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Future Strategies
Summary
The Future: Total Scarring Control
Significant advances have been made in developing new treatments and refining existing treatments for the prevention of scarring after disease, trauma, or surgical intervention. The advent of new technologies in addition to traditional chemical drugs such as dendrimers, nanoparticles, aptamers, ribozymes, gene therapy with viral vectors, and RNA interference, opens the door to a new generation of therapies to prevent fibrosis after glaucoma surgery. The ability to fully control fibrotic processes in the eye offers the tantalizing prospect of 100% success of glaucoma surgery, with pressure around 10 mmHg associated with minimal progression over a decade. Genetic mapping may allow accurate prediction of a patient's wound-healing response to surgery, and accurate intervention for minimal scarring.
Introduction
Scarring still poses the major threat to the long-term success of glaucoma filtration surgery (GFS). It is the wound-healing response that determines the percentage of patients who achieve final intraocular pressures associated with virtually no glaucoma progression. The use of antifibrotic agents to inhibit scarring of trabeculectomy blebs is now well established. Antimetabolites such as mitomycin C (MMC) and 5-fluorouracil (5-FU) inhibit fibroblast function and survival when applied locally. However, they are associated with severe complications such as hypotony, and endophthalmitis that may lead to blindness. Furthermore there are some patients whose scarring process remains refractory, and despite antimetabolite treatment, their blebs still fail. There is therefore a need to develop efficacious alternatives that are not toxic. In this chapter we aim to review newer agents currently in development that modulate the wound-healing response in glaucoma surgery. Many promising new agents are in the stages of clinical evaluation and in vitro assessment ( Table 95-1 ).
Table 95-1
Modulation Targets and Mechanisms of Action
| Modulation Target | Mechanism of Action |
|---|---|
| SURGICAL STRATEGIES | |
| Cease topical treatment | Decreases inflammatory state and fibroblast activation (particularly drops causing ocular surface irritation/red eye) |
| Preoperative steroids | May deactivate cells and prevent early release of inflammatory mediators |
| Gentle tissue handling and hemostasis | Avoids bleeding and release of inflammatory mediators, including profibrotic cytokines |
| SPACERS | |
| Amniotic membrane | Innermost of the three fetal membranes, first used therapeutically as skin graft material |
| Potent anti-inflammatory properties | |
| Provides mechanical protection of covered tissues | |
| Hyaluronic acid | Hygroscopic polymer provides spacer effect between conjunctiva and sclera |
| May also have antifibrotic properties | |
| Cross-linked hyaluronic acid has a longer half-life | |
| Ologen implant | Resorbable collagen spacer acts as a temporary scaffold for ECM |
| ANTI-INFLAMMATORIES | |
| Steroids Synthetic derivatives of glucocorticoids |
Targets inflammatory cell gene expression |
| Reduces the number of leukocytes and neutrophils in wounds and inhibits macrophage function | |
| Lessens leakage of plasma and clotting factors by decreasing vascular permeability | |
| Inhibits the arachidonic acid pathway, resulting in an inhibition of the production of prostaglandins and leukotrienes | |
| Nonsteroidal antiinflammatory drugs (NSAIDs) | Inhibition of cyclooxygenase, resulting in a reduction of prostaglandins, prostacyclin, and thromboxane A2 |
| Direct antiproliferative effect on human ocular fibroblasts | |
| d (+)-glucosamine and d (+)- glucosamine 6-sulfate dendrimers | d (+)-glucosamine and d (+)-glucosamine 6-sulfate dendrimers have immunomodulatory and anti-angiogenic properties, respectively |
| Cyclosporine | First isolated from the fungus Tolyplocadium inflatum |
| Inhibits lymphocyte-mediated immune responses | |
| GROWTH FACTORS | |
| Tranilast ( (N-(3′,4′-dimethoxycinnamoyl) anthranilic acid) | First described as inhibitor of histamine release from mast cells |
| Inhibitor of TGF-β activity | |
| Anti-TGF-β antibody | Recombinant human monoclonal antibody specific to the active form of TGF-β |
| Anti-TGF-β oligonucleotides | Synthetic molecules which bind to specific intracellular messenger RNA strands |
| Inhibits transcription of the mRNA with subsequent inhibition of synthesis of the protein TGF-β | |
| Anti - TGF-β siRN A | Small interfering RNA sequence complementary to messenger RNA blocks translation and the production of the TGF-β protein |
| ACUTE PHASE PROTEINS | |
| Serum amyloid P | Inhibits activation of circulating monocytes to fibroblasts |
| ANTIANGIOGENESIS | |
| Bevacizumab and ranibizumab | Humanized monoclonal antibodies that inhibit vascular endothelial growth factor (VEGF) |
| Inhibits endothelial new blood vessel formation and existing vessel permeability | |
| CELL PROLIFERATION | |
| β-Irradiation | Ionizing radiation affects DNA and inhibits cell replication |
| Photodynamic therapy | 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM) is a fluorescent probe and an intracellularly acting photosensitizer |
| It is applied locally in its inactive form, diffuses into adjacent cells, and is then cleaved and rendered fluorescent by intracellular esterases | |
| After illumination (activation) with blue light, it exerts a photo-oxidative effect that is only destructive within the targeted cells | |
| Chymase inhibitors | Inhibits chymotrypsin activation of fibroblasts. Chymase may also activate angiotensin I to angiotensin II, and latent TGF-binding protein |
| Antiproliferative gene insertion | p21(WAF-1/Cip-1) is a transcription factor that mediates cell cycle arrest in response to cellular stress |
| CELL MIGRATION AND COLLAGEN CONTRACTION | |
| Matrix metalloproteinase inhibitors (MMPis) | Enzymes with zinc containing catalytic site expressed during embryogenesis, tissue remodeling and repair |
| Inhibition of enzymes prevents collagen contraction and prevents scarring in a model of glaucoma surgery acellular matrix proteins | |
| Etoposide | Stabilizes a normally transient DNA-topoisomerase II complex, thereby increasing double-stranded DNA breaks |
| Paclitaxel (Taxol) | First isolated from the bark of the Pacific yew tree, Taxus breviofolia , Taxaceae |
| Promotes the assembly of microtubules and inhibits the tubulin disassembly process | |
New Surgical Techniques, Including Surgical Biomaterials
Very simple changes in surgical technique and antimetabolite application may radically reduce side effects, even when the same concentrations are used ( Fig. 95-1 ). Minimal disturbance of tissues and a wider surface area of antimetabolite exposure results in improved bleb morphology. Tight control of intraocular pressure using releasable or adjustable sutures reduces the risk of early hypotony.
Physical spacers have been suggested as alternative adjuncts to antimetabolites. These may be solid, liquid, or gas. Human amniotic membrane appears to have antiangiogenic, anti-inflammatory, and antifibrotic characteristics both in animal models and in humans. The Ologen implant is a collagen spacer designed to create a scaffold for extracellular matrix (ECM) in the filtering bleb of a trabeculectomy. Resorption of the collagen implant appears to leave loosely formed ECM architecture. Animal model experiments were encouraging, however there is a paucity of long-term clinical data with one randomized trial, at the time of writing, reaching 2 years and there have been anecdotal reports of some inflammatory reaction to collagen implants in in vivo models. Perfluoropropane gas or sodium hyaluronate 2.3% in the subconjunctival space may improve drainage by the creation of more diffuse blebs. Crosslinked hyaluronic acid has been reported to be successful as a spacer for trabeculectomy. Polytetrafluoroethylene (PTFE), Seprafilm (a biodegradable membrane made of sodium hyaluronate and carboxymethylcellulose), ADCON-L (a polyglycan ester), Interceed (a cellulose matrix), sodium hyaluronate and polyglactin mesh, and other variations may help in the future. Devices made of relatively inert materials inserted into other spaces such as the suprachoroidal space may also help to keep flow spaces open and free of scar tissue.
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