Wound Modulation After Filtration Surgery
Filtration surgery for the treatment of glaucoma presents a unique challenge to surgeons. Although most incisional surgeries require adequate and complete wound healing for a successful outcome, filtration surgery relies on an abbreviated and incomplete healing process for long-term success. It is, in fact, a vigorous and robust healing process that accounts for the failure of most surgery in glaucoma.
After the conjunctiva is incised during surgery, a sequential and complex process of wound healing begins. This cascade of events begins with vascular leakage and coagulation. Blood vessels leak platelets, blood cells, plasma proteins, clotting factors, numerous tissue growth factors, and chemokines. The coagulation cascade is stimulated and clot formation begins, augmented by platelet aggregation. This insoluble fibrin-fibronectin matrix serves as the initial scaffold for future inflammatory cells to invade. Cellular migration and proliferation constitute the next phase of wound healing. Within a few days, inflammatory cells such as neutrophils, macrophages, and monocytes migrate to the wound site and begin tissue debridement and control of infection. Macrophages also serve to provide several pro-inflammatory growth factors such as platelet derived growth factor, fibroblast growth factor, and transforming growth factor beta (TGF-β).
During the proliferative phase, quiescent fibroblasts differentiate into a more active state—termed myofibroblasts. These activated fibroblasts not only produce loose connective tissue but they begin the process of remodeling existing extracellular matrix with the aid of matrix metalloproteinases. Pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), help to stimulate angiogenesis with the arrival of endothelial cells to create new capillary networks. The resultant primitive granulation tissue is then remodeled into a mature scar in the final phase of healing. Immature collagen fibrils are crosslinked, condensed, and dehydrated, whereas fibroblasts undergo apoptosis and disappear. Primitive vessels are remodeled, and a mature scar is completed.
Successful glaucoma filtration surgery hinges on the incomplete closure of newly created aqueous outflow pathways and the formation of filtration blebs. Therefore, several methods have been used in an attempt to augment or blunt the natural wound healing response during the preoperative, intraoperative, and postoperative periods. This concept of wound modulation is especially valid in patients at high risk for surgical failure, including those with aphakia, pseuodophakia, neovascular glaucoma, uveitic glaucoma, African-American origin, or previous failed filtration surgery.
The first and most obvious choice for modification of the normal wound healing pathway are anti-inflammatory agents. Glucocorticoids in particular have been shown to successfully inhibit postoperative scarring and increase bleb survival rates. Steroids achieve this through the alteration of several stages in wound healing. Early on, the concentration and migration of neutrophils and macrophages are mitigated through steroidal effect. Resultant phagocytosis and growth factor release is blunted as well. Within the cell, steroids block the production of arachidonic acid and its down-stream mediators such as leukotrienes, prostaglandins, and thromboxanes. Due to their broad effects, steroids are frequently used at the operative and postoperative phases with repeatedly proven success. Preoperative steroidal use has also been found to be beneficial to long-term trabeculectomy success. While not as extensively studies, limited evidence suggests an equivalent benefit with nonsteroidal agents as well.
In clinical practice today, antifibrotic agents such as 5-FU and mitomycin C (MMC) have emerged as the preferred wound modulation agents worldwide. Although steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit early wound healing, antifibrotic agents help to prevent end-stage scar formation by direct modification of fibroblast proliferation and activity at the wound site.
The antimetabolite 5 -FU is a fluorinated pyrimidine analogue that competitively inhibits the further synthesis of thymidine nucleotides. By blocking normal production of the essential nucleotide, DNA synthesis is prevented and cell death results. Experimental studies have illustrated 5-FU’s strong inhibition of human Tenon’s fibroblast activity and growth, as well as interfering with fibroblast-mediated collagen contraction. This desirable effect in the laboratory quickly translated to clinical use, initially as a series of subconjunctival injections after filtration surgery. The Fluorouracil Filtering Surgery Study (FFSS) was a major National Eye Institute-sponsored multicenter, randomized, prospective clinical study on the use of postoperative 5-FU in patients at high risk for failure. A total of 213 patients who had undergone cataract surgery or had 1 failed filtering surgery were randomized to either trabeculectomy alone or trabeculectomy with 1 week of twice-daily 5-mg 5-FU injections, followed by 1 week of daily injections. At 5 years, the failure rate was significantly less in the 5-FU group (51%) compared with the control group (74%). The greatest benefit of 5-FU injections appears to be within the first 18 months, after which the rate of failure progresses at a similar, steady rate in both groups. Subsequent studies have found similar success with the use of 5-FU intraoperatively, typically applied to the surgical bed for up to 5 minutes with a sponge soaked in 25 to 50 mg/mL of the drug. This method of administration has gained favor due to the 1-time dosing and eliminated need for frequent postoperative injection visits.
The most commonly reported adverse event with the postoperative use of the antimetabolite involves corneal toxicity. Findings include punctuate epitheliopathy, filamentary keratopathy, gross epithelial defects, and melanokeratosis. The frequency of such corneal findings is dependent on the dose and frequency of injection but may exceed 50% in large accumulative doses. The intraoperative use of 5-FU has dramatically reduced this complication rate by reducing or eliminating the need for sunconjunctival injections. More serious complications, such as bleb leaks, were also found to be more common in the FFSS trial (2% in controls, 9% in 5-FU). Although no randomized trial has shown an increase in endophthalmitis with 5-FU use, the increase in bleb leaks has been shown to be a significant risk factor for infection.
MMC is an antibiotic agent derived from the fungus Streptomyces caespitosus that is now commonly utilized during filtration surgery for its antiproliferative actions. The drug acts as a cell cycle, nonspecific alkylating agent that crosslinks DNA, preventing proliferation. As a wound-modulating agent, MMC has been shown to be more potent and durable than 5-FU, requiring only single intraoperative applications at doses approximately 100 times less. Cell culture experiments found that while 5-FU is fairly specific for inhibition of fibroblasts, MMC was toxic to both fibroblasts and endothelial cells.
The initial success of MMC as a wound-modulating agent in glaucoma surgery was established by Chen et al in 1983, in which they found that the agent prolonged bleb survival in high-risk patients. Subsequent animal and human studies have also shown MMC to be effective at achieving lower intraocular pressure (IOP) after surgery and enhancing bleb survival rates. In primary trabeculectomy, prospective and placebo-controlled studies have found MMC to significantly reduce failure rates at 1 year, but IOP reduction was similar to controls. One large review of intermediate long-term results of MMC (0.2 to 0.5 mg/mL) in trabeculectomy found survival rates of 94.2% at 1 year and 88.7% at 3 years. In patients undergoing combined trabeculectomy and phacoemulsification, 2 separate prospective, randomized, placebo-controlled trials found that the MMC group produced significantly lower IOP compared to placebo in the first year of follow-up. Filtration blebs were also found to be larger, and patients required fewer medications to achieve target IOP. Subgroup analysis from a later, large prospective study found improved outcomes with MMC only in patients with either African-American origin, IOP greater than 20 mm Hg on maximum medical therapy, or using at least 2 medications. Recent publications have also shown the superiority of MMC over 5-FU with regard to efficacy in IOP-lowering and survival rates. However, this applied only to high-risk eyes, as primary or low-risk eyes showed similar outcomes between the 2 antifibrotics.
The potency and duration of action of MMC comes at the cost of potentially more serious complications. The use of MMC has been associated with the development of thin-walled, avascular blebs that have a higher propensity to develop late-onset bleb leaks, over-filtration, hypotony, infection, and endophthalmitis. The infection rate with MMC-augmented surgeries has been found to be as high as 2.1% at 16 months and hypotony rate as high as 14%. Recent reviews of bleb-associated endophthalmitis found more than 80% of the identified cases were after MMC-augmented surgeries.
New Methods of Wound Modulation
Despite the efficacy of current antifibrotic agents, safety concerns have driven the research and development of new methods to modulate the healing process in filtration surgery. Newer agents offer a more targeted and potentially safer approach to impeding wound healing. Several methods have been studied in vitro and in animals, although few have progressed to human use and clinical trials.
A large area of research centers on the blockade of growth factors involved in stimulating the healing process. The anti-VEGF agents, bevaci-zumab and ranibizumab, have been used in several small series and trials as an intravitreal or subconjunctival adjunct to trabeculectomy. Most reports found good outcomes with the agents, particularly in cases of neovascular glaucoma, without any significant adverse events. TGF-β is a significant catalyst in the scarring process and has become a target for inhibition. A novel monoclonal antibody against TGF-β2, CAT-152, was found to be effective at inhibiting fibroblasts in vitro and prolonging bleb survival in rabbits. However, subsequent human trials failed to show a benefit of the antibody over placebo. Other drugs utilized for their inhibitory effects on growth factors include suramin and tranilast. Both agents have shown good success in vitro and in rabbits. Initial small human trials have been at least as efficacious as MMC, but larger trials are needed.
Multiple other approaches have been attempted and are involved in ongoing study. Inside the cell, signal pathway transduction is being targeted to block the effects of pro-inflammatory factors like TGF-β. Gene therapy and siRNA molecules are also being utilized for their ability to selectively impede the proliferation and activity of Tenon’s fibroblast cells. Serum amyloid P is a naturally occurring protein with the ability to interfere with the monocyte–macrophage response at the site of wound creation. In vitro, the blockade of macrophage action has been found to significantly alter fibroblast activation and proliferation. One alternative to pharmacologic agents is the use of beta radiation at the time of surgery. Initial human studies found no improvement of success over placebo in low-risk cases, but in later work, failure rates did significantly decline with beta radiation in a more high-risk population. Finally, photodynamic therapy (PDT) has been employed as a method to localize treatment to bleb area alone. In the lone human trial, a small group of patients showed good success rates with PDT, but no placebo-controlled trials have been published.
Although it is challenging to compare these agents given the wide variability in study design and patient populations, none of these newer methods have been proven as efficacious as the more established antimetabolites. Research is ongoing and more extensive human trials are needed to fully characterize the effectiveness and safety profile of these newer agents.
- The wound healing process after filtration surgery is quite complex, occuring in overlapping and sequential stages.
- Successful glaucoma surgery depends on modification of normal wound healing to prevent scarring.
- Steroids are an important agent to prolong bleb survival.
- The antifibrotic agents 5-FU and MMC can reduce surgical failure rates and may help achieve lower IOP postoperatively.
- These agents must be used with caution, as they may lead to adverse events such as increased rates of hypotony and bleb-related infections.
- Multiple new agents are being researched to achieve a safer and more effective wound modulating agent.
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