Ophthalmic innovation by the decades: The 2000s

The 2000s were dominated by advances in refractive surgery technologies including wavefront-guided LASIK, the femtosecond laser for refractive and cataract surgery, the introduction of effective anti-vascular endothelial growth factor (VEGF) drug treatments for retinal diseases, advances in imaging technologies, and the approval of new intraocular lens (IOL) types for cataract patients.

LASIK

Femtosecond laser

This technology introduced in 2001 revolutionized LASIK by replacing the mechanical microkeratome for flap creation, enhancing precision, and reducing complications that occur in LASIK surgery. Laser-created flaps were highly accurate and safer than could be achieved with the microkeratome, making this the new standard for flap creation.¹

The femtosecond laser has revolutionized corneal and refractive surgery with respect to its increased safety, precision, and predictability over traditional microkeratomes. The advantages of bladeless femtosecond-assisted LASIK over conventional microkeratome-assisted LASIK include reduced dry eye symptomatology, reduced risk of flap button hole or free cap formation,^2,3 and a gentler approach with minimal or no transient visual loss (blackout period) due to close physiologic maintenance of intraocular pressure throughout the procedure, especially in femtosecond laser platforms that employ a curved contact surface. This configuration allows better approximation of the corneal surface and reduced suction pressure compared to flat contact surface laser interfaces and traditional microkeratomes.¹

The femtosecond laser also offered the ability to consistently create thinner, more precise flaps, which increased the pool of patients who could be considered eligible to undergo a LASIK procedure.¹

Wavefront-guided LASIK

The procedure, approved in 2002, facilitated customized LASIK procedures. This technology creates a detailed three-dimensional map of the eye to correct subtle vision imperfections, ie, higher order aberrations, that older methods could not address. By addressing the unique aberrations, visual outcomes are improved and side effects reduced.

The aim was to achieve vision beyond 20/20 for most patients by correcting refractive errors and higher order aberrations.⁴

During the 2000s, refinements in the LASIK procedure continued that focusedon enhancing the accuracy of correcting refractive error (myopia, astigmatism, hyperopia) and improving the quality of day and night vision.⁵

Medical advances in treatments for retinal diseases

In the early 2000s, scientists began creating drugs that interfered with retinal disease processes. These drugs block a protein called VEGF. Before their creation, people with wet AMD were almost certain to develop severe vision loss or blindness.⁶

One of the first drugs was photodynamic therapy (PDT) with verteporfin (Visudyne, Bausch & Lomb), which wasapproved in 2000 to slow the progression of wet age-related macular degeneration (AMD). PDT was the first treatment to effectively prevent the loss of visual acuity in patients with subfoveal choroidal neovascularization secondary to AMD, pathological myopia, or presumed ocular histoplasmosis syndrome.⁷

Pegaptanib (Macugen, EyeTech Pharmaceuticals, Inc.) was approved in 2004, marking the first approved anti-VEGF therapy for neovascular AMD.⁸Pegaptanib binds to a subset of VEGF-A isoforms and reduced the average number of letters lost in neovascular AMD by 50% at 54 weeks.⁹ Unlike the standard of care at the time, Visudyne, pegaptanib was effective for treating all forms of neovascular AMD.⁹

Bevacizumab (Avastin, Genentech, Inc.), initially developed to treat cancer, began to be used as an off-label treatment of neovascular AMD due to its effectiveness.^10,11Bevacizumab is a full-length, humanized monoclonal antibody directed against all the biologically active isoforms of VEGF-A. In 2005, Philip Rosenfeld, MD, and colleagues at the Bascom Palmer Eye Institute, Miami, reported the first successful off-label use of an intravitreal injection of bevacizumab for a patient with wet AMD. Researchers noticed a similarity in the underlying mechanism of VEGF-driven vessel growth in cancer and in wet AMD.

Following approval by the FDA, bevacizumab was used in ophthalmology to treat various types of neovascular diseases. Since the first report on the effects of bevacizumab was published in 2005, by 2007, more than 100 publications shared the experience with bevacizumab in ophthalmology.¹²

The reports of the drug’s dramatic success led to the rapid and widespread adoption of intravitreal bevacizumab in clinical practice worldwide. Its low cost compared to similar FDA-approved drugs for the eye made it a highly attractive option.

Ranibizumab (Lucentis, Genentech)approved in 2006 was developed specifically for ocular use and, based on the superior visual outcomes reported in pivotal trials, became the standard of care.⁶

The drug was instrumental in stopping the progression of wet AMD in the majority of patients and some of patients were able to regain vision lost to AMD.

This success spurred a great deal of interest and research into new drugs and led to the development of several successful treatments for wet AMD, diabetic retinopathy (DR), and retinal vein occlusion.¹³

During the same decade, intravitreal injections of anti-VEGF therapies were also found to be beneficial for DR and diabetic macular edema (DME): Studies in the 2000s confirmed the effectiveness of anti-VEGF medications, administered as injections into the eye, for improving visual acuity in patients with DME. This led to a new standard of care, offering the possibility of reversing vision loss in some cases and slowing the progression of DR in others.¹⁴

The decade also ushered in observations about positive effects of vitamins on AMD. The National Eye Institute-sponsored Age-Related Eye Disease Study found that high-dose antioxidants and zinc could significantly slow the progression of AMD.¹⁵ At the study’s end in 2001, the researchers concluded that high levels of antioxidants and zinc can reduce by 25% some individuals risk of progression to wet macular degeneration.

Diagnostics and imaging

Optical coherence tomography (OCT) improvements

Significant advancements were made in the speed and resolution of OCT, a non-invasive imaging technique. Wider bandwidth light sources were introduced in 2001, allowing for submicrometer resolution.¹⁶The transition from time-domain (TD-OCT) to Fourier-domain (FD-OCT) was the most impactful development. TD-OCT used a moving reference mirror that limited image acquisition speed, while FD-OCT systems, which emerged in the early to mid-2000s, detected reflected light signals simultaneously.¹⁶

Spectral-domain OCT,first applied to retinal imaging around 2002, used a spectrometer to achieve acquisition speeds of 27,000 to over 50,000 A-scans/second by the mid-2000s. The increased speed and higher resolution (down to 3–7 µm) allowed for detailed three-dimensional retinal mapping and precise analysis of the retinal layers.¹⁶

Adaptive optics imaging enabled high-resolution imaging of the human retina in real-time, improving the detection of aberrations.In 2003, researchers reported combining adaptive optics with OCT to correct for the eye's natural aberrations. This improved transverse resolution but was limited by a narrow depth of focus.¹⁷

When high-frequency ultrasonic imaging was developed it was considered by many to be the next frontier in ultrasound. It has many clinical applications ranging from imaging the eye and skin to small animal imaging. Small animal imaging has recently generated intense interest for evaluating the efficacy of drugs and gene therapy. Commercial high-frequency scanners often termed “ultrasonic biomicroscope” (UBM), all use mechanically scanned single element transducers at frequencies between 30 to 60 MHz with a frame rate of 30 frames/second or lower. To alleviate problems with UBMs, such as mechanical motion and fixed focusing issues, high frequency linear arrays and imaging systems in the 20- to 50-MHz range were developed. These changes enabled visualization of microscopic structures in the eye's anterior segment.¹⁸

In glaucoma patients, UBM can help differentiate many glaucoma types, evaluate the anatomy of the angle or the position and shape of the iris.^19,20

UBM can measure the dimensions of the anterior segment structures²¹ and classify glaucoma patients as primary closed-angle cases, including congenital, juvenile, or adult onset, secondary closed angle, or even certain types of secondary open angle glaucoma. UBM also can identify several subtypes of glaucoma.^22-24 UBM also proved valuable in evaluation of tumors and masses and for observing changes in eyes filled with silicone oil.

Surgical advances

Significant advances in cataract surgery that developed during the 2000s transformed the procedure from one that simply restored sight to one providing refractive correction. Key developments involved less-invasive surgical methods, IOLs, and computer-assisted technologies that improved patient outcomes and reduced recovery time.

IOLs

In 2000, the pioneering Array lens (Allergan and later Abbott Medical Optics) was the only approved multifocal lens, while better multifocals, accommodative, and phakic lenses were still in their investigational stages. Some lens designs, such as the early one-piece versions, were prone to complications and some IOL materials left much to be desired regarding biocompatibility. Toric IOL technology was in its infancy, and the first aspheric lens was not approved until 2004. Injectors were still a work in progress in 2000. Today, they are used routinely in the vast majority of cataract surgeries. They have helped advance small-incision surgery and greatly improved surgical efficiency and safety.²⁵

Femtosecond laser-assisted cataract surgery, first performed in 2008, uses the Nd:glass lasers to create focused, ultrashort pulses at a 1,053-nm wavelength to photodisrupt tissue by creating cavitation bubbles. This laser can be used to create corneal incisions, relaxing incisions, capsulotomy, and lens fragmentation, which can be later removed by phacoemulsification. It was performed in the first human eye in Hungary in 2008, and it integrates artificial intelligence, and promises to revolutionize cataract surgery, in terms of precision, reproducibility, accuracy, safety, and limiting collateral damage and inflammation.²⁶

Vitrectomy advances

Significant advances in vitrectomy during the 2000s primarily was centered on the widespread adoption of microincision vitrectomy surgery, which facilitated shorter operative times, less pain, and faster visual recovery.²⁷

This period saw a major shift from 20-gauge instruments to smaller 23- and 25-gauge systems, which led to numerous improvements in surgical outcomes and patient recovery.²⁷

Other surgical advances in the 2000s included introduction of the chandelier illumination and probes.²⁷

Glaucoma management

Selective Laser Trabeculoplasty (SLT)

This glaucoma treatment was approved for commercial use in the US in 2001. It uses a lower energy laser than older methods, reducing the risk of side effects and theoretically allowing for repeat procedures.²⁸

SLT, with its low-energy pulses to treat the trabecular meshwork and improve aqueous outflow, incites less tissue destruction when compared to its predecessor, argon laser trabeculoplasty, which was first introduced in 1979.²⁸

Other noteworthy advances

Genomics Research

Launched in October 1990 and completed in April 2003, the Human Genome Project’s signature accomplishment, ie, generating the first sequence of the human genome, provided fundamental information about the human blueprint, which has since accelerated the study of human biology and improved the practice of medicine.²⁹

Antibacterial agents

The fourth-generation fluoroquinolones, moxifloxacin and gatifloxacin, were introduced in 2003 and promised improved spectrum of activity and delayed development of microbial resistance. Although these topical agents have recently been introduced in commercial form in 2004, there was already a growing body of evidence showing excellent potency in the war on ocular infections.³⁰

References

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