Rozprawy doktorskie: „Drug Delivery engineering”

1

Albed, Alhnan Mohamed. "Engineering polymethacrylic microparticles for oral drug delivery". Thesis, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543262.

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2

Wendel, Sebastian Oliver. "Bacteria as drug delivery vehicles". Diss., Kansas State University, 2014. http://hdl.handle.net/2097/18804.

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Doctor of Philosophy
Department of Chemical Engineering
Stefan H. Bossmann
Both chemotherapy for cancer treatment and antibiotic therapy for bacterial infections require systemic applications of the drug and a systemic application is always linked to a number of disadvantages. To circumvent these a targeted drug delivery system was developed. It utilizes the ability of phagocytes from the hosts own immune system to recognize and internalize antigens. Deactivated M. luteus, a non-pathogenic gram positive bacteria was loaded with high concentrations (exceeding the IC50 at least 60 fold in local intracellular concentration) the chemotherapeutics doxorubicin or DP44mt or with the bactericidal chlorhexidine. The modified bacteria is fed to phagocytes (Monocytes/Macrophages or neutrophils) and serves as protective shell for the transporting and targeting phagocyte. The phagocyte is recruited to the tumor site or site of infection and releases the drug along with the processed M. luteus via the exosome pathway upon arrival. The chlorhexidine drug delivery system was successfully tested both in vitro and in vivo, reducing the pathogen count and preventing systemic spread of a F. necrophorum infection in a mouse model. The doxorubicin drug delivery system reduced the viability of 4T1 cancer cells to 20% over the course of four days in vitro.

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3

Bansode, Ratnadeep V. "Functional ionic liquids in crystal engineering and drug delivery". Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14563.

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The objective of this research is to explore the use of ionic liquds in crystal engineering and drug delivery. Ionic liquids have a wide range of applications in pharmaceutical field due to their unique physicochemical propertie ssuch as chemical, thermal stability, low melting point, nonvolatility, nonflamability, low toxicity and recyclability which offer unique and interesting potential for pharmaceuitcal applications. Currently, many research groups are working on the development of ionic liquids to use in this field but there is need to develop systematic understanding about new techniques for synthesis and applications of ionic liquids to obtain new crystal form and potential of drug ionic salts. The synthesis of fifteen phosphonium ionic liquids under microwave irradiation and their physicochemical properties was investigated. The reaction time was significantly reduced compared to conventional methods, and higher yields were reported. The crystallisation of pharmaceutical drugs such as sulfathiazole, chlorpropamide, phenobarbital and nifedipine were investigated using imidazolium ionic liquids. The supramolecular complex of sulfathiazole and phenobarbital with imidazolium ionic liquids and polymorphic change in chlorpropamide was achieved. The ionic liquids provides unique environment for the crystallisation. The imidazolium salts of ibuprofen and diclofenac were synthesised and evaluated for physicochemical properties and their pharmaceutical performances especially transdermal absorption. The investigation of physicochemcal properties and pharmaceutical performance of imidazolium drug salts indicated opportunity to optimise lipophilicity and other physicochemical properties such as molecular size, osmolality, viscosity to achieve desired skin deposition and permeation. This study will provide a new approach to design of new drug salts develop using the interdisciplinary knowledge of chemical synthesis and drug delivery.
Social Justice Department, Government of Maharashtra, India.

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Bansode, Ratnadeep Vitthal. "Functional ionic liquids in crystal engineering and drug delivery". Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14563.

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The objective of this research is to explore the use of ionic liquds in crystal engineering and drug delivery. Ionic liquids have a wide range of applications in pharmaceutical field due to their unique physicochemical propertie ssuch as chemical, thermal stability, low melting point, nonvolatility, nonflamability, low toxicity and recyclability which offer unique and interesting potential for pharmaceuitcal applications. Currently, many research groups are working on the development of ionic liquids to use in this field but there is need to develop systematic understanding about new techniques for synthesis and applications of ionic liquids to obtain new crystal form and potential of drug ionic salts. The synthesis of fifteen phosphonium ionic liquids under microwave irradiation and their physicochemical properties was investigated. The reaction time was significantly reduced compared to conventional methods, and higher yields were reported. The crystallisation of pharmaceutical drugs such as sulfathiazole, chlorpropamide, phenobarbital and nifedipine were investigated using imidazolium ionic liquids. The supramolecular complex of sulfathiazole and phenobarbital with imidazolium ionic liquids and polymorphic change in chlorpropamide was achieved. The ionic liquids provides unique environment for the crystallisation. The imidazolium salts of ibuprofen and diclofenac were synthesised and evaluated for physicochemical properties and their pharmaceutical performances especially transdermal absorption. The investigation of physicochemcal properties and pharmaceutical performance of imidazolium drug salts indicated opportunity to optimise lipophilicity and other physicochemical properties such as molecular size, osmolality, viscosity to achieve desired skin deposition and permeation. This study will provide a new approach to design of new drug salts develop using the interdisciplinary knowledge of chemical synthesis and drug delivery.

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5

Lee, Heejin 1976. "Drug delivery device for bladder disorders". Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/58169.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2009.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 100-104).
Several pathologies associated with the bladder have wide impacts on society. Overactive bladder (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS) are chronic urological conditions characterized by pain, urinary frequency, and urgency with or without urinary incontinence. The estimated prevalence of OAB and IC/PBS is more than 34 million people in the U.S. alone. The American Cancer Society estimated a total of 68,810 new bladder cancer cases and 14,100 deaths from bladder cancer in the U.S. in 2008. Treatment options include oral medications, transdermal patches and intravesical instillations of therapeutic solutions. Direct intravesical instillation is considered an effective option, especially for those who remain refractory to oral and transdermal formulations due to intolerable side effects and skin irritations, respectively. Intravesical treatment, however, requires repeated instillations due to rapid drug voiding by urination, and the frequent urinary catheterizations involve risk of urinary infection and patient discomfort. An alternative, site-specific local delivery approach was created using a reservoir-based drug delivery device. This novel passive device was designed to release drug in a predetermined manner once inside the bladder. The device also possesses a retention feature to prevent accidental voiding. The device can be implanted into and retrieved from the bladder by a non-surgical cystoscopic procedure.
(cont.) In vivo tests using lidocaine, a local anesthetic used for IC/PBS treatment, showed that a sustained and local treatment to the bladder can be achieved with the device. The lidocaine bladder tissue concentration was found to be a thousand-fold higher than the lidocaine plasma concentration at three and six days in a rabbit model. The device approach has the potential to achieve localized therapy to the bladder while minimizing side effects. Future studies may use the device for other therapeutic agents in the treatment of OAB, IC/PBS, and bladder cancer.
by Heejin Lee.
Ph.D.

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6

Dellal, David (David M. ). "Microneedle gastric retention for drug delivery". Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/118020.

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Thesis: S.B., Massachusetts Institute of Technology, Department of Mechanical Engineering, June 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 25-28).
Traditional drug delivery methods, such as injection and ingestion, are associated with many challenges, including patient needle-phobia and patient adherence to a medication regimen. Biologic molecules, in particular, must be injected due to degradation by enzymes in the GI tract. Previous scientists have developed a method with the potential to inject macromolecules in the GI tract using microneedles that can implant themselves in the stomach lining; however, they do not provide long-term drug delivery. To create a controlled release micro injection, I hypothesize that a hooked needle will latch onto the muscularis mucosae layer in the stomach and reside.upwards of a week to deliver drugs. A number of trials and simulations have been designed to test the efficacy of this retention mechanism. Coupled with work in the creation of new pharmaceutical formulations, these needles can be loaded with any drug to ensure uptake into the blood stream over the course of several days.
by David Dellal.
S.B.

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7

Chauhan, Vikash Pal Singh. "Re-Engineering the Tumor Microenvironment to Enhance Drug Delivery". Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10405.

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Tumors are similar to organs, with unique physiology giving rise to an unusual set of transport barriers to drug delivery. Cancer therapy is limited by non-uniform drug delivery via blood vessels, inhomogeneous drug transport into tumor interstitium from the vascular compartment, and hindered transport through tumor interstitium to the target cells. Four major abnormal physical and physiological properties contribute to these transport barriers. Accumulated solid stress compresses blood vessels to diminish the drug supply to many tumor regions. Immature vasculature with high viscous and geometric resistances and reduced pressure gradients leads to sluggish and heterogeneous blood flow in tumors to further limit drug supply. Nonfunctional lymphatics coupled with highly permeable blood vessels result in elevated hydrostatic pressure in tumors to abrogate convective drug transport from blood vessels into and throughout most of the tumor tissue. Finally, a dense structure of interstitial matrix and cells serves as a tortuous, viscous, and steric barrier to diffusion of therapeutic agents. In this dissertation, I discuss the origins and implications of these barriers. I then highlight strategies I have developed for overcoming these barriers by modulating either drug properties or the tumor microenvironment itself to enhance the delivery and effectiveness of drugs in tumors.
Engineering and Applied Sciences

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8

Lei, Wang S. "Fabrication of drug delivery MEMS devices". Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/58271.

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Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2007.
"May 2007." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 19).
There is considerable amount of interest in the immediate treatment of personnel involved in high risk situations on the battlefield. A novel approach to drug delivery on the battlefield based on MEMS technology is discussed. By combining three separately fabricated layers, a single implantable drug delivery device capable of delivering up to 100 mm3 of a vasopressin solution was developed. In vitro release of vasopressin was observed and the I-V response of the bubble generator was characterized. Results show that the voltage at the time of release is ~11V while the current is ~0.35A, giving a power output of 3.79W. The time to total release of the drug was less than 2 minutes.
by Wang Lei.
S.B.

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9

Dyer, Robert J. (Robert Joseph) 1977. "Needle-less injection system for drug delivery". Thesis, Massachusetts Institute of Technology, 2003. http://hdl.handle.net/1721.1/89388.

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Forbes, Zachary Graham Barbee Kenneth A. "Magnetizable implants for targeted drug delivery /". Philadelphia, Pa. : Drexel University, 2005. http://dspace.library.drexel.edu/handle/1860/472.

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11

Yuan, Quan. "ENGINEERING OF POLYAMIDOAMINE (PAMAM) DENDRIMERS FOR GENE AND DRUG DELIVERY". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2766.

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Dendrimers are a class of polymers with a highly branched, three-dimensional architecture composed of an initiator core, several interior layers of repeating units and multiple surface groups. They have been recognized as the most versatile compositionally and structurally controlled nanoscale building blocks throughout the fields of engineering, materials science, chemistry, and biology, and they have been widely investigated for drug and gene delivery. Polyamidoamine (PAMAM) dendrimers have inherent properties for gene delivery because of their high buffering capacity, polycationic surface and numerous surface groups for biofunctionlization. This dissertation is organized into four independent sections. The first section investigates a series of polyamidoamine-polyethylene glycol-poly (D,L-lactide) (G3.0- PEG1500-PDLLA, G3.0-PEG6000-PDLLA, and G3.0-PEG12000-PDLLA) for gene delivery. Western Blot, fluorescence microscopy and flow cytometry were used as analysis methods. According to gene transfection studies, G3.0-PEG1500-PDLLA has been shown to be capable of inducing higher gene expression than the parent dendrimer compared to unmodified dendrimer, G3.0-PEG6000-PDLLA and G3.0-PEG12000- PDLLA. The second section aims to evaluate an epidermal growth factor (EGF)-containing PAMAM G4.0 dendrimer vector labeled with quantum dots for targeted imaging and nucleic acid delivery. Targeting efficiency, cell viability, proliferation, and intracellular signal transduction were evaluated. We found that EGF-conjugated dendrimers did not stimulate growth of epidermal growth factor receptor (EGFR)-expressing cells at the selected concentration. Consistent with this, minimal stimulation of post-receptor signaling pathways was observed. These nanoparticles can localize within cells that express the EGFR in a receptor-dependent manner, whereas uptake into cells lacking the receptor was low. Vimentin short hairpin RNA (shVIM) and yellow fluorescent protein (YFP) small interfering RNA (siRNA) were used to test the delivery and transfection efficiency of the constructed targeted vector. Significant knockdown of expression was observed, indicating that this vector is useful for introduction of nucleic acids or drugs into cells by a receptor-targeted mechanism. The third section introduces PEGylated polyamidoamine (PAMAM) dendrimer G4.0 conjugates with a novel bis-aryl hydrazone (BAH) linkage for gene delivery. It was found that the incorporation of BAH linkages into the vector significantly enhanced the buffering capacity of the vector with a high degree of PEGylation. According to gene transfection studies, this new vector has been shown to be capable of both transfecting more cells and inducing higher gene expression than the parent dendrimer. This work demonstrates that the use of the BAH linkage in coupling of PEG to the dendrimer helps maintain or increase the buffering capacity of the functionalized dendrimer and results in enhanced transfection. In the fourth section, we explored PAMAM dendrimer G4.5 as the underlying carrier to construct central nervous system (CNS) therapeutic nanoparticles and tested the buccal mucosa as an alternative absorption site for administration of the dendritic nanoparticles. Opioid peptide DPDPE was chosen as a model CNS drug. It was coupled to PAMAM dendrimer G4.5 with PEG or with PEG and transferrin receptor monoclonal antibody OX26. The therapeutic dendritic nanoparticles labeled with 5-(aminoacetamido) fluorescein (AAF) or fluorescein isothiocyanate (FITC) were studied for transbuccal transport using a vertical Franz diffusion cell system mounted with porcine buccal mucosa. Coadministration of bile salt sodium glycodeoxycholate (NaGDC) or application of mucoadhesive gelatin/PEG semi-interpenetrating network (sIPN) enhanced the permeability of dendritic nanoparticles by multiple folds. These results indicate that transbuccal delivery is a possible route for administration of CNS therapeutic nanoparticles. In summary, enhanced nucleic acids delivery by biofunctionalized PAMAM dendrimers was demonstrated. Transbuccal delivery of CNS therapeutic dendritic nanoparticles was demonstrated. These vectors will be useful in gene and drug delivery and could be extended to covalently conjugate other functional moieties for gene and drug delivery.

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Zhang, Hao. "Biodegradable microspheres for controlled drug/cell delivery and tissue engineering". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:28e1e1fd-d050-43f4-bddc-d0ec2cd49580.

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The synthetic biodegradable polymer poly(lactide-co-glycolide) (PLGA) has been widely explored as substrate biomaterials for controlled drug delivery and tissue engineering. ECM component heparin and bone mineral hydroxyapatite (HA) are attractive biomaterials which can functionalize the PLGA surface to improve cell cell response and to bring in the dual growth factor delivery, because heparin and HA both can improve cell responses and bind with various proteins. To combine the osteoconductivity of HA and the controlled drug release of PLGA microspheres, HA coated PLGA microspheres were developed by a 3 hour rapid HA precipitation on the PLGA microsphere surface. Effects of various fabrication parameters on microsphere and HA coating morphology were evaluated. This core-shell composite worked as a dual drug delivery device and demonstrated better cell cell response than PLGA microspheres without HA coating. Three different methods, including osmogen, extractable porogen and gas-foaming porogen, were evaluated to fabricate porous microspheres as injectable cell scaffolds in the tissue engineering. The gas-foaming method produced covered porous PLGA microspheres, on which a skin layer covered all the surface pores. The skin layer was hydrolysed by NaOH to control the surface porosity. The modified open porous microspheres have large continued surface areas between pores, which provided more continued areas for cell adhesion. The porous microspheres with controllable surface porosity and large surface continuity between pores could be novel injectable cell scaffolds. Heparin was immobilized on the open porous PLGA microspheres by a facile layer-by-layer assemble to combine the advantages of porous structure and the protein binding from heparin. The heparin-coated porous microspheres promoted cell adhesion, spreading, proliferation and osteogenic differentiation. Growth factor-like protein lactoferrin was immobilized on the heparin coated porous microspheres, which further enhanced MG-63 proliferation and osteogenic differentiation. The heparin-coated porous microspheres are promising multi-functional devices for controlled drug delivery and injectable cell delivery.

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ARNALDI, PIETRO. "Engineered biopolymeric systems for tissue engineering and drug delivery applications". Doctoral thesis, Università degli studi di Genova, 2022. http://hdl.handle.net/11567/1090662.

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The advent of biodegradable polymers constituted an important development tool for the realization of modern systems that can be used in biomedicine. Biodegradable polymers are essential when it is necessary to have easily workable materials with suitable properties to obtain an excellent biological response, for this reason they found applications in a wide range of tissue engineering and drug delivery systems. The main limitation of biopolymers is however in the properties of the materials themselves, sometimes too poor compared to the application field in which they need to be used to provide efficient support or therapy. The fabricated systems exposed in this thesis work, aim to provide useful tools not only for the improvement of previously developed polymeric systems but also for the achievement of new objectives in the field of neuronal cultures and controlled drug release. Specifically, Chitosan (CHI) has been used as a bulk material to produce engineered neuronal networks both at the two-dimensional level and, in the currently essential passage towards biologically more relevant models, at the 3D one. Gold nanorods (GNRs) have been used thanks to their good interaction with chitosan to provide thermo-plasmonic properties to a composite ink developed to be able to be printed using a commercial ink-jet printer, with the aim of creating a platform for simple and scalable neuronal networks stimulation for potential studies to better understand brain diseases (such as epilepsy). Moreover, chitosan was used to manufacture porous microparticles by means of air-assisted jetting technique and phase inversion gelation. These systems can be used in various fields such as tissue engineering, as a bottom-up 3D scaffolds, or in drug delivery for local drug release. Precisely in these two directions I worked during my PhD research activity to develop systems that, by using Chitosan as a base, exploited the interactions with other materials to improve the properties of the biopolymer. Interactions between CHI and graphitic materials have been exploited to provide to scaffolds, formed by assemblies of neurons and chitosan microspheres, electrical conductivity, mechanical strength, and degradative resistance in physiological and/or injury conditions. With this in mind, graphite oxide and graphite nanoplatelets were used both as filler and by electrostatic surface interaction, evaluating the different impact on the bulk properties of CHI and on the material-cell interface.Afterwards, with a conservative approach, I used CHI microparticles as a potential carrier for drug release in the gastrointestinal tract. The poor degradative resistance of CHI in harsh conditions made it necessary to apply a surface coating. The biocompatible synthetic polymer already widely used in drug delivery Poly-(styrene-co-maleic anhydride) (PSMA), thanks to the strong grafting reaction with CHI, made it possible to obtain a system with a limited burst effect in the release of molecules in the first hour of administration. The overall findings of this thesis support the efforts in making novel bio-fabricated systems as greatly promising tools for tissue engineering and controlled drug delivery. Specifically, the interaction between biopolymers and synthetic polymers can introduce interesting innovations in the fields of drug delivery, while interactions between biopolymers and carbon-based materials could be a key point for the next years perspective in neuro-engineering.

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Xu, Leyuan. "Engineering of Polyamidoamine Dendrimers for Cancer Therapy". VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3773.

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Dendrimers are a class of polymers with a highly branched, three-dimensional architecture comprised of an initiator core, several interior layers of repeating units, and multiple active surface terminal groups. Dendrimers have been recognized as the most versatile compositionally and structurally controlled nanoscale building blocks for drug and gene delivery. Polyamidoamine (PAMAM) dendrimers have been most investigated because of their unique structures and properties. Polycationic PAMAM dendrimers form compacted polyplexes with nucleic acids at physiological pH, holding great potential for gene delivery. Folate receptor (FRα) is expressed at very low levels in normal tissues but expressed at high levels in cancers in order to meet the folate demand of rapidly dividing cells under low folate conditions. Our primary aim was to investigate folic acid (FA)-conjugated PAMAM dendrimer generation 4 (G4) conjugates (G4-FA) for targeted gene delivery. The in vitro cellular uptake and transfection efficiency of G4-FA conjugates and G4-FA/DNA polyplexes were investigated in Chapter 4. It was found the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes was in a FR-dependent manner. Free FA competitively inhibited the cellular uptake of G4-FA conjugates and G4-FA/DNA polyplexes. G4-FA/DNA polyplexes were preferentially taken up by FR-positive HN12 cells but not FR-negative U87 cells. In contrast, the cellular uptake of G4 dendrimers and G4/DNA polyplexes was non-selective via absorptive endocytosis. G4-FA conjugates significantly enhanced cytocompatibility and transfection efficiency compared to G4 dendrimers. This work demonstrates that G4-FA conjugates allow FR-targeted gene delivery, reduce cytotoxicity, and enhance gene transfection efficiency. The in vivo biodistribution of G4-FA conjugates and anticancer efficacy of G4-FA/siRNA polyplexes were investigated in Chapter 5. Vascular endothelial growth factor A (VEGFA) is one of the major regulators of angiogenesis, essential for the tumor development. It was found G4-FA/siVEGFA polyplexes significantly knocked down VEGFA mRNA expression and protein release in HN12 cells. In the HN12 tumor-bearing nude mice, G4-FA conjugates were preferentially taken up by the tumor and retained in the tumor for at least 21 days following intratumoral (i.t.) administration. Two-dose i.t. administration of G4-FA/siVEGFA polyplexes significantly inhibited tumor growth by lowering tumor angiogenesis. In contrast, two-dose i.t. administration of G4/siVEGFA polyplexes caused severe skin lesion, presumably as a result of local toxicity. Taken together, this work shows great potential for the use of G4-FA conjugates in targeted gene delivery and cancer gene therapy. We also explored polyanionic PAMAM dendrimer G4.5 as the underlying carrier to carry camptothecin (CPT) for glioblastoma multiforme therapyin Chapter 6. "Click" chemistry was applied to improve polymer-drug coupling reaction efficiency. The CPT-conjugate displayed a dose-dependent toxicity with an IC50 of 5 μM, a 185-fold increase relative to free CPT, presumably as a result of slow release. The conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. This work indicates highly efficient "click" chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery. Immobilizing PAMAM dendrimers to the cell surface may represent an innovative method of enhancing cell surface loading capacity to deliver therapeutic and imaging agents. In Chapter 7, macrophage RAW264.7 (RAW) was hybridized with PAMAM dendrimer G4.0 (DEN) on the basis of bioorthogonal chemistry. Efficient and selective cell surface immobilization of dendrimers was confirmed by confocal microscopy. It was found the viability and motility of RAW-DEN hybrids remained the same as untreated RAW cells. Furthermore, azido sugar and dendrimer treatment showed no effect on intracellular AKT, p38, and NFκB (p65) signaling, indicating that the hybridization process neither induced cell stress response nor altered normal signaling. This work shows the feasibility of applying bioorthogonal chemistry to create cell-nanoparticle hybrids and demonstrates the noninvasiveness of this cell surface engineering approach. In summary, these studies indicate surface-modification of PAMAM dendrimer G4 with FA can effectively target at FR-positive cells and subsequently enhance in vitro transfection efficiency and in vivo gene delivery. G4-FA conjugates may serve as a versatile targeted gene delivery carrier potentially for cancer gene therapy. PAMAM dendrimers G4.5 may serve as a drug delivery carrier for the controlled release of chemotherapeutics. The immune cell-dendrimer hybrids via bioorthogonal chemistry may serve as an innovative drug and gene delivery carrier potentially for cancer chemotherapy. Taken together, engineering of PAMAM dendrimers may advance anticancer drug and gene delivery.

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Mualem-Burstein, Odelia Wheatley Margaret A. "Drug loading onto polymeric contrast agents for ultrasound drug delivery /". Philadelphia, Pa. : Drexel University, 2008. http://hdl.handle.net/1860/2811.

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Ostroha, Jamie L. Lowman Anthony M. Dan Nily. "PEG-based degradable networks for drug delivery applications /". Philadelphia, Pa. : Drexel University, 2006. http://dspace.library.drexel.edu/handle/1860%20/842.

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Aduba, Donald Jr. "Semi-interpenetrating nanofiber scaffolds for transbuccal drug delivery". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2743.

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The oral buccal mucosa is a promising absorption site for drug administration because it is permeable, highly vascularized and allows ease of administration. Although there are many platforms that have been used for drug delivery, nanofiber scaffolds as a platform for local or systemic drug delivery through the oral mucosa have not been fully explored. In this thesis, we fabricated a biocompatible electrospun gelatin nanofiber scaffold for local drug delivery at the oral mucosa. To stabilize the electrospun gelatin nanofibers and allow non-invasive incorporation of therapeutics into the scaffold, photo-reactive polyethylene-glycol (PEG)-diacrylate was employed to crosslink the scaffold to form semi-interpenetrating networks (sIPNs). The crosslinking parameters including concentration of PEG-diacrylate, amount of photoinitiator, and crosslinking incubation time of the scaffold were systematically investigated. The resulting scaffolds were characterized in terms of their morphology, tensile properties, porosity, swelling and degradation. The results confirmed that gelatin electrospun nanofiber scaffolds after being photo-crosslinked with PEG-diacrylate retain fiber morphology and show improved structural stability and mechanical properties. The mucoadhesiveness of the sIPN nanofiber scaffold was confirmed. Nystatin, a drug to treat fungal infections such as candidiasis was loaded to the sIPN nanofiber scaffold. Its release kinetics was also studied.

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Ho, Duc Hong Linh 1978. "Packaging for a drug delivery microelectromechanical system". Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/30262.

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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2005.
Includes bibliographical references (p. 52-55).
Local drug delivery is a fast expanding field, and has been a center of attention for researchers in medicine in the last decade. Its advantages over systemic drug delivery are clear in cancer therapy, with localized tumors. A silicon microelectromechanical drug delivery device was fabricated for the purpose of delivering chemotherapeutic agents such-as carmustine, a potent brain cancer drug, directly to the site of the tumor. Limitations in the delivery capacity of the device led to the design of a new package. This package is made from thermally bonded Pyrex® 7740 frames that are anodically bonded to the drug delivery chip. It increases the capacity of the chip, is smaller than the previous package and possesses true hermeticity, because of the bonding processes involved. This work describes the fabrication steps of the new package and a problem with the thermal bonding of Pyrex® frames preventing the achievement of a package true to the original design. A temporary solution was devised and the completed package was tested with regards to its intended goals. It managed to increase the load capacity of the chip by a, factor of 10, with potential for more, while decreasing the overall size of the package. Short-term hermeticity was achieved for this package by using a UV-cured epoxy to bond some pieces, which was not in the original design. Future work will focus on finding a permanent solution to the aforementioned problem, and directions for it were suggested.
by Hong Linh Ho Duc.
S.M.

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Guan, Jingjiao. "Microfabricated particulate devices for drug delivery". Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1118247862.

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Thesis (Ph. D.)--Ohio State University, 2005.
Title from first page of PDF file. Document formatted into pages; contains xxiii, 163 p.; also includes graphics. Includes bibliographical references (p. 118-123). Available online via OhioLINK's ETD Center

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Wilson, Andrew Nolan. "Drug delivery with feedback control in bioresponsive hydrogels". Thesis, Clemson University, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3624014.

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Bioresponsive hydrogels are emerging with technological significance in targeted drug delivery, biosensors and regenerative medicine. The design challenge is to effectively link the conferred biospecificity with an engineered response tailored to the needs of a particular application. Moreover, the fundamental phenomena governing the response must support an appropriate dynamic range, limit of detection and the potential for feedback control. The design of these systems is inherently complicated due to the high interdependency of the governing phenomena that guide sensing, transduction and actuation of the hydrogel. The objective of the dissertation is to review the current state of bioresponsive hydrogel technology and introduce a method of extending the technology through integrated control loops; explore fundamental phenomena which affect ion transport within biomimetic hydrogels; and investigate, via in silico studies, the fundamental design parameters for the implementation of a feedback control loop within a bioresponsive hydrogel.

In one study, effects of valence number, temperature and polymer swelling on release profiles of monovalent potassium and divalent calcium ions elucidates mechanistic characteristics of polymer interactions with charged species. For comparison, ions were loaded during hydrogel formulation or loaded by partitioning following construct synthesis. Using the Korsmeyer-Peppas release model, the diffusional exponents were found to be Fickian for pre- and post-loaded potassium ions while preloaded calcium ions followed an anomalous behavior and postloaded calcium ions followed Case II behavior. Results indicate divalent cations interact through cation-polyelectrolyte anion complexation while monovalent ions do not interact with the polymer. Temperature dependence of potassium ion release was shown to follow an Arrhenius relation and calcium ion release was temperature independent.

In another study, data generated from the previous Chymotrypsin system is used to build and validate a finite element model. The model provides insight into key engineering parameters for the design of an enzymatically actuated, feedback controlled release. A drug delivery platform comprising a biocompatible, bioresponsive hydrogel and possessing a covalently tethered peptide-inhibitor conjugate was engineered to achieve stasis, via a closed control loop, of the external biochemical activity of the actuating enzyme. The FEM model was used to investigate the release of a competitive protease inhibitor, MAG283, via cleavage of Acetyl-Pro-Leu-Gly|Leu-MAG-283 by MMP-9 in order to achieve targeted homeostasis of MMP-9 activity, a goal for the treatment of chronic wound pathophysiology. It was found the key engineering parameters for the delivery device are the radii of the hydrogel microspheres and the concentration of the peptide-inhibitor conjugate loaded into the hydrogel.

Homeostatic drug delivery, where the focus turns away from the drug release rate and turns towards achieving targeted control of biochemical activity within a biochemical pathway, is an emerging approach in drug delivery methodologies for which the potential has not yet been fully realized. By understanding mechanistic phenomena and key engineering parameters for design, advancements in bioresponsive hydrogels will continue to produce novel technologies in biomedical applications.

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Ho, Duc Hong Linh 1978. "Emergency delivery of Vasopressin from an implantable MEMS rapid drug delivery device". Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/52790.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2009.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student submitted PDF version of thesis.
Includes bibliographical references.
An implantable rapid drug delivery device based on micro-electro-mechanical systems (MEMS) technology was designed, fabricated and validated for the in vivo rapid delivery of vasopressin in a rabbit model. In vitro characterization of device performance found the device capable of reliably and reproducibly delivering 85% of its loaded drug solution. A comparison of intraperitoneal and subcutaneous injections of vasopressin in rabbits was performed to determine the implantation location for the device. Both routes of delivery were found to be viable implantation locations, and the less invasive subcutaneous site was chosen. Vasopressin was released from the subcutaneously implanted device in anesthetized rabbits and found to exert a measurable effect on blood pressure. The bioavailability of vasopressin delivered from the device was found to be 6.2% after one hour. Proof-of-concept experiments were also conducted to address long-term stability of drugs in the implanted device and wireless activation of the device. These experiments defined areas of future research for improvement of the device.
by Hong Linh Ho Duc.
Ph.D.

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22

Bright, Anne M. "Towards an improved ocular drug delivery system". Thesis, Aston University, 1992. http://publications.aston.ac.uk/9801/.

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The ultimate aim of this project was to design new biomaterials which will improve the efficiency of ocular drug delivery systems. Initially, it was necessary to review the information available on the nature of the tear fluid and its relationship with the eye. An extensive survey of the relevant literature was made. There is a common belief in the literature that the ocular glycoprotein, mucin, plays an important role in tear film stability, and furthermore, that it exists as an adherent layer covering the corneal surface. If this belief is true, the muco-corneal interaction provides the ideal basis for the development of sustained release drug delivery. Preliminary investigations were made to assess the ability of mucin to adhere to polymer surfaces. The intention was to develop a synthetic model which would mimic the supposed corneal/mucin interaction. Analytical procedures included the use of microscopy (phase contrast and fluorescence), fluorophotometry, and mucin-staining dyes. Additionally, the physical properties of tears and tear models were assessed under conditions mimicking those of the preocular environment, using rheological and tensiometric techniques. The wetting abilities of these tear models and opthalmic formulations were also investigated. Tissue culture techniques were employed to enable the surface properties of the corneal surface to be studied by means of cultured corneal cells. The results of these investigations enabled the calculation of interfacial and surface characteristics of tears, tear models, and the corneal surface. Over all, this work cast doubt on the accepted relationship of mucin with the cornea. A corneal surface model was designed, on the basis of the information obtained during this project, which would possess similar surface chemical properties (i.e. would be biomimetic) to the more complex original. This model, together with the information gained on the properties of tears and solutions intended for ocular instillation, could be valuable in the design of drug formulations with enhanced ocular retention times. Furthermore, the model itself may form the basis for the design of an effective drug-carrier.

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Nguyen, Phuong Ph D. Massachusetts Institute of Technology. "Amphiphilic linear-dendritic block copolymers for drug delivery". Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/42432.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2007.
Includes bibliographical references.
Polymeric drug delivery systems have been widely used in the pharmaceutical industry. Such systems can solubilize and sequester hydrophobic drugs from degradation, thereby increasing circulation half-life and efficacy. However, there are still challenges in the design of drug delivery vehicles to achieve efficient drug delivery in a site-specific manner. In this thesis, an amphiphilic linear-dendritic block copolymer was designed, synthesized, and applied as a new polymeric drug delivery platform. First, to develop the drug delivery vehicle, an ABA dendritic-linear-dendritic block copolymer consisting of poly(amidoamine) (PAMAM) and poly(propylene oxide) (PPO) was synthesized. In order to determine the viability of the linear-dendritic block copolymer as a drug delivery vehicle, the solution-phase self-assembly behavior and the self-assembled structures were characterized experimentally and through molecular dynamics simulations. The triblock self-assembles in aqueous media to form stable micelles with low CMC values. Dynamic light scattering results and TEM indicate the formation of particles ranging from 9 to 18 nm in diameter, with smaller diameters exhibited at higher generations. Static light scattering also confirmed the trend where the aggregation number decreased with higher generations. The experimental characterization results indicated that the physical characteristics of the PPO-PAMAM micelles were desirable and within the design specifications necessary for drug delivery. The experimental results were utilized to set up simulations where further knowledge of the microstructure of the micelles formed could be gained. It was found that the block copolymers simulated formed micelles in the same size range that was seen experimentally. However, the simulations indicated that the micelles displayed greater asphericity than dendrimers.
(cont) Backfolding of the terminal amine ends was encountered, which would have implications for the configuration and spacing of any additional targeting ligand attached to the dendritic ends. Further analysis revealed that with increasing generation, the porosity of the micelles increased, which could affect the diffusion rate of drugs released out of the system. Another important finding detailed the preferential localization of a model hydrophobid drug, triclosan, in an equilibrated micelle structure. Additional experiments were performed to assess the feasibility of the nanoparticles for drug delivery applications. Drug loading studies were performed with a model hydrophobic drug, triclosan, resulting in high loading efficiencies. In comparison, linear block copolymers were half as efficient in loading triclosan. It was determined that the dendritic block synergistically increased the drug loading due to either acting as an additional block capable of encapsulating drug or sterically favoring the seclusion of the drug in the core. The linear-dendritic block copolymer synthesized was found to be a promising candidate for drug delivery due to its relative stability in aqueous solution and its drug encapsulation and release properties. Overall, the linear-dendritic block copolymer displayed physical characteristics and self-assembly behavior that satisfied the design criteria for a viable drug delivery vehicle. As a further step, the potential benefits of the novel linear-dendritic architecture were explored in two different drug delivery applications. First, PPO-PAMAM was explored as a circulating nanoparticle with the capability of multivalently targeting to specific cells, due to the presence of the dense functional groups on the dendritic block forming the corona of the micelles. PPO-PAMAM was functionalized with galactose and targeted to hepatocellular carcinoma cells. It was found that the polymer was not cytotoxic and could bind to the asialoglycoprotein receptor.
(cont) The galactose-functionalized micelles were loaded with a chemotherapeutic, doxorubicin, and delivered to the carcinoma cells more efficiently than non-functionalized micelles and bare doxorubicin. The results from in vitro testing showed that PPO-PAMAM micelles with targeting capability are promising circulating drug delivery vehicles. In order to ensure success of subsequent testing in vivo of the targeted linear-dendritic block copolymer system, some improvements to the system were explored. First, PPO-PAMAM micelles were stabilized by physical entrapment of the hydrophobic core. An emulsion polymerization of hydrophobic methacrylate monomers created an interpenetrating polymer keeping the micelles intact at concentrations below the CMC and in a solubilizing solvent, methanol. This improvement would ensure that once injected into the bloodstream, the micelles would not destabilize and release high concentrations of drug. Another improvement that was explored was the synthesis of a new linear-dendritic block copolymer composed of a hydrophobic poly(amino acid) and a polyester dendron. Additionally, poly(ethyleneglycol) (PEG) groups were attached to the outer surface of the polyester dendron. The new system synthesized has a low CMC and is thermodynamically slow to break apart in the bloodstream. Furthermore, the micelles formed would be able to circulate for longer times with PEG aiding in evading the reticuloendothelial system. The second drug delivery application explored, which advantageously utilized the dendritic blocks on the outer surface of the block copolymer micelles was as a localized drug delivery coating created by the layer-by-layer (LbL) assembly approach. The electrostatic LbL assembly approach offers large potential in the area of drug delivery from thin films and surfaces; however, because the processing technique is aqueous-based, there have been few strategies proposed to incorporate hydrophobic molecules into these films.
(cont) Here we created an LbL film that is capable of incorporating hydrophobic drug at high loadings via encapsulation with linear-dendritic block copolymer micelles and demonstrate for the first time release times of a hydrophobic antibacterial agent over a period of several weeks--a significant improvement over reports of other micelle-encapsulated thin films with release times of several minutes. The PAMAM block, which is polycationic, enabled LbL deposition with negatively charged poly(acrylic acid) (PAA). The stable PPO-PAMAM micelles incorporated into the LbL films encapsulated a hydrophobic bactericide, triclosan. Film thickness and UV-vis measurements confirm the formation of the LbL film and incorporation of triclosan into the film. Fluorescence measurements of PPO-PAMAM/PAA films with pyrene indicated the presence of hydrophobic domains in the film. GISAXS revealed regular spacing of approximately 10.5 nm in the direction parallel to the film substrate, which is approximately the same size as the PPO-PAMAM micelles in aqueous solution. Volume fraction measurements based on elemental analysis and TGA confirm the GISAXS data. An in vitro release study revealed long release times of triclosan on the order of weeks, and a Kirby Bauer test was performed on Staphylococcus Aureus demonstrating that the drug released was still active to inhibit the growth of bacteria. Linear-dendritic block copolymer micelles were successfully used in two different drug delivery applications where the dendritic block could be fully utilized. It is hoped that with the research and results presented in this thesis further development of this drug delivery platform can result in a product successfully treating a serious disease.
by Phuong Nguyen.
Ph.D.

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24

Angel, Aimee B. (Aimee Brigitte) 1977. "A controllable, nano-volumetric, transdermal drug delivery device". Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/89352.

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Pavlov, Atanas (Atanas Ivanov). "Needle-free drug delivery using shock wave techniques". Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/36245.

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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2006.
"June 2006."
Includes bibliographical references (leaves 93-94).
A recent advancement in the area of needle-free injection systems has been the development of devices capable of epidermal delivery of powder medications. These devices use high-pressure compressed gas to accelerate drug particles 2 to 50 gpm in size to velocities of 200 to 1000 m/s. At these speeds the particles have sufficient momentum to penetrate the skin barrier and reach the viable epidermal layers. The devices offer much better control over the depth of penetration than traditional hypodermic needles, a factor particularly important in vaccine delivery. However they still have not found wide spread use, because of their cost. We studied the parameters determining the performance of these devices and used that knowledge to create a simple and reusable device capable of delivering 3 to 10 mg of powder formulation to the viable epidermis. Furthermore we showed that hydrogen-oxygen combustion could be used to create the shock wave required to accelerate the drug particles. This proves that portable reusable devices powered by hydrogen can be constructed and used for vaccine and medication delivery.
by Atanas Pavlov.
S.M.

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26

Mitragotri, Samir. "Ultrasound-mediated transdermal drug delivery : mechanisms and applications". Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/11263.

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Cohen, Sarah J. (Sarah Jennifer). "Biocompatibility of an implantable ophthalmic drug delivery device". Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/39871.

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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007.
Includes bibliographical references (p. 90-94).
Diseases of the posterior eye present clinicians with a treatment challenge mainly due to the region's inaccessible location. Several drugs, including those available for the treatment of exudative age-related macular degeneration, are currently delivered by periodic injection into the eyeball. To avoid the risks and complications associated with this method, several implantable, timed release devices have been investigated to deliver these drugs directly to affected areas. Draper Laboratory and Massachusetts Eye and Ear Infirmary have proposed an implantable, fully programmable, mechanical device for long-term drug delivery to the eye wall. To investigate the biocompatibility of this solution, test devices containing gears or a ball bearing were designed to mimic elements of its moving parts, geometry and materials. Cell culture studies identified a polytetrafluoroethylene filter with 100m pores as a promising addition to seal devices from interaction with fibroblasts. Test devices with or without this membrane were implanted on the rabbit eye for 2 or 10 week periods. They were evaluated mechanically after implant, and surrounding tissues were inspected histologically. Gross observation revealed a significant amount of tissue formation around the devices, especially in the conjunctiva.
(cont.) Devices had to be cut away from the eye surface, and there was a significant amount of tissue inside the gear devices. Notably less tissue surrounded and invaded the ball bearing devices. Histological evaluation identified the invading tissue as fibrotic at both time points, though significantly more was seen at longer implant times. Eye wall tissue was typically unharmed during implant, though an additional layer of fibrosis between the eye and the device was common. Mechanical testing of long-term gear devices after implant revealed a 1000 fold increase in torque required to turn the elements, but long-term ball bearing devices were significantly less affected (100 fold increase). Torque also increased in devices with membrane covers, due to similar fibrosis. However, in these implants, tissue was forced to enter through only the 0.002in. openings around the base of the devices. Biocompatibility for this device may best be achieved by minimizing the amount of relative micro motion allowed between the device and the eye and by sealing all openings with a porous polytetrafluoroethylene filter.
by Sarah J. Cohen.
S.M.

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Fuller, Jason E. Ph D. Massachusetts Institute of Technology. "Non-viral drug delivery systems for immune modulation". Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/43202.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008.
Includes bibliographical references.
Biodegradable polymer particles have diverse applications in drug delivery. The main objective of this thesis was to apply these delivery systems to modulating the immune system. We optimized particle formulations for the delivery of three novel immune modulating compounds, small inhibiting RNA, immunostimulatory RNA, and 3-1,6-glucan. Because microparticles formulated from PLGA and Poly(3-amino-ester) have been shown to target and transfect DNA in antigen presenting cells we studied their ability to knock down genes with siRNA. We discovered ways to improve particle morphology, encapsulation efficiency, and buffer the acidic microenvironment of degrading microparticles, all significant challenges with siRNA. We next used fluorescent nanoparticles as imaging agents to study these siRNA delivery challenges. Cationic polymers were deposited on the surface of fluorescent core-shell silica nanoparticles electrostatically; the resulting particles were complexed with a nucleic acid and delivered to cells. We screened a library of 60 unique formulations to identify an optimal protocol for DNA transfection demonstrating efficiency equal to PEI. We screened a library of 30 unique formulations for siRNA delivery and demonstrated knockdown of 25%. Confocal imaging showed that polymer coating increased localization of the nanoparticles to the cell membrane, endosomes and nucleus. Polycation surface-modification seemed broadly extendable to a biodegradable polymer particle delivery system for siRNA. Cationic lipids or lipidoids were promising polycations to apply to biodegradable particle surface-modification because they efficiently deliver siRNA. We screened 30 lipidoid formulations for optimal knockdown in P388-D1 macrophage cells, and isolated formulations that demonstrated up to 40% knockdown in P388-D1, 80% knockdown in primary macrophage, and 65% knockdown in mouse macrophage in vivo.
(cont.) We formulated microparticles from PLGA/lipidoid blends that demonstrated nearly 80% knockdown in P388-D1. This same formulation also induced sequence specific interferon response to immunostimulatory RNA in human peripheral blood mononuclear cells. Finally we used PLGA microparticles to deliver a novel fungal cell wall component, 3-1,6-glucan, to neutrophils. This approach induced neutrophil expression of reactive oxygen species in vitro. In a mouse model of blood stream Candida albicans infection 60% of mice survived lethal doses when treated with the particles.
by Jason E. Fuller.
Ph.D.

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Verma, Malvika. "Gastric resident systems for large dose drug delivery". Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/123066.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2019
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 154-176).
Lack of medication adherence is a worldwide problem. As many as 50-70% of patients have trouble following treatment recommendations. Whereas adherence is driven by many factors including the socioeconomic status of a patient and the quality of the health care team, drug regimen complexity also affects treatment outcomes. For example, adherence decreases as the number of pills per dose and the number of doses per day increases. For diseases where potent medications are available, depot formulations provide sustained drug release to simplify dosing. For diseases lacking potent compounds for treatment, there remains an unmet need for depot systems that could transform medication adherence. Tuberculosis (TB) is one such disease with a high pill burden, where poor patient adherence to the treatment regimen is a major cause of treatment failure and contributes to the emergence of drug-resistant TB strains.
For example, an average 60-kg patient with TB needs to take 3.3 g of antibiotics per day, which is a dose that exceeds the largest swallowable capsule and current depot systems. According to the World Health Organization (WHO), 10 million people developed TB in 2017 with a global economic burden amounting to $12 billion annually. This thesis presents a solution to the challenge of prolonged dosing for regimens such as TB that require multigram drug dosing. First, a gastric resident system (GRS) compatible with transesophageal administration was designed using biocompatible materials. The GRS consists of a series of drug pills on a coiled superelastic nitinol wire; the ends are protected with a retainer and tubing. Safe administration, gastric retention for 1 month, and retrieval of the GRS were demonstrated in a swine model. Next, sustained release formulations for 6 TB antibiotics were formulated into drug-polymer pills, and first-order drug release kinetics were achieved in vitro.
Then, the GRS was demonstrated to be capable of safely encapsulating and releasing 10 grams of an antibiotic over the period of weeks in a swine model. Lastly, end-user assessment was evaluated with a field questionnaire in India and an economic model to estimate the impact of the GRS on the health care system. There are multiple applications of the GRS in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.
"Funding and Resources: -- Bill and Melinda Gates Foundation -- National Institutes of Health -- National Science Foundation Graduate Research Fellowship -- MIT Tata Center and leadership team for believing in and guiding our project"
by Malvika Verma.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering

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30

Kambhampati, Siva Pramodh. "Dendrimer based nanotherapeutics for ocular drug delivery". Thesis, Wayne State University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3700635.

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PAMAM dendrimers are a class of well-defined, hyperbranched polymeric nanocarriers that are being investigated for ocular drug and gene delivery. Their favorable properties such as small size, multivalency and water solubility can provide significant opportunities for many biologically unstable drugs and allows potentially favorable ocular biodistribution. This work exploits hydroxyl terminated dendrimers (G4-OH) as drug/gene delivery vehicles that can target retinal microglia and pigment epithelium via systemic delivery with improved efficacy at much lower concentrations without any side effects.

Two different drugs Triamcinolone acetonide (TA) and N-Acetyl Cysteine (NAC) conjugated to G4-OH dendrimers showed tailorable sustained release in physiological relevant solutions and were evaluated in-vitro and in-vivo. Dendrimer-TA conjugates enhanced the solubility of TA and were 100 fold more effective at lower concentrations than free TA in its anti-inflammatory activity in activated microglia and in suppressing VEGF production in hypoxic RPE cells. Dendrimers targeted activated microglia/macrophages and RPE and retained for a period of 21 days in I/R mice model. The relative retention of intravitreal and intravenous dendrimers was comparable, if a 30-fold intravenous dose is used; suggesting intravenous route targeting retinal diseases are possible with dendrimers. D-NAC when injected intravenously attenuated retinal and choroidal inflammation, significantly reduced (∼73%) CNV growth at early stage of AMD in rat model of CNV. A combination therapy of D-NAC + D-TA significantly suppressed microglial activation and promoted CNV regression in late stages of AMD without causing side-effects.

G4-OH was modified with linker having minimal amine groups and incorporation of TA as a nuclear localization enhancer resulted in compact gene vectors with favorable safety profile and achieved high levels of transgene expression in hard to transfect human retinal pigment epithelial cells (hRPE). Prepared dendrimer-gene complexes were non-toxic and achieved significant cell uptake and safe delivery of gene in to the nucleus. Further, polyethylene glycol (PEG) surface coating enhanced colloidal stability in physiological relevant solutions without affecting its transfection efficacy.

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Alipourasiabi, Niloofar. "Modeling of Controlled Drug Delivery from a Chitosan Microparticle". University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470352546.

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Huynh, Grace. "Convection administered drug delivery to the brain". Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3251934.

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Wikman, Maria. "Rational and combinatorial protein engineering for vaccine delivery and drug targeting". Doctoral thesis, Stockholm : Department of Biotechnology, Royal Insitute of Technology, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-231.

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Wang, Yiwei. "Improving 3D matrices for tissue engineering using advanced drug delivery techniques". Thesis, Kingston University, 2007. http://eprints.kingston.ac.uk/20391/.

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Micro/macroporous matrices comprising a continuous phase of poly([epsilon]-caprolactone) . (PCL) and a dispersed phase of water soluble particles (lactose and gelatin) with defined size range (45-90, 90-125 and l25-250[mu]m) were produced by rapid cooling solutions of PCL in acetone followed by solvent extraction from the hardened material. This novel approach enables high loading (29-44% w/w) of particles (lactose and gelatin) to be achieved in PCL matrices by suspension of particulates in the PCL solution prior to casting. Highly efficient protein release (90%) was obtained over time periods of 3 days to 3 weeks by variation of particle loading and particle size range. The good particle distribution throughout the matrix and efficient extraction of the water-soluble phase allows formation of a macroporous structure with defined pore architecture by incorporation of particles of a specific shape and size range. SEM analysis revealed the porous surface morphology. Micro computed tomography (micro-CT) and image analysis enabled visualization of the internal 3-D pore structure, quantification of the frequency distribution of equivalent pore diameter and porosity (%) in peL matrices. Micro/macroporous PCL tubes exhibited a burst strength of 125 to l45MPa under hydrostatic loading at 37[degree]C and good recovery of tube diameter following short-duration flow rates of 1000 ml/min under continuous increasing and pulsatile conditions. Sustained release of incorporated enzymes (lysozyme, collagenase and catalase) occurred over 11 days from the PCL matrices, with retained activity dependent on the particular enzyme used (collagenase 100% at 11 days, lysozyme 75-80% at 11 days, catalase 10-20 % at 5 days). Swiss3T3 fibroblasts exhibited strong attachment and successful colonization of the surface. of PCL matrices over 8 to 15 days in cell culture. These findings demonstrate the potential of micro/macroporous PCL matrices for scaffold production in tissue engineering and for controlling drug delivery.

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Korde, Sachin A. "Solvent free technologies for polymer based crystal engineering and drug delivery". Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/14132.

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Current research focuses on the effect of different continuous solid state shear based processing for the production of pharmaceutical amorphous system and cocrystals for poorly water soluble APIs. The S3M technology is getting first time reported for its application in pharmaceutical field and it is considered as technology with good potential for development of pharmaceutical dosage forms. The main objectives of this study include the effect of two solid state shear processes on the product properties in case of solid dispersions and cocrystals. Hot melt extrusion technology has been widely explored for the production of pharmaceutical solid dispersions and cocrystals, it would be helpful to compare how the new invented S3M technology will differ from the existing solid state shear process. The S3M has been also explored for the advantages over HME process in terms of residence time, plasticiser free dispersions, effect of process on degradation of drugs during processing. For this purpose, the process and material modifications during operation of these two technologies was important aspects of this study. The pharmaceutical drugs chosen for the solid dispersion purpose were carbamazepine, ibuprofen, glibenclamide which are BCS class II drugs and paracetamol from BCS class III drug was selected as model drug for solid dispersion manufacturing with PVP. VA64, HPMCP HP55, HPMCAS, Ethyl cellulose as polymers. In case of cocrystals selected drugs were carabamazepine, caffeine, paracetamol and ibuprofen with co-formers nicotinamide, saccharin, salicylic acid, glutaric acid, oxalic acid, maleic acid. The selections of co-formers were done on the basis of functional group complementarity between drug and co-former. All the details about the pairs for cocrystals and for solid dispersions are given in experimental section. Carbamazepine has been explored in depth for solid dispersions with different polymers and with different co-formers in case of cocrystals. The effect of process variables and amount of shear applied during processing was deciding factor in product output and quality. The end product in case of both the solid dispersions and cocrystals varied in their physicochemical, morphological and drug release properties HME process needed addition of plasticisers during preparation of solid dispersions whereas S3M was plasticiser free process which gave good insight on how this will affect the product performance during evaluation studies. The solid dispersions in case of HME were had smooth surfaces and which are non-porous in nature whereas in case of S3M the solid dispersions were highly porous in nature. The differences in the structural and morphological features of solid dispersions somehow did not affect the drug release of drug during in-vitro dissolution studies and both the solid dispersions did not show much difference in drug release. In case of cocrystals processing on S3M it was observed that the S3M process is dependent on the use of polymer as process aid. For this purpose PEO, PVP VA64 and HPMCP HP55 were selected as model polymer as process aid during processing of cocrystals, out of which PEO has been explored widely as processing aid due to its process suitability, low melting and ability to withstand high shear during processing. PVP VA64 was used only in case of carbamazepine cocrystals with salicylic acid and HPMCP HP55 in case of caffeine cocrystals with maleic acid. The effect of concentration of PEO in case of carbamazepine cocrystals as processing aid was studied (concentration range 5%, 10%, 15%, 25% w/w). The concentration of PEO in case of HME cocrystals had direct effect on the drug release of drug dissolution studies which was reduced in case of higher concentration of PEO (25% w/w), which was not observed in case of S3M processes carbamazepine cocrystals. The product in case of cocrystals by S3M was thread like structures whereas in case of HME cocrystals were in form of screw shaped compact mass. The difference in morphological and structural properties of cocrystals did not had major effect on drug release in case of S3M process but in case of HME processed cocrystals the higher amount of polymer slowed the drug release. The degradation studies in case of drugs carbamazepine, paracetamol were carried out whereas in case of polymer for HPMCP HP55 were carried out. It was found that HME processed samples showed higher degradation as compared to S3M processed one in both the cases solid dispersions and cocrystals. This can be attributed to high residence time in case of HME as compared to S3M process. The effect of two high shear processes HME and S3M had significant effect on the morphological and structural properties of the solid dispersions and cocrystals. The variation in the structural and morphological properties did not have direct effect on the drug release of drug during dissolution studies. HME and S3M both the processes had some positive and some negative aspects within them for processing of pharmaceutical dispersions and cocrystals. In case of HME the use of plasticiser is mandatory to maintain low torque levels during processing and to avoid blockage of extruder barrel, whereas in case of S3M the process is plasticiser independent and processing of solid dispersion is very easy as compared to HME with low residence time. Processing of plain drug or co-former was easy in case of HME whereas in case of S3M processing it was mandatory to use polymer as processing aid specially during processing of cocrystals. In case of process controls HME has excellent control over the process parameters which can be controlled and manipulated as per requirement, whereas S3M technology needs to have technical modifications to have better control over its processing parameters. The S3M can be a revolutionary technology for pharmaceutical industry once it is upgraded with better control and optimised process parameters.

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Huang, Guofeng. "ENGINEERING RGD-MODIFIED LIPOSOMES FOR TARGETED DRUG DELIVERY TO ACTIVATED PLATELETS". Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1153187042.

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Williamson, Matthew R. "Novel biodegradable fibres for applications in tissue engineering and drug delivery". Thesis, Aston University, 2003. http://publications.aston.ac.uk/11000/.

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The preparation and characterisation of novel biodegradable polymer fibres for application in tissue engineering and drug delivery are reported. Poly(e-caprolactone) (PCL) fibres were produced by wet spinning from solutions in acetone under low shear (gravity flow) conditions. The tensile strength and stiffness of as-spun fibres were highly dependent on the concentration of the spinning solution. Use of a 6% w/v solution resulted in fibres having strength and stiffness of 1.8 MPa and 0.01 GPa respectively, whereas these values increased to 9.9 MPa and 0.1 GPa when fibres were produced from 20% w/v solutions. Cold drawing to an extension of 500% resulted in further increases in fibre strength (up to 50 MPa) and stiffness (0.3 GPa). Hot drawing to 500% further increased the fibre strength (up to 81 MPa) and stiffness (0.5 GPa). The surface morphology of as-spun fibres was modified, to yield a directional grooved pattern by drying in contact with a mandrel having a machined topography characterised by a peak-peak separation of 91 mm and a peak height of 30 mm. Differential scanning calorimetery (DSC) analysis of as-spun fibres revealed the characteristic melting point of PCL at around 58°C and a % crystallinity of approximately 60%. The biocompatibility of as-spun fibres was assessed using cell culture. The number of attached 3T3 Swiss mouse fibroblasts, C2C12 mouse myoblasts and human umbilical vein endothelial cells (HUVECs) on as-spun, 500% cold drawn, and gelatin coated PCL fibres were observed. The results showed that the fibres promoted cell proliferation for 9 days in cell culture and was slightly lower than on tissue culture plastic. The morphology of all cell lines was assessed on the various PCL fibres using scanning electron microscopy. The cell function of HUVECs growing on the as-spun PCL fibres was evaluated.

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38

Lee, Jae Hwan. "DRUG DELIVERY MICRODEVICE: DESIGN, SIMULATION, AND EXPERIMENTS". VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3100.

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Ocular diseases such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting millions of adults in US and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This research focused on an implantable ocular drug delivery device design, simulation and experiments with design requirements including constant diffusion rate, extended period of time operation, the smallest possible volume of device and reservoir. The drug delivery device concept uses micro-/nano-channels module embedded between top and bottom covers with a drug reservoir. Several microchannel design configurations were developed and simulated using commercial finite element software (ANSYS and COMSOL), with a goal to investigate how the microchannel dimensions affect the diffusion characteristics. In addition to design simulations, various microchannel configurations were fabricated on silicon wafer using photolithography techniques as well as 3D printing. Also, the top and bottom covers of the device were fabricated from PDMS through replica molding techniques. These fabricated microchannel design configurations along with top and bottom covers were all integrated into the device. Both single straight microchannels (nine different sizes of width and depth) as well as four micro-channel configurations were tested using citric acid (pH changes) and Brimonidine drug (concentration changes using the Ultra-Violet Visible Spectrophotometer) for their diffusion characteristics. Experiments were conducted to obtain the diffusion rates through various single micro-channels as well as micro-channel configurations using the change in pH neutral solution to verify the functionality and normalized diffusion rate of microchannels and configurations. The results of experimental data of diffusion rate were compared with those obtained from simulations, and a good agreement was found. The results showed the diffusion rate and the optimum size of microchannel in conjunction with the required drug release time. The results obtained also indicate that even though specific diffusion rates can be obtained but delivering the drug with constant amount needs a mechanism at the device outlet with some control mechanism. For future studies, this result may be used as a baseline for developing a microfabricated device that allows for accurate drug diffusion in many drug delivery applications.

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39

Duguay, Daniel G. "Magnetically responsive polylactic acid microspheres for targetable drug delivery". Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22436.

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A novel magnetic Polylactic acid microsphere was developed and produced. Various magnetic materials like Iron, Nickel and Magnetite were introduced into the microspheres, at concentrations of 5 to 10% by weight. The resulting microspheres were characterized for their magnetic responsiveness with a continuous flow apparatus which simulated the vascular system. The effect of specific experimental parameters on the rate of magnetic retention were evaluated using factorial and fractional factorial designs. The observed parameters were the flow tube diameter, test fluid flow rate, magnetic field strength and the mass of added microspheres. The effect of magnetic material type and concentration, microsphere size and test fluid viscosity were also observed. The magnetic retention profiles were photographically recorded and characterized. Computer simulations of various characteristics were completed to interpret several underlying phenomenas of the retention process.

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40

Daniel, Karen D. "An implantable device for localized drug delivery and sensing". Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/46608.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009.
Includes bibliographical references (p. 117-120).
There are many potential clinical applications for localized drug delivery and sensing systems, such as cancer, vaccinations, pain management, and hormone therapy. Localized drug delivery systems reduce the amount of drug required for a therapeutic effect and the severity of side effects. Delivery of multiple chemicals has been demonstrated previously from a polymeric microreservoir device. This dime-sized device contains small reservoirs loaded with drug and separated from the outside environment by a degradable polymer membrane. This device was modified to allow minimally invasive implantation with a large-bore needle and has demonstrated in vitro pulsatile release of a model compound after a mock implantation step. A biodegradable sealing method was developed for the polymeric microreservoir device, which makes the device completely resorbable and eliminates the surgical removal step needed with a non-resorbable device. Localized sensing systems will allow early detection of diseases and provide a tool for developing personalized treatment programs. The polymer microchip platform has been combined with magnetic relaxation switch (MRSw) nanoparticle sensors to create an in vivo sensing device. MRSw are magnetic nanoparticles (iron oxide core, crosslinked dextran shell) that can detect a variety of analytes. MRSw are kept in the device by a molecular weight cut-off (MWCO) membrane which allows analytes free access to the nanoparticle sensors.
(cont.) The MRSw aggregate in the presence of the analyte they were designed to detect and this aggregation causes a decrease in the transverse relaxation time (T2), which can be detected with magnetic resonance imaging (MRI) or nuclear magnetic resonance relaxometry. In vitro sensing experiments were used to optimize the device design and characterize its performance. In vivo device-based sensing of hCG, a soluble biomarker that is elevated in testicular and ovarian cancer, has been demonstrated. Cell lines secreting hCG were used to produce ectopic tumors in nude mice. The sensing device was implanted and magnetic resonance imaging (MRI) quantified a T2 decrease in mice with tumors compared to control mice (no tumors). This device may be the first continuous monitoring device for cancer that can be implanted at the tumor site and demonstrates feasibility of MRSw measurements in vivo.
by Karen D. Daniel.
Ph.D.

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41

Johnson, Mark E. "Biophysical aspects of transdermal drug delivery and chemical enhancement". Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/10912.

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42

Hu, Yuhua Ph D. Massachusetts Institute of Technology. "pH-sensitive core-shell nanoparticles for intracellular drug delivery". Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/42942.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Vita.
Includes bibliographical references (p. 193-208).
Therapeutics such as proteins, DNA, or siRNA, can only exert their function in the cell cytosol or nucleus. However, most of them are cell membrane impermeable molecules that can only be taken up by cells via endocytosis or phagocytosis. Such drug molecules are thus confined in endolysosomes, where reduced pH and degradative enzymes may destroy them without therapeutic gain. Efficient escape of drug molecules to the cytosol before destruction in endolysosomes is a major challenge for intracellular drug delivery. To address this issue, we designed a pH-sensitive core-shell nanoparticle to segregate the functions of the particle into an endosome-disrupting pH-responsive core that would absorb protons at endolysosomal pH, and a shell whose composition could be tuned to facilitate particle targeting, cell binding, and drug binding. Two-stage surfactant-free emulsion polymerization of 2-diethylamino ethyl methacrylate (DEAEMA) (core) and 2-amino ethyl methacrylate (AEMA) (shell) in the presence of a crosslinker was used for the synthesis of monodisperse core-shell hydrogel nanoparticles of 200 nm in diameter. The protonation of tertiary amine groups on the polyDEAEMA core on moving from extracellular to endolysosomal pH resulted in reversible swelling of the nanoparticles with a 2.8-fold diameter change. With the aid of pH-sensitivity of these nanoparticles, efficient cytosolic delivery of calcein (with ~95% efficiency) was achieved by disrupting endolysosomes via proton sponge effect. The primary amine rich shell was found to facilitate cell and drug binding, and provided negligible cytotoxicity by sequestering the proton sponge component from any direct interactions with cells. These particles demonstrated a useful means to deliver therapeutic molecules to the cytosol of cells of interest efficiently.
(cont.) The applications of nanoparticles showed significant improvement in delivering a model antigen vaccine protein ovalbumin (OVA) to primary dendritic cells for T cell activation, and promising knockdown of mRNA by delivering siRNA to epithelial cells for gene silencing. To extend this approach to a fully biodegradable system, nanoparticles with a cleavable crosslinker bis (acryloyl) cystamine (BAC) were synthesized. Preliminary explorations of this approach showed that such particles can degrade in the presence of glutathione in vitro, a reducing peptide present at mM concentrations in the cytosol of mammalian cells. This design could potentially serve as a drug releasing mechanism to further improve delivery efficiency.
by Yuhua Hu.
Ph.D.

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43

Prausnitz, Mark R. "Electroporation of tissue and cells for drug delivery applications". Thesis, Massachusetts Institute of Technology, 1994. http://hdl.handle.net/1721.1/32647.

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44

Dogan, Alan B. "LEVERAGING THERMODYNAMIC INTERACTIONS TO ENHANCE DRUG DELIVERY". Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case161901882802915.

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45

Zhao, Tianxin Zhao. "Silk Based Porous Microneedle Array for Programmable Drug Delivery". University of Akron / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=akron1468852925.

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46

Chau, Ying. "Targeted drug delivery by novel polymer-drug conjugates containing linkers cleavable by disease-associated enzymes". Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/32332.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005.
Includes bibliographical references.
We have conceptualized a new class of polymer-linker-drug conjugates to achieve targeted drug delivery for the systemic treatment of cancer and other inflammatory diseases. The physiochemical properties of the polymer allow the conjugate to circulate longer in the body by minimizing renal and hepatic clearance, thereby improving the pharmacokinetics of the attached drugs. Traditionally, linkers are degraded by acidity or by some ubiquitous intracellular enzymes. We incorporate linkers that are sensitive to a specific extracellular enzyme whose overexpression is co-localized with the diseased tissue. The drug molecules remain inactive when attached to the polymer, thus preventing normal tissues from harmful side effects. When the conjugate is transported to the diseased area where there is a high level of the target enzyme, the linkers are cleaved to release the drugs at the specific site. As an example, we designed and synthesized two generations of novel polymer-peptide-drug conjugates for the tumor-targeted delivery of chemotherapeutics. To allow for passive targeting and enhanced permeation and retention (EPR), dextran with a size greater than 6 nm was selected as the polymeric carrier. This biocompatible and biodegradable carrier was chemically modified to allow for conjugation with doxorubicin and methotrexate, two common chemotherapeutics with undesirable side effects.
(cont.) Since matrix-metalloproteinases (MMPs) are associated with a number of types of cancer and their functions are essential to disease progression, including degrading extracellular matrix, releasing angiogenic factors and activating growth factors, we explored the possibility of MMP-mediated drug release. The synthesis procedures combined solid phase and solution phase techniques to enable flexibility in the linker design and in the charge modification of the polymer. This scaleable and robust process produced new conjugates that demonstrated excellent stability under physiological conditions and optimized sensitivity to enzymatic cleavage by MMP-2 and MMP-9. The new conjugate, dextran-peptide-methotrexate, was assessed for its in vivo anti-tumor efficacy and systemic side effects. It was compared to free methotrexate and a similar conjugate, differing by an MMP-insensitive linker, at equivalent intraperitoneal dosages administered weekly. The MMP-sensitive conjugate resulted in effective inhibition of in vivo tumor growth in each of the two separate tumor models that overexpress MMP-2 and MMP-9 (HT-1080 and U- 87). In contrast, free methotrexate resulted in no significant tumor reduction in the same models. Neither free methotrexate nor the conjugate caused any tumor inhibition in mice bearing RT- 112, a slower-growing model which expresses significantly less MMP than HT-1080 and U-87 . The anti-proliferative effect of the drug contributed to the inhibition of tumor growth. Systemic side effects caused by the MMP-sensitive conjugates were tolerable.
(cont.) MMP-insensitive conjugates, though able to inhibit tumor growth, caused toxicity in the small intestine and bone marrow and the experiment was terminated after one injection. We conducted a biodistribution study in HT-1080 bearing mice to investigate the targeting mechanism of the new conjugate. Independent of the linker sequence, passive targeting was evidenced by the prolonged plasma circulation and higher tissue accumulations of the conjugates in comparison with free methotrexate. The ratios of drug accumulation at the tumor versus the major site of side effects (small intestine) for both conjugates were enhanced by the EPR effects. The difference in the drug accumulation at the tumor site was insignificant between conjugates with MMP-sensitive and MMP-insensitive linkers. We concluded that the tumor targeting effect of the dextran-peptide-methotrexate conjugate was dominantly due to passive targeting and EPR. The difference in the systemic side effects observed for the conjugates with different linkers was attributed to their varying susceptibility towards enzymes in normal tissues.
by Ying Chau.
Ph.D.

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47

Hamilton, Lloyd George. "New injectable scaffolds for cell and drug delivery". Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/11017/.

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An injectable scaffold system for the delivery of cells and growth factors was developed in this project to enhance healing of bone fractures. The project was focused to meet the clinical need for an off-the-shelf synthetic biodegradable bone graft material. The concept required the injection of a paste to fill defects then rapidly solidify to a mechanically supportive macroporous structure. The injectable paste was developed from a two-component biodegradable microparticle scaffold based on poly(lactic-co-glycolic acid) (PLGA) and comprised of a versatile temperature insensitive (type 1) carrier and an adhesive (type 2) component made temperature sensitive with the addition of poly(ethylene glycol) (PEG) as a plasticizer. The plasticized adhesive type 2 component achieved wet compressive strengths up to 18 MPa at 37 °C after 24 hours. The sintering strategy utilised the changes in viscoelastic and mechanical properties that occur in the glass transition region of amorphous polymers. The specific mechanism devised in this thesis exploited the biocompatibility and diffusivity of PEG to increase polymer glass transition temperature in the wet sintering process. The solidification speed was demonstrated by rheological assessment of storage modulus and wet compressive strengths up to 2 MPa after 15 minutes at 37 °C. Restricting particle size distribution to narrow 100 µm bands controlled porosity between 35-65%. The interconnectivity of the macroporous structures was demonstrated by the invasion of 3T3 cells seeded on the outer surface of the scaffold and evaluated by microcomputed tomography. The innocuous nature of the solidification process was demonstrated by the survival and proliferation of in situ seeded primary human fibroblasts, osteoblasts and murine C2C12 cells. The multifunctional type 1 component acted as a porous spacer, protein delivery vehicle and cell carrier when modified with polyethylenimin. The potential use of the scaffold as a controlled delivery system for recombinant human bone morphogenetic protein-2 (rhBMP-2) was demonstrated by the sustained differentiation of murine C2C12 myoblast to osteogenic alkaline phosphatase positive cells over 28 days. In this thesis a novel sintering mechanism has been developed that facilitates control of pore size and porosity of injectable scaffolds. The benign nature of the process facilitates the potential use of this injectable system as a delivery vehicle for cell and growth factor therapy.

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48

Salem, Aliasger K. "An injectable degradable porous polymer scaffold for tissue engineering and drug delivery". Thesis, University of Nottingham, 2002. http://eprints.nottingham.ac.uk/11918/.

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Cell transplantation on biodegradable scaffolds is an established approach in tissue engineering to the problem of the regeneration of diseased or damaged tissues. As cells grow and organise themselves, they secrete their own extracellular matrix, while the polymer degrades into natural metabolites resulting in eventual natural tissue replacement. Polymeric materials used for these scaffolds must satisfy a number of requirements. These include defined cell-interactive properties, porosity, biodegradability, mechanical and controlled release properties. To date, scaffolds have been designed to conform to these requirements. However, the need to perform defined three-dimensional structures requires prior knowledge of the dimensions of the defect or cavity to be filled. Furthermore the general use of toxic solvents in the processing of these scaffolds prevents the incorporation of biological agents and cells during fabrication. Therefore, poor transportation of cells through the scaffolds can result in low cell seeding efficiencies. Finally such scaffolds require an invasive operation for transplantation of the material. In contrast a number of injectable materials have been proposed and investigated. The transformation from liquid pre-cursor to gel in such systems can, however, require cell harmful trigger signals such as UV exposure or pH changes. Furthermore, these injectable gels lack a porous structure preventing effective cell migration and restricting tissue formation and vascularisation tothe barrier of diffusion for signalling and nutrient molecules. The work in this thesis presents a scaffold that is both injectable and conforms to the requirements of water-insoluble porous scaffolds. This starts with the synthesis of a biotinylated poly (lactic acid)-poly (ethylene glycol) (PLA-PEG) copolymer. The polymer is degradable, protein resistant and cell interactive when used in conjunction with biotinylated cell adhesive peptides. The biotin unit tethered to the PEG-PLA also provides the polymer with self-assembling properties when used in conjunction with avidin. In contrast to alternative injectable materials, the scaffold presented in this thesis is porous. This porosity is necessary for tissue ingrowth and vascularization. Therefore, before progressing on to the manufacture of the scaffold, a systematic study of two cell types involved in vascularisation was carried out over defined pore features. These studies revealed that cell behaviour over pore features was related to cell type, cell density and pore size. This had significant implications for the injectable scaffold in development because proposed advantages were delivery of a variety of cell types, controlled porous structure, and efficient cell seeding. Microparticles were then manufactured from the PLA-PEG-biotin using a single emulsion manufacturing process. Surface Plasmon Resonance (SPR) confirmed that these microparticles would bind efficiently to avidin. The condition for optimum self-assembling of particles was then determined using aggregation studies. These studies showed that a critical quantity of avidin was required for microparticles to aggregate together. The ability to aggregate particles of different sizes leads to the potential for controlling scaffold porosity. Rheological testing showed that the scaffold's mechanical properties could be tailored to that of the tissue in which regeneration is required. The self-assembly of microparticles was also demonstrated to form complex three-dimensional scaffolds without the use of toxic solvents. Scaffolds prepared in simulated tissues maintained shape upon injection. Scaffolds were then self-assembled with cells entrapped within them. Cell viability within the self-assembling scaffolds was confirmed by Alamar Blue assays. In vivo studies have demonstrated that cell-scaffold composites permit tissue ingrowth and thus readily undergo vascularisation. The novel molecular-interaction mechanism of self-assembly of these scaffolds differentiates this material from other injectable systems. The formation of porous scaffolds within a cavity or a soft-tissue could be a pre-requisite for tissue remodelling using new cell sources that are dependent on vascularisation and tissue ingrowth. The basic component of the scaffold is a biodegradable microparticle that presents a protein resistant surface with biotinylated moieties. Therefore, standard controlled release technologies and biotin-avidin mediated surface engineering can be combined with the self-assembly to form biomimetic scaffolds that stimulate integrin-mediated cell adhesion and then release growth factors.

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49

Zeng, Xian Ming. "The influence of particle engineering on drug delivery by dry powder aerosols". Thesis, King's College London (University of London), 1997. https://kclpure.kcl.ac.uk/portal/en/theses/the-influence-of-particle-engineering-on-drug-delivery-by-dry-powder-aerosols(abf7b52d-6271-462c-96a7-e12b6acc7f32).html.

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50

Wen, Amy M. "Engineering Virus-Based Nanoparticles for Applications in Drug Delivery, Imaging, and Biotechnology". Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1452954511.

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