In the future, punctal plugs could deliver copper sulfate to the ocular surface to help stabilize the corneas of keratoconus patients.

In the future, punctal plugs could deliver copper sulfate to the ocular surface to help stabilize the corneas of keratoconus patients. Photo: Irving Martinez Navé. Click image to enlarge.

The distinctive green patina that copper coins and statues acquire over time is evidence of the element’s readiness to oxidize. The process of oxidization is also necessary for corneal collagen fibers to bond tightly and maintain rigidity of the structure. Keratoconus’s underlying cause may not yet be known, but research has revealed that certain physiological changes are associated with the condition; these include both a decrease in collagen crosslinking (CXL) and decreased activity of the enzyme lysyl oxidase (LOX) as well as several other immune system-related molecules. One of these physiological changes is already targeted as a treatment option via the CXL procedure using riboflavin and UV light. However, no current therapies exist targeting lysyl oxidase activity.

At ARVO 2024 early this week, a study was presented by researchers from the University of Oregon that explored a novel approach to help keratoconus patients by delivering a sustained reservoir of copper to the eye, since copper is known to upregulate LOX. To test this, primary cell cultures were taken from corneal tissue of healthy donors and keratoconus patients undergoing corneal transplantation. These samples were treated with different cupric lactate dosages (0.1µM to 50µM), with LOX activity being measured. Then, cupric lactate was incorporated into two different biocompatible and bioresorbable polymers—polyethylene glycol diacrylate (PEGDA) and polycaprolactone (PCL)—using photo-crosslinking and nanoprecipitation methods. Multiple solvent combinations were tested to arrive at a combination allowing for greater incorporation of copper by nanoprecipitation; results looked most favorable with tetrahydrofuran, dichloromethane, ethanol, acetone and water.

The study researchers found that LOX activity was indeed significantly upregulated after the cupric lactate treatment in both healthy and keratoconus corneal cells. The most effective doses were in the ranges of 10µm to 20µm and didn’t affect cell viability. Cylinder molds were successfully made from copper-loaded PEGDA and PCL, with acceptable dimensions for punctal plug implants (2mm to mm in length and 0.4mm to 0.5mm in diameter). Copper amount was 4µm to 8µm in the PEGDA implants and 9µm to 15µm in the PCL ones.

Both these polymers could be successfully loaded with copper and molded to sizes comparable with commercially available punctal plugs. This is in line with the authors’ aim, which is to “develop a biocompatible punctal plug implant for effective and sustained delivery of copper to the eye for upregulating LOX with no or minimal immune responses, complications and side effects.”

The present work was limited to materials science needed to develop a punctal plug deliver method, but other studies by this group using a topical eyedrop formulation showed about two diopters of corneal flattening from the administration of copper sulfate to the eye.

Although these methods are still far way from clinical implementation, the authors reflect that “our results are promising, and we hope they will lead to a novel therapy and delivery system to enhance LOX and potentially treat keratoconus.”

Original abstract content @2024 Association for Research in Vision and Ophthalmology.

Kumar SR, Archer BJ, Ambati BK. Copper loaded polymer implants for sustained delivery to the eye. ARVO 2024 annual meeting.