Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals – Carrier is inorganic
Reexamination Certificate
2000-03-16
2004-08-03
Chin, Christopher L. (Department: 1641)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
Carrier is inorganic
C435S007100, C435S968000, C435S973000, C436S164000, C436S166000, C436S172000, C436S518000, C436S523000, C436S524000, C436S536000, C436S539000, C436S540000, C436S541000, C436S805000, C356S301000, C356S317000, C356S318000, C356S337000
Reexamination Certificate
active
06770488
ABSTRACT:
BACKGROUND OF THE INVENTION
Generally, this invention relates to a method of determining the concentration of an analyte in a mixture using a spectrographic method of analysis and unique methods of spectral analysis. Specifically, the invention covers the use of Raman spectroscopy, desiccated metal particles, molecular specific coatings, sample containers, and multivariate analysis to determine the concentration of an analyte.
One of the first examples of the importance of chemical analysis in the chemical industry comes from Pliny the Elder (AD 23-79). Pliny the Elder was concerned about contamination of copper sulfate with iron sulfate. Copper sulfate was the principle ore for making copper and bronze. The purity of the copper ore ultimately determined the purity of the copper or bronze. Pliny the Elder found that the extract of gallnuts turned black in the presence of iron sulfate. This simple visual test was the first example of what today is known as Analytical Chemistry.
Since this early work in metallurgical process control the field of analytical chemistry has expanded greatly. The methods of analysis encompass 4 categories. The oldest, represented by Pliny the Elder's work, is wet chemistry. This method involves mixing chemicals together to observe a quantitative change. The other three categories are more modern and represent an improvement in sensitivity, measurement time, and selectivity over wet chemical methods. These methods are: spectroscopy, chromatography, and electrochemistry.
This invention relates to a spectroscopic analysis known as Raman spectroscopy. Raman scattering involves the inelastic scattering of light by vibrational modes within a molecule. This can be very advantageous as no two molecules exhibit exactly the same Raman spectrum. This makes it possible to distinguish between similar components in a mixture.
This advantage in specificity associated with Raman spectroscopy is overshadowed by an inherent lack of sensitivity. Typically about one in a million photons of light incident on a sample will take the form of Raman scattering. In practical terms Raman is limited to about one part in a thousand detection levels when the analyte is in a matrix.
The Discovery of Surface Enhanced Raman Scattering
Surface enhanced Raman scattering (SERS) like many scientific discoveries, evolved out of serendipitous events. In the early 1970's electrochemists began using optical methods to study electrode surfaces. Flieschmann and Hendra decided to experiment with Raman spectroscopy as a method of analyzing electrode surfaces. Due to the low sensitivity of Raman spectroscopy they chose silver as the electrode material since it is easily roughened by oxidation-reduction cycles in the presence of chloride. The growth of silver chloride crystals and reduction back to silver leads to a roughened surface with many times the surface area of a smooth polished electrode. This will increase the Raman signal as there are more molecules in the laser beam. They chose pyridine as the probe molecule as it should adsorb through the pyridine nitrogen and it is an inherently strong Raman scatterer. Their experiment was a success. They did not know it but this was the first experiment using SERS. It was not until four years later that this experiment was correctly interpreted. In 1977 Van Duyne at Northwestern University was also trying to study electrodes with Raman spectroscopy. His approach was to use resonantly enhanced molecular probes to overcome the sensitivity problem. He had performed calculations to determine the amount of resonance enhancement needed to observe a monolayer on an electrode. This number was at least 1000 for a strong scatterer like pyridine. This made Flieschmann and Hendra's results look anomalous. To test if the enhancement was due to increased surface roughness Van Duyne's student David Jeanmaire tried a milder oxidation-reduction cycle and achieved even stronger signals. This lead to the first announcement of an anomalous phenomena at silver surfaces.
It is now known that the SERS effect arises through an electromagnetic resonance that can occur strongly in noble metal particles and to a lesser extent in some other metals. The resonance occurs because the electrons in the particle are affected by the excitation light to produce a polarization in the particle that makes it more likely to become more polarized. This phenomenon will produce very large electric fields near the particle surface and thus amplify optical events near the surface that are dependent on the electromagnetic field. Raman scattering is just one class of such events. Others might include fluorescence and absorbance. Further, each may be enhanced through a surface phenomenon as in the case of surface enhanced Raman spectroscopy.
While SERS was discovered on electrode surfaces, it is not limited to these. Today SERS is being performed on evaporated metal surfaces, etched metal foils, microlithographically produced surfaces, carefully assembled particle arrays, colloidal suspensions, and with other methods that are capable of producing small submicron sized particles. An excellent discussion regarding aspects and uses of Raman Spectroscopy in a detection context is contained in the document “Method and Apparatus for Detection of a Controlled Substance”, International Application Published Under The Patent Cooperation Treaty (PCT), WO 98/59234, United States National Stage Application No. 09/446,168.
Several problems have plagued the development of SERS into a practical analytical tool. One such problem is the delicate nature of the SERS substrate. The SERS phenomenon is associated with particles or roughness features that are about {fraction (1/10 )} the size of the wavelength of the light used for excitation. Typically this means 40 to 100 nanometers (a nanometer is one billion of a meter). Particles this size are very susceptible to chemical damage, aggregation, and photo damage.
A survey of the different SERS substrates produces one type that stands out with respect to practical analytical chemistry. These are colloidal suspensions. Two significant advantages are found with colloidal suspensions. First, a large volume of colloidal particles can be made at one time. Within this batch of colloids every sample will be identical. This overcomes the irreproducibility of non free floating particulate surfaces. The second advantage is that the colloidal particles are suspended in a solution and therefore tend to be much less susceptible to thermal damage. They also are subject to Brownian motion which tends to continually refresh the particles in the excitation beam, thus eliminating problems with photodegradation of the sample.
In addition to problems with SERS substrate stability and reproducibility an additional factor needs to be included in the analysis. The SERS substrates are typically noble metal particles. The noble metals are aptly named for their ability to resist the aggressions of other materials. In a practical sense this is good for stability of the surfaces, but is impractical in terms of attracting an analyte to the surface. In order for the SERS substrate to act as a tool for detecting an analyte, it must attract the analyte to the surface or in some way be specifically affected by the analyte to show a spectroscopic response.
Initially SERS was seen as advantageous because of its strong enhancement. This invention realizes a different aspect of SERS. The localization of the SERS enhancement near the surface very effectively separates the signal from the analyte that is in close proximity with the surface from analyte or other material in the sample matrix. The locality of the analyte can be used to a strong advantage with respect to the ease of analysis. SERS allows one to measure an analyte in the presence of species that would strongly interfere and cripple other methods of analysis that do not have a localized area of detection.
The problem of inertness with noble metal SERS active surfaces can be overcome with a coating material that attracts or
Carron Keith T.
Corcoran Robert C.
Sulk Roberta Ann
Chin Christopher L.
Santangelo Law Offices P.C.
The University of Wyoming
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