Naturally antimicrobial

Medical device and equipment manufacturers that want to prevent their products from serving as reservoirs for bacteria and other micro-organisms now have a technology to turn embrace. By utilizing the natural antimicrobial properties of silver, with inherent controlled-release characteristics of a clay-like mineral, together with advanced production methods, Agion Technologies is producing a high-performance additive for plastics, coatings, and textiles. Evaluating the use environment, manufacturing process, and performance criteria required by the application has shown that in the vast majority of cases, the antimicrobial can be incorporated into a product’s existing manufacturing process with little or no modification of the existing methods, since the antimicrobial is a ceramic powder, similar in size and processing behavior to common particulate additives such as pigments or radiopacifiers. Therefore, the skills required to incorporate Agion into a product are well established in the supply chain and often readily available either in the partner’s own factories, or with existing toll processors.

The Process
A common approach to creating an antimicrobial protected surface on a device or piece of medical equipment is to incorporate Agion into the polymer from which the device is made. For example, Agion would provide a catheter manufacturer with a concentrate, or masterbatch, of the selected Agion powder grade blended into the appropriate polymer. This is often the exact grade used to make the device, or a compatible carrier. That concentrate is blended with virgin resin and “let down” to the desired final concentration. If desired, the polymer can also be provided with the Agion powder loading at the desired end-use level.

Once molded, the surface of the device, or piece of equipment, is protected from bacterial colonization by an array of particles at the surface of the part. The silver ion release mechanism is activated in the event of bacterial contamination of the device. This generally occurs via some fluid coming in contact with the device, such as sweat or blood through hand contact, or a cough or sneeze droplet landing on the device’s surface.


Erodes to New
Incorporating silver ions throughout the polymer has several advantages in addition to maintaining manufacturing processes. For extruded devices such as catheters, an additional advantage is that the lumen of the catheter is protected as well as the external surface. It is very difficult for coating processes to properly treat a lumen and not impact flow. Another benefit, more likely realized by durable medical equipment than implantable devices, derives from the fact that even when worn and scratched, the polymer is protected. All polymer surfaces gradually erode with use. However, studies have shown that by eroding only 5µm of a polymer containing Agion, a completely fresh, unused layer of particles is revealed.


Easy Approach
Agion antimicrobial can be readily incorporated into coatings as well as plastics. The most common approach is the same as that used to put pigments or matting agents into a coating. The powders are pre-dispersed in the coating or the primary solvent in the coating system. Once fully dispersed, the concentrate is blended with the coating to the desired level and applied to the substrate. Two factors generally drive the use of a coating on a device or piece of medical equipment. The primary reason a coating is used is that the existing non-antimicrobial product is coated, in which case there is generally no other option. For example, some catheters are coated for a particular purpose (lubricity, for example), in which case Agion can be added to that coating. A coating can be selected for economic efficiency, for example, if the section is thick and incorporation through the whole part is too expensive. However, the cost of adding an antimicrobial through a thick section has to be balanced against the added cost of introducing a new manufacturing process – a coating step.

Textiles in healthcare play a range of roles, from wound care, to surgical respirators, to privacy curtains. Agion can be incorporated into these products using the textile analogs of the polymer and coating approaches – going through the fiber spinning process or applied as a topical fabric treatment. Each method has advantages for particular segments of the textile market. The blending of Agion into the polymer from which the fiber is spun is an appropriate approach for markets that use a large amount of a single type of fiber, such as surgical respirators or privacy curtains. Agion is incorporated into fibers using the same melt processing methods used for injection molding: compounding a concentrate of powder and polymer, and fiber spinning using conventional techniques. For shorter run textiles, such as hospital garments of varying style and weight, or wound care products, topical treatment is more versatile. In this case, the antimicrobial powder is blended with a dilute binder solution and applied to the fabric using conventional finishing processes.

 Agion’s antimicrobial is incorporated into Vygon’s catheter manufacturing process.
 

Naturally-Occuring
Agion’s antimicrobial technology resides at the intersection of three natural materials characteristics:

1. The safety and biological efficacy of silver at very low concentrations;
2. The high capacity and ion exchange selectivity of the Agion zeolite mineral for silver; and
3. The physical, chemical, and thermal durability of zeolite.

All three of these characteristics are necessary to achieve high antimicrobial performance for an extended period of time in a very broad range of materials and processes.

Natural ionic silver provides several benefits as an antimicrobial relative to the alternatives – synthetic chemical biocides or antibiotic drugs. With respect to durable antimicrobial applications, as opposed to short-use liquid disinfectants, few practical alternatives exist. Triclosan, a chlorinated phenoxy phenol, can be incorporated into polymers with low processing temperature, however, higher temperature processes (>200ºC) can result in significant off-gassing and loss of product. Furthermore, triclosan is particularly ineffective against certain common bacteria of the Pseudomonas genus, which can result in displacement of some strains, to the benefit of others.

The other primary alternative for hard surfaces and textiles is the category of quaternary ammonium compounds (quats). Some quats have been combined with siloxane compounds to provide adhesion to surfaces. The quat is not released, but remains attached to the siloxane. Although such a strategy avoids the question of a sufficient reservoir, it also offers some challenges. Being a few molecular monolayers in thickness, such a surface treatment may not have the durability that some applications require, especially if it involves physical contact or abrasion. The mechanism of contact-only interaction with bacteria poses another challenge, since a soil load, or a layer of dead bacteria, serves as insulation against the now-passivated antimicrobial surface. So once a layer is built-up, the active ingredient is covered and cannot come into contact with the bacteria.


The Solution
Agion is used in several medical devices that can be associated with infections. Catheters are one of the most common devices that can facilitate bacterial contamination and infection. The mechanism can be migration of bacteria into the body along the outside of the catheter, or through contamination of a luer resulting in migration of the bacteria through the lumen into the body. For customers that prefer protection on both the outer surface and the catheter lumen, Agion is incorporated into the polymer so all surfaces are protected.

Agion works by harnessing the natural antimicrobial properties of silver. While there are several types of silver-based antimicrobials, all work by releasing silver ions. Therefore, the technical challenge is to modulate the release kinetics to fit the environment and the performance requirements. Agion accomplishes this by using a controlled-release technology that limits the delivery of silver unless the environment for bacterial growth – moisture and nutrients – exist. Therefore no loss of the activity exists when the product is in storage or is not in contact with blood or other bodily fluids that often carry contaminants. Even when silver is being released, a very low concentration (in parts per billion) is reached, which is precisely the concentration range at which bacterial growth begins to be inhibited.

Bacteria are affected by silver through various mechanisms. Silver interacts with enzymes that are fundamental to the cell’s metabolisms and renders them inactive, which effectively starves, or suffocates the cell. In addition, silver can impact transport of nutrients across the cell wall and interrupt cell division. These mechanisms, and the low concentration required, make silver the most effective antimicrobial compound that can be incorporated into plastics and coatings.

Co-Development
Agion engages with medical device manufacturers in a co-development project to integrate the antimicrobial benefit with the non-antimicrobial functionality of the device. Once a customer enters into the product development process, the real work begins. Initially, the focus is usually on design and formulation of the antimicrobial component of the product. This may involve making laboratory samples or pilot runs of material in order to evaluate the controlled release profile and total antimicrobial content in the finished part, since the FDA requires detailed information about devices containing antimicrobials.

A project usually starts with an initial proof of concept experiment in which samples of the customer’s materials containing Agion are prepared, sometimes at various loadings using different grades. These samples are evaluated for controlled release and antimicrobial efficacy against the desired bacteria. Once a particular optimized formulation is selected, scale-up to a pilot production run commences. This is an important stage that often involves the development of QC metrics and criteria, allows for production scale process optimization, and provides sample material for the longer term, more thorough evaluations required for the FDA submission. These evaluations include shelf life, efficacy, release kinetics, and several other aspect of the device that need to be included.

As a customer prepares for their 510k submission Agion provides access to Agion’s FDA device master file, or DMF, which significantly helps our customers by providing biocompatibility data and information on the various predicate devices that contain Agion antimicrobial.

The other contribution Agion’s technology makes to the customer’s product launch is the protection of patented technology. Agion holds patents issued or pending that cover antimicrobial applications of silver to device coatings, catheters, orthopedic devices, and vascular grafts.

Recent 510(k) clearances for products which incorporate Agion’s Natural Antimicrobial include a pain management catheter and Medegen’s needleless valve; such clearances bode well for other devices and environmental products which utilize the long lasting silver technology.

Finally, the high performance and longevity of Agion’s technology in these devices has allowed Vygon to complete two clinical trials on their catheter containing Agion, which demonstrated reduce bacterial colonization and reduced infection.

Agion Technologies Inc.
Wakefield, MA
agion-tech.com