Almost always, an analytical technology can meet the needs of different end-user markets. However, the successful transition of a technology from one market, in which it may be well established, to an entirely new and different market is often a precise and dedicated process. In this article, IBO examines three research technologies that have made the move into new markets, and how three companies reconfigured their products, established partnerships and targeted specific market needs in order to make the transitions.

MALDI Biotyper CA

Transitioning a research technology, especially one as complex and multifaceted as MS, to the regulated clinical market is neither straightforward nor simple. The latest case of such a transition is Bruker’s MALDI Biotyper CA System, which gained FDA 510(k) approval last month for the identification of gram-negative bacterial colonies cultured from human specimens. Based on the company’s benchtop microflex LT MALDI MS system, the Biotyper CA includes software, IVD-labeled reagents, a 48-spot MALDI target and a micro-organism reference library. “The MALDI Biotyper CA System is intended for use in conjunction with other clinical and laboratory findings to aid in the diagnosis of gram-negative bacterial infections,” said George Goedesky, vice president, MALDI Biotyper, Americas. Among the applications is antibiotic sensitivity testing (AST). The MALDI Biotyper CA is used to identify the pathogen, which is followed by a second test to determine the antibiotic that will be most effective against the pathogen. “Throughout the world, we have connected the MALDI Biotyper to and send identification results to all of the major AST systems including the Siemens Walkaway, BD Phoenix and bioMérieux Vitek, in addition to many different LIMS/LIS [laboratory information system] platforms,” he explained.

The MALDI Biotyper CA identifies an organism’s molecular fingerprint, primarily through the measurement of ribosomal proteins, and matches the organism’s spectra profile to reference spectra in the system’s database. According to Mr. Goedesky, “Our MALDI Biotyper CA has 100 species of gram negatives grouped into species or species complexes. This claim would allow MALDI results to be generated for over 98% of a routine laboratory’s gram-negative workflow.”

Advantages of the MALDI Biotyper CA for clinical microbiology applications compared with biochemical and genomic techniques include speed, low consumables cost, the requirement of only one colony for testing, and applicability to a wide range of organisms. As Mr. Goedesky told IBO, if multiple tests are unable to identify an organism, instead of sending the sample to another lab for sequencing, which can be expensive and time consuming, the MALDI Biotyper CA can be used. To gain FDA approval, the MALDI Biotyper CA was shown to be comparable to 16S ribosomal RNA sequencing.

Initially introduced as the CLINPROT Biotyper in 2006, the MALDI Biotyper gained an EU CE mark in 2009. The system was used during the period as part of numerous collaborations with European organizations, including the German Collection of Microorganisms and Cell Cultures, which is Germany’s German National Resource Centre for Biological Material and helped to build the Biotyper’s database of organism profiles.

In the US, the European developments drove interest. In turn, US collaborations generated additional publications. “Collaborating with the initial sites in the US was key, as these sites published extensively on their results and experiences with the system and demonstrated that the excellent results seen in the EU were reproduced using US isolates,” explained Mr. Goedesky. Initial publications were generated by the NIH, the Mayo Clinic, ARUP Laboratories, Dynacare Laboratories and BJC-Children’s Hospital, among others.

Collaborations with firms that supply clinical microbiology instrumentation were also important. Bruker formed a comarket and codevelopment partnership with Becton Dickinson in 2010 for AST involving the MALDI Biotyper and the BD Phoenix. In 2011, Bruker and Siemens Healthcare Diagnostics agreed to integrate and comarket the MALDI Biotyper with Copan’s WASP (Walk-Away Specimen Processor).

The transition to the regulated clinical market was also made possible by a system and workflow design that made MALDI analysis robust, easy to use, fast and routine. “MALDI as a technology for microbiology is not new,” said Mr. Goedesky. “But the issue was getting it to a point of a workflow system that was reproducible, robust and one that, as I said, a production microbiology lab can do.” Collaborations were important as well to improving the system’s design. “Bruker’s history of collaboration with its customers provided us with key inputs into the system design, which when coupled with our expertise in MALDI technology resulted in a system which has sold over one thousand systems to microbiology laboratories around the world to date,” he noted.

Mr. Goedesky cited Smart Spectra as a feature that enhanced usability in clinical labs. “We created and released an improvement called SmartSpectra which resulted in a throughput of around 200 samples per hour, as well as lengthening the useful life of the laser, making it the system of choice for high-volume laboratories.” SmartSpectra stops the firing of the laser when sufficient data for identification is obtained.

SmartSpectra is also an example of how Bruker’s vertical integration helped adapt the MALDI Biotyper for the clinical market, according to him. “As the only vertically integrated supplier of MALDI-based microbiology solutions, we worked to improve the ease of use and robustness of the technology to make it applicable for production microbiology laboratories,” said Mr. Goedesky. Other features to enhance the speed and reproducibility required of clinical instrumentation continue to be released. Next year, to enhance the automation of the MALDI Biotyper, Bruker will release the MALDI Biotyper Galaxy for quality controlled automated deposition.

BovineLD BeadChip

DNA microarrays have also moved into labs outside of research markets. Although microarrays are widely used in agricultural research, they are also employed for commercial applications. Within the agricultural market, livestock breeding is one commercial segment that increasingly relies on microarrays. According to Rob Cohen, director of Product Marketing and Market Development at Illumina, the technology initially made in roads for use with dairy cows due to several factors. “The first reason is because pedigree records have been kept using the milk recording system. So, essentially, the USDA requires that farmers keep records on the milk production, and that was actually then tied to the genetic markers that existed in particular animals,” he told IBO. “The second is that artificial insemination has helped centralize the genetic information in a small number of key breeding bulls over the last 30 years.” The third reason was a definitive list of traits for which cows are bred. “Then, there are a small and easily measurable number of traits—milk production, fat in the milk, protein in the milk, longevity and utter quality—that breeders want to optimize.”

Illumina currently offers three Bovine BeadChips, as well as custom solutions. Designed for research applications, the BovineHD BeadChip contains around 777,000 SNPs and is used to map traits and create cross-breed reference populations. The BovineSNP50 is intended for both research and commercial applications and can be utilized for genome-wide selection, quantitative trait loci identification, the evaluation of genetic merit, and comparative genetic studies. Containing around 7,000 SNPs, the 24-sample BovineLD is designed for commercial applications, such as parentage, trait identification and genetic prediction. As many as 80,000 custom markers can be added to the BovineLD.

Developments in microarray and sequencing technology contributed to the adoption of microarrays by the livestock industry. “The advancement on the genetic side was really the advancement of the sequencing of the bovine genome, and then the realization that you can tie genetic markers—that you don’t necessarily need to know the function of—to the phenotype.” Established breeding methods, such as marker-assisted selection (MAS), rely on the recording of an animal’s phenotype and genotype. Using microarrays, an animal’s phenotypic information is not required, enabling so-called predictive breeding. Lower cost sequencing resulted in the sequencing of the bovine genome and genome-wide association studies, leading to the discovery of SNPs associated with specific traits. Using the SNPs of a reference population with the desired trait, a statistical model and equation can determine the genomic estimated breeding value of each animal. This equation can then be applied to other animals. The process is faster and less expensive than other breeding methods.

As Mr. Cohen explained, “The main advancement that’s been made, at least from the standpoint of the last couple of years, is the ability to add content onto that chip. So we offer the BovineLD as a backbone, and then investigators or breeding associations or whomever can add their own markers on to measure production, reproduction, health, appearance and all those things they care about, in their breeds of interest.” This model has been translated by Illumina to other agricultural markets, both plant and animal.

Also key to the adoption of microarray technology by the commercial livestock market has been microarray economics. A decline in price made microarray affordable for the end-market. “The number of samples that have been processed over the last five years has grown tremendously despite the drop in price,” explained Mr. Cohen. “The volume offsets the price decline, and that is driven largely by the expansion of the existing arrays in the existing species, so more BovineLD but also the replication, again, of this model in other species.”

Collaborations were important for market adoption as well. The BovineLD was developed as part of a consortium, which included the USDA Agricultural Research Service and French National Institute for Agricultural Research. Collaborations were also important for entering the market and gaining user acceptance. Asked about how Illumina overcame barriers to adoption, Mr. Cohen told IBO, “At the beginning, it was education. As it gained momentum and people knew the existence of the technology, groups centered around the different species came together, knowing that the consortium would give them economies of scale, drop the price per sample, as we could amoritize the cost of our array portfolio, or array synthesis, over many, many samples.”

The adoption of genomic selection techniques by breeding organizations was also key. “The Holstein and [American] Jersey [Cattle] Associations were early adopters, and so they evangelized it as well,” noted Mr. Cohen. In Europe, the industry organization Eurogenomics has adopted the technology. “Demonstrating the value in the community of genomic selection was a huge, and continues to be, a barrier,” he commented. To address this, he said peer-reviewed research articles and presentations are important. He added, “Also getting people to understand the concept of a genomic breeding value.”

T-Gauge

As with taking a research technology into commercial markets, taking such a technology into factories presents its own unique set of challenges. Advanced Photonix’s time-domain terahertz technology has made this transition. Located between microwaves and the far IR on the electromagnetic spectrum, terahertz radiation can be used for imaging as well as chemical analysis. Like X-rays, it is nondestructive and non-contact. “We have what is essentially an extremely fast radar system able to interrogate optical media that is otherwise opaque in the optical regime,” explained Steve L. Williamson, CTO of Advanced Photonix. “So, with terahertz, as long as it’s not a metallic material or it’s not aqueous, we can get through pretty much everything else.” He added, “Because the pulse is at so high a frequency, it has some unique characteristics. With this pulse, we can do near-photographic imaging of objects embedded. We can also measure thicknesses of embedded layers with a precision down to tens of microns.” Other possible measurements include sub-surface defect detection and delamination detection.

The T-Gauge is based on the T-Ray 4000, which was introduced for research applications. A development contract with the Department of Homeland Security to replace nuclear gauges for industrial applications led to the development of the T-Gauge for the quality control and process control markets. Nuclear gauges are used to measure physical properties such as thickness, moisture content and density. The T-Gauge system was introduced in 2012. The current application in which it replaces nuclear gauges is online physical measurements in paper manufacturing.

The technology can also be used in the manufacturing of extruded products, including building products such as shingles and flat roofing material. Other applications include the manufacturing of packaging, extruded pipes, tire rubber and pharmaceuticals. In these markets, terahertz can replace existing process analysis techniques, such as ultrasonic testing. “Ultrasonic needs a medium to transmit through to take its measurements, whereas we are standoff, non-contact and we don’t need anything [to transmit through],” noted Richard D. Kurtz, CEO of Advanced Photonix.”

Partnerships are enabling the effective transition of the technology to manufacturing applications. “The paper industry was our first partner relative to an end-user,” said Mr. Kurtz. In that industry, Advanced Photonix has partnered with Appivon, a supplier of thermal, carbonless and security papers. “Appivon is interested in higher resolution, more precise measurements and in eliminating the nuclear gauge component, we’ll say, from the factory floor,” explained Mr. Kurtz. “One of the things that we’re working with them on is to combine a lot of physical measurements together into one gauge, which cannot be done with a singular nuclear gauge,” he said. The measurements include the paper’s coating thickness, density and moisture content. Advanced Photonix has also been able to use Appivon’s plants as a demonstration cite.

Partnerships also are integral to how Advanced Photonix sells and installs the T-Gauge. As Mr. Kurtz explained, “Now, when we have to deploy this to the factory floor, we need what is referred to as value-added resellers [VARs], who can do that installation integration and provide the human-machine interface, not only to the operator but also to the process control of the manufacturing line itself.” Among the company’s VARs are Thermo Fisher Scientific and ACT Automation Control Technologies.

The T-Gauge system differs from the research systems in numerous ways. “The T-Gauge is more specifically designed, has more embedded intelligence into it and is really focused on that process control or quality control market—UL [Underwriter Laboratories] approved and the like. There is the controller box, which is the main portion, and then we have a number of different end effectors that can be attached via a cable that are used to transmit and receive the terahertz pulse itself,” explained Mr. Kurtz. “The final generation that we have is now industrially hardened, so it can go into a pretty harsh environment and run day-in and day-out, 24-7, 365,” said Mr. Williamson. “This is giving, in some ways, a red light/green light to the operators on the floor and, more importantly, they can use the intelligence of this to feed back or feed forward on their equipment in order to adjust on-the-fly the factory calendars or whatever it is that is making controls to the material being made.” According to Mr. Kurtz, the T-Gauge is the only UL-certified terahertz system.

Discussing adoption barriers, Mr. Kurtz cited the value of early adopters, VARs and the establishment of a clear cost advantages. “It’s the ROI [return-on-investment] aspect. You have to convince them that you are taking more accurate or more precise [measurements] than existing technologies, and you are taking more than one measurement at the same time,” said Mr. Kurtz. “The second thing is, since it’s a new technology, everyone wants to know what is the reliability. By getting the UL, that helps with the uncertainty of the new technology.” The end-users that one targets is also important. “There are a number of customers in all of those markets that we could be going after, but you want to find the one that is the new adopter, that isn’t afraid of new technology, shall we say.”