Lithographic Manufacturing Proposed for SERS Using Nano Void Metallodielectric Photonic Crystals

D3 Technologies Limited details its improvements in metrology by using a metal nano-void photonic crystal for surfaced enhanced Raman spectroscopy (SERS) in U.S. Patent Application 20090273779. The system provides a platform, system, and method for surface enhanced Raman spectroscopy that provides reproducible Raman signal enhancements for a low concentration of analyte molecules as well as the added functionality of pre- and post-processing which can be integrated on a single platform. Also provided is a method of mass fabrication of the platform using lithographic technology. 

Metallodielectric photonic crystals (PC) are used to extract a SERS signal from low concentrations of analyte molecules embedded inside the PC lattice, according to inventors Jeremy Baumberg, Sven Mahnkopf, Majd Zoorob, John Lincoln and James Wilkinson. The system encompasses four main aspects, namely a photonic crystal (PC)-based surfaced enhanced Raman spectroscopy (SERS) active platform, a system and method for obtaining a SERS signal from an analyte, and a fabrication method for the PC-based SERS platform.

Major improvements provided by the D3 Technologies system compared to many prior art systems include the following aspects. The topologies allow the launch of light from the side, hence facilitating easier and more reproducible means of launching light to the SERS active region. Secondly, the integration of many functional system blocks into one highly integrated chip will furthermore reduce the system complexity due to a reduced number of required external components and hence reduced system cost. The more compact system architecture will furthermore be appreciated for example in in-vivo endoscopy. Thirdly, the separation of light launch, Raman signal generation and light extraction can be used to optimize each functional block to its specific task (for example light extraction as opposed to maximum SERS enhancement).

Finally, compared to topologies that rely on colloidal crystals, the proposed fabrication method that defines the pattern by lithographic means as opposed to self-assembly promises greater reproducibility and increased yield. The scalability of the novel anisotropic wet and deep Silicon etching fabrication processes for the generation of SERS substrates provides a cost-effective method of mass producing identical SERS substrates while still maintaining high reproducibility of signals across different experiments; different substrates on the same wafer; and/or different substrates on different wafers

Raman spectroscopy is used for a variety of applications, most commonly to study vibrational quanta, such as vibrations in molecules or phonons in solids, although other quantized entities can also be studied. Raman spectroscopy can provide detailed information relating to the physical state of sample materials and can be used to distinguish various states of otherwise chemically identical molecules, such as various molecular isomers, from one another.

Raman spectroscopy finds wide-ranging use in numerous different industries. By way of example, Raman spectroscopy finds application in the pharmaceutical, chemical, bio-analysis, medical, materials science, art restoration, polymer, semiconductor, gemology, forensic, research, military, sensing and environmental monitoring fields.

Although Raman spectroscopy is an extremely useful analytical tool, it does suffer from a number of disadvantages. The principal drawbacks associated with Raman spectroscopy arise because of the small scattering cross-section. Typically, only 10.sup.-7 of the photons incident on the sample material will undergo Raman scattering. Hence, in order to detect Raman scattered photons, Raman spectrometers typically employ high power laser sources and high sensitivity detectors. Not only is the scattering cross-section small in an absolute sense, but it is small relative to Rayleigh scattering in which the scattered photon is of the same energy as the incident photon. This means that there are often problems related to separating out the small Raman signal from the large Rayleigh signal and the incident signal, especially when the Raman signal is close in energy to the incident signal.

High power sources are not only both bulky and expensive, but at very high power the intensity of the optical radiation itself can destroy the sample material, thus placing an upper limit on the optical radiation source intensity. Similarly, high sensitivity detectors are often bulky and expensive, and even more so where forced cooling, such as with liquid nitrogen, is necessary. Additionally, detection is often a slow process as long integration periods are required to obtain a Raman spectrum signal having an acceptable signal-to-noise ratio (SNR).

The problems associated with Raman spectrometry have been known long since C. V. Raman discovered the effect itself in 1928. Since that date, various techniques have been applied to improve the operation of Raman spectrometers

Laser Manufacturing to Compete with Lithography in Multi Billion Dollar Molecular Diagnostics Market

Molecular diagnostics are an increasingly important part of biotechnology. The ability to detect small quantities of genomic, proteomic, and other biological materials enables sensitive clinical tests to be performed, as well as enabling laboratory research that affects drug development and functional biology. Molecular sensing modalities include radioactivity, mass spectroscopy, and electrical and optical techniques. The worldwide market for molecular biomarkers, diagnostics, and related services exceeded $6 billion in 2003 and is predicted to reach a value of more than $92 billion by 2016. Molecular diagnostics or the analysis of DNA and RNA at the molecular level is a fast-growing market.

Steven M. Ebstein, president of Lexitek Inc (Wellesley, MA), has created a laser-processed substrate for molecular diagnostics. The substrate when used in Surface Enhanced Raman Scattering (SERS) and related modalities offers greatly enhanced sensitivity and selectivity for detection of molecular species through the excitation of plasmon modes and their coupling to molecular vibrational modes. It is also cheaper to manufacture the substrate using lasers than processes using nanolithography.

The invention is an apparatus for use in performing a diagnostic assay of an analyte. The apparatus consists of a base that has been structured using laser processing so as to provide at least one patterned surface by melting and resolidification of the base, wherein the patterned surface is characterized by structures ranging in scale from 10 to 2000 nanometers. The pattern is stochastic in all three spatial dimensions; and a metal is applied to the at least one patterned surface so as to provide at least one metalized patterned surface.

One of the chief obstacles to widespread application is the availability of suitable nanostructured materials that exhibit strong enhancement of Raman scattering. Ebstein has created materials that are inexpensive to fabricate, and are reproducible. He describes nanostructured surfaces for SERS and other photonic sensing that use semiconductor and metal surfaces fabricated using femtosecond laser processing in U.S. Patent Application 20090279085.

A noble metal film (e.g., silver or gold) is evaporated onto the resulting nanostructured surfaces for use as a substrate for SERS. These surfaces are inexpensive to produce and can have their statistical properties precisely tailored by varying the laser processing. Surfaces can be readily micropatterned and both stochastic and self-organized structures can be fabricated. This material has application to a variety of genomic, proteomic, and biosensing applications including label free applications including binding detection. Using this material, monolithic or arrayed substrates can be designed. Substrates for cell culture and microlabs incorporating microfluidics and electrochemical processing can be fabricated as well. Laser processing can be used to form channels in the substrate or a material sandwiched onto it in order to introduce reagents and drive chemical reactions. The substrate can be fabricated so application of an electric potential enables separation of materials by electrophoresis or electro-osmosis.

A performance goal of interest to the pharmaceutical industry is 100,000 measurements per instrument per day. This parameter is a familiar benchmark to pharmaceutical industry personnel doing lead discovery. For a nominal ten second measurement per array position, this benchmark would require 12 detection channels in parallel, assuming no time for the robotic motion. Ebstein believes his device can meet this goal. “It can be achieved by using multiple fibers, and the corresponding instruments can take advantage of numerous optical components that have been developed for telecom applications that can handle multiple fiber inputs and outputs and do so with very regular positioning so no alignment is required.”

Ebstein’s approach is low cost while still retaining great flexibility to co-manufacture microarrays, microfluidic, and electrochemical features. Ebstein’s approach also has much greater control, through the laser pulse energy and polarization, than a controlled evaporation apparatus or a photolithography and etching process can economically achieve. The ability to do laser machining of the substrates adds a dimension that enhances the capabilities of my arrayed substrates. While photonic crystals offer good reproducibility and potential for microarrays similar to his approach, they are more expensive to manufacture. Moreover, the reproducibility relies on controlling a photolithography and etching process. Many manufacturers of MEMS devices have found that this can be costly to achieve in practice.

In a contrasting molecular diagnostics market estimate, Illumina CEO Jay Flatley at the JPMorgan Healthcare Conference in San Francisco January 2009 conference estimated that the molecular diagnostics market will grow from $3 billion to $5 billion by 2011and the genome sequencing market will grow from $1.1 billion to $1.5 billion during that period. This year Illumina made an $18 million investment into UK-based startup Oxford Nanopore Technologies. Oxford's nanopore sequencing technology "holds tremendous promise to be one of the first technologies to reach the sub-$1,000 genome and become the cheapest and fastest way to sequence DNA, according to Flatley.

The molecular diagnostics market was predicted to grow from a 2006 level of approximately $17.9 billion to over $92.1 billion by 2016 with an average annual growth rate of 41.5 per cent, by Dr Kenneth Krul, in a 2007 report from, entitled "Molecular Diagnostics: Major World Markets" from Kalorama Information.

The growth in the pharmacogenetic market is expected to dwarf that of other sectors with annual growth predicted at a rate of 184 per cent, with the segment expected to reach over $60 billion by 2016. The expected growth is based on the new understanding of the relationship between the genetic signatures of neuropsychiatric disorders and optimal treatment procedures, advances in the viral infection market and advances in cancer therapy.

The use of molecular diagnostics in oncology is predicted to be the second fastest growth application sector, expected to grow at a rate of over 68 per cent per year, reaching $9.8bn by 2016. The growth in this area is expected to be fuelled by the use of molecular diagnostics to assess cancer susceptibility, diagnosis and management, according to Krul’s report