Niches and Nanotech The future keeps getting smaller, and potential benefits loom large. MICHAEL J. FELTON he chemical enterprise—whether focused can have hundreds of on producing and developing chemicals or millions of transistors, and Tanalytical techniques—is exploring the Texas Instruments and new frontiers of the microscale and nanoscale. Intel have announced Instruments have been getting smaller and detec- that new chips will be tion limits have been lowered. The move to produced with features as interacting with the world at these very small small as 65 nm. dimensions is changing the nature of the modern While engineers and scientists at Intel and laboratory, providing new life to existing tools and other companies were making the “computer on fertile ground for new methods of chemical analy- a chip” trillions of times over, several companies sis and production. were using the same fabrication techniques to produce very different devices. In 1968, H. C. Computer on a Chip Nathanson and colleagues at Westinghouse first The development of microtechnology demonstrated that 3-D structures began with innovation in the elec- could be made out of silicon using tronics industry. In 1947, the first integrated-circuit fabrication tech- transistor was invented, which niques. In 1974, National Semicon- allowed vacuum tubes to be replaced ductor applied the fabrication by a very small piece of germanium techniques to mass-produce strain and, later, silicon. By 1954, the tran- gauges. These developments led to sistor radio was developed, but more- products such as microfabricated complicated electronics were difficult accelerometers, which are used in to make because wiring numerous cars to trigger air bags during a crash. transistors was labor-intensive and Integrated-circuit fabrication Top: Richard E. Smalley (r), prone to errors. In July 1958, Jack techniques were applied to more Luminaries of the Chemical Sciences, Kilby at Texas Instruments decided to try to make than mechanical and electrical systems. One of 2002 an entire electrical circuit, not just the transistor, the first liquid applications of microtechnology was Center: Gyrolab microlaboratory disc, out of silicon, thus reducing the size and making ink-jet printing. The ink-jet concept was proven courtesy of Gyros AB circuits easier to produce. Shortly after, in January in 1878 in England by Lord Rayleigh and was 1959, Robert Noyce at Fairchild Semiconductor finally transformed into working technology in independently developed an entire circuit on sili- 1951 by Siemens. However, these early printers con. Both technologies were patented, but interest produced continuous streams of ink, which wasted in the so-called integrated circuits waned. ink. In the late 1970s, several companies Almost a decade later, in 1968, Noyce and were researching drop-on-demand ink-jet fellow engineer Gorden Moore left Fairchild Semi- printing, and in 1979, Canon succeeded, conductor and started Intel Corp. Intel first followed shortly by Hewlett-Packard. The produced silicon-based memory chips, but it was ink-jet printer heads contain etched silicon approached by a Japanese company, Busicom, to wafers with microscopic channels that allow design and build 12 integrated-circuit chips for ink to flow to hundreds of nozzles. incorporation into a handheld calculator. An engineer at Intel, Ted Hoff, suggested designing Lab-on-a-Chip one chip that could perform the function of all 12 Making analytical instruments using integrated- chips. After negotiating with Busicom for the rights circuit fabrication techniques was a conceptual to the design of this first microprocessor, Intel leap. In 1975, Stanford University researcher S. C. marketed its 4004 integrated circuit as a “computer Terry reported on an idea to make a gas chromato- on a chip.” The 4004 had 2300 transistors and had graph etched in silicon, but little was done about wires as small as 10 µm wide, but by 1982, Intel’s producing one. Much later, Stephen Fodor at Affy- 286 microprocessor had 134,000 transistors with max used a technique similar to photolithography, wires as small as 1.5 µm. Today’s integrated circuits which is used in making integrated circuits, to ENTERPRISE OF THE CHEMICAL SCIENCES 125 make a microarray of oligonucleotides. Affymetrix columns, and new companies such as SLS Micro was formed to commercialize the product, which are producing entire instruments consisting of was a dramatic success for biotechnology. Other microscale components. companies developed competing microarray fabri- A new generation of companies, started by cation methods using ink-jet technology. For researchers, is just beginning to introduce and NICHES AND NANOTECH example, Agilent used Hewlett-Packard ink-jet develop products. George Whitesides, the Harvard technology to deliver DNA or proteins for making University professor who invented soft lithography microarrays. that uses poly(dimethylsiloxane), is behind a Mass- During the same period (late 1980s and early achusetts company, Surfacelogix. And Caltech 1990s), Andreas Manz and others used silicon researcher Stephen Quake has started a company fabrication techniques to produce the first liquid called Fluidigm to commercialize his highly paral- pump on a chip, thus starting the field known as lel microfluidic system that resembles computer microfluidics. Manz coined the term µTAS, for microprocessors. micro total analytical system, to describe the goal of making microdevices that would perform Nanotechnology analytical functions. Researchers soon replicated The concept of nanotechnology was first succinct- liquid chromatography within a microchannel, ly explained by Richard Feynman in a lecture at proving that analytical techniques could be repli- Caltech on December 29, 1959, titled, “There is cated at this scale. Regardless of the terminology, Plenty of Room at the Bottom.” Feynman’s view the description is similar to the products that Intel, was that there was a vast amount of promise in Canon, and Hewlett-Packard had developed to building objects from the bottom up, from individ- Above: Microfluidics channel schematics, Modern Drug make computers and later printers on a chip. ual atoms, rather than the current situation, where Discovery, 2002 New companies such as Aclara Biosciences, technology can handle only millions of atoms at a Caliper Technologies (now Caliper Life Sciences), time. Feynman is cited so often as the father of Orchid Technologies, Gyros, and Cepheid, as well nanotechnology that it is easy to forget simply how as integrated-circuit companies such as Motorola, prophetic he was. He stated, “In the year 2000, began developing “lab-on-a-chip” products. when they look back at this age, they will wonder One of the first microflu- why it was not until the year 1960 that anybody idics products was the LabChip began seriously to move in this direction.” LARRY BOCK system jointly developed by The term nanotechnology was coined in 1974 Beginning with the biotechnology and Internet Caliper Technologies and by Japanese researcher Norio Taniguchi, who was booms in the 1990s, new technology was not Agilent. Caliper, founded in using energy beams to etch nanometer-scale chan- only in the domain of large corporations or uni- 1995, developed a disposable nels at the University of Tokyo. He defined nano- versities—venture capitalism was becoming microfluidic chip that could technology as “production technology to get the commonplace. And one of the most prolific process multiple samples and extra-high accuracy and ultrafine dimensions. and successful venture capitalists is Larry developed a prototype reading The smallest bit size of stock removal, accretion, Bock. Bock began his career at Genentech, instrument to obtain results or flow of materials is probably of one atom or one where he witnessed the biotechnology boom. from reactions on the chip. In molecule, namely 0.1–0.2 nm in length.” But this son of an investment banker and the late 1990s, the company Very little happened with the theory of gourmet chef found starting companies more partnered with Hewlett- nanotechnology until there was a way to see mole- rewarding. Bock founded and was the initial Packard. The partnership cules and atoms at the nanometer level. Feynmen CEO of ARIAD Pharmaceuticals, Neurocrine allowed Hewlett-Packard, foresaw this in 1959 when he said, “For us to make Biosciences, Pharmacopeia, GenPharm which soon changed its labo- more rapid progress is to make the electron micro- International, Argonaut Technologies, Caliper ratory instrument division scope 100 times better.” In 1981, researchers Gerd Technologies, Illumina Technologies, Idun name to Agilent Technolo- Binnig and Heinrich Rohrer at IBM’s Zurich Pharmaceuticals, and Fast Track Systems. He gies, to apply its instrument Research Laboratory invented the scanning tunnel- also cofounded Athena Neurosciences, Vertex expertise toward the refine- ing microscope (STM). The device uses a probe Pharmaceuticals, and Onyx Pharmaceuticals. ment of the analyzing hard- with an extremely precise tip that is held in place Several of these companies have become ware that became the Agilent by piezoelectric disks. The probe travels over a successful, one of which, Caliper Technologies 2100 Bioanalyzer. In 1999, surface and measures the changing current caused (now Caliper Life Sciences), became one of the the Bioanalyzer and Caliper’s by electrons that tunnel across the extremely small major microfluidic instrument makers. Bock is LabChip microfluidic chips distance between the probe