641 research outputs found

    A Fabrication System for Chondroitin Sulfate Methacrylate Particles for Drug Release

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    Pediatric neuroblastoma patients have relatively high mortality rates and are commonly treated with systemic chemotherapy. Systemic chemotherapy causes adverse side effects that are especially harmful to the pediatric population. Localized, sustained release of chemotherapy drugs is a desirable alternative to systemic chemotherapy. There is a need for a drug delivery system to facilitate local delivery of chemotherapy drugs as well as to sustain the drug release over time. This project aims to design, fabricate, and validate a microparticle fabrication system for producing drug carrier microparticles for the delivery of chemotherapy drugs. The final drug-loaded microparticles were evaluated for induction of cytotoxicity in a neuroblastoma cell line

    Mechanistic Analysis of In Vitro and In Vivo Drug Release from PLGA Microspheres.

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    Poly (lactic-co-glycolic) acid (PLGA) microspheres have been extensively studied for controlled drug delivery, and more than a dozen PLGA formulations are currently on the market. However, surprisingly little information is available about how the administration environment affects microsphere properties that result in drug release in vivo, and there is a lack of in vitro-in vivo correlation data for microsphere formulations. As a result, in vitro tests used to predict drug release during development are rarely designed to represent actual formulation behavior in vivo. Two microsphere formulations encapsulating a model drug, triamcinolone acetonide, were prepared from PLGAs of different molecular weights and end-capping (18 kDa acid-capped, 54 kDa ester-capped). In vitro release and the corresponding mechanisms (hydrolysis, erosion, water uptake, and diffusion) were studied in four release media: PBST pH 7.4 (standard condition), PBST pH 6.5, PBS + 1.0% triethyl citrate (TC), and HBST pH 7.4. The release mechanism in PBST and HBST without TC was primarily polymer erosion-controlled in both formulations as indicated by the similarity of release and mass loss kinetics. The addition of TC resulted in primarily diffusion-controlled release from the low MW PLGA. By using a novel cage implant to restrain microspheres in the SC space, similar analyses were performed on microspheres administered in vivo. Drug release was much faster in vivo than in any of the in vitro media studied (release over 2-3 weeks vs. 4-7 weeks). Furthermore, PLGA water uptake, hydrolysis and mass loss were greatly augmented in the subcutaneous space. The study of microsphere morphology revealed an osmotically induced pore network in the higher MW formulation, indicating the potential for release controlled by water uptake, a mechanism previously unseen in vitro. Therefore, in vitro tests could benefit by incorporating relevant components of interstitial fluid, which more closely mimic those conditions that control key release mechanisms in vivo. The novel application of the cage model to uncover significant changes to mechanism-indicating processes of PLGA microspheres in vivo is highly significant. Hence, this thesis demonstrates the importance of understanding in vivo release mechanisms in order to design release tests, which accurately predict release upon administration.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/116766/1/amydoty_1.pd

    Microfluidic Production of Polymeric Functional Microparticles

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    This dissertation focuses on applying droplet-based microfluidics to fabricate new classes of polymeric microparticles with customized properties for various applications. The integration of microfluidic techniques with microparticle engineering allows for unprecedented control over particle size, shape, and functional properties. Specifically, three types of microparticles are discussed here: (1) Magnetic and fluorescent chitosan hydrogel microparticles and their in-situ assembly into higher-order microstructures; (2) Polydimethylsiloxane (PDMS) microbeads with phosphorescent properties for oxygen sensing; (3) Macroporous microparticles as biological immunosensors. First, we describe a microfluidic approach to generate monodisperse chitosan hydrogel microparticles that can be further connected in-situ into higher-order microstructures. Microparticles of the biopolymer chitosan are created continuously by contacting an aqueous solution of chitosan at a microfluidic T-junction with a stream of hexadecane containing a nonionic detergent, followed by downstream crosslinking of the generated droplets by a ternary flow of glutaraldehyde. Functional properties of the microparticles can be easily varied by introducing payloads such as magnetic nanoparticles and/or fluorescent dyes into the chitosan solution. We then use these prepared microparticles as "building blocks" and assemble them into high ordered microstructures, i.e. microchains with controlled geometry and flexibility. Next, we describe a new approach to produce monodisperse microbeads of PDMS using microfluidics. Using a flow-focusing configuration, a PDMS precursor solution is dispersed into microdroplets within an aqueous continuous phase. These droplets are collected and thermally cured off-chip into soft, solid microbeads. In addition, our technique allows for direct integration of payloads, such as an oxygen-sensitive porphyrin dye, into the PDMS microbeads. We then show that the resulting dye-bearing beads can function as non-invasive and real-time oxygen micro-sensors. Finally, we report a co-flow microfluidic method to prepare uniform polymer microparticles with macroporous texture, and investigate their application as discrete immunological biosensors for the detection of biological species. The matrix of such microparticles is based on macroporous polymethacrylate polymers configured with tailored pores ranging from hundreds of nanometers to a few microns. Subsequently, we immobilize bioactive antibodies on the particle surface, and demonstrate the immunological performance of these functionalized porous microbeads over a range of antigen concentrations

    PLANNING FOR AUTOMATED OPTICAL MICROMANIPULATION OF BIOLOGICAL CELLS

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    Optical tweezers (OT) can be viewed as a robot that uses a highly focused laser beam for precise manipulation of biological objects and dielectric beads at micro-scale. Using holographic optical tweezers (HOT) multiple optical traps can be created to allow several operations in parallel. Moreover, due to the non-contact nature of manipulation OT can be potentially integrated with other manipulation techniques (e.g. microfluidics, acoustics, magnetics etc.) to ensure its high throughput. However, biological manipulation using OT suffers from two serious drawbacks: (1) slow manipulation due to manual operation and (2) severe effects on cell viability due to direct exposure of laser. This dissertation explores the problem of autonomous OT based cell manipulation in the light of addressing the two aforementioned limitations. Microfluidic devices are well suited for the study of biological objects because of their high throughput. Integrating microfluidics with OT provides precise position control as well as high throughput. An automated, physics-aware, planning approach is developed for fast transport of cells in OT assisted microfluidic chambers. The heuristic based planner employs a specific cost function for searching over a novel state-action space representation. The effectiveness of the planning algorithm is demonstrated using both simulation and physical experiments in microfluidic-optical tweezers hybrid manipulation setup. An indirect manipulation approach is developed for preventing cells from high intensity laser. Optically trapped inert microspheres are used for manipulating cells indirectly either by gripping or pushing. A novel planning and control approach is devised to automate the indirect manipulation of cells. The planning algorithm takes the motion constraints of the gripper or pushing formation into account to minimize the manipulation time. Two different types of cells (Saccharomyces cerevisiae and Dictyostelium discoideum) are manipulated to demonstrate the effectiveness of the indirect manipulation approach

    A practical review on the measurement tools for cellular adhesion force

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    Cell cell and cell matrix adhesions are fundamental in all multicellular organisms. They play a key role in cellular growth, differentiation, pattern formation and migration. Cell-cell adhesion is substantial in the immune response, pathogen host interactions, and tumor development. The success of tissue engineering and stem cell implantations strongly depends on the fine control of live cell adhesion on the surface of natural or biomimetic scaffolds. Therefore, the quantitative and precise measurement of the adhesion strength of living cells is critical, not only in basic research but in modern technologies, too. Several techniques have been developed or are under development to quantify cell adhesion. All of them have their pros and cons, which has to be carefully considered before the experiments and interpretation of the recorded data. Current review provides a guide to choose the appropriate technique to answer a specific biological question or to complete a biomedical test by measuring cell adhesion

    Synthesis of anisotropic microparticles and capsules via droplet microfluidics

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    We have developed simplified microfluidic droplet generators and employed them to fabricate anisotropic polymer particles and capsules in the size range of 100–500 ΞΌm. We used cheap and generally available materials and equipment to design and assemble microfluidic devices. All our devices were made of standard wall borosilicate capillaries (OD 1.0mm, ID 0.58mm), steel dispensing needles without bevel (30 G, 32 G), microscopy glass slides, fast-curing epoxy glue (Araldite-80805) and diamond scribe to process the glass. We designed four different geometries for each device, which can be separated for two groups: single and double droplet generators. The performance of the devices was validated using computational fluid dynamics and laboratory experiments. First of all, we tried to fabricate intricate single emulsion droplets and then moved on to double emulsion droplets. The range of the fabricated particles and capsules includes anisotropically-shaped amphiphilic polymer β€œmicrobuckets”, biphasic particles, capsules with various fillers and stimuli responsive polymer vesicles. To produce such objects we employed different functional monomers, for instance β€œclickable” glycidyl methacrylate or hydrophilic 2-hydroxyethyl methacrylate. We also utilized several chemical and physical phenomena such as internal phase separation, wettability or polymer chain cross-linking to tune the properties of the synthesized particles. We investigated properties of the above mentioned particles and capsules. For example, β€œmicrobuckets” which are hydrophilic at the exterior surface, but hydrophobic inside the cavity, were able to withdraw oil droplets from an aqueous phase and β€œarrest” them inside the cavity

    Continuous focusing and separation of microparticles with acoustic and magnetic fields

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    Microfluidics enables a diverse range of manipulations (e.g., focusing, separating, trapping, and enriching) of micrometer-sized objects, and has played an increasingly important role for applications that involve single cell biology and the detection and diagnosis of diseases. In microfluidic devices, methods that are commonly used to manipulate cells or particles include the utilization of hydrodynamic effects and externally applied field gradients that induce forces on cells/particles, such as electrical fields, optical fields, magnetic fields, and acoustic fields. However, these conventional methods often involve complex designs or strongly depend on the properties of the flow medium or the interaction between the fluid and fluidic channels, so this dissertation aims to propose and demonstrate novel and low-cost techniques to fabricate microfluidic devices to separate microparticles with different sizes, materials and shapes by the optimized acoustic and magnetic fields. The first method is to utilize acoustic bubble-enhanced pinched flow for microparticle separation; the microfluidic separation of magnetic particles with soft magnetic microstructures is achieved in the second part; the third technique separates and focuses microparticles by multiphase ferrofluid flows; the fourth method realizes the fabrication and integration of microscale permanent magnets for particle separation in microfluidics; magnetic separation of microparticles by shape is proposed in the fifth technique. The methods demonstrated in this dissertation not only address some of the limitations of conventional microdevices, but also provide simple and efficient method for the separation of microparticles and biological cells with different sizes, materials and shapes, and will benefit practical microfluidic platforms concerning micron sized particles/cells --Abstract, page iv
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