The thought of sticking a needle into the eye might make you shudder. For many patients with ocular diseases, this painful and invasive procedure may be the only way to administer drugs into the eyes. A recent study published in Science Advances offers smaller, gentler alternatives (1).
Clinicians often administer drugs into the eye by direct injection to preserve the efficacy and bioavailability of a medication. But this method is invasive and can cause inflammation. Topical eye drops or ointments, while less invasive, can cause blurriness and often don’t reach deep enough into the eye. Ophthalmologists are desperately searching for painless, convenient alternatives for ocular drug delivery with fewer side effects.
Chi Hwan Lee, a biomedical and mechanical engineer at Purdue University, spearheaded the creation of drug-loaded silicon nanoneedles that can be incorporated onto tear-soluble contact lenses to treat corneal diseases. The base diameter of these nanoneedles is about 900 nm, which is at least 80-fold smaller than normal intravitreal injection needles.
“The cornea is exceptionally sensitive,” said Lee. Even with anesthesia, a conjunctival injection into the inside of the eyelid can still be very painful. Not only are the new drug-loaded silicon nanoneedle contact lenses less painful, but drugs delivered using the lenses were more effective in rabbits when compared to injected drugs.
The size of the needle and the frequency of treatment were two main considerations when designing this contact lens. According to Lee, researchers previously attempted a similar strategy using microneedles made from biodegradable polymers to deliver ocular drugs. But the needles were too big — typically 0.3 mm in diameter — and degraded too fast in the presence of tear fluid, requiring frequent re-application.
To tackle these problems, the scientists developed silicon-based nano needles. These tiny nano needles are 10 times smaller and degrade in the body 30 times slower than polymeric microneedles. While silicon on a macro scale is almost as hard as diamond, its nano-version can be dissolved in a medically-useful timeframe.
Fabricating 3D silicon nanostructures is usually done on the surface of silicon wafers using a technique called photolithography. Separating the nanostructures from the micro-sized wafers is a crucial step for this application since the wafers are not suitable for the eye. “A silicon wafer is around 500 microns in size and it's going to take more than 500 years to be completely dissolved in the eyes,” said Lee. Separating the tiny structure is challenging due to the brittle nature of silicon.
Lee collaborated with Dong Rip Kim, a mechanical engineer at Hanyang University to uniformly crack the silicon nanoneedles using a polymer layer. They first coated the nanoneedles with polymethyl methacrylate (PMMA), a common synthetic polymer. Once a uniform layer formed, they peeled the polymer off of the silicon wafer using a mechanical peeler, which removed the needles embedded within the polymer layer. They then coated the base of the cone-shaped nanoneedles with a second polymer, polyvinyl alcohol (PVA). They subsequently removed the PMMA layer, leaving the silicon nanoneedles sitting on top of a tear-soluble PVA layer.
To test the efficacy of the silicon nanoneedle to deliver drugs into eyes, the scientists molded the needle-PVA construct into a contact lens shape. They loaded the lens with the ocular drug bevacizumab, which is commonly used to treat macular degeneration, and applied it to rabbits with surgically-induced corneal neovascularization (CNV), a condition where new blood vessels invade the cornea and cause vision loss.
Over the course of 28 days, the scientists noted an almost complete reduction in CNV in the rabbits treated with the contact lenses. In contrast, they saw only partial CNV reduction in animals that received conjunctival injections of bevacizumab.
Corneal treatments are often limited to smaller sized drugs due to the cornea’s impenetrable barrier. “If you have a protein drug like bevacizumab, for example, the bioavailability of the topical administration is basically zero,” said Arto Urtti, professor of biopharmaceutics at the University of Helsinki and University of Eastern Finland who was not involved in this study. This bioavailability challenge makes bevacizumab a good choice of drug to study, he said.
While the study results are promising, these contact lenses aren’t ready for the clinic yet.
“There has been a lot of research on contact lenses for ocular drug delivery for many decades, but none has resulted in any clinical applications. And I think there are some practical issues here,” said Urtti. According to Urtti, most commercial contact lenses are stored in aqueous containers. This raises the question of how these drug-loaded contact lenses should be stored to ensure that the drug does not leak out before use.
It is also unclear if the needles will cause discomfort to human eyes. “Since they were using anesthetized rabbits, any possible discomfort may be masked by the anesthesia,” Urtti said.
Ghanashyam Acharya, an expert in ocular drug delivery at Baylor College of Medicine who wasn’t involved in the study, pointed out that the researchers need a clear understanding of the drug’s pharmacokinetics to make sure that the contact lens meets the safety standards for clinical use.
Acharya was also concerned about silicon nanoneedles in patients’ eyes after treatment. “Whether that may cause any fibrosis, steady scarring, or inflammation needs to be investigated in depth,” he said. The paper reported no evidence that the needles dissolved completely after the drug was released.
Despite these concerns, Acharya is optimistic about the technology. “It provides a new strategy, a new method to deliver drugs to the cornea or to the eye,” he said.
- Park et al. Biodegradable silicon nanoneedles for ocular drug delivery Sci. Adv. 8, eabn1772 (2022)