PhD, University of Cincinnati, 2018, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

Controlled release oral dosage form offers great advantages over conventional dosage form by providing steady drug plasma concentration, decreasing the frequency of administration, and providing enhanced patient compliance. However, orally ingested tablet is exposed to varying pH conditions and fluctuating mechanical agitations during its travel through the gastrointestinal tract (GIT). Selection of materials that provide controlled release mechanism to the oral dosage form is important as they can a) minimize drug release rate fluctuations for ionizable drugs during its travel along the changing pH environment of the GIT and b) maintain the release rate mechanism even when subjected to the physiological mechanical agitation forces. To examine these two important requirements, matrix tablets prepared using low glass transition temperature (Tg) silicone pressure sensitive adhesive (PSA) were evaluated and compared with matrix tablets prepared using high Tg ethyl cellulose (EC). Specifically, the effect of dissolution medium pH on drug release from binary tablets consisting of the polymer and ionizable model drugs verapamil hydrochloride and diclofenac sodium was studied using USP dissolution apparatus (without mechanical stress). The effect of simulated physiological mechanical stress agitation on drug release was studied using dissolution stress test apparatus for non-ionizable model drug acetaminophen. Mechanical properties, physical structures, electrical resistance, water uptake, and contact angle of pure polymer films and of matrix tablets were studied to understand the relationships of these factors to drug release. Our study indicated that increasing polymer amount decreased drug release rate from both silicone PSA and EC tablets using USP dissolution apparatus. However, silicone PSA tablets showed lower friability compared to EC tablets. The application of physiological simulated mechanical stress affected drug release from high Tg EC tablets that resulte (open full item for complete abstract)

Committee: Kevin Li Ph.D. (Committee Chair); Pankaj Desai Ph.D. (Committee Member); Sergey Grinshpun Ph.D. (Committee Member); Gerald Kasting Ph.D. (Committee Member); Gary Kelm Ph.D. (Committee Member); R. Randall Wickett Ph.D. (Committee Member) Subjects: Pharmaceuticals

PhD, University of Cincinnati, 2021, Engineering and Applied Science: Chemical Engineering

The complex structure of the eye and the blood-ocular barriers have impeded the drug delivery via conventional administration routes. Innovative on-demand drug delivery system targeted to the eye has been considered as a promising strategy and received great attention in recent years. Hence, we investigated drug nanocarriers which can be activated by near infrared (NIR) laser to release the payload in a controlled manner over a long period. We first evaluated gold nanorod (AuNR)-coated perfluorocarbon (PFC) nanodroplets with two different PFC cores, perfluoropentane (C5F12, PF5) and perfluorohexane (C6F14, PF6). These PFC nanodroplets undergo a liquid-to-gas phase-transition and “burst” to release the payload with NIR laser. The size, encapsulation efficiency, number density, and cytotoxicity were similar between PF5 and PF6 nanodroplets. The feasibility of both PF5 and PF6 nanodroplets on suppressing the in vitro angiogenesis was demonstrated. PF6 nanodroplets performed better in long-term stability at physiological conditions but showed lower phase-transition efficiency than PF5. Subsequently, AuNR-coated nanosized liposomes (diameter˜100 nm) were studied with a focus on structure reversibility. Laser-triggered drug release tests demonstrated that these AuNR-liposomes released drug repetitively with multiple irradiation cycles (5sec per cycle, 1.1W) and the released amounts were proportional to cycle numbers. It was also proved that AuNR prominently increased the temperature of lipid bilayers via plasmonic heating effect and facilitated drug-releasing when irradiated by NIR laser. In addition, the number density of liposomes remained the same after laser irradiation. These results implied that the structures of AuNR-liposomes are likely to be reversible after exposure to NIR laser. Next, we fabricated micron-sized (diameter˜1.5 µm) AuNR-liposomes by reverse-phase evaporation method. Similarly, these micron-sized liposomes showed repetitive drug releases wi (open full item for complete abstract)

Committee: Yoonjee Park Ph.D. (Committee Chair); Jonathan Nickels (Committee Member); Winston Kao Ph.D. (Committee Member); Gregory Beaucage Ph.D. (Committee Member) Subjects: Chemical Engineering

Doctor of Philosophy, Case Western Reserve University, 2020, Biomedical Engineering

Glioblastoma multiforme (GBM) is resilient to the current standard of care treatment of surgical resection followed by concurrent radiotherapy and temozolomide (TMZ) chemotherapy. GBM patient responses are poor and variable, resulting in more than 90% tumor recurrence and grim survival. The high mortality of GBM is attributed to its invasive peripheral growth, partially intact blood-brain barrier (BBB), regions of hypoxia, and high cellular heterogeneity that includes brain tumor initiating cells (BTICs) and immunosuppressive cells. These features of GBM work together to restrict the delivery of drugs throughout the tumor, suppress immune recognition of tumor cells, and facilitate tumor progression. Nanoparticles are well-suited to address limitations associated with the treatment of GBM by enhancing drug delivery to the tumor and reducing side effects. The overall objective of the work in this dissertation is to develop systemically administered nanoparticles that overcome barriers to drug distribution and cellular heterogeneity in GBM to improve therapeutic responses. In murine GBM models, the effective delivery of Doxorubicin (DOX) chemotherapy, BTIC inhibitor, and immune-stimulating agonists were evaluated using two distinct mesoporous silica nanoparticles (MSNs): 1) the Fe@MSN particle and 2) the immuno-MSN particle. First, drug release from the Fe@MSN particle was triggered using an external radiofrequency (RF) field to enhance the distribution of DOX and/or BTIC inhibitor across the partially intact BBB and into the tumor interstitium. The effective delivery of drugs facilitated by Fe@MSN particles translated into suppressed GBM growth, depleted stem-like cell phenotypes in hypoxic regions, and prolonged or cancer-free survival. Second, towards further improving GBM treatment strategies, the immuno-MSN particle delivered immune-stimulating agonists to dysfunctional immune cells in GBM to reverse the effects of immunosuppression. Immuno-MSN particles facilitat (open full item for complete abstract)

Committee: Efstathios Karathanasis Ph.D. (Advisor); Agata Exner Ph.D. (Advisor); Dominique Durand Ph.D. (Committee Chair); Jennifer Yu M.D., Ph.D. (Committee Member) Subjects: Biomedical Engineering; Immunology

PhD, University of Cincinnati, 2017, Engineering and Applied Science: Chemical Engineering

Cancer is still a major threat to public health worldwide. Thanks to the extensive studies in cancer biology and growing understanding in cancer, many novel and effective therapeutic agents and drug combinations have been discovered and designed. However, many of them are challenged in reaching their targeted site. Nano-scaled drug carriers that target and deliver therapeutic agents to the sites of diseases have shown great promises in cancer treatment. As a starting point, we designed a human epidermal growth factor receptor 2 (HER-2) targeting pH sensitive nanoparticle combining the advantages of polyhistidine (PHis) and Herceptin. This nanoparticle contains a pH sensitive hydrophobic core in which chemotherapeutic drug is loaded and hydrophilic layer which stabilizes the whole nanoparticle while providing active targeting to HER-2. This nanoparticle shows a pH triggered drug release (i.e. fast drug release at acidic condition and sustained release at physiological condition), a capability of endosomal escape which allows delivery of cargo to cytoplasm, and HER-2 targeting which enhances cellular uptake of the nanoparticle. This work is described in detail in chapter 2. In addition, there are growing needs in delivery of micro RNA inhibitor (miRi) for RNA interferences (RNAi). In chapter 3, a novel lipid coated calcium phosphate miRi complex was made to address poor encapsulation of hydrophilic RNA molecules in hydrophobic polymeric core for co-delivery of molecules with different physicochemical properties. This novel complex was co-encapsulated with paclitaxel in nanoparticle to achieve co-delivery. The co-delivery nanoparticle was found effective in regulating gene expression in vitro. The synergistic effects of co-delivery of miRi and paclitaxel were confirmed in culture cells. In the last part of the study, chapter 4-5 were focused on developing drug delivery systems address the unmet needs for systematic sequential delivery of combination th (open full item for complete abstract)

Committee: Joo Youp Lee Ph.D. (Committee Chair); Chia Chi Ho Ph.D. (Committee Member); Yoonjee Park Ph.D. (Committee Member); Susan Waltz Ph.D. (Committee Member) Subjects: Chemical Engineering

PhD, University of Cincinnati, 2008, Engineering : Biomedical Engineering

Ultrasound contrast agents (UCAs) stabilized against gas diffusion in the bloodstream yet triggered for destruction by specially designed pulses of ultrasound are desirable for clinical applications in vivo. Echogenic liposomes (ELIP) are nano-sized phospholipid vesicles that contain both gas and fluid. With incorporation of a drug, such as recombinant tissue-Plasminogen Activator (rt-PA), these liposomes may be able to deliver a high local concentration of rt-PA by site-specific delivery of the drug directly to thrombi, with a lower systemic dose overall. Therefore, it is necessary to assess ELIP stability and destruction thresholds in vitro before their application in clinical diagnostic imaging and targeted drug delivery. Several researchers have used optical and acoustic techniques to identify three dominant mechanisms of UCA destruction; static diffusion, acoustically driven diffusion, and fragmentation (Chomas et al, 2001a; Bouakaz et al., 2005; Porter et al., 2006). We have developed new acoustic techniques to assess these three destruction thresholds of an FDA-approved UCA, Optison®, and unmodified ELIP utilizing a clinical diagnostic ultrasound scanner (Porter et al., 2006; Smith et al., 2007a). Recently, in vitro studies were performed with an innovative drug-encapsulated contrast agent, rt-PA-loaded ELIP. Their stability during contrast imaging was assessed using low output B-mode pulses and rt-PA was found to remain associated with the lipid bilayer. They were also fragmented using color Doppler pulses for determination of drug delivery by spectrophotometrically measuring the concentration of rt-PA released (Smith et al., 2007b). The primary objective of this dissertation was to characterize a novel echogenic lipid-based drug-encapsulated UCA using a diagnostic ultrasound scanner for its potential use in both image-guided and ultrasound-triggered drug delivery.

Committee: Christy K. Holland PhD (Committee Chair); William S. Ball MD (Committee Member); George J. Shaw MD, PhD (Committee Member); T. Douglas Mast PhD (Committee Member) Subjects: Acoustics; Biomedical Research; Engineering; Health; Pharmaceuticals; Physics; Radiology; Scientific Imaging

Doctor of Philosophy, Case Western Reserve University, 2011, Biomedical Engineering

An in situ forming implant (ISFI) is a drug delivery vehicle that can be injected as a liquid solution that subsequently solidifies into a controlled release polymer matrix when exposed to an aqueous environment. The injectable nature of these implant devices makes them particularly suitable for adjuvant therapy with minimally invasive techniques for solid tumor treatment. The initial drug release dynamics from an ISFI depend on many factors, which limit its potential clinical application. To elucidate the process of ISFI formation and its corresponding effect on drug release, this thesis presents a combination of experimental studies and mathematical modeling of ISFI structure and function. The effects of varying formulation parameters including drug loading, surfactant/excipient additives, and polymer molecular weight (Mw) on drug release were determined in vitro. A mathematical model was developed to track the mass concentration dynamics of different components present in the experimental system. To describe and predict drug release under a variety of conditions, this mathematical model was based on mechanisms of mass transport and reaction processes. Key model parameters were estimated by least-squares fitting of the model output to experimental data. In vivo studies were conducted to examine implant formation and release behavior in a variety of tissue environments including the subcutaneous space as well as necrotic, non-necrotic, and ablated tumor tissues. These experimental studies quantify the significant effect of implant formation on drug release, which are highly dependent on formulation properties. Model simulations successfully fit experimental data under different in vitro release scenarios. ISFI studies in vivo, however, demonstrated significantly different responses than from in vitro studies. This suggests that implant formation and drug release depend on tissue compliance and implant compressibility.

Committee: Agata Exner PhD (Advisor); Gerald Saidel PhD (Committee Chair); Ruth Keri PhD (Committee Member); John Haaga MD (Committee Member); Horst von Recum PhD (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, Case Western Reserve University, 2010, Macromolecular Science and Engineering

Polyhedral oligosilsesquioxane (POSS)-based biodegradable polymers were investigated as stent coating for drug delivery from drug-eluting stents and as polymeric scaffold for fully bioabsorbable stents. A highly efficient and precise electrospraying technique, one of the electrostatic processing techniques, was developed for the stent coating application. The roughness of stent coatings produced was varied conveniently by the electrospraying technique utilizing different electrospraying mode or Coulombic fission, and was further modified using post-treatments of pure solvent electrospraying or vapor welding. Abluminal stent coatings were achieved utilizing the targeting nature of the charged electrospraying droplets to avoid luminal coating on stents by applying nonconductive materials temporarily contacting the inner surface of the stents.Long-standing questions of paclitaxel (PTx)-polymer blend miscibility and interactions were studied for particular polymer blends using characterization methods. It was found that paclitaxel is amorphous in all proportions in the blends of paclitaxel with POSS-based thermoplastic polyurethanes (POSS TPUs), and serves as an antiplasticizer by increasing the blend Tg gradually from the polymer Tg up to the substantially higher Tg of amorphous paclitaxel. The polyethylene glycol (PEG) segment incorporated in POSS TPUs exhibited specific hydrogen-bonding interactions with the paclitaxel and promoted the miscibility in the blends. Highly adjustable release of paclitaxel was achieved from both thermoplastic stent coatings utilizing P(DLLA-co-CL)-based POSS TPUs, and thermoset stent coatings employing PLGA-POSS end-linked thiol-ene network. Using a newly-developed drug release approximation model describing the entire drug release profile, paclitaxel release mechanisms from these biodegradable stent coatings were interpreted quantitatively, including the effects of polymer glass transition temperature, polymer initial molecular weight, (open full item for complete abstract)

Committee: Patrick T. Mather (Advisor); Gary E. Wnek (Committee Member); Lei Zhu (Committee Member); Horst A. von Recum (Committee Member) Subjects: Biomedical Research; Polymers

Doctor of Philosophy, Case Western Reserve University, 2022, Biomedical Engineering

Vascular pathologies, such as myocardial infarction, stroke, and pulmonary embolism, are major causes of morbidities and mortalities in the US and globally. A primary event in such pathologies is the formation of an occlusive clot in the blood vessel, preventing blood flow. Current clinical treatment involves intravascular administration of plasminogen activators (PA) for rapid recanalization of the blood vessel. However, systemic administration of such drugs can have off-target drug action, which affects hemostatic capabilities and can lead to substantial hemorrhagic risks. Therefore, there is significant clinical interest in strategies for enhanced drug delivery to clots while minimizing systemic effects. One such strategy is the utilization of drug-carrying nanoparticles surface-decorated with clot-binding ligands. To this end, I hypothesize that thrombolytic drug-loaded nanoparticles delivered intravenously that can bind and anchor to the clot site under flow and undergo site-specific degradation for localized payload release can enhance targeted thrombolytic efficacy while minimizing off-target side effects. To test this hypothesis, I have developed multiple lipid-based nanoparticle platforms for targeted thrombolysis. For the first technology, a lipid nanovesicle was developed that could protect encapsulated thrombolytic drug streptokinase from off-target action, anchor to platelets in the clot, and allow localized drug release via clot-relevant enzyme phospholipase A2. This platform demonstrated similar levels of thrombolysis while minimizing systemic hemorrhaging in a FeCl3-induced thrombosis mouse model. The second technology improved upon the clot-targeting aspect, demonstrating that combination targeting of both platelets and fibrin enhanced clot-anchorage compared to targeting either clot component individually. Finally, in the last technology, I designed a thrombin-responsive nanoparticle platform that binds to both platelets and fibrin, encapsulated pl (open full item for complete abstract)

Committee: Anirban Sen Gupta (Advisor); Kandice Kottke-Marchant (Committee Member); Xin Yu (Committee Member); Steven Eppell (Committee Chair) Subjects: Biomedical Engineering

Master of Science in Engineering, Youngstown State University, 2022, Department of Civil/Environmental and Chemical Engineering

Precise control over the release of drugs from wearable bioelectronic devices on wound sites, such as quantity and timing, is highly desirable in order to optimize wound treatment. The aim of this study is to obtain and characterize an electro-responsive ferrocene-chitosan/alginate polyelectrolyte complex (PEC) hydrogel that can be used as a smart wound dressing. First, chitosan/alginate PEC hydrogel was obtained as a control and characterized in terms of chemical properties and drug release kinetics. Natural chitosan (CHI) was chemically conjugated with ferrocene (Fc) moieties to create Fc-CHI. The Fc-CHI was interacted with alginate (ALG) to form Fc-CHI/ALG PEC through electrostatic interaction. The turbidity test was performed to find the optimum ratio between the Fc-CHI and ALG, thus the stoichiometric PEC hydrogel. The PEC hydrogel was characterized by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR), Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectrometer (EDS), in addition to the swelling behavior and gel content tests. Comparative analysis of the ATR-FTIR spectra of CHI, Fc-CHI, ALG, and their mixtures indicated the formation of a polyelectrolyte complex. The SEM images showed the porosity of the PEC. The EDS analysis proved the incorporation of the Fc into the CHI by the appearance of the Fc peaks in the analysis. The PEC hydrogel showed a comparative swelling percentage to be 4400% and also showed excellent stability, proved by almost 100% gel content after incubation in phosphate buffer saline (PBS) solution. To demonstrate the drug delivery potential of the developed PEC-based wound dressing, fluorescence (FITC) and FITC-Dextran were used as model drugs. First, the drug loading and release kinetics of the PEC were studied in solution. In three days, about 83% and 61% were released of the FITC, and FITC-Dextran, respectively in PBS solution. Secondly, the drug release properties on the phantom skin surface (a (open full item for complete abstract)

Committee: Byung-Wook Park PhD (Advisor); Pedro Cortes PhD (Committee Member); Holly Martin PhD (Committee Member) Subjects: Biomedical Engineering; Chemical Engineering; Materials Science

Master of Science, University of Toledo, 2019, Bioengineering

Musculoskeletal tissue injuries affect around 1 in 3 Americans and 1.7 billion people worldwide. This is a huge economic burden, costing an estimated $120 billion in the US alone. With limited success from surgery or subcutaneous injections of medicine, where only temporary relief or complications can occur, alternative measures should be explored. Injectable biologically-loaded hydrogels are one avenue and act as drug delivery systems. They provide a minimally invasive approach to release biologics in a sustained and controlled manner to provide long-lasting relief without toxic effects and with less risk of surgical complications. In this study, the immunological application of a previously-developed nanofibrous PCL-interspersed collagen hydrogel, (PNCOL) was explored by loading PNCOL with the cytokine IL-4 and identifying its effect upon macrophages. Furthermore, the effect of a simulated digestive inflammatory environment (DIE) had upon protein release kinetics as well as scaffold integrity were characterized. Genipin crosslinking was then explored to improve scaffold resistance to degradation, and an optimal genipin concentration was identified to impart sufficient scaffold crosslinking, increased mechanical strength, and a prolonged release profile, with minimal cytotoxic effects. Lastly, the immunomodulatory effect of IL-4 released from crosslinked and uncrosslinked scaffolds were investigated through identifying the impact of IL-4 on macrophage differentiation. The IL-4 released from PNCOL polarized macrophages toward an anti-inflammatory, pro-healing state, while genipin crosslinking with and without IL-4's presence appeared to lower macrophage activity.

Committee: Eda Yildirim-Ayan PhD (Advisor); Eda Yildirim-Ayan PhD (Committee Chair); Halim Ayan PhD (Committee Member); Arun Nadarajah PhD (Committee Member) Subjects: Biology; Biomedical Engineering; Biomedical Research; Cellular Biology; Materials Science

Master of Science, University of Akron, 2019, Polymer Science

Adequate post-operative pain management has been proven to enhance the healing and recovery of patients following most major procedures.1 However, it remains significantly under managed and is a serious unmet need in the medical field. The mainstay of post-operative pain management is the prescription of oral opioids, which, although effective, have many pitfalls. Most notably, opioids prescriptions are currently based on a “one-size-fits-all” model, providing an imbalance of doses given to patients and leaving the medication at the risk for misuse and abuse. Opioids are still in practice today ultimately due to a lack of a better solution. Herein, we propose a drug-loaded polymer film to control post-operative pain. Poly(ester urea)s were used to load drugs into solvent cast blade-coated films and tested for drug release of non-opioids agents. Specifically, etoricoxib, a selective cyclooxygenase isoform 2 (COX-2) was used to monitor the efficacy of delivery from these films both in vitro and in a rat model. To obtain different release profiles, film thickness, drug-load, and polymer composition was analyzed in order to get desired profile for analgesic release. The polymer analogs that were implemented for this study are copolymers, 10%, 20% and 30% 1-PHE-6 P(1-VAL-8), and homopolymers, P(1-VAL-8), P(1-VAL-10), and P(1-VAL-12). Moreover, a multi-modal analgesia model with bupivacaine (a local anesthetic) has been sought out to show the versatility of this device. The goal of this study was to study a controlled release system that will produce little to no inflammation while providing pain relief for 3-5 days following a surgical procedure. Ultimately, this device's intended purpose is to replace or minimize the need for prescription opioids. We hypothesize that by tuning the multiple factors available with PEUs that a variety of drug release profiles can be obtained to fit a number of different applications (i.e. acute to chronic pain).

Committee: Matthew Becker (Advisor); Andrey Dobrynin (Committee Member) Subjects: Biomedical Research; Polymers

Doctor of Philosophy, The Ohio State University, 2019, Biomedical Engineering

Natural plant surfaces, such as lotus leaves, rice leaves, and rose petals, possess unique wetting properties. Lotus leaves contain hierarchic micro/nano-topographies with a waxy coating and exhibit isotropic and ultralow flow resistance. A water droplet can roll off the surfaces that are tilted at a small angle regardless of the tilting direction. Rose petals also own hierarchic micro/nano-topographies, but with larger characteristic dimensions. The petal surfaces possess a high water flow resistance and can pin small water droplets on the surfaces even if the surfaces are positioned vertically or upside down. On the other hand, the petal surfaces are superhydrophobic so that the droplets can move without leaving any residue. A rice leaf has linearly arranged micro/nanopapillae, which lead to anisotropic flow resistance that can move water droplets preferably along the alignment. In this dissertation, bioinspired smart surfaces are investigated to mimic the distinct wetting properties on natural plant surfaces. In-plane mechanical stretching of the smart surfaces can dynamically and repeatedly modulate the characteristic dimensions of the micro-wrinkles, and in turn switch the surface wetting properties. With proper hydrophobic treatment, the wetting properties of the smart surfaces can be switched between lotus-like and rose-like; or lotus-like and rice-like. The surface wetting states can also be changed from Cassie Baxter state to Wenzel state by mechanical straining. In order to validate the efficacy of the smart surfaces in biomedical applications, droplet-based open channel microfluidics, and strain activated drug release are established respectively. In particular, lossless droplet transfer, droplet splitting, and modulation of droplet mobility are demonstrated on the lotus-rose switchable smart surfaces. Dynamic modulation of wetting anisotropy is exhibited on the lotus-rice switchable smart surfaces. Mechanical strain activated stepwise drug releas (open full item for complete abstract)

Committee: Yi Zhao (Advisor); Derek Hansford (Committee Member); Jun Liu (Committee Member); Kubilay Sertel (Other) Subjects: Biomedical Engineering

Master of Science, Miami University, 2018, Chemical, Paper and Biomedical Engineering

Five to ten percent of bone fractures are classified as critical size defects (CSD), which are fractures that will not fuse without medical intervention. Currently the preferred course of treatment is autografts or allografts however both have high complication rates and require aggressive surgeries. BMP2 is a drug known to promote bone growth when implanted in vivo and is currently used for some orthopedic treatments. However, the amount administered and release rate are critical to its therapeutic success. Keratin hydrogels have been shown to be excellent implant materials, promoting cell proliferation and integration. Direct ink write (DIW) 3D printing allows for hydrogel materials to be 3D printed in customizable shapes using various materials, but printing requires knowledge of the fluid properties of the hydrogel. In this study we show that the printing pressure and speed for printing a hydrogel can be predicted. And we show that DIW printing can be used to tune a drug's release profile if the diffusivity is low enough.

Committee: Jessica Sparks (Advisor); Justin Saul (Committee Member); Jason Berberich (Committee Member); Jens Mueller (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, University of Akron, 2017, Chemical Engineering

This dissertation describes the design and development of several sustained delivery systems based on alginate for delivering small hydrophilic drugs. The release behaviors and specific release mechanisms were investigated to determine how each system prolongs the release of hydrophilic drugs from alginate. The first approach utilizes the coating of a hydrophobic organosilane, octadecyltrichlorosilane (OTS), to hydrophilic alginate microspheres (Alg-Ms), the hydrogel drug carrier, to sustain the release of sodium benzoate (NaB), a model hydrophilic drug. The hydrophobicity of Alg-Ms increased with the incorporated OTS concentration, prolonging the release duration of NaB from hours to days. The release mechanism of NaB from Alg-Ms switched from combined diffusion/polymer relaxation to diffusion as the amount of OTS incorporated increased. The results demonstrate the simplicity of improving hydrophobicity of hydrogel drug carriers using OTS to broaden the drug delivery applications of hydrogels in delivering small hydrophilic drugs. The second coating based method applies layer-by-layer (LbL) deposition of polyelectrolyte to alginate microgels. The polyelectrolyte shell acted as an effective diffusion barrier to extend the release of hydrophilic compounds of NaB and zosteric acid (ZA) from a few hours up to 3 days and 5 days, respectively, as the LbL deposited layer thickness increased. The deposition of polyelectrolyte onto Alg-Ms was confirmed by with microscopic imaging. The release of NaB and ZA was found to be proportional to the bilayers' number and followed the Fickan 2nd law of diffusion. The results indicate that LbL polyelectrolytes coated Alg-Ms have a potential as controlled drug-delivery devices for hydrophilic drugs. The third platform involves a modified double-emulsion technique to generate alginate based poly lactic-co-glycolic acid (PLGA) microparticles for controlling hydrophilic drug (e.g., NaB) delivery. The formulation parameters, such as (open full item for complete abstract)

Committee: Bi-min Zhang Newby Dr (Advisor); Gang Cheng Dr (Committee Member); Jie Zheng Dr (Committee Member); Leah Shriver Dr (Committee Member); Marnie Saunders Dr (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Chemical Engineering; Chemistry; Materials Science; Medicine; Pharmaceuticals; Polymer Chemistry; Polymers

Doctor of Philosophy, University of Akron, 2018, Chemical Engineering

This dissertation presents the first report of local in vitro release of anti-inflammatory drugs, Zafirlukast and Aspirin, from an electrospun drug-eluting fiber mat made from novel non-commercialized, polyisobutylene-based thermoplastic elastomers. This drug-eluting fiber mat is a potential candidate for reducing the inflammatory response to silicone breast prosthesis. Linear poly(styrene-b-isobutylene-b-styrene) triblock copolymer (SIBS) is used in clinical practice as the drug-eluting polymeric coating on the TAXUSTM coronary stent for its excellent bioinertness and biostability. Over 6 million patients have benefited from this device, but due to the low permeability of the polymer, only ~10% of the encapsulated drug, Taxol, eluted from the coating in 330 days at 8.8 wt% loading. The next generation PIB-based thermoplastic elastomer (TPE), Arbomatrix with an arborescent polyisobutylene (PIB) core & poly(p-methyl styrene) (PMS) end blocks, was also shown to be bioinert in a rabbit model. Another novel PIB-based TPE, poly(alloocimene-b-isobutylene-b-alloocimene) (AIBA), which is a linear block copolymer developed by Puskas and coworkers, is also a suitable candidate for biomedical applications. Breast cancer is the most commonly diagnosed form of cancer and the second leading cause of cancer-related deaths in American women (246,660 new cases and 40,450 deaths in 2016). Approximately one-third of American women diagnosed with breast cancer undergo mastectomy, with approximately 70% of these women opting for silicone implant-based reconstruction. Capsular contracture is the most commonly reported problem with this approach. Capsular contracture is a distortion of an implant caused by tension resulting from the fibrous capsule forming around it due to an inflammatory response by the body against silicone rubber. Electrospinning is a versatile and unique process of creating fibers in the micron, sub-micron and nano diameter ranges with the help of electrostatic for (open full item for complete abstract)

Committee: Judit Puskas (Advisor); Teresa Cutright (Committee Member); Darrell Reneker (Committee Member); George Chase (Committee Member); Jie Zheng (Committee Member) Subjects: Biomedical Research; Chemical Engineering; Materials Science; Medicine; Morphology; Polymers; Textile Research

Doctor of Philosophy, University of Akron, 2016, Polymer Engineering

The first part of this study presents a strategy for the synthesis of novel bimodal amphiphilic grafts consisting of hydrophilic poly (N,N-dimethylacrylamide) (PDMAAm) main chains carrying two different molecular weight hydrophobic polydimethylsiloxane (PDMS) branches whose crosslinking leads to bimodal amphiphilic conetworks (ß-APCNs). The effect of crosslinker ratio and amount of high molecular weight PDMS on the conetwork's morphology, swelling characteristics and mechanical properties were evaluated. The materials exhibited bulk microphase separation with short-range ordering, and superficial demixing with only the hydrophobic phase present at the surface. A multi-scale, composition-dependent, elastic wrinkling-instability was shown to control surface morphology. The coexistence of low and high molecular weight PDMS in ß-APCNs greatly improved ultimate mechanical properties. The second study concerns the structure development of ß-APCNs during film processing from solution. Time-resolved gravimetry, low contact angles and negative out-of-plane birefringence provided strong experimental evidence of transitory trapping of thermodynamically unfavorable hydrophilic moieties at the air-film interface due to fast asymmetric solvent depletion. We also find that slow-drying hydrophobic elements progressively substitute hydrophilic domains at the surface as the surface-energy is minimized. The third study proposes a novel approach to zero-order, constant-rate drug delivery from ß-APCN-based contact lenses. Quasi-Case II non-Fickian transport was achieved by non-uniform drug and diffusivity distributions within three-layer bimodal amphiphilic conetworks. We demonstrated experimentally and by modeling that the combined effect of non-uniform distribution of drug loading and diffusion constants within the three-layer lens maintains low local drug concentration at the lens-fluid interface and yields zero-order drug delivery. The final study uses in-situ ellipsometry (open full item for complete abstract)

Committee: Mukerrem Cakmak Dr. (Advisor); Min Younjin Dr. (Committee Chair); David Simmons Dr. (Committee Member); Mathew Becker Dr. (Committee Member); Nic Leipzig Dr. (Committee Member) Subjects: Biomedical Engineering; Plastics; Polymer Chemistry; Polymers

Doctor of Philosophy, University of Akron, 2015, Polymer Science

Linear poly(styrene-b-isobutylene-b-styrene) (l-SIBS) and arborescent poly(styrene-b-isobutylene-b-styrene) (arb-SIBS) are a type of polyisobutylene-based thermoplastic elastomers (PIB-based TPE) characterized by an excellent mechanical, thermal and chemical stability, low permeability and excellent biostability and biocompatibility. PIB-based TPE are prepared by living carbocationic polymerization with sequential monomer addition which allows to obtain narrow molecular weight distribution and to synthesize a wide variety of architectures. These materials have been extensively used for biomedical applications, however they have a unique combination of properties, not available in any other TPE, that make them suitable for potential uses in other areas as well. This work reports the evaluation of three new potential technological applications for l-SIBS and arb-SIBS. In the first part of this work a new method for the preparation of a flexible piezoelectric polymer by incorporating a bent-core liquid crystal (BLC) in a PIB-based TPE, l-SIBS was shown. The polymer composite material containing 10 wt. % of BLC showed a piezoelectric charge constant d33 (~1 nm V-1) greater than commercially available piezoelectric ceramics. Small angle X-ray scattering (SAXS) results show that the liquid crystal–polymer composite becomes aligned during compression molding leading to macroscopic polarization without electric poling. In the second part of this work l-SIBS and arb-SIBS were sulfonated to prepare block copolymer ionomers. The materials were successfully sulfonated to various sulfonation degrees (SD), and characterized for water uptake and ionic conductivity. This modification significantly increased water uptake of both S-l-SIBS and S-arb-SIBS; the associated proton conductivity of the S-l-SIBS increased with the SD, however it did not rise at the desirable levels. For the S-arb-SIBS low values of proton conductivity were obtained, possibly due to the limited solub (open full item for complete abstract)

Committee: Judit E. Puskas Dr (Advisor); Gary R. Hamed Dr. (Committee Member); Mesfin Tsige Dr. (Committee Member); Darrell H. Reneker Dr. (Committee Member); Thein Kyu Dr. (Committee Member) Subjects: Materials Science; Polymer Chemistry; Polymers

Doctor of Philosophy, Case Western Reserve University, 2014, Biomedical Engineering

Alteration of cell behavior is at the core of pathological diseases and design of drug delivery systems. Among those behaviors are cell morphogenesis, engraftment and migration. I have investigated how implantable polymer matrices can be engineered to treat different diseases using these cell behaviors as targets. Doing so have taken me to synthesize polymers containing different affinity binding ligands for the delivery of molecules of different sizes at the time scales needed in vivo. To meet these different cellular demands we have made use of the strength of binding between the drug or biomolecule to be delivered and the polymer. By using strong non-covalent interactions between molecules we can increase the total amount of drug loaded into the polymer matrix, modulate its release from the device and present this molecules in a local scenario. We have not only engineered the release rate of these polymers but also analyzed and evaluated their performance in vitro. Using surface plasmon resonance to determine the association constant of the host-guest complexes that form inside the polymer we have been able to predict which molecule pair will make good affinity guest and hosts. This characterization method has correlated well with the capacity of our affinity polymers to slow the delivery of a diverse set of molecules. To test the activity of the drugs loaded into these polymers we have made use of different longitudinal in vitro cell migration assays. This workflow of strength of binding prediction, polymer synthesis and in vitro testing has found applications in a variety of settings from cancer treatment to regenerative medicine. For cancer treatment we have evaluated the release of small (MW< 500) anti-angiogenic molecules to slowly release over time. When implanted into animals this slow releasing polymers delay the growth of a glioblastoma tumors in a mouse animal model. Using the same principles we have also engineered polymers capable of releasing (open full item for complete abstract)

Committee: Horst von Recum (Advisor); Adonis Hijaz (Committee Member); Agata Exner (Committee Member); Zheng-Rong Lu (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, Case Western Reserve University, 2014, Biomedical Engineering

Although several formulations of nanomedicines are approved to treat cancer, their therapeutic efficacy has been limited in the clinic. The delivery of nanoparticles, which is driven by blood flow, is hindered by high interstitial pressures in primary tumors. Moreover, clinically approved nanoparticles are not well designed to target metastasis, which is the leading cause of death from cancer. To effectively treat tumors, it is essential to improve a nanoparticle's ability to marginate (drift) to the blood vessel wall, overcome interstitial pressures, and bind to overexpressed receptors at a tumor. We assert that nanoparticle size and shape are both design parameters which must be optimized to target and treat tumors effectively. Shape, in particular, heavily influences a nanoparticle's pharmacokinetics, margination, and binding avidity to receptors. To evaluate the effect of size and shape on nanoparticle margination, the wall deposition of different classes of nanoparticles was compared under flow in a microfluidic chamber. With the knowledge that flow influences nanoparticle intravascular transport, we then employed an in vivo multimodal imaging protocol to evaluate the effect of blood flow on the intratumoral deposition of untargeted and targeted nanoparticles of unique sizes. These studies established that convection heavily influences the deposition of large nanoparticles, while active targeting to cell receptors improves the retention of smaller nanoparticles. Furthermore, these studies allowed us to derive design rules to improve the site-specific performance of nanoparticles for hard-to-treat cancers. For example, in contrast to primary tumors, micrometastatic lesions lack the hyperpermeable vasculature that allows nanoparticles to passively accumulate in the tumor interstitium. Thus, we developed a chain of iron oxide nanoparticles targeted to the alpha-v-beta-3 integrin, which is overexpressed on the vascular wall in metastatic lesions. (open full item for complete abstract)

Committee: Efstathios Karathanasis Ph.D. (Advisor); James Basilion Ph.D. (Committee Chair); Stanton Gerson M.D. (Committee Member); Harihara Baskaran Ph.D. (Committee Member); Mark Griswold Ph.D. (Committee Member) Subjects: Biomedical Engineering; Nanotechnology

PhD, University of Cincinnati, 2011, Engineering and Applied Science: Biomedical Engineering

Cardiovascular disease (CVD) is the leading cause of death in the United States and globally. CVD-related mortality, including coronary heart disease, heart failure, or stroke, generally occurs due to atherosclerosis, a condition in which plaques build up within arterial walls, potentially causing blockage or rupture. Targeted therapies are needed to achieve more effective treatments. Echogenic liposomes (ELIP), which consist of a lipid membrane surrounding an aqueous core, have been developed to encapsulate a therapeutic agent and/or gas bubbles for targeted delivery and ultrasound image enhancement. Under certain conditions ultrasound can cause nonlinear bubble growth and collapse, known as “cavitation.” Cavitation activity has been associated with enhanced drug delivery across cellular membranes. However, the mechanisms of ultrasound-mediated drug release from ELIP have not been previously investigated. Thus, the objective of this dissertation is to elucidate the role of acoustic cavitation in ultrasound-mediated drug release from ELIP. To determine the acoustic and physical properties of ELIP, the frequency-dependent attenuation and backscatter coefficients were measured between 3 and 30 MHz. The results were compared to a theoretical model by measuring the ELIP size distribution in order to determine properties of the lipid membrane. It was found that ELIP have a broad size distribution and can provide enhanced ultrasound image contrast across a broad range of clinically-relevant frequencies. Calcein, a hydrophilic fluorescent dye, and papaverine, a lipophilic vasodilator, were separately encapsulated in ELIP and exposed to color Doppler ultrasound pulses from a clinical diagnostic ultrasound scanner in a flow system. Spectrophotometric techniques (fluorescence and absorbance measurements) were used to detect calcein or papaverine release. As a positive control, Triton X-100 (a non-ionic detergent) was added to ELIP samples not exposed to ultrasound in order to (open full item for complete abstract)

Committee: Christy Holland PhD (Committee Chair); Melvin Klegerman PhD (Committee Member); David Manka PhD (Committee Member); T. Douglas Mast PhD (Committee Member); Daria Narmoneva PhD (Committee Member); George Shaw PhD (Committee Member) Subjects: Biomedical Research