A White Paper – Laser Hair Removal: An Application Whose Time has Come

This White Paper was prepared under a clients’ sponsorship, but was prepared on an independent basis by the author. The portion presented here, a part of the complete report, provides the early history of laser-based hair removal. The study was prepared and presented to the client (and sent out to others) in October 1996

Irving J. Arons
Managing Director
Spectrum Consulting

Introduction

Elective cosmetic laser surgery has "exploded" onto the dermatology scene over the past two years, with laser skin resurfacing leading the way. Now that laser ablation of wrinkles by the CO2 laser has been accepted by the dermatological community, the use of lasers to remove unwanted hair will be the next innovation.

In order to help physicians and the laser and financial communities understand this area of laser technology and keep everyone up-to-date, I have looked into the story-behind-the-story in order to put the facts into your hands. In this "white paper", I intend to discuss the market potential for both hair laser manufacturers and service providers; the science and technology of laser hair removal; where the various corporate players stand in their quest to enter or enlarge the market; what the latest clinical results show; and the current patent situation.

This "white paper" was prepared after a comprehensive review of the literature pertaining to the science and technology of hair removal and the companies involved; interviews with key personnel in the industry; and a review of the issued patents. As noted in the disclaimer, all of the companies mentioned were given the opportunity to review and comment on the materials written about them.

It is the author's intention, to provide an unbiased and objective portrait of this evolving application.

The U.S. Market for Hair Removal

Potential Market for Lasers

There are two ways of looking at the potential market for unwanted hair removal: treatment at a salon, the way it is done at present through waxing and electrolysis; or treatment by a physician, where the laser treatment will be performed either by a dermatologist or a cosmetologist working under the physician's direction. I expect the market will be a mixture of both. According to my research, there are currently 24,000 to 26,000 beauty care salons that specialize in either skin care (about 19,000 to 20,000 self-standing units) and 11,000 to 15,000 electrologists, operating either on their own or as part of a beauty/skin care salon. If 15% to 25% of these operations were to get involved in laser hair removal, it would create a market for about 5000 to 9000 laser systems. However, if the market progresses via the professional/physician route, you could expect that 20% to 35% of the U.S.-based 13,000 dermatologist/plastic surgeons might purchase 2600 to 4600 laser systems. But, if both entities get involved, the total potential market could be 7500 to 14,000 systems (or some fraction of that total!). This projects to a market for hair removal laser systems of $600 million to over $1 billion (at an average laser selling price of about $80,000).

Potential Provider Market

According to my research more than 70% of women use depilatories, epilators, shaving or waxing kits on a regular basis to remove unwanted facial and body hair. This market is estimated at $500 to $600 million annually for the 80 million women using these products. In addition, another 1 million women use professional electrologists or have waxing done in a personal care salon. The cost for removal of upper lip facial hairs, for example, can involve multiple half-hour visits over several months and cost in excess of $1000. "Electrolysis is a laborious, painful process that works by heating and coagulating tiny blood vessels in the hair follicles, one at a time. Removing the 1000 to 2000 hairs in a typical moustache can take 30 to 50 visits to an electrolysis center, costing a total of about $1000", according to the director of corporate development of ThermoLase. It is estimated that women (and some men) spend upwards of $1 billion for removal of unwanted hair via the professional salon route.

If the results with the laser are relatively long-lasting (at least six months -- or more), are less painful and quicker than electrolysis, I expect that at least 5 million laser procedures would be done annually, once sufficient laser systems are in place, and would progress to some 20 million annual procedures over time. With the treatment for facial hair costing $750 initially (full backs or legs, for example, would cost considerably more) and dropping to $350 with time and competition, laser hair removal could result in a professional service market of at least $3.75 to $7.0 billion.

Science and Technology

Although, it is not known precisely which portion of the hair growing process needs to be destroyed to provide permanent hair removal, it is believed that the hair follicle, the hair shaft, the hair bulb from which the hair grows, and the hair bulge (located 1 mm below the skin) which controls the growth stage or cycling of the hair, must be effected. The secret for success is to do this without damaging the surrounding dermal tissue and/or the epidermis.

Hair growth proceeds through three cyclic stages, as shown in Figures 2a-d. During the rapid growth or anagen stage, the cells making up the hair shaft proliferate for a fixed duration, growing both outward and inward, which determines the maximum hair length. During the transitional, or catagen stage, the hair matrix cells regress and retract, moving the hair bulb upward toward the hair bulge. Finally, during the resting/dormant or telogen stage, the hair bulb dies and their is no active hair growth until onset of anagen, again, when the old hair shaft is moved upward and out of the skin (hair loss). The hair bulge then prevails to induce new cells to form a new hair bulb and start the process over again, or a renewed anagen stage. Depending upon the location of the hair on the body, the lengths of the anagen (growth) stage of hair cycling may vary. For fast growing areas such as the scalp, beard, and mustache, from 65% to 85% of the hairs may be in the anagen stage; while for slower growing areas such as the legs and thighs or pubic areas, 70% to 80% of the hairs are in the telogen stage. (The catagen stage represents only a short period of a few weeks for all hairs.) The anagen stage can last for months to years, while the telogen stage is measured in weeks to months.

It is not clear yet, which growth stage is most amenable to laser treatment. Although the hair bulb is at its deepest position below the skin during anagen, it is probably most susceptible to death during this proliferation stage. However, because only a percentage of hairs are in the anagen stage at any given time, it will probably take multiple laser treatments to permanently remove all the hair in a given body area. A single treatment will only remove those hairs that are in anagen, while a second treatment, several months later may be necessary to affect the new hairs that are then beginning or are progressing through their anagen growth stage. Multiple treatments consistent with the follicular cycling are probably needed for permanent hair removal.

There are several different approaches on how to accomplish laser hair removal, and the clinical data to support the various methodologies used is still being developed. Let me first describe the several approaches.

Laser-Based Approaches

ThermoLase, the first company to gain FDA marketing approval for their approach (in April 1995), uses the concept of delivering carbon black particles ("India ink") as the laser energy absorber, from a surface applied cream or lotion, into the hair follicles (following epilation or waxing to remove the hair shafts to allow the diffusion of the particles into the follicles). The company then uses a Q-switched pulsed Nd:YAG laser, similar to the pulsed YAG laser used to remove tattoos, to selectively heat the target particles, imparting that heat to the hair follicles (and hopefully to the hair bulb). In reality, the follicle destruction is probably accomplished by micro-explosions/fracture of the carbon particles, again, similar to the removal of black tattoos, causing shock waves and cavitation to create local damage, rather than through transfer of the small amount of heat energy absorbed by the carbon particles, which would quickly dissipate into surrounding tissue structures.

In use, the process is quite time consuming, as waxing or epilation of the area to be treated must first be done, followed by application of the carbon-containing lotion, massaging the lotion into the skin (and hair follicles), and removal of the topical coating. This is followed by passing the laser over the treatment zone, using a 5-6 mm spot. After treatment, the skin is cleaned, moisturized, and again massaged. A topical anesthetic/cooling lotion is applied for pain control. Depending on the size of the area treated and because of the small diameter laser spot, the hair removal process can take an hour or more.

Both Palomar Medical Technologies and Laser Industries/Sharplan (as well as Mehl/Biophile), rely on "selective photothermolysis" for effectively removing the unwanted hair. This phenomenon, invented by Drs. John Parrish and Rox Anderson of the Wellman Laboratories of Photomedicine at Massachusetts General Hospital, uses the principle of delivering pulsed laser energy to a selected chromophore within the target tissue, without damaging surrounding tissue. In the case of hair removal, the chromophore is melanin, found both within the hair shaft and in its surrounding covering (the follicle). The use of a ruby laser, operating at 694 nm, allows both penetration of the laser energy into the dermal tissue, as well as selective absorption by the melanin chromophore, with little absorption by other chromophores in the tissue (namely hemoglobin). One problem, however, is that melanin is also present at the base of the epidermis, at its interface with the dermis, which could conceivably block the laser energy from reaching deep within the hair follicle. Both Palomar and Laser Industries have found a way around this dilemma. By carefully selecting the pulse width of the laser beam, researchers for both companies have found that the laser energy can be delivered to the melanin within the hair follicle, while minimizing enery deposition into the melanin contained in the epidermal tissue. Also, by using cooling devices, the surface tissue can be selectively cooled, reducing potential surface skin damage as the heat absorbed by the melanin at the base of the epidermis is quickly and selectively removed.

As put by Dr. Melanie Grossman and the Wellman team in a soon to be published clinical report on the effects of long-pulse ruby energy on hair removal, "In theory, the optimal pulse duration for selective photothermolysis is less than or about equal to the thermal relaxation time of the target structure." According to the theory, the thermal relaxation time, in seconds, is about equal to the square of the target dimension, in millimeters. For a hair follicle about 200-300 microns in diameter, the thermal relaxation time would be in the range of 40-100 ms, and the ideal pulse duration should fall within that range. Further, since the epidermis thickness is about 100 microns, its critical pulse width would be in the range of 3-10 ms. With a pulsewidth setting of about 30-50 ms, the epidermis should not be harmed while heat is concentrated in the target melanin in the hair follicle and shaft as desired. (It should be noted that the researchers performed the clinical work reported in this Wellman Laboratory study at 270 us, well below the estimated thermal relaxation time/pulse widths that are considered as ideal.)

The idea is to choose a long pulsewidth (3-10 ms) to minimize laser energy absorption in the thin layer of melanin within the epidermis, and thus spare damage to this layer of skin. But, according to the Wellman Lab researchers, this approach is safe and effective at 3 ms, although it would be even better if a longer pulsewidth could be used, especially with darker skinned individuals. The problem is the technical difficulty of achieving pulse widths longer than about 3 ms with normal-running ruby lasers. This is technically difficult and expensive to do.

Both Palomar and Laser Industries/Sharplan (and Mehl/Biophile) use long-pulse ruby lasers, with Mehl/Biophile using 0.5 ms pulsewidths; Sharplan 0.8 ms; while Palomar's laser is set to operate at 3 ms pulses.

Another critical laser parameter is the ability to deliver the laser energy deep into the dermis to destroy the hair bulb, which typically lies 3-4 mm below the skin surface. (The depth of the hair bulb can be anywhere from 1 mm to 7 mm below the skin surface, depending on the body area.) Because of optical scattering and reflectance caused by the tissue, only a fraction of the laser energy applied to the skin surface is delivered to the target. In the case of the MGH/Wellman/Palomar approach, an actively cooled glass sapphire prism/lens is used to deliver a convergent beam (20 mm focal length) to the skin surface. Also, by pressing the lens against the skin surface, conduction of heat from the epidermis is accomplished both before, during, and after each laser pulse. The forceful compression of the skin both eliminates blood from the area and reduces the distance between the surface and the target.

Laser Industries/Sharplan also uses a cooling device and a transparent gel to optimize the laser beam coupling into the skin and minimize reflectance and scattering. The cooling device ensures deep cooling of the dermis and epidermis to avoid skin temperature elevation and acts to contract blood vessels in the vicinity.

Another variable is laser spot size. Both Laser Industries/Sharplan and Mehl/Biophile use about a 5 mm laser spot, while Palomar, with a higher energy, dedicated laser, uses a 10-12 mm spot. The larger spot means that more hairs can be treated with a single pulse. The larger spot also increases the depth of penetration of laser energy by more closely approximating a planar diffusion geometry. The 2½ times larger spot size enables their laser to treat 5 times more hairs per unit area. Depending on the location of the body being treated, the number of hair follicles per square centimeter vary from about 60-70 hairs (arms, legs and thighs, trunk and pubic area) to 350-800 hairs (scalp, cheeks, beard, moustache/upper lip).

And then finally there is laser fluence. In order to obtain temperatures in the range of 70-100°C deep into the hair shaft and bulb, as well as to the hair bulge, for effective destruction of these bodies, a fluence level of about 30-40 J/cm2 at the skin surface is required to overcome optical scattering and reflectance. There is also a dependency on a minimum spot size of at least 2 mm to get depth penetration of the laser energy. With a small spot of 2-3 mm, a lower powered laser can be used, still achieving the desired fluence, but only one, or two hairs at most, are removed per treatment pulse. Conversely, a larger delivered spot size of 5-12 mm would remove more hairs per single treatment, but requires a higher-powered laser.

Both Palomar and Sharplan shave the area to be treated to allow the laser energy to reach down into the hair follicles. This is followed by application of the clear gel and the cooling device, in Sharplan's case, prior to use of the laser. Single pulses of laser energy are applied to each area of skin to be treated. For the Palomar method, the cooling of the epidermis is accomplished via the laser handpiece which contains an active cooling system attached to the sapphire lens applied directly to the skin. In both cases, post-treatment includes use of a moisturizer lotion and/or an anti-bacterial/anti-inflammatory cream if needed.

Non-Laser Based Approaches

In addition to the various laser-based approaches noted above, there are at least two companies using non-laser based light energy approaches to hair removal.

ESC Medical Systems has adapted its intense, pulsed, flashlamp light energy delivery system, used primarily for the treatment of vascular lesions, for the selective heating of hair follicles, similar to the approach taken with lasers mentioned above. Since a broad beam of filtered light can be delivered by the ESC system, supposedly a large area of skin can be epilated with a single pulse. It remains to be seen if the safety and efficacy of this broad beam energy system can be proven for effective hair removal without damaging the epidermal tissue. (Company officials have assured me, however, that their technique is safe and efficacious.) It is believed that a cooling gel is applied to the skin's surface to reduce possible damage. The major advantages of this non-laser approach appear to be the larger spot size that enables removal of large amounts of hair with a single treatment and the ability to adjust the wavelength and pulse width in accordance with skin and hair color.

DUSA Pharmaceuticals has adapted its photodynamic therapy approach, used for treating skin abnormalities and cancers, to the selective removal of unwanted hair. By applying a lotion or cream containing its lead drug, aminolevulinic acid (ALA), to the skin surface, it is believed that the active drug penetrates into the hair follicle where it stimulates the synthesis of protoporphyrin, a photosensitizer, which upon activation with a red light source (laser or non-laser) forms singlet oxygen which destroys the host cells.

In use, the body area to be treated is waxed to remove the hair, followed by application of the lotion containing the ALA drug. A few hours wait is required to allow accumulation of the protoporphyrin in the target hair follicles, after which the treatment area is exposed to a red light source for a few minutes. The advantages of the system are its low cost and the ability to treat large areas of the body in a single treatment. The DUSA approach is independent of hair or skin color. The only drawback of the system in pilot studies to date has been the need to apply the ALA lotion hours ahead of the light treatment.

This technology is still in an early developmental stage and much experimentation with appropriate drug dose and light energy levels remains to be done.

Psoriasis -- An Overview of the Causes, Incidence, and Current Treatment

This tutorial on psoriasis, was part of a client-sponsored report looking at potential applications for a new (then) diode laser. It was completed and presented to the client in March 1994.

Irving J. Arons
Ophthalmic and Medical Laser Consulting Group
Arthur D. Little

Background

Psoriasis is a non-contagious, chronic skin disorder characterized by sharply defined scaly lesions on the skin. The patches are at first discrete but may subsequently become enlarged and produce a silvery white surface scale. The surface scales come off easily and are shed constantly, but those below the surface are quite adherent. When forcibly removed, they may reveal small punctate areas of bleeding known as Auspitz's signs.

The lesions or plaques may cover large areas of skin and merge into each other. Often the lesion appears in the same place on both right and left sides of the body. Lesions range in size and shape from individual to individual.

Although heredity seems to play a role, the basic cause of the disease is unknown. The hyper proliferation of the epidermis may result from a primary or secondary defect in the mechanism that regulates epidermal cell division.

It is thought that some type of biochemical stimulus triggers the abnormal cell growth that characterizes psoriasis. A normal skin cell matures in 28 to 30 days, while a psoriatic cell moves to the top of the skin in 3 to 4 days. The excessive skin cell that are produced "heap up" and form the elevated, red, scaly lesions that characterize the disease. The white silvery scale that covers the red underlying plaque is composed of dead cells that are continually being cast off. The redness of the underlying plaque is caused by the increased blood supply necessary to feed the area of rapidly dividing skin cells.

Skin injury, emotional stress, and some forms of infection are thought to trigger the episodes. For example, psoriasis will sometimes appear at a surgical incision or may follow a drug reaction or streptococcal throat infection.

Since the etiology of the disease is unknown, there is not at this time a known cure for the disorder. However, there are treatments that temporarily clear the plaques and significantly improve the skin appearance in most cases. Psoriasis treatments are aimed at slowing the excessive cell division. Treatment-induced remission can last from a few weeks to a year or more.

Incidence of the Problem

According to published reports, the disorder affects between 0.5% to 2.8% of the world's population (about 2% of the 276 million Americans, or between 5 to 6 million people in the United States), with nearly equal frequency in men and women. In the U.S., the treatment of psoriasis accounts for about 10% of physician visits for consultation or treatment.

Psoriasis is evaluated in terms of the extent of body surface affected and its location on the body. A case of psoriasis is considered mild when less than 10% of the body surface is involved. Ten to 30% coverage is considered a moderate disorder, while more than 30% coverage is considered a severe case.

Psoriasis may involve only a small are of the body and yet have a severe impact on the person's ability to function. Psoriasis of the palm of the hand or sole of the foot can be severe enough to be physically debilitating. For most people, psoriasis remains limited to one or two patches on the skin, most commonly on the scalp, elbows, trunk, and lower extremities.

In 1992, it was estimated that between 4 and 8 million people in the U.S. spent about $600 million for various drugs and related therapies, none very effective. Most of the expenditures were made by the approximately 400,000 people with severe psoriasis, who spend between $1000 to $3000 annually on treatments. About 200,000 new cases of psoriasis are diagnosed annually. About 5% to 7% of patients with psoriasis contract psoriatic arthritis, an inflammatory arthropathy that may damage the joints, especially in the hands and feet.

Current Methods of Treatment

The aim of treatment is to clear the skin of the psoriatic lesions for periods of time. Occasionally, psoriasis will go into a spontaneous remission of its own without treatment and, sometimes, a treatment that works to keep the psoriasis in check will stop working. The psoriasis simply becomes resistant, and a new type of treatment has to be tried.

There is a wide spectrum of treatment options available. Although all of the treatments are known to be effective for some patients, none are effective for all. In other words, response to a treatment will vary from individual to individual. Consequently, it is useful to try a spectrum of therapeutic choices to find the one that is most effective. Frequently, a physician will rotate a patient through a variety of therapies to avoid or minimize long-term side effects from any one therapy.

Treatments for psoriasis can be divided into three categories: topical agents (potions, lotions, and creams that are topically applied to the psoriatic lesions); phototherapy (the use of ultraviolet light, either with or without a light activating agent); and internal medications (pills and injections). Generally speaking, treatments for psoriasis usually involve a 1-2-3 approach. As a first step, the topical agents are tried, and if not effective or appropriate because of the severity of the lesions, the second level of treatment, the use of phototherapy is recommended. The use of drugs is usually reserved for only the most severe or non-responsive cases, primarily because of the additional risk of potential side effects.

a. Topical Agents

The topical agents used in step 1 include topical steroids, for mild to moderate cases; coal tar; anthralin; moisturizers; bath solutions; non-prescription medications; and sunbathing. The steroids are simple to apply and cosmetically elegant in that they do not stain skin or clothing and have no offensive odor. Coal tar is an old remedy but is usually unpleasant to use since it can have an unpleasant odor and can stain clothing. Coal tar is sometimes used in conjunction with ultraviolet B phototherapy, and is sometimes used along with sunbathing. The tar makes the skin more sensitive to light and must be used cautiously when combined with sunbathing.

Anthralin is a topical compound that also has been used for many years to treat psoriasis. It can be irritating to normal skin, and somewhat like coal tar, can cause skin to stain. Moisturizers can give some sufferers relief, although they are generally not as effective as other therapeutics. However, they can produce an acceptable cosmetic result and help with itching. Keeping the skin moist every day helps to reduce inflammation and maintain skin flexibility.

Bathing or soaking in water can be beneficial in keeping psoriatic skin comfortable, if not improved in appearance. Adding oil to the bath water can help, especially if followed by the application of a moisturizer. Non-prescription medications that can be purchased in the drug store generally help by moisturizing and soothing the lesions. Natural ingredients such as jojoba, oils and vitamins are frequently used. Plus there are medications that contain small amounts of coal tar and/or ingredients that may eliminate the scaling of psoriasis.

Finally, it is well documented that the UV light exposure during sunbathing can clear psoriasis lesions. Ultraviolet light B (commonly referred to as UVB) is found in natural sunlight, and exposure on a regular basis can help to eliminate lesions or at least decrease their activity. The only drawback to sunbathing is the possible development of skin cancer, apparently more prevalent today, possibly because of a reduction in the ozone layer in the air that absorbs most of the UVA light that can cause cancer.

b. Phototherapy with UV Light

Step 2 therapy involves phototherapy, or the use of ultraviolet light on a controlled basis. By exposing the psoriatic skin to UVB light, both stubborn and unmanageable lesions either widespread over the body or on a localized basis can be effectively treated. The light is administered by placing the patient into a light box or exposing the psoriatic skin to a light source or panel. The optimal exposure time to ultraviolet light differs for different parts of the body. Typically, the elbows and shins require much more light than the trunk or back.

There is another source of phototherapy called PUVA that involves the use of an internal medication called psoralen and UVA light, thus the acronym PUVA. The most common administration of psoralen is via an ingestible pill or oral medication, followed a short time later by exposure to UVA light. PUVA can also be done by a topical treatment rather than systemically, by "painting" a psoralen preparation (either in an ointment or lotion form) onto the affected body area. It can also be applied by soaking the affected body parts such as the hands or feet in a solution containing psoralen. The UVA light is applied via a light box, with appropriate protection given for the eyes. PUVA treatment is more labor intensive and poses a higher risk of burning the skin, and therefore, requires close medical supervision and meticulous modulation of the light dose. Moreover, PUVA treatment has been shown to cause a sixteen fold increase in the risk of squamous cell carcinoma.

As noted earlier, when psoriasis is resistant to one of the standard therapy methods, a combination of therapies may be used. For example, a low dose of an internal medication may be used with either PUVA or UVB treatment. Using several different therapies may also decrease the likelihood that a patient becomes resistant to a particular therapy.

c. Internal Medications/Drugs

In the case of persistent or severe psoriasis, the physician may resort to step 3 therapy or the use of internal medications. These include methotrexate, etretinate (retinoids), hydroxyurea, sulfasalazine and cyclosporin A. These medications are among an array of prescription drugs that are used to treat psoriasis. All may have systemic side effects and their use must be monitored carefully.

Experimental Techniques Under Development

a. Biotechnology/Drug Approaches

There are extensive R&D efforts underway by many companies in exploring a variety of approaches to develop new agents for the treatment of autoimmune and inflammatory disorders such as psoriasis and rheumatoid arthritis. To date none has produced effective therapies. Most novel drugs are in the preclinical or very early clinical stages with few results reported. According to a recent article in a trade journal, more than 75 companies are investigating more than 100 drug approaches for these ailments. Some of the major efforts include the following:

Non-steroidals

Prodrug G-201 from Genta (San Diego, CA) is a topical treatment for skin inflammation, which combines salicylic acid with a mucolytic deblocking agent. In animal studies the prodrug was more effective than the combined effect of its constituents. In a preliminary human study, G-201 greatly reduced UV light induced inflammation. The company has recently completed a Phase I clinical trial of the prodrug.

Immunosuppressive Agents

Human studies of oral Cyclosporin A to treat psoriasis have been underway for nearly 9 years. Thousands of patients with severe psoriasis have been treated worldwide with a 98% success rate. Efficacy has been established, as has the relative safety for up to two years of therapy, but long-term safety is of concern because experience is still limited.

FK-506 from Fujisawa, a macrolide antibiotic that inhibits the lymphocyte production of IL-2, IL-3, IL-8 and interferon gama, supposedly has an immunosuppressive activity of 100 times greater than cyclosporin A. However, serious toxicities, including neurotoxicity, hypertension, and hypomangesmia are of concern. Fujisawa is developing FK-507 that supposedly retains the effectiveness of FK-506 without its deleterious side effects.

Cytokines -- Inhibitors and Release Modifiers

TGF alpha and interleukins are cytokines that also act as inhibitors and release modifiers. Genta, in collaboration with researchers at University of Michigan, are in preclinical study of TGF alpha that may inhibit cell proliferation in a psoriasis cell culture. Several companies are experimenting with various interleukins as cell receptor modifiers. Synergen (Boulder, CO) entered into Phase I/II clinical trials in late 1992 with an IL-1 receptor antagonist for treatment of psoriasis.

Non-Systemic Antiproliferative Agents

Antiproliferative agents act by controlling over proliferation of keratinocytes and immune cells associated with psoriasis. Systemic methotrexate is used for the treatment of severe psoriasis, but no topical formulation of methotrexate is approved for use in the United States. Genta, Matrix Pharmaceutical (Menlo Park, CA), and Advanced Polymer Systems (Redwood City, CA) are developing drug delivery systems that will enhance the penetration of systemic drugs like methotrexate through the skin.

Cellular Adhesion Inhibitors

Cellular adhesion molecules are targets for treating immune-mediated diseases. During periods of hyperimmune activity, particular members of this protein family are expressed on surfaces of endothelial cells where they act as anchors for various types of immune cells circulating in the blood, including white blood cells. Once anchored to endothelial cells, white blood cells can migrate between them, leaving blood vessels and traveling into tissues and organs to propagate the inflammatory response, causing acute and chronic tissue damage and disease. Several companies are targeting drugs that will inhibit various cell adhesion molecules from attaching to the endothelial cells.

Retinoids

During the past two decades, retinoids have revolutionized dermatologic practice, especially in the treatment of acne. Some psoriasis conditions also react favorably to treatment with retinoids, such as etretinate and acitretin, the latter a second generation monoaromatic retinoid.

Monoclonal Antibodies

In collaboration with SmithKline Beecham, Idec Pharmaceuticals (La Jolla, CA) is developing a so-called primatized anti-CD4 antibody for the treatment of rheumatoid arthritis and other autoimmune diseases, including psoriasis. These engineered antibodies are similar to human antibodies, and it is hoped that they will be useful for long-term therapy of chronic diseases. FDA has approved an IND for testing this new MAb.

b. Phototherapy/Laser Approaches

There appears to be at least two valid laser-based approaches for attacking the blood supply feeding the hyper proliferating cells associated with psoriatic plaques: the use of photodynamic therapy (PDT) and selective photothermolysis of the blood vessels.

In the PDT approach, the theory is that either an exogenous or endogenous photoactivatable compound is either intravenously injected or topically applied to the diseased skin. The compound becomes concentrated in either or both the hyperproliferating cells and/or the blood vessels, and is then activated by laser light to selectively destroy the diseased tissue or blood vessels from within.

In the direct laser approach, an appropriate wavelength and pulse duration is selected so that the light energy is selectively absorbed within the hemoglobin of the blood, raising the temperature and destroying the capillaries feeding the hyperproliferating cells.

1) PDT

According to our research, there are at least four companies developing photoactivatable compounds that are currently under evaluation as a potential treatment for psoriasis. As shown in Table 1, the five photosensitizers differ in chemical makeup, how they are applied, and in the wavelength needed for activation. Those compounds that are activated at the lower wavelengths may not be as effective as those activated at the higher wavelengths as the longer wavelengths usually can penetrate deeper into the skin, and the blood vessels feeding the hyperproliferating cells are typically deeper into the dermal layers because of the "heaped up" effect of the proliferating cells. To our knowledge, only the Quadra Logic Technology' (QLT) benzoporphyrin derivative (BPD) and hematoporphyrin derivative (Photofrin), and the DUSA's 5-aminolevulinic acid (ALA) are currently in human clinical trials, with the PDT Systems' tin ethyl etiopurpurin (SnET2) in pre-clinical trials. The status of the Nippon Petrochemical's mono aspertyl chlorin e6 (NPe6) for treating psoriasis is unknown, although, it is reportedly in Phase I clinical trials for treating skin cancer and Kaposi's carcinoma.

A Phase I/II clinical trial of the QLT BPD compound for treating psoriasis has been underway at the Wellman Laboratory of Photomedicine in Boston since January 1993. According to QLT, "Preliminary research suggests that BPD may be effective in treating a variety of diseases that are characterized by rapidly dividing cells which are fed by an abnormal blood supply, such as...psoriasis...Based on our research experience with cancer, we believe that there is a common thread in the way BPD accumulates in diseased tissue." In a midyear review article, the Wellman group reported that six patients had been treated, "With the study answering some questions and raising others". Four patients treated at the lowest dosage of medication had some response and no toxicity observed. The therapy seems to "selectively damage the blood supply," and also have "some direct effects on cells". Since the proliferation of the disease is dependent on rapid development of new cells, curbing the blood flow -- a necessary component of cell replication -- could slow the disease's progression.

QLT's Photofrin is currently being evaluated for the treatment of portwine stains (PWS) and psoriasis at the Beckman Laser Institute and Medical Clinic in Irvine, CA. Encouraging preliminary clinical results on the treatment of PWS were reported by Dr. Stuart Nelson at the Biomedical Optics conference at OE/LASE in January 1993. At that time, it was noted that at least 25 patients were also being treated with Photofrin for psoriasis, but no results of that study had yet been reported on or published. It should be noted, however, that people treated with Photofrin retain prolonged photosensitivity to sunlight, a major drawback of this photosensitizer.

According to DUSA's first quarter 1993 report to shareholders, the company (now known as DUSA Pharmaceuticals) received FDA permission in February 1993 to enter into Phase I/II human clinical trials for the topical application of ALA to treat actinic keratoses and psoriasis on more than 100 patients at the University of California, Irvine, under the direction of Dr. Gerald Weinstein. (In addition, two other physician sponsored IDE studies using ALA to treat basal cell carcinomas have been under way for one to two years.) In October 1993, another article discussed the clinical trials being conducted with ALA. According to one of the team physicians at UCal/Irvine, the investigations of the drug's potential have been satisfactory. One of the reasons that ALA therapy is potentially useful for treating psoriasis is that it resembles current therapy, the use of psoralen and ultraviolet light (PUVA). The change to a different drug and a different light source for psoriasis therapy appears to be trivial. The effect of light exposure, however, is hoped to be considerably different, since PUVA has been shown to cause skin cancer, while PDT therapy is a treatment for cancer. The doctor reports that, "It is too early to make conclusions about the usefulness of the drug yet, but they hope to have data for presentation to the FDA by the end of 1993".

A news release from the company in December 1993, stated that results from the UCal/Irvine study were presented by Dr. Weinstein at the annual meeting of the Photomedicine Society in Washington, D.C. According to Dr. Weinstein, "Nine lesions per patient of fourteen psoriasis patients were treated with 10% to 20% ALA on selectively sensitized psoriatic plaques, with nearly 50% of treated sites having greater than a 50% improvement after only 4 weekly treatments".

As has been noted, ALA is applied topically to the skin, and because of its small molecular structure, easily penetrates the epidermis and causes an accumulation of a natural photosensitizer, protoporphyrin IX (PPIX) in some tissues. As in the case of Photofrin (porfimer sodium), light activation of PPIX causes the release of singlet oxygen that is toxic to cells in which it is contained. ALA is currently the only topical agent available for PDT treatment. While other photosensitizers may exist in cream or lotion form, none has yet been used successfully in topical applications. (Other photosensitizers, formulated for topical use, should begin clinical trials later this year.)

2) Direct Laser Intervention

Over the past ten years, several physical methods including the use of local hyperthermia, cryotherapy, dermabrasion, surgical removal, and the use of both argon and CO2 lasers have been used to treat psoriatic plaques, mostly unsuccessfully or without lasting effects. More recently, several researchers have attempted to use pulsed dye lasers hoping to achieve selective photothermolysis of the blood supply in the vasculature supporting the hyperproliferating skin cells. The experimental work reported by Hacker and Rasmussen was only partially successful. Although 57% of the 19 patients treated had a positive short term outcome, none achieved complete clearing of the psoriasis under the clinical parameters attempted. However, the pioneering, but unreported work of Dr. Adrianna Scheibner, an Australian physician, using both continuous wave and pulsed dye lasers to treat psoriasis was more encouraging. Beginning in 1983, Dr. Scheibner has treated some thirty psoriasis patients using the dye laser at 577 nm. In 28 of the 30 patients, she noted virtually complete clearing of plaques in areas subjected to the laser with essentially no reoccurrence in the treated areas over an average of 3 to 4 years followup. Untreated areas on the same patients continued to show signs of psoriatic plaque.

Although the latter results are considered encouraging, the work was not conducted as a rigorous study and never published (or peer reviewed), and the fluence level used was well above levels considered safe for scarring of normal skin. Thus, the results have shown that a safe, controlled study attacking the blood supply of psoriatic plaques with fluence levels below the damage level could lead to a successful modality for treating psoriasis. This is the approach taken by Star Medical.

3) The Star Medical Technologies Pulsed Diode Laser Approach

Using the model of selective photothermolysis, established using the pulsed dye laser to destroy abnormal blood vessels in the treatment of portwine stains, the company will use its pulsed diode laser system to interrupt the blood flow to psoriatic tissue by destroying the blood vessels feeding the hyperproliferating cells. Star Medical has chosen the 800 nm wavelength to achieve deeper penetration -- from 0.8 mm to 1.4 mm -- as compared to the 0.4 mm average penetration achievable with the 577 nm wavelength of the pulsed dye laser. The deeper penetration will allow access to the highly exaggerated papillary loop which can extend to depths of about 0.8 mm. The company believes that the destruction of the deep vessels is a key to a successful laser therapy for psoriasis. Further, the company has chosen a 5 ms pulse width which should enable the laser energy to destroy larger vessels (>50 microns). With the longer pulse, smaller vessels fed by the larger vessels are not directly destroyed by the laser energy as they can cool to surrounding tissue temperature, but they will be destroyed because the larger feeding vessels are destroyed. This is likely to lead to less damage to surrounding tissue structures concomitant with the heating of the vessels themselves. Previous research on the importance of pulse duration supports this view, concluding that longer pulses were preferable.

The diode laser at 800 nm was chosen for both the deeper penetration ability noted above and for the selectivity of absorbance in blood as compared to tissue. Experiments at the Wellman Labs have shown the blood absorption at 800 nm is 30 times higher than surrounding tissue. Thus, the 800 nm light is highly absorbed in the blood and can be used efficiently in selective destruction of blood vessels within the skin.

In the clinical trials, a fluence of 15 to 20 J/cm2 will be evaluated, which should be sufficient to heat the blood vessels in the skin to a depth of nearly 1 mm. A specially designed handpiece (described in Section IV) will be used to deliver single and multiple pulses of 6x6 mm spots of laser energy to the skin surface.

Oculinum (Botox) Applications: New Products Occupy Allergan’s Plans for Future

This column was originally published in Ocular Surgery News, April 14, 1992.

Technology Update

Irving J. Arons
Ophthalmic Consulting Group
Arthur D. Little

Allergan, which was hit by a spate of negative news this past fall, also has some good news to celebrate in terms of promising products in development.

The company was beset by problems surrounding its contact lens business because of a continuing flat market. The company also met increasing competition to its PhacoFlex IOL line. Through restructuring and consolidation, and the new focus on pharmaceuticals for both ophthalmic and non-ophthalmic applications, Allergan hopes to turn itself around and look to brighter days ahead.

Announced a year ago and confirmed in recent private correspondance, Allergan has realigned itself to focus on its growing therapeutic and skin care businesses. In skin care, the company has completed Phase II studies of a patented retinoid with demonstrated efficacy for treating psoriasis as a topical formulation. The company also has secured a license from Syntex to develop and market a new topical steroid for treating inflammations of both the skin and eyes.

Product Pipeline

New ophthalmic products in the pipeline include a surgically implanted shunt to relieve intraocular pressure in treating glaucoma; new foldable silicone lens designs, including a bifocal lens; and a teledioptric system for patients with age-related macular degeneration. The latter system employs an implant that functions with specially engineered eyeglasses to provide a telescope-like effect for the visually impaired.

Several new contact lens and lens care products are in the works, including a one-bottle chemical disinfectent, an improved hydrogen peroxide solution (recently approved for marketing), and an opaque tinted contact lens.

Also for chronic treatment of glaucoma, in addition to the shunt mentioned above, Phase III results have shown promising activity for an alpha-2 agonist and preclinical development continues on prostaglandin prodrug compounds. Extended Phase III studies were recently completed on a combined Betagan (levobunolol HCL) and Propine (dipivefrin HCL) product for topically relieving intraocular pressure.

Dystonia Treatment

But perhaps the most exciting new area of development is the treatment of dystonias, or muscle disorders, with Oculinum/BOTOX (botulinum toxin Type A). Allergan acquired the rights to distribute Oculinum in December 1989 from Oculinum, Inc. (Berkeley, CA), and announced the acqusition of substantially all of the assets of the company this past July. Thus Allergan now has the rights to manufacture, market, and conduct future research into its uses.

The product was originally discovered in 1970 by ophthalmologist Alan B. Scott of Smith Kettlewell Research Institute in San Francisco, who assigned manufacturing rights to Oculinum, Inc. Allergan now assumes that responsibility.

Given orphan drug status by the FDA (providing market exclusivity for seven years following FDA marketing approval for each indication), the drug was fast tracked through clinical trials and won marketing approval in December 1989 to treat eye muscle disorders including blepharospasm and adult strabismus. The latter, although technically not a dystonia, is treated by injecting the toxin into the muscle.

The approval enabled Allergan to begin marketing the drug to treat these two disorders by injection of the purified, sterile botulinum toxin. Upon approval, the FDA has estimated that about 15,000 of the approximately 100,000 annual diagnosed cases of strabismus might be helped by the drug, and about 3000 to 5000 blepharospasm patients might be aided. However, since the drug is not yet approved for use with children, which account for the greatest number of diagnosed strabismus cases, this estimate might be high.

According to Allergan, the drug's benefits last for about three to three and a half months, and the injection can be repeated. About half of the strabismus patients treated require repeated treatments, while other muscle disorders may require chronic treatments.

Toxic Mechanism

Side effects of blepharospasm treatment include droopy eyelids and irritated eyes. The toxin is believed to work by "turning off" the muscle through paralysis. Scientists theorize that the paralysis affects muscle pairs by causing the injected muscle to lengthen, thus causing the opposing muscle to shorten. In a recent study of 677 strabismus patients, 55% showed improvements for as long as six months after treatment. In some cases, correction may become permenant provided the injected muscle is paralyzed long enough and the opposing muscle is intact.

Other dystonias for Oculinum/BOTOX under investigation by Allergan include torticollis, a debilitating condition of the neck muscles that forces the head to one side, and a non-dystonia-type problem, juvenile cerebral palsy. Additional probe studies for essential tremor and spasticity are planned.

In an excellent review article entitled, "Therapeutic Uses of Botulinum Toxin", written by Drs. Joseph Jankovic and Mitchell Brin, the doctors describe the various focal and generalized dystonias potentially treatable by Oculinum and other therapeutic agents. Dystonias are defined as involuntary sustained or spasmodic, patterned, repetitive muscle contractions, frequently causing twisting (torticollis), flexing or extending (writers cramp) and squeezing (blepharospasm) movements or abnormal postures. Several of the dystonias potentially treatable by Oculinum include blepharospasm, cervical dystonia (spasmodic torticollis), oromandibular dystonia (spasms of the jaws, mouth and tongue), spasmodic dysphonia (laryngeal dystonia), and others. In addition, high amplitude and task specific tremors that respond poorly to other pharmacological therapies, may be alleviatied by injection with Oculinum/BOTOX. In a pilot study of 51 patients with disabling tremors of the head and neck and hand, a marked to moderate reduction of the tremors was note in 67% of the patients.

Expansion Endorsement

A Consensus Development Conference Panel of NIH and the American Academy of Neurology issued a report endorsing expanded indications for Oculinum therapy. The report cites Oulinum as a promising new treatment for neck muscle spasms, mouth and jaw dystonia, facial and segmental limb dystonia, stuttering and vocal and other tremors.

It appears that Allergan has a "breakthrough therapy" on its hands, and at an annual therapy cost of better than $2000 per patient for some treatments (cervical dystonia for example), the company -- which markets the product directly to the treating physician without a detailing/selling force for the most part – stands to do quite well. Analysts estimate that total Oculinum worldwide sales could reach $175 million by 1995.

Addendum to White Paper on Corneal Sculpting

In the November 2005 issue of Cataract & Refractive Surgery Today, I wrote a letter about a previously published article on the 193nm wavelength lasers, in which I told how I became involved in ophthalmic lasers and refractive surgery. The letter references both the White Paper and also another report that I wrote some years earlier that is probably the first marketing report on refractive surgery. Here’s a part of that letter (and links to the two reports):

...I began writing (and consulting) about ophthalmic lasers in 1983, following the first approvals of the YAG laser for capsulotomies. I became intrigued with the laser’s capabilities in medicine and decided to become an “expert” in the field. Part of my learning experience was attending a Gordon Research Conference on Biomedicine in the summer of either 1984 or 1985; I can’t remember the year. At that conference, I met several of the pioneers working on the excimer laser, including Carmen Puliafito, Fran L’Esperance, Steve Trokel, Charles Munnerlyn, David Muller, and I am sure others. It was there that Munnerlyn first showed his infamous chart showing the ablation depth versus dioptric correction for various optical zone sizes.

After meeting the experts at the Gordon Conference, in December 1985, I was hired by Fran L’Esperance and Anthony Pilaro (Fran L’Esperance’s financial backer and the founder of the Duty-Free shops found at every international airport) to prepare a marketing report forecasting the potential of what I then called laser refractive keratoplasty. That report was finished in March 1986 and was used to raise the initial monies from Alcon Laboratories, Inc., to fund Taunton Technologies (which later became Visx Incorporated). The report is also the basis for the per-procedure fee that became the moneymaker for the companies involved. It was Tony Pilaro’s idea, and he asked me to incorporate it into my report.

In September 1989, I published a white paper titled, “The Evolution and Prospects for Laser Refractive Keratoplasty.” In it, I believe I coined the term corneal sculpting. I updated the report for publication in the March 1992 issue of Laser Focus World.

Injectable IOLs are Possible but not Probable

This article was published in Ocular Surgery News on September 1, 1991.

Irving J. Arons
Ophthalmic Consulting Group
Arthur D. Little

The injectable lens, which has been called the “lens of the future,” remains only a possibility. A factor that could delay or block its introduction to the marketplace is the war underway between industry and government agencies for gaining control of the spiraling health care costs. That war could have a dampening effect on the development of new technologies.

The concept of injecting a soft polymer into an evacuated lens capsule was first conceived by Kessler, MD, in 1964. But it was the work of David Schanzlin, MD, and his co-workers at the Doheny Eye Clinic that futhered the research efforts started by Kessler. Initial work was sponsored by the Beckman Institute and later by Allergan Medical Optics, when Schanzlin, Jim Davenport, Duane Mason, and George Wright formed Innovative Surgical Products.

The early idea was to use phacoemulsification techniques to remove most of the lens nucleus, leaving the lens capsule intact. An enzyme solution would then be injected to remove any remaining lens epithelial cells, and then a polymerizable silicone polymer was to be inserted through a 22-gauge syringe needle. The polymer would gel, sealing off the opening to form a soft lens that would completely fill the lens capsule and hopefully be capable of achieving accommodation using the ciliary muscles attached through the zonules to the capsule.

Elusive Dream

According to our notes from a private meeting attended in 1985 and reports of the program in early 1987, the "dream" was close to fruition. However, several problems were encountered that led to the eventual shutdown of this major research project. It later reverted to a smaller effort within the overall research efforts being carried out at AMO.

Some of the major obstacles yet to be overcome, included requirements of a biomaterial for use as an injectable IOL as listed below.

The material must:

● be optically transparent and of appropriate refractive index, and remain clear throughout its useful life;
● be a liquid or semi-solid and be injectable through a small gauge needle;
● quickly set up or polymerize without leaking from the injection hole, and with minimal shrinkage, heating or gas release;
● completely fill the lens capsule without voids (i.e., a known volume of material has to be delivered/the volume of the filled capsule must be known or calculable);
● be soft/pliable, but firm (similar to the natural lens), biocompatible, adhere to the capsule walls, and contain an appropriate UV inhibitor to protect the back of the eye from incident UV radiation;
● be cytotoxic, or contain cytotoxins to inhibit growth of lens epithelial cells to prevent opacification of the capsule walls.

Research efforts

Low-level research efforts are under way by at least two companies, AMO and Domilens (with research into the use of collagen materials as the injectable polymer at the latter company), and at several eye research institutes: Bascom Palmer and Bethesda Eye Institutes, Doheny Eye Institute at the University of Southern California School of Medicine, and the Center for IOL Research at the University of Utah.

In addition to the work in progress on developing injectable polymers and insertion techniques, work is also under way in the use of inflatable balloons to contain and form the injectable lens. This latter work is being done by Drs. Okihiro Nishi of Osaka, Japan; Irvin Kalb of Westport, Connecticut; and Jim Deacon of the Department of Bioengineering and Ophthalmology at the University of Utah.

At one time, Vision Technologies International claimed to have been undertaking a research effort aimed at developing an injectable IOL, but recent correspondence with that firm has confirmed that its efforts have ceased.

One of the major problems encountered in the various research efforts has been the residual lens epithelial cells causing opacification of the lens capsule. Research under way at Houston Biotechnology, originated at Baylor College of Medicine, is aimed at preventing this occurrence. The firm has developed a monoclonal antibody, now in clinical test, that can be injected into the capsular space at the time of the cataract removal to inhibit or prevent the opacification action by binding to the epithelial cells.

"No incision" laser surgery

One of the major problems encountered with the development of the injectable lens was the need for complete removal of all lens fragments and cellular matter before a liquid lens could be injected. The usual methods employed involved various solutions that could be injected to soften and emulsify the lens protein, including enzymes. However, according to the researchers at Innovative Surgical Products, the pioneers in this technique, these techniques were difficult to perform in the animal models employed.

One of the hopes for the future of injectable lenses is the possibility of using laser energy to emulsify the lens cortex for complete and easy removal. Several research groups have made attempts at combining laser probes with irrigation/aspiration removal equipment. Several years ago, a small start-up firm in Southern Florida, Photon Sources, developed a prototype laser-I/A device, but after its first announcement, was never heard from again.

More recently, two ophthalmologists independently developed laser phaco-type devices. Drs. Patricia Bath, MD, and James Dodick, MD, have both lectured on and demonstrated their respective devices, one a direct laser ablator and the other utilizing a titanium shield at the end of a laser probe to generate shock waves to fracture the lens material. However, the most likely laser devices to accomplish this task are based on newer non-invasive photocoagulation techniques.

Two recent laser development stage companies, Phoenix Laser Systems and Intelligent Surgical Laser, both located in California, have independently developed accurately focused photocoagulation laser systems that can be scanned into and across the lens cortex, causing it to emulsify within the capsule without damaging surrounding capsular tissue. Neither laser system requires the use of probes entering the lens capsule as both rely on the accurate focus of the laser beam from outside the eye to accomplish the emulsification of the lens material.

If early experiments with this technique are successful in animal models (and the first trial results reported by ISL were encouraging), it could possibly lead to the long-awaited method for cleanly breaking up the bulk of the lens material for easy removal by an irrigation/aspiration device. This would be followed by a syringe injection of an enzyme to remove the remaining cortical debris, leaving a clean capsule for injection of a liquid polymer to recreate a potentially viable "soft" lens that might retain accommodation from the intact capsular zonules attached to the ciliary muscles.

Since both the laser work and development of a truly injectable lens material are still several years from reality, we do not anticipate an injectable lens will be ready for use in clinical practice for the forseeable future.

I Can See Clearly Now: The High-Tech Look of the Future!

This column was published in Ophthalmology Management in February 1991.

TECHNOLOGY UPDATE

Irving J. Arons
Ophthalmic Consulting Group
Arthur D. Little

Five or six years ago, Rob Webb of the Eye Research Institute in Boston (now the Retina Institute), invited me in to see a demonstration of a new device that he and others at the ERI had invented. It was the scanning laser ophthalmoscope. I can clearly recall the room full of instrumentation -- the large optical bench spilling over with beam splitters, mirrors, lenses and lasers -- and the TV monitor across the room from the slit lamp stand. Rob, his eyes dilated for the demonstration, sat down at the slit lamp and eased his chin into the support and we all watched in awe as first his cornea, and than other eye structures were clearly visible on the TV monitor as his eye approached the slit lamp objective. Finally, his retina was in full view, magnified on the screen, and by manipulation of a joy stick, could be panned.

This was my first exposure to the SLO, now a commercial diagnostic tool marketed by Rodenstock under license from ERI, and to diagnostic retinoscopy and confocal microscopy. (How they managed to get that work bench full of instrumentation into the small box is another story for another day.) Then, two years ago, at the Bausch & Lomb National Research Symposium, held in Boston that year, Dwight Cavanagh of Georgetown University Medical Center wowed his audience with a video taped demonstration of the passage into his cornea using a confocal microscope that he and his research team had built. The tape showed, in real time, a cellular level trip through his epithelium, through Bowman's membrane, into the stroma -- showing nerve tissue and keratocytes -- and finally, the fine structure of his endothelial cells. It was a remarkable demonstration, one I understand he has repeated at several other conferences with the same type of audience response.

These demonstrations opened my eyes to the possibilities of both retinal scanning and confocal microscopy. Since then, I have attempted to gain a better understanding of both these fascinating diagnostic techniques, and others like them, as I see these tools as the future for performing both corneal and retinal diagnoses in collaboration with both surgical and therapeutic treatment of these important eye structures.

In very basic terms, the SLO works like a TV, sweeping a small spot of low intensity laser light across the retina (or other target tissue) in a raster pattern. Light reflected back through the pupil is collected by a photomultiplier and converted into an electronic signal which feeds a video monitor. By combining the output of two incident laser beams, a high degree of contrast is achieved. The scientists at ERI have also developed a confocal version of the SLO. By combining the focus of the flying illumination spot with the focus of the detector array, i.e., conjugate foci or confocal focus, the imaging contrast is increased independent of the illuminating wavelength. This is accomplished in the confocal scanning laser ophthalmoscope by reusing the source optics for detection. The major advantage of this instrument is the crisp and complete retinal images formed using a low power HeNe laser source, without the need for dilating the pupil.

The confocal microscope, demonstrated by Dr. Cavanagh, is also a light scanning system, but employs an incoherent white light source focused through a scanning/rotating disc (Nipkow disc) made up of multiple pinholes arranged in an Archimedian spiral. Each spot of light is focused on a plane to rebuild the field visualized in the confocal image. By focusing the reflected light through the same pinhole but 180° out of phase (the Petran and Hadravsky or dual/tandem light path model), or through the same pinhole (the Kino single light path scheme), internal reflections are minimized and the resulting signal to noise ratio maximized. Thus, only the spot in the focal plane of both the illuminating source and the detector (through the pinhole) is in focus, and all other images are defocussed.

Over the past two years, several new instruments for performing diagnosis of various eye structures have been introduced. These include the scanning laser ophthalmoscopes from several firms; Carl Zeiss, Rodenstock, the now defunct Heidelberg Instruments, and developmental models from Allergan/Humphrey and this year from Kowa-Optimed. In addition, at this years AAO meeting (1990), Innovision demonstrated its retinal scanner/tracking device to be marketed this summer, and Nidek unveiled its 3-D camera which takes a 3-dimensional image of the retina captured on special film, that after processing, can be viewed without special glasses or a viewer, just by being held up to a white light source.

Yes, the times are changing and new diagnostic instruments are reaching the market that will make a difference in both diagnosing and treating eye disease. I will try and keep you apprised of these new technologies as they are introduced.

The State of Eyecare in the Soviet Union

This column was published in Vision Monday in August 1990.

Irving J. Arons
Arthur D. Little

I have just returned from a two week tour of four cities within the Soviet Union. I had anticipated telling you about the state of eyecare within the USSR, but unfortunately, our visit to the premier Moscow Research Institute of Eye Microsurgery was canceled at the last minute, as we were informed by Dr. Fyodorov that the "Institute will be closed in July for preventative maintenance," and that "your visit at the term (sic) you have stated is inexpedient." We had originally been invited following my February letter requesting to have our delegation visit the clinic. In fact, in late June we were told that we were welcome to visit the clinic, which was scheduled to shut down in August for holiday.

Apparently, the hotel we stayed at in Moscow, the Kosmos, is part of the Intourist program to provide visitors with eye care at Fyodorov's Moscow clinic. We found a brochure advertising "Beautiful Eyes for Everybody," and describing how the Moscow Research Institute of Eye Microsurgery "treats 22,000 people annually, restoring or improving vision and removing the need to wear eyeglasses for many." In addition to RK, the clinic claims to do laser treatment of secondary cataract, laser treatment of glaucoma, and laser treatment of "complicated myopia of high degree." (It must be one of the only facilities with surgical lasers in the USSR, as we visited a laser research institute and three hospitals and saw very few surgical lasers -- mostly therapeutic HeNe and GaAs biostimulation type devices.)

The brochure goes on to state that your pre-operative stay is arranged at the Kosmos, and following the outpatient surgery, your post-operative treatment is done at the hotel by a team of qualified doctors and nurses. Foreign patients are offered a program of excursions, including theater tickets (the ballet only costs 4 rubles -- the equivalent of 30 cents at the black market exchange rate) and other services offered by Intourist. Fyodorov hopes to treat 20,000 foreigners a year by 1992.

A recent profile of Fyodorov in Fortune (May 1989) talked about the Fyodorov entrepreneurship, with his clinic being a $75 million a year business, and growing at 30% a year annually. The clinics have over 5000 employers located at nine treatment centers across the Soviet Union, and include two factories producing eyeglasses and surgical instruments. (In addition, Dr. Fyodorov recently spent some $12 million outfitting an 11,000 ton "floating eye hospital" called the Floks, which travels from port to port in the Persian Gulf offering RK and other eye surgeries.)

Having missed out on the opportunity to visit with Dr. Fyodorov, I would like to offer some personal observations about eye care in the Soviet Union. As previously mentioned, our People-to-People delegation of medical laser specialists visited Moscow (Soviet Russia), Tblisi (Soviet Georgia), Kharkov (Soviet Ukraine), and Leningrad (back in Russia). We saw very few optical shops (none that were open) and only a small number of Soviet citizens wearing eyeglasses! One ophthalmologist at a central hospital in Kharkov told me that 50% of the people need corrective lenses -- similar to the percentages in the rest of the world -- but we saw very few people wearing lenses. If 5% of the people in the streets had glasses, that's a lot. This says that Western technology and entrepreneurship could provide a needed service in the Soviet Union if a way could be found to open (and stock) optical retail shops in the major cities. However, you must remember that the average citizen only earns about 200 rubles per month (the equivalent of about $350/month at the "official" business exchange rate or about $10-15/month at the black market exchange rate of 10-15 rubles to the dollar). Therefore, the price of eyewear would have to be low for the average person to be able to afford it -- unless the health care system can be convinced to reimburse or pay for the glasses. (The government health care system pays Fyodorov's clinic the equivalent of $300 for each RK procedure carried out.)

If a Moscow McDonalds can generate hours long lines for a $5 "Big Mac", why not $20-40 eyeglasses at a Moscow Lenscrafters or a Leningrad Pearle Vision Center?

The State of Healthcare in the Soviet Union: The Lack of Medical Lasers

This article was published in both Medical Laser Industry Report, October 1990 and Laser Report, December 15, 1990.

Irving J. Arons
Arthur D. Little

During late July 1990, I was priviledged to join a delegation of medical laser specialists and other health care professionals, under the auspices of the People to People Ambassador Program, invited to tour the medical community in the Soviet Union. Our group, organized by the American Society for Lasers in Medicine and Surgery, was composed of specialists in gynecology, plastic surgery, thoracic surgery, urology, general medicine, and myself, representing the field of ophthalmology. In addition to the ASLMS group, a veterinarian working with lasers, a health care safety specialist, and two medical technical/clinical lab specialists were included in our delegation.

We were able to visit a medical laser research institute in Moscow, and four hospitals, one each in Moscow (Soviet Russia), Tbilisi (Soviet Georgia), Kharkov (Soviet Ukraine), and Leningrad/St. Petersburg (Soviet Russia, again).

Our overall impression was that the facilities and equipment in use were woefully decrepit and/or non-existent or years behind Western standards. However, the medical personnel we met were dedicated professionals.

Of particular note, we found that the hospitals -- even one claimed to be only three years old -- were ill kept and falling apart. The facades were cracked and broken, the hallways and stairwells unswept, and the grounds surrounding the buildings not cared for at all. In counterpoint, we found the patient rooms were clean and staffed with dedicated nurses and doctors doing their best with what they had. This was particularly evident at the Karzigan Childrens Hospital in Moscow. The wards were filled with children with trauma of all kinds, but they were all smiling and very well cared for by an attentive staff of nurses and aides. It was here that we learned that a typical doctor with less than 10 years service earns between 240-260 rubles a month (the equivalent to about $40 at the official exchange rate of 6 rubles to the dollar, and only $20-30 at the black market exchange rate of 10-15 rubles to the dollar), a beginning research worker earns 140-150 rubles per month, and a surgical nurse get about 110 rubles for regular shifts. (In contrast, the bus drivers providing our transportation were paid 400 rubles/month and we were told that street sweepers earned as much as 700 rubles/month!)

The hospital equipment, especially for diagnosis and surgery, was particularly non-existent, and, according to our laboratory clinicians, the clinical laboratory equipment was barely adequate to care for the patients in the wards. But we must emphasize, both the hospital administration and medical staff were dedicated to providing the best care possible to their patients. What they lacked in equipment they more than made up with in numbers and dedication.

As for medical lasers, and new medical treatments using lasers, except for the laser institute in Moscow, the only lasers that the hospitals seemed to have were low powered therapeutic types, basically HeNes and GaAs infrared lasers. The hospital in Leningrad had several CO2 lasers, and claimed to have other surgical equipment, but we only saw therapeutic lasers in operation. We were told that only about 100 of approximately 15,000 hospital-based physicians in Kharkov have access to or use surgical lasers. We would guess that the percentages are not much different in the other 14 Soviet Republics. At the hospitals we visited, the majority of the half dozen lasers they claimed to have -- if they had any -- were either HeNe or GaAs therapy lasers, used to treat open sores, pain, and in one hospital in Tbilisi (Soviet Institute of Clinical & Therapeutical Research), for treating myocardial infarctions by clearing viruses in the blood through intravenous use of a HeNe laser connected to a fiber inserted through an arm vein. The same hospital also used a scanning HeNe laser to alleviate angina chest pain by scanning the laser beam across the patient's chest.

At a trauma hospital in Leningrad (the Ambulatory Institute Hospital), we saw a 40-50 watt CO2 laser in the corner of an operating room, and another upstairs in a storeroom along with the usual HeNe lasers. We saw no evidence of a YAG laser although the laser specialist at this hospital claimed to have just received one, but which he had not yet unpacked. In the same storeroom with the spare CO2 laser, we were told that a small laser sitting on top of packing crates was a new UV laser, apparently solid-state since there was no evidence of any gas bottles or connections for one. (An interesting side note, we observed a burn therapy ward at this hospital, and it was disconcerting to see flypaper strips hanging from the ceiling.)

At the hospital in Kharkov (The Central Regional Hospital), we were told that they had an Ar laser used in ophthalmic treatments (but we did not see it).

The National Research Institute of Laser Surgery in Moscow claimed to be doing considerable research with medical lasers, performing 47,000 laser procedures annually. It is supposedly, one of 52 laser centers in the Soviet Union. We were given a presentation about the clinical research they were doing with five types of high power lasers, mostly CO2 and YAG -- and two prototype free electron lasers, used for PDT studies. The FELs, according to the slides shown us, may be revolutionary, in that they appeared to be about the size of a large sized desk, much smaller than any other FEL I have seen -- and I have seen the Stanford FEL and pictures of others. Attempts to find out more about this laser development were fruitless, however I plan to get back in touch with my contact at the Institute to see if I can possibly learn more about this exciting laser development. (Several weeks after my return to the States, I received a call telling me that a defector from the Moscow Laser Institute wanted me to know that he had built the laser in question and it was not an FEL, but rather an electron beam generator pumping a chemical laser use in their PDT work.) When we asked to see their lasers, we were politely told that they were in another building and couldn't be shown to us. Apparently, the person holding the key to the lab was not available!

According to a profile of the Soviet healthcare community recently published by Medistat, a UK healthcare publication, what we saw in the Soviet Union this summer is typical and not out of line with what others have reported. The Medistat profile stated that the Soviet Union has some 23,000 hospitals with 3.6 million beds, and in addition, some 38,000 polyclinics and other outpatient centers. Capital investment in recent years has concentrated on the construction of new facilities to boost the number of beds, but many of the new facilities have been built at unsuitable sites, and the majority of Soviet hospitals having little in modern equipment with some lacking the basic necessities of adequate sanitary facilities or even heating.

The polyclinic is the main unit in the primary healthcare network, and the first point of contact for most Soviet patients. They serve districts of 50,000 to 60,000 inhabitants and are staffed by doctors responsible for around 2000 patients. In addition to general doctors, each polyclinic has specialists in area such as cardiovascular disease, oncology and renal medicine.

The Soviet Union has the highest number of doctors per capita, with a total of 1.3 million doctors serving a population of 275 million. In addition, there are 3.3 million medical assistants. Women doctors are well represented, accounting for about 70% of all doctors. (We were told the percentage was closer to 50%, at least at the facilities we visited.)

As you know, until recently, all planning was done centrally, and for five years in advance -- the so called Five Year Plan. The most recent healthcare plan was put together in August 1987. That five-year plan attempted to address the chronic underfunding of the healthcare system, calling for new hospitals while neglecting older ones which will now need to undergo drastic major refurbishment. Expenditures for medical equipment had also been limited in the past, with the majority of funds allocated for new buildings. But the new policy included allocation of more resources for the purchase of modern equipment, in particular the polyclinic facilities were to be upgraded with proper diagnostic and treatment services to enable the patients to be treated at the clinic rather than to be referred to local hospitals. According to Medistat, 5.4 million rubles had been allocated for the purchase of new equipment over the two year period 1988-1989.

Discussing the state of the Soviet medical equipment market, Medistat states that the USSR suffers from a chronic shortage of equipment, particularly in the high tech areas such as computerized scanning, ultra-sound, renal equipment, and as we found out, laser treatment devices. Even basic equipment such as electrocardiographs and routine surgical instruments and disposable syringes are in short supply, with the problem being further aggravated by the fact that much of the Soviet produced equipment is sub-standard.

The current five-year plan envisages accelerating development in the medical industry and raising the technological level both within its industry and in its healthcare facilities. We hope that this can be accomplished. It is sorely needed.

A similar report, written by Dr. Bryan Shumaker, the tour director, appeared in the official journal of the ASLMS, Lasers in Medicine and Surgery, 10:597-600 (1990). In his writeup, Dr. Shumaker used portions of my writeup taken from this source, thus the similarities. Here is a link to Dr. Shumaker’s writeup.

Inlays, Onlays, Rings & Things

This column was published in Ophthalmology Management in May 1990.

TECHNOLOGY UPDATE

Irving J. Arons

As pointed out by Bill Link at the recent ASCRS meeting in Los Angeles (1990), there is a surge of interest in various surgical approaches to correcting impaired vision. From a mild renewed interest in RK, probably brought on by the intense interest in excimer laser wide area ablation and the inability of a large number of surgeons to participate in the human clinical trials limited by the FDA, to the renewed interest in other means of changing refractive correction by changing the shape of the cornea.

Under investigation -- some in human clinical trials -- are differing forms of epikeratophakia using onlays of both human tissue and synthetic lenticle materials; inlays and rings using both hard and soft plastics; and standard and multifocal IOLs for correcting myopia in phakic eyes. In addition to the implantation of rigid or soft IOLs, some researchers are still investigating the possibility of injecting either a hydrogel or silicone into a cleaned-out capsule to provide corrected vision with some degree of accommodation.

Epi-Inlays

In addition to traditional keratophakia, where recipient cornea is cut, frozen and reshaped on a cryolathe, synthetic collagen and hydrogels are being used to replace the removed corneal tissue. Lypholized donor corneal tissue (Kerato-Lens and Kerato-Patch) is still processed for some researchers by Allergan Medical Optics (AMO), along with its hydrogel material (Kerato-Gel). Human trials with the latter for both aphakic and myopic correction are underway. Alcon Surgical is also sponsoring clinical trials with its proprietary hydrogel material.

In addition, the Choyce polysulfone inlay program is still going strong. The newest version is microperforated, having thousands of 2 micron holes that allow nutrient and gas permeation. The trials are sponsored by Surgidev and FDA approval to expand the availability of the inlays is hoped for late in 1990.

Still another inlay program is being sponsored by Optical Radiation. ORC has developed a hydrogel Fresnel intracorneal lens which is flat and thus of relatively uniform thickness. Since the degree of correction is controlled by the Fresnel design, the lens can be placed into a narrow pocket dissection.

The other inlay trial, still in pre-clinical study, is with the Keravision intra-corneal ring (ICR). This PMMA 6-8mm ring is inserted in a channel in the peripheral cornea and is tightened to steepen the cornea for correcting hyperopia and loosened to flatten the cornea for correcting myopia. Much work still needs to be done to optimize the device and procedures before human clinicals start.

Epi-Onlays

Several companies, including Chiron Ophthalmics and G.E. Medical Systems are sponsoring programs to place either hydrogels or collagen onlays onto a de-epithelized cornea and have the epithelium regrow and hold the onlay in place. The Chiron program, with a proprietary hydrogel, is in limited pilot testing, with two non-seeing eyes outside of the U.S. having been tested to date. The G.E. Medical Systems' collagen onlay program, called LASE (Laser Adjustable Synthetic Epikeratoplasty) is underway at Emory University, under the auspices of Keith Thompson and Khalil Hanna. In this program, the collagen onlay (supplied by Domilens) can be reshaped as needed using an excimer laser, prior to re-epithelization.

Injectable Lenses

As noted in our February 1990 column, work continues on perfecting technology on an injectable IOL with the hope of retaining some accommadation. Allergan Medical Optics continues a low level effort on the original program in this field, initiated in the early 1980s by its then subsidiary Innovative Surgical Products. ISP had planned to inject an enzyme into the capsule to dissolve the cataractous lens and then follow this with a liquid polymerizable silicone polymer. As I recall experiments with monkeys had taken place but with many unresolved problems. In France, Domilens has a research program underway using a collegan material, while another research program announced by Vision Technology a year or two ago has apparently been halted. We expect other programs in this area are quietly underway at other research institutes.

So the field of surgical vision correction is humming. Lasers may have the spotlight, but a lot is going on both in the footlights and backstage.

White Paper -- The Evolution and Prospects for Laser Refractive Keratoplasty

This White Paper was published by Arthur D. Little in September 1989.

IRVING J. ARONS
ARTHUR D. LITTLE

I. Overview

The American public spends more than $16 billion annually for vision care. More than 60 million eye examinations are given annually and nearly 60 million pairs of eyeglasses and 3 to 4 million pairs of contact lenses are dispensed. In addition, more than 1 million surgical procedures are performed to correct vision deficiencies or for therapeutic reasons.

The laser has and continues to play an important role in the treatment of eye disease. Soon after the laser's discovery, ophthalmologists were putting this unique tool to use in stopping retinal bleeding and repairing retinal tears. Today, more than 90% of all ophthalmologists own or have access to a laser for performing a myriad of treatments including retinal photocoagulation, retinal reattachment, punching holes through the trabecular network to alleviate glaucomas, clearing vitreous strands and membranes, treating senile macular degeneration, and clearing clouded posterior capsules or "secondary cataracts". Procedures under investigation include photophacoemulsification (softening or fragmenting the lens prior to cataract surgery), thermal sclerotomy, and treatment of ocular cancers either through tumor vaporization or use of photo dynamic therapy (PDT), among others.

One of the most important new procedures, if it can be shown to be safe and efficacious, will be the use of a laser to reshape the front surface of the eye, or as I have coined the term, "corneal sculpting". (The more formal designations are laser refractive keratoplasty or laser refractive keratectomy, or LRK for short, and photorefractive keratectomy or PRK.)

The surgical potential of the use of ultraviolet radiation was first reported by scientists in both the health sciences field (Taboada and colleagues) and in the materials and electronics industries (Rhodes; Ruderman; and Srinivasan). Dr. Rangaswamy "Srini" Srinivasan of IBM's Watson Research Center reported in 1982 and 1983 that the excimer laser could make precise cuts in organic plastic materials for use in the electronics industry, or in human tissue such as hair. Subsequently, two researchers began to exploit the use of excimer lasers in the field of ophthalmology. Dr. Stephen Trokel, an ophthalmologist at Columbia-Presbytarian Medical Center in New York, heard about Srinivasan's experiments and arranged to observe the procedure. This led to Dr. Trokel's first experiments in Dr. Srinivasan's laboratories on bovine eyes in 1983. The work was originally done in the hopes of using the laser to make more precise cuts in the cornea in a radial keratotomy-type procedure, then coming into vogue for correcting myopia. At about the same time, an associate of Dr. Trokel's, Dr. Francis L'Esperance, a pioneer in the use of lasers in ophthalmology, saw a wider application for the excimer laser to ablate the front surface of the cornea, "corneal sculpting", and began efforts to develop both the technology and the medical research to exploit it. Today, at least three companies in the United States, and several more in Europe and Japan are funding research in an attempt to commercialize this procedure. Almost all of the work is being done with the argon fluoride (ArF) excimer laser, operating at 193nm, since experiments have shown that this wavelength appears to provide the "cleanest" cuts in corneal tissue, removing cellular matter by breaking molecular bonds one cell at a time, in a cold ablation or photodecomposition process without damaging adjacent tissue. The 193nm wavelength also appears to have non-mutagenic effects on corneal tissue.


Author’s Note: Through the magic of this new electronic age, I was able to send this article from my Journal to Dr. Srinivasan, formerly of IBM. He responded that there was an error in what I had written back in 1989. And, as this Journal is meant to be historical resource, I felt it was appropriate to point out the error for the record. Here in his words, Dr. Srinivasan would like to correct what was written:

“I would like to point out a serious error in the history of the discovery of excimer laser ablation of tissue as you have narrated it. The error is serious because it misstates the priority of the discovery. It is true the blog is merely a reproduction of what you had put down two decades back. If such errors had not crept in the minds of the concerned people then, a lot of the subsequent patent litigation would have been unnecessary. Don't you think that the blog would be more useful if it is factually correct at least at this date?

The error concerns the statement that 'I made the cuts on hair and only on hair' because you do not mention any thing else. Actually, we, in 1983, had already shown that precise cuts can be made on human aortal wall (from a cadaver) and we had histological sections and photographs to back it up. I showed this to Trokel when he first visited me in June 1983. He was so impressed that he showed my photos at a talk that he gave before ophthalmologists in Manhattan that same year in September. That was how L'Esperance first came to know about our work. There is documentation to verify all the above.

To say that Trokel performed HIS (emphasis added) experiments in my lab is ridiculous. Trokel had never seen an excimer laser before, could not operate one even if he had one and certainly did not know the optimum conditions to perform tissue ablation. Under my instruction, my technician (B. Braren) performed the experiments on the bovine eyes that Trokel brought with him.

All of the above facts were discussed at great length at the ITC trial between VISX and Nidek that was held in 1999. VISX lost that case on every point.”

(Dr. Srninivasan is referring to the trial that was held by the International Trade Commission, brought by VISX against Nidek, which, as pointed out by Dr. Srinivasan, was won by Nidek.)


In the procedure, which is being performed under FDA investigational device exemption (IDE) protocols, a corneal surface scan or refractive data is fed into a computer and the computer program determines how much corneal stroma material must be removed (usually only about 10 to 15% of the corneal thickness in selected sectors) to form a contact lens-like reshaping of the corneal contour. The laser procedure takes about 30 seconds, with the total procedure taking about 30 minutes. The epithelium, or top surface layer of the cornea, regenerates in about 48 hours. Thus, the eye must be bandaged for one or two days before the healing is completed. Using the procedure, or modifications of it, nearsightedness, farsightedness and astigmatism can all be corrected, replacing the need for eyeglasses or contact lenses for the majority of people who elect the procedure once it becomes generally available. The problems seen to date are involved with the healing of the cornea. In some animal studies and early clinical trials, several of the corneas treated have become cloudy (hazy) and taken months to clear. It is felt that this is a matter of technique. With shallower, smoother cuts, less haze has been seen in later patients. With improved techniques, and perhaps in combination with the newly developed epithelial growth factors that speed corneal healing, it is believed that it is only a matter of time before this problem is resolved. A second early complication has been regression, or thickening of the epithelium during regrowth. Again, with smoother, shallower ablations, the amount of regression or corneal epithelium thickening is appreciably reduced.

In an earlier study done in March 1986 for Dr. L'Esperance's group, your author forecast that within five years after commercial introduction (following FDA marketing approval), a minimum of 800 systems would be sold annually in the U.S., more than 2000 would be in use, and 4 to 5 million procedures performed annually. Thus, we forecast that the successful introduction of this procedure could have a marked impact on the increased use of lasers in ophthalmology. This forecast was based on very preliminary information, before any of the three companies now involved had built their laser systems.

In our latest study, completed in August 1989, after more careful consideration of the clinical work now underway and the attitudes of the ophthalmic community, we believe that fewer systems will be sold annually in the U.S., because of slower adoption by the medical community, and that closer to 2 million sculpting procedures will be performed annually after about five years following FDA marketing approval. However, we remain confident that the successful introduction of this revolutionary technology into ophthalmic practices will change the way vision is corrected forever. Further, the new technique will eventually change the way ophthalmologists practice and result in an increase in dispensing of glasses and contact lenses by the remainder of the optical professions, as ophthalmologists find it more lucrative to become involved in laser refractive surgery than in simple refractions and the dispensing of eyewear.

II. Other Medical Applications of the Excimer Laser

The major application for the excimer laser in ophthalmology is for refractive correction, including the correction of myopia, hyperopia and low to moderate degrees of astigmatism. The latter is being approached in two ways; with the use of "T" cuts, similar to the way RK correction of astigmatism was done, and with the use of selected area ablation. The former technique has been successfully demonstrated both by U.S. clinicians and in West Germany by Theo Seiler, using the Summit Technology ExciMed UV200 laser. The latter technique, using area ablation to correct astigmatism, is under clinical investigation with the Taunton Technologies LV2000 laser. (And we believe this technique could also be incorporated into the Visx Twenty/Twenty Excimer Laser system.)

Besides the "cosmetic" refractive corrections, several therapeutic applications are under clinical study. Superficial keratectomy or excimer laser smoothing of the cornea is being investigated by all three of the companies noted above. In some cases, the use of a viscous liquid, methylcellulose, is used to fill in the irregularities, and then the filled in surface is smoothed without duplicating the irregularities originally present. The laser is also used to remove calcium deposits, known as band keratopathies, and for the removal of wedge-shaped growths known as pterygiums. Corneal scars are also being removed with the restoration of normal sight to some patients in the clinical studies.

One company, Summit Technology, is investigating the use of their laser for treatment of glaucoma through the formation of a partial window or filtration bleb, in a process known as partial excimer trabeculectomy. Apparently, the process is self limiting, as the escaping fluids prevents further tissue penetration.

In addition to the ophthalmic applications noted above, the excimer laser is under investigation in several other medical specialties. Probably the largest potential is in laser angioplasty, or the clearing of peripheral and coronary arteries obstructed with plaque. Summit Technology, as well as at least seven other companies, is experimenting with excimer lasers, and is among the more than two dozen companies seeking a laser solution to the clearance of clogged arteries.

Other potential medical applications for excimer laser technology include arthroscopy and dentistry. In arthroscopy the laser may be used for the removal of both tissue and bone fragments in endoscopic procedures, while in dentistry, the laser may be used in penetrating enamel for access to caries (dental decay), which can then be removed with a pulsed YAG laser in "painless/drilless dentistry".

III. The Participants

In the United States, there are three companies currently developing excimer laser systems for use in corneal sculpting, and at least two others experimenting with competing technologies. In Europe and Japan, another three or four companies are developing excimers and perhaps working on other technologies as well.

U.S. Companies Involved in Excimer Laser Development

Summit Technology -- Watertown, MA

Summit has developed and built a compact ophthalmic excimer laser system, the ExciMed UV200, that is under study in both the U.S. and in Europe. The unit has a built-in operating microscope and computer for controlling the sculpting and therapeutic procedures. Its lasers are also sold in Japan through a distribution agreement with Canon Sales.

The company presently has four IDEs for clinical trials in ophthalmology and at least one for clinical investigation in coronary artery disease. The four ophthalmic IDEs include: 1) Superficial Keratectomy; 2) Photorefractive Keratectomy; 3) Partial Excimer Trabeculectomy for Glaucoma; and, 4) T-Excisions for Astigmatism.

Some of the principal investigators include:

John Hunkler - Kansas City, KS
Robert Fenzyl - Garden Grove, CA
Theo Seiler - Berlin, West Germany
John Marshall - London, United Kingdom
Roger Steinert - Boston, MA
George Waring - Atlanta, GA

Taunton Technologies -- Monroe, CT

Taunton has developed a sophisticated, integrated, diagnostic/therapeutic advanced technology excimer laser system, the LV2000, that incorporates a digital keratoscope and Zeiss operating microscope into the laser system. Colored displays of the dioptric power of the cornea guide the surgeon in computing the changes to be made. Taunton holds IDEs for both refractive corrections, including correction of both myopia and hyperopia and removal of superficial scars, and for selected area ablation correction of astigmatism. Taunton has an agreement with Alcon Laboratories to handle worldwide marketing to the ophthalmic community.

Principle investigators include:

Jim Rowsy - Oklahoma City, OK
Richard Lindstrom - Minneapolis, MN

Visx -- Sunnyvale, CA

Visx has taken over the former CooperVision excimer laser program. This system is perhaps the largest of the three and incorporates a high resolution observation/alignment operating microscope and video display, along with a mobile computer-controlled workstation for guiding the operator through the procedure and storing the patient data. A modified version of an autorefractor can be used for both pre-op and post-op patient diagnostics. The company holds at least two IDEs for both refractive and therapeutic corrections.

Principle investigators include:

Herb Kaufman and Marguerite McDonald - New Orleans, LA
Walter Stark - Baltimore, MD

Non-Excimer Laser U.S. Companies

Phoenix Laser Systems -- San Francisco, CA

Phoenix is a newly public company (August 10, 1989) developing a pulsed doubled YAG, which they claim operates in a photodisruptive (plasma) mode to selectively remove corneal tissue. As far as is known, no IDEs have yet been obtained to begin clinical trials.

Intelligent Surgical Lasers -- San Diego, CA

This private company is developing a fast pulsed, variable wavelength, solid state laser system for working on the eye. According to their issued patent, the laser is a diode-pumped Er:YAG or Ho:YAG that can produce multiple wavelengths from a dispersion line device for spreading the wavelengths in each pulse. The laser can also contain a frequency doubler to split the beam into components of different wavelengths.

Excimer Laser Development Work Underway Outside the U.S.

Aesculap-Meditec (West Germany) has reported on masked excisions for making RK-type cuts and for making corneal transplant cuts.

Lumonics (Canada) had been funding university research on the use of its excimer laser in surgical correction of the eye, but no recent references have been noted.

Nidek (Japan) is reported to be investigating the use of excimer lasers in the treatment of ocular disease and in correcting vision. Attempts to obtain more definitive information have as yet been unsuccessful.

Synthelabo (France) showed an excimer laser at the 1988 Academy of Ophthalmology Meeting in Dallas and is supposedly completing the development of its system. They recently reported on animal eye studies but not as yet on humans.

IV. Results of the ADL/ORC Survey

As part of the recently completed study of the prospects for "corneal sculpting", Arthur D. Little and its subsidiary, Opinion Research Corporation, collaborated in seeking the knowledge level and interest in corneal sculpting of the ophthalmic community. One thousand randomly selected ophthalmologists, located in metropolitan areas, were sent a comprehensive questionnaire that attempted to determine how they felt about becoming involved in corneal sculpting once FDA marketing approval was obtained. One hundred and eighty nine responses (19%) were received, of which 163 were included in the tabulation of results, having been received before the cut-off date. The general findings are reported below.

o Of the 163 tabulated respondents, 55% were in solo practice, 15% in partnerships and 25% participated in group practices. The overwhelming majority, 72%, considered themselves "general ophthalmologists" as opposed to specialists, and they were fairly evenly split in terms of years in practice and location around the country.

o Knowledge of our respondents regarding corneal sculpting was on the low side. Eight percent knew little or nothing about it, and only 9% considered themselves very knowledgeable. The remainder had either attended a seminar (13%), had heard about it (33%), or read about it (59%). Their impressions about the ophthalmic community's knowledge of sculpting was decidedly on the low side, with their belief that 76% of their colleagues had only slight to no knowledge about the technique. They felt that only 2% of their peers had a great deal of knowledge about the process, and only 21% were moderately knowledgeable.

o In terms of interest in learning more on the subject, 67% of those surveyed were moderately to extremely interested in participating in the technology once it receives FDA marketing approval. Ten percent were undecided and 9% were not interested.

o Our respondents felt that the most important ophthalmic application for the excimer laser was for sculpting to correct myopia (65%), while 55% were in favor of ablating for correction of astigmatism, as compared to 37% in favor of T-cuts. Correction of hyperopia and removal of scars was favored by 45%, while glaucoma filtration got a 51% favorable rating.

o Most of the doctors (57%) would accept " 1/2 diopters of correction for myopia and/or hyperopia, while an additional 30% would accept " 3/4 to 1 diopter accuracy.

o Fifty-two percent said that they would charge between $1000 to $1500 per eye, and an additional 29% claimed to be able to charge more than $1500. On a weighted basis, a mean charge of $1360 would be charged, with a higher $1510 fee in the Northeast, and a lower fee of $1270 in the West.
o The mean number of procedures that would be done per week was 4.9. Only 28% expected to do 5 or more procedures per week, while 30% expected to do 2 to 4, and 21% thought that they would do one or less.

o Acceptance of the procedure will only happen after it is reported on by their peers (27%), and/or in common practice (47%). Only 15% reported that they would get involved either before general release (8%) or soon thereafter (7%).