Drug delivery

At present, postoperative GFS management is vital for the prevention of failure due to prolonged scarring. Therefore, more effective drug delivery methods are needed. The long-term requirement of treatment and the narrow therapeutic window of drugs in current use still limit the control of scarring. Sustained release delivery systems, including liposome encapsulation (Shinohara et al., 2003), microspheres (Herrero-Vanrell and Refojo, 2001), scleral plugs (Yasukawa et al., 2001), and biodegradable implant polymers, may have a very significant future role. With our ability to combine agents will come better efficacy. An example is the combination of 5-FU and heparin we used to prevent PVR (Asaria et al., 2001), which was the first clinical trial to show a statistically significant reduction in PVR.

Future directions: total scarring control and tissue regeneration

Significant advances have been made in developing new treatments and refining existing treatments for the prevention of scarring after disease, trauma, or surgical intervention. In addition to traditional chemical drugs, the advent of new technologies such as dendrimers, antibodies, aptamers, ribozymes, gene therapy with viral vectors, and RNA interference opens the door to a whole 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 a near 100% success of glaucoma

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surgery, with pressure around 10 mmHg associated with minimal progression over a decade as found in our long-term MRC glaucoma surgery study. Finally, most exciting is the prospect that neutralizing the fibrotic response to disease and injury will allow us to revert to the ‘‘fetal’’ mode when regeneration is the ‘‘normal’’ process, such as shown in a recent report which demonstrated that induction of bcl-2 gene expression together with downregulation of gliosis results in axonal regeneration in mice (Cho et al., 2005). Modifying matrix and cell conditions allows intrinsic stem cells to differentiate into different cells of the retina like lower species that can regenerate a severely damaged complex retina. Ultimately, it is likely that our ability to fully modulate the scarring processes will lead toward a much more regenerative reparative process after injury and disease.

Acknowledgments

The authors acknowledge the support of Guide Dogs for the Blind, the Wellcome Trust, Medical Research Council, Moorfields Trustees, the Haymans Trust, the Ron and Liora Moskovitz Foundation, the Michael and Ilse Katz Foundation, A G Leventis Foundation, the Helen Hamlyn Trust in memory of Paul Hamlyn, and Fight for Sight (UK). This research has received a proportion of its funding from the UK Department of Health’s National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed in this chapter are those of the authors and not necessarily of the Department of Health.

BLOOD CLOTTING

AND

FIBRIN FORMATION • Recombinant Hirudin

Prevention of tissue damage and avoid of bleeding

Reduction of recruitment of inflammatory cells and release of inflammatory mediators and pro-fibrotic cytokines like TGF-β

Prevention of adhesions between conjunctiva and sclera

Reduction of IOP (Drolsum et al., 2006), anti-angiogenic, anti-inflammatory and anti-fibrotic effect

(Barton et al., 2001; Demir et al., 2002; Fujishima et al., 1998; Bruno et al., 2001)

Keep free space for aqueous outflow. Side effect: Potential inflammatory reaction due to presence of biomaterials

Naturally occuring anticoagulant from the leech Hirudo medicinalis. Direct irreversible thrombin inhibitor.

Lyse blot clots after surgery and may lower IOP

INFLAMMATION

Infiltration of inflammatory cells

Cytokine release and action

•Steroids

(Intrableb triamcinolone acetonate injection)

•Synthetic derivatives of glucocorticoids

•NSAIDs

•D(+)-glucosamine and D(+)- glucosamine 6- sulfate dendrimers

•Cyclosporine A

•Amniotic membrane

•Tranilast ((N-(3',4'- dimethoxycinnamoyl) anthranilic acid)

•Genistein Isoflavone from soy products

•Suramin Polycyclic trypan dye derivative

•Conversion of angiotensin I to II

•Chymase inhibitors. Chymase is an enzyme released by mast cells

•Anti TGF-ß antibody Recombinant human monoclonal antibody against active TGF-ß2

•SiRNA against TGF-β mRNA

•SiRNA against TGF-β receptor mRNA

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Present mainly intracellular activity by alteration of gene expression.

Clinically beneficial for IOP reduction (Tham et al., 1996)

a)Inhibit macrophage function and reduce the recruitment of leucocytes and neutrophils in wounds.

b)Decrease vascular permeability, leakage of plasma and clotting factors. c) Inhibit the arachidonic acid pathway and subsequently the production of prostaglandins and leukotrienes

a) Inhibition of cyclooxygenase, leading to reduction of prostaglandins, prostacyclin and thromboxane A b)Inhibition of platelet aggregation and function

D(+)-glucosamine and D(+)-glucosamine 6-sulfate dendrimers have immuno-modulatory and

antiangiogenic properties, respectively (Shaunak et al., 2004)

Inhibition of lymphocyte-mediated immune responses.

Potent anti-inflammatory properties, maintenance of oxygenation and moisture and mechanical protection of covered tissues

Inhibition of TGF-ß activity (Chihara et al., 2002)

Inhibition of TGF-ß activity, tyrosine kinases, matrix metalloproteinases, and angiogenesis (Kim et al., 1998)

Inhibition of TGF-ß activity and reduction of fibrosis after experimental GFS (Mietz and Krieglstein, 2001)

Angiotensin II regulates TGF-ß1 expression via angiotensin receptor-ligand binding, which contributes to myofibroblast conversion (Sakaguchi et al., 2002)

Chymase activates angiotensin I to angiotensin II, and

latent TGF-ß binding protein to TGF-ß (Sakaguchi et al., 2002)

Inhibition of TGF-ß2 activity (Siriwardena et al., 2002)

Inhibition of transcription of the mRNA with subsequent inhibition of synthesis of the protein TGF-ß (Cordeiro et al., 2003)

Reduction of inflammation and ECM deposition in vivo

(Nakamura et al., 2004)

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Cell Proliferation, differentiation and collagen contraction

Proliferation of

HTFs

•Encapsulated SiRNA in poly (D,L-lactide- co-glycolide)

microspheres against TGF-β2

•Smad-7 gene transfer

•ROCK inhibitors (mainly Y-27632)

•Aptamers ARC126 and ARC127

•Adenoviral transfer of a dominant negative p38MAPK gene

•Ribozymes. RNA molecules which can cleave specific bonds in other RNA molecules

•Decorin

•Simvastatin, Inhibitor of the enzyme, HMGCoA reductase.

•Follistatin

•Photodynamic therapy

•Daunorubicin Anthracycline antibiotic isolated from the fermentation broths of Streptomyces

Increased bleb survival after experimental GFS (Gomes dos Santos et al., 2006)

Suppression of TGF-β action and protection against the development of lung, liver and renal fibrosis (Schiller et al., 2004)

Control of GTPase Rho activation, which is triggered by TGF-β. Inhibition of HTF collagen I contraction in

vitro and increase of bleb survival in vivo (Honjo et al., 2007)

PDGF activates ocular fibroblasts. ARC126 and

ARC127 bind and block PDGF-B (Akiyama et al., 2006) and may improve the success of GFS

Inhibition of Smad3 activation. Reduction of the differentiation of fibroblasts to myofibroblasts in

vitro (Meyer-ter-Vehn et al., 2006) and reduction of conjunctival scarring in vivo (Yamanaka et al., 2007)

Cleavage of TGF-ß-mRNA with subsequent inhibition of synthesis of the protein TGF-ß

Small proteoglycan, natural inhibitor of TGF-β . Delay of IOP increase and decrease of fibrosis after GFS (Grisanti et al., 2005)

Inhibition of the connective tissue growth factor gene and protein expression, a downstream mediator of TGF- ß (Watts et al., 2005)

Inhibitor of activin A. Reduction of liver and lung fibrosis (Aoki et al., 2005; Patella et al., 2006). Potential application in GFS

2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM) is a fluorescent probe and is 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 cell destructive within the targeted cells (Jordan et al., 2003). Alternatively, ethyl etiopurin

(Hill et al., 1997) verteporfin can be used as photosensitizers (Grisanti et al., 1999)

Inhibits cellular proliferation by several mechanisms, including DNA binding, free radical formation,

membrane binding, and metal ion chelation (Zimmermann et al., 1997; Dadeya et al., 2002; Rabowsky et al., 1996)

HTF differentiation to myofibroblasts

Neovascularisation

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Cell migration and collagen contraction

Collagen I binding from fibroblasts

Matrix Remodelling

Cleavage of collagen I by MMP-1

Promoting apoptosis and targeted cell death