Bioactive glass (BAG) is a bone substitute that can be used in orthopaedic surgery. Following implantation, the BAG is expected to be replaced by bone via bone growth and gradual degradation of the BAG. However, the hydroxyapatite mineral forming on BAG resembles bone mineral, not providing sufficient contrast to distinguish the two in X-ray images. In this study, we co-registered coded-excitation scanning acoustic microscopy (CESAM), scanning white light interferometry (SWLI), and scanning electron microscopy with elemental analysis (Energy Dispersive X-ray Spectroscopy) (SEM-EDX) to investigate the bone growth and BAG reactions on a micron scale in a rabbit bone ex vivo. The acoustic impedance map recorded by the CESAM provides high elasticity-associated contrast to study materials and their combinations, while simultaneously producing a topography map of the sample. The acoustic impedance map correlated with the elemental analysis from SEM-EDX. SWLI also produces a topography map, but with higher resolution than CESAM. The two topography maps (CESAM and SWLI) were in good agreement. Furthermore, using information from both maps simultaneously produced by the CESAM (acoustic impedance and topography) allowed determining regions-of-interest related to bone formation around the BAG with greater ease than from either map alone. CESAM is therefore a promising tool for evaluating the degradation of bone substitutes and the bone healing process ex vivo.
Bone Substitutes , Microscopy, Acoustic , Animals , Rabbits , Bone Substitutes/chemistry , Glass/chemistry , Osteogenesis , Interferometry , Microscopy, Electron, Scanning
We investigated and monitored in situ the wetting and dissolution properties of polymeric nanofibers and determined the solid-state of a drug during dissolution. Piroxicam (PRX) was used as a low-dose and poorly-soluble model drug, and hydroxypropyl methylcellulose (HPMC) and polydextrose (PD) were used as carrier polymers for electrospinning (ES). The initial-stage dissolution of the nanofibers was monitored in situ with three-dimensional white light microscopic interferometry (SWLI) and high-resolution optical microscopy. The physical solid-state characterization of nanofibers was performed with Raman spectroscopy, X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). We showed that PRX recrystallizes in a microcrystalline form immediately after wetting of nanofibers, which could lead to enhanced dissolution of drug. Initiation of crystal formation was detected by SWLI, indicating: (1) that PRX was partially released from the nanofibers, and (2) that the solid-state form of PRX changed from amorphous to crystalline. The amount, shape, and size of the PRX crystals depended on the carrier polymer used in the nanofibers and dissolution media (pH). In conclusion, the present nanofibers loaded with PRX exhibit a quasi-dynamic dissolution via recrystallization. SWLI enables a rapid, non-contacting, and non-destructive method for in situ monitoring the early-stage dissolution of nanofibers and regional mapping of crystalline changes (re-crystallization) during wetting. Such analysis is crucial because the wetting and dissolution of nanofibers can greatly influence the performance of nanofibrous drug delivery systems in pharmaceutical and biomedical applications.
Theoretical, numerical, and experimental methods are presented for multiple scattering of light in macroscopic discrete random media of densely-packed microscopic particles. The theoretical and numerical methods constitute a framework of Radiative Transfer with Reciprocal Transactions (R2T2). The R2T2 framework entails Monte Carlo order-of-scattering tracing of interactions in the frequency space, assuming that the fundamental scatterers and absorbers are wavelength-scale volume elements composed of large numbers of randomly distributed particles. The discrete random media are fully packed with the volume elements. For spherical and nonspherical particles, the interactions within the volume elements are computed exactly using the Superposition T-Matrix Method (STMM) and the Volume Integral Equation Method (VIEM), respectively. For both particle types, the interactions between different volume elements are computed exactly using the STMM. As the tracing takes place within the discrete random media, incoherent electromagnetic fields are utilized, that is, the coherent field of the volume elements is removed from the interactions. The experimental methods are based on acoustic levitation of the samples for non-contact, non-destructive scattering measurements. The levitation entails full ultrasonic control of the sample position and orientation, that is, six degrees of freedom. The light source is a laser-driven white-light source with a monochromator and polarizer. The detector is a mini-photomultiplier tube on a rotating wheel, equipped with polarizers. The R2T2 is validated using measurements for a mm-scale spherical sample of densely-packed spherical silica particles. After validation, the methods are applied to interpret astronomical observations for asteroid (4) Vesta and comet 67P/Churyumov-Gerasimenko (Figure 1) recently visited by the NASA Dawn mission and the ESA Rosetta mission, respectively.
Absorption, Radiation , Light , Planets , Scattering, Radiation , Electromagnetic Fields , Monte Carlo Method , Refractometry , Silicon Dioxide/chemistry , Space Flight
The group refractive index is important in length calibration of Fourier domain interferometers by transparent transfer standards. We demonstrate accurate group refractive index quantification using a Fourier domain short coherence Sagnac interferometer. Because of a justified linear length calibration function, the calibration constants cancel out in the evaluation of the group refractive index, which is then obtained accurately from two uncalibrated lengths. Measurements of two standard thickness coverslips revealed group indices of 1.5426±0.0042 and 1.5434±0.0046, with accuracies quoted at the 95% confidence level. This agreed with the dispersion data of the coverslip manufacturer and therefore validates our method. Our method provides a sample specific and accurate group refractive index quantification using the same Fourier domain interferometer that is to be calibrated for the length. This reduces significantly the requirements of the calibration transfer standard.
Mobile devices with interactive displays are ubiquitous commodities. Efficient quality control (QC) drives competitiveness. Scanning white light interferometry imaging offers a fast and nondestructive tool for QC purposes. Relying on optical compensation and image stitching, one can rapidly and cost-effectively produce sharp 3D images of a display's inner structures with a few nanometers' accuracy along the z direction. As a practical example, 3D images of a mobile device display revealed 0.92±0.02 µm height variation in the top glass assembly. The proposed method improves quality assurance methods of display manufacturing.
In the present work, we have investigated the combination of a superresolution microsphere-assisted 2D imaging technique with low-coherence phase-shifting interference microscopy. The imaging performance of this technique is studied by numerical simulation in terms of the magnification and the lateral resolution as a function of the geometrical and optical parameters. The results of simulations are compared with the experimental measurements of reference gratings using a Linnik interference configuration. Additional measurements are also shown on nanostructures. An improvement by a factor of 4.7 in the lateral resolution is demonstrated in air, thus giving a more isotropic nanometric resolution for full-field surface profilometry in the far field.
Capability to simulate the coherence function is important when tuning an interference microscope in an effort to reduce sidelobes in interference signals. The coherence function cannot directly be derived from the light source spectrum since the microscope's effective spectrum is affected by e.g. spatial coherence effects. We show this by comparing the true system spectrum measured using a spectrometer against the effective system spectrum obtained by Fourier analysis of the interference data. The results show that a modulation function that describes the scattering-induced spatial coherence dampening in the system is needed to correct the observed difference between these two spectra. The validity of this modulation function is further verified by quantifying the arithmetic mean roughness of two specified roughness standards. By providing a spectral transfer function for scattering, our method can simulate a sample specific coherence function, and thus shows promise to increase the quality of interference microscope images.
We present quantitative three dimensional images of grooves on a writable Blu-ray Disc based on a single objective Mirau type interferometric microscope, enhanced with a microsphere which is considered as a photonic nanojet source. Along the optical axis the resolution of this microsphere assisted interferometry system is a few nanometers while the lateral resolution is around 112 nm. To understand the physical phenomena involved in this kind of imaging we have modelled the interaction between the photonic jet and the complex disc surface. Agreement between simulation and experimental results is demonstrated. We underline that although the ability of the microsphere to generate a photonic nanojet does not alone explain the resolution of the interferometer, the nanojet can be used to try to understand the imaging process. To partly explain the lateral super-resolution, the potential role of coherence is illustrated. The presented modality may have a large impact on many fields from bio-medicine to nanotechnology.
The reconstructed image of a moving sample always shows a distorted representation of reality. Therefore, one needs to calibrate, for example, out-of-plane nano-videos for quality control of nano-microelectromechanical systems (N-MEMS). Here we discuss how to calibrate and obtain confidence limits for stroboscopic scanning white light interferometry (SSWLI) data when there are differences in speed and amplitude across the field of view. Many N-MEMS devices rely on oscillating structures; consequently, one must calibrate movie recordings of these structures to have global standards and to allow inter-device comparison. We propose to use a quartz tuning fork driven off-resonance as a transfer standard. This approach allows a broad range of traceable frequencies and out-of-plane amplitudes to be introduced into selected parts of the field of view of the SSWLI device featuring similar optical surface properties to many N-MEMS devices without demanding an additional reference surface.
Graphene has attracted attention as a potential strengthening material and functional component in suspended membranes as utilized in micro and nanosystems. Development of a practical and scalable fabrication process is a necessary step to allow the exceptional material properties of graphene to be fully exploited in composite structures. Using standard and scalable microfabrication processes, we fabricated free-standing chemical vapor deposition monolayer graphene-reinforced Al2O3 composite membranes, 0.5 mm in diameter, that are strong and robust. Bulge tests revealed that the graphene reinforcement increased the membrane fracture strength by a factor of at least three and maximum sustainable strain from 0.28% to at least 0.69%. We show that the graphene-reinforced membranes are even tolerant to significant cracking without loss of membrane integrity. The graphene composite membranes' freestanding area of â¼ 200 000 µm(2) is almost a thousand times larger than suspended graphene membranes reported elsewhere. The presented graphene composite membranes may be seen as representing an interesting new class of durable composite materials warranting further study and having potential for broad applicability in a variety of fields.
The developments in printing technologies allow fabrication of micron-size nano-layered delivery systems to personal specifications. In this study we fabricated layered polymer structures for drug-delivery into a microfluidic channel and aimed to interferometrically assure their topography and adherence to each other. We present a scanning white light interferometer (SWLI) method for quantitative assurance of the topography of the embedded structure. We determined rapidly in non-destructive manner the thickness and roughness of the structures and whether the printed layers containing polymers or/and active pharmaceutical ingredients (API) adhere to each other. This is crucial in order to have predetermined drug release profiles. We also demonstrate non-invasive measurement of a polymer structure in a microfluidic channel. It shown that traceable interferometric 3D microscopy is a viable technique for detailed structural quality assurance of layered drug-delivery systems. The approach can have impact and find use in a much broader setting within and outside life sciences.
Drug Delivery Systems , Pharmaceutical Preparations/chemical synthesis , Precision Medicine/methods , Imaging, Three-Dimensional , Interferometry/methods , Microfluidic Analytical Techniques , Microscopy, Interference , Nanostructures , Polymers/chemistry , Printing , Surface Properties
We showed that scanning white light interferometry (SWLI) can provide nanometer depth resolution in 3D topographic analysis of electrospun drug-loaded nanofibrous mats without sample preparation. The method permits rapidly investigating geometric properties (e.g. fiber diameter, orientation and morphology) and surface topography of drug-loaded nanofibers and nanomats. Electrospun nanofibers of a model drug, piroxicam (PRX), and hydroxypropyl methylcellulose (HPMC) were imaged. Scanning electron microscopy (SEM) served as a reference method. SWLI 3D images featuring 29 nm by 29 nm active pixel size were obtained of a 55 µm × 40 µm area. The thickness of the drug-loaded non-woven nanomats was uniform, ranging from 2.0 µm to 3.0 µm (SWLI), and independent of the ratio between HPMC and PRX. The average diameters (n=100, SEM) for drug-loaded nanofibers were 387 ± 125 nm (HPMC and PRX 1:1), 407 ± 144 nm (HPMC and PRX 1:2), and 290 ± 100 nm (HPMC and PRX 1:4). We found advantages and limitations in both techniques. SWLI permits rapid non-contacting and non-destructive characterization of layer orientation, layer thickness, porosity, and surface morphology of electrospun drug-loaded nanofibers and nanomats. Such analysis is important because the surface topography affects the performance of nanomats in pharmaceutical and biomedical applications.
Interferometry/methods , Nanofibers , Nanotechnology/methods , Piroxicam/administration & dosage , Electrochemical Techniques , Hypromellose Derivatives , Imaging, Three-Dimensional , Methylcellulose/analogs & derivatives , Methylcellulose/chemistry , Microscopy, Electron, Scanning/methods , Particle Size , Piroxicam/chemistry , Porosity , Surface Properties
We present work on matching 2-mm-thick wires using optical 3D imaging methods. Marks on such small surfaces are difficult to match using a comparison microscope as this 2D imaging method does not provide height data about the sample surface. Moreover, these 2D microscopy images may be affected by illumination. Hence, the reference and investigated sample should be present at the same time. We employed scanning white light interferometry and confocal microscopy to provide quantitative 3D profiles for reliable comparison of samples that are unavailable for simultaneous analysis. We show that 3D profiling offers a solution by allowing illumination-independent sample comparison. We correctly identified 74 of 80 profiles using consecutive matching striae (CMS) criteria, and we were able to match samples based on profiles measured using different 3D imaging devices. The results suggest that the used methods allow matching cutter marks on thin wires, which has been difficult previously.
We present a supercontinuum (SC) light source designed for stroboscopic white light interferometry. The compact, cost-effective SC source is built from off-the-shelf optical components and operates both in the visible and near-IR at arbitrary repetition rates in the 10 kHz-1 MHz frequency range. We estimate that our source allows performing dynamic white-light interferometric characterization of rapidly oscillating objects up to several tens of megahertz. Its current potential is demonstrated by capturing the movement of a microelectromechanical system oscillating at 2.16 MHz with sub-100 nm accuracy.
Stroboscopy/methods , Imaging, Three-Dimensional , Interferometry , Light
Stroboscopic scanning white light interferometry (SSWLI) allows precise three dimensional (3D) measurements of oscillating samples. Commercial SSWLI devices feature limited pulsing frequency. To address this issue we built a 400-620 nm wideband 150 mW light source whose 1.6 µm wide interferogram is without side peaks. The source combines a non-phosphor white LED with a cyan LED. We measured a calibration artifact with 10 nm precision and obtained 40 nm precision when measuring the 3D profile of a capacitive micromachined ultrasonic transducer membrane operating at 2.72 MHz. This source is compatible with solid state technology.
We combined conventional inkjet printing technology with flexographic printing to fabricate drug delivery systems with accurate doses and tailored drug release. Riboflavin sodium phosphate (RSP) and propranolol hydrochloride (PH) were used as water-soluble model drugs. Three different paper substrates: A (uncoated woodfree paper), B (triple-coated inkjet paper) and C (double-coated sheet fed offset paper) were used as porous model carriers for drug delivery. Active pharmaceutical ingredient (API) containing solutions were printed onto 1 cm × 1 cm substrate areas using an inkjet printer. The printed APIs were coated with water insoluble polymeric films of different thickness using flexographic printing. All substrates were characterized with respect to wettability, surface roughness, air permeability, and cell toxicity. In addition, content uniformity and release profiles of the produced solid dosage forms before and after coating were studied. The substrates were nontoxic for the human cell line assayed. Substrate B was smoothest and least porous. The properties of substrates B and C were similar, whereas those of substrate A differed significantly from those of B, C. The release kinetics of both printed APIs was slowest from substrate B before and after coating with the water insoluble polymer film, following by substrate C, whereas substrate A showed the fastest release. The release rate decreased with increasing polymer coating film thickness. The printed solid dosage forms showed excellent content uniformity. So, combining the two printing technologies allowed fabricating controlled-release oral dosage forms that are challenging to produce using a single technique. The approach opens up new perspectives in the manufacture of flexible doses and tailored drug-delivery systems.
Delayed-Action Preparations/administration & dosage , Drug Compounding/methods , Drug Delivery Systems , Printing/methods , Cell Line , Cell Survival/drug effects , Delayed-Action Preparations/chemistry , Humans , Paper , Propranolol/administration & dosage , Propranolol/chemistry , Riboflavin/administration & dosage , Riboflavin/chemistry , Surface Properties , Viscosity
Scratch resistance (SR) of externally plasticized hydroxypropyl methylcellulose (HPMC) films intended for tablet film coatings was studied. Special attention was paid to effects of short-term aging and ultraviolet (UV) treatment on the SR properties of these films. Controlled scratching of the films was performed with a Lloyd LRX materials tester featuring a spherical steel tip. Scratch surface profiles were measured by scanning white light interferometry (SWLI). The influence of using an external plasticizer on the SR was studied by comparing scratch dimensions in non-plasticized films to samples plasticized either with glycerol or polyethylene glycol (PEG) 400. The study demonstrates that both the amount and type of plasticizer influences the SR of aqueous HPMC films. It also shows that SWLI can quantitatively evaluate the effect of plasticizer content and aging on the SR of pharmaceutical films. This knowledge could be used to optimize pharmaceutical film coating formulations.
Methylcellulose/analogs & derivatives , Plasticizers/chemistry , Tablets/chemistry , Technology, Pharmaceutical/methods , Glycerol/chemistry , Hardness , Hypromellose Derivatives , Materials Testing/instrumentation , Materials Testing/methods , Methylcellulose/chemistry , Polyethylene Glycols/chemistry , Time Factors , Ultraviolet Rays
A supercontinuum light source was incorporated into a custom-built scanning white-light interferometer. This light source based on a Nd:YAG pumped microstructured optical fiber exhibits 1.21+/-0.10 microm temporal coherence length. The device operation was validated by characterizing the step height on a microelectromechanical system component. The measured step height- 7.027+/-0.020 microm-agreed with results obtained by employing traditional light sources: a halogen lamp and a white light-emitting diode. The new light source features high output intensity of 20-35 mW, which is beneficial when measuring low-reflectivity samples. As the supercontinuum light source may be modulated at frequencies exceeding 10 MHz, it holds potential for stroboscopic dynamic measurements.
