Valproic Acid Application to Modify Post Surgical Fibrosis in a Model of Minimally Invasive Bleb Surgery

PURPOSE: To evaluate different routes of valproic acid (VPA) administration in modulating various phases of wound healing events after minimally invasive bleb surgery (MIBS). METHODS: Thirty New Zealand White rabbits underwent surgical implantation of PRESERFLO MicroShunts. Animals were divided into treatment groups of mitomycin C (MMC) 0.4 mg/mL, MMC 0.1 mg/mL, VPA 1 mg/mL, and VPA 30 mg/mL. Treatments with topical and subconjunctival administration were investigated in the combination groups of low-dose MMC (0.1 mg/mL) and VPA. IOP was measured and slit-lamp photographs were taken weekly. Fibrotic gene expression was analyzed in the bleb by quantitative polymerase chain reaction and western blot. Histology was performed following sacrifice on day 28. RESULTS: Low-dose MMC (0.1 mg/mL) combined with VPA resulted in prolonged bleb survival to day 28. This was associated with reduced collagen 1 and fibronectin gene and protein expression (P < 0.05). There was also a favorable extracellular matrix structure on histological analysis due to the presence of fine immature collagen fibrils surrounding the shunt opening. Intraocular pressure lowering was seen, with a reduction of 20% from baseline IOP until day 14. Both topical and subconjunctival administration of VPA demonstrated similar outcomes, with no overt side effects observed throughout the experimental period at different doses or dosing regimens. CONCLUSIONS: VPA is a versatile and effective adjunctive agent that can be used in combination with low-dose MMC to produce favorable bleb characteristics in MIBS. TRANSLATIONAL RELEVANCE: VPA is both efficacious and safe as an antifibrotic agent, and different routes of administration are available to target different stages of fibrosis after filtration surgery.