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Flexible microfluidic devices supported by biodegradable insertion scaffolds for convection-enhanced neural drug delivery

Conor P. Foley, Nozomi Nishimura, Keith B. Neeves, Chris B. Schaffer, and William L. Olbricht

Biomed Microdevices (2009)

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Convection enhanced delivery (CED) can improve the spatial distribution of drugs delivered directly to the brain. In CED, drugs are infused locally into tissue through a needle or catheter inserted into brain parenchyma. Transport of the infused material is dominated by convection, which enhances drug penetration into tissue compared with diffusion mediated delivery. We have fabricated and characterized an implantable microfluidic device for chronic convection enhanced delivery protocols. The device consists of a flexible parylene-C microfluidic channel that is supported during its insertion into tissue by a biodegradable poly(DL-lactide-co-glycolide) scaffold. The scaffold is designed to enable tissue penetration and then erode over time, leaving only the flexible channel implanted in the tissue. The device was able to reproducibly inject fluid into neural tissue in acute experiments with final infusate distributions that closely approximate delivery from an ideal point source. This system shows promise as a tool for chronic CED protocols.

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Light and Matter Interactions: Going with the Grain

Chris B. Schaffer

Nature Photonics (2008)

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Non-reciprocal optical phenomena — effects that depend on the direction of light propagation —are rare. Researchers have now observed non-reciprocal material modification when moving a beam of ultrashort light pulses through a lithium niobate crystal.

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Large two-photon absorptivity of hemoglobin in the infrared range of 780-880 nm

G. Omar Clay, Chris B. Schaffer, and David Kleinfeld

Journal of Chemical Physics (2007)

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Porphyrin molecules have a highly conjugated cyclic structure and are theorized to have unusually large two-photon absorptivities (σTPA), i.e., σTPA ~ 10^2 GM. The authors tested this claim. Ultrafast two-photon absorption (TPA) spectroscopy was performed on solutions of hemoglobin, which contains a naturally occurring metaloporphyrin. They used a pump-probe technique to directly detect the change in transmission induced by TPA over the wavelength range of λ0=780–880 nm. As controls, they measured the TPA of the dyes rhodamine 6G and B; their measurements both verify and extend previously reported values. In new results, hemoglobin was found to have a peak two-photon absorptivity of σTPA~150 GM at λ0=825 nm, near a resonance of the Soret band. This value supports theoretical expectations. They also found a significant difference in the TPA of carboxyhemoglobin versus oxyhemoglobin, e.g., σTPA=61 GM versus σTPA=18 GM, respectively, at λ0=850 nm, which shows that the ligand affects the electronic states involved in TPA.

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Penetrating arterioles are a bottleneck in the perfusion of neocortex

Nozomi Nishimura, Chris B. Schaffer, Beth Friedman, Patrick D. Lyden, and David Kleinfeld

Proceedings of the National Academy of Sciences (2007)

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Penetrating arterioles bridge the mesh of communicating arterioles on the surface of cortex with the subsurface microvascular bed that feeds the underlying neural tissue. We tested the conjecture that penetrating arterioles, which are positioned to regulate the delivery of blood, are loci of severe ischemia in the event of occlusion. Focal photothrombosis was used to occlude single penetrating arterioles in rat parietal cortex, and the resultant changes in flow of red blood cells were measured with two-photon laser-scanning microscopy in individual subsurface microvessels that surround the occlusion. We observed that the average flow of red blood cells nearly stalls adjacent to the occlusion and remains within 30% of its baseline value in vessels as far as 10 branch points downstream from the occlusion. Preservation of average flow emerges 350 µm away; this length scale is consistent with the spatial distribution of penetrating arterioles. We conclude that penetrating arterioles are a bottleneck in the supply of blood to neocortex, at least to superficial layers.

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 Supplement 1

Photonic band-gap fiber gas cell fabricated using femtosecond micromachining

Christopher J. Hensley , Daniel H. Broaddus, Chris B. Schaffer, and Alexander L. Gaeta

Optics Express (2007)

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Femtosecond laser drilling is used to produce a variable-pressure fiber gas cell. Tightly focused laser pulses are used to produce micrometer-diameter radial channels in a hollow-core photonic band-gap fiber (HC-PBGF), and through these microchannels the core of the fiber is filled with a gas. The fiber cell is formed by fusion splicing and sealing the ends of the HC-PBGF to standard step-index fiber. As a demonstration, acetylene is introduced into an evacuated fiber at multiple backing pressures and spectra are measured.

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Suppressed neuronal activity and concurrent arteriolar vasoconstriction may explain negative blood oxygenation level-dependent signal

28. Devor A, Tian P, Nishimura N, Teng IC, Hillman EM, Narayanan SN, Ulbert I, Boas DA, Kleinfeld D, Dale AM.

Journal of Neuroscience (2007)

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Synaptic transmission initiates a cascade of signal transduction events that couple neuronal activity to local changes in blood flow and oxygenation. Although a number of vasoactive molecules and specific cell types have been implicated, the transformation of stimulus-induced activation of neuronal circuits to hemodynamic changes is still unclear. We use somatosensory stimulation and a suite of in vivo imaging tools to study neurovascular coupling in rat primary somatosensory cortex. Our stimulus evoked a central region of net neuronal depolarization surrounded by net hyperpolarization. Hemodynamic measurements revealed that predominant depolarization corresponded to an increase in oxygenation, whereas predominant hyperpolarization corresponded to a decrease in oxygenation. On the microscopic level of single surface arterioles, the response was composed of a combination of dilatory and constrictive phases. Critically, the relative strength of vasoconstriction covaried with the relative strength of oxygenation decrease and neuronal hyperpolarization. These results suggest that a neuronal inhibition and concurrent arteriolar vasoconstriction correspond to a decrease in blood oxygenation, which would be consistent with a negative blood oxygenation level-dependent functional magnetic resonance imaging signal.

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Laser photoablation: a new biomedical tool

Nozomi Nishimura, Chris Schaffer, Beth Friedman, Philbert Tsai, Patrick Lyden, and David Kleinfeld

SPIE Newsroom (2006)

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Ultrashort laser pulses can be used to produce lesions in single blood vessels located in the cortex of live rats, thus enabling the study of microstrokes.

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Numerical aperture dependence of damage and supercontinuum generation from femtosecond laser pulses in bulk fused silica

Jonathan B. Ashcom, Rafael R. Gattass, Chris B. Schaffer, and Eric Mazur

Journal of the Optical Society of America (2006)

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Competing nonlinear optical effects are involved in the interaction of femtosecond laser pulses with transparent dielectrics: supercontinuum generation and multiphoton-induced bulk damage. We measured the threshold energy for supercontinuum generation and bulk damage in fused silica using numerical apertures (NAs) ranging from 0.01 to 0.65. The threshold for supercontinuum generation exhibits a minimum near 0.05 NA and increases quickly above 0.1 NA. For NAs greater than 0.25, we observe no supercontinuum generation. The extent of the blue broadening of the supercontinuum spectrum decreases significantly as the NA is increased from 0.01 to 0.08, showing that weak focusing is important for generating the broadest supercontinuum spectrum. Using a light-scattering technique to detect the onset of bulk damage, we confirmed bulk damage at all NAs studied. At a high NA, the damage threshold is well below the critical power for self-focusing.

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Spectroscopic analysis of the oxygenation state of hemoglobin using coherent anti-Stokes Raman scattering

Hilde A. Rinia, Mischa Bonn, Erik M. Vartiainen, Chris B. Schaffer, and Michiel Müller

Journal of Biomedical Optics (2006)

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A method for noninvasively determining blood oxygenation in individual vessels inside bulk tissue would provide a powerful tool for biomedical research. We explore the potential of coherent anti-Stokes Raman scattering (CARS) spectroscopy to provide this capability. Using the multiplex CARS approach, we measure the vibrational spectrum in hemoglobin solutions as a function of the oxygenation state and observe a clear dependence of the spectral shape on oxygenation. The direct extraction of the Raman line shape from the CARS data using a maximum entropy method phase retrieval algorithm enables quantitative analysis. The CARS spectra associated with intermediate oxygenation saturation levels can be accurately described by a weighted sum of the fully oxygenated and fully deoxygenated spectra. We find that the degree of oxygenation determined from the CARS data agrees well with that determined by optical absorption. As a nonlinear optical technique, CARS inherently provides the 3-D imaging capability and tolerance to scattering necessary for biomedical applications. We discuss the challenges in extending the proof of principle demonstrated to in vivo applications.

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Spectroscopy of third-harmonic generation: evidence for resonances in model compounds and ligated hemoglobin

G. Omar Clay, Andrew C. Millard, Chris B. Schaffer, Juerg Aus-der-Au, Philbert S. Tsai, Jeffrey A. Squier, and David Kleinfeld

Journal of the Optical Society of America (2006)

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We report on third-harmonic generation (THG) of biomolecular solutions at the fluid/glass interface as a means to probe resonant contributions to their nonlinear absorption spectra that could serve as contrast mechanisms for functional imaging. Our source was 100 fs laser pulses whose center wavelength varied from 760 to 1000 nm. We find evidence of a two-photon resonance in the ratio of third-order susceptibilities, Xsample(3w)/Xglass, for aqueous solutions of Rhodamine B, Fura-2, and hemoglobin and a three-photon resonance in Xsample(3w)/Xglass for solutions of bovine serum albumin. Consistent with past work, we find evidence of a one-photon resonance of Xsample(3w)/Xglass for water, while confirming a lack of resonant enhancement for benzene. At physiological concentrations, hemoglobin in different ligand-binding states could be distinguished on the basis of features of its THG spectrum.

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