Profiling and Biomarker Discovery Using a Multiplexed Antibody Fc Characterization Platform
    (Georgia Institute of Technology, 2023-05-02) Saha, Anushka
    Antibodies secreted by plasma cells play a significant role in disease outcomes and encode precise information due to the tunable structure of both the Fab and the crystallizable fragment (Fc) region. Several studies measure antigen-specific antibody titers to report changes within the Fab region, yet the Fc region, responsible for communicating with host immune cells to modulate function, is often unmeasured. This thesis characterizes the Fc-specific changes in serum antibodies to improve diagnostics and gain insight into immune pathways underlying disease outcomes. Post-translation, antibodies are modified with sugars, or N-glycans, which affect binding to downstream immune cells due to effects on the protein structure or charge, altering its function. Current gold standard methods to measure protein glycosylation are mass spectrometry with high-performance liquid chromatography (LC-MS) or capillary electrophoresis, which can be nearly impossible with small volumes of samples. MS requires isolation of high concentrations of target protein and an hour runtime for a single sample. This remains the bottleneck in glycoprofiling limited patient sample volumes from diseases which still lack clear diagnostics such as Schistosomiasis and Antibody-mediated rejection (ABMR). Our solution to probe antigen-specific glycosylation at a high throughput and low-cost is to couple antigens of interest to microspheres, apply patient serum, and use plant-based lectins which bind to N-linked glycans. My research uses beads coated with disease-specific antigens and unique Fc-binding probes including subtypes, Fcgamma receptors, and lectins RCAI and SNA to characterize antibody profiles of patient serum samples using flow cytometry; computational analysis methods are then applied to the data to identify key antibody features which classify disease from no disease. In this thesis, I will address two aims: 1. Optimize a multiplexed binding assay to detect antibody glycosylation as an alternative to mass spectrometry using fluorescently labeled lectins. 2. Apply this method to measure antibody N-linked glycosylation and other tunable Fc properties to define robust biomarkers from clinical sample cohorts in Schistosomiasis and ABMR.
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    Foot Perfusion Measurements in Diabetic Patients with Pedal Ulcers Using Multimodal MRI
    (Georgia Institute of Technology, 2023-05-02) Edwards, Scott J.
    Hyperglycemia, a hallmark of uncontrolled type-2 diabetes mellitus (T2DM), is associated with several microvascular complications such as calcification of blood vessels, peripheral neuropathy, and slowed wound healing. In many cases, patients with T2DM will develop unresolved wounds on their feet called diabetic foot ulcers (DFUs), which are thought to occur in response to impaired microvascular function starving wound sites of critical nutrients and oxygen. The goal of this thesis is to examine the feasibility of using perfusion MRI to determine differences in perfusion in the feet of three age and body mass index matched groups: diabetic patients with foot ulcers (DFU, N=10), diabetic patients without DFUs and with controlled glycemia (DP, N=5) and healthy controls (HC, N=5). This thesis describes a pipeline to analyze the resting microvascular properties, characterized using intra-voxel incoherent motion imaging, and microvascular reactivity, characterized using blood-oxygenation level dependent imaging during a reactive hyperemia cuff- occlusion challenge, in feet with and without DFUs. We find that the DFU patients showed greater resting microvascular volume fraction (MVF) than DP patients (Hedge’s g MVF, MP = 1.46; g MVF, LP = 1.33), suggesting a hyperperfusion at rest. Additionally, the DFU patients also showed a greater ischemic reaction (g Min. Isch, LP = 1.50), and a blunted reperfusion reaction (g peak rep., MP = 2.37, g peak rep., LP = 1.22) compared to the DP during the cuff-occlusion challenge, suggesting a lowered ability for microvascular reactivity and arteriovenous shunting within the capillary beds. These findings suggest that parameters derived from multimodal MRI show a complimentary picture of underlying microvasculature dysfunction in patients with DFUs.
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    Engineering A Hydrogel Based Biomaterial Encapsulating FTY720 and RAW Macrophages to Stimulate Accelerated Wound Healing in an Oro-Nasal Fistula
    (Georgia Institute of Technology, 2023-04-25) Behara, Monica
    Aberrant wound healing can sometimes be characterized as a prolonged exposure of pro-inflammatory immune cells and cytokines to the site of injury. This prolonged immune response can further damage tissue, often resulting in irreparable damage. Current studies in the field of wound healing attempt to modulate the immune system response to injury to reduce further complications from aberrant wound healing. FTY720 is an FDA approved drug for the treatment of multiple sclerosis to control immune cell circulation into the blood, reducing relapsing symptoms of poor voluntary muscle control and spasms. This work assesses the engineering and development of a biomaterial fabrication that encapsulates both FTY720 and RAW264.7 macrophages to serve as a supplement to wound healing in an oro-nasal fistula. An oro-nasal fistula arises as a complication to cleft palate repair, that can often lead a child to have developmental issues with speaking and eating. The oro-nasal fistula describes the abnormal opening between the oral and nasal cavities that is difficult to close once the wound forms. This leaves a pressing need to find a minimally invasive technique to heal this wound organically, leading to the development of an immunoregenerative strategy. In this work, a hydrogel fabrication with PEG-4MAL, RGD and GPQ was developed to fully encapsulate RAW264.7 macrophages and FTY720 into one construct that will deliver these components to the area of the oronasal fistula wound to accelerate wound healing. This innovation was hypothesized to accelerate wound healing and generate cytokines to stimulate the pro-regenerative environment and effect of this biomaterial. This delivery of macrophages was introduced after studies involving nanofiber scaffold release of FTY720-P showed promise to a greater pro-regenerative effect through optimal M2 polarization and decreased migration. The hydrogel biomaterial was optimized to find the number of macrophages required for proliferation within the hydrogel matrix, as well as cytokine release and migratory capacity of these encapsulated macrophages. It was found that the macrophages optimally proliferate at 200,000 cells per 20 μL hydrogel and show decreases in pro-inflammatory cytokines and increases in pro-regenerative cytokines at the 10 μM concentration of FTY720-P. Additionally, the migratory capacity of these macrophages was assessed in normal growth media conditions as well as swelling with artificial saliva, and it was found that the migratory capacity in both cases was optimal at 5 μM of FTY720-P stimulation. Once the biomaterial was characterized in vitro, an in vivo experimental model was carried out to further test the wound healing capacity of this biomaterial in an oro-nasal fistula. It was found that the implantation of an FTY720-P and RAW264.7 macrophage hydrogel does significantly enhance wound healing of an oro- nasal fistula and can be further corroborated by the proven recruitment of significantly greater M2 macrophages and significantly fewer M1 macrophages over 7 days. Overall, the development of this new biomaterial was found to have pro-regenerative effects on the oro-nasal fistula injury environment, showing that the implantation of both macrophages and FTY720 in one biomaterial does have potential to accelerate wound healing in humans. The next steps for this study would be to incorporate human macrophages and optimize based on size and behavior of the human macrophages, harvested from human tissue, like tonsil tissue. This therapeutic can potentially help a variety of pediatric patients suffering from oro-nasal fistula and can aid in accelerating wound healing to limit developmental problems that may ail the patient later in life.
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    The Modernization of Preoperative Correction Methods for Pediatric Patients
    (Georgia Institute of Technology, 2022-12-15) Brenner, Charles
    Pediatric scoliosis and kyphosis are defined by abnormal curvatures in the coronal and sagittal planes, respectively. Moderate cases can be treated with a customized brace, but severe cases require surgical intervention. Candidates for scoliosis corrective surgery have large curvatures that impeded cardiopulmonary function. Corrective surgery occasionally requires preoperative spinal distraction which can decrease curve magnitude and can safely stretch compressed soft tissues over time. The most common form of preoperative correction is Halo Gravity Traction (HGT), in which weights are used to pull up on the patient’s halo with a system of cables, pullies, and gantry. HGT is effective, but diminishes a patient’s quality of life due to limited mobility, access to transportation, education, and age-appropriate play. In addition, the cost of inpatient care is very taxing on patients and their families. Thus, there is a clinical need for a preoperative correction method that increases accessibility, affordability, and overall quality of life. The Halo Intrinsic Traction (HIT) device was developed to meet these needs and improve the current standard of care. HIT builds upon the current method of applying constant, controlled upward force to the patient’s halo, but implements them in a wearable form factor with outpatient capabilities. The HIT device matches the same safety and efficacy standard as the current method in terms of traction magnitude and resolution. In addition, it allows for a clinician to adjust the medial-lateral angle of force imparted in the patient’s halo, which may be advantageous in some clinical scenarios. The development of the HIT system constitutes the modernization of preoperative curvature methods for pediatric patients.
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    Magnetic Nanoparticle Targeting of a 3D Bioprinted Model of Pulmonary Vasculature to Address Restenosis
    (Georgia Institute of Technology, 2022-12-02) Zanella, Stefano
    Pulmonary Vein Stenosis (PVS) is a cardiovascular condition characterized by progressive lumen size reduction in one or more of the pulmonary veins. Central characteristics associated with pathological PVS state include the overgrowth of connective tissue and the deposition of fibrotic tissue within the lumen of the affected vessels. Neointimal lesions in PVS are characterized by deposition of myofibroblast-like cells which originate, in part, from vascular endothelial cells (ECs), a process known as endothelial-to-mesenchymal transition (EndMT), during which ECs lose their lineage-specific cell markers and take on myofibroblast properties. These cells can then move into the neointima, proliferate, secrete extracellular matrix (ECM) proteins, and form stenoses. As a result of these uncontrolled cellular overgrowths, typical in PVS, the condition causes obstruction of blood flow from the lungs to the heart and can result in elevated pulmonary venous pressure, pulmonary hypertension, potentially cardiac failure, and death. Current treatment options for PVS are limited to the use of catheterization or surgery techniques to keep the veins patent. Furthermore, these methods only remove the lesion cells and cannot prevent their regrowth and restenosis. Currently, there are no treatments that can ensure a long-lasting control over restenosis mechanisms in the surgically treated pulmonary veins. Untreated restenosis can ultimately lead to catastrophic outcomes for the patient, including impairment of cardiac functions, hypoxia, and even death. Recent clinical trials have demonstrated that adding chemotherapy (systemic administration of anti-proliferative drugs) to the standard treatment regimens can significantly inhibit the abnormal cellular growth, and hence, reduce the risk of restenosis. However, noticeable toxic side-effects have been reported from such systemic delivery of antiproliferative drugs. In this thesis work, we investigated a novel approach involving the delivery of magnetic nanoparticles (NPs), coated with an anti-proliferative drug (rapamycin), to locally control cellular overgrowth in a 3D bioprinted in vitro model of pulmonary vasculature. Bioprinted bifurcated vein-like constructs with 2 mm lumens were seeded with human ECs and perfused using a custom-designed bioreactor platform to simulate the in vivo flow hemodynamics. Computational flow dynamics (CFD) modeling identified a vascular geometry recapitulated by an idealized bifurcation intersection model as a region at high risk of (re)stenosis, with greatest levels of alterations in wall shear stress. A 3.96 mm rare-earth magnet was incorporated within the perfusion chamber to target NP delivery to this vascular region at risk of intimal hypoplasia. The results of this study demonstrated the robust capacity of the engineered model to recapitulate the flow perturbation and endothelial dysfunction in the context of PVS. Targeted delivery of rapamycin-loaded NPs was successfully conducted under a 7-day dynamic culture, yielding a significant impact on the human vascular cell proliferation and overgrowth within the lumen space. Together, these results support the robust potential of 3D bioprinted in vitro platforms, such as the one described here, to develop, analyze, and optimize novel pharmacotherapeutic approaches to treat PVS and be adapted to address other cardiovascular pathologies.
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    Development And Useability Assessment of Ultra-Low-Cost iOS Application Used for Combating Maternal Mortality by Predicting Risk of Cephalopelvic Disproportion in Rural Ethiopia
    (Georgia Institute of Technology, 2022-08-05) Zamitalo, Alexandra Anne
    Women’s access to maternal healthcare in underdeveloped countries is incredibly limited by factors pertaining to the scarcity of affordable and accessible options for most women. Ethiopia is an example of this. Cephalopelvic disproportion (CPD), an example of a labor obstruction leading to potential morbidity or mortality if undetected, is a condition treated by caesarian sections in modern countries; however, due to the lack of affordable and accessible healthcare options for women in this region, Ethiopian women are disproportionately affected by this condition. The Gleason lab has worked to develop a variety of CPD early detection methods including 3D body scans and hand-collected tape measurements which range in the complexity of both the resources and technique used for data collection. One of these methods involves anthropomorphic measurements collected by nurses at health clinics and recorded for later evaluation when it is converted to a risk score. This report develops and assesses an iOS application to stand in place of the analog data recording and processing techniques used for these risk score developments. Results found that nurses felt generally positive about all aspects of the iOS application according to several questionnaires, the error-catching techniques successfully detected values outside of an expected range, the self-contained data collection instructions seemed to be effective in training nurses who were otherwise naïve to the collection protocol, and with more experience with data entry into the app, nurses seemed to be gaining familiarity with the interface. These results illustrate the positive impact that this application has on the data collection process in both the speed with which the patient can receive risk feedback and the accuracy of the risk communicated to the patients.
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    Muscle spindle force sensitivity is conserved in the presence of increased tendon compliance
    (Georgia Institute of Technology, 2022-08-03) Stephens, Jacob
    Muscle spindles are complex sensory organs that relay vital mechanosensory information to the central nervous system to coordinate movement and control balance. However, the information that muscle spindles encode and the effects of muscle-tendon unit (MTU) mechanics on muscle spindle feedback are not well understood. Here, we applied sinusoidal length changes to the passive medial gastrocnemius of adult rats with and without added series elasticity to effectively increase tendon compliance. We measured the length change and force of the MTU, the length change of the muscle fascicle, and the resulting stretch responses of muscle spindles. We then compared various models of muscle spindle responses based on both MTU and fascicle-level mechanics to find the model that best describes muscle spindle behavior across a changing mechanical environment. We hypothesize that muscle spindles respond to the force and yank (the first time-derivative of force) exerted on muscle spindle fibers, and thus predict that muscle spindle responses will be best described by a model of the force and yank within the muscle fascicle. Our results demonstrate that while tendon compliance may affect muscle spindle behavior, muscle spindle responses are best described across mechanical conditions by force and yank models. Thus, any sensory loss due to increases in tendon compliance may be compensated for by increasing the forces exerted on muscle spindle fibers.
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    Proof-of-Concept of a Jagged1-functionalized PEG-4MAL Hydrogel
    (Georgia Institute of Technology, 2022-08-01) Ravikumar, Nithin
    Craniofacial bone deformities can arise from injuries, congenital defects, cancer, or other causes, leaving patients with impairments and psychological stress. Reconstruction of bone through bone grafts or bone anabolic agents such as bone morphogenetic protein-2 (BMP-2) have been clinically successful but have drawbacks with limited alternative therapies. Growing interest in delivering and presenting the Notch ligand Jagged1 (JAG1) has inspired research into leveraging it for osteoinductive biomaterials. Recent work from our lab as produced a proof-of-concept delivery strategy in which JAG1 is immobilized on dynabeads and delivered in a 4-arm poly(ethylene glycol) maleimide (PEG-4MAL) hydrogel. Despite success in inducing osteogenic differentiation and bone formation, the lack of FDA approval for dynabeads is an obstacle for translation that motivates the search for an alternative immobilization strategy. In this thesis, we explore a potential strategy for immobilizing JAG1 onto a PEG-4MAL hydrogel. We modified JAG1 through PEGylation with a thiol-terminated linear chain PEG that adds free thiols (-SH) capable of conjugating with the maleimide groups of hydrogel backbone. The resulting modified protein, JAG1-PEG-SH, exhibited increased immobilization compared to its unmodified form. Additionally, hydrogels with the PEGylated JAG1 demonstrated osteoinductive properties without diminished bioactivity that suggest that this platform may have future potential as a novel bone-regenerating biomaterial.