A. James Clark School of Engineering
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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
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Item PREPARATION OF A NANOSUSPENSION OF THE PHOTOSENSITIZER VERTEPORFIN FOR PHOTODYNAMIC AND LIGHT-INDEPENDENT THERAPY IN GLIOBLASTOMA(2024) Quinlan, John Andrew; Huang, Huang-Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Photodynamic therapy (PDT) using verteporfin (VP) has treated ocular disease for over 20 years, but recent interest in VP’s light-independent properties has reignited interest in the drug, particularly in glioblastoma (GBM) (NCT04590664). Separate efforts to apply PDT to GBM using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) have also garnered attention (NCT03048240), but, unfortunately, clinical trials using 5-ALA-induced PpIX-PDT have yet to yield a survival benefit. Previous studies have shown VP to be a superior PDT agent than 5-ALA-induced PpIX. Our lab has shown that 690 nm light activates VP up to 2 cm into the brain, while 635 nm light only activates PpIX at depths <1 cm into the brain. Additionally, VP is a more effective photosensitizer than PpIX because it has a higher singlet oxygen yield and is active in the vasculature as well as target tumor cells. However, the hydrophobicity of VP limits effective delivery of the drug to the brain for treatment of GBM.In this context, this thesis aims to re-evaluate the delivery method for VP. VP traditionally requires lipids for delivery as Visudyne. Recent shortages of Visudyne and potential drawbacks of liposomal carriers motivated our development of a carrier-free nanosuspension of VP, termed NanoVP. Previous work has shown that cellular uptake of VP is greater when delivered as NanoVP rather than liposomal VP, resulting in improved cell killing after light activation. This thesis builds on this previous work by (1) evaluating synthesis and storage parameters for NanoVP, (2) determining the pharmacokinetics, biodistribution, and brain bioavailability of NanoVP, and (3) evaluating the potential efficacy of NanoVP as a PDT and a chemotherapy agent, and by supporting development of a zebrafish model of the blood-brain barrier (BBB) for mechanistic studies of improved drug delivery to the brain.Item Engineering Cell Surfaces with Polyelectrolyte Materials for Translational Applications(MDPI, 2017-01-28) Zhang, Peipei; Bookstaver, Michelle L.; Jewell, Christopher M.Engineering cell surfaces with natural or synthetic materials is a unique and powerful strategy for biomedical applications. Cells exhibit more sophisticated migration, control, and functional capabilities compared to nanoparticles, scaffolds, viruses, and other engineered materials or agents commonly used in the biomedical field. Over the past decade, modification of cell surfaces with natural or synthetic materials has been studied to exploit this complexity for both fundamental and translational goals. In this review we present the existing biomedical technologies for engineering cell surfaces with one important class of materials, polyelectrolytes. We begin by introducing the challenges facing the cell surface engineering field. We then discuss the features of polyelectrolytes and how these properties can be harnessed to solve challenges in cell therapy, tissue engineering, cell-based drug delivery, sensing and tracking, and immune modulation. Throughout the review, we highlight opportunities to drive the field forward by bridging new knowledge of polyelectrolytes with existing translational challenges.Item Effect of a Cationic Surfactant on Microemulsion Globules and Drug Release from Hydrogel Contact Lenses(MDPI, 2019-06-06) Torres-Luna, Cesar; Hu, Naiping; Koolivand, Abdollah; Fan, Xin; Zhu, Yuli; Domszy, Roman; Yang, Jeff; Yang, Arthur; Wang, Nam SunThe present study evaluates the in vitro release of diclofenac sodium (DFNa) from contact lenses based on poly-2-hydroxyethyl methacrylate (pHEMA) hydrogels containing an embedded microemulsion to extend release duration. The oil (ethyl butyrate)-in-water microemulsion systems are prepared with two non-ionic surfactants, Brij 97 or Tween 80, together with a long-alkyl chain cationic surfactant, cetalkonium chloride (CKC). Without CKC, Brij 97 or Tween 80-based microemulsions showed average droplet sizes of 12 nm and 18 nm, respectively. The addition of CKC decreased the average droplet sizes to 2–5 nm for both non-ionic surfactants. Such significant reduction in the average droplet size corresponds to an increase in the DFNa release duration as revealed by the in vitro experiments. Contact lens characterization showed that important properties such as optical transparency and water content of Brij 97-based contact lenses with cationic microemulsions was excellent. However, the optical transparency of the corresponding Tween 80 based contact lenses was unsatisfactory. The results indicate that cationic microemulsion-laden contact lenses can benefit from combinatory effects of microemulsions and cationic surfactant at low CKC weight percentage, e.g., with the release of 70% of the drug in 45, 10, and 7 h for B97-CKC-0.45%, CKC-0.45%, and control lenses, respectively. However, the microemulsion effect on extending DFNa release became negligible at the highest CKC weight percentage (1.8%).Item Formation of Drug-Participating Catanionic Aggregates for Extended Delivery of Non-Steroidal Anti-Inflammatory Drugs from Contact Lenses(MDPI, 2019-10-10) Torres-Luna, Cesar; Koolivand, Abdollah; Fan, Xin; Agrawal, Niti R.; Hu, Naiping; Zhu, Yuli; Domszy, Roman; Briber, Robert M.; Wang, Nam Sun; Yang, ArthurThis paper focuses on extending drug release duration from contact lenses by incorporating catanionic aggregates. The aggregates consist of a long-chain cationic surfactant, i.e., cetalkonium chloride (CKC), and an oppositely charged anti-inflammatory amphiphilic drug. We studied three non-steroidal anti-inflammatory (NSAID) drugs with different octanol–water partition coefficients; diclofenac sodium (DFNa), flurbiprofen sodium (FBNa), and naproxen sodium (NPNa). Confirmation of catanionic aggregate formation in solution was determined by steady and dynamic shear rheology measurements. We observed the increased viscosity, shear thinning, and viscoelastic behavior characteristic of wormlike micelles; the rheological data are reasonably well described using a Maxwellian fluid model with a single relaxation time. In vitro release experiments demonstrated that the extension in the drug release time is dependent on the ability of a drug to form viscoelastic catanionic aggregates. Such aggregates retard the diffusive transport of drug molecules from the contact lenses. Our study revealed that the release kinetics depends on the CKC concentration and the alkyl chain length of the cationic surfactant. We demonstrated that more hydrophobic drugs such as diclofenac sodium show a more extended release than less hydrophobic drugs such as naproxen sodium.Item Effect of Carbon Chain Length, Ionic Strength, and pH on the In Vitro Release Kinetics of Cationic Drugs from Fatty-Acid-Loaded Contact Lenses(MDPI, 2021-07-10) Torres-Luna, Cesar; Hu, Naiping; Domszy, Roman; Fan, Xin; Yang, Jeff; Briber, Robert M.; Wang, Nam Sun; Yang, ArthurThis paper explores the use of fatty acids in silicone hydrogel contact lenses for extending the release duration of cationic drugs. Drug release kinetics was dependent on the carbon chain length of the fatty acid loaded in the lens, with 12-, 14- and 18-carbon chain length fatty acids increasing the uptake and the release duration of ketotifen fumarate (KTF) and tetracaine hydrochloride (THCL). Drug release kinetics from oleic acid-loaded lenses was evaluated in phosphate buffer saline (PBS) at different ionic strengths (I = 167, 500, 1665 mM); the release duration of KTF and THCL was decreased with increasing ionic strength of the release medium. Furthermore, the release of KTF and THCL in deionized water did not show a burst and was significantly slower compared to that in PBS. The release kinetics of KTF and THCL was significantly faster when the pH of the release medium was decreased from 7.4 towards 5.5 because of the decrease in the relative amounts of oleate anions in the lens mostly populated at the polymer–pore interfaces. The use of boundary charges at the polymer–pore interfaces of a contact lens to enhance drug partition and extend its release is further confirmed by loading cationic phytosphingosine in contact lenses to attract an anionic drug.Item BIOMATERIALS REPROGRAM ANTIGEN PRESENTING CELLS TO PROMOTE ANTIGEN-SPECIFIC TOLERANCE IN AUTOIMMUNITY(2023) Eppler, Haleigh B; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The immune system is tightly regulated to balance the killing of disease-causing organisms while protecting host tissue from accidental damage. When this balance is disrupted, immune dysfunctions such as autoimmune diseases occur. Autoimmune diseases like type 1 diabetes and multiple sclerosis (MS) develop when self-tissue is mistakenly attacked and damaged by immune cells. For example, during MS, the immune system mistakenly attacks the myelin sheath that insulates neurons, causing loss of motor function and burdening patients and caregivers. Recent advances in immunotherapies offer exciting new treatments; however, even monoclonal antibody therapies cannot differentiate between healthy and disease-causing cells. Biomaterials provide powerful capabilities to help address these shortcomings. In particular, control over the concentration, duration, location, and combination of signals that are received by immune cells could be transformative in developing more selective immunotherapies that are safe and promote antigen-specific tolerance during autoimmune disease. This dissertation uses two biomaterial approaches to deliver regulatory cargo to antigen presenting cells (APCs). An important APC function is to detect disease-causing organisms by sensing pathogen associated molecular patterns (PAMP) through motif-specific receptors. CpG rich motifs are PAMPs that activate toll-like receptor 9 (TLR9) on DCs and B cells. TLR9 signaling activates B cells and DCs. In MS, TLR9 signaling is aberrantly elevated on certain DCs contributing to systemic inflammation. In MS, B cells signaling through the TLR9 pathwway induced the expression of more inflammatory cytokines as compared to B cells from healthy controls. Controlling this overactive TLR signaling restrains inflammation and is a possible tolerogenic therapeutic approach in MS. The first part of this dissertation uses biomaterials-based polyelectrolyte multilayers (PEMs) to deliver tunable amounts of GpG – an oligonucleotide that inhibits TLR9 signaling – to dendritic cells (DCs). These studies demonstrate that PEMs inhibit DC activation and reduce pathway-specific inflammatory signaling. Furthermore, this work demonstrates that these changes to DCs promote tolerance in downstream T cell development as shown by increasing regulatory T cells. These studies demonstrate this biomaterial delivery system selectively inhibits TLR signaling and DC activation. These changes to DCs promote myelin-specific T cells to adopt a regulatory phenotype, demonstrating a potential approach to developing tolerance inducing antigen-specific immunotherapies for MS. The second part of this dissertation uses a degradable polymer microparticle (MP) system to control the local microenvironment of lymph nodes (LNs). LNs are key sites in the development of immune responses. LNs are composed of different microdomains that coordinate immune cell interactions such as germinal centers (GCs), where B cells develop. These MPs are loaded with myelin self-antigen (MOG35-55) and an mTOR inhibitor, rapamycin (rapa). The MPs are designed to be too large to passively diffuse from the LNs; instead, they slowly degrade releasing encapsulated immune cues to immune cells within the lymph node (LN). Our previous work demonstrates this treatment approach induces antigen-specific tolerance in a preclinical model of MS, but the role of APCs – including DCs and B cells - has not been elucidated. This dissertation reveals that MP treatment alters key LN structural components responsible for interactions between cells in GCs. In addition, MPs alter interactions between B cells/DCs and T cells, as measured by presentation of encapsulated antigen and inhibition of T cell costimulatory molecules by encapsulated rapa. These changes inhibit myelin-specific T cell proliferation and promote regulatory T cells. Finally, B cells from MOG/rapa and MOG MP treated lymph nodes transfer myelin-specific efficacy to mice induced with EAE. These findings illustrate how LN and cellular processes can be regulated by MPs to promote myelin-specific tolerance informing the development of myelin-specific immunotherapies for MS. Together, this body of work provides insight into how biomaterials can be designed to exploit native LN and immune cell functions in the design of next-generation approaches to safely induce myelin-specific tolerance during MS or other autoimmune diseases.Item Tissue-Targeted Drug Delivery Strategies to Promote Antigen-Specific Immune Tolerance(Wiley, 2022-11-23) Rui, Yuan; Eppler, Haleigh B.; Yanes, Alexis A.; Jewell, Christopher M.During autoimmunity or organ transplant rejection, the immune system attacks host or transplanted tissue, causing debilitating inflammation for millions of patients. There is no cure for most of these diseases. Further, available therapies modulate inflammation through nonspecific pathways, reducing symptoms but also compromising patients’ ability to mount healthy immune responses. Recent preclinical advances to regulate immune dysfunction with vaccine-like antigen specificity reveal exciting opportunities to address the root cause of autoimmune diseases and transplant rejection. Several of these therapies are currently undergoing clinical trials, underscoring the promise of antigen-specific tolerance. Achieving antigen-specific tolerance requires precision and often combinatorial delivery of antigen, cytokines, small molecule drugs, and other immunomodulators. This can be facilitated by biomaterial technologies, which can be engineered to orient and display immunological cues, protect against degradation, and selectively deliver signals to specific tissues or cell populations. In this review, some key immune cell populations involved in autoimmunity and healthy immune tolerance are described. Opportunities for drug delivery to immunological organs are discussed, where specialized tissue-resident immune cells can be programmed to respond in unique ways toward antigens. Finally, cell- and biomaterial-based therapies to induce antigen-specific immune tolerance that are currently undergoing clinical trials are highlighted.Item Thermomechanical Soft Actuator for Targeted Delivery of Anchoring Drug Deposits to the GI Tract(Wiley, 2022-12-04) Levy, Joshua A.; Straker, Michael A.; Stine, Justin M.; Beardslee, Luke A.; Borbash, Vivian; Ghodssi, RezaCurrent systemic therapies for inflammatory gastrointestinal (GI) disorders are unable to locally target lesions and have substantial systemic side effects. Here, a compact mesoscale spring actuator capable of delivering an anchoring drug deposit to point locations in the GI tract is demonstrated. The mechanism demonstrated here is intended to complement existing ingestible capsule-based sensing and communication technologies, enabling treatment based on criteria such as detected GI biomarkers or external commands. The 3D-printed actuator has shown on command deployment in 14.1 ± 3.0 s, and a spring constant of 25.4 ± 1.4 mN mm−1, sufficient to insert a spiny microneedle anchoring drug deposit (SMAD) into GI tissue. The complementary SMAD showed a 22-fold increase in anchoring force over traditional molded microneedles, enabling reliable removal from the actuator and robust prolonged tissue attachment. The SMAD also showed comparable drug release characteristics (R2 = 0.9773) to penetrating molded microneedles in agarose phantom tissue with a drug spread radius of 25 mm in 168 h. The demonstrated system has the potential to enable on command delivery and anchoring of drug-loaded deposits to the GI mucosa for sustained treatment of GI inflammation while mitigating side effects and enabling new options for treatment.Item LIGHT ACTIVATABLE PURE PORPHYRIN NANOPARTICLES FOR THE PHOTODYNAMIC OPENING OF THE BLOOD-BRAIN BARRIER AND GLIOBLASTOMA TREATMENT(2022) Inglut, Collin Thomas; Huang, Huang Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Glioblastoma (GBM) consistently recurs due to infiltrating cancer cells that cannot be removed by surgery and chemotherapy. The diffusive nature of GBM makes complete surgical resection unsafe, and the intact blood-brain barrier (BBB) prevents the penetration and accumulation of nearly all chemotherapy in infiltrative GBM cells. Existing BBB opening strategies are often associated with increased risk of edema, hemorrhage, or neurotoxicity and thus have limited clinical success. Photodynamic therapy (PDT) is a photochemistry-based treatment modality that has shown promise in treating GBM and opening the BBB in the clinic. In fact, a single adjunctive dose of PDT has been shown to add as much as 18 months to patient survival. However, the full potential of PDT is limited by the light activation depth of the ‘gold standard’ pro-drug photosensitizer, 5-aminolevulinic acid (5-ALA). In addition, large doses of PDT can result in edema and neurotoxicity. To address these issues, our lab has developed a photodynamic priming (PDP) strategy using the verteporfin (VP) photosensitizer, which operates at low optical energy to enhance intratumoral drug accumulation without damaging the healthy brain tissues. Unfortunately, VP is hydrophobic and requires liposomal encapsulation for intravenous administration, which can alter the photosensitizers cellular pharmaceutics. Here, we develop and compare a novel carrier-free pure-photosensitizer nanoparticle to a clinically relevant liposomal formulation.This dissertation covers a complementary, four-pronged approach to enhance drug delivery to brain tumors and treat GBM: (1) Understand the photoactivation depth of clinically relevant photosensitizers in the rodent brain for the targeting of infiltrative GBM cells. (2) Explore the mechanisms of photochemistry-induced BBB opening. (3) Engineer light-activable nanotechnology that can open the BBB, improve drug delivery, and eradicate GBM cells. And (4) develop a high-throughput model to examine the BBB integrity and efflux transporter function. The central hypothesis of this dissertation is the delivery of photoactivatable pure-photosensitizer nanoparticles can eradicate GBM cells and enhance drug delivery to microscopic GBM tumors.Item GENETICALLY ENGINEERED PROBIOTICS FOR DIAGNOSTICS AND DRUG DELIVERY: APPLICATIONS FOR CROHN’S DISEASE(2018) McKay, Ryan; Bentley, William E; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In the history of medicine, therapies have evolved while their mode of delivery has remained largely static. Generally, the active ingredient is formulated with an excipient to confer stability, and is ultimately delivered orally or intravenously in most applications. Crohn’s disease (CD), an illness with increasing global prevalence characterized by chronic inflammation of the intestines, is commonly treated with intravenously administered biologics. When these medicines spread throughout the body, only a small percentage acts at the desired site and side effects often arise. Thus, a targeted system is desired to localize treatment at sites of colonic inflammation. There is an entire field dedicated to localized delivery that typically employs drug-laden particles or capsules that can respond to local chemical or physical cues. We believe that bacteria can be “programmed” to respond analogously, and ultimately synthesize and deliver therapeutics. Nitric oxide (NO) levels are elevated at sites of intestinal inflammation, and thus serves as a targeting molecule that can attract programmed bacteria via a process called pseudotaxis. This is achieved by rewiring the native motility circuits of bacteria to respond to high NO levels. Additionally, localized treatment is attained by an NO- specific response whereby the designed bacteria produce and secrete a human protein reported to reduce inflammation in CD patients. This system may improve CD treatment via: 1) site-specific targeting to minimize side effects and increase efficacy, 2) in situ synthesis of the therapeutic avoids payload loss in the digestive tract and manufacturing obstacles associated with biologics, 3) probiotics are reported to provide innate benefits to CD patients, and 4) oral delivery is preferred by patients versus intravenous. We have also developed probiotics that fluoresce in response to NO which may serve as an ingestible biosensor for CD. We believe these reporter probiotics can assist in the diagnosis of CD by utilizing visualization of bacteria in a stool sample to reduce the need for invasive colonoscopies and biopsies. Overall, we have developed a platform of probiotic cells that respond to NO with applications for Crohn’s disease in mind, translating to noninvasive methods for both the diagnosis and treatment of CD.