Re-Thinking Wound Healing in Glaucoma Surgery: The Promise of Targeted Antifibrotics.
Glaucoma surgery remains a cornerstone of care for patients with advanced disease or those uncontrolled on medications and laser [1] and [2]. Yet, despite decades of refinement, the major barrier to long-term success has not changed: postoperative conjunctival scarring [3, 4]. Whether in trabeculectomy or more recent minimally invasive bleb surgery (MIBS) procedures, the biological tendency of Tenon's fibroblasts to initiate and propagate fibrosis undermines surgical outcomes [5]. For all the ingenuity invested in new devices, the real battle continues to be fought in the microscopic wound-healing pathways of the conjunctiva. The burden of fibrosis is starkly illustrated in experimental models, particularly the rabbit eye, which is characterised by a highly aggressive scarring response. This exaggerated biology has often been seen as a limitation, yet it also creates a powerful platform for testing novel antifibrotic approaches under the most hostile conditions. A therapy that demonstrates efficacy in this setting may hold even greater potential in the more permissive environment of the human conjunctiva. Thus, advances in experimental wound modulation remain central to the future of surgical glaucoma care. Currently, mitomycin C (MMC) is the most widely used adjunct to control postoperative scarring [6]. Its use has undeniably improved the success of filtering procedures, but it comes at a price. MMC is a potent, nonspecific cytotoxic agent that can occassionally result in the formation of thin, avascular blebs prone to leakage and infection [7]. In this respect, MMC represents more of a blunt instrument than a tailored solution. The search for safer, more selective wound-modulating strategies has therefore become one of the most important unmet needs in glaucoma surgery. Potential targets include oxidative stress, inflammation, angiogenesis, and fibroblast activation, all of which contribute to the cascade of conjunctival fibrosis. In this issue, the study “Inhibitory Effects of 3’,4’-Dihydroxyflavonol in a Rabbit Model of Minimally Invasive Glaucoma Surgery with PreserFlo MicroShunt” adds important new insights [8]. The authors evaluated the antioxidant flavonoid 3′,4′-dihydroxyflavonol (DiOHF) in a rabbit model of bleb-forming MIBS. Animals were randomised to receive topical vehicle, topical DiOHF, or intraoperative MMC. Remarkably, daily topical DiOHF inhibited postoperative fibrosis by reducing collagen accumulation, angiogenesis, inflammation, and fibroblast expression in the bleb. This antifibrotic effect was accompanied by restoration of redox balance, as demonstrated by reduced staining for the oxidative stress biomarker 3-nitrotyrosine. Importantly, blebs treated with DiOHF were smaller and less ischaemic than those exposed to MMC, suggesting healthier long-term tissue architecture. These findings not only strengthen the evidence that oxidative stress is a central driver of conjunctival fibrosis but also identify DiOHF as a potential candidate for clinical translation. By providing a safer, more targeted method of modulating wound healing, such approaches could shift the paradigm away from reliance on nonspecific cytotoxins like MMC. Another emerging approach is modulation of lymphangiogenesis [9]. In a similar rabbit trabeculectomy model, subconjunctival VEGF-C promoted lymphatic vessel growth, reduced fibrosis and inflammation, and lowered IOP compared with controls. Unlike the thin avascular blebs seen with MMC, VEGF-C encouraged more physiological remodelling by enhancing fluid drainage and potentially increasing the function of the bleb—highlighting the potential of harnessing, rather than suppressing, wound-healing pathways. Direct translation of these findings is challenging, as rabbits are not primates; while they share similar conjunctival volume, they tend to scar more aggressively than human eyes. Still, the demanding rabbit model provides strong proof-of-concept [4, 10]. Complementing these recent innovations, Yu-Wai-Man and colleagues performed the first genome-wide RNA sequencing analysis of human conjunctival fibrosis after glaucoma surgery, identifying a distinct gene signature that could differentiate fibrotic from non-fibrotic conjunctival cell lines [11]. Validated by quantitative PCR and with more than 200 genes dysregulated, these findings create a molecular roadmap for novel antifibrotic therapies, potentially moving the field beyond empirical use of cytotoxics and towards rational drug development. In this light, the future of glaucoma surgery may lie less in hardware innovation and more in biological modulation. Recent laboratory research highlights multiple promising directions and the development of targeted antifibrotic therapies—whether antioxidants, cytokine blockers, or fibroblast-specific inhibitors—has the potential to transform surgical outcomes. Safer alternatives to MMC are urgently needed, and the work presented here highlights a promising pathway [12, 13]. With continued investment in translational science and careful clinical testing, agents such as DiOHF may help realise the true potential of trabeculectomy surgery and other minimally invasive filtering procedures. In conclusion, the high failure rates of glaucoma surgery reflect a persistent challenge: the conjunctiva's innate tendency to scar. While devices continue to evolve, it is our ability to modulate wound healing that will ultimately determine surgical success. Studies such as these underscore that the future of glaucoma surgery is not only about engineering new stents or shunts but also about engineering the wound-healing response. The author declares no conflicts of interest.
Read more
3