Accommodating lens refilling procedure may begin clinical trials by 2005

In post-mortem human eyes, researchers at Bascom Palmer achieved up to 13 D of accommodation.

An injectable polymer gel, designed to replace the crystalline lens and restore accommodation, is getting closer to clinical trials. A group of researchers who have long been developing the technique and material for the lens may apply to the Food and Drug Administration this summer for permission to conduct clinical trials as early as 2005.

Research led by Jean-Marie Parel, PhD, of the Bascom Palmer Eye Institute, University of Miami School of Medicine, in cooperation with the Vision Cooperative Research Center (Vision CRC) in Sydney, Australia, has been successful in restoring accommodation in presbyopic post-mortem eyes.

“The polymer gel lens replacement has achieved up to 13 D of accommodation in human donor and primate eyes,” Dr. Parel told Ocular Surgery News.

Similar results, which achieved up to 11 D of accommodation in a 17-year-old human donor eye, were reported by Steven A. Koopmans, MD, and colleagues in the Journal Investigative Ophthalmology and Visual Sciences in 2003.

The aim of lens refilling, a concept introduced to ophthalmology by Julius Kessler, MD, in 1960, is to cure presbyopia with a polymer material that — once injected to fill the lens capsule — turns to a gel lens that mimics the physiology of a young human lens.

“The concept is in line with Mother Nature,” Dr. Parel said. “The polymer lens molds to fit inside each individual bag uniquely, to achieve the highest degree of accommodation.”

Accommodative advantages

Experts in the fields of optics and accommodation call this idea the Holy Grail of cataract surgery.

“This is an area of tremendous clinical interest and importance. Lens refilling is going to prove itself very valuable, if successful,” said Adrian Glasser, PhD, a professor of physiological optics specializing in presbyopia and accommodation, at the University of Houston’s College of Optometry.

“It’s a fabulous idea,” agreed Paul Kaufman, PhD, an investigator of accommodation at the University of Wisconsin-Madison.

According to Drs. Kaufman and Glasser, polymer lens refilling could afford patients a degree of restored accommodation far superior to the 1.5 D of accommodation that has been demonstrated with the Crystalens accommodating IOL, manufactured by eyeonics.

“The real benefit to the polymer approach is the optical change that is accomplished when the polymer lens undergoes a change in surface curvatures. Change in surface curvatures is key to achieving accommodation,” Dr. Glasser said.

A small change in surface curvature can produce a large change in the optical system of the eye, he said.

“The ciliary muscles contract with accommodative effort. This releases the tension on the zonular fibers, which then allows the capsule to mold the natural lens,” Dr. Glasser explained.

A three-dimensional, malleable polymer lens may be able to adapt to the contours and curvatures imposed on the capsule by accommodative effort.

The current monofocal IOL technologies — acrylic and silicone lenses that are relatively flat — do not mold to fit the interior of the lens capsule, Dr. Glasser noted. As a result, he said, accommodation is rarely possible in patients with the current generation of nonaccommodative IOLs.

Achieving accommodation

“In order to produce 2 D or 3 D of accommodation in the eye, you would have to have an IOL move 3 or 4 mm in the bag. This is exceedingly unlikely,” Dr. Glasser said. He said the movement needed for the IOL to accommodate exceeds the normal movement of accommodation in the natural human lens.

Dr. Parel and his colleagues have reported achieving more than 10 D of accommodation in their experimental work with lens refilling. However, Drs. Kaufman and Glasser said that not more than 6 D of change is necessary to restore youthful levels of accommodation.

“You really want 4 D or 5 D of accommodation, so that you can use 3 D most of the time,” Dr. Kaufman said. “To achieve this, you need a lens to give you 5 or 6 D of accommodation.”

“Three diopters to 6 D would be phenomenal,” Dr. Glasser said. “Even if the lens only restores 3 D, it would still be of considerable benefit to many presbyopes. So even if there is a small contraction of the ciliary muscles, it may well be sufficient to produce 3 or 4 D of change in power.”

Dr. Glasser called lens refilling an “exceedingly worthwhile investigation.”

“We want to try to see if we can succeed in restoring accommodation in a way that more closely resembles the way the natural accommodative mechanism occurs in the human eye,” he said.

Phaco-Ersatz lens refilling procedure. Image courtesy of Jean-Marie Parel, PhD.

Collaborative efforts

Through a grant from Vision CRC — an Australian government-funded organization that connects networks of scientific researchers throughout the world — Dr. Parel and his team at Bascom Palmer were able to speed up their 30-year research on lens refilling.

Six years ago, Vision CRC paired Dr. Parel with polymer chemists from the Commonwealth Scientific and Industrial Research Organization in Melbourne, Australia, who subsequently developed a biocompatible polymer to replicate the characteristics of the natural human lens, and with scientists from the Save Sight Institute in Sydney. Researchers in India, Finland and other parts of Europe are also involved in Vision CRC projects.

Other researchers independently studying lens refilling and accommodation include Okihiro Nishi, MD, of the Nishi Eye Hospital in Osaka, Japan; Steven Koopmans, MD, in conjunction with Pharmacia (now Pfizer); and Dr. Glasser with the Medennium SmartLens.

Prepping the capsule

The lens refilling procedure developed by Dr. Parel and colleagues begins with the creation of a small clear corneal incision. A minicapsulorrhexis is cut into the lens capsule.

“We make a very small capsulorrhexis on the periphery of the lens, about 0.8 to 0.9 mm,” Dr. Parel said. He has designed instrumentation to fit through the smaller-than-average clear corneal opening and minicapsulorrhexis.

Phacoemulsification is performed, and cortical material is aspirated out as in standard cataract surgery. Dr. Parel has designed a special valve, called a minicapsulorrhexis valve (MCV), to “plug” and seal the minicapsulorrhexis.

“This device is placed in the hole to seal the bag, like a balloon,” Dr. Parel said. “The valve also allows us to go in and out of the bag with instrumentation, without compromising the capsular structure.”

Polymerization

Surgeons enter the capsule through the MCV to inject pharmacological products that kill lens epithelial cells to prevent posterior capsular opacification.

“Lens epithelial cells are always present on the anterior surface of the capsule and the equator. They are attached to the inner wall of the capsule. If you don’t remove them, they will proliferate,” Dr. Parel said.

The product is left in the bag for 60 seconds before it is aspirated out of the capsule. “Once the bag is deflated, we inject the polymer gel,” Dr. Parel said.

The refractive power of the IOL is determined by the quantity of polymer injected. Dr. Parel uses an intraoperative laser to determine each eye’s refractive characteristics.

“We can find out the focus of the lens,” he said. “Then, we put in a certain volume of gel depending on the refraction.”

Once the eye appears to be emmetropic, the injection is stopped and the gel is cured to a gelatin-like substance.

“The consistency of the lens becomes firm like Jell-O, but not hard like a plastic IOL. If it was hard, it would never be flexible or able to adapt to the varying curvature of the lens,” Dr. Parel said.

Polymerization and crosslinking of the gel is activated by blue light. The light radiates from a slit lamp attached to the microscope. Throughout the injection procedure, a yellow filter is placed over the slit lamp to block the blue light. Once the injection is complete, the filter is taken off.

“Blue light activates the polymerization process,” Dr. Parel said. “When we want to polymerize the gel, all we need to do is remove the filter and the light of the microscope does the polymerization.”

Future research

Dr. Parel said he planned to start an in vivo primate study with the polymer gel in April of this year. The gel must be approved by the FDA for clinical use before he can plan clinical trials, he said.

Arthur Ho, MOptom, PhD, FAAO, program director of presbyopia for Vision CRC, suggests that one of the potential sites for early human research with Dr. Parel’s lens refilling procedure is in India, under the direction of Gullapalli Rao, MD, at the L.V. Prasad Eye Institute in Hyderabad, possibly as early as 2005.

Technical challenges lie ahead for lens refilling

Before lens refilling becomes a clinical reality, surgical and biological challenges must be overcome, said Adrian Glasser, PhD. “Serious challenges lie ahead for ophthalmologists,” Dr. Glasser, an expert on accommodation at the University of Houston’s College of Optometry, told Ocular Surgery News. “It may take some time to meet these challenges, but I think ultimately it’s an investigation that must be undertaken.” Obstacles to successful lens refilling include mastering the creation of a minicapsulorrhexis, regulating the refractive index and quantity of the polymer gel, preventing posterior capsular opacification effectively with minimal risk and ensuring an airtight, leak-free capsule, he said. “These technical challenges need to be met before we are likely to succeed in clinical trials,” said Paul Kaufman, PhD, a professor at the University of Wisconsin-Madison. Minicapsulorrhexis Drs. Kaufman and Glasser agreed that the learning curve for experienced ophthalmologists who eventually will perform lens refilling will not be steep. There will, however, be difficulty involved in creating a minicapsulorrhexis. “There are technical and skill-related challenges to successfully performing a small capsulorrhexis,” Dr. Glasser said. The success of the lens refilling technique relies on the lens capsule’s ability to change shape and shift focus. Therefore, trauma to the capsule must be minimized. “A large capsulorrhexis tears and disrupts the very tissue that is required to produce an accommodative change in the lens. So by putting a capsulorrhexis in the capsule, you are removing tissue and losing energy needed to alter the lens,” Dr. Glasser explained. An average-sized capsulorrhexis for cataract surgery is typically 4 mm to 5 mm in diameter, but the capsulorrhexis required for lens refilling surgery may be only 0.8 mm in diameter. “The creation of this very small incision will be quite a challenge,” Dr. Kaufman said. A second technical challenge to capsulorrhexis creation is ensuring that the polymer will not leak from the bag. “You need to make sure that the polymer stays put once in the lens,” he said. Polymer refraction How much polymer to inject into the capsule is another factor that requires thorough investigation, Dr. Kaufman said. “The question is how much to put in,” he said. “If you put in too much refractive power, the eye at rest will be too far off emmetropia. However, if you put in too little, you have the opposite problem and the system may not change enough for accommodation.” Each patient will require a different amount of polymer depending on his or her refractive error. “It’s an effort to try to ensure that you get a good balance between accommodative performance and a good final refractive outcome,” Dr. Glasser explained. “Perhaps the ideal solution is to intraoperatively measure the refractive state of a patient’s eye as the polymer is being injected into the capsule, and to know when the appropriate time is to stop that injection once the patient’s eye has achieved emmetropic refraction.” Preventing PCO Preventing PCO is another challenge of lens refilling surgery. “YAG laser is contraindicated in the case of capsular refilling because you would disrupt the integrity of the capsule, compromise the accommodative performance and maybe even produce bulging of the lens,” Dr. Glassed explained. YAG laser treatments can also cause capsular changes and potentially alter the refractive state of the eye, he added. “This would eliminate any of the accommodative benefits that a polymer procedure might afford,” Dr. Glasser said. “So you really have to preserve the lens capsule as much as possible, because that’s the vessel through which you will attain better vision.” “It’s very important to preserve the capsule and the living cells around it,” Dr. Kaufman agreed. Compounds that are flushed through the lens to “kill” residual epithelial cells may pose a threat to surrounding cells in the trabecular meshwork, posterior surface of the cornea or corneal epithelium, he said. “You don’t want these things in the eye,” Dr. Kaufman said. “What you want is something that loosens the cells up so that they can be safely aspirated out.” He noted that there may be mechanical as well as biological approaches to loosening epithelial cells and aspirating them out of the lens capsule. “Future methods may eliminate the possibility of PCO with a lot less toxicity,” Dr. Kaufman said. Clinical trials With these challenges in mind, Drs. Kaufman and Glasser said that it will probably take most lens refilling researchers at least 5 more years to overcome the present obstacles. “The race is on,” Dr. Kaufman said. “The first company who makes it with something safe and effective – achieving at least 4 or 5 D of accommodation — has tremendous market advantage.”

For Your Information:

• Jean-Marie Parel, PhD, can be reached at the Bascom Palmer Eye Institute, 900 N.W. 17th St., Miami, FL 33136; 305-326-6000; e-mail: jmparel@med.miami.edu.
• Adrian Glasser, PhD, can be reached at the College of Optometry, University of Houston, 4901 Calhoun Rd., Houston, TX 77204; 713-743-1876; fax: 713-743-2053; e-mail: aglasser@uh.edu.
• Paul Kaufman, PhD, can be reached at the University of Wisconsin, Madison, WI 53792; 608-263-6074; fax: 608-263-1466; e-mail: kaufmanp@mhub.ophth.wisc.edu.
• Arthur Ho, MOptom, PhD, FAAO, can be reached at the Vision Cooperative Research Center, Level 4, Rupert Myers Building, University of New South Wales, Gate 14, Barker St., UNSW Sydney, NSW, 2052, Australia; 61-2-9385-7453; fax: 61-2-9385-7572; a.ho@visioncrc.org.