The Future of Glaucoma Therapy? Microneedles and the Reduction of Intraocular Pressure
Around 75 million people suffer from glaucoma, making it the world’s leading eye disorder that causes irreversible blindness. Vision loss in glaucoma patients is often accompanied by the dysfunction of the retinal ganglion cell axons. This is believed to be caused by elevated intraocular pressure (IOP). Individuals with glaucoma and IOP elevation always have outflow in the aqueous humor of the eye. This is the clear liquid found in the anterior and posterior chambers of the eyeball. This outflow drains the primary trabecular meshwork located on the outer circumference of the anterior chamber. Modern glaucoma treatments are categorized into two main types: medication and surgery.
Medications
Medications (often in the form of eye drops) are applied to facilitate the outflow of aqueous humor or to decrease the production rate of aqueous humor. The primary issue with medications is the repeated administration which often results in poor patient adherence and translates into inadequate IOP control. Additionally, patients who take the medicine for a long time develop a tolerance to it.
Surgery
Surgical procedures such as incisional surgery, laser surgery, and device implantation are other alternative treatments. Most patients refrain from them because they are usually expensive, invasive, and may have reduced effect upon repeated surgeries. Some surgical procedures can also have serious side effects which can result in a need for repeated surgery.
A study exploring a new option for the treatment of glaucoma
The need for a safe and effective method to lower IOP is crucial in patients. They need drug-free, nonsurgical, low-cost treatment that will stop or delay the progression of vision loss.
Common treatments use the trabecular meshwork to clear the aqueous humor, however, it can also be drained from the anterior chamber by uveoscleral outflow. The aqueous humor can pass through the extracellular matrix of the ciliary muscle and into the suprachoroidal space (SCS). Drainage via this pathway can increase and reduce IOP either through pharmacological solutions or by using a drainage implant in the eye.
However, studies have also found the SCS to be a good route for drug delivery to the eye. Using a microneedle, drugs can be administered without needing invasive procedures. After the injection, the fluid can flow inside and around the SCS.
Recent trials have shown that SCS injections are successful and can lead to alteration of IOP. Microneedle insertions into the SCS can cause the IOP to drop below the baseline for a few days. When high viscous formulations are used, the results persist even longer.
In this study, researchers hypothesize that the reduction in IOP is caused by the expansion of the SCS. The researchers designed formulations of hyaluronic acid (HA) hydrogel to maintain the expansion of the SCS for months after a single injection.
Results
The study showed that reduction of IOP for four months by the expansion of the SCS in situ from a HA hydrogel administration is possible using a microneedle. In time, this research can be developed and potentially turned into a drug-free nonsurgical procedure. It could be a low-cost treatment for ocular hypertension and glaucoma without the need for medication or invasive surgical interventions.
Researchers hypothesized that a hydrogel injection into the anterior SCS could expand the SCS of a rabbit eye in vivo and reduce IOP without the use of drugs or surgery. To test this hypothesis, researchers used a microneedle to inject the formulation of HA gel in order to expand the SCS and they measured IOP over time.
By allowing gelation to occur within the SCS, the injection can be performed using a low-viscosity solution. HA was used to form the gel because it is naturally found in the eye as part of the vitreous humor, the extracellular matrix, the choroid, cornea, and other tissues.
The researchers first used a commercial HA hydrogel which is often used as a skin filler to treat wrinkles. Using the rabbit model, the researchers observed that a single microneedle injection of 50 µL gel can get into the SCS. Over time, IOP approached the baseline value. Analysis by linear regression showed that gel treated eyes had significantly lower IOP compared to the pre-injected values for 35 days.
To extend IOP reduction, the researchers formulated a new HA hydrogel that would resist degradation. It’s goal was to sustain SCS expansion and IOP reduction. The researchers successfully did this by adding thiol groups to the HA (HA-SH) and co-formulating with polyethylene glycol diacrylate as a cross-linker.
The researchers found that a single SCS injection of the crosslinked HA-XL gel formulation in normotensive rabbits led to an IOP reduction of ≈4 mmHg immediately after injection, which then extended to an IOP drop of ≈6 mmHg.
IOP increased over time and again approached baseline levels. However, statistical analysis showed that mean IOP in the eye which received HA-XL injection was significantly lower than pre-injection IOP values for 119 days after injection.
Discussion
In this study, IOP reduction did correlate with SCS expansion. The crosslinked HA appeared safe. Throughout the study, the rabbits had clinical tests to ensure the safety of the SCS injection. Results showed that injections did not cause any measurable changes in their external features after injection or over the course of the study. The study demonstrates that a single SCS injection of an in-situ forming hydrogel can reduce IOP for four months without complications. This shows an opportunity new strategy for IOP control that involves increased uveoscleral outflow by the mechanical expansion of the SCS.
Microneedles have been shown, in other recent studies, to have the capacity to deliver sulforhodamine B as well as other nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig, and human eyes. Volumes up to 35 μL have administered consistently. Current research for SCS microneedle particle delivery is expanding and is an exciting topic for upcoming developments in the treatment of many eye conditions.
Limitations of the Study
The study used a normotensive rabbit eye. In order to translate findings to human glaucoma, it should be performed on other species in hypertensive and glaucomatous eyes. A previous study with rhesus macaque model as subjects reported reduced IOP by 3-6.5mm Hg for more than 14 days. The study on a non-human primate may suggest that SCS expansion to reduce IOP over a sustained period may also be effective in humans. However, further research is needed. Several more studies will be needed to validate the findings of the hydrogel injection into SCS.
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