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August 18, 2004 | Thoughts of high-throughput science has been a much broader trend toward high-throughput research and miniaturization, particularly in the pharmaceutical industry and in clinical medicine. Drug development companies are demanding high-throughput tools, and they represent a much larger market than the academic and biotechnology industries.

This knowledge formed the backdrop behind the establishment of Nanostream, a provider of high-throughput microfluidic systems, founded in 1999. Many, if not most, companies start with a technology and look for an application. Nanostream's CEO and founder, Stephen O'Connor, took a different approach. He had been involved in establishing three other technology companies, including Clinical Micro Sensors, acquired by Motorola in 1999. O'Connor felt that microfluidics companies had taken an overly complex approach to R&D and manufacturing. His aim at Nanostream was to find a more systematic way to develop products that would automate small-scale fluid manipulation. O'Connor and colleagues first engaged in market research, asking drug developers where their bottlenecks were and what solutions they would like to see.

PARALLEL PROCESSING: Nano-stream's 24-column Brio cartridge can analyze multiple samples at once.
An important item on the pharma wish list was a way to miniaturize the process of high-performance liquid chromatography (HPLC) to render it more cost-effective and faster. "The basic technology of HPLC had not changed in 50 years, but the demand for its use continued to grow, requiring significant time, labor, and lab space for pharma companies that needed to run millions of samples per week," O'Connor says. The pharmas not only wanted the process adapted to high-throughput format, they wanted versatility and seamless integration of the process with other up- and downstream functions in a core lab. The process also had to be compatible with the organic solvents that are used to solubilize small-molecule drug candidates.

O'Connor had come out of Caltech, and was able to call upon a network of scientists. They created a device for micro parallel liquid chromatography (µPLC) in a cartridge format, called Brio. Made by thin-film processing of polymers, and incorporating a variety of hydrodynamic tools such as valves and pumps, the device is used with Nanostream's Veloce µPLC system. It was designed to integrate with existing workflows and increase the throughput of established HPLC techniques.

Although the device was designed to bring the reagent cost down by two orders of magnitude, this is not nanotechnology. According to O'Connor, keeping the device within the micro range provides a benefit in terms of miniaturization while still allowing the user to employ standard HPLC methods. "Drug developers did not need to go any smaller — the cost and time savings were already there," he says.

The Brio cartridge is the heart of the Veloce system. It enables multiple samples to be analyzed in parallel for increased throughput. Cartridges incorporate columns of varying lengths and a range of stationary phases. Veloce includes a detection system and pump, and the system uses open-architecture software compatible with existing HPLC software. Initial applications include assays of purity and stability of compounds and oligonucleotides, biochemical assays, physiochemical profiling (such as early-stage ADME), and compound solubility and lipophilicity (Log P).

The main competitors for Veloce are makers of high-quality HPLC systems, such as Waters, Agilent, and Shimadzu, whose instruments can be found in the labs of most pharmaceutical companies. Other providers of options for higher-throughput versions of standard HPLC include SEPIAtec and Eksigent Technologies, both of which offer 8X HPLC formats. For assays of compound solubility and lipophilicity, pION sells a microplate dish platform with significant throughput.

Robert M. Frederickson is a biotech writer based in Seattle. He can be reached via e-mail at 

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