ReviewPrevention of posterior capsular opacification
Introduction
Posterior capsular opacification (PCO) is a common complication of cataract surgery. In cataract surgery, the crystalline lens fibers from the natural opaque lens nucleus and cortex are removed, followed by implantation of an intraocular lens (IOL) in the remaining lens capsular bag. Within two to five years after this surgery, PCO can cause a decreased visual acuity in 20–40 percent of patients (Fig. 1) (Awasthi et al., 2009).
PCO is a fibrotic condition initiated by an inflammatory response due to tissue trauma caused by cataract surgery and combined with a foreign body reaction towards the implanted IOL. The eye lens has been considered to be a model for organ fibrosis in general because of the PCO response (Eldred et al., 2011). The PCO response is a consequence of proliferation, migration, and transdifferentiation of lens epithelial cells (LECs) that are normally situated in a single layer on the inner side of the anterior lens capsule and remain in the capsular bag after cataract surgery (Apple et al., 1992, Marcantonio and Vrensen, 1999, Raj et al., 2009). Surgeons remove most of these LECs during cataract surgery, however, there are always residual cells in the capsular bag. Proliferation rates of these residual cells are highest three to four days after surgery and they are age-dependent, since younger patients are more at risk for PCO (Dawes et al., 2013, Maltzman et al., 1989). The exact mechanism which initiates the proliferation is unknown. It could be related to the change in extracellular matrix (ECM) components and growth factors due to the inflammatory response (Eldred et al., 2011, Nishi, 2012, Oharazawa et al., 1999, Saika et al., 2002). The second process is the migration of LECs to the posterior capsule. Migration over the posterior lens capsule towards the posterior visual axis is possible due to cell adhesion molecules involved in formation and disruption of cell–cell and cell-ECM contacts, such as intracellular adhesion molecule-1 (ICAM-1), various integrin-ligands, and CD44 (McLean et al., 2005, Nishi et al., 1997a, Saika et al., 1998, Zhang et al., 2000). Furthermore, during the formation of PCO, LECs transdifferentiate. LECs in the equator can differentiate into cells which resemble normal crystalline lens fibers (Marcantonio and Vrensen, 1999, Wormstone et al., 2009). LECs on the anterior side of the capsule can undergo transdifferentiation to myofibroblasts resulting in PCO (Apple et al., 1992, de Iongh et al., 2005).
Epithelial to mesenchymal transformation (EMT) is the process of transdifferentiation of epithelial cells into mesenchymal cells (Nieto, 2011). Mesenchymal cells have migratory and invasive properties. As a consequence of the transdifferentiation of LECs to myofibroblasts, which contain α-smooth muscle actin (αSMA) and have contractile properties, the lens capsule surface can become wrinkled (Marcantonio et al., 2003, Wormstone, 2002). When these wrinkles are situated in the visual axis they cause visual disturbances. The specific mechanisms of EMT in PCO formation are described in detail in Section 2.
PCO in the central visual axis is usually treated with a neodymium: YAG (Nd:YAG) laser capsulotomy of the posterior lens capsule and occasionally with a surgical posterior capsulotomy. These treatments result in an opening in the central posterior lens capsule, providing a clear visual axis. Surgical posterior capsulotomy concerns an invasive procedure with additional risks for the patient. Similarly, complications have been described for the Nd:YAG laser capsulotomy, including damage to the IOL, elevation of intraocular pressure, cystoid macular edema, and an increased incidence of retinal detachment (Aslam et al., 2003, Awasthi et al., 2009, Ge et al., 2000, Steinert et al., 1991, Trinavarat et al., 2001). Beside the complications, the considerable high procurement costs of a Nd:YAG laser make laser capsulotomy not universally available for all patients suffering from PCO. Hence, there is a strong need to prevent PCO instead of treating it with a laser capsulotomy.
In this review current knowledge on mechanisms of EMT is summarized and possible ways to interfere in these processes for the prevention of PCO are indicated. In the last section we will broach the potential of new strategies using nanotechnological advances for the prevention of PCO.
Section snippets
Mechanisms of epithelial to mesenchymal transformation
Epithelial to mesenchymal transformation is the process of transdifferentiation of epithelial cells into mesenchymal cells. This process can be triggered by an inflammatory response (Lopez-Novoa and Nieto, 2009), such as the response in the eye after cataract surgery (Wormstone et al., 2009). Damaged ocular tissue releases chemokines which attract cells of the immune system in order to remove damaged tissue and to facilitate subsequent tissue repair. Clinically, this is characterized by the
Prevention of posterior capsular opacification
Targets for PCO prevention were discussed in Section 2. In this chapter we focus on general measures, pharmacological measures, and non-pharmacological measures which were evaluated in various experimental models.
Potential of nanomaterials
Nanomedicine involves the medical application of nanotechnology and is of growing importance in all fields of medicine, including ophthalmology (Etheridge et al., 2013). Nanotechnology makes use of nanomaterials, which are structures between 1 and 1000 nm in size, but usually smaller than 100 nm (Kreyling et al., 2010). Nanomaterials can consist of a broad variety of materials of either organic or inorganic origin occurring in various organizational constructs, which can be reversibly or
Future perspectives
In this review we described recent progress in research for the prevention of PCO and the development of new techniques and therapeutic strategies in PCO prevention. So far, major steps were made with the recognition of the signaling pathways concerning TGF-β and other growth factors involved in the PCO process. Yet effects of treatment are difficult to compare because quantification of treatment effects is not standardized and none of the methods interfering with these biological processes are
Summary
PCO is a common complication after cataract surgery. The development of PCO consists of a combination of the processes of proliferation, migration, and transdifferentiation of the residual cells on the lens capsule. Usually, PCO in the central visual axis is treated with a Nd:YAG laser capsulotomy. Since this treatment entails risks on complications to other structures of the eye, the need for PCO prevention becomes increasingly important. During the past decades, various forms of prevention
Acknowledgments
This work was supported by the European Fund for Regional Development, Samenwerkingsverband Noord-Nederland (grant number 249-Bioactive interface layers for medical implants), and NanoNextNL, a micro and nanotechnology consortium of the Government of the Netherlands and 130 partners. The authors want to thank Annemarie Tuin for providing the scanning electron microscopic images.
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