Optics: measuring and testing – By particle light scattering – With photocell detection
Reexamination Certificate
2001-07-13
2004-03-30
Chang, Audrey (Department: 2872)
Optics: measuring and testing
By particle light scattering
With photocell detection
Reexamination Certificate
active
06714299
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns the field of development and quality control of devices and materials for fluid handling, control, flow, and deposition.
At presen methods for analyses in these applications typically rely upon detection of fluorescent or chromogenic dyes using a time-lapse or high-speed video device. For flow analysis, a fine stream of the fluorescent or chromogenic detection agent can be introduced into the system. However, information obtained using these methods is of limited utility with respect to a significant area of the flow channel because of limited sensitivity and rapid diffusion and dilution of the detected agent.
Resonance light scattering (RLS) particles have been shown to provide highly sensitive labels in bioanalytical assays in a variety of different formats. Such uses are described, for example, in Yguerabide at al., PCT/US97/06584, Yguerabide et al., PCT/US98/23160, Yguerabide et al, U.S. application Ser. No. 08/844,217, now U.S. Pat. No. 6,214,560, and Yguerabide et al., U.S. application Ser. No. 08/953,713, and the patents and publications cited in the backgrounds thereof, all of which are hereby incorporated by reference herein in their entireties, including drawings.
Particles with similar composition have also been used in connection with electron microscopy and as cytological stains, utilizing their associated absorbence properties.
SUMMARY OF THE INVENTION
The present invention relates to the use of resonance light scattering (RLS) particles as tools to guide and refine design, manufacture, and quality control parameters in production of fluid-containing devices and processes. The use of such particles is particularly advantageous for small volume devices, such as micro, nano, and pico volume fluidic, capillary, or deposition instruments, devices, and products.
These applications of RLS particles relate to the capability provided by such particles to obtain detailed information associated with micro-scale, nano-scale, and pico-scale flow, as well as static properties or parameters, using appropriately formulated RLS particles. Such information can be readily obtained using simple instrumentation for detection, or even using detection by eye with appropriate magnification, though more complex apparatus, especially those having electronic analysis and/or control capabilities are advantageous in many applications.
Using such RLS particles, it is possible to detect light scattering from the particles continuously, without the bleaching experienced with fluorophores, and with very high sensitivity and signal stability. Detection can even be readily performed on single particles.
Thus, in a first aspect, the invention provides a method for determination of a dynamic property of a fluid volume. The dynamic property is determined by determining the distribution or location or both of at least one light scattering particle using detection of light scattered from the particle or particles in at least a portion of said fluid volume. For some devices it may be useful to view the particles in the entire device simultaneously, while in other cases, it may be useful to view only a portion of the device, e.g., a valve, flow channel, or mixing chamber. In still other cases, it may be advantageous to follow a particle or set of particles as they are transported through a device or portion of a device.
A variety of flow properties can be involved, and the determination can involve one or more than one such property, determined simultaneously or sequentially. For example, the dynamic property may be flow rate, or particle distribution. In certain embodiments, the particles are directly or indirectly attached to a biological molecule such as a nucleic acid molecule such as nucleic acid probe, a polypeptide such as an antibody or antibody fragment, a lectin, a carbohydrate, or a cell. Thus, the attached light scattering particle provides a method for determining the distribution of biological molecule or cell in a volume or on a surface. In preferred embodiments, the device is an array, or other device on which molecules are deposited or bound in a localized manner, e.g., spotted on a solid phase surface or deposited in a well.
Similarly, in preferred embodiments, the dynamic property is uniformity (or lack of uniformity) of drying on a solid surface. This is particularly applicable to development and quality control of arrays, e.g., nucleic acid or polypeptide arrays. Uniformity (or lack of uniformity) can be uniformity across discrete areas, where the areas are evaluated individually (though the individual evaluations can then be compared), thereby providing a larger scale evaluation or comparison). Examples of such discrete areas are the individual features on a planar array. Alternatively, the uniformity can be evaluated across multiple discrete areas. As an example, the number of functional probes bound in the various features on a planar array can be evaluated. In either type of evaluation, lack of uniformity is typically shown by a pattern to the particle distribution. Such a pattern may, for example, be irregular differences in concentration or density of RLS particle, or a gradient in such concentration or density across an area or volume. In such embodiments, the uniformity can be evaluated continuously, or at discrete times, or at endpoint, or in combinations.
In preferred embodiment, the deposited volume and/or number of features is as described for embodiments of other aspects involving arrays herein.
In another example, the dynamic property is a flow pattern in a device or portion of a device. For example, the device may be a multi-channel device. Such a flow pattern, can for example, be the distribution of particles across a flow channel, presence and/or size of eddies or turbulence zones, flow velocity in a portion of a device, or a flow velocity profile across a channel, chamber, or other device portion.
In yet another example, the dynamic property is fluid mixing. The fluid mixing may be evaluated in one or more portions or elements of a device, or throughout the entire device. For example, the portion may, for example, be a mixing chamber, a port, a flow channel, a pump, or a flow channel intersection or junction. Such fluid mixing (as well as flow patterns and other properties or parameters) can be evaluated as a function of device parameters and/or other process parameters. Such other process parameters include, for example, fluid type (e.g., identity of solvent), electrical conductivity of the fluid, presence or absence or amount of one or more dissolved or suspended species, and viscosity of the fluid.
In preferred embodiments, the device is a small volume device, which may, for example, be a micro volume device such as a microchannel device; a nano volume device; a pico volume device; an array chip, plate, or slide; a pump, a port; a valve; a spotting pin; a channel junction, or a jet head.
Device and process evaluations can also be performed in devices or portions of multiple devices that have fluid connection. In this way, interactions between devices in a system can be determined and adjusted in beneficial ways.
In another aspect, the invention provides a method for analyzing deposition characteristics of features (spots) on an array, or other surface arrangement. The method involves depositing at least one fluid volume on a portion of a solid substrate, where the fluid volume contains a plurality of light scattering particles, and detecting the light scattering particles by detecting light scattered from the particles. The distribution or number or both of the particles is indicative of the deposition characteristics. Alternatively, another molecule(s) can be deposited on the array or other surfaces to which light scattering particles can be directly or indirectly bound. Then the presence, amount, and/or distribution of the light scattering particles serves as an indicator of the presence, amount, and/or distribution of the deposited molecule(s). The determinations can also involve other deposition cha
Peterson Todd
Warden Laurence
Yguerabide Evangelina
Yguerabide Juan
Allen Denise S.
Chang Audrey
Genicon Sciences Corporation
Jones Day
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