By: Klearsen Corporation

  June 15, 2000

Klearsen Corporation has developed proprietary technology and techniques for controlling infection. Klearsen's technology is based on the use of silver iontophoresis whereby broad spectrum antibacterial silver ions are delivered into the tissue, at a controlled rate and dosage, to effectively treat (or prevent) infection directly at the site of the infection. Klearsen's proprietary technology relates specifically to electrode material composition, iontophoresis control electronics, remote energy coupling, remote therapy programmability and control, and treatment protocol for maintaining a sterile barrier within an implantable medical device or for wound care using an active bandage. The technology can be effectively employed in medical and healthcare applications ranging from skin care dermatology and cosmetics to wound care and the antiseptic maintenance of long term indwelling or transcutaneous medical devices.

For the skin care application; Klearsen currently markets an OTC skin care product that employs the silver iontophoresis modality for treating herpes cold sores, fever blisters, and other minor infections under the surface of the skin. This product, called the "DermaSeptic", is a battery powered microcircuit device about the size of a small matchbox. The product is currently being marketed through direct internet sales at http://klearsenbuy.stratnet2000.com and through select retail stores.

For the implantable and wound care applications; Klearsen is seeking a partner in a major medical company with development, manufacturing and distribution resources sufficient to bring an Active Antiseptic product line to the medical market. Klearsen has proposed a development program to be conducted in phases intended to 1) validate the efficacy of the therapy, 2) optimize the materials or coatings, delivery fields, and the treatment protocols, 3) cost reduce and miniaturize the implantable electronics where applicable, and 4) produce selected products suitable for clinical trials. For initial testing purposes, the micro-circuitry used in the DermaSeptic product can be programmed for use in testing active wound care and for testing Active Antisepsis ™ for indwelling devices. In this program, Klearsen proposes to provide scientific and engineering resources to support efficacy and optimization testing of the technology and to design and develop the prototype products. The development partner will be expected to provide capital resources for the program, define the products of developmental interest, perform in-vitro and in-vivo testing and validation, and conduct clinical trials for regulatory approvals.

The anti-microbial properties of silver are well documented. Silver has been used for centuries to keep water and food pure. The early settlers used to drop silver dollars into their milk to ward off spoilage. Early physicians used silver wraps around flesh wounds to avoid infection. Silver has long been used as a dietary supplement to promote general health and it is recognized by the FDA as a dietary mineral supplement. More recently, medical companies have been impregnating urethane and silicone implant products with silver to create a "sterile barrier" and to inhibit infection.

Although the early uses of silver as a germicide were well intentioned, they were often only marginally effective. These uses of silver as a broad-spectrum antimicrobial agent ignored one very important criterion for efficacy; the silver should be in ionic form and it should be administered to the infected tissue in a controlled and sufficient concentration to have a strong antimicrobial effect. In general, the small amount of silver that can be released from the matrix of urethane chains of implant products over time, limits the antimicrobial effectiveness of these products. This also poses problems for long-term release as the surfaces become coated with protein complexes or biofilms.

Dr. Robert 0. Becker and his research colleagues performed some research work on iontophoretically* diffused metals into dishes of agar. This work was a natural offshoot of their research into "the current of injury" and cell regeneration. As they studied the effect of current from various electrodes and the effects that this had on healing and cell re-growth, they noted that the silver electrode produced a sterile region surrounding the anode.

In a separate experiment (Electrically Generated Silver Ions: Quantitative Effects on Bacterial and Mammalian Cells T.J. Berger, J.A. Spadaro, S.E. Chapin and R.O. Becker : Antimicrobial Agents and Chemotherapy, Fe. 1976, p. 357-358) Becker et al specifically examined the performance of silver electrodes on cultured bacteria in agar. The results showed a profound inhibition of bacterial growth. They then tested the effect of silver on mammalian cells to ensure that there were no toxic or teratogenic effects. They found none. The tests indicated that silver did not interfere with the function or health of several different types of mammalian cells.

Over the last couple of decades, there has been a resurgence of interest into the use of silver products for treating infection. Unfortunately, a number of the resulting products use large silver based molecules and silver salts that are not delivered effectively and have shown rather un-remarkable performance. It is the iontophoretic delivery of silver ions that has consistently proved to be orders of magnitude better than the chemical preparations and statically bound systems. Simply stated, the silver ions must be delivered to the right place, in the right concentration over time, and in the right form to achieve dramatic antimicrobial performance.

Work performed at Klearsen and by other researchers in this field has shown that maintaining a region of tissue ionically enhanced with silver ions, is paramount to producing a sterile barrier. Regions that are perfused with silver ions over time, in a controlled protocol concentration offer effective resistance to bacteria and virus by attenuating their population many orders of magnitude in a matter of hours. The key to utilizing this technique in a long-term indwelling device is to provide control of the ion density while the conditions of the surface and surrounding environments change. It is neither necessary nor advantageous to continuously dispense silver ions into the tissue. Antiseptic treatments can be administered at pre-programmed intervals or (as a pre-treatment) whenever the transcutaneous device is accessed. It is this control of ion density, through active penetration of tissue that Klearsen Corporation is offering in its Active Antisepsis ™ systems.

The heart of the system is a microprocessor based iontophoresis generator that can be remotely powered, programmed, and controlled. The iontophoresis may be battery powered or powered by a remotely applied field. The rate at which ions are introduced into the surrounding tissue is controlled by the microprocessor and is remotely programmable through modulation of the applied fields.

*Iontophoresis is the induced movement of a substance that contains a charge imbalance (an ion) through another region of substance which is neutral. This movement is produced by the application of an external electric field.

Utilizing these techniques, the specific surfaces to be energized, the time that they are energized, the depth of penetration, and the rate at which the ions are perfused into the surrounding tissue can all be precisely controlled to provide effective antiseptic treatment for diverse clinical requirements.

Recent testing of the Klearsen Active Antisepsis ™ by an independent laboratory showed a dramatic advantage over hydrophilic-lubricious materials and antimicrobial coated materials. This in vitro testing was conducted in accordance with the FDA's guidance for conventional and antimicrobial Foley catheters against Staphylococcus aureus biofilms. The results of these initial studies showed that " the Klearsen Corporation technology is superior to all commercially available anti-infective coating technologies." The Active Antisepsis technique had accomplished what no other antisepsis technique had yet shown, namely the penetration of a dead layer of cells to kill a newly grown biofilm layer.

Klearsen Corporation’s iontophoresis control system is presently embodied in a product called the DermaSeptic. The DermaSeptic is currently being marketed as a battery operated, pocket sized device for treating dermatological infections. It is a particularly effective therapy for infectious lesions such as herpes sores, acne, warts as well as minor cuts and abrasions. The circuitry used in the DermaSeptic can be readily adapted to meet the requirements for the indwelling and wound care applications testing. The current circuitry occupies approximately 1 square inch. It is specifically designed to be easily miniaturized. It can occupy less than 1/4 of a square inch and have volume cost of goods less than a few dollars. The power required for operation is less than 2 mw (0.002 watts). This power can readily be provided by internal battery, inductive transcutaneous power or by external connections as required.

For wound care applications, Klearsen plans to use the same integrated circuit controller that is used in the DermaSeptic to drive a disposable bandage suitable for large area wound protection and antisepsis. This bandage could find ready application to burns, Herpes Zoster (shingles) and eczema conditions which are too large to be conveniently treated by the DermaSeptic.

The iontophoretic control circuitry used in the existing DermaSeptic product can be used in miniaturized form for antisepsis of long term indwelling and transcutaneous medical devices. The treatment (rate/time dosage) can be controlled and powered remotely either transcutaneously or by direct connection. In this application, the tiny control module can be embedded within the indwelling device and the active surfaces of the device are coated with the silver compound.

In the case of the subcutaneous infusion port, the control circuitry can activate any number of selected, treated surfaces with any number of waveforms and iontophoretic perfusion levels. The operational parameters for the treatment can be conveyed to the implantable device via the applied energy field. This would allow a nurse to place a small hand-held unit over the device and control a disinfecting cycle for 5 minutes subsequent to accessing the port.

Should the medical device that is intended to be disinfected be smaller than would allow embedding of the control circuitry (i.e. a catheter cuff) provision would be made to allow connection to the treated surfaces externally by means of conductive polymers. The device would then be attached to the hand-held power and control unit and the disinfecting cycle would once again be accomplished in the minutes subsequent to accessing the device.
 

The development course that is proposed here consists of three phases. The first phase involves application of the currently available control system to demonstrate efficacy in the particular product embodiment. Experiments will be directed to quantify the levels of antimicrobial effectivity relative to dose, time, penetration and protocol. Laboratory tests have suggested that iontophoretically perfused tissue may continue to be antiseptically effective for many hours after treatment. Testing in this phase will quantify the levels of bacterial inhibition that can be achieved and how long the antimicrobial inhibition remains effective in terms of dose concentrations in various tissue types. This will provide information on optimizing treatment protocols and in tailoring the control system for the specific needs of the long-term indwelling applications. This phase will utilize state-of-the-art biofilm laboratory protocols for comparing Klearsen Active Antisepsis ™ products against other industry leading products.

The second phase of the development can overlap the first phase and will involve optimizing and miniaturizing the control circuitry for specific product applications. It is anticipated that this will be accomplished through "chip-on-board" technology and potted into a bio-compatable material. The resultant control system will then be the approximate size of a dime or smaller. This will allow the integration of the control system into specific indwelling devices. Work will involve the design for manufacturability of the device/controller interface and the appropriate surface treatments for effective ion dispersion. Prototypes of phase 2 development will be tested using the in vitro protocols developed in phase 1. The phase 2 prototype units will then be ready for animal testing.

The third phase of the development process will involve in vivo testing. These tests will verify efficacy and safety of the devices and provide necessary information for improvements to the product design. Phase 3 is expected to last 12 to 18 months and will culminate in a product design that is ready for manufacture.

Klearsen Corporation has developed an Active Antisepsis ™ technology for controlling infection. This technology may be readily applied for treatment of infections of the skin, for wound care, and for the antiseptic maintenance of long term indwelling medical devices. Klearsen's technology is based on proprietary control and application of silver iontophoresis. Ionic silver is well recognized as a safe and effective, broad-spectrum antimicrobial agent. Proprietary aspects of Klearsen's technology relate specifically to:

1. Use of controlled silver iontophoresis for active antisepsis of indwelling medical devices, treatment of wounds, herpes sores, warts, pimples, and other infections of the skin
2. Effectivity of the silver electrodes or coatings (material composition and surface finish)
3. Means and the electric fields associated with effective delivery of the antimicrobial ions into the tissue (controlling penetration, dispersion, etc.)
4. Control of treatment area through selective activation of specific surfaces
5. Means of powering and controlling the iontophoresis process through the application of external inductive fields
6. Control of the ion treatment protocol relative to dosage, rate of delivery, and depth of penetration into the tissue

For the medical applications of indwelling device antisepsis and for wound care, Klearsen is seeking a development partner to bring an Active Antiseptic ™ product line to market. Klearsen currently markets an OTC product for skin care applications. The circuitry employed in the existing OTC product can be modified and programmed for use in the initial testing and efficacy evaluations of the Active Antisepsis ™ technology. Klearsen has outlined a development program beginning with an efficacy evaluation phase. An interested development partner can begin a relationship in the development of Klearsen's Active Antisepsis technology by securing an exclusive option on the technology during the initial evaluation and proof of efficacy phase. Upon satisfactory completion of the evaluation and efficacy phase, the prospective partner may elect to continue the development partnership and negotiate an acquisition or licensing agreement.

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