Chemotherapy regimens, one of the most common cancer treatments, are often dictated by dose-limiting toxicities. Also, the largest hurdle for translating novel biological therapies such as siRNA into the clinic is lack of an efficient delivery mechanism to get the therapeutic into malignant cells. Both of these situations would benefit from a minimally-invasive controlled release system that only delivers a therapeutic to the site of malignant tissue. This thesis presents work towards the creation of such a delivery platform using two novel material components: a thermally responsive poly[N-isopropylacrylamide-co-acrylamide] (NIPAAm-co-AAm) hydrogel and gold-silica nanoshells. Thermally responsive hydrogels undergo a physical property transition at their lower critical solution temperature (LCST). When transitioning from below to above the LCST, the hydrogel material expels large amounts of water and absorbed molecules. This phase change can be optically triggered by embedded gold-silica nanoshells, which rapidly transfer near-infrared (NIR) light energy into heat energy due to the surface plasmon resonance phenomena. When this material is loaded with absorbed drug molecules, drug release can be externally triggered by exposure to an NIR laser. Initial characterization of this material was accomplished using bulk hydrogel-nanoshell composites. Poly(NIPAAm-co-AAm)-nanoshell composites were synthesized via free radical polymerization. The LCST of the poly(NIPAAm-co-AAm) hydrogels was determined to be from 39-45 deg C, or slightly above physiologic temperature. The material was swollen in a drug solution of either doxorubicin (a common chemotherapeutic) or a 21bp dsDNA olgio (a model molecule for siRNA). Composites were then exposed to an 808 nm laser, which was found to trigger release of the therapeutics from the composite material. Further work has been done in translating this composite material to nano-scale sized particles, such that it could be injected intravenously, passively accumulate in tumor tissue, and be externally triggered to release therapeutics by exposure to an NIR laser. Sub-micron composite particles were synthesized using dissolvable gelatin templates with 500 nm wells. Analysis by transmission electron microscopy (TEM) indicates that these particles consist of gold nanoshells surrounded by a hydrogel coating. Dynamic light scattering (DLS) measurements were used to show that these particles display the same thermal properties as seen in the bulk material: collapsing in response to increased temperatures or NIR light exposure. Ultimately, the work in this thesis advances the development of a minimally-invasive, optically-triggered drug delivery platform.

Modeling interstitial fluid flow involves processes such as fluid diffusion, convective transport in the extracellular matrix, and extravasation from blood vessels. In all of these processes, computational fluid dynamics can play a crucial role in elucidating the mechanisms of fluid flow in solid tumors and surrounding tissues. To date, microvasculature flow modeling has been most extensively studied with simple tumor shapes and their capillaries at different levels and scales. With our proposed numerical model, however, more complex and realistic tumor shapes and capillary networks can be studied. First, a mathematical model of interstitial fluid flow is developed, based on the application of the governing equations for fluid flow, i.e., the conservation laws for mass and momentum, to physiological systems containing solid tumors. Simulations of interstitial fluid transport in a homogeneous solid tumor demonstrate that, in a uniformly perfused tumor, i.e., one with no necrotic region, the interstitial pressure distribution results in a non-uniform distribution of drug particles. Pressure distribution for different values of necrotic radii is examined, and two new parameters, the critical tumor radius and critical necrotic radius, are defined. In specific ranges of these critical dimensions the interstitial fluid pressure is relatively lower, which in turn leads to a diminished opposing force against drug movement and a subsequently higher drug concentration and potentially enhanced therapeutic effects. In this work, the numerical model of fluid flow in solid tumors is further developed to incorporate and investigate non-spherical tumor shapes such as prolate and oblate ones. Using this enhanced model, tumor shape and size effects on drug delivery to solid tumors are then studied. Based on the assumption that drug particles flow with the interstitial fluid, the pressure and velocity maps of the latter are used to illustrate the drug delivery pattern in a solid tumor. Additionally, the effects of the surface area per unit volume of the tissue, as well as vascular and interstitial hydraulic conductivity on drug delivery efficiency, are investigated. Using a tumor-induced microvasculature architecture instead of a uniform distribution of vessels provides a more realistic model of solid tumors. To this end, continuous and discrete mathematical models of angiogenesis were utilized to observe the effect of matrix density and matrix degrading enzymes on capillary network formation in solid tumors. Additionally, the interactions between matrix-degrading enzymes, the extracellular matrix and endothelial cells are mathematically modeled. Existing continuous and discrete models of angiogenesis were modified to impose the effect of matrix density on the solution. The imposition has been performed by a specific function in movement potential. Implementing realistic boundary and initial conditions showed that, unlike in previous models, the endothelial cells accelerate as they migrate toward the tumor. Now, the tumor-induced microvasculature network can be applied to the model developed in Chapters 2 and 3. Once the capillary network was set up, fluid flow in normal and cancerous tissues was numerically simulated under three conditions: constant and uniform distribution of intravascular pressure in the whole domain, a rigid vascular network, and an adaptable vascular network. First, governing equations of sprouting angiogenesis were implemented to specify the different domains for the network and interstitium. Governing equations for flow modeling were introduced for different domains. The conservation laws for mass and momentum, Darcy’s equation for tissue, and a simplified Navier Stokes equation for blood flow through capillaries were then used for simulating interstitial and intravascular flows. Finally, Starling’s law was used to close this system of equations and to couple the intravascular and extravascular flows. The non-continuous behavior of blood and the adaptability of capillary diameter to hemodynamics and metabolic stimuli were considered in blood flow simulations through a capillary network. This approach provided a more realistic capillary distribution network, very similar to that of the human body. This work describes the first study of flow modeling in solid tumors to realistically couple intravascular and extravascular flow through a network generated by sprouting angiogenesis, consisting of one parent vessel connected to the network. Other key factors incorporated in the model for the first time include capillary adaptation, non-continuous viscosity blood, and phase separation of blood flow in capillary bifurcation. Contrary to earlier studies which arbitrarily assumed veins and arteries to operate on opposite sides of a tumor network, the present approach requires the same vessel to run and from the network. Expanding the earlier models by introducing the outlined components was performed in order to achieve a more-realistic picture of blood flow through solid tumors. Results predict an almost doubled interstitial pressure and are in better agreement with human biology compared to the more simplified models generally in use today.

Self-assembling peptides have emerged as new nanobiomaterials in the areas of nanoscience and biomedical engineering. In this category are self-assembling, ionic-complementary peptides, which contain a repeating charge distribution and alternating hydrophobic and hydrophilic residues in the amino acid sequence, leading to a unique combination of amphiphilicity and ionic complementarity. These peptides can self-assemble into stable nanostructures or macroscopic membranes that can withstand conditions of high temperature, extreme pH, many digesting enzymes and denaturation agents. Moreover, they exhibit good biocompatibility with various cultured mammalian cells, and do not have detectable immune responses when introduced into animals. These properties make them ideal materials for tissue scaffolding, regenerative medicine and drug delivery. This thesis focuses on the utilization of self-assembling peptides for hydrophobic anticancer drug delivery. The hydrophobic anticancer agent ellipticine was selected as a model drug. The studies include: (i) characterization of the photophysical properties of ellipticine in different environments; (ii) study of the formation of peptide-ellipticine complexes and the release kinetics; (iii) investigation of the cellular toxicity of the complexes and ellipticine uptake; (iv) study of the peptide sequence effect on the complex formation and in vitro delivery. Prior to applying ellipticine to the peptide-based delivery system, the fundamental studies on the effect of solution conditions, especially solvent polarity and hydrogen bonding, on the fluorescence of ellipticine were carried out. Ultraviolet (UV) absorption and fluorescence emission of ellipticine were found to be solvent/environment dependent. The absorption and emission maxima shifted to higher wavelengths (red shift) with increased solvent polarity. Large Stokes’ shifts were due to intramolecular charge transfer (ICT), which was enabled by large solvent polarity and hydrogen bonding of ellipticine with the solvents. The photophysical response of ellipticine to changes in solvent polarity and hydrogen bond formation could be used to infer the location of ellipticine in a heterogeneous medium, such as liposomes and cultured cells. EAK16-II, a model self-assembling peptide, was found to be able to stabilize ellipticine in aqueous solution. The equilibration time required to form peptide-ellipticine complex suspensions was found to be peptide concentration-dependent and related to the peptide critical aggregation concentration (CAC, ~0.1 mg/mL). With different combinations of EAK16-II and ellipticine concentrations, two molecular states (protonated or crystalline) of ellipticine could be obtained in the complexes. The release kinetics of ellipticine from the complex into egg phosphatidylcholine (EPC) vesicles (cell membrane mimics) was also affected by the peptide concentration used in the drug formulation. A higher peptide concentration resulted in a faster transfer rate, in relation to the size of the resulting complexes. Subsequent cellular studies on two cancer cell lines, A549 and MCF-7, showed that the complexes with protonated ellipticine were more effective against both cell lines, but their dilutions were not very stable. In addition, it was found that ellipticine uptake in both cell lines was very fast and through direct membrane permeation. Three peptides, EAK16-II, EAK16-IV and EFK16-II, either having a different charge distribution (EAK16-II vs. EAK16-IV) or hydrophobicity (EAK16-II vs. EFK16-II), were tested for the complexation and in vitro delivery of ellipticine. It was found that EAK16-II and EAK16-IV were able to stabilize protonated or crystalline ellipticine depending on the peptide concentration; EFK16-II, on the other hand, could stabilize neutral ellipticine molecules and ellipticine (micro)crystals. The viability results showed that the charge distribution of the peptides seemed not to affect the complex formation and its therapeutic efficacy in vitro; however, the increase in hydrophobicity of the peptides significantly altered the states of stabilized ellipticine and increased the stability of the complexes. This work provides essential information for peptide sequence design in the development of self-assembling peptide-based delivery of hydrophobic anticancer drugs.

The purpose of this research was to develop the pseudo-ternary phase diagrams for a model drug delivery system consisting of vitamin E (model drug) + soybean oil + surfactant + co-surfactant (anhydrous glycerol) + water. The model drug (vitamin E) was loaded in the oil phase. The effects of different surfactants (pure and mixed) on the phase diagram, especially the microemulsion region, were investigated. The influence of drug loading level on the phase diagram was also determined. The surfactants studied were Tween 20, Tween 80, Cremopher EL, and their mixtures. The size (area) of the microemulsion region of the phase diagram was found to be dependent on the type of surfactant used and the loading level of drug (vitamin E). The phenomenon of phase inversion from W/O microemulsion to O/W microemulsion was also investigated for the drug delivery system consisting of soybean oil (0% w/w Vitamin E loading or 30% w/w Vitamin E loading) + Tween 80 + anhydrous glycerol + water. The inversion of phases was detected by observing changes in the viscosity of the system.

Biomedical engineering is the application of engineering principles and techniques to the medical field. It combines the design and problem solving skills of engineering with medical and biological sciences to improve healthcare diagnosis and treatment. As the result of improvements in robotics and micro technology science in the 20th century, micro electromechanical system technology has joined with medical applications which results in micro robotic medical applications. Drug delivery is one of the most important and controversial topics which scientists and engineers have tried to improve in medical applications. For diseases like cancer, localized drug delivery is a highlight target involving bombarding a small area of a human’s body and this technology has not been completely achieved yet. The ultimate objective of this thesis is the development of wireless capsule robot controlled by a magnetic drive unit. A magnetic drive unit is a system that consists of electromagnets, which produce the magnetic field from outside of the patient’s body. The capsule robot, which is the slave robot in the system, moves inside a human’s gastrointestinal tract. This project is focused mainly on a human esophagus and all the experiments are done in a prototype of the human’s esophagus. Drug delivery for diseases like cancer is the objective of the capsule robot. The proposed design consists of a slave permanent magnet for the motion of capsule robot in a tube, a reservoir of drug, and a micro mechanical mechanism for drug release. The capsule robot is fabricated and developed in a 12mm length and 5mm diameter with the weight of 1.78 grams without the built-in permanent magnet. The drug delivery system is a semi-magnetized system, which can be controlled by an external magnetic field. It consists of a mechanical plunger and spring, which can be open and close through an external magnetic field manipulation. The amount of drug for a desired location can be controlled by manipulating the external magnetic field. To achieve this target, analytical modeling is conducted. A numerical simulation and an experimental setup demonstrate that a capsule robot in a human esophagus in a simple and multi channel system. Horizontal control is set for the capsule robot, using a custom-designed controller and a colored liquid is released with the external magnetic field. The present study with its fabricated prototype is a research is this area to prove the concept of wireless control of a robot inside a human body and the potential for a drug delivery system. It is expected that the results achieved in this project will help realize and promote capsule robot for medical treatments.

Craniofacial defects resulting from trauma and resection present many challenges to reconstruction due to the complex structure, combinations of tissues, and environment, with exposure to the oral, skin and nasal mucosal pathogens. Tissue engineering seeks to regenerate the tissues lost in these defects; however, the composite nature and proximity to colonizing bacteria remain difficult to overcome. Additionally, many tissue engineering approaches have further hurdles to overcome in the regulatory process to clinical translation. As such these studies investigated a two stage strategy employing an antibiotic-releasing porous polymethylmethacrylate space maintainer fabricated with materials currently part of products approved or cleared by the United States Food and Drug Administration, expediting the translation to the clinic. This porous space maintainer holds the bone defect open allowing soft tissue to heal around the defect. The space maintainer can then be removed and one regenerated in the defect. These studies investigated the individual components of this strategy. The porous space maintainer showed similar soft tissue healing and response to non-porous space maintainers in a rabbit composite tissue defect. In humans, the porous space maintainers were well tolerated and maintained a soft tissue envelope for closure after implantation of a bone regeneration technology. The antibiotic-releasing space maintainers showed release of antibiotics from 1-5 weeks, which could be controlled by loading and fabrication parameters. In vivo, space maintainers releasing a high dose of antibiotics for an extended period of time increased soft tissue healing over burst release space maintainers in an infected composite tissue defect model in a rabbit mandible. Finally, stabilization of bone defects and regeneration could be improved through scaffold structures and delivery of a bone forming growth factor. These studies illustrate the possibility of the two stage strategy for repair of composite tissue defects of the craniofacial complex.

Self-assembling peptides have emerged as new nanobiomaterials in the areas of nanoscience and biomedical engineering. In this category are self-assembling, ionic-complementary peptides, which contain a repeating charge distribution and alternating hydrophobic and hydrophilic residues in the amino acid sequence, leading to a unique combination of amphiphilicity and ionic complementarity. These peptides can self-assemble into stable nanostructures or macroscopic membranes that can withstand conditions of high temperature, extreme pH, many digesting enzymes and denaturation agents. Moreover, they exhibit good biocompatibility with various cultured mammalian cells, and do not have detectable immune responses when introduced into animals. These properties make them ideal materials for tissue scaffolding, regenerative medicine and drug delivery. This thesis focuses on the utilization of self-assembling peptides for hydrophobic anticancer drug delivery. The hydrophobic anticancer agent ellipticine was selected as a model drug. The studies include: (i) characterization of the photophysical properties of ellipticine in different environments; (ii) study of the formation of peptide-ellipticine complexes and the release kinetics; (iii) investigation of the cellular toxicity of the complexes and ellipticine uptake; (iv) study of the peptide sequence effect on the complex formation and in vitro delivery. Prior to applying ellipticine to the peptide-based delivery system, the fundamental studies on the effect of solution conditions, especially solvent polarity and hydrogen bonding, on the fluorescence of ellipticine were carried out. Ultraviolet (UV) absorption and fluorescence emission of ellipticine were found to be solvent/environment dependent. The absorption and emission maxima shifted to higher wavelengths (red shift) with increased solvent polarity. Large Stokes’ shifts were due to intramolecular charge transfer (ICT), which was enabled by large solvent polarity and hydrogen bonding of ellipticine with the solvents. The photophysical response of ellipticine to changes in solvent polarity and hydrogen bond formation could be used to infer the location of ellipticine in a heterogeneous medium, such as liposomes and cultured cells. EAK16-II, a model self-assembling peptide, was found to be able to stabilize ellipticine in aqueous solution. The equilibration time required to form peptide-ellipticine complex suspensions was found to be peptide concentration-dependent and related to the peptide critical aggregation concentration (CAC, ~0.1 mg/mL). With different combinations of EAK16-II and ellipticine concentrations, two molecular states (protonated or crystalline) of ellipticine could be obtained in the complexes. The release kinetics of ellipticine from the complex into egg phosphatidylcholine (EPC) vesicles (cell membrane mimics) was also affected by the peptide concentration used in the drug formulation. A higher peptide concentration resulted in a faster transfer rate, in relation to the size of the resulting complexes. Subsequent cellular studies on two cancer cell lines, A549 and MCF-7, showed that the complexes with protonated ellipticine were more effective against both cell lines, but their dilutions were not very stable. In addition, it was found that ellipticine uptake in both cell lines was very fast and through direct membrane permeation. Three peptides, EAK16-II, EAK16-IV and EFK16-II, either having a different charge distribution (EAK16-II vs. EAK16-IV) or hydrophobicity (EAK16-II vs. EFK16-II), were tested for the complexation and in vitro delivery of ellipticine. It was found that EAK16-II and EAK16-IV were able to stabilize protonated or crystalline ellipticine depending on the peptide concentration; EFK16-II, on the other hand, could stabilize neutral ellipticine molecules and ellipticine (micro)crystals. The viability results showed that the charge distribution of the peptides seemed not to affect the complex formation and its therapeutic efficacy in vitro; however, the increase in hydrophobicity of the peptides significantly altered the states of stabilized ellipticine and increased the stability of the complexes. This work provides essential information for peptide sequence design in the development of self-assembling peptide-based delivery of hydrophobic anticancer drugs.

The purpose of this research was to develop the pseudo-ternary phase diagrams for a model drug delivery system consisting of vitamin E (model drug) + soybean oil + surfactant + co-surfactant (anhydrous glycerol) + water. The model drug (vitamin E) was loaded in the oil phase. The effects of different surfactants (pure and mixed) on the phase diagram, especially the microemulsion region, were investigated. The influence of drug loading level on the phase diagram was also determined. The surfactants studied were Tween 20, Tween 80, Cremopher EL, and their mixtures. The size (area) of the microemulsion region of the phase diagram was found to be dependent on the type of surfactant used and the loading level of drug (vitamin E). The phenomenon of phase inversion from W/O microemulsion to O/W microemulsion was also investigated for the drug delivery system consisting of soybean oil (0% w/w Vitamin E loading or 30% w/w Vitamin E loading) + Tween 80 + anhydrous glycerol + water. The inversion of phases was detected by observing changes in the viscosity of the system.

Biomedical engineering is the application of engineering principles and techniques to the medical field. It combines the design and problem solving skills of engineering with medical and biological sciences to improve healthcare diagnosis and treatment. As the result of improvements in robotics and micro technology science in the 20th century, micro electromechanical system technology has joined with medical applications which results in micro robotic medical applications. Drug delivery is one of the most important and controversial topics which scientists and engineers have tried to improve in medical applications. For diseases like cancer, localized drug delivery is a highlight target involving bombarding a small area of a human’s body and this technology has not been completely achieved yet. The ultimate objective of this thesis is the development of wireless capsule robot controlled by a magnetic drive unit. A magnetic drive unit is a system that consists of electromagnets, which produce the magnetic field from outside of the patient’s body. The capsule robot, which is the slave robot in the system, moves inside a human’s gastrointestinal tract. This project is focused mainly on a human esophagus and all the experiments are done in a prototype of the human’s esophagus. Drug delivery for diseases like cancer is the objective of the capsule robot. The proposed design consists of a slave permanent magnet for the motion of capsule robot in a tube, a reservoir of drug, and a micro mechanical mechanism for drug release. The capsule robot is fabricated and developed in a 12mm length and 5mm diameter with the weight of 1.78 grams without the built-in permanent magnet. The drug delivery system is a semi-magnetized system, which can be controlled by an external magnetic field. It consists of a mechanical plunger and spring, which can be open and close through an external magnetic field manipulation. The amount of drug for a desired location can be controlled by manipulating the external magnetic field. To achieve this target, analytical modeling is conducted. A numerical simulation and an experimental setup demonstrate that a capsule robot in a human esophagus in a simple and multi channel system. Horizontal control is set for the capsule robot, using a custom-designed controller and a colored liquid is released with the external magnetic field. The present study with its fabricated prototype is a research is this area to prove the concept of wireless control of a robot inside a human body and the potential for a drug delivery system. It is expected that the results achieved in this project will help realize and promote capsule robot for medical treatments.

The peak and valley problems caused by oral administration, injection or other conventional methods, call for developing systems that can deliver therapeutics more effectively. As one of the techniques, diffusion-controlled drug release membranes have significant interest due to great ease with which they can be designed to achieve near-zeroth-order release kinetics. Since diffusion is the rate-limiting step in these systems, determining the permeability and diffusivity of drug molecules in the membrane is therefore important in evaluating drug release performance. This study focuses on the Membrane Permeation Controlled Release (MPC) system, which involves a non-porous (dense) membrane, comprising of two biopolymers, sericin and chitosan. Ciprofloxacin hydrochloride and (+)-cis-diltiazem hydrochloride were used as hydrophilic model drugs, and nitro-2-furaldehyde semicarbazone (Nitrofurazon) was used as a hydrophobic model drug. Permeation experiments were carried out in a semi-infinite reservoir/receptor system to simulate in-vitro drug release. The intrinsic permeability and diffusivity (P, D) of the drugs through the membranes were determined using a modified time-lag method based on short time permeation and mass balance method based on long time permeation. The partition coefficients Kd of the drugs in the membranes and the swelling degree of the membranes were determined by sorption/desorption experiments. The diffusivities of the drugs were also determined from the sorption/desorption kinetics. Over the experimental ranges tested, the drug concentration and membrane cross-linking did not have significant effects on these parameters presumably due to the relatively low drug concentrations and mild crosslinkings of the membranes. The diffusivity coefficients of ciprofloxacin hydrochloride, (+)-cis-diltiazem hydrochloride and nitrofurazon in the membranes were found to be in the range of (2.0-2.6)×〖10〗^(-9)±2.6×〖10〗^(-10) cm2/s, (2.5-2.6) ×〖10〗^(-9)±1.1×〖10〗^(-10) and (38-134) ×〖10〗^(-9)±33.1×〖10〗^(-9) (cm2/s), respectively, and their permeability coefficients were in the range of (24-29)×〖10〗^(-8),(51-52) ×〖10〗^(-8) and (131-169) ×〖10〗^(-8) (cm2/s), respectively. The partition coefficients were determined to be around 0.91±0.21, 25±0.12 and 26±0.31, respectively. The diffusivity coefficients determined from sorption experiments for ciprofloxacin hydrochloride, diltiazem hydrochloride and nitrofurazon were found to be in the range of (3.2-7.6) ×〖10〗^(-9)±6.3×〖10〗^(-8), (6-10) ×〖10〗^(-9)±2.6×〖10〗^(-8) and (15-18) ×〖10〗^(-9)±2.7×〖10〗^(-7) (cm2/s), respectively. Also the diffusivity coefficients determined from sorption experiments for ciprofloxacin hydrochloride, diltiazem hydrochloride and nitrofurazon were in the range of (20-47) ×〖10〗^(-9), (12-24) ×〖10〗^(-9) and (11-20) ×〖10〗^(-9) (cm2/s), respectively. Nonetheless the differences in the diffusivities calculated from permeation and sorption/desorption experiments are considered to be acceptable, in view of the different experimental techniques used in this work, for the purpose of comparison of the membrane diffusivity and permeability.