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Filter Technology—Separating the Good from the Bad

Medical Device & Diagnostic Industry Magazine MDDI Article Index An MD&DI July 1998 Column As filter membranes become more sophisticated and specialized in the handling of specific fluids and gases, new applications are emerging for medical uses, creating a wide range of opportunities for manufacturers.

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI July 1998 Column

As filter membranes become more sophisticated and specialized in the handling of specific fluids and gases, new applications are emerging for medical uses, creating a wide range of opportunities for manufacturers.

The basic principle behind filters is simple—the separation of particles from fluid or air. In the most elementary of filters, gravity alone does the job of moving the substance through the filter. Of course, this does not work in modern medical applications. New mechanical filtration methods require materials that can withstand high pressures, maintain integrity, and perform at high levels. Although few companies specialize in manufacturing filter membranes, the vast number of medical arenas open to new filter applications is capturing the attention of manufacturers currently involved in this relatively small niche.

A filter can be any porous, fibrous, or granular substance used to separate particles from fluid or air. Filters can be subdivided by the manner in which they separate. In a depth filter, liquid flows through long, tortuous passages as the particles become entrained and removed from the solution. Depth filters generally need to be thick and fashioned from materials such as asbestos, glass fiber sheets, cloth, and paper. Surface filters trap particles at the top of the matrix as the fluid flows easily through. Membrane filters can almost always be classified as surface filters.

One common filter membrane is polytetrafluoroethylene (otherwise known as PTFE or Teflon). Photo provided by Pall Corp. (East Hills, NY)

Filters were once thought of as a sheet with holes in it, like a kitchen colander. However, scanning electron micrographs demonstrate that membrane filter structures are more like very thin sponges with spaces for fluid to flow through. In fact, most membranes are only about 150 µm thick, and 80—85% of that volume is open space, which accounts for high fluid-flow rates. A high percentage of openness also means that there is a large void volume in which fluids are irreversibly trapped. Small-diameter filters are preferred for small quantities or valuable liquids. The openness of a membrane is called porosity, which should not be confused with pore size.

PORE SIZE

Pore size is the average diameter of the individual pores in a membrane. Although manufacturers report pore diameters in precise terms, the pores are not neat circular holes, except for the ones in Nuclepore's (Pleasanton, CA) nucleation-track polycarbonate membrane filters, whose pore size is determined by electron microscopy. Membrane manufacturing processes have strict tolerances, but pore size is usually determined statistically by the average dimension of the smallest particle that will pass through it.

There is no absolute method to determine pore size or even the exact properties of a membrane. Keeping that in mind, pore-size ratings reflect performance rather than actual pore size and are expressed as nominal or absolute. A nominal rating means that some predetermined proportion of particles, usually 98%, are retained. A filter with an absolute rating will retain 100% of the particles larger than its reported pore size.

Several standardized tests are available to determine pore size. The bubble point test is nondestructive and evaluates performance under aqueous conditions. Pore size is calculated from measurements of capillary force, pressure, and water height. The method is described in ASTM F 316.

The bubble point test cannot be used for hydrophobic membranes, as they do not wet evenly. The water intrusion pressure method calculates pore size based on the pressure needed to force water through the filter. Membranes designed to filter air can be affected by wetting, so their pore size can be measured using mercury intrusion. Although mercury intrusion can be more accurate than water intrusion, it is not necessarily an accurate indicator of performance under actual use conditions.

In the real world, particles are rarely perfectly spherical. Thus, many factors will contribute to the success of a specific filtration application. For example, in applications like sterilization, the largest pore size is more critical than the average size.

Most laboratory and medical applications call for membrane filters that are generally less than 0.1 mm thick with a precise pore diameter. Modern membranes are manufactured under rigid parameters to deliver high porosity and support high flow rates.

There is a wide variety of IV filters and devices including microinfusion filters, needlefree connectors, check valves, vent caps and gross inline filters (Filtertek; Hebron, IL).

Two broad applications for filters are the production of particle-free solutions and particle capture. These particles might be microorganisms for culturing or cells for counting. Membranes are also commonly used as supports for diagnostic assays like electrophoresis, cytology of fluids, and DNA hybridization. Other systems where membranes are found include oxygen detectors, pH and ion electrodes, and drug-delivery devices.

Particles separated by membrane filtration are normally smaller than 100 µm in diameter—a particle range between 0.1 and 1 µm are not uncommon. In descending order of pore size and resultant function, filtration can be subdivided into sieving, filtration, and membrane filtration. Sieving occurs when large particles are separated from smaller ones. Filtration by definition is the removal of all particles. As pore size decreases further, membrane filters perform microfiltration, removing particles too small to be seen by the naked eye, and ultrafiltration, removing particles of molecular size. At the minuscule end of the spectrum, dialysis membranes have pores small enough to remove ionic-level particles.

FILTER CONSTITUENTS

Selecting the right filter for the job depends on the specific application, the fluid or gas to be filtered, and the filter material. Only through testing can manufacturers be certain that a specific filter membrane is proper for their applications.

Filter membranes have graded permeabilities based on their pore sizes and level of uniformity. Cellulose is a natural high-molecular-weight glucose polymer with an ordered, crystalline structure. The majority of membrane filters are made of cellulose esters, formed by substituting hydroxyl groups with the appropriate reactive groups. For example, in the two most ubiquitous forms, cellulose nitrate and cellulose acetate, the hydroxyl group is interchanged with the nitro group and acid anhydride or acid chloride, respectively. Other common membrane filter materials include vinyl, nitrile, nylon, polypropylene, and polytetra- fluoroethylene (PTFE or, more familiarly, the DuPont brand name Teflon). While each material offers unique properties, the applications discussion below focuses on the widely used cellulose nitrate, cellulose acetate, and PTFE membranes.

Commercially available membranes are typically made from a single polymer, but some composite membranes incorporate a backing material to increase physical integrity. PTFE membranes require the added strength of a polyethylene or polypropylene backing for easy handling. During production, membranes can be dyed different colors or have grid lines added for cell counting. Hydrophobic borders can help prevent spillover. Membranes can come in flat sheets or assembled in cartridges.

OTHER CHARACTERISTICS

Cellulose esters, plastics, and PTFE are generally hydrophobic, which obviously hinders filtration of aqueous solutions. Water can be forced through hydrophobic filters, but the pressure required to force water through pores smaller than 1 µm becomes prohibitively high, and the risk of uneven wetting increases. Thus, most membranes are treated with wetting agents, such as gylcerol, Tween, and Triton X-100, which allow water to flow freely.

Since membrane filtration deals with very small particles, electric charge can greatly affect filter efficiency and performance. When wet, most filters have a negative charge. At neutral pH, most cells, viruses, and macromolecules also exhibit a negative charge. The repulsion of like charges can overcome electrostatic attraction and van der Waals forces needed to adsorb small particles into the membrane, leading to less than optimal performance. For sterilization purposes, asbestos is often chosen because of its high positive charge when wet. Raising the ionic strength of the solution can also reduce negative charge.

Isotrophy refers to the uniformity of pore size throughout the membrane. In an isotrophic membrane, pores are of the same size from top to bottom. Anisotrophic membranes have a gradation of pore sizes from top to bottom. Manufacturing processes make some degree of anisotrophy unavoidable. In some applications, such as bacterial culture, anisotrophy is desirable, because cells trapped in the larger pores on the top of the membrane remain surrounded by media or fluid and respond better to culture.

Inks or dyes can be blotted on a membrane to test for isotrophy consistency. An isotrophic membrane will wick in a uniform manner and form circular-shaped stains. Any uneven stains may be attributed to anisotrophy or hydrophobic regions.

CHOOSING THE RIGHT MEMBRANE

For specific applications, several factors must be considered for optimal performance, including clogging rates, chemical compatibility, and extractables.

During filtration, the membrane pores get clogged with particles, and the flow rate ultimately decreases. Large-pore prefilters or anisotrophic membranes can reduce clogging by trapping larger particles before they reach smaller pores. Even isotrophic filters can exhibit different clogging rates depending on which side the fluid enters. The side facing up in the package is generally the side with the larger pores. This slight difference in isotrophic filters often is of no practical consequence.

Another important characteristic is chemical compatibility. Of the cellulose esters, cellulose nitrate is the least tolerant of organic solvents. Cellulose acetate behaves similarly to cellulose nitrate but is resistant to alcohols. Most other membranes exhibit sensitivity to acids and ketones, but PTFE is resistant to almost anything.

Extractables are substances that originate from the filter and pass through to the filtrate. Wetting agents, filter material dust, and ions are typical extractables. Extractables must not be toxic to growth in applications that involve cell culture. Extractables are also a concern in applications involving filtration of substances for human injection. Washing the filters prior to use can alleviate these problems. Despite manufacturers' efforts to precisely characterize and qualify their membranes, a filter's suitability for an application must be tested empirically.

APPLICATIONS

So what does this technology mean for the medical device manufacturer? Only a small number of suppliers produce the majority of filter media and membranes in the United States. However, several of the largest filtration material producers work closely with medical manufacturers, and many have separate divisions devoted to the research and development of medical and health-care applications. Because the majority of materials produced are nonpatented commodities, like nitrocellulose or nylon, suppliers compete to lure OEM customers. This intense competition over technological development also creates a climate of secrecy. Many filter makers and medical device OEMs developing filter applications are reluctant to discuss their products. However, there is no shortage of new project development, and the areas of research are rapidly increasing.

An electron scan micrograph of a filter membrane shows its spongelike characteristics.

Most medical device filters form barriers that keep harmful substances, like viruses and bacteria, away from patients. A few keep vital substances from escaping the body—keeping water within the lungs, for example, so that a patient on a ventilator doesn't get dehydrated. Other filters protect a device's electronic components from coming into contact with damaging liquids. Some of the newest technologies and areas of research are discussed below.

VIRUS REMOVAL

Although fewer than 2% of all reported AIDS cases in the United States were traced to tainted blood transfusions, this still translates to several hundred infections each year. Despite new, increasingly stringent blood bank protocols, the rate of transmission has remained fairly constant during the past 10 years.

Pall Corp. (East Hills, NY) has developed a virus removal filter that appears capable of removing 100% of certain large viruses, including HIV, from blood-derivative products. China's Ministry of Public Health recently mandated Pall's Ultipor filter for use with blood-derivative products in that country. Sales and usage of the Ultipor filter are expected to increase in the United States and Europe as well as in China.

Although the Ultipor filter can remove some viruses from noncellular components, there is currently no approved way to inactivate those viruses residing within the red blood cells and platelets used for transfusions. To address this problem, Pall has teamed with V.I. Technologies, Inc. (VITEX; Melville, NY). VITEX has had its own success with inactivating viruses. In May, VITEX was granted FDA approval for its virally inactivated, or SD (solvent detergent) plasma for use in transfusions.

Most complications from allogenic blood transfusions result from leukocyte (white cell) contamination of the red blood cell and platelet components. Leukocytes reportedly cause febrile reactions or alloimmunization that may lead to platelet refractoriness in subsequent transfusions. They can also harbor intracellular viruses like cytomegalovirus (CMV) and human T-cell lymphoma leukemia virus (HTLV-1). CMV is any of a group of viruses that cause cellular enlargement; many are also infectious agents in immunosuppressed diseases such as AIDS.

Despite these risks, most patients still receive blood transfusions. Filter systems can deplete leukocytes from freshly drawn or cold stored blood. Pall's Purecell high-efficiency leukocyte reduction filter is a bedside version that filters blood immediately before transfusion.

GAS REMOVAL

Sterility of the blood returning to the patient was the primary concern when the heart-lung bypass machine was introduced. Just as important, however, is gas removal to prevent embolisms. Pall developed the first manually vented extracorporeal 40-mm bypass filter for open heart surgeries.

More recently, doctors have become aware of the adverse effects that can develop when blood is diverted from the patient's body and is exposed to foreign surfaces of the bypass circuit, activating white blood cells. The lungs are primary targets for damage and compromised function during surgery, leading to longer ventilator support and slower recovery times. Studies have shown that filters used in bypass circuits help decrease the length of hospital stays.

Hydrophobic membranes retain fluids in ostomy and urine bags while allowing air to escape. For liquid barrier applications, Pall's Repel process can render any material hydrophobic. PTFE membranes treated with the Repel process can be used to retain moisture in a collection bag or repel liquids from electronic equipment.

A secondary advantage of hydrophobic membranes is that PTFE is physiologically inert. One nontraditional application under study involves PTFE fashioned in a mesh structure similar to a screen door, which could one day serve as a support for wound dressings.

RETAINING MOISTURE

While removing air bubbles is important in blood filters, retaining moisture is one of the main functions of ventilator filters. During anesthesia or mechanical ventilation, the filters conserve a patient's exhaled humidity, minimizing dehydration. Many bidirectional filters also capture aerosolized pathogens flowing from either direction across the membrane. This not only protects patients from infection but also helps limit disease transmission from patients to health-care workers. The newest pulmonary filters trap contaminants yet add a clinically insignificant amount of resistance to airflow.

Filtertek (Hebron, IL) claims to be marketing the only needle-free, sterile IV connectors. Compatible with ISO/ANSI luer syringes or devices, Filtertek's connectors maintain sterility with a dual-sealing wiper system that prevents bacterial contamination. The connectors should be cost-effective as well; they are expected to withstand up to 200 actuations without performance loss.

DRUG DELIVERY

Filter membranes can also aid drug delivery. PTFE media treated with Pall's radiation grafting technology creates IonClad electrically driven separation membranes. While most current applications are industrial, research has shown that drugs carried by IonClad media enter the body transdermally when an electric field is pulsed through the filter membrane.

Patients allergic to preservatives in certain eye drops can use charge-modified filters that adsorb the preservative before the drop reaches the eye. With the filter placed across the neck of the bottle, the preservative is captured as the drop is squeezed out. This application is currently being pursued in Europe along with a unique study to determine if filtering patient cerebrospinal fluid can alleviate the symptoms caused by the Epstein-Barr virus, which can lead to mononucleosis or a group of symptoms linked to a condition often referred to as chronic fatigue syndrome.

DIAGNOSTIC USES

The filters discussed above act mainly as microsieves or as barriers. Most filters used for diagnostics, on the other hand, act as substrates to contain or collect analytes. Some new membranes can also contribute to the assay process.

The serum, or liquid fraction of the blood, is analyzed when testing for viruses, glucose, or analytes. Traditionally, plasma is separated from the blood by centrifugation, but the equipment is fairly unwieldy. Further, it does not lend itself well to automation or microvolumes.

New membranes not only absorb and hold blood, they can also fractionate them into cellular and plasma components. A finger stick drop of blood can be separated by chromatography, where the plasma migrates faster than the red blood cells. Pall's Hemasep V medium is comprised of three levels designed for use in diagnostic devices. The top level creates a uniform distribution of blood that is wicked vertically by the second. The third, or bottom, level captures purified plasma that can be used to detect analytes or viruses. The separation takes less than 10 seconds for a normal finger stick quantity of blood. According to Pall, its research has demonstrated that bacteriaphage M13 spiked into whole blood could be detected by polymerase chain reaction after separation by Hemasep V medium.

Whatman, Inc. (Fairfield, NJ), offers the Plasmasep LS to separate blood components. Plasmasep LS is a fibrous matrix with a proprietary coating that prevents red blood cell deformation and allows plasma to pass unaltered. The original development was conducted at NASA with technology licensed from DBCD, Inc. (Webster, TX). Plasmasep devices were taken on the space shuttle and used in place of traditional centrifugation.

Another area of intense development is the use of filter membranes for lateral-flow assays. Both economical and easy to use, lateral-flow assays are ideal for detecting glucose, cholesterol, and analytes in serum.

Other common uses for lateral-flow assays include home pregnancy, drug abuse, and infectious disease tests. Separation properties are not required for tests involving saliva and urine. Cellulose and its derivatives have been the traditional media for these types of assays and are still used by the majority of manufacturers. Pall's Predator membrane was developed to combat problems associated with nitrocellulose, such as inconsistency and poor durability.

Chemiluminescent and colormetric detection methods have become preferred over those using potentially hazardous radioisotopes. With chemiluminescence, an enzymatic reaction causes light emission, while colormetric assays involve a change in the color of the substrate or surrounding environment. The technology is now sophisticated enough to allow rapid clinical diagnostic applications. At first, standard nitrocellulose membranes were not sensitive enough for rapid assays, but new nylon-based, hydrophilic membranes are capable of such assay support. Pall's Biodyne A nylon 6,6 membrane accepts the antigen or antibody immobilization needed for ELISA (enzyme-linked immunosorbent blocking assay) while not inhibiting fluorescence or light emission. ELISA format assays are popular because of their convenience and versatility.

CONCLUSION

While applications for filters and membranes continue to expand, the number of companies manufacturing them is shrinking, similar to the conglomeration readily apparent in most industries. Pall and Gelman Sciences have merged. Millipore has teamed with Amicon and Tylan. British-founded Whatman has spent the last 250 years building its business but has just recently entered the medical device market.

However, new mechanical filtration methods and the research behind new materials have expanded the range and use of filters, which may lead to more manufacturers getting involved in R&D in this area of medical devices. Because core filtration technologies are similar, manufacturers have emphasized innovative products and increased customer service to make a place for themselves in this specialized market.

BIBLIOGRAPHY

Brock TD, Membrane Filtration: A User's Guide and Reference Manual, Madison, WI, Science Tech, 1983.

Gary Woo is a freelance writer based in Woodland Hills, CA.

 


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