Medical Device Link.

Originally Published IVD Technology October 2003

Filters, membranes, and bioseparation equipment and supplies

Schleicher & Schuell BioScience (Keene, NH) is a provider of quality membranes, paper, glass, and nonwoven components for point-of-care platforms.

The Human Genome Project started a revolution that has spawned a cluster of new molecular biological technologies. Created out of research in the areas of genomics and proteomics, this early work has opened up new business opportunities for IVD manufacturers willing to explore the biological pathways of health and disease. A growing understanding of more of the biological processes will fuel the shift in technology from conventional clinical testing to modes in which diagnosis is based more on the profiling of molecular change. And as comprehension of molecular processes in disease states increases, so will the rate of technology development answering the challenge to diagnose and treat them.

Emerging trends in IVD technology feature an emphasis on new formats that will accommodate multifunctional tests capable of detecting several analytes simultaneously. The validation of new targets such as biomarkers will advance the work being done in the field of clinical proteomics through the use of microarrays to screen large numbers of markers in patient samples.

Other areas of increasing interest currently in development are in vivo imaging, genotyping, and predisposition diagnostic testing. Advances in these technology areas will introduce business opportunities for companies involved in the manufacture of platforms such as biochips, microarrays, and instrumentation for biosensors and handheld analyzers. Commercialization of any new diagnostic test will not come without investments of time and money in development, validations, and meeting the regulatory requirements. However, the continuing market demand for faster, more-sensitive tests will ensure that innovative molecular technologies will be realized and one day be routine in the clinical diagnostic laboratory repertory.

The IVD industry finds itself today in a complicated situation. On the one hand, it is now a mature industry encumbered with the regulatory and cost pressures familiar to large, well-established healthcare sectors. But on the other, it is driven at a pace more like that of the electronics industry, where changes and advancements seem to be cycling more on the order of days than of years. Ultimately, the market will decide what the market needs, and suppliers need to be prepared.

Whatever developments in IVD technology may unfold in the future, the basic processes of sample collection, filtration, isolation, immobilization, binding, and detection will remain just that—basic to IVD testing. To take advantage of the market opportunities headed their way, IVD manufacturers will have to supply products that can easily, reliably, and cost-effectively carry out these basic functions. The formats, the combinations, and even the techniques may change dramatically over time, but the jobs to be done will still be:

• Sample and reagent preparation.
• Sample collection and storage.
• Chemistry support.
• Signal development and analysis.

In many instances, such tasks can and will best be accomplished using traditional materials and associated processes. Even though a new IVD test kit may appear to be a product of novel, leading-edge technologies in all respects, it, like nearly all IVDs, probably will rely to some extent on technologies and materials with a long history of use in the liquid-processes industry. The following sections discuss some of the key ways that filters, membranes, and bioseparation equipment continue to contribute to the advancement of IVD assays, genomic and other types.

Sample and Reagent Preparation

Preparation of patient samples and assay reagents can be achieved through centrifugation, chromatography, electrophoresis, and filtration, including dia-, ultra-, micro-, and macrofiltration.

Centrifugation is a proven technique for separating a complex sample. In microformats, and following the advances in sealing technologies for multiwell plates featuring ultrafiltration membranes, this traditionally time-consuming process is now adaptable to automation for high-throughput applications.

For capturing antibodies, the use of affinity media is certainly a technology option that springs immediately to mind. The increasing demand for selectivity and concentration, combined with the emergence of new media and formats, appears to be revitalizing this most traditional tool. The range of media is expanding, and the formats now available include powerful, small-scale, simple-to-use systems like membrane absorbers.

Diafiltration or ultrafiltration has been widely used for the concentration, desalting, and fractionation of mixtures of biomolecules. Sample-preparation requirements for new applications in molecular diagnostics could very well dictate a greater use of this technology. Preparation from many bulk samples could not be achieved without first performing a simple, but still essential, filtration step.

Electrophoresis is an essential technology for the blotting methods employed in nucleic acid testing. Using electrophoresis, researchers can electrically entice proteins to separate from one another, and thus potentially provide clues to new disease states.

Filter media play an important role in current-generation IVDs, eliminating impurities and other substances that interfere with test results. In the future, the filtration and separation industry and IVD industry may finally combine aspects of their technologies to create a new generation of filter devices that exponentially improves patient outcomes. With continued advances in this field, the day may come when, in the therapeutic area, physicians can selectively remove specific disease-causing pathogens from a patient by means of an apheresis procedure that has become routine.

Sample Collection and Storage

GE Osmonics (Minnetonka, MN) offers membranes for medical device filtration and separation applications.

Urine, serum, blood, saliva, and, in fact, nearly every other bodily fluid may now be sampled and diagnostically tested. IVD manufacturers can find handling such a wide variety of patient samples almost as much of a challenge as detecting the analytes they contain. While use of the traditional cup and pipette will never totally disappear, today a wide variety of materials are suitable for collecting and storing the ever-expanding range of samples being encountered.

With so-called simpler tests that incorporate several processes in one device, the tasks needing to be performed in any such test become more complex. A key issue with these is the ability to use a more basic or unprocessed sample. Whole blood samples, for example, have been problematic for a long time. Materials such as asymmetric membranes that allow the application of whole blood to a test, and perform the sample purification in place are now available. This allows reliable serum analysis without complication from contamination by red cells or other components. As glucose monitoring moves toward nonoptical methods, clean plasma from whole blood is essential.

The demands placed on collection and storage media are determined by the jobs they must accomplish for the assay. In some cases, as with tests conducted for a suspected heart attack victim, the sample fluids are tested immediately after collection. In others, such as a DNA registry, samples may be stored for testing at a later date. As sample sizes decrease from fractions of a milliliter to fractions of a microliter, new factors in sample preparation will become important. It will then fall to the IVD industry material suppliers to respond to the emergent demands.

Chemistry Support

At the heart of an IVD are the chemistries of detection, which may come in the form of a paste mixed from enzymes and dyes (such as that used for many blood measurements) or as liquid sprays or dips (such as the antibodies and gold colloid used in most pregnancy tests). In rapid-test kits, the solid-phase support for such test chemistries is provided by porous substrates.

When immunochemistry testing evolved from the enzyme-linked immunosorbent assay (ELISA) plate to the dipstick, microporous substrates were what made the leap forward possible. The colorimetric detection of blood sugar levels, which has transformed diabetes treatment, was made possible through the impregnation of microporous substrates. And the most successful of all rapid tests, pregnancy test kits, also have at their core a microporous solid-phase substrate—specifically, a nitrocellulose membrane.

In the past, the unique binding properties of nitrocellulose and other microporous membrane materials were sufficient to qualify them for use in IVD applications. But times are changing. Soon, binding alone will not be enough.

The characteristics required of such substrates today differ with the application. Surface modifications for enrichment or depletion applications can be effected by functionalizing the membrane with nucleic acids, proteins, or ligands. This affinity interaction can be used for sample concentration or removal of contaminating biomolecules. Other membranes may need to exhibit little or no protein absorption, in order to prevent localization of signal. Membranes may have to have large pores to allow rapid lateral flow, or especially small pores to ensure the exclusion of blood cells. More and more, IVD manufacturers are searching for substrates providing combinations of such characteristics in order to attain the desired final function. Substrates used in today’s IVD applications need to be exactingly consistent, millimeter for millimeter, meter for meter, and beyond.

One reason for the increasingly precise, and diverse, demands on substrates is the clinician’s need to obtain quantitative rather than merely qualitative test results. To meet the requirements of manufacturers that are developing such quantitative tests, substrate suppliers have had to move beyond offering one particular product for all applications. As the array of analytes and targeted systems increases, suppliers will be required to go further, even to the point of providing materials that are specific to a particular target analyte.

Signal Development and Analysis 

Millipore Corp. (Billerica, MA) has a number of bioseparation tools that are available for various IVDs.

When an IVD test functions and its chemistries work, the test generates a signal. But determining the best signal format and how best to process the data is a complex matter of which there is no better illustration than the analysis of the genome. Supercomputers and high-speed analysis were key to the outcome of that project. But simple tests that generate merely qualitative results are also a mainstay of diagnostics. 

The call for quantification is an uneven imperative, affected by considerations of cost versus function, target market and target user, and perceived versus actual value. Clinicians may demand that test kits provide a quantitative readout so that a targeted treatment can begin immediately, but, on the other hand, no one can ever be half pregnant. An increasingly differentiated market will clearly require the full range of results. Therefore, manufacturers will have to evaluate the technology—hardware and software—necessary to process the results in the form most relevant to an application.

The application of IVD technologies is not limited to human medicine. From their origins in human clinical science, diagnostic technologies have branched out and entered many sectors of the global economy. Veterinary diagnostics helps breeders by genotyping livestock for proof of descent, paternity, and identity. In addition, many mammals and birds can now be risk-profiled for a variety of disease states. To help ensure food safety, IVD technologies are key tools for detecting genetically modified foods and certifying the origins of meat and meat products. And environmental monitoring of bioremediation projects is being made easier and more cost-effective through advances in diagnostic technologies. Another quickly emerging area in nonclinical diagnostics is the biodefense market. Events like the anthrax scare have made the population understand that the threat of bioterrorism is real. People hope that products will be available to meet this potential menace.

This is an exciting time to be doing business in the IVD field. More outlets for suppliers’ technologies exist than ever before. But success will not be automatic. Flexibility and accommodation will be essential qualities of any supplier that can meet the ever-increasing demands of IVD manufacturers in this fast-changing environment.

Michael Hagen and Richard McDonogh, Pall Corp. (East Hills, NY)

Copyright ©2003 IVD Technology