Anand Doraiswamy

Medical prototyping using two photon polymerization

Two photon polymerization involves nearly simultaneous absorption of ultrashort laser pulses for selective curing of photosensitive material. This process has recently been used to create small-scale medical devices out of several classes of photosensitive materials, such as acrylate-based polymers, organically-modified ceramic materials, zirconium sol-gels, and titanium-containing hybrid materials. In this review, the use of two photon polymerization for fabrication of several types of small-scale medical devices, including microneedles, artificial tissues, microfluidic devices, pumps, sensors, and valves, from computer models is described. Necessary steps in the development of two photon polymerization as a commercially viable medical device manufacturing method are also considered.

Two-photon polymerization of microneedles for transdermal drug delivery

Importance of the field: Microneedles are small-scale devices that are finding use for transdermal delivery of protein-based pharmacologic agents and nucleic acid-based pharmacologic agents; however, microneedles prepared using conventional microelectronics-based technologies have several shortcomings, which have limited translation of these devices into widespread clinical use. Areas covered in this review: Two-photon polymerization is a laser-based rapid prototyping technique that has been used recently for direct fabrication of hollow microneedles with a wide variety of geometries. In addition, an indirect rapid prototyping method that involves two-photon polymerization and polydimethyl siloxane micromolding has been used for fabrication of solid microneedles with exceptional mechanical properties. What the reader will gain: In this review, the use of two-photon polymerization for fabricating in-plane and out-of-plane hollow microneedle arrays is described. The use of two-photon polymerization-micromolding for fabrication of solid microneedles is also reviewed. In addition, fabrication of microneedles with antimicrobial properties is discussed; antimicrobial microneedles may reduce the risk of infection associated with the formation of channels through the stratum corneum. Take home message: It is anticipated that the use of two-photon polymerization as well as two-photon polymerization-micromolding for fabrication of microneedles and other microstructured drug delivery devices will increase over the coming years.

Inkjet Printing of Bioadhesives

Over the past century, synthetic adhesives have largely displaced their natural counterparts in medical applications. However, rising concerns over the environmental and toxicological effects of the solvents, monomers, and additives used in synthetic adhesives have recently led the scientific community to seek natural substitutes. Marine mussel adhesive protein is a formaldehyde-free natural adhesive that demonstrates excellent adhesion to several classes of materials, including glasses, metals, metal oxides, and polymers. In this study, we have demonstrated computer aided design (CAD) patterning of various biological adhesives using piezoelectric inkjet technology. A MEMS-based piezoelectric actuator was used to control the flow of the mussel adhesive protein solution through the ink jet nozzles. Fourier transform infrared spectroscopy (FTIR), microscopy, and adhesion studies were performed to examine the chemical, structural, and functional properties of these patterns, respectively. FTIR revealed the piezoelectric inkjet technology technique to be nondestructive. Atomic force microscopy was used to determine the extent of chelation caused by Fe(III). The adhesive strength in these materials was correlated with the extent of chelation by Fe(III). Piezoelectric inkjet printing of naturally-derived biological adhesives may overcome several problems associated with conventional tissue bonding materials. This technique may significantly improve wound repair in next generation eye repair, fracture fixation, wound closure, and drug delivery devices.

Evaluation of the impact of light scatter from glistenings in pseudophakic eyes

Purpose To study the impact of light scatter from glistenings in pseudophakic eyes using ray tracing in a model eye Setting Department of Research, Advanced Vision Science, Inc., Goleta, California, USA. Design Mathematical modeling and simulation. Methods A pseudophakic eye model was constructed in Zemax using the Arizona eye model as the basis. The Mie scattering theory was used to describe the intensity and direction of light as it scatters for a spherical particle immersed in a given media (intraocular lens [IOL]). The modeling and evaluation of scatter and modulation transfer function (MTF) were performed for several biomaterials with various size and density of glistenings under scotopic, mesopic, and photopic conditions. Results As predicted by the Mie theory, the amount of scatter was a function of the relative difference in refractive index between the media and the scatterer, the size of the scatterer, and the volume fraction of the scatterer. The simulation demonstrated that an increase in density of glistenings can lead to a significant drop in the MTF of the IOL and the pseudophakic eye. This effect was more pronounced in IOLs with smaller cavitations, and the observation was consistent for all tested biomaterials. Conclusions Mathematical modeling demonstrated that glistenings in IOLs will lead to reduction in the MTF of the IOL and the pseudophakic eye. The loss in MTF was more pronounced at high densities and small cavitation sizes across all biomaterials. Inconsistent and poor clinical quantification of glistenings in IOLs may explain some inconsistencies in the literature. Financial Disclosure Dr. DeHoog is a consultant to and Dr. Doraiswamy is an employee of Advanced Vision Science, Inc.

Two-photon polymerization for fabrication of biomedical devices

Two-photon polymerization (2PP) is a novel technology which allows the fabrication of complex three-dimensional (3D) microstructures and nanostructures. The number of applications of this technology is rapidly increasing; it includes the fabrication of 3D photonic crystals [1-4], medical devices, and tissue scaffolds [5-6]. In this contribution, we discuss current applications of 2PP for microstructuring of biomedical devices used in drug delivery. While in general this sector is still dominated by oral administration of drugs, precise dosing, safety, and convenience are being addressed by transdermal drug delivery systems. Currently, main limitations arise from low permeability of the skin. As a result, only few types of pharmacological substances can be delivered in this manner [7]. Application of microneedle arrays, whose function is to help overcome the barrier presented by the epidermis layer of the skin, provides a very promising solution. Using 2PP we have fabricated arrays of hollow microneedles with different geometries. The effect of microneedle geometry on skin penetration is examined. Our results indicate that microneedles created using 2PP technique are suitable for in vivo use, and for integration with the next generation of MEMS- and NEMS-based drug delivery devices.

Matrix-assisted pulsed-laser evaporation of DOPA-modified poly(ethylene glycol) thin films

3,4-Dihydroxyphenyl-L-alanine-modified poly(ethylene glycol) (mPEG-DOPA3) is a biologically-inspired material that exhibits unique adhesion properties. In this study, mPEG-DOPA3 thin films were prepared using a novel laser process known as matrix-assisted pulsed-laser evaporation (MAPLE). The films were examined using Fourier transform infrared spectroscopy, atomic force microscopy, profilometry, antifouling studies and cell adhesion studies. The Fourier transform infrared spectroscopy data demonstrated that the main functional groups in the MAPLE-deposited mPEG-DOPA3 films remained intact. Profilometry and atomic force microscopy studies confirmed that MAPLE provides excellent control over film morphology, as well as film thickness. High resolution patterns of mPEG-DOPA3 thin films were obtained by masking. MAPLE-deposited mPEG-DOPA3 thin films demonstrated an absence of cytotoxicity and acceptable antifouling properties against the marine bacterium Cytophaga lytica. MAPLE-deposited mPEG-DOPA3 thin films potentially have numerous biomedical and marine applications.

Vascular tissue engineering by computer-aided laser micromachining

Many conventional technologies for fabricating tissue engineering scaffolds are not suitable for fabricating scaffolds with patient-specific attributes. For example, many conventional technologies for fabricating tissue engineering scaffolds do not provide control over overall scaffold geometry or over cell position within the scaffold. In this study, the use of computer-aided laser micromachining to create scaffolds for vascular tissue networks was investigated. Computer-aided laser micromachining was used to construct patterned surfaces in agarose or in silicon, which were used for differential adherence and growth of cells into vascular tissue networks. Concentric three-ring structures were fabricated on agarose hydrogel substrates, in which the inner ring contained human aortic endothelial cells, the middle ring contained HA587 human elastin and the outer ring contained human aortic vascular smooth muscle cells. Basement membrane matrix containing vascular endothelial growth factor and heparin was to promote proliferation of human aortic endothelial cells within the vascular tissue networks. Computer-aided laser micromachining provides a unique approach to fabricate small-diameter blood vessels for bypass surgery as well as other artificial tissues with complex geometries.

Inkjet Printing of Cyanoacrylate Adhesive

In this study, we have demonstrated the use of piezoelectric inkjet printing to fabricate microscale patterns of Vetbond® n-butyl cyanoacrylate tissue adhesive. Optical microscopy, atomic force microscopy, nanoindentation, and a cell viability assay were used to examine the structural, mechanical, and biological properties of microscale cyanoacrylate patterns. The ability to rapidly fabricate microscale patterns of medical and veterinary adhesives will enable reduced bond lines between tissues, improved tissue integrity, and reduced toxicity. We envision that piezoelectric inkjet deposition of cyanoacrylates and other medical adhesives may be used to enhance wound repair in microvascular surgery.

Evaluation of loss in optical quality of multifocal intraocular lenses with glistenings

Purpose To study the impact of loss in optical quality from glistenings in diffractive multifocal intraocular lenses (IOLs) using ray tracing in a model eye. Setting Independent research laboratory, Irvine, California, USA. Design Experimental study. Methods A pseudophakic eye model was constructed in Zemax, an optical ray‐tracing program, using the Arizona eye model as the basis. The Mie scattering theory was used to describe the intensity and direction of light as it scattered for a spherical particle immersed in a diffractive multifocal IOL. To evaluate the impact of glistening scatter, a more advanced eye model was constructed in Fred, a nonsequential optical ray‐tracing software. An evaluation of scatter and modulation transfer function (MTF) was performed for a hydrophobic biomaterial with a refractive index of 1.54 for various sizes and densities of glistenings under mesopic conditions. Results As predicted by the Mie theory, the amount of scatter was a function of the change in the refractive index, size of the scatterer, and volume fraction of the scatterers. This modeling showed that an increase in density of glistenings can lead to a significant drop of MTF of the IOL. This effect was more pronounced in multifocal IOLs than in monofocal IOLs. Conclusions Mathematical modeling showed that glistenings in multifocal IOLs lead to a reduction in MTF of the IOL and the pseudophakic eye. The relative loss of MTF in multifocal IOLs was more significant than in monofocal IOLs because of the nature of the design. Financial Disclosures Drs. DeHoog and Doraiswamy are consultants to Advanced Vision Science, Inc.

Microscale Patterning of Two-Component Biomedical Hydrogel

In this study, piezoelectric inkjet technology was used for microscale patterning of a two-component medical hydrogel (sold under the registered trademark Coseal®). A MEMS-based piezoelectric actuator was used to control the flow of polyethylene glycol in a sodium phosphate/sodium carbonate solution through inkjet nozzles. A hydrogen chloride solution was subsequently used to cross-link the polyethylene glycol material. Optical microscopy, scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and nanoindentation studies were performed to examine the structural, chemical, and mechanical properties of the inkjetted hydrogel material. Scanning electron micrographs revealed that the inkjetted material exhibited randomly oriented cross-linked networks. Fourier transform infrared spectroscopy revealed that the piezoelectric inkjet technology technique did not alter chemical bonding in the material. Piezoelectric inkjet printing of medical hydrogels may improve wound repair in next generation eye surgery, fracture fixation, and wound closure devices.