Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space. In nanotoxicology studies, this lung mimic revealed that cyclic mechanical strain accentuates toxic and inflammatory responses of the lung to silica nanoparticles. Mechanical strain also enhances epithelial and endothelial uptake of nanoparticulates and stimulates their transport into the underlying microvascular channel. Similar effects of physiological breathing on nanoparticle absorption are observed in whole mouse lung. Mechanically active "organ-on-a-chip" microdevices that reconstitute tissue-tissue interfaces critical to organ function may therefore expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.

http://science.sciencemag.org/content/sci/328/5986/1662.full.pdf

Reconstituting Organ-Level Lung Functions on a Chip

▪ Abstract Soft lithography, a set of techniques for microfabrication, is based on printing and molding using elastomeric stamps with the patterns of interest in bas-relief. As a technique for fabricating microstructures for biological applications, soft lithography overcomes many of the shortcomings of photolithography. In particular, soft lithography offers the ability to control the molecular structure of surfaces and to pattern the complex molecules relevant to biology, to fabricate channel structures appropriate for microfluidics, and to pattern and manipulate cells. For the relatively large feature sizes used in biology (≥50 μm), production of prototype patterns and structures is convenient, inexpensive, and rapid. Self-assembled monolayers of alkanethiolates on gold are particularly easy to pattern by soft lithography, and they provide exquisite control over surface biochemistry.

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Soft Lithography in Biology and Biochemistry

This Account summarizes techniques for fabrication and applications in biomedicine of microfluidic devices fabricated in poly(dimethylsiloxane) (PDMS). The methods and applications described focus on the exploitation of the physical and chemical properties of PDMS in the fabrication or actuation of the devices. Fabrication of channels in PDMS is simple, and it can be used to incorporate other materials and structures through encapsulation or sealing (both reversible and irreversible).

Poly(dimethylsiloxane) as a material for fabricating microfluidic devices.

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Micro Total Analysis Systems. 1. Introduction, Theory, and Technology

Microscale technologies are emerging as powerful tools for tissue engineering and biological studies. In this review, we present an overview of these technologies in various tissue engineering applications, such as for fabricating 3D microfabricated scaffolds, as templates for cell aggregate formation, or for fabricating materials in a spatially regulated manner. In addition, we give examples of the use of microscale technologies for controlling the cellular microenvironment in vitro and for performing high-throughput assays. The use of microfluidics, surface patterning, and patterned cocultures in regulating various aspects of cellular microenvironment is discussed, as well as the application of these technologies in directing cell fate and elucidating the underlying biology. Throughout this review, we will use specific examples where available and will provide trends and future directions in the field.

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Microscale technologies for tissue engineering and biology

M. Grell, D. Lupo, A. Yasuda, Synth. Met. 2000, 111±112, 173. [9] K. S. Whitehead, M. Grell, D. D. C. Bradley, M. Jandke, P. Strohriegl, Appl. Phys. Lett. 2000, 76, 2946. [10] V. N. Bliznyuk, S. A. Carter, J. C. Scott, G. Glärner, R. D. Miller, D. C. Miller, Macromolecules 1999, 32, 391. [11] M. Redecker, D. D. C. Bradley, M. Inbasekaran, W. W. Wu, E. P. Woo, Adv. Mater. 1999, 11, 241. [12] J. P. Chen, G. Klaerner, J.-I. Lee. D. Markiewicz, V. Y. Lee, R. D. Miller, J. C. Scott, Synth. Met. 1999, 107, 129. [13] G. Klaerner, M. H. Davey, W. D. Chen, J. C. Scott, R. D. Miller, Adv. Mater. 1998, 10, 993. [14] M. Kreyenschmidt, G. Klärner, T. Fuhrer, J. Ashenhurst, S. Karg, W. D. Chen, V. Y. Lee, J. C. Scott, R. D. Miller, Macromolecules 1998, 31, 1099. [15] Y. He, S. Gong, R. Hattori, J. Kanicki, Appl. Phys. Lett. 1999, 74, 2265. [16] D. Sainova, T. Miteva, H. G. Nothofer, U. Scherf, H. Fujikawa, I. Glowacki, J. Ulanski, D. Neher, Appl. Phys. Lett. 2000, 76, 1810. [17] S. Janietz, D. D. C. Bradley, M. Grell, C. Giebeler, M. Inbasekaran, E. P. Woo, Appl. Phys. Lett. 1998, 73, 2453. [18] K. Meerholz, H. Gregorius, K. Müllen, J. Heinze, Adv. Mater. 1994, 6, 671. [19] D. M. Pai, J. F. Yanus, M. Stolka, J. Chem. Phys. 1984, 88, 4414. [20] C. D. Müller, T. Braig, H. Nothofer, M. Arnoldi, M. Groû, U. Scherf, O. Nuyken, K. Meerholz, Chem. Phys. Chem. 2000, 1, 207. [21] M. Jandke, P. Strohriegl, J. Gmeiner, W. Brütting, M. Schwoerer, Adv. Mater. 1999, 11, 1518. [22] H. G. Nothofer, Ph.D. Thesis, University of Potsdam, Potsdam, Germany 2001. [23] T. Yamamoto, Prog. Polym. Sci. 1992, 17, 1153. [24] E. P. Woo, M. Inbasekaran, W. Shiang, G. R. Roof, Int. Patent Appl. WO97/05 184, 1997. [25] M. Inbasekaran, W. Wu, E. P. Woo, US Patent 5 777 070, 1998. [26] A. J. Bard, L. A. Faulkner, Electrochemical MethodsÐFundamentals and Applications, Wiley, New York 1984.

Topographical Micropatterning of Poly(dimethylsiloxane) Using Laminar Flows of Liquids in Capillaries

Methods and systems for effecting responses on surfaces utilizing microlens arrays including microoptical components embedded or supported by a support element and positioned from the surface at a distance essentially equal to the image distance of the microoptical component with spacer elements are disclosed. Microlens arrays can be used to manipulate incident energy or radiation having a distribution in characteristic property(s) defining an object pattern to form a corresponding image pattern on a substrate surface. The energy can be light having a pattern or a specific wavelength, intensity or polarization or coherence alignment. The image pattern can have features of order 100 nm in size or less produced from corresponding object patterns having features in the order millimeters. The size of the object pattern can be reduced by the microlens arrays described by a factor of 100 or more using a single step process to form the image patterns.

Microlens for projection lithography and method of preparation thereof

This letter demonstrates the use of an array of transparent microspheres in forming repetitive, micrometer-scale patterns in photoresist, starting from masks with centimeter-scale patterns. A transparent microsphere with diameter d>1.5 μm acts as a lens and reduces centimeter-scale images into micrometer-scale images on its image plane. A planar array of microspheres projects the image of an illuminated mask onto a corresponding array of micropatterns on their common image plane. We have prepared arrays of polystyrene microspheres (d=1.5–10 μm) embedded in a transparent membrane to generate repetitive patterns in photoresist, and have transferred the resulting patterns into metal films by liftoff. The optical system of this technique is related to that used in conventional projection photolithography, but differs in that the lens that accomplishes size reduction is positioned within 10 μm of the photoresist. The microspheres generate uniform patterns over an area of ∼2 cm2, using a mask with area ∼25×25 c...

Fabrication of arrays of two-dimensional micropatterns using microspheres as lenses for projection photolithography

This paper describes several methods for the fabrication of microlenses, and demonstrates a lithographic technique that uses a microlens array to pattern the intensity of light incident on photoresist. Three different methods were used to fabricate microlenses: (i) self-assembly of transparent microspheres, (ii) melting and reflow of photoresist on glass substrates and (iii) self-assembly of liquid polymers on functionalized surfaces. These methods provide different advantages and convenience for the fabrication of microlenses. Microlens arrays produced by these techniques were used in photolithography to produce arrays of micropatterns in photoresist. The distribution of these micropatterns replicates the distribution of the microlenses in the array. Two types of illumination are used for exposure in this technique: collimated flood illumination and illumination through a mask. Depending on which type of exposure is used, a single microlens array can produce different patterns on its image plane: (i) an array of circular or noncircular microlenses under collimated illumination produces an array of optical micropatterns on an image plane positioned within micrometer distances from the lens array. The array of optical micropatterns corresponds to the distribution of spatial irradiance generated by simple lensing of the microlens array. The shapes of these micropatterns depend on the shapes and profiles of the microlenses. (ii) Under illumination patterned by a mask, each microlens approximately replicates the image of the patterned light source and produces a micro-scale image of this source on its image plane. The array of microlenses generates an array of repetitive micropatterns on the common image plane of the lens array. The shapes of the micropatterns depend on the patterns of the masks. Gray-scale masks can be used to produce repetitive microstructures with controlled profiles. Both techniques can generate microstructures with submicron resolution. We demonstrate that both methods produce arrays of uniform micropatterns over an area larger than 10 cm2.

https://iopscience.iop.org/article/10.1088/0960-1317/12/6/305/pdf

Fabrication of two-dimensional arrays of microlenses and their applications in photolithography

We describe a convenient lithographic technique that can produce simple, repetitive micropatterns over large areas (several square centimeters). The technique uses an illuminated array of micrometer-scale lenses to generate an array of optical patterns in an image plane located within micrometer distances from the lens array. A layer of photoresist, placed in the image plane, records the patterns. Microlenses with different sizes, profiles, composition, and indices of refraction produce corresponding patterns in exposed and developed photoresist. Both spherical and nonspherical microlenses were examined. Several types of optical element containing arrays of microlenses were fabricated and used to demonstrate that this technique can generate uniform micropatterns over large areas (>4 cm2) in a single exposure. The smallest features produced had dimensions of ∼100 nm.

Ming-Hsien Wu

Papers

Topographical Micropatterning of Poly(dimethylsiloxane) Using Laminar Flows of Liquids in Capillaries

Microlens for projection lithography and method of preparation thereof

Fabrication of arrays of two-dimensional micropatterns using microspheres as lenses for projection photolithography

Fabrication of two-dimensional arrays of microlenses and their applications in photolithography

Patterning flood illumination with microlens arrays