Investigation of properties affecting controlled release of macromolecules from PLGA microspheres

Poly(lactide-co-glycolide), or PLGA, microspheres offer a widely-studied biodegradable option for controlled release of therapeutics. An array of fabrication methodologies have been developed to produce these microspheres with the capacity to encapsulate therapeutics of various types; and produce microspheres of a wide range of sizes for different methods of delivery. The encapsulation, stability, and release profiles of therapeutic release based on physical and thermodynamic properties has also been studied and modeled to an extent. Much research has been devoted to tailoring formulations for improved therapeutic encapsulation and stability as well as selective release profiles. Despite the breadth of available research on PLGA microspheres, further analysis of fundamental principles regarding the microsphere degradation, formation, and therapeutic encapsulation is necessary. This work aims to examine additional fundamental principles related to PLGA microsphere formation and degradation from solvent-evaporation of preformed polymer. In particular, mapping the development of the acidic microenvironment inside the microsphere during degradation and erosion is discussed. Also, the effect of macromolecule size and conformation is examined with respect to microsphere diameter and PLGA molecular weight. Lastly, the effects of mechanical shearing and protein exposure to aqueous media during microsphere formation are examined. In an effort to better understand the acidic microenvironment development across the microsphere diameter, pH sensitive dye conjugated to protein that undergoes conformational change at different acidic pH values was encapsulated in PLGA microspheres of diameters ranging from 40 µm to 80 µm, and used in conjunction with fluorescence resonance energy transfer to measure the radial pH change in the microspheres. Qualitative analysis of confocal micrographs was used to correlate fluorescence intensity with pH value, and obtain the radial pH across the center of the microsphere. Therapeutic encapsulation and release from polymeric microspheres is governed by an interconnected variety of factors, including the therapeutic itself. The globular protein bovine serum albumin, and the elongated and significantly smaller enzyme, lysozyme, were encapsulated in PLGA microspheres ranging from 40 µm to 80 µm in diameter. The initial surface morphology upon microsphere formation, release profiles, and microsphere erosion characteristics were explored in an effort to better understand the effect of protein size, conformation, and known PLGA interaction on the formation and degradation of PLGA microspheres and macromolecule release, with respect to PLGA molecular weight and microsphere diameter. In addition to PLGA behavior and macromolecule behavior, the effect of mechanical stresses during fabrication was examined. Two similar solvent extraction techniques were compared for the fabrication of albumin loaded microspheres. In particular, the homogeneity of the microspheres as well as capacity to retain encapsulated albumin were compared. This preliminary study paves the way for a more rigorous treatment of the effect of mechanical forces present in popular microsphere fabrication. Several factors affecting protein release from PLGA microspheres are examined herein. The technique explored for spatial resolution of the pH inside the microsphere proved mildly effective in producing a reliable method of mapping microsphere pH changes. However, notable trends with respect to microsphere size, PLGA molecular weight, and microsphere porosity were observed. Proposed methods of improving spatial resolution of the acidic microenvironment are also provided. With respect to microsphere formation, studies showed that albumin and lysozyme had little effect on the internal homogeneity of the microsphere. Rather, ionic interactions with PLGA played a more significant role in the encapsulation and release of each macromolecule. Studies also showed that higher instances of mechanical stress led to less homogeneous microspheres with lower protein encapsulation. This suggests that perhaps instead of or in addition to modifying the microsphere formation formulation, the fabrication technique itself should be more closely considered in achieving homogeneous microspheres with desired loading.

Manufacturing challenges with fabrication of large size mechanical harmonic drives

Mechanical harmonic transmissions are relatively new kind of drives having several unusual features. For example, they can provide reduction ratio up to 500:1 in one stage, have very small teeth module compared to conventional drives and very large number of teeth (up to 1000) on a flexible gear. If for conventional drives manufacturing methods are well-developed, fabrication of large size harmonic drives presents a challenge. For example, how to fabricate a thin shell of 1.7m in diameter and wall thickness of 30mm having high precision external teeth at one end and internal splines at the other end? It is so flexible that conventional fabrication methods become unsuitable. In this paper special fabrication methods are discussed that can be used for manufacturing of large size harmonic drive components. They include electro-slag welding and refining, the use of special expandable devices to locate and hold a flexible gear, welding peripheral parts of disks with wear resistant materials with subsequent machining and others. These fabrication methods proved to be effective and harmonic drives built with the use of these innovative technologies have been installed on heavy metallurgical equipment and successfully tested.

Nanopore processing in dielectric materials and dielectric template-assisted nanoarray synthesis : using pulsed bias to enhance process throughput and precision

An effective technique to improve the precision and throughput of energetic ion condensation through dielectric nanoporous templates and reduce nanopore clogging by using finely tuned pulsed bias is proposed. Multiscale numerical simulations of ion deposition show the possibility of controlling the dynamic charge balance on the upper template's surface to minimize ion deposition on nanopore sidewalls and to deposit ions selectively on the substrate surface in contact with the pore opening. In this way, the shapes of nanodots in template-assisted nanoarray fabrication can be effectively controlled. The results are applicable to various processes involving porous dielectric nanomaterials and dense nanoarrays.

Device Fabrication of insoluble donor-acceptor-donor structured molecule by pulsed laser deposition- A comparative study using different laser source

Many of the conducting polymers though having good material property are not solution processable. Hence an alternate method of fabrication of film by pulsed laser deposition, was explored in this work. PDTCPA, a donor-acceptor-donor type of polymer having absorption from 900 nm to 300 nm was deposited by both UV and IR laser to understand the effect of deposition parameters on the film quality. It was observed that the laser ablation of PDTCPA doesn't alter its chemical structure hence retaining the chemical integrity of the polymer. Microscopic studies of the ablated film shows that the IR laser ablated films were particulate in nature while UV laser ablated films are deposited as smooth continuous layer. The morphology of the film influences its electrical characteristics as current-voltage characteristic of these films shows that films deposited by UV laser are p rectifying while those by IR laser are more of resistor in nature.

Fabrication and control of miniature McKibben actuators

This paper investigates the development of miniature McKibben actuators. Due to their compliancy, high actuation force, and precision, these actuators are on the one hand interesting for medical applications such as prostheses and instruments for surgery and on the other hand for industrial applications such as for assembly robots. During this research, pneumatic McKibben actuators have been miniaturized to an outside diameter of 1.5 mm and a length ranging from 22 mm to 62 mm. These actuators are able to achieve forces of 6 N and strains up to about 15% at a supply pressure of 1 MPa. The maximal actuation speed of the actuators measured during this research is more than 350 mm/s. Further, positioning experiments with a laser interferometer and a PI controller revealed that these actuators are able to achieve sub-micron positioning resolution. © 2010 Published by Elsevier B.V. All rights reserved.

Precision transfer printing of ultra-thin AlInGaN micron-size light-emitting diodes

We report the fabrication of a mechanically-flexible 16×16 array of thin-film, micron-size LEDs emitting at 480 nm. Devices were transfer-printed onto a mechanically-flexible ITO backplane using a modified, high-precision (placement accuracy ±25 nm) assembly system. © 2013 IEEE.

Stability improvement of selective oxidation during the fabrication of InGaAs/GaAs vertical cavity surface emitting laser

The effects of the carrier gas flow and water temperature on the oxidation rate for different reaction temperatures were investigated. The optimum conditions for stable oxidation were obtained. Two mechanisms of the oxidation process are revealed. One is the flow-controlling process, which is unstable. The other is the temperature-controlling process, which is stable. The stable region decreases for higher reaction temperatures. The simulation results for the stable oxidation region are also given. With optimum oxidation conditions, the stability and precision of the oxidation can be dramatically improved.

Stability improvement of selective oxidation during the fabrication of InGaAs/GaAs vertical cavity surface emitting laser

The effects of the carrier gas flow and water temperature on the oxidation rate for different reaction temperatures were investigated. The optimum conditions for stable oxidation were obtained. Two mechanisms of the oxidation process are revealed. One is the flow-controlling process, which is unstable. The other is the temperature-controlling process, which is stable. The stable region decreases for higher reaction temperatures. The simulation results for the stable oxidation region are also given. With optimum oxidation conditions, the stability and precision of the oxidation can be dramatically improved.

Design and fabrication of infrared filters for remote sounding instrumentation

Cooled infrared filters have been used in pressure modulation and filter radiometry to measure the dynamics, temperature distribution and concentrations of atmospheric elements in various satellite radiometers. Invariably such instruments use precision infrared bandpass filters and coatings for spectral selction, often operating at cryogenic temperatures. More recent developments in the use of spectrally-selective cooled detectors in focal plane arrays have simplified the optical layout and reduced the component count of radiometers but have placed additional demands on both the spectral and physical performance requirements of the filters. This paper describes and contrasts the more traditional radiometers using discrete detectors with those which use focal plane detector array technology, with particular emphasis on the function of the filters and coatings in the two cases. Additionally we discuss the spectral techniques and materials used to fabricate infrared coatings and filters for use in space optics, and give examples of their application in the fabrication of some demanding long wavelength dichroics and filters. We also discuss the effects of the space environment on the stability and durability of high performance infrared filters and materials exposed to low Earth orbit for 69 months on the NASA Long Duration Exposure Facility (LDEF).

Design and fabrication of nano-sinusoid LSPR devices

Applications of LSPR nano-particles in various areas of solar cells, LSPR biosensors, and SERS biosensors, based on interaction of light with noble metal nano-particles is increasing. Therefore, design and nano-fabrication of the LSPR devices is a key step in developing such applications. Design of nano-structures with desirable spectral properties using numerical techniques such as finite difference time domain (FDTD) is the first step in this work. A new structure called nano-sinusoid, satisfying the some desirable LSPR characteristics, is designed and simulated using the FDTD method. In the next stage, analytical method of electro static eigen mode method is used to validate the simulation results. The, nano-fabrications method of electron beam lithography (EBL) is implemented to fabricate the proposed profile with high precision. Finally, atomic force microscopy (AFM) is used to investigate the shape of the fabricated nano-particles, and the dark field microscopy is employed to demonstrate the particular spectral characteristics of the proposed nano-sinusoids.

In vitro evaluation of the precision of working casts for implant-supported restoration with multiple abutments

Objective: The purpose of this study was to compare the accuracy of two working cast fabrication techniques using strain-gauge analysis. Methods: Two working cast fabrication methods were evaluated. Based on a master model, 20 working casts were fabricated by means of an indirect impression technique using polyether after splinting the square transfer copings with acrylic resin. Specimens were assigned to 2 groups (n=10): Group A (GA): type IV dental stone was poured around the abutment analogs in the conventional way; Group B (GB), the dental stone was poured in two stages. Spacers were used over the abutment analogs (rubber tubes) and type IV dental stone was poured around the abutment analogs in the conventional way. After the stone had hardened completely, the spacers were removed and more stone was inserted in the spaces created. Six strain-gauges (Excel Ltd.), positioned in a cast bar, which was dimensionally accurate (perfect fit) to the master model, recorded the microstrains generated by each specimen. Data were analyzed statistically by the variance analysis (ANOVA) and Tukey's test (α= 5%). Results: The microstrain values (με) were (mean±SD): GA: 263.7±109.07με, and GB: 193.73±78.83με. Conclusion: There was no statistical difference between the two methods studied.

Fabrication and characterization of room temperature operating single electron transistors using focused ion beam technologies

The single electron transistor (SET) is a Coulomb blockade device, whose operation is based on the controlled manipulation of individual electrons. Single electron transistors show immense potential to be used in future ultra lowpower devices, high density memory and also in high precision electrometry. Most SET devices operate at cryogenic temperatures, because the charging energy is much smaller than the thermal oscillations. The room temperature operation of these devices is possible with sub- 10nm nano-islands due to the inverse dependance of charging energy on the radius of the conducting nano-island. The fabrication of sub-10nm features with existing lithographic techniques is a technological challenge. Here we present the results for the first room temperature operating SET device fabricated using Focused Ion Beam deposition technology. The SET device, incorporates an array of tungsten nano-islands with an average diameter of 8nm. The SET devices shows clear Coulomb blockade for different gate voltages at room temperature. The charging energy of the device was calculated to be 160.0 meV; the capacitance per junction was found to be 0.94 atto F; and the tunnel resistance per junction was calculated to be 1.26 G Ω. The tunnel resistance is five orders of magnitude larger than the quantum of resistance (26 k Ω) and allows for the localization of electrons on the tungsten nano-island. The lower capacitance of the device combined with the high tunnel resistance, allows for the Coulomb blockade effects observed at room temperature. Different device configurations, minimizing the total capacitance of the device have been explored. The effect of the geometry of the nano electrodes on the device characteristics has been presented. Simulated device characteristics, based on the soliton model have been discussed. The first application of SET device as a gas sensor has been demonstrated.

New technology enables high precision multislit collimators for microbeam radiation therapy

During the past decade microbeam radiation therapy has evolved from preclinical studies to a stage in which clinical trials can be planned, using spatially fractionated, highly collimated and high intensity beams like those generated at the x-ray ID17 beamline of the European Synchrotron Radiation Facility. The production of such microbeams typically between 25 and 100 microm full width at half maximum (FWHM) values and 100-400 microm center-to-center (c-t-c) spacings requires a multislit collimator either with fixed or adjustable microbeam width. The mechanical regularity of such devices is the most important property required to produce an array of identical microbeams. That ensures treatment reproducibility and reliable use of Monte Carlo-based treatment planning systems. New high precision wire cutting techniques allow the fabrication of these collimators made of tungsten carbide. We present a variable slit width collimator as well as a single slit device with a fixed setting of 50 microm FWHM and 400 microm c-t-c, both able to cover irradiation fields of 50 mm width, deemed to meet clinical requirements. Important improvements have reduced the standard deviation of 5.5 microm to less than 1 microm for a nominal FWHM value of 25 microm. The specifications of both devices, the methods used to measure these characteristics, and the results are presented.

In vitro precision of fit of computer-aided design and computer-aided manufacturing titanium and zirconium dioxide bars

OBJECTIVES Optical scanners combined with computer-aided design and computer-aided manufacturing (CAD/CAM) technology provide high accuracy in the fabrication of titanium (TIT) and zirconium dioxide (ZrO) bars. The aim of this study was to compare the precision of fit of CAD/CAM TIT bars produced with a photogrammetric and a laser scanner. METHODS Twenty rigid CAD/CAM bars were fabricated on one single edentulous master cast with 6 implants in the positions of the second premolars, canines and central incisors. A photogrammetric scanner (P) provided digitized data for TIT-P (n=5) while a laser scanner (L) was used for TIT-L (n=5). The control groups consisted of soldered gold bars (gold, n=5) and ZrO-P with similar bar design. Median vertical distance between implant and bar platforms from non-tightened implants (one-screw test) was calculated from mesial, buccal and distal scanning electron microscope measurements. RESULTS Vertical microgaps were not significantly different between TIT-P (median 16μm; 95% CI 10-27μm) and TIT-L (25μm; 13-32μm). Gold (49μm; 12-69μm) had higher values than TIT-P (p=0.001) and TIT-L (p=0.008), while ZrO-P (35μm; 17-55μm) exhibited higher values than TIT-P (p=0.023). Misfit values increased in all groups from implant position 23 (3 units) to 15 (10 units), while in gold and TIT-P values decreased from implant 11 toward the most distal implant 15. SIGNIFICANCE CAD/CAM titanium bars showed high precision of fit using photogrammetric and laser scanners. In comparison, the misfit of ZrO bars (CAM/CAM, photogrammetric scanner) and soldered gold bars was statistically higher but values were clinically acceptable.