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Georgia Tech
1.
Perez Cuevas, Monica Beatriz.
Hepatitis B vaccination using a dissolvable microneedle patch.
Degree: MS, Chemical and Biomolecular Engineering, 2017, Georgia Tech
URL: http://hdl.handle.net/1853/59807 
► Despite improved vaccination rates against hepatitis B, there remain critical barriers to addressing gaps in vaccination coverage. The need of an effective supply chain, vaccine…
(more)
▼ Despite improved vaccination rates against hepatitis B, there remain critical barriers to addressing gaps in vaccination coverage. The need of an effective supply chain, vaccine waste management, trained healthcare providers and cost are all issues that impede mass vaccination campaigns around the world. Microneedle patches have been proposed as an alternative mode of vaccination. Microneedle patches consist of micron-scale projections that are capable of disrupting the stratum corneum by creating holes in the skin to deliver therapeutic agents. Small and lightweight, microneedle patches are a promising alternative to the bulky multi-dose vials and syringes currently used in mass vaccination campaigns. Furthermore, the high density of antigen presenting cells in the the skin make transcutaneous immunization via microneedles advantageous, as they target vaccine cargo to the topmost layer of the skin. The key goal of this project was to develop a microneedle patch for hepatitis B vaccination that is simple to administer and of comparable immunogenicity to conventional intramuscular vaccination. Trehalose was used as a stabilizing excipient for both coated metal and dissolvable microneedles. Moreover, patches were used in vivo to compare the elicited immune response in both mice and rhesus macaques. Additionally, the mechanical properties of our microneedle patch were evaluated via both theoretical and experimental approaches to predict failure force. This work shows that microneedle patches can successfully encapsulate and deliver hepatitis B antigen to generate a strong and sustained immune response in multiple animal models.
Advisors/Committee Members: Prausnitz, Mark R. (advisor), Garcia, Andres J. (committee member), Bommarius, Andreas S. (committee member).
Subjects/Keywords: Microneedles; Hepatitis b
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APA (6th Edition):
Perez Cuevas, M. B. (2017). Hepatitis B vaccination using a dissolvable microneedle patch. (Masters Thesis). Georgia Tech. Retrieved from http://hdl.handle.net/1853/59807
Chicago Manual of Style (16th Edition):
Perez Cuevas, Monica Beatriz. “Hepatitis B vaccination using a dissolvable microneedle patch.” 2017. Masters Thesis, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/59807.
MLA Handbook (7th Edition):
Perez Cuevas, Monica Beatriz. “Hepatitis B vaccination using a dissolvable microneedle patch.” 2017. Web. 16 Apr 2021.
Vancouver:
Perez Cuevas MB. Hepatitis B vaccination using a dissolvable microneedle patch. [Internet] [Masters thesis]. Georgia Tech; 2017. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/59807.
Council of Science Editors:
Perez Cuevas MB. Hepatitis B vaccination using a dissolvable microneedle patch. [Masters Thesis]. Georgia Tech; 2017. Available from: http://hdl.handle.net/1853/59807
Georgia Tech
2.
Hyland, Kelly Elise.
Immobilization of adhesive protein domains in PEG hydrogels.
Degree: MS, Materials Science and Engineering, 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61656
► The fundamental goal of biomaterials design for regenerative medicine is to promote the restoration of functional tissue. In wound healing research, one strategy is to…
(more)
▼ The fundamental goal of biomaterials design for regenerative medicine is to promote the restoration of functional tissue. In wound healing research, one strategy is to introduce space-filling materials, or scaffolds, to intervene and prevent scarring. The scaffold must be nontoxic, permit high rates of oxygen and small molecule diffusion, and offer tissue-matching stiffness. Critically, they must also promote attachment of wound healing cells. A class of materials called synthetic hydrogels meet the first three criteria, but must be functionalized with bioactive ligands to promote cell attachment.
Synthetic hydrogels, most numerously poly(ethylene glycol) (PEG) hydrogels, offer a modular platform for biomaterials design because the bioactive ligand identity and density, as well as hydrogel stiffness, can be precisely and independently controlled. However, PEG hydrogels have seldom been used as a 3D platform for investigating differences in cell behavior when in contact with different extracellular matrix protein domains. Using recombinant protein design, expression, and characterization, this study compares cell behavior when cultured on PEG hydrogels presenting structured protein domains and minimum sequence peptides. We observe differences in cell morphology, protease production and attachment force when cultured on hydrogels with different adhesive protein domains.
Advisors/Committee Members: Champion, Julie A. (advisor), Garcia, Andres J. (committee member), Milam, Valeria (committee member).
Subjects/Keywords: Protein engineering; Hydrogel; Tissue engineering; Wound healing; Regenerative medicine
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APA (6th Edition):
Hyland, K. E. (2018). Immobilization of adhesive protein domains in PEG hydrogels. (Masters Thesis). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61656
Chicago Manual of Style (16th Edition):
Hyland, Kelly Elise. “Immobilization of adhesive protein domains in PEG hydrogels.” 2018. Masters Thesis, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/61656.
MLA Handbook (7th Edition):
Hyland, Kelly Elise. “Immobilization of adhesive protein domains in PEG hydrogels.” 2018. Web. 16 Apr 2021.
Vancouver:
Hyland KE. Immobilization of adhesive protein domains in PEG hydrogels. [Internet] [Masters thesis]. Georgia Tech; 2018. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/61656.
Council of Science Editors:
Hyland KE. Immobilization of adhesive protein domains in PEG hydrogels. [Masters Thesis]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61656
Georgia Tech
3.
Schwaner, Stephen Andrew.
Finite element modeling of optic nerve head biomechanics in a rat model of glaucoma.
Degree: PhD, Mechanical Engineering, 2019, Georgia Tech
URL: http://hdl.handle.net/1853/62268
► Glaucoma is the leading cause of irreversible blindness and is characterized by the dysfunction of retinal ganglion cells (RGC), the cells that send vision information…
(more)
▼ Glaucoma is the leading cause of irreversible blindness and is characterized by the dysfunction of retinal ganglion cells (RGC), the cells that send vision information from the retina to the brain. All current therapies focus on lowering intraocular pressure (IOP), a causative risk factor in the disease. However, they are not always effective. Although it is well-accepted that elevated IOP-induced biomechanical insult to the optic nerve head (ONH), the region in the posterior eye where RGC axons exit, is key to glaucoma pathophysiology, the mechanisms by which biomechanical insult leads to RGC death are unknown. Rat glaucoma models present an opportunity for understanding glaucoma biomechanics and are widely used in the field. However, rat ONH biomechanics have not been characterized and rat ONH anatomy differs substantially from the human. Therefore, the purpose of this thesis was to provide the first characterization of rat ONH biomechanics to the glaucoma field. To this end, we completed three specific aims. First, we used inverse modeling combined with whole-eye inflation testing to extract material properties from the rat sclera. Second, we conducted a sensitivity study to investigate the effects of anatomical and material property variation on rat ONH strains using a parameterized finite element model of the rat ONH. Lastly, we developed a methodology for building rat ONH FE models with individual-specific geometry and simulated the effects of elevated IOP. Key results include the finding that the patterns of strain in the rat ONH are less symmetric than those in the human, and the highest strains occur in the inferior nerve. In all three aims, the results emphasized the importance of collagen fiber organization on optic nerve strains. Lastly, the patterns and magnitude of optic nerve strain in the parameterized model showed good concordance with those observed in the individual-specific models, suggesting that the higher throughput parameterized models may be able to replace individual-specific models of the rat ONH moving forward. The results from this work can serve to inform future modeling studies on rat ONH biomechanics and provide context for interpreting rat glaucoma studies with the goal of learning more about the link between biomechanical insult and RGC pathophysiology in glaucoma.
Advisors/Committee Members: Ethier, Ross (advisor), Garcia, Andres J. (committee member), Gleason, Rudolph L. (committee member), Dixon, Brandon (committee member), Sigal, Ian A. (committee member).
Subjects/Keywords: Biomechanics; Finite element modeling; Glaucoma; Eye; Rat; Optic nerve head
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APA (6th Edition):
Schwaner, S. A. (2019). Finite element modeling of optic nerve head biomechanics in a rat model of glaucoma. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/62268
Chicago Manual of Style (16th Edition):
Schwaner, Stephen Andrew. “Finite element modeling of optic nerve head biomechanics in a rat model of glaucoma.” 2019. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/62268.
MLA Handbook (7th Edition):
Schwaner, Stephen Andrew. “Finite element modeling of optic nerve head biomechanics in a rat model of glaucoma.” 2019. Web. 16 Apr 2021.
Vancouver:
Schwaner SA. Finite element modeling of optic nerve head biomechanics in a rat model of glaucoma. [Internet] [Doctoral dissertation]. Georgia Tech; 2019. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/62268.
Council of Science Editors:
Schwaner SA. Finite element modeling of optic nerve head biomechanics in a rat model of glaucoma. [Doctoral Dissertation]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/62268
Georgia Tech
4.
Zhou, Dennis Wei.
Force-signaling coupling at single focal adhesions.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2019, Georgia Tech
URL: http://hdl.handle.net/1853/62651
► Integrin-mediated adhesion to extracellular matrices (ECM) provides forces and signals that direct cell processes central to tissue organization, homeostasis, and disease. Recent studies show an…
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▼ Integrin-mediated adhesion to extracellular matrices (ECM) provides forces and signals that direct cell processes central to tissue organization, homeostasis, and disease. Recent studies show an important relationship between cell adhesive force generation and focal adhesion (FA) assembly, yet it remains unclear how forces are transduced into adhesive signals. Our work seeks to identify coupling between cell adhesive force generation and signaling at FAs. To measure forces, we used Microfabricated Post-Array-Deflectors (mPADs), which are an array of PDMS ~1.8 µm diameter microposts. Based on the micropost deflections, we can calculate the forces exerted by cells. We previously showed that vinculin regulates force transmission at FAs. Vinculin residence time in FAs correlated with applied force, supporting a mechanosensitive model in which forces stabilize vinculin’s active conformation to promote force transfer. We first examined the relationship between traction force and vinculin-paxillin localization to single FAs in the context of substrate stiffness and actomyosin contractility. Substrate stiffness and contractility regulated vinculin localization to FAs, and vinculin auto-inhibition is a crucial regulatory step in this process that overrides the effects of cytoskeletal tension and substrate stiffness. Vinculin and paxillin FA area did not correlate with traction force magnitudes at single FAs, and this was consistent across different ECM stiffness and cytoskeletal tension states. Vinculin residence time at FAs linearly varied with applied force for stiff substrates, but this coupling was disrupted on soft substrates and in the presence of contractility inhibitors. In contrast, paxillin residence time at FAs was independent of force, substrate stiffness, and cytoskeletal contractility. Lastly, substrate stiffness and cytoskeletal contractility regulated whether vinculin and paxillin turnover dynamics are correlated to each other at single FAs. We also found that pFAK Y397 levels are linearly coupled to force at single FAs on stiff substrates. On soft substrates, however, this positive relationship is eliminated. We found that talin is required for FAK localization and Y397 phosphorylation at FAs and mediates force-FAK linear coupling at FAs via talin-FAK binding. Furthermore, averaged levels of FAK localization and Y397 phosphorylation at FAs are relatively insensitive to vinculin expression. However, a full-length vinculin molecule that binds talin and actin is required for linear coupling to occur between force-FAK localization and force-FAK Y397 phosphorylation at individual FAs. Lastly, we demonstrate that a full-length vinculin molecule that binds talin and actin is required to promote YAP nuclear accumulation. These findings suggest that force generation and signaling are coupled at FAs and underscore the role of environmental stiffness, talin, and vinculin in regulating force-signaling coupling at FAs. Our results generate new insights into how cell adhesive forces are integrated into biochemical signals.…
Advisors/Committee Members: Garcia, Andres J. (advisor), Zhu, Cheng (committee member), Curtis, Jennifer E. (committee member), Kowalczyk, Andrew P. (committee member), del Campo, Aranzazu (committee member).
Subjects/Keywords: Focal adhesions; Mechanobiology; FAK; Mechanotransduction; Vinculin; YAP
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APA (6th Edition):
Zhou, D. W. (2019). Force-signaling coupling at single focal adhesions. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/62651
Chicago Manual of Style (16th Edition):
Zhou, Dennis Wei. “Force-signaling coupling at single focal adhesions.” 2019. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/62651.
MLA Handbook (7th Edition):
Zhou, Dennis Wei. “Force-signaling coupling at single focal adhesions.” 2019. Web. 16 Apr 2021.
Vancouver:
Zhou DW. Force-signaling coupling at single focal adhesions. [Internet] [Doctoral dissertation]. Georgia Tech; 2019. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/62651.
Council of Science Editors:
Zhou DW. Force-signaling coupling at single focal adhesions. [Doctoral Dissertation]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/62651
Georgia Tech
5.
Mukherjee, Abhirup.
Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway.
Degree: PhD, Chemical and Biomolecular Engineering, 2019, Georgia Tech
URL: http://hdl.handle.net/1853/63559
► A combined theoretical and computational model was proposed to elucidate the fundamental mechanism of the Wnt/beta-catenin signaling pathway. Analysis suggested that the partial inhibition of…
(more)
▼ A combined theoretical and computational model was proposed to elucidate the fundamental mechanism of the Wnt/beta-catenin signaling pathway. Analysis suggested that the partial inhibition of both beta-catenin phosphorylation and ubiquitination results in an increase in cytosolic concentration of beta-catenin. The inhibition of these post-translational modification steps stems from the partial disassembly of a fraction of the intracellular destruction complexes, and this disassembly is correlated with these destruction complexes relocating to the plasma membrane upon Wnt stimulation. The understanding of the Wnt/beta-catenin pathway was leveraged to design a synthetic dimeric activator of the canonical Wnt signaling pathway, with levels of activation comparable to that of wild-type Wnt-3a. Next, a toolbox of novel optogenetic photoswitches, with tunable dissociation dynamics, was designed by engineering the canonical Wnt protein, LRP6. Finally, transcription-activation based switches were proposed to determine different cell specifications in order to ensure high quality of cardiomyocyte production from human pluripotent stem cells (hPSCs). Taken together, the work discussed in this thesis can serve as a platform for future investigations into several developmental pathways.
Advisors/Committee Members: Kane, Ravi S. (advisor), Garcia, Andres J. (committee member), Champion, Julie A. (committee member), Lu, Hang (committee member), McGrath, Patrick T. (committee member).
Subjects/Keywords: Wnt signaling; Synthetic Wnt agonist; Optogenetics; Transcriptional switches
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APA (6th Edition):
Mukherjee, A. (2019). Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/63559
Chicago Manual of Style (16th Edition):
Mukherjee, Abhirup. “Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway.” 2019. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/63559.
MLA Handbook (7th Edition):
Mukherjee, Abhirup. “Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway.” 2019. Web. 16 Apr 2021.
Vancouver:
Mukherjee A. Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway. [Internet] [Doctoral dissertation]. Georgia Tech; 2019. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/63559.
Council of Science Editors:
Mukherjee A. Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway. [Doctoral Dissertation]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/63559
Georgia Tech
6.
Garcia, Jose.
Hydrogel engineering for enhancing vascularization and augmenting immunomodulation of encapsulated mesenchymal stem cells.
Degree: PhD, Mechanical Engineering, 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61618
► Since the discovery of adult human mesenchymal stem cells in the late 1900’s, the potential of utilizing these cells in the clinic for cell-therapy applications…
(more)
▼ Since the discovery of adult human mesenchymal stem cells in the late 1900’s, the potential of utilizing these cells in the clinic for cell-therapy applications has been an ever-present goal. Unfortunately, clinical trials using these cells have garnered lackluster results with a high degree of variability in patient outcome and in many cases no difference between patients who received these adult stem cell or placebo. Various factors account for such results including the inability to properly control cell presence via the routine method of intravenous administration, the inability to control cell phenotype once the cells are injected into the patient and the harsh microenvironment cells are injected into. Biomaterials can provide solutions for these factors through engineering scaffolds to present needed signals to both encapsulated stem cells and the surrounding microenvironment. The objective of this project is to engineer bioartificial hydrogels presenting specific signals in the form of integrin-specific ligands and covalently-bound proteins to enhance mesenchymal stem cell activity and efficacy in wound and disease models. We investigated the application of these bioarticifial hydrogels towards two different goals: 1) to enhance vascularization and associated stem cell survival in a critical size bone defect and 2) to enhance immunomodulation of stem cells in a wound regeneration model. For our first goal, we found that hydrogels presenting the α2β1 ligand ‘GFOGER’ resulted in enhanced vascularization of bone defects compared to hydrogels presenting the αvβ3 ligand ‘RGD’ in the absence of vasculogenic protein. For our second goal, we found that hydrogels functionalized tethered IFN-γ enhanced the immunomodulatory properties of encapsulated hMSCs which led to enhanced tissue resolution in a colonic wound model. Together, our findings elucidate novel ways to enhance adult stem cell efficacy and further the applicability of these cells in clinical settings.
Advisors/Committee Members: Garcia, Andres J. (advisor), Guldberg, Robert E. (committee member), Botchwey, Edward (committee member), Taylor, W. Robert (committee member), Fernandez-Nieves, Alberto (committee member).
Subjects/Keywords: Mesenchymal stem cells; Hydrogel; Biomaterials; Vascularization; Bone engineering; Immunomodulation
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APA (6th Edition):
Garcia, J. (2018). Hydrogel engineering for enhancing vascularization and augmenting immunomodulation of encapsulated mesenchymal stem cells. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61618
Chicago Manual of Style (16th Edition):
Garcia, Jose. “Hydrogel engineering for enhancing vascularization and augmenting immunomodulation of encapsulated mesenchymal stem cells.” 2018. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/61618.
MLA Handbook (7th Edition):
Garcia, Jose. “Hydrogel engineering for enhancing vascularization and augmenting immunomodulation of encapsulated mesenchymal stem cells.” 2018. Web. 16 Apr 2021.
Vancouver:
Garcia J. Hydrogel engineering for enhancing vascularization and augmenting immunomodulation of encapsulated mesenchymal stem cells. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/61618.
Council of Science Editors:
Garcia J. Hydrogel engineering for enhancing vascularization and augmenting immunomodulation of encapsulated mesenchymal stem cells. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61618
Georgia Tech
7.
Alvarado-Velez, Melissa.
Immuno-suppressive hydrogels for stem cell therapy after traumatic brain injury.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2019, Georgia Tech
URL: http://hdl.handle.net/1853/62340
► During a traumatic brain injury (TBI) an external force disrupts the brain tissue and the proper functioning of neuronal pathways. This initial insult activates multiple…
(more)
▼ During a traumatic brain injury (TBI) an external force disrupts the brain tissue and the proper functioning of neuronal pathways. This initial insult activates multiple cellular mechanisms that further propagate the tissue damage causing a secondary injury that exacerbates neurological deficits. This phase, known as the secondary injury, opens a therapeutic window in which neuroprotective treatments that successfully contain the propagation of the initial damage could significantly reduce neurological deficits associated with TBI. Mesenchymal stem cell transplantation (MSC) after TBI has been found to ameliorate neurological deficits due to the ability of the stem cells to modulate inflammation and immune cells and to increase the expression of neurotrophic factors that promote the survival of the neuronal tissue surrounding the injury site. However, the active rejection of the transplanted MSC by the host immune system could strongly diminish the stem cell's survival and therapeutic effect. In this thesis, we used immunosuppressive hydrogels, specifically designed to induce the apoptosis of cytotoxic CD8+ T cells, to enhance the survival of transplanted MSC in the injured brain. We demonstrated that creating localized immunosuppression near the MSC transplantation site resulted in a higher presence of MSC near the injury site. We also demonstrate that enhancing MSC survival by using immunosuppressive hydrogels increased the protein expression of the neurotrophic factors, which could lead to reduced neuronal damage. Therefore, the development of immune-suppressive hydrogels for stem cell transplantation could be a successful approach to enhance stem cell therapy after TBI.
Advisors/Committee Members: Bellamkonda, Ravi V. (advisor), Garcia, Andres J. (committee member), Babensee, Julia E. (committee member), Champion, Julie (committee member), LaPlaca, Michelle (committee member).
Subjects/Keywords: Hydrogel; Stem cell therapy; Immuno-modulation; Allogeneic; Traumatic brain injury
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APA (6th Edition):
Alvarado-Velez, M. (2019). Immuno-suppressive hydrogels for stem cell therapy after traumatic brain injury. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/62340
Chicago Manual of Style (16th Edition):
Alvarado-Velez, Melissa. “Immuno-suppressive hydrogels for stem cell therapy after traumatic brain injury.” 2019. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/62340.
MLA Handbook (7th Edition):
Alvarado-Velez, Melissa. “Immuno-suppressive hydrogels for stem cell therapy after traumatic brain injury.” 2019. Web. 16 Apr 2021.
Vancouver:
Alvarado-Velez M. Immuno-suppressive hydrogels for stem cell therapy after traumatic brain injury. [Internet] [Doctoral dissertation]. Georgia Tech; 2019. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/62340.
Council of Science Editors:
Alvarado-Velez M. Immuno-suppressive hydrogels for stem cell therapy after traumatic brain injury. [Doctoral Dissertation]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/62340
Georgia Tech
8.
Paunovska, Kalina.
An investigation of parameters that influence non-hepatocyte RNA delivery in vivo.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2020, Georgia Tech
URL: http://hdl.handle.net/1853/63571
► Lipid nanoparticle (LNP)-mediated nucleic acid delivery can regulate the expression of any gene, making it a promising way to treat disease. However, clinically relevant delivery…
(more)
▼ Lipid nanoparticle (LNP)-mediated nucleic acid delivery can regulate the expression of any gene, making it a promising way to treat disease. However, clinically relevant delivery of RNA therapeutics to non-hepatocytes in vivo remains challenging. Most LNPs are created by mixing an ionizable lipid with PEG, a phospholipid, and cholesterol, allowing the possibility for thousands of chemically distinct LNPs. These nanoparticles are typically screened in vitro in easily expandable cell lines, yet these cell culture conditions are not representative of in vivo tissue microenvironments. LNPs that deliver their payload (e.g. DNA, RNA) successfully in vitro are then validated in vivo. However, because LNPs that tend to work in vitro do not necessarily work in vivo, this often leads to a small number of viable candidates. The objective of this thesis is to use high-throughput DNA barcoding to ask fundamental questions about in vivo drug delivery. In particular, this work presents four significant contributions to the field of nucleic acid delivery. First, this work explores in vitro and in vivo LNP delivery in many cell types (e.g. endothelial, macrophage) from many tissues (e.g. heart, lung, bone marrow) and reveals that in vitro LNP delivery is not predictive of in vivo delivery. Second, cholesterol structure – a previously unperturbed LNP component – is found to impact LNP delivery in vivo. Cholesterol variants are naturally trafficked in lipoproteins (e.g. LDL, VLDL) suggesting that LNP targeting can be tuned by using naturally- or synthetically-derived cholesterol variants. Third, LNPs that deliver RNA to non-hepatocytes more efficiently than to hepatocytes are identified. Fourth, manipulating cell metabolism through exogenous administration of a small molecule is found to impact LNP-delivered mRNA translation in vivo. Finally, the potential for related works and new directions worthy of pursuit within the field nucleic acid drug delivery are discussed. Taken together, this work enables understanding and optimization of the factors that influence non-hepatocyte RNA delivery in vivo.
Advisors/Committee Members: Dahlman, James E. (advisor), Garcia, Andres J. (committee member), Santangelo, Philip J. (committee member), Champion, Julie A. (committee member), Botchwey, Edward A. (committee member).
Subjects/Keywords: Lipid nanoparticles; DNA barcoding; Nucleic acid delivery; RNA therapeutics; Gene therapy
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APA (6th Edition):
Paunovska, K. (2020). An investigation of parameters that influence non-hepatocyte RNA delivery in vivo. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/63571
Chicago Manual of Style (16th Edition):
Paunovska, Kalina. “An investigation of parameters that influence non-hepatocyte RNA delivery in vivo.” 2020. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/63571.
MLA Handbook (7th Edition):
Paunovska, Kalina. “An investigation of parameters that influence non-hepatocyte RNA delivery in vivo.” 2020. Web. 16 Apr 2021.
Vancouver:
Paunovska K. An investigation of parameters that influence non-hepatocyte RNA delivery in vivo. [Internet] [Doctoral dissertation]. Georgia Tech; 2020. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/63571.
Council of Science Editors:
Paunovska K. An investigation of parameters that influence non-hepatocyte RNA delivery in vivo. [Doctoral Dissertation]. Georgia Tech; 2020. Available from: http://hdl.handle.net/1853/63571
Georgia Tech
9.
Ruehle, Marissa Ashley.
Cell-Based Vascular Therapeutics for Bone Regeneration.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2019, Georgia Tech
URL: http://hdl.handle.net/1853/63520
► Bone is a highly vascularized tissue, and adequate vascularity is an essential requirement for proper bone healing. Revascularization is a challenge in critical-sized defects, especially…
(more)
▼ Bone is a highly vascularized tissue, and adequate vascularity is an essential requirement for proper bone healing. Revascularization is a challenge in critical-sized defects, especially those with concomitant muscle damage typical of traumatic injury. Patients with these injuries heal slowly and exhibit higher rates of infection and non-union, underscoring the critical importance of vasculature to bone healing. Additionally, the bone defect environment is a complex niche, involving mechanical cues in addition to a host of biochemical signals. It is well known that mechanical loading affects bone growth and remodeling, and while flow-mediated mechanics influence the vasculature, remarkably little is known about the effects of bulk matrix deformation on neovascularization. The overall objective of this thesis was to leverage mechanical cues to enhance vascular network formation and to use enhanced vascularization to improve bone regeneration.
First, we evaluated the effect of multicellular microvascular fragments (MVF) co- delivered with BMP-2 to a model of composite bone-muscle trauma using collagen sponge, the clinically available BMP-2 delivery vehicle. MVF did not improve bone healing as hypothesized; however, we also investigated the effect of a modestly increased BMP-2 dose, which did significantly improve functional healing. While MVF maintained viability within the collagen sponge in vitro, they first dissociated to single cells, which we speculated may have prevented their inosculation with the host vasculature. Next, we developed and characterized decorin-supplemented collagen gels for use as both an in vivo co-delivery vehicle for MVF and BMP-2 and as a dimensionally stable biomaterial scaffold to investigate the effects of compressive loading on MVF growth in vitro. Despite in vitro results demonstrating synergistic effects of BMP-2 and MVF, there was no effect of MVF on bone healing, and MVF significantly decreased early revascularization following injury. However, the addition of decorin increased the compressive properties and dimensional stability of collagen while still supporting robust in vitro MVF growth.
We then evaluated the effects of dynamic compressive loading on MVF growth. While the vasculature has long been recognized as mechanosensitive, the effects of abluminal forces experienced by healing tissues on angiogenesis are poorly understood. We demonstrated that delayed compressive loading led to longer, more extensively branched microvascular networks than early loading at all strain magnitudes tested. Across strain magnitudes, delayed loading increased vascular network length and branching compared to non-loaded controls; however, early high strain loading inhibited network formation. Gene expression analysis revealed differential mechanoregulation of gene expression profiles by early vs. delayed loading. Genes associated with angiogenic sprout tip cells were downregulated by early loading and upregulated by delayed loading. Delayed loading also led to the upregulation of genes involved in…
Advisors/Committee Members: Guldberg, Robert E (advisor), Willett, Nick J (advisor), Boerckel, Joel D (committee member), Garcia, Andres J (committee member), Hoying, James B (committee member), Levit, Rebecca D (committee member).
Subjects/Keywords: Angiogenesis; Tissue Engineering; Regenerative Medicine; Bone Regeneration
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APA (6th Edition):
Ruehle, M. A. (2019). Cell-Based Vascular Therapeutics for Bone Regeneration. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/63520
Chicago Manual of Style (16th Edition):
Ruehle, Marissa Ashley. “Cell-Based Vascular Therapeutics for Bone Regeneration.” 2019. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/63520.
MLA Handbook (7th Edition):
Ruehle, Marissa Ashley. “Cell-Based Vascular Therapeutics for Bone Regeneration.” 2019. Web. 16 Apr 2021.
Vancouver:
Ruehle MA. Cell-Based Vascular Therapeutics for Bone Regeneration. [Internet] [Doctoral dissertation]. Georgia Tech; 2019. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/63520.
Council of Science Editors:
Ruehle MA. Cell-Based Vascular Therapeutics for Bone Regeneration. [Doctoral Dissertation]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/63520
10.
Dumbauld, David W.
The role of vinculin in the cell adhesion strengthening process.
Degree: PhD, Mechanical Engineering, 2011, Georgia Tech
URL: http://hdl.handle.net/1853/43729
► Cell adhesion to extracellular matrices (ECM) is essential to numerous physiological and pathological processes. Cell adhesion is initiated by binding of the transmembrane integrin family…
(more)
▼ Cell adhesion to extracellular matrices (ECM) is essential to numerous physiological and pathological processes. Cell adhesion is initiated by binding of the transmembrane integrin family of receptors to an ECM ligand such as fibronectin (FN). Once bound, integrins cluster together and form focal adhesions (FA). FAs serve as structural links and signal transduction elements between the cell and its extracellular environment. While a great deal of progress has been made in identifying the biochemical components that comprise focal adhesions and the roles they play in migration, cell spreading, and signaling, the contributions of these proteins to mechanical interactions between the cell and its environment remain poorly understood.
A FA adhesion protein of particular importance is vinculin. When localized to focal adhesions, vinculin forms a ternary complex with talin and 1-integrin. This 1-integrin-talin-vinculin complex plays a central role in the regulation of FA assembly and cell spreading and migration. Nevertheless, the specific contribution to adhesive force generation of the 1-integrin-talin-vinculin complex remains poorly understood.
The objective of this project was to analyze the role of vinculin in the cell adhesion strengthening process. Our central hypothesis is that vinculin modulates adhesion strength via regulating the size and/or composition of the integrin-talin-vinculin complex. We used a novel combination of biochemical reagents and engineering techniques along with quantitative and sensitive adhesion strength measurements to provide new insights into how the structure of vinculin contributes to cell adhesion strength.
Advisors/Committee Members: Garcia, Andres J. (Committee Chair), Craig, Susan (Committee Member), Kowalczyk, Andrew (Committee Member), Lu, Hang (Committee Member), Zamir, Evan (Committee Member), Zhu, Cheng (Committee Member).
Subjects/Keywords: Vinculin; Cell adhesion; Spinning disk; Vinculin; Cell adhesion; Extracellular matrix
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APA (6th Edition):
Dumbauld, D. W. (2011). The role of vinculin in the cell adhesion strengthening process. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/43729
Chicago Manual of Style (16th Edition):
Dumbauld, David W. “The role of vinculin in the cell adhesion strengthening process.” 2011. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/43729.
MLA Handbook (7th Edition):
Dumbauld, David W. “The role of vinculin in the cell adhesion strengthening process.” 2011. Web. 16 Apr 2021.
Vancouver:
Dumbauld DW. The role of vinculin in the cell adhesion strengthening process. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/43729.
Council of Science Editors:
Dumbauld DW. The role of vinculin in the cell adhesion strengthening process. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/43729
11.
Whitmire, Rachel Elisabeth.
Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery.
Degree: PhD, Mechanical Engineering, 2012, Georgia Tech
URL: http://hdl.handle.net/1853/43587
► The goal of this thesis was to develop a new drug-delivering material to deliver anti-inflammatory protein for treating OA. Our central hypothesis for this work…
(more)
▼ The goal of this thesis was to develop a new drug-delivering material to deliver anti-inflammatory protein for treating OA. Our central hypothesis for this work is that a controlled release/presentation system will more effectively deliver anti-inflammatory protein therapies to the OA joint.
The primary goal of this work was to synthesize a block copolymer that could self-assemble into injectable, sub-micron-scale particles and would allow an anti-inflammatory protein, IL-1ra, to be tethered to its surface for efficient protein delivery. The block copolymer incorporated an oligo-ethylene monomer for tissue compatibility and non-fouling behavior, a 4-nitrophenol group for efficient protein tethering, and cyclohexyl methacrylate, a hydrophobic monomer, for particle stability. We engineered the copolymer and tested it in both in vitro culture experiments and an in vivo model to evaluate protein retention in the knee joint. The rationale for this project was that the rational design and synthesis of a new drug- and protein-delivering material can create a modular polymer particle that can deliver multi-faceted therapies to treat OA.
This work characterizes the in vitro and in vivo behavior of our polymer particle system. The protein tethering strategy allows IL-1ra protein to be tethered to the surface of these particles. Once tethered, IL-1ra maintains its bioactivity and actively targets synoviocytes, cells crucial to the OA pathology. This binding happens in an IL-1-dependent manner. Furthermore, IL-1ra-tethered particles are able to inhibit IL-1beta-induced NF-kappaB activation. These studies show that this particle system has the potential to deliver IL-1ra to arthritic joints and that it has potential for localizing/targeting drugs to inflammatory cells of interest as a new way to target OA drug treatments.
Advisors/Committee Members: Garcia, Andres. J. (Committee Chair), Babensee, Julia (Committee Member), Levenston, Marc (Committee Member), Lyon, L. Andrew (Committee Member), McCarty, Nael (Committee Member), Murthy, Niren (Committee Member).
Subjects/Keywords: IL-1ra; Rats; Biomaterials; Osteoarthritis; Polymeric drug delivery system; Nanoparticles; Self-assembly (Chemistry); Osteoarthritis; Anti-inflammatory agents
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APA (6th Edition):
Whitmire, R. E. (2012). Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/43587
Chicago Manual of Style (16th Edition):
Whitmire, Rachel Elisabeth. “Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery.” 2012. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/43587.
MLA Handbook (7th Edition):
Whitmire, Rachel Elisabeth. “Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery.” 2012. Web. 16 Apr 2021.
Vancouver:
Whitmire RE. Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery. [Internet] [Doctoral dissertation]. Georgia Tech; 2012. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/43587.
Council of Science Editors:
Whitmire RE. Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery. [Doctoral Dissertation]. Georgia Tech; 2012. Available from: http://hdl.handle.net/1853/43587
12.
Raynor, Jenny E.
Surface modification of titanium substrates with polymer brushes to control cell adhesion for bioapplications.
Degree: PhD, Chemistry and Biochemistry, 2008, Georgia Tech
URL: http://hdl.handle.net/1853/26653
► Modification of the surface chemistry of materials used as implants in biomedical applications affords the ability to control cell adhesion, prevent inflammation and enhance integration…
(more)
▼ Modification of the surface chemistry of materials used as implants in biomedical applications affords the ability to control cell adhesion, prevent inflammation and enhance integration with the host. Titanium and its alloys are strong and lightweight thereby making them desirable for applications such as hip and knee replacements, dental implants, and cardiac pacemaker implants. However, the lifetime of these implants is often limited by poor incorporation into the surrounding bone which results in loosening and wear. In order to overcome these limitations we have studied the modification of titanium substrates with a self-assembled monolayer that can be used to perform surface-initiated atom transfer radical polymerization (SI-ATRP) of a monomer to afford polymer brushes that effectively prevent the adhesion of cells. In addition, the polymer brushes afford the ability to tether a peptide sequence. Specific peptides containing adhesion sequences have been tethered to the polymer brushes. The resulting surfaces promote cell adhesion and osteoblast differentiation, thereby increasing bone tissue formation around the implant resulting in better incorporation of the implant.
Advisors/Committee Members: Collard, David M. (Committee Chair), Garcia, Andres J. (Committee Co-Chair), France, Stefan (Committee Member), Ragauskas, Arthur (Committee Member), Temenoff, Johnna (Committee Member).
Subjects/Keywords: Bioactive ligands; Peptide tethering; Non-fouling; SAMS; Surface modification; Polymer brushes; Titanium alloys; Surfaces (Technology); Cell adhesion; Biomedical materials; Protective coatings; Polymers in medicine
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APA (6th Edition):
Raynor, J. E. (2008). Surface modification of titanium substrates with polymer brushes to control cell adhesion for bioapplications. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/26653
Chicago Manual of Style (16th Edition):
Raynor, Jenny E. “Surface modification of titanium substrates with polymer brushes to control cell adhesion for bioapplications.” 2008. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/26653.
MLA Handbook (7th Edition):
Raynor, Jenny E. “Surface modification of titanium substrates with polymer brushes to control cell adhesion for bioapplications.” 2008. Web. 16 Apr 2021.
Vancouver:
Raynor JE. Surface modification of titanium substrates with polymer brushes to control cell adhesion for bioapplications. [Internet] [Doctoral dissertation]. Georgia Tech; 2008. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/26653.
Council of Science Editors:
Raynor JE. Surface modification of titanium substrates with polymer brushes to control cell adhesion for bioapplications. [Doctoral Dissertation]. Georgia Tech; 2008. Available from: http://hdl.handle.net/1853/26653
13.
Cardenas Lizana, Paul Antonio.
The mechanobiology of the T-Cell Receptor: Structurally connecting catch bonds with ligand binding and triggering.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2017, Georgia Tech
URL: http://hdl.handle.net/1853/60659
► The mechanism of the recognition of antigens and the activation of CD3 signaling domains by the T-Cell Receptor (TCR) are studied. The first part is…
(more)
▼ The mechanism of the recognition of antigens and the activation of CD3 signaling domains by the T-Cell Receptor (TCR) are studied. The first part is focused to investigate how the information encoded in the peptide is decoded mechanically by the TCR and what is the structural role of catch bonds. It is proposed that TCRs uses catch bonds to determine whether or not the presented antigen is a threat. It is demonstrated for the first time that catch bonds formed experimentally between a TCR and a peptide-loaded major histocompatibility complex (pMHC) can be predicted a priori by using "in silico" biology and that catch bonds are required to effectively recognize epitopes. TCRs must rotate around the pMHC binding axes to form catch bonds and thus induce functional conformational states of the peptide. The second part studies how information read from the TCR distal-membrane binding site is propagated to the CD3 signaling domains. It is proposed the peptide-decoding process and intracellular signaling are connected by conformational changes traveling across the TCR. It is shown that TCRs are deformable proteins that can experience large conformational changes and they use mechanical forces to modulate their conformations. The ability of TCRs to deform without releasing the peptide ligands is the key to understand this complex mechanism. Finally, it is unveiled the molecular mechanism of how TCRs uses their Cβ FG loop to propagate information and interact with the CD3 signaling domains.
Advisors/Committee Members: Zhu, Cheng (advisor), Garcia, Andres J. (committee member), Gumbart, James C. (committee member), Grakoui, Arash (committee member), Lou, Jizhong (committee member).
Subjects/Keywords: Fg loop; TCR; pMHC; Catch bonds; Molecular dynamics simulations; Molecular lever; CD3 signaling domains
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APA (6th Edition):
Cardenas Lizana, P. A. (2017). The mechanobiology of the T-Cell Receptor: Structurally connecting catch bonds with ligand binding and triggering. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/60659
Chicago Manual of Style (16th Edition):
Cardenas Lizana, Paul Antonio. “The mechanobiology of the T-Cell Receptor: Structurally connecting catch bonds with ligand binding and triggering.” 2017. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/60659.
MLA Handbook (7th Edition):
Cardenas Lizana, Paul Antonio. “The mechanobiology of the T-Cell Receptor: Structurally connecting catch bonds with ligand binding and triggering.” 2017. Web. 16 Apr 2021.
Vancouver:
Cardenas Lizana PA. The mechanobiology of the T-Cell Receptor: Structurally connecting catch bonds with ligand binding and triggering. [Internet] [Doctoral dissertation]. Georgia Tech; 2017. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/60659.
Council of Science Editors:
Cardenas Lizana PA. The mechanobiology of the T-Cell Receptor: Structurally connecting catch bonds with ligand binding and triggering. [Doctoral Dissertation]. Georgia Tech; 2017. Available from: http://hdl.handle.net/1853/60659
14.
Wang, Ke.
Mechanical properties of trabecular meshwork.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2018, Georgia Tech
URL: http://hdl.handle.net/1853/59824
► Glaucoma is the second leading cause of blindness. However, the precise mechanisms leading to vision loss in this disease remain unknown. Increased intraocular pressure (IOP)…
(more)
▼ Glaucoma is the second leading cause of blindness. However, the precise mechanisms leading to vision loss in this disease remain unknown. Increased intraocular pressure (IOP) has been recognized as the most important risk factor, and lowering IOP is currently the only effective treatment for glaucoma. Unfortunately, pressure lowering usually only slows progression and does not cure the disease. The mechanical properties of the trabecular meshwork (TM) have been suggested to differ significantly between glaucomatous eyes versus unaffected eyes. This is important because the TM has a major influence on IOP. The objective of this work is to develop computer modeling and experimental tools to characterize TM stiffness in situ for human and mouse eyes, and to evaluate the role of mechanical properties of TM in influencing IOP across different conditions. We developed an inverse finite element method to estimate TM stiffness in dissected anterior wedges from 6 normal and 5 glaucomatous human eyes, in combination with optical coherence tomography (OCT) imaging. The results obtained from this method were also compared to direct measurements using atomic force microscopy (AFM). We showed that TM stiffness was higher, but only modestly so, in glaucomatous patients. Interestingly, outflow facility in both normal and glaucomatous human eyes appeared to associate with TM stiffness. We then went on to study TM in mice, first developing a cryosection-based AFM technique to localize and directly measure compressive Young’s modulus of TM. We found a significant correlation between TM stiffness and outflow resistance in wild-type mice. Further, we found that local DEX treatment in live mice can induce higher IOP and stiffer TM, and that a significant correlation between TM stiffness and outflow resistance also existed in DEX-treated mice. Together these findings suggest that TM stiffness might be a surrogate marker for conventional outflow pathway function. This work motivates development of therapies to alter TM stiffness, or the factors underlying TM biomechanical property regulation, as potential novel alternative treatments for control of ocular hypertension in glaucoma.
Advisors/Committee Members: Ethier, C. Ross (advisor), Stamer, W. Daniel (committee member), Pardue, Machelle (committee member), Garcia, Andres J. (committee member), Sulchek, Todd (committee member).
Subjects/Keywords: Glaucoma; Trabecular meshwork; Stiffness
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APA (6th Edition):
Wang, K. (2018). Mechanical properties of trabecular meshwork. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/59824
Chicago Manual of Style (16th Edition):
Wang, Ke. “Mechanical properties of trabecular meshwork.” 2018. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/59824.
MLA Handbook (7th Edition):
Wang, Ke. “Mechanical properties of trabecular meshwork.” 2018. Web. 16 Apr 2021.
Vancouver:
Wang K. Mechanical properties of trabecular meshwork. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/59824.
Council of Science Editors:
Wang K. Mechanical properties of trabecular meshwork. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/59824
15.
Cruz-Acuna, Ricardo.
Synthetic hydrogels recapitulate epithelial morphogenesis programs.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61624
► Understanding the contributions of the ECM biophysical and biochemical properties to epithelial cell responses has been a major goal for biomaterials scientists in order to…
(more)
▼ Understanding the contributions of the ECM biophysical and biochemical properties to epithelial cell responses has been a major goal for biomaterials scientists in order to engineer materials that can recapitulate ECM-mediated epithelial morphogenesis programs. Although 3D natural matrices have been found suitable for the study of many cellular processes, they are limited by lot-to-lot compositional and structural variability, inability to decouple mechanical and biochemical properties, and in some cases, their tumor-derived nature limits their clinical translational potential. Therefore, there is a significant need for a biomaterial matrix that can recapitulate epithelial morphogenetic programs while overcoming these limitations. This project aims to develop an engineered synthetic hydrogel matrix that presents independently-tunable basement membrane-like bioactivity and mechanical properties, and can support epithelial cell survival, proliferation, polarization, and assembly into 3D multicellular structures recapitulating different epithelial morphogenesis program. This synthetic material has the capacity to present adhesive peptides and protease-degradable crosslinks that support cell functions and promote cell engraftment in vivo. As part of this project, we have developed an engineered synthetic hydrogel platform that recapitulates the morphogenetic program of human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs), and has been established as a delivery vehicle for HIOs to mucosal intestinal wounds in mice. Furthermore, in order to prove the versatility of our hydrogel platform, we aim to engineer a synthetic hydrogel that recapitulates the mouse inner medullary collecting duct (IMCD) cell morphogenetic program. We hypothesize that these engineered hydrogels will be superior to naturally-derived materials by supporting these different epithelial morphogenetic programs while overcoming the imitations of natural and other synthetic materials. This synthetic hydrogel technology is significant as it allows the study of the independent contributions of ECM properties to different epithelial morphogenetic programs, and will form a basis for the adaptation to in vitro generation and in vivo delivery of human PSC-derived organoids for regenerative medicine.
Advisors/Committee Members: Garcia, Andres J. (advisor), Nusrat, Asma (committee member), Roy, Krishnendu (committee member), Temenoff, Johnna S. (committee member), Fernandez-Nieves, Alberto (committee member).
Subjects/Keywords: Hydrogels; Biomaterials; Organoids; Epithelia; Morphogenesis; Regenerative medicine
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APA (6th Edition):
Cruz-Acuna, R. (2018). Synthetic hydrogels recapitulate epithelial morphogenesis programs. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61624
Chicago Manual of Style (16th Edition):
Cruz-Acuna, Ricardo. “Synthetic hydrogels recapitulate epithelial morphogenesis programs.” 2018. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/61624.
MLA Handbook (7th Edition):
Cruz-Acuna, Ricardo. “Synthetic hydrogels recapitulate epithelial morphogenesis programs.” 2018. Web. 16 Apr 2021.
Vancouver:
Cruz-Acuna R. Synthetic hydrogels recapitulate epithelial morphogenesis programs. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/61624.
Council of Science Editors:
Cruz-Acuna R. Synthetic hydrogels recapitulate epithelial morphogenesis programs. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61624
16.
Cermeno, Efrain.
Adhesion signature based enrichment of tumor initiating cells.
Degree: PhD, Mechanical Engineering, 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61635
► In spite of major therapeutic advances, cancer relapse and low rates of patient response to cancer therapeutics persist. This failure is due in part to…
(more)
▼ In spite of major therapeutic advances, cancer relapse and low rates of patient response to cancer therapeutics persist. This failure is due in part to a small subpopulation of tumor initiating cells (TICs) with stem cell-like properties that are responsible for the growth of the tumor and the progression of metastasis. These cells are capable of surviving chemotherapy, rendering them highly resistant to conventional cancer therapies. Although the question of whether TICs are stem cells remains a controversial topic in the cancer field, it has become increasingly evident that a better understanding of their biology and function is necessary to effectively treat cancer and eradicate tumors without allowing for relapse to occur. This project aimed to develop an objective, label-free, fast, and scalable method for cancer cell and TIC enrichment based on the adhesion strength signature of these cells. Currently, no efficient and reliable methods to isolate TICs exist. Although many in the field rely on surface marker expression profiles, these are variable and subjective, which hinders the study of TIC biology. Our lab has developed a technology to isolate cells based on their unique adhesion binding strength to a matrix. The novel technology (micro-Stem cell High- Efficiency Adhesion based Recovery [μSHEAR]) consists of a microfluidic device that applies varying degrees of detachment shear forces to adherent cells. Using this device, human pluripotent stem cells and their progeny have been isolated with high reproducibility, yield (>97%), purity (95-99%), and survival (>95%) rates (Singh et al, Nature Methods 2013). The process is fast (<10 min), label free, and scalable. Our hypothesis was that subtypes of cancer cells will exhibit distinct ‘adhesive force signatures’ that can be exploited to selectively purify TICs with high efficiency using the μSHEAR technology. The significance of this work was the development of a novel platform for objective, reliable, and scalable TIC purification.
Advisors/Committee Members: Garcia, Andres J. (advisor), Thomas, Susan N. (advisor), Huang, Emina H. (committee member), Lu, Hang (committee member), McDevitt, Todd C. (committee member).
Subjects/Keywords: Cancer stem cells; Tumor initiating cells; Cell adhesion; Cancer; Microfluidics
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APA (6th Edition):
Cermeno, E. (2018). Adhesion signature based enrichment of tumor initiating cells. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61635
Chicago Manual of Style (16th Edition):
Cermeno, Efrain. “Adhesion signature based enrichment of tumor initiating cells.” 2018. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/61635.
MLA Handbook (7th Edition):
Cermeno, Efrain. “Adhesion signature based enrichment of tumor initiating cells.” 2018. Web. 16 Apr 2021.
Vancouver:
Cermeno E. Adhesion signature based enrichment of tumor initiating cells. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/61635.
Council of Science Editors:
Cermeno E. Adhesion signature based enrichment of tumor initiating cells. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61635
Georgia Tech
17.
Wayman, Annica M.
Kinetic study of E-selectin-mediated adhesion under flow.
Degree: PhD, Mechanical Engineering, 2006, Georgia Tech
URL: http://hdl.handle.net/1853/11531
► During inflammation and thrombosis, leukocytes tether to and roll on vascular surfaces and platelets through selectin molecules under shear flow. This selectin family of cell…
(more)
▼ During inflammation and thrombosis, leukocytes tether to and roll on vascular surfaces and platelets through selectin molecules under shear flow. This selectin family of cell adhesion molecules includes P-, E-, and L-selectin. The association and dissociation of two or more selectin-mediated bonds under mechanical load produce the rolling motion of the leukocytes. Although much has been uncovered about the properties of selectins, the complete story of the selectin-mediated adhesion process is yet to be told. The goal of this research is to gain a more quantitative understanding of this receptor-ligand binding through the study of the dissociation kinetics of E-selectin-mediated adhesion using flow chamber techniques.
From transient tethering experiments, the dissociation rate of E-selectin-mediated adhesion was found to have a triphasic shear dependence at low shear stresses, where the bond transitioned from a slip to a catch then again to a slip bond. This trend was further supported by observations of the average rolling velocity of cells adhering to E-selectin at various shear stresses. A triphasic force dependence of the rolling velocity was revealed that showed that regions of increasing rolling velocity corresponded to the slip bond regime where tether lifetime decreased with increasing shear stress. Decreasing rolling velocity coincided with the catch bond regime, a regime of prolonged tether lifetime with increasing shear stress.
An invertible flow chamber was used in hopes of directly quantifying the dissociation rate of rollingly adherent cells on E-selectin to compare it to the dissociation rate data obtained through transient tethering experiments. However, tether formation, which relates to the association rate, and its role in the stability of rolling seemed to be a key factor in the dissociation rate of rollingly adherent cells over the low shear stress range. Overall, these results provide supporting evidence of a shear threshold for E-selectin as well as data to suggest that tether formation, in coordination with off-rate, determine the rolling velocity behavior of cells on E-selectin substrates.
Advisors/Committee Members: Zhu, Cheng (Committee Chair), Giddens, Don P. (Committee Co-Chair), Garcia, Andres J. (Committee Member), McEver, Rodger P. (Committee Member), Smith, Marc K. (Committee Member).
Subjects/Keywords: Bioengineering; Biomedical engineering; Biophysics; Cellular engineering; Shear flow; Cell adhesion; Biomedical engineering; Selectins
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APA (6th Edition):
Wayman, A. M. (2006). Kinetic study of E-selectin-mediated adhesion under flow. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/11531
Chicago Manual of Style (16th Edition):
Wayman, Annica M. “Kinetic study of E-selectin-mediated adhesion under flow.” 2006. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/11531.
MLA Handbook (7th Edition):
Wayman, Annica M. “Kinetic study of E-selectin-mediated adhesion under flow.” 2006. Web. 16 Apr 2021.
Vancouver:
Wayman AM. Kinetic study of E-selectin-mediated adhesion under flow. [Internet] [Doctoral dissertation]. Georgia Tech; 2006. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/11531.
Council of Science Editors:
Wayman AM. Kinetic study of E-selectin-mediated adhesion under flow. [Doctoral Dissertation]. Georgia Tech; 2006. Available from: http://hdl.handle.net/1853/11531
Georgia Tech
18.
Reyes, Catherine Diane.
Collagen- and Fibronectin-Mimetic Integrin-Specific Surfaces That Promote Osseointegration.
Degree: PhD, Mechanical Engineering, 2006, Georgia Tech
URL: http://hdl.handle.net/1853/11599
► Cell adhesion to the extracellular matrix through cell-surface integrin receptors is essential to development, wound healing, and tissue remodeling and therefore represents a central theme…
(more)
▼ Cell adhesion to the extracellular matrix through cell-surface integrin receptors is essential to development, wound healing, and tissue remodeling and therefore represents a central theme in the design of bioactive surfaces that successfully interface with the body. This is especially significant in the areas of integrative implant coatings since adhesion triggers signals that regulate cell cycle progression and differentiation in multiple cellular systems. The interactions of osteoblasts with their surrounding extracellular matrix are essential for skeletal development and homeostasis and the maintenance of the mature osteoblastic phenotype. Our objective was to engineer integrin-specific bioactive surfaces that support osteoblastic differentiation and promote osseointegration by mimicking these interactions. We target two specific integrins essential to osteoblast differentiation the type I collagen receptor alpha2beta1 and the fibronectin receptor alpha5beta1. The central hypothesis of this project was that the controlled presentation of type I collagen and fibronectin binding domains onto well-defined substrates would result in integrin-specific bioadhesive surfaces that support osteoblastic differentiation, matrix mineralization, and osseointegration. We have demonstrated that these biomimetic peptides enhance bone formation and mechanical osseointegration on titanium implants in a rat tibia cortical bone model. We have also shown that the presentation of multiple integrin-binding ligands synergize to enhance intracellular signaling and proliferation. Finally, we demonstrate the advantage of the short biomimetic peptides over the native ECM proteins. This research is significant because it addresses current orthopaedic implant limitations by specifically targeting cellular responses that are critical to osteoblastic differentiation and bone formation. This biomolecular approach provides a versatile and robust strategy for developing bioactive surfaces that enhance bone repair and osseointegration of orthopaedic implants.
Advisors/Committee Members: Garcia, Andres J. (Committee Chair), Bellamkonda, Ravi (Committee Member), Boyan, Barbara D. (Committee Member), Chaikof, Elliot L. (Committee Member), Collard, David M. (Committee Member), Guldberg, Robert E. (Committee Member).
Subjects/Keywords: Biomimetics; Bone; Implants; Peptides; Cell adhesion; Titanium; Osteoblast; Biomaterials; Collagen; Fibronectin; Differentiation; Mineralization; Osseointegration; Osseointegration; Orthopedic implants; Integrins; Cell adhesion; Biomimetics; Biomedical materials; Adhesion
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Reyes, C. D. (2006). Collagen- and Fibronectin-Mimetic Integrin-Specific Surfaces That Promote Osseointegration. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/11599
Chicago Manual of Style (16th Edition):
Reyes, Catherine Diane. “Collagen- and Fibronectin-Mimetic Integrin-Specific Surfaces That Promote Osseointegration.” 2006. Doctoral Dissertation, Georgia Tech. Accessed April 16, 2021.
http://hdl.handle.net/1853/11599.
MLA Handbook (7th Edition):
Reyes, Catherine Diane. “Collagen- and Fibronectin-Mimetic Integrin-Specific Surfaces That Promote Osseointegration.” 2006. Web. 16 Apr 2021.
Vancouver:
Reyes CD. Collagen- and Fibronectin-Mimetic Integrin-Specific Surfaces That Promote Osseointegration. [Internet] [Doctoral dissertation]. Georgia Tech; 2006. [cited 2021 Apr 16].
Available from: http://hdl.handle.net/1853/11599.
Council of Science Editors:
Reyes CD. Collagen- and Fibronectin-Mimetic Integrin-Specific Surfaces That Promote Osseointegration. [Doctoral Dissertation]. Georgia Tech; 2006. Available from: http://hdl.handle.net/1853/11599
. 
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