Cyclosporine A-Loaded Drug Delivery Systems Inhibit Scar Formation After Glaucoma Surgery in Rabbits
Glaucoma is a leading cause of irreversible blindness worldwide, and surgical intervention becomes necessary when intraocular pressure (IOP) cannot be adequately controlled with medications. However, the success of glaucoma surgery is often compromised by local fibroblast proliferation and collagen deposition, which lead to stenosis of drainage channels and scar formation in the filtration area. These complications are the primary reasons for the failure of antiglaucoma surgery. While mitomycin C is commonly used during surgery to modulate wound healing, recent studies suggest that there is room for improvement in its application. Cyclosporine A (CsA), a drug known for its anti-inflammatory and immunosuppressive properties, has shown potential in suppressing scar formation after filtration surgery. This study explores the efficacy of CsA-loaded drug delivery systems (DDS) in inhibiting scar formation and improving surgical outcomes in a rabbit model of glaucoma surgery.
The wound healing process after glaucoma surgery is most active within the first three months, peaking in the first month. Therefore, sustained drug delivery systems that maintain stable local drug concentrations are crucial for effectively regulating this process. The researchers developed two such systems: a poly(DL-lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(DL-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) thermogel and a poly(lactic-co-glycolic acid) (PLGA) coating. These systems were designed to provide a controlled and sustained release of CsA to the surgical site.
The study involved the implantation of glaucoma drainage devices (GDDs) with or without CsA-loaded DDS into both eyes of nine New Zealand rabbits. The rabbits were housed under natural light conditions with free access to food and water, and all experimental protocols adhered to ethical guidelines for animal research. The eyes were randomized into three groups: a coat group (CsA-PLGA coating), a gel group (CsA-PLGA-PEG-PLGA thermogel), and a control group (GDD without CsA). All surgical procedures were performed by the same ophthalmologist, and the evaluator was blinded to the group allocations during assessments.
To enhance the visibility of the gel, a lipophilic orange-red fluorescent dye, DiI, was mixed into the drug-loaded gel. Postoperative IOP was measured weekly using a Tono-pen, and bleb morphology was analyzed using an imaging system and a slit lamp. The researchers monitored for side effects such as bleb leakage, conjunctival edema, hyphemia, shallow anterior chamber, and infection. The Indian Bleb Appearance Grading Scale (IBAGS) was used to assess bleb morphology, and mean IBAGS scores were calculated for each group at each time point. Statistical analyses were performed using two-way repeated-measures analysis of variance, with Dunnett’s T3 post hoc test for multiple comparisons.
Anterior chamber radiography was conducted four weeks after surgery to evaluate the patency of the drainage pathways. Eyes were injected with 1% fluorescein, and the diffusion of the dye was observed under cobalt blue light. The number of open pathways and the extent of fluorescence diffusion were recorded for each group. Twelve weeks after surgery, the rabbits were sacrificed, and the eyes were fixed in paraformaldehyde, embedded in paraffin, and sectioned for histological analysis. The sections were stained with hematoxylin and eosin (H&E) and examined under a microscope to assess bleb morphology and scar tissue formation.
The results showed that the mean IOP in all three groups decreased significantly within seven days after surgery compared to preoperative levels. However, the IOP in the coat group was significantly lower than in the control group, while the gel group did not show a significant difference in IOP compared to the control group. This suggests that CsA, particularly when applied as a coat on the GDD, effectively reduces postoperative IOP.
Bleb morphology assessment revealed that the blebs in all three groups initially showed rapid congestion and uplift, reaching a maximum within seven days post-surgery. Over time, the blebs gradually flattened, with the gel group showing a slower rate of flattening compared to the coat and control groups. The area of the blebs was significantly larger in both CsA groups than in the control group, indicating better filtration function. The vascularization score was significantly lower in the coat group than in the control group, suggesting that CsA reduces vascularization in the surgical area.
Anterior chamber radiography demonstrated that the proportion of open drainage pathways was greater in the gel and coat groups than in the control group. While only three eyes in the control group had open pathways, all eyes in the CsA groups showed open pathways. The diffusion area of fluorescence was also significantly larger in the CsA groups, providing direct evidence that CsA improves the patency of drainage pathways.
Histological analysis of the surgical area revealed less scar tissue in the gel and coat groups compared to the control group. The blebs were significantly larger in the CsA groups, and the smaller blebs in the control group were likely due to scar tissue contraction. These findings further support the anti-scar effects of CsA.
In conclusion, this study demonstrates that CsA is a promising drug for preventing scar tissue formation after glaucoma surgery. The use of CsA-loaded DDS, particularly the PLGA coating, significantly improves postoperative outcomes by reducing IOP, enhancing bleb morphology, and maintaining the patency of drainage pathways. These findings suggest that CsA-loaded DDS could be a valuable addition to the armamentarium of treatments for glaucoma surgery, potentially improving the long-term success rates of these procedures.
doi.org/10.1097/CM9.0000000000000234
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