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Elution Profile of Caspofungin from Anti-fungal Loaded Bone Cement

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Advancements in healthcare and the emergence of an aging population has led to an increase in the number of prosthetic joint procedures in the United States. According to Healthcare Cost and Utilization Project, 660,876 and 348,970 total hip and knee

Advancements in healthcare and the emergence of an aging population has led to an increase in the number of prosthetic joint procedures in the United States. According to Healthcare Cost and Utilization Project, 660,876 and 348,970 total hip and knee arthroplasties were performed in 2014[1].The percentage of total hip or knee procedures that are revised due to an infection is 1.23% and 1.21% respectively[3], [4]. Although the percent of infections may be small, an infection can have a tremendous burden on the patient and healthcare system. It is expected that prosthetic joint infections (PJIs) will cost the healthcare system an estimated $1.62 billion by 2020[5]. PJIs are often difficult to treat due to the formation of biofilm at the site of the infection. A large majority of PJIs are the result of a bacterial biofilm, but around 1% of PJIs are due to fungal infections[3]. The current method of treatment is to surgically remove all infected tissue at the site of infection through a process called debridement and then insert a medicated bone cement spacer[7], [10]–[12]. One such medication that is loaded into the bone cement is caspofungin, a member of the echinocandin class of compounds that inhibit the synthesis of 1,3-β-D-glucan which is a crucial element of the cell wall of the target fungi[13]–[15]. For the studies reported herein, the caspofungin-loaded bone cement samples were made at 5 dosage strengths according to standard operating room practices. The elution of the drug was analyzed using ultraviolet spectrophotometry. The elution profiles were analyzed for 19 days consecutively, during which the 70 mg, 1 g, and 5 g dosage groups showed a prolonged, sustained release of the caspofungin. The 70 mg and 1 g dosage cumulative mass release profiles were not statistically significant, but it is unlikely that the difference would not have a clinical significance especially in the treatment of a fungal biofilm infection. The determination of the elution profile for caspofungin from loaded-bone cement can provide clinicians with a basis for how the drug will release into the infected joint.

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2019-05

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Norepinephrine and Adenosine Infused Microparticles for Brown Adipose Tissue Stimulation

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With microspheres growing in popularity as viable systems for targeted drug therapeutics, there exist a host of diseases and pathology induced side effects which could be treated with poly(lactic-co-glycolic acid) [PLGA] microparticle systems [6,10,12]. While PLGA systems are already applied

With microspheres growing in popularity as viable systems for targeted drug therapeutics, there exist a host of diseases and pathology induced side effects which could be treated with poly(lactic-co-glycolic acid) [PLGA] microparticle systems [6,10,12]. While PLGA systems are already applied in a wide variety the clinical setting [11], microparticles still have some way to go before they are viable systems for drug delivery. One of the main reasons for this is a lack of fabrication processes and systems which produce monodisperse particles while also being feasible for industrialization [10]. This honors thesis investigates various microparticle fabrication techniques \u2014 two using mechanical agitation and one using fluid dynamics \u2014 with the long term goal of incorporating norepinephrine and adenosine into the particles for metabolic stimulatory purposes. It was found that mechanical agitation processes lead to large values for dispersity and the polydispersity index while fluid dynamics methods have the potential to create more uniform and predictable outcomes. The research concludes by needing further investigation into methods and prototype systems involving fluid dynamics methods; however, these systems yield promising results for fabricating monodisperse particles which have the potential to encapsulate a wide variety of therapeutic drugs.

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2018-12

Long Term Susceptibility of Biofilms Treated with Antimicrobials

Description

The concentration necessary to kill bacterial biofilms with antimicrobials is the minimum biofilm eradication concentration (MBEC). This is usually determined using an in vitro approach and will vary within different strains of bacteria. Biomedical implants produce biofilm-related infections presenting a

The concentration necessary to kill bacterial biofilms with antimicrobials is the minimum biofilm eradication concentration (MBEC). This is usually determined using an in vitro approach and will vary within different strains of bacteria. Biomedical implants produce biofilm-related infections presenting a unique challenge due to the combination of subpopulations of the bacterial community and the polysaccharide matrix presented by biofilms. The purpose of this investigation is to determine how exposure times in the order of weeks to months affect the MBEC. Using an in vitro approach, Staphylococcus aureus (UAMS-1) and methicillin-resistant Staphylococcus aureus (MRSA) biofilms were produced with a 24 hour growth time and exposed to two antimicrobials, tobramycin and vancomycin, and one combination treatment that consisted of 1:1 tobramycin: vancomycin by weight. Crystal violet screening was used in order to ensure the integrity of the biofilm matrix throughout the full time of exposure. It was determined that UAMS-1 MBECs were lowered after 56 days of exposure than after 5 days for all three treatment groups. MRSA MBECs after 5 days of exposure decreased only with in vancomycin treatment group.

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2016-05

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Pharmacologic Modulation of the Blood-Brain Barrier

Description

One of the most prominent biological challenges for the field of drug delivery is the blood-brain barrier. This physiological system blocks the entry of or actively removes almost all small molecules into the central nervous system (CNS), including many drugs

One of the most prominent biological challenges for the field of drug delivery is the blood-brain barrier. This physiological system blocks the entry of or actively removes almost all small molecules into the central nervous system (CNS), including many drugs that could be used to treat diseases in the CNS. Previous studies have shown that activation of the adenosine receptor signaling pathway through the use of agonists has been demonstrated to increase BBB permeability. For example, regadenoson is an adenosine A2A receptor agonist that has been shown to disrupt the BBB and allow for increased drug uptake in the CNS. The goal of this study was to verify this property of regadenoson. We hypothesized that co-administration of regadenoson with a non-brain penetrant macromolecule would facilitate its entry into the central nervous system. To test this hypothesis, healthy mice were administered regadenoson or saline concomitantly with a fluorescent dextran solution. The brain tissue was either homogenized to measure quantity of fluorescent molecule, or cryosectioned for imaging with confocal fluorescence microscopy. These experiments did not identify any significant difference in the amount of fluorescence detected in the brain after regadenoson treatment. These results contradict those of previous studies and highlight potential differences in injection methodology, time windows, and properties of brain impermeant molecules.

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2015-05

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Synthesis of Dual Layered Microparticles for Tunable Delayed Release Profile

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The primary objective of this research project is to develop dual layered polymeric microparticles with a tunable delayed release profile. Poly(L-lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) phase separate in a double emulsion process due to differences in hydrophobicity, which

The primary objective of this research project is to develop dual layered polymeric microparticles with a tunable delayed release profile. Poly(L-lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) phase separate in a double emulsion process due to differences in hydrophobicity, which allows for the synthesis of double-walled microparticles with a PLA shell surrounding the PLGA core. The microparticles were loaded with bovine serum albumin (BSA) and different volumes of ethanol were added to the PLA shell phase to alter the porosity and release characteristics of the BSA. Different amounts of ethanol varied the total loading percentage of the BSA, the release profile, surface morphology, size distribution, and the localization of the protein within the particles. Scanning electron microscopy images detailed the surface morphology of the different particles. Loading the particles with fluorescently tagged insulin and imaging the particles through confocal microscopy supported the localization of the protein inside the particle. The study suggest that ethanol alters the release characteristics of the loaded BSA encapsulated in the microparticles supporting the use of a polar, protic solvent as a tool for tuning the delayed release profile of biological proteins.

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2015-05

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Targeted Delivery of Antibiotics to Skin Infections via Hydrogel Band-Aids to Reduce Adverse Side Effects: A Study

Description

The aim of the present study was to review the symptoms and current treatment options of the most common skin infections seen in outpatient settings and develop a preliminary alternative treatment solution. The specific skin infections evaluated were those caused

The aim of the present study was to review the symptoms and current treatment options of the most common skin infections seen in outpatient settings and develop a preliminary alternative treatment solution. The specific skin infections evaluated were those caused by Staphylococcus and Streptococcus bacterial species, and are frequently treated with a wide variety of systemic antibiotics or topical ointments. Systemic antibiotics have shown increased occurrence of adverse side effects as well as the development of antibiotic-resistant bacteria. Additionally, these medications are usually overprescribed, which may further exacerbate negative side effects. Another issue that is addressed is the development of infections following treatment of a new laceration or other trauma to the skin. A patient may be treated for their wound with stitches or another alternative, but there is still the possibility of developing an infection later.
This study synthesizes information found from extensive research and provides a review of the most optimal techniques for developing an alternative to systemic antibiotics. The final deliverable is a report detailing the significant findings and discussing the ways that this solution may be developed further and implemented in a clinical setting. The solution is a hydrogel bandage designed to deliver antibiotics directly to the wound site, while also offering protection and enhanced wound healing. The target population is patients suffering from skin conditions in an outpatient setting. The antibiotics of interest for this solution are clindamycin, doxycycline, and trimethoprim-sulfamethoxazole (co-trimoxazole), as they offer excellent treatment against gram-positive bacteria and methicillin-resistant Staphylococcus aureus. However, other broad-spectrum antibiotics could potentially be incorporated to protect against gram-negative bacteria. The design features a polyvinyl alcohol (PVA) hydrogel that has shown many properties that are beneficial to biomedical applications, including biocompatibility, flexibility, high drug-loading capacity, high absorption of wound exudate, increased promotion of wound healing, and more. Preliminary mathematical models of the hydrogel’s drug delivery behaviors are also included. Due to the scope and timeframe of this project, the majority of findings herein are based on research of prior literature instead of development of the novel device. Future directions would include further research and development of the mechanisms behind the device, creation of a physical prototype, experimental testing, and statistical analyses to verify device specifications and capabilities.

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2020-05

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NIPAAm co-DEAEMA Hydrogels Prolong Ketorolac Release

Description

NIPAAm co-DEAEMA hydrogels are a potential solution for sustained, local delivery of ketorolac tromethamine. Current methods of postoperative pain management, such as local anesthetics, NSAIDs, and opioids, can be improved by minimizing side effects while still effectively treating severe and

NIPAAm co-DEAEMA hydrogels are a potential solution for sustained, local delivery of ketorolac tromethamine. Current methods of postoperative pain management, such as local anesthetics, NSAIDs, and opioids, can be improved by minimizing side effects while still effectively treating severe and extreme pain. Though high doses of ketorolac can be toxic, sustained, local delivery via hydrogels offers a promising solution. Four ketorolac release studies were conducted using PNDJ hydrogels formulated by Sonoran Biosciences. The first two studies tested a range of JAAm concentration between 1.4 and 2.2 mole percent. Both had high initial release rates lasting less than 7 days and appeared to be unaffected by JAAm content. Tobramycin slowed down the release of ketorolac but was unable to sustain release for more than 6 days. Incorporating DEAEMA prolonged the release of ketorolac for up to 14 days with significant reductions in initial burst release rate. Low LCST of NIPAAM co-DEAEMA polymer is problematic for even drug distribution and future in vivo applications.

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Date Created
2020-05

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Acanthamoeba Prevalence in a Simulated Reclaimed Water Distribution System

Description

With dwindling water resources due to drought and other pressures, water utilities are seeking to tap into alternative water sources as a means to improve water sustainability. Reclaimed water consists of treated wastewater and is widely used for non-potable purposes,

With dwindling water resources due to drought and other pressures, water utilities are seeking to tap into alternative water sources as a means to improve water sustainability. Reclaimed water consists of treated wastewater and is widely used for non-potable purposes, such as irrigation, both agricultural and recreational. However, the reclaimed water distribution system can be subject to substantial regrowth of microorganisms, including opportunistic pathogens, even following rigorous disinfection. Factors that can influence regrowth include temperature, organic carbon levels, disinfectant type, and the time transported (i.e., water age) in the system. One opportunistic pathogen (OP) that is critical to understanding microbial activity in both reclaimed and drinking water distribution systems is Acanthamoeba. In order to better understand the potential for this amoeba to proliferate in reclaimed water systems and influence other OPs, a simulated reclaimed water distribution system was studied. The objective of this study was to compare the prevalence of Acanthamoeba and one of its endosymbionts, Legionella, across varying assimilable organic carbon (AOC) levels, temperatures, disinfectants, and water ages in a simulated reclaimed water distribution system. The results of the study showed that cooler temperatures, larger water age, and chlorine conditions yielded the lowest detection of Acanthamoeba gene copies per mL or cm2 for bulk water and biofilm samples, respectively.

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2016-12

Alginate Microsphere Drug Delivery Modeling

Description

Alginate microspheres have recently become increasingly popular in the realm of drug delivery for their biocompatibility, nontoxicity, inexpensiveness, among other factors. Recent strict regulations on microsphere size have drastically increased manufacturing cost and waste, even though the effect of size

Alginate microspheres have recently become increasingly popular in the realm of drug delivery for their biocompatibility, nontoxicity, inexpensiveness, among other factors. Recent strict regulations on microsphere size have drastically increased manufacturing cost and waste, even though the effect of size variance on drug delivery and subsequent performance is unclear. If sphere size variance does not significantly affect drug release profiles, it is possible that future ordinances may loosen tolerances in manufacturing to limit waste produced and expenditures. We use a mathematical model developed by Nickel et al. [12], to theoretically predict drug delivery profiles based on sphere size, and correlate the expected release with experimental data. This model considers diffusion as the key component for drug delivery, which is defined by Fick’s Laws of Diffusion. Alginate, chosen for its simple fabrication method and biocompatibility, was formed into microspheres with a modified extrusion technique and characterized by size. Size variance was introduced in batches and delivery patterns were compared to control groups of identical size. Release patterns for brilliant blue dye, the mock drug chosen, were examined for both groups via UV spectrometry. The absorbance values were then converted to concentration value using a calibration curve done prior to experimentation. The concentration values were then converted to mass values. These values then produced curves representing the mass of the drug released over time. Although the control and experimental values were statistically significantly different, the curves were rather similar to each other. However, when compared to the predicted release pattern, the curves were not the same. Unexpected degradation caused this dissimilarity between the curves. The predictive model was then adjusted to account for degradation by changing the diffusion coefficient in the code to a reciprocal first order exponent. The similarity between the control and experimental curves can insinuate the notion that size tolerances for microsphere production can be somewhat lenient, as a batch containing fifteen beads of the same size and one with three different sizes yields similar release patterns.

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Date Created
2022-05

Alginate Microsphere Drug Delivery Modeling

Description

Alginate microspheres have recently become increasingly popular in the realm of drug delivery for their biocompatibility, nontoxicity, inexpensiveness, among other factors. Recent strict regulations on microsphere size have drastically increased manufacturing cost and waste, even though the effect of

Alginate microspheres have recently become increasingly popular in the realm of drug delivery for their biocompatibility, nontoxicity, inexpensiveness, among other factors. Recent strict regulations on microsphere size have drastically increased manufacturing cost and waste, even though the effect of size variance on drug delivery and subsequent performance is unclear. If sphere size variance does not significantly affect drug release profiles, it is possible that future ordinances may loosen tolerances in manufacturing to limit waste produced and expenditures. We use a mathematical model developed by Nickel et al. [12], to theoretically predict drug delivery profiles based on sphere size, and correlate the expected release with experimental data. This model considers diffusion as the key component for drug delivery, which is defined by Fick’s Laws of Diffusion. Alginate, chosen for its simple fabrication method and biocompatibility, was formed into microspheres with a modified extrusion technique and characterized by size. Size variance was introduced in batches and delivery patterns were compared to control groups of identical size. Release patterns for brilliant blue dye, the mock drug chosen, were examined for both groups via UV spectrometry. The absorbance values were then converted to concentration value using a calibration curve done prior to experimentation. The concentration values were then converted to mass values. These values then produced curves representing the mass of the drug released over time. Although the control and experimental values were statistically significantly different, the curves were rather similar to each other. However, when compared to the predicted release pattern, the curves were not the same. Unexpected degradation caused this dissimilarity between the curves. The predictive model was then adjusted to account for degradation by changing the diffusion coefficient in the code to a reciprocal first order exponent. The similarity between the control and experimental curves can insinuate the notion that size tolerances for microsphere production can be somewhat lenient, as a batch containing fifteen beads of the same size and one with three different sizes yields similar release patterns.

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Date Created
2022-05