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MPharm. Faculty of Health Sciences, University of the Witwatersrand, 2007

Controlled drug delivery systems have been utilized to enhance the therapeutic effects of many current drugs by effectively delivering drugs in a time-dependent and repeatable manner. The ability to control the delivery of drugs, whether through sequential, instantaneous, sustained, delayed and/or enhanced release has the potential to provide effective dosing regimens with enhanced therapeutic effects for a plethora of diseases and injuries. For instance, such systems can enhance anti-tumoral responses or, alternatively, promoting tissue regeneration. The current need for organ and tissue replacement, repair and regeneration for patients is continually growing such that supply is not meeting the high demand primarily due to a paucity of donors as well as biocompatibility issues that lead to immune rejection of the transplant. To overcome this problem, scientists working in the field of tissue engineering and regenerative medicine have investigated the use of scaffolds as an alternative to transplantation. These scaffolds are designed to mimic the extracellular matrix (ECM) by providing structural support as well as promoting attachment, proliferation, and differentiation with the goal of yielding functional tissues or organs. Continued advancement and hybrid approaches using different material combinations and printing methodologies will further advance the progress of 3D printing technologies toward developing scaffolds, and other implantable drug delivery devices, capable of being utilized in the clinic. Such advancements will not only make inroads into improving structural integrity of implantable devices but will also provide platforms for controlled drug delivery from such devices. The primary focus of this thesis will be on controlled drug delivery as well as the integration of controlled drug delivery into 3D printed devices aimed at promoting tissue regeneration. We initially assessed the efficacy of a controlled drug delivery system for the treatment of cancer using on-demand, and sustained, release of an anticancer drug, doxorubicin (DOX), for the treatment of melanoma in a murine model. Using a melanoma model, we investigated the antitumor potential of combining ultrasound (US) with poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with DOX. An in vitro release assay demonstrated an ability of US to affect the release kinetics of DOX from DOX-loaded PLGA microspheres by inducing a 12% increase in rate of release where this treatment resulted in synergistic tumor cell (B16-F10 melanoma cells) killing. Melanoma-bearing mice treated intratumorally with DOX (8 µg)-loaded microspheres and subjected to US treatment at the tumor site were shown to significantly extended survival compared to untreated mice or mice subjected to either treatment alone. The synergistic increase in survival of melanoma-challenged mice treated with the combination of US and DOX-loaded microspheres implicates a promising additional tool for combatting an otherwise currently incurable cancer. We then further investigated other novel control drug delivery systems which included a 3D printed device (tube) for the purposes of sequential drug delivery. 3D printed hollow alginate tubes were fabricated through co-axial bioprinting and then injected with PLGA to provide sequential release of distinct fluorescent dyes (model drugs), where fluorescein was initially released from alginate followed by the delayed release (up to 55 h) of rhodamine B in PLGA. With an alginate shell and a PLGA core, the fabricated tubes showed no cytotoxicity when incubated with the human embryonic kidney (HEK293) cell line or bone marrow stromal stem cells (BMSC). Microscale printing through two-photon polymerization (2PP) was then investigated for controlled drug delivery potential. Poly(ethylene glycol) dimethacrylate (PEGDMA) devices were fabricated using a Photonic Professional GT two-photon polymerization system while rhodamine B was homogenously entrapped inside the polymer matrix during photopolymerization. These devices were printed with varying porosity and morphology and using varying printing parameters such as slicing and hatching distance. Overall, tuning the hatching distance, slicing distance, and pore size of the fabricated devices provided control of rhodamine B release due to resulting changes in the motility of the small molecule and its access to structure edges. In general, increased spacing provided higher drug release while smaller spacing resulted in some occlusion, preventing media infiltration and thus resulting in reduced drug release. 2PP was further explored for its ability to tailor topographical cues in addition to controlled drug release. These physical cues, similar to those of the ECM, have been seen to promote differentiation. With 2PP, we explored microscale topographies with nanoscale precision, where different star size topographies were fabricated. It was observed that the smallest star size topographies differentiated human iPSCs towards the endoderm and mesoderm germ layer. Integrating the facility for controlled drug release into 3D printed devices provides a demand for constructs that not only need to fulfill their purpose of temporarily substituting for the missing tissue at the site of injury, but also providing the necessary cues to promote appropriate tissue regeneration. With 3D printing technology, novel drug delivery constructs were fabricated and tested to appraise functionality such as the ability to control drug delivery and the ability to function as a non-toxic medium for cellular attachment, proliferation, and forced differentiation.

Contents: Chitosan -- Controlled drug delivery -- Indomethacin -- Inotropic gelation -- Tripolyphosphate (TPP) -- Explotab® -- Ac-Di-Sol® -- Vitamin C / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

Tissue engineering is an interdisciplinary field that seeks to address the needs by applying the principles of chemistry, biology and engineering for the development of viable substitutes that restore and maintain the function of human bone and cartilage tissues. In tissue engineering, scaffolds play an important role as temporary supports for the transplantation of specific cells and tissues. In this study, poly(ester-urethane)urea (PEUU) and poly(caprolactone) (PCL) scaffolds were fabricated. Scaffolds were characterized by SEM. Porosities of scaffolds vary from 67 % to 80 %. Controlled drug delivery systems release drugs at predetermined rates for extended periods. In this study / firstly poly(lactic-co-glycolicolide/tricalcium phosphate) (PLGA/TCP) and poly(L-lactide)/tricalcium phosphate (PLLA/TCP) composites loaded with Gentamicin or Vancomycin were prepared as controlled drug delivery systems for the local treatment of osteomyelitis. The release behavior of drugs were monitored by UV-VIS spectrometer. It was shown that, Vancomycin loaded samples released higher amounts of drug than the samples loaded with Gentamicin. Secondly, porous ceramic samples were coated with PLGA and PLLA and they were loaded with dexamethasone. The release behavior of samples were monitored by UV-VIS spectrometer.The cubic ceramics released higher amounts of dexamethasone than cylindrical ceramics. When the mechanical properties of porous ceramic samples were concerned, PLLA coated samples had better mechanical properties.

Conventional methods of chemotherapy requires novel therapy systems due to serious side effects and inefficiency of drug administration. In recent years many studies are carried out to improve drug delivery systems. Polymers are one of the most important elements for drug delivery research due to their versatility. By the discovery of dendritic polymers, drug delivery studies gained a new vision. Highly branched monodisperse structure, multiple sites of attachment, well-defined size and controllable physical and chemical properties make them efficient drug delivery systems. In this research hyperbranched dendritic polymers were sythesized and characterized for hydrophobic drug delivery. Dipentaerythritol which was used as core molecule, esterified with dimethylol propionic acid. Ricinoleic acid was esterified with the end groups of dimethylol propionic acid and hyperbranched resin (HBR) was formed. By considering the properties of HBR, hydrophobic tamoxifen and idarubicin were used for drug delivery study. The most efficient loading was determined as 73% for tamoxifen and 74% for idarubicin. Drug-HBR interactions and changes in properties of HBR were determined by FTIR, zeta potential and particle size measurements. FTIR results indicated that idarubicin chemically interacted with HBR while tamoxifen physically loaded to HBR. Drug delivery profile of HBR was studied in the absence and presence of lipase from Pseudomonas sp. and sodium dodecyl sulfate (SDS). Results revelaed that lipase and SDS increased the release rate of tamoxifen while idarubicin release rate was not affected. The effect of lipase was also tested for the degradation of HBR and it was indicated that lipase sustain a faster degradation. Finally toxicity of HBR and drug loaded HBR on MCF-7 breast cancer cell line was determined with XTT proliferation assay. Empty HBR did not cause significant toxicity on MCF-7 cells while drug loaded HBR was more toxic than free drug. By this study the efficiency of novel synthesized hyperbranched polymer in drug delivery was shown.

There are several studies in order to control drug delivery, decrease the toxicity of drugs and also for novel biomedical applications. It is necessary to be able to control the release of the drug within the body by using drug delivery systems. Mesoporous silica compounds have only been discovered twenty years ago and they have already attracted many researchers to study these materials for several applications. SBA-15 particles have a highly ordered regular structure and are a good matrix for guest-host applications. The aim of this study is to be able to address whether the surface functionalization of SBA-15 samples would improve the loading of a drug into these particles. The synthesized SBA-15 particles were surface functionalized by post - grafting synthesis method in order to be used as carrier materials for drug delivery. Amoxicillin was used as a model drug. These mesoporous materials have been characterized using X-ray diffraction (XRD), small-angle X-ray spectroscopy (SAXS), fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), N2 adsorption/ desorption, solid-state silicon nuclear magnetic resonance (Si-NMR), high-performance liquid chromatography (HPLC), ultra-violet (UV) spectroscopy, elemental and thermo gravimetric analysis (TGA). The effect of concentration difference and the type of alkoxysilanes used for the functionalization have been discussed in terms of loading amoxicillin and controlling the delivery. Drug delivery systems have many further applications that still need to be investigated in areas such as neurosciences, cancer and biomedical engineering.

Chitosan has proven through the years as a versatile biomaterial to be used in pharmaceutical applications. Its mucoadhesive properties as well as its ability to manipulate the tight junctions in epithelium membranes have qualified it as an effective drug carrier in controlled drug delivery systems. Microparticles or beads as they are forward called in this study have advantages over conventional drug dosage forms because of a large surface to volume ratio and have the ability to target a specific site for drug release. Indomethacin is an anti-inflammatory drug that causes gastrointestinal side effects in conventional immediate-release dosage forms. The goal is to manipulate the drug delivery vehicle to target the intestines/colon as the site for drug delivery and to minimize this side effect. Thus chitosan beads have been chosen as a drug delivery system for indomethacin in this study. Chitosan beads have been prepared through the ionotropic gelation method using tripolyphophate (TPP) as a cross-linking agent. To prepare the most effective bead to encapsulate indomethacin different formulation and system variables (pH of the TPP solution, the concentration of the TPP solution as well as the indomethacin concentration) have been evaluated according to the following parameters: morphology, drug loading capacity and swelling capability. The ideal pH of the TPP solution was determined at 8.7 and the most effective TPP and indomethacin concentration were 5% w/v and 4% w/v respectively. The chitosan concentration was kept at 3% w/v throughout the study. These concentrations were used to examine the effect of pharmaceutical excipients on the indomethacin release from chitosan beads. The effect of the different excipients namely, ExplotabⒽ(0.25% w/v), Ac-Di-SolⓀ (0.5% w/v) and Vitamin C (0.25% w/v), on the morphology, drug loading capacity, swelling capability as well as the drug release of indomethacin chitosan beads (ICB's) were also studied. The excipients were used in the individually above mentioned concentrations and in combination with each other in the same concentrations. These formulations were used in dissolution studies over a period of 6 hours in PBS pH 7.4 solutions. The indomethacin release rate increased when an excipient was added to the formulation and it dramatically increased when the excipients were added in their various combinations, compared to the formulation that did not contain excipients. / Contents: Chitosan -- Controlled drug delivery -- Indomethacin -- Inotropic gelation -- Tripolyphosphate (TPP) -- Explotab® -- Ac-Di-Sol® -- Vitamin C / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

Recent advances in micro technologies have equipped researches with novel tools for interacting with biological molecules and cells. This thesis focuses on the design, fabrication and application of microfluidic platforms for stimuli-responsive drug delivery and the electromechanical characterization of single cells. Stimuli-responsive hydrogels are promising materials for controlled drug delivery due to their ability to respond to changes in local environmental conditions. In particular, nanohydrogel particles have been a topic of considerable interest due to their rapid response times compared to micro and macro-scale counterparts. Owing to their small size and thus low drug-loading capacity, these materials are unsuitable for prolonged drug delivery. To address this issue, stimuli-responsive implantable drug delivery micro devices by integrating microfabricated drug reservoirs with smart nano-hydrogel particles embedded composite membranes have been proposed. In one proposed glucose-responsive micro device, crosslinked glucose oxidase enables the oxidation of glucose into gluconic acid, producing a microenvironment with lower pH values to modulate the pH-responsive nanoparticles. In vitro glucose-responsive drug release profiles were characterized and normoglycemic glucose levels in diabetic rats with device implantation were also recorded. The biophysical properties of single cells have recently been demonstrated as an important indicator of disease diagnosis. Existing technologies are capable of characterizing single parameter either electrical or mechanical rapidly, but not both, which could only collect limited information for cell status evaluation. To address this issue, two microfluidic platforms capable of simultaneously characterizing both the electrical and mechanical properties of single cells based on electrodeformation and integrated impedance spectroscopy with micropipette aspiration have been proposed. In one proposed microfluidic device, a negative pressure was used to suck cells continuously through the aspiration channel with impedance profiles measured. By interpreting impedance profiles, transit time and impedance amplitude ratio can be quantified as cellular mechanical and electrical property indicators. Neural network based cell classification was conducted, demonstrating that two biophysical parameters could provide a higher cell classification success rate than using electrical or mechanical parameter alone.

Recent advances in micro technologies have equipped researches with novel tools for interacting with biological molecules and cells. This thesis focuses on the design, fabrication and application of microfluidic platforms for stimuli-responsive drug delivery and the electromechanical characterization of single cells. Stimuli-responsive hydrogels are promising materials for controlled drug delivery due to their ability to respond to changes in local environmental conditions. In particular, nanohydrogel particles have been a topic of considerable interest due to their rapid response times compared to micro and macro-scale counterparts. Owing to their small size and thus low drug-loading capacity, these materials are unsuitable for prolonged drug delivery. To address this issue, stimuli-responsive implantable drug delivery micro devices by integrating microfabricated drug reservoirs with smart nano-hydrogel particles embedded composite membranes have been proposed. In one proposed glucose-responsive micro device, crosslinked glucose oxidase enables the oxidation of glucose into gluconic acid, producing a microenvironment with lower pH values to modulate the pH-responsive nanoparticles. In vitro glucose-responsive drug release profiles were characterized and normoglycemic glucose levels in diabetic rats with device implantation were also recorded. The biophysical properties of single cells have recently been demonstrated as an important indicator of disease diagnosis. Existing technologies are capable of characterizing single parameter either electrical or mechanical rapidly, but not both, which could only collect limited information for cell status evaluation. To address this issue, two microfluidic platforms capable of simultaneously characterizing both the electrical and mechanical properties of single cells based on electrodeformation and integrated impedance spectroscopy with micropipette aspiration have been proposed. In one proposed microfluidic device, a negative pressure was used to suck cells continuously through the aspiration channel with impedance profiles measured. By interpreting impedance profiles, transit time and impedance amplitude ratio can be quantified as cellular mechanical and electrical property indicators. Neural network based cell classification was conducted, demonstrating that two biophysical parameters could provide a higher cell classification success rate than using electrical or mechanical parameter alone.