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Hyaluronan-methylcellulose Hydrogels for Cell and Drug Delivery to the Injured Central Nervous SystemCaicco, Matthew 21 November 2012 (has links)
Spinal cord injury and stroke are two devastating neurological events that lack effective clinical treatments. Recent neuroregenerative approaches involving the delivery of cells or drugs to the injured tissue have shown promise, but face critical challenges to clinical translation. Herein, hyaluronan-methylcellulose (HAMC) hydrogels were investigated as a versatile means of overcoming the challenges facing central nervous system cell and drug delivery. HAMC was shown to support the viability of encapsulated human umbilical tissue-derived cells, demonstrating utility as a scaffold for therapeutic cell delivery to the injured spinal cord. In a drug delivery context, release of the neuroregenerative drug cyclosporin A from the hydrogel was tunable over 2-28 days and the drug diffused to the stem cell niche in the brain and persisted for up to 24 days at a stable concentration when the HAMC-based system was implanted epi-cortically. HAMC is thus a promising tool for emerging neuroregenerative therapies.
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Hyaluronan-methylcellulose Hydrogels for Cell and Drug Delivery to the Injured Central Nervous SystemCaicco, Matthew 21 November 2012 (has links)
Spinal cord injury and stroke are two devastating neurological events that lack effective clinical treatments. Recent neuroregenerative approaches involving the delivery of cells or drugs to the injured tissue have shown promise, but face critical challenges to clinical translation. Herein, hyaluronan-methylcellulose (HAMC) hydrogels were investigated as a versatile means of overcoming the challenges facing central nervous system cell and drug delivery. HAMC was shown to support the viability of encapsulated human umbilical tissue-derived cells, demonstrating utility as a scaffold for therapeutic cell delivery to the injured spinal cord. In a drug delivery context, release of the neuroregenerative drug cyclosporin A from the hydrogel was tunable over 2-28 days and the drug diffused to the stem cell niche in the brain and persisted for up to 24 days at a stable concentration when the HAMC-based system was implanted epi-cortically. HAMC is thus a promising tool for emerging neuroregenerative therapies.
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Preparation and analysis of crosslinked lignocellulosic fibers and cellulose nanowhiskers with poly(methyl-vinyl ether co maleic acid) â " polyethylene glycol to create novel water absorbing materialsGoetz, Lee Ann 13 November 2012 (has links)
The search for cellulosic based products as a viable alternative for petroleum-based products was the impetus for covalently crosslinking lignocellulosic fibers and nanocellulose whiskers with poly(methyl vinyl ether) co maleic acid (PMVEMA) - polyethylene glycol (PEG). The lignocellulosics used were ECF bleached softwood (pine) and ECF bleached birch kraft pulp. This thesis also tests the hypothesis that water absorption and retention can be improved by grafting PMVEMA-PEG to the surface of ECF bleached kraft pulp hardwood and softwood fibers via microwave initiated crosslinking. The crosslinking of the PMVEMA to hardwood and softwood kraft ECF bleached pulp fibers resulted in enhanced water absorbing pulp fibers where the PMVEMA is grafted onto the surface of the fibers. The crosslinking was initiated both thermally and via microwave irradiation and the water absorption and water retention was measured as the percent of grafted PMVEMA. This was the first application of microwave crosslinking of pulp fibers with the goal of creating water absorbing pulp fibers. Ultimately, the water absorption values ranged from 28.70 g water per g dry crosslinked pulp fiber (g/g) to 230.10 g/g and the water retention values ranged from 26% to 71% of the water retained that was absorbed by the crosslinked pulp fibers. The microwave initiated crosslinked fibers had comparable results to the thermally crosslinked fibers with a decreased reaction time, from 6.50 min (thermal) to 1 min 45 sec (microwave).
Cellulose nanowhiskers, crystalline rods of cellulose, have been investigated due to their unique properties, such as nanoscale dimensions, low density, high surface area, mechanical strength, and surface morphology and available surface chemistry. Prior to this study, the crosslinking of cellulose whiskers with the matrix via solution casting of liquid suspensions of whiskers and matrix had not been explored. The hypothesis to be investigated was that incorporating cellulosic whiskers with the PMVEMA-PEG matrix and crosslinking the whiskers with the matrix would yield films that demonstrate unique properties when compared to prior work of crosslinking of PMVEMA-PEG to macroscopic ECF bleached kraft pulp fibers.
Solution cast composites of cellulose nanowhiskers-PMVEMA-PEG were crosslinked at 135 °C for 6.5 min and analyzed for crosslinking, thermal stability, strength and mechanical properties, whisker dispersion, and water absorption and uptake rates. The whisker-composites demonstrated unique properties upon crosslinking the whiskers with PMVEMA-PEG, especially the elongation at break and tensile strength upon conditioning of the final materials at various relative humidities. In addition, the whiskers improved the thermal stability of the PMVEMA-PEG matrix. This is significant as methods of improving processing thermal stability are key to developing new materials that utilize cellulose whiskers, PMVEMA, and PEG. This thesis addresses the hypothesis that cellulose nanowhiskers that are crosslinked with a matrix can create new whisker-matrix composites that behave differently after crosslinking.
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Fabrication of alginate hydrogel scaffolds and cell viability in calcium-crosslinked alginate hydrogelCao, Ning 03 August 2011
Tissue-engineering (TE) is one of the most innovative approaches for tackling many diseases and body parts that need to be replaced, by developing artificial tissues and organs. For this, tissue scaffolds play an important role in various TE applications. A tissue scaffold is a 3D (3D) structure with interconnected pore networks and used to facilitate cell growth and transport of nutrients and wastes while degrading gradually itself. Many fabrication techniques have been developed recently for incorporating living cells into the scaffold fabrication process and among them; dispensing-based rapid prototyping techniques have been drawn considerable attention due to its fast and efficient material processing. This research is aimed at conducting a preliminary study on the dispensing-based biofabrication of 3D cell-encapsulated alginate hydrogel scaffolds.
Dispensing-based polymer deposition system was used to fabricate 3D porous hydrogel scaffolds. Sodium alginate was chosen and used as a scaffolding biomaterial. The influences of fabrication process parameters were studied. With knowledge and information gained from this study, 3D hydrogel scaffolds were successfully fabricated. Calcium chloride was employed as crosslinker in order to form hydrogels from alginate solution. The mechanical properties of formed hydrogels were characterized and examined by means of compressive tests. The influences of reagent concentrations, gelation time, and gelation type were studied. A post-fabrication treatment was used and characterized in terms of strengthening the hydrogels formed. In addition, the influence of calcium ions used as crosslinker on cell viability and proliferation during and after the dispensing fabrication process was examined and so was the influence of concentration of calcium solutions and exposing time in both media and alginate hydrogel. The study also showed that the density of encapsulated cells could affect the viscosity of alginate solution.
In summary, this thesis presents a preliminary study on the dispensing-based biofabrication of 3D cell-encapsulated alginate hydrogel scaffolds. The results obtained regarding the influence of various factors on the cell viability and scaffold fabrication would form the basis and rational to continue research on fabricating 3D cell-encapsulated scaffolds for specific applications.
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Synthesis of Stimuli-responsive Hydrogels from GlycerolSalehpour, Somaieh 18 January 2012 (has links)
Due to an increased environmental awareness and thus, concerns over the use of fossil-based monomer for polymer production, there is an ongoing effort to find alternatives to non-renewable traditional monomers. This has ushered in the rapid growth in the development of bio-based materials such as green monomers and biodegradable polymers from vegetable and animal resources. Glycerol, as a renewable bio-based monomer, is an interesting candidate for sustainable polymer production. Glycerol is a renewable material that is a by-product of the transesterification of vegetable oils to biodiesel. Utilization of the excess glycerol derived from the growing biodiesel industry is important to oleochemical industries. The main objective of this thesis was to produce high molecular weight polyglycerol from glycerol and synthesize stimuli-responsive polyglycerol hydrogels. The work began with an investigation of the step-growth polymerization of glycerol to relatively high molecular weight polyglycerol using several catalysts. The catalytic reaction mechanisms were compared and the polymer products were fully analyzed. High molecular weight partially branched polyglycerol with multimodal molecular weight distributions was obtained. The polymerization of glycerol proceeded fastest with sulphuric acid as catalyst as indicated by the highest observed conversion of monomer along with the highest molecular weights. Theoretical models were used to predict the gel point and to calculate monomer functionality. High molecular weight polyglycerol was used to synthesize novel stimuli-responsive hydrogels. Real-time monitoring of step-growth polymerization of glycerol was investigated using in-line and off-line Attenuated Total Reflectance/Fourier Transform infrared (ATR-FTIR) technique.
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Lipid Deposition on Hydrogel Contact LensesLorentz, Holly January 2006 (has links)
The primary objective of this study was to quantify and characterise lipid deposition on soft (hydrogel) contact lenses, particularly those containing siloxane components. Studies involving a variety of <em>in vitro</em> doping and <em>in vivo</em> worn contact lenses were undertaken, in which lipid deposition was analyzed by either TLC or HPLC. Specific experiments were completed to optimize a method to extract the lipid from the lens materials, to compare the total lipid deposition on nine different hydrogel lenses and to analyze the effect that lipid deposition had on wettability. A method for extracting lipid from contact lenses using 2:1 chloroform: methanol was developed. This study also showed that siloxane-containing contact lens materials differ in the degree to which they deposit lipid, which is dependent upon their chemical composition. Small differences in lipid deposition that occur due to using variations in cleaning regimens were not identifiable through TLC, and required more sophisticated analysis using HPLC. Contact lens material wettability was found to be influenced by <em>in vitro</em> lipid deposition. Specifically, conventional hydrogels and plasma surface-treated silicone-hydrogel materials experienced enhanced wettability with lipid deposition. Reverse-phase HPLC techniques were able to quantify lipid deposits with increased sensitivity and accuracy. From the HPLC studies it was found that contact lens material, concentration of the lipid doping solution, and the composition of the lipid doping solution in <em>in vitro</em> deposition studies influenced the ultimate amount and composition of lipid deposits. <em>In vivo</em> HPLC studies showed that the final lipid deposition pattern was influenced by the interaction between the composition of the tear film and the various silicone hydrogel contact lens materials. In conclusion, HPLC analysis methods were more sensitive and quantitative than TLC. Lipid deposition was ultimately influenced by the concentration and composition of the lipid in the tear film and the contact lens material. Contact lens wettability was influenced by the presence and deposition of lipid onto the contact lens surfaces. Finally, this reverse-phase HPLC lipid analysis protocol was not the most sensitive, robust, or accurate. In the future, other methods of analysis should be explored.
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Protein Deposition and Bacterial Adhesion to Conventional and Silicone Hydrogel Contact Lens MaterialsNagapatnam Subbaraman, Lakshman January 2009 (has links)
Introduction
Contact lenses suffer from the same problems of deposition that other biomaterials exhibit, being rapidly coated with a variety of proteins, lipids and mucins. The first event observed at the interface between a contact lens and tear fluid is protein adsorption. Protein deposits on contact lenses are associated with diminished visual acuity, dryness and discomfort and lid-related inflammatory changes.
The aim of this thesis was to determine the quantity and the conformational state of lysozyme deposited on contact lens materials over various time periods and also to determine the clinical relevance of protein deposits on contact lenses. The specific aims of each chapter of this thesis were as follows:
• Chapter 4: To determine the total lysozyme deposition on conventional and silicone hydrogel contact lens materials as a function of time by artificially doping lenses with 125I-labeled lysozyme.
• Chapter 5: To determine the conformational state of lysozyme deposited on conventional and silicone hydrogel contact lens materials as a function of time using an in vitro model.
• Chapter 6: To quantify the total protein, total lysozyme and the conformational state of lysozyme deposited on a novel, lathe-cut silicone hydrogel contact lens material after three-months of wear.
• Chapter 7: To determine the relationship between protein deposition and clinical signs & symptoms after one-day wear of etafilcon lenses in a group of symptomatic and asymptomatic lens wearers.
• Chapter 8: To determine the influence of individual tear proteins (lysozyme, lactoferrin and albumin) on the adhesion of Gram positive and Gram negative bacteria to conventional and silicone hydrogel contact lens materials.
Methods
• Chapter 4: Conventional hydrogel FDA group I (polymacon), group II (alphafilcon A and omafilcon A), group IV (etafilcon A and vifilcon A), polymethyl methacrylate and silicone hydrogel lens materials (lotrafilcon A, lotrafilcon B, balafilcon A, galyfilcon A and senofilcon A) were incubated in a lysozyme solution containing 125I-labeled lysozyme for time periods ranging from 1 hour to 28 days. After each time period, lysozyme deposited on contact lens materials was determined using a Gamma Counter.
• Chapter 5: Conventional hydrogel FDA groups I, II, IV and silicone hydrogel lens materials were incubated in lysozyme solution for time periods ranging from 1 hour to 28 days. After each time period, the lysozyme deposited on the lenses was extracted and the sample extracts were assessed for lysozyme activity and total lysozyme.
• Chapter 6: 24 subjects completed a prospective, bilateral, daily-wear, nine month clinical evaluation in which the subjects were fitted with a novel, custom-made, lathe-cut silicone hydrogel lens material (sifilcon A). After 3 months of wear, the lenses were collected and total protein, total lysozyme and active lysozyme deposition were assessed.
• Chapter 7: 30 adapted soft contact lens wearers (16 symptomatic and 14 asymptomatic) were fitted with etafilcon lenses. Objective measures and subjective symptoms were assessed at baseline and after hours 2, 4, 6 and 8. After 2, 4, 6 and 8 hour time points, lenses were collected and total protein, total lysozyme and active lysozyme deposition were assessed.
• Chapter 8: Three silicone hydrogel (balafilcon A, lotrafilcon B & senofilcon A) and one conventional hydrogel (etafilcon A) lens materials were coated with lysozyme, lactoferrin and albumin. Uncoated and protein-coated contact lens samples were incubated in a bacterial suspension of Staphylococcus aureus 31 and two strains of Pseudomonas aeruginosa (6294 & 6206). The total counts and the viable counts of the adhered bacteria were assayed.
Results
• Chapter 4: Lysozyme accumulated rapidly on conventional hydrogel FDA group IV lenses, reached a maximum on day 7 and then plateaued with no further increase. PMMA showed a deposition pattern similar to that seen on lotrafilcon A and lotrafilcon B silicone hydrogel lenses. After 28 days, conventional hydrogel FDA group IV lenses deposited the most lysozyme.
• Chapter 5: After 28 days, lysozyme deposited on group IV lenses exhibited the greatest activity. Lysozyme deposited on polymacon, lotrafilcon A and lotrafilcon B exhibited the lowest activity. Lysozyme deposited on omafilcon, galyfilcon, senofilcon, and balafilcon exhibited intermediate activity.
• Chapter 6: The total protein recovered from the custom-made lenses was 5.3±2.3 µg/lens and the total lysozyme was 2.4±1.2 µg/lens. The denatured lysozyme found on the lenses was 1.9±1.0 µg/lens and the percentage of lysozyme denatured was 80±10%.
• Chapter 7: Correlations between subjective symptoms and protein deposition showed poor correlations for total protein/ lysozyme and any subjective factor, and only weak correlations between dryness and active lysozyme. However, stronger correlations were found between active lysozyme and subjective comfort.
• Chapter 8: Different tear proteins had varying effects on the adhesion of bacteria to contact lens materials. Lysozyme deposits on contact lenses increased the adhesion of Gram positive Staphyloccocus aureus 31 strain, while albumin deposits increased the adhesion of both the Gram positive Staphyloccocus aureus and Gram negative Pseudomonas aeruginosa 6206 & 6294 strains. Lactoferrin deposits increased the total counts of both the Gram positive and Gram negative strains, while they reduce the viable counts of the Gram negative strains.
Conclusions
• Chapter 4: Lysozyme deposition is driven by both the bulk chemistry and also the surface properties of conventional and silicone hydrogel contact lens materials. The surface modification processes or surface-active monomers on silicone hydrogel lens materials also play a significant role in lysozyme deposition.
• Chapter 5: The reduction in the activity of lysozyme deposited on contact lens materials is time dependent and the rate of reduction varies between lens materials. This variation in activity recovered from lenses could be due to the differences in surface/ bulk material properties or the location of lysozyme on these lenses.
• Chapter 6: Even after three-months of wear, the quantity of protein and the conformational state of lysozyme deposited on these novel lens materials was very similar to that found on similar surface-coated silicone hydrogel lenses after two to four weeks of wear. These results indicate that extended use of the sifilcon A material is not deleterious in terms of the quantity and quality of protein deposited on the lens.
• Chapter 7: In addition to investigating the total protein deposited on contact lenses, it is of significant clinical relevance to determine the conformational state of the deposited protein.
• Chapter 8: Uncoated silicone hydrogel lens materials bind more Gram positive and Gram negative bacteria than uncoated conventional hydrogel lens materials. Lysozyme deposited on contact lens materials does not possess antibacterial activity against all bacterial strains tested, while lactoferrin possess an antibacterial effect against certain Gram negative strains tested in this study.
This thesis has provided hitherto unavailable information on contact lens deposition and its influence on subjective symptoms and bacterial binding. These results suggest that protein deposition has a significant potential to cause problems. Therefore, it is important that practitioners advise their patients regarding the importance of lens disinfection and cleaning and appropriate lens replacement schedules. These results will also be useful for the contact lens industry and the general field of biomaterials research.
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Bioactive Poly(ethylene glycol)-based Hydrogels for Characterization of Matrix Influences on a Lung Cancer Metastasis ModelGill, Bj 16 September 2013 (has links)
Pathological changes to tumor extracellular matrix (ECM) composition, mechanics, and architecture promote cancer progression and metastasis. Exploration of tumor-ECM interactions using in vitro matrix-mimetic culture systems has largely been restricted to naturally-derived matrix materials that permit limited experimental control. Such study of a novel lung adenocarcinoma model in Matrigel™ (MG) has suggested key matrix cues that mediate epithelial-mesenchymal transition (EMT) and metastasis. In this thesis work, synthetic hydrogel scaffolds based on poly(ethylene glycol) (PEG) featuring high experimental control and modular bioactivity were used to study matrix influences on the EMT-prone model line 344SQ.
Encapsulation of 344SQ cells in PEG hydrogels modified for cell adhesivity and cell-mediated enzymatic degradability induced formation of lumenized, polarized spheres mimicking the epithelial phenotype observed in three-dimensional MG. Tuning matrix stiffness, adhesive ligand concentration, and ligand spatial presentation altered epithelial morphogenesis. Exploration of the EMT phenotype of PEG-encapsulated 344SQ cells revealed TGFβ-initiated changes in morphology, polarity, expression levels of EMT marker genes and their epigenetic controller, and the organization of cell-secreted ECM. Notably, a potent role for adhesive ligand was illuminated as matrices with low PEG-RGDS concentration even in the absence of TGFβ induced formation of spheres with a post-EMT phenotype by several of these measures. A matrix-invasive phenotype was also revealed by altering matrix structural parameters and tuned with incorporation of an alternative protease-cleavable sequence. Finally, the influence of cell-cell contacts was explored by covalent incorporation of cadherin proteins into the matrix. Matrix-tethered E- and -N-cadherin affected 344SQ sphere development in otherwise non-cell-adhesive matrices and modulated polarity and the degree of TGFβ response. Further, in 344SQ with a knockdown of the essential polarity-determining protein Scribble, matrix-tethered cadherin influenced the formation of a phenotype with partially normalized epithelial polarity with corresponding differences in membrane localization of cell-expressed E-cadherin.
Overall, this thesis demonstrates the utility of the more experimentally controllable PEG system in studying ECM influences on cancer progression with findings providing greater insight into stromal biomechanical, biochemical, and cell-cell factors that mediate lung adenocarcinoma epithelial morphogenesis and EMT. These contributions help advance the state of the field towards a goal of developing new metastasis-targeting cancer therapeutics.
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Lysozyme Deposition Studies on Silicone Hydrogel Contact Lens MaterialsNagapatnam Subbaraman, Lakshman January 2005 (has links)
Over 60 proteins have been detected in the tear film and among these lysozyme has attracted the greatest attention. Several techniques for elucidating the identity, quantity and conformation of lysozyme deposited on soft contact lenses have been developed. Lysozyme also deposits on the newly introduced silicone hydrogel (SH) lens materials, but in extremely low levels compared to conventional hydrogel lenses. Hence, a major analytical complication with the study of the SH contact lens materials relates to the minute quantity of deposited lysozyme.
The first project of this thesis involved the development of a method whereby lysozyme mass extracted from SH lens materials would be preserved over time and would be compatible with an optimized Western blotting procedure. This methodological development was incorporated into a clinical study (CLENS-100® and Silicone Hydrogels ? CLASH study) wherein the difference in the degree of total protein, the difference in lysozyme deposition and activity recovered from lotrafilcon A SH lens material when subjects used surfactant containing rewetting drops (CLENS-100®) versus control saline was investigated. The remaining experiments were in vitro experiments wherein the lenses were doped in artificial lysozyme solution containing <sup>125</sup>I-labeled lysozyme. These experiments were performed to gain insight into the kinetics of lysozyme deposition on SH lens materials and also the efficacy of a reagent in extracting lysozyme from SH lens materials.
A protocol was developed whereby the percentage loss of lysozyme mass found on lotrafilcon A SH lenses was reduced from approximately 33% to <1% (p<0. 001), following extraction and resuspension. The results from the CLASH study demonstrated that when subjects used a surfactant containing rewetting drop instead of a control saline drop total protein deposition (1. 2±0. 7 µg/lens versus 1. 9±0. 8 µg/lens, p<0. 001), lysozyme deposition (0. 7±0. 5 µg/lens versus 1. 1±0. 7 µg/lens, p<0. 001) and percentage lysozyme denaturation (76±10% versus 85±7%, p=0. 002) were all reduced. The results from the kinetics study demonstrated that lysozyme accumulated rapidly on etafilcon A lenses (1 hr, 98±8 µg/lens), reached a maximum on the 7th day (1386±21 µg/lens) and then reached a plateau (p=NS). Lysozyme accumulation on FDA Group II and SH lenses continued to increase across all time periods, with no plateau being observed (p<0. 001). The results from the extraction efficiency study showed that 0. 2% trifluoroacetic acid/ acetonitrile was 98. 3±1. 1% and 91. 4±1. 4% efficient in extracting lysozyme deposited on etafilcon A and galyfilcon lenses, while the lysozyme extraction efficiency was 66. 3±5. 3 % and 56. 7±3. 8% for lotrafilcon A and balafilcon lens materials (p<0. 001).
The results from these studies re-emphasize that novel SH lens materials are highly resistant to protein deposition and demonstrate high levels of biocompatibility.
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Lipid Deposition on Hydrogel Contact LensesLorentz, Holly January 2006 (has links)
The primary objective of this study was to quantify and characterise lipid deposition on soft (hydrogel) contact lenses, particularly those containing siloxane components. Studies involving a variety of <em>in vitro</em> doping and <em>in vivo</em> worn contact lenses were undertaken, in which lipid deposition was analyzed by either TLC or HPLC. Specific experiments were completed to optimize a method to extract the lipid from the lens materials, to compare the total lipid deposition on nine different hydrogel lenses and to analyze the effect that lipid deposition had on wettability. A method for extracting lipid from contact lenses using 2:1 chloroform: methanol was developed. This study also showed that siloxane-containing contact lens materials differ in the degree to which they deposit lipid, which is dependent upon their chemical composition. Small differences in lipid deposition that occur due to using variations in cleaning regimens were not identifiable through TLC, and required more sophisticated analysis using HPLC. Contact lens material wettability was found to be influenced by <em>in vitro</em> lipid deposition. Specifically, conventional hydrogels and plasma surface-treated silicone-hydrogel materials experienced enhanced wettability with lipid deposition. Reverse-phase HPLC techniques were able to quantify lipid deposits with increased sensitivity and accuracy. From the HPLC studies it was found that contact lens material, concentration of the lipid doping solution, and the composition of the lipid doping solution in <em>in vitro</em> deposition studies influenced the ultimate amount and composition of lipid deposits. <em>In vivo</em> HPLC studies showed that the final lipid deposition pattern was influenced by the interaction between the composition of the tear film and the various silicone hydrogel contact lens materials. In conclusion, HPLC analysis methods were more sensitive and quantitative than TLC. Lipid deposition was ultimately influenced by the concentration and composition of the lipid in the tear film and the contact lens material. Contact lens wettability was influenced by the presence and deposition of lipid onto the contact lens surfaces. Finally, this reverse-phase HPLC lipid analysis protocol was not the most sensitive, robust, or accurate. In the future, other methods of analysis should be explored.
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