Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010

are selected with great care. The Boston and OOKP devices, with their biological supports and PMMA cores, can achieve functional and anatomical outcomes for years in some patients. PMMA offers many good properties, such as transparency and chemical stability, but it is a very stiff material and while providing acceptable functional outcomes it may account for some of the anatomical failures. This issue may have been reduced by the soft modulus and porous nature of the PHEMA material used in the AlphaCor one-piece device. The development of posterior segment complications such as retroprosthetic membranes and retinal detachments may be addressed by improved KPro designs and new surgical techniques. Removal of opacified tissue in preparation for the implantation of KPro devices is traumatic to the corneal tissue. Less aggressive surgical techniques using new technological advances in equipment may help to achieve better outcomes in full-thickness corneal replacement. Infection with KPro devices is an issue that plagues this type of surgery and, although endophthalmitis can be treated with antibiotics, devices with anti-microbial strategies incorporated into/on to the materials could assist in reducing this problem. Epithelial growth over the anterior surface of the device would be ideal in protecting against necrosis and in assisting to retain the device in the cornea but the epithelium would need to be stable and multilayered to be beneficial (Hicks et al., 1997; Allan, 1999).

Rigid polymers like PMMA would not support epithelial growth nor would many hydrogels. Clearly, epithelial growth would not be a possibility in patients with compromised epithelial status (very dry eye or limbal damage) unless concurrent transplant therapies were used in combination, such as cleverly modified surfaces pre-colonised with stem cells.

4.6Future trends

Much has been studied and attempted in the field of synthetic implants in the cornea but there is still a need for safe and effective long-term solutions. The successes and failures of previous work are instructive and provide a foundation for future approaches. Clearly, there is a need for systems that bring together innovations in materials, device design and surgical instrumentation combined with a knowledge and understanding of corneal biology, anatomy, physiology, neurobiology and wound healing.

4.6.1Corneal implants to treat refractive errors

Intracorneal implants aimed at changing the refractive power of the eye should be manufactured from materials that are biostable in the corneal environment. These materials should also be transparent and highly permeable with low-fouling surfaces to address issues of loss of long-term clarity. Better optical designs that provide stable and predictable outcomes from

110 Biomaterials and regenerative medicine in ophthalmology

the smallest and thinnest lens possible are most likely to succeed. Materials should also offer high levels of dimensional stability to provide stable optical outcomes. Improved manufacturing processes that enable porous materials to be made to specification are needed to address issues such as permeability and nerve regeneration. Pores should be small enough to not interfere with the scatter of light, numerous enough to provide adequate nutritional flux and ideally should provide for the regeneration of some nerves. Material treatments should reflect an understanding of corneal biology and, for onlays, be bi-functional, promoting epithelial growth and the sustained adhesion of a stratified epithelium on the anterior surface with anti-fibrotic treatments to reduce keratocyte activation on the posterior face. Microand nano-patterning may be used to encourage tissue adhesion on the anterior lens surface to compliment or even reduce the need for the addition of biological signals such as extracellular matrix molecules, peptides or growth factors to the polymer surface. Alternatively, layer-by-layer technology could be used to deliver signals in a specific temporal sequence. Patterning on the posterior surface could be used to reduce the chronic responses of the stromal tissue and minimise epithelial undergrowth. Minimally invasive surgical procedures, ideally above Bowman’s layer, using instrumentation designed to reduce trauma to corneal tissue and allow centration of the implant would contribute to more predictable and stable refractive outcomes. New adhesive strategies based on chemistry rather than on physical glues or sutures could be used to attach a lens to a debrided stromal surface or beneath an epithelial pocket and assist in centration and prevention of device expulsion caused by epithelial undergrowth. Whatever the approaches, they need to be well integrated and involve multidisciplinary teams to achieve a synthetic intracorneal implant that offers rapid visual rehabilitation with a predictable refractive outcome in a fully reversible procedure.

4.6.2Corneal replacement and repair: tissue regeneration

The challenge of corneal replacement and repair also requires new approaches, as the benefit of currently available technologies is limited to carefully selected patients and, even then, outcomes are not optimal. Solutions should be safe and effective in the long term. For the most part, emerging technologies in this area are being directed at scaffolds for corneal regeneration and may be used alone or pre-colonised with cells in tissue culture prior to implantation. Many involve new treatments and fabrication techniques for fully synthetic materials. Other strategies employ a tissue engineering approach using biologically based materials stabilised by chemical cross-linking or copolymerisation with synthetic polymers to optimise the characteristics of the material. These scaffolds are likely to have great potential in corneal

regeneration and may be used in the replacement of specific layers of the cornea providing an alternative to the trauma of penetrating keratoplasty where the full thickness of corneal tissue is removed and replaced with either transplanted cadaver corneal tissue or KPro devices. Target areas for the partial-thickness replacement of the cornea are the endothelial layer in cases of endothelial decompensation (e.g. endothelial dystrophies) or corneal stoma where it has been damaged by disease or trauma.

Stanford University’s Bio-X initiative has enabled a cross-disciplinary group to design and fabricate a photolithographically patterned hydrogel construct (DuoptixTM arising from Stanford University in California, USA) based on an optic made from a double network of high water content polyethylene glycol/polyacrylic acid (PEG/PAA), with an interpenetrating skirt made of a microperforated hydrogel poly(hydroxyethyl acrylate) (PHEA) (Myung et al., 2007; Myung et al., 2008a). The design principles of this KPro reflect knowledge gained from all precedent devices and recognise many aspects of corneal biology. The skirt material is porous with microperforations created using photolithographic techniques to allow stromal ingrowth to anchor the device (Myung et al., 2007). The optic component is permeable to the glucose flux that occurs from the aqueous humour to the epithelium to promote epithelialisation of the anterior surface of the device (Myung et al., 2008b). The necessity of cell adhesion to the core and skirt material has been recognised and a coating of collagen I is provided to both to facilitate this process (Myung et al., 2007). Recent data have shown that the PEG/

PAA materials used in the optic support epithelial closure in an in vitro organ culture system when coated with collagen I (Myung et al., 2009). This bioengineered cornea arising from the cross-disciplinary initiative has the potential to be used as a corneal replacement and possibly also as a material for a corneal implant (inlay or onlay) to correct refractive error.

The University of Ottawa Eye Institute (Griffith group) has developed a biosynthetic corneal matrix replacement that is intended to stabilise damaged tissue and allow for regeneration. Initial testing was conducted on hydrated collagen and N-isopropylacrylamide copolymers which formed a transparent, permeable biosynthetic material that supported cell and nerve growth in vitro (Li et al., 2003). Since then, various collagen types have been stabilised by cross-linking with water-soluble carbodiimide chemistry and tested in animal corneas using lamellar keratectomy procedures. Stabilised porcine collagen type I implants showed evidence of stable integration in the stroma with some nerve regeneration at 6 months (Liu et al., 2006). Mechanical testing of these implants at 12 months demonstrated ‘seamless integration’ in the host cornea which was attributed to the gradual turnover of the implanted matrix during the natural remodelling process (McLaughlin et al., 2008). Stabilised human recombinant collagen types I and III have also been compared over 12 months with similar outcomes, including maintenance of optical clarity,

112 Biomaterials and regenerative medicine in ophthalmology

stable integration in the corneal stroma and regeneration of the tear film, corneal cells and nerves (Liu et al., 2008b; Merrett et al., 2008). The crosslinked human recombinant collagen III was shown to be superior to a human amniotic membrane as a scaffold for the transplantation of limbal stem cells when tested in vitro (Dravida et al., 2008). The ability of this co-polymeric extracellular matrix replacement material to support nerve regeneration and the growth of corneal epithelial, stromal and stem cells in vitro shows great promise (Griffith et al., 2009). Recent reports on clinical testing of these corneal substitutes in patients with keratoconus and corneal scarring using a deep lamellar procedure reveal that keratocyte ingrowth occurred with these bioengineered implants, which also supported nerve ingrowth and resurfacing by host epithelium for 9 months (Fagerholm et al., 2009).

McMasterUniversityinToronto(Sheardowngroup)hasidentifiedsignificant biological issues that were problematical to the success of KPro devices and has endeavoured to solve these issues using surface immobilisation strategies applied to PDMS. This material was selected as it possesses many of the target properties needed for a corneal replacement, including transparency, oxygen permeability and appropriate mechanical properties. The inherently hydrophobic surface of the PDMS was altered using gas plasma polymerisation techniques which enabled the linkage of various growth factors aimed at controlling cell adhesion. A ‘growth factor therapy’ approach was directed at the problems identified with existing KPro devices. One such problem was the downgrowth of corneal epithelial tissue, which contributes to the extrusion of KPro devices in vivo. TGF-β-modified surfaces, intended to increase stromal cell adhesion (needed for device anchorage) and decrease epithelial cell adhesion (the cause of downgrowth), were tested in vitro but this surface strategy failed to satisfy either requirement fully (Merrett et al., 2003). Another issue tackled with this approach was to improve the retention time of artificial corneal devices by promoting epithelial tissue adhesion to the anterior surface. To address this issue, epidermal growth factor (EGF) was covalently tethered to plasma-modified PDMS substrates and in vitro assays showed that this growth factor did increase the growth and proliferation of epithelial cells (Klenkler et al., 2005). More recently, slow release of growth factors has been achieved in vitro using cross-linked collagen matrices modified with heparin to deliver basic fibroblast growth factor (FGF-2) (Princz and

Sheardown, 2008). Cell-adhesion peptides have also been incorporated into stabilised collagen scaffolds using similar dendrimer methodology and these have been shown to support corneal epithelial cell stratification using in vitro systems (Duan and Sheardown, 2007). The long-term stability and efficacy of these types of surfaces in vivo remains to be tested.

Biomimetic approaches to corneal replacement and/or repair are demonstrating the impact of combining new materials with fabrication technologies. The University of Wisconsin (Murphy and Nealey group) have

considered the surface on which corneal epithelial cells would be migrating and growing if a synthetic material were implanted below the epithelium. Initial work used a range of microscopy techniques to characterise the topographical and morphological features of the corneal epithelial basement membrane in rhesus monkeys (Abrams et al., 2000a) and humans (Abrams et al., 2000b). This information was used to create replicates of basement membrane topography on culture substrates using lithographic techniques which were tested with corneal epithelial cells in vitro. Data showed that the cells were extremely sensitive to the defined surface features for their alignment and spreading behaviour (Teixeira et al., 2003), strength of adhesion to the surface (Karuri et al., 2004), migration over the surface (Diehl et al., 2005), proliferation and differentiation (Liliensiek et al., 2006) and protein adsorbed to the test surfaces (Fraser et al., 2008). A collaborative approach in Europe (coordinated by David Hulmes) has produced a three-dimensional scaffold made from collagen fibrils aligned using horizontal magnetic fields in combination with a series of gelation–rotation–gelation cycles to produce orthogonal packing that resembles the lamellae of the corneal stroma (Torbet et al., 2007). The California Institute of Technology (Tirrell group) is developing regenerative scaffolds for corneal repair using genetically engineered protein hydrogels with specified macromolecular architectures tuned to match the mechanical and erosion characteristics of the target tissue (Maskarinec and Tirrell, 2005; Shen et al., 2006). The University of Sheffield (MacNeil/Rimmer collaboration) has developed a biocompatible, non-degradable material treatment for use in corneal replacement. This involves the chemical modification of the surface of low-adhesive hydrogel materials with plasma techniques to allow the attachment, migration and growth of corneal epithelial cells, which has shown promising outcomes when tested over the short term in co-culture with stromal cells in vitro

(Rimmer et al., 2007). The technology has been commercialised (CellTran

Ltd) for a range of applications including corneal repair where corneal epithelial cells isolated from a healthy contra-lateral eye are expanded on the modified substrates under culture conditions and then transferred to help heal the damaged eye.

Research in the fields of biology, biochemistry and protein chemistry is also being directed at the challenge of corneal repair and replacement. At the University of Aarhus in Denmark (Enghild group), proteomics is being directed at the development of new therapies for treating corneal diseases by comparing proteins in normal corneas to those in disease states such as granular and lattice dystrophies that would usually require a transplant (Karring et al., 2005). Various groups in the UK (Sandeman, Lloyd, Tighe) have worked together to screen materials for KPro devices by developing in vitro assays to model the inflammatory processes that occur following implantation of corneal replacement devices (Sandeman et al., 2003). Biological

114 Biomaterials and regenerative medicine in ophthalmology

studies at University College in London and the University of Auckland in New Zealand have shown that cell–cell communication through connexin 43 (Cx43) gap junction channels plays a major role in the epithelial and stromal wound-healing process following epithelial injury in cornea (Qiu et al., 2003) and skin (Coutinho et al., 2005; Mori et al., 2006). This technology is being developed in a spin-out company (CoDa Therapeutics Inc., San Diego, California, USA) with a gel product containing Cx43 antisense that results in a transient downregulation of Cx43 protein levels and an increase in the rate of wound closure after a single topical application.

Concurrent developments in surgical techniques and instruments may reduce damage associated with surgery, speeding recovery and improving both anatomical and refractive outcomes in corneal replacement and repair. SupraDescemetic implantation is one new surgical technique which involves removal of the central corneal epithelium and stroma leaving Descemet’s membrane and the endothelium intact. This potentially avoids the perforation of the anterior chamber, with its associated risks of leakage and infection, that occurs with conventional KPro surgery. Various synthetic materials have been tested in rabbit corneas to test this supraDescemetic synthetic cornea (sDSC) procedure (Stoiber et al., 2004; Stoiber et al., 2005) and have demonstrated that it is possible to implant a KPro device into the cornea without perforating Descemet’s membrane, but progress has been thwarted by complications such as the formation of neovascularised tissue at the device–Descemet’s membrane interface, which may prevent the long-term utility of this type of surgery. Descemet-stripping endothelial keratoplasty (DSEK) is a relatively new surgical procedure that is being used to replace the corneal endothelium in patients with endothelial dysfunction as an alternative to penetrating keratoplasty (Ham et al., 2009). While the technique was developed to transplant donor Descemet’s membrane carrying its endothelium (Ham et al., 2009), other materials such as chitosan are being tested as degradable supports for the transfer of corneal endothelial cells (Gao et al., 2008). The femtosecond laser is being used in a variety of surgical techniques and has allowed improved precision in making corneal incisions with laser energy focused to a particular depth minimising injury to the surrounding tissue (Donate et al., 2004). At the current time, the femtosecond laser has been approved for use in a variety of refractive and corneal surgeries including LASIK flaps, and intrastromal incisions such as those used with ring implants, lamellar keratoplasty as well as penetrating keratoplasty.

4.7Conclusions

materials and material treatments, surgery and surgical instrumentation. The events involved in corneal wound healing are complex and involve an interaction of all constituent cell and tissue types. Overlying corneal biology and physiology with mathematical disciplines such as biological modelling and network science may speed the understanding of the complexity of the interactions that occur between cells, tissues, nerves, proteins, functional molecules, etc. (Mete et al., 2008; Winkler, 2008). Combinatorial approaches based on these and other initiatives can be expected to lead to the development of new multifunctional materials and designs offering innovative solutions for improving and restoring vision with intracorneal implants that augment, repair or replace specific parts or the entire cornea.

4.8Acknowledgements

The authors would like to thank their colleagues Jukka Moilanen, Andrea Petznick, Tim Hughes and Keith McLean for their helpful comments during the preparation of this chapter.

4.9References

American Academy of Ophthalmology (AAO) (2008), ‘Academy testifies at FDA meeting on Lasik outcomes and satisfaction’, Medical News Today, 28 April 2008, http:// www.medicalnewstoday.com/articles/105545.php.

Abrams GA, Goodman SL, Nealey PF, Franco M and Murphy CJ (2000a), ‘Nanoscale topography of the basement membrane underlying the corneal epithelium of the rhesus macaque’, Cell Tissue Res, 299, 39–46.

Abrams GA, Schaus SS, Goodman SL, Nealey PF and Murphy CJ (2000b), ‘Nanoscale topography of the corneal epithelial basement membrane and Descemet’s membrane of the human’, Cornea, 19, 57–64.

Alio JL, Mulet ME, Zapata LF, Vidal MT, De Rojas V and Javloy J (2004), ‘Intracorneal inlay complicated by intrastromal epithelial opacification’, Arch Ophthalmol, 122, 1441–46.

Alio JL (2007), ‘Presbyopia-correcting surgery: What, when and where to do it’, OSN SuperSite, March 2007, http://www.osnsupersite.com/print.asp?rID=20917.

Allan B (1999), ‘Artificial corneas’, BMJ, 318, 821–22.

Ambrósio RJ, Tervo T and Wilson SE (2008), ‘LASIK-associated dry eye and neurotrophic epitheliopathy: pathophysiology and strategies for prevention and treatment’, J Refract Surg, 24, 396–407.

Anderson NJ, Edelhauser HF, Sharara N, Thompson KP, Rubinfeld RS, Devaney DM,

L’hernault N and Grossniklaus HE (2002), ‘Histologic and ultrastructural findings in human corneas after successful laser in situ keratomileusis’, Arch Ophthalmol, 120, 288–93.

Andrews PM (1976), ‘Microplicae: characteristic ridge-like folds of the plasmalemma’,

J. Cell Biol, 68, 420–29.

Aquavella JV (1994), ‘Major refractive surgical techniques’, Ophthalmic Surg, 25,

573–75.

116 Biomaterials and regenerative medicine in ophthalmology

Aquavella JV, Qian Y, McCormick GJ and Palakuru JR (2006), ‘Keratoprosthesis – current techniques’, Cornea, 25, 656–62.

Aumailley M (1995), ‘Structure and supramolecular organisation of basement membranes’,

Kidney Int, 47, S4–S7.

Azar DT, Pluznik D, Jain S and Khoury JM (1998), ‘Gelatinase B and A expression after laser in situ keratomileusis and photorefractive keratectomy’, Arch Ophthalmol,

116, 1206–08.

Azar DT, Ang RT, Lee JB, Kato T, Chen CC, Jain S, Gabison E and Abad JC (2001),

‘Laser subepithelial keratomileusis: electron microscopy and visual outcomes of flap photorefractive keratectomy’, Curr Opin Ophthalmol, 12, 323–28.

Azar DT, Ghanem RC, de la Cruz J, Hallak JA, Kojima T, Al-Tobaigy FM and Jain

S (2008), ‘Thin-flap (sub-Bowman keratomileusis) versus thick-flap laser in situ keratomileusis for moderate to high myopia: Case-control analysis’, J Cataract Refract Surg, 34, 2073–78.

Barber JC (1988), ‘Keratoprosthesis: past and present’, Int Ophthalmol Clin, 28, 103–09. Barnham JJ and Roper-Hall MJ (1983), ‘Keratoprosthesis: a long-term review’, Br J

Ophthalmol, 67, 468–74.

Barraquer JI (1949), ‘Queratoplastia refractiva. estudios e informaciones oftalmologicas’, 2, 10–30.

Barraquer JI (1966), ‘Modification of refraction by means of intracorneal inclusions’,

Int Ophthalmol Clin, 6, 53–79.

Beebe DC and Masters BR (1996), ‘Cell lineage and the differentiation of corneal epithelial cells’, Invest Ophthalmol Vis Sci, 37, 1815–25.

Beekhuis WH, McCarey BE, Waring GO and Van Rij G (1986), ‘Hydrogel keratophakia: a microkeratome dissection in the monkey model’, Br J Ophthalmol, 70, 192–98.

Beekhuis WH, McCarey BE, Van Rij G and Waring GO (1987), ‘Complications of hydrogel intracorneal lens in monkeys’, Arch Ophthalmol, 105, 116–22.

Belin MV (2007), ‘Boston KPro collaborative study results’, Acta Ophthalmol Scand,

85, s240.

Bergmanson JPG (2008), Clinical Ocular Anatomy and Physiology (Texas Eye Research and Technology Center, Houston, Texas). ISBN-13:978-0-9800708-0-4

Bethke W (2007), ‘Treating presbyopia from inside the cornea’, Rev Ophthalmolo News, 14:09, http://www.revophth.com/index.asp?page=1_13509.htm.

Beuerman RW and Thompson HW (1992), ‘Molecular and cellular responses of the corneal epithelium to wound healing’, Acta Ophthalmol Suppl, 202, 7–12.

Beuerman RW and Pedroza L (1996), ‘Ultrastructure of the human cornea’, Micros Res Tech, 33, 320–35.

Binder PS, Deg JK, Zavala EY and Grossman KR (1981/82), ‘Hydrogel keratophakia in non-human primates’, Curr Eye Res, 1, 535–42.

Binder PS and Zavala EY (1987), ‘Why do some epikeratoplasties fail?’, Arch Ophthalmol, 105, 63–69.

Binder PS, Rock ME, Schmidt KC and Anderson JA (1991), ‘High voltage electron microscopy of normal human cornea’, Invest Ophthalmol Vis Sci, 32, 2234–43.

Binder PS (2006), ‘One thousand consecutive IntraLase laser in situ keratomileusis flaps’,

J Cat Refract Surg, 32, 962–69.

Birk DE, Fitch JM and Linsenmayer TF (1986), ‘Organisation of collagen types I and V in the embryonic chick cornea’, Invest Ophthalmol Vis Sci, 27, 1470–77.

Borrodori L and Sonnenberg A (1999), ‘Structure and function of hemidesmosomes: more than simple adhesion complexes’, J Invest Dermatol, 112, 411–18.

Bourne WM and McLaren JW (2004), ‘Clinical responses of the corneal endothelium’,

Exp Eye Res, 78, 561–72.

Brown SI and Dohlman CH (1965), ‘A buried corneal implant serving as a barrier to fluid’, Arch Ophthalmol, 73, 635–39.

Browning AC, Shah S, Dua HS, Maharajan SV, Gray T and Bragheeth MA (2003), ‘Alcohol debridement of the corneal epithelium in PRK and LASEK: an electron microscopic study’, Invest Ophthalmol Vis Sci, 44, 510–13.

Buck RC (1983), ‘Ultrastructural characteristics associated with the anchoring of the corneal epithelium in several classes of vertebrates’, J Anat, 137, 743–56.

Burgeson RE, Lundstrum GP, Rokosova B, Rimberg CS, Rosenbaum LM and Keene DR (1990), ‘The structure and function of type VII collagen’, Ann N Y Acad Sci, 580, 32–43.

Buschke W (1949), ‘Morphologic changes in cells of corneal epithelium in wound healing’, Arch Ophthalmol, 41, 306–16.

Camellin M and Wyler D (2008), ‘Epi-LASIK versus epi-LASEK’, J Refract Surg, 24,

S57–S63.

Carrasquillo KG, Rand J and Talamo JH (2007), ‘Intacs for keratoconus and post-LASIK ectasia: mechanical versus femtosecond laser-assisted channel creation’, Cornea, 26,

956–62.

Casey TA (1966), ‘Osteo-odonto-keratoprosthesis’, Proc R Soc Med, 59, 530–1. Cenedella RJ and Fleschner CR (1990), ‘Kinetics of corneal epithelium turnover in vivo.

Studies of lovastatin’, Invest Ophthalmol Vis Sci, 31, 1957–62.

Chang CY, Green CR, McGhee CN and Sherwin T (2008), ‘Acute wound healing in the human central corneal epithelium appears to be independent of limbal stem cell influence’, Invest Ophthalmol Vis Sci, 49, 5279–86.

Chaouk H, Wilkie JS, Meijs GF and Cheng HY (2001), ‘New porous perfluoropolyether membranes’, J Appl Polym Sci, 80, 1756–63.

Chen CC, Chang JH, Lee JB, Javier J and Azar DT (2002), ‘Human corneal epithelial cell viability and morphology after dilute alcohol exposure’, Invest Ophthalmol Vis Sci, 43, 2593–602.

Chen WL, Chang HW and Hu FR (2008), ‘In vivo confocal microscopic evaluation of corneal wound healing after epi-LASIK’, Invest Ophthalmol Vis Sci, 49, 2416–23.

Chirila TV, Constable IJ, Crawford J, Vijayasekaran S, Thompson DE, Chen Y-C,

Fletcher WA and Griffin BJ (1993), ‘Poly(2-hydroxyethyl methacrylate) sponges as implant materials: in vivo and in vitro evaluation of cellular invasion’, Biomaterials,

14, 26–38.

Chirila TV, Vijayasekaran S, Horne R, Chen Y-C, Dalton P, Constable IJ and Crawford GJ (1994), ‘Interpenetrating polymer network (IPN) as a permanent joint between the elements of a new type of artificial cornea’, J Biomed Mater Res, 28, 745–53.

Chirila TV and Crawford GJ (1996), ‘A controversial episode in the history of artificial cornea: the first use of poly(methyl methacrylate)’, Gesnerus, 53, 236–42.

Chirila TV, Hicks CR, Vijayasekaran S, Lou X, Hong Y, Clayton AB, Ziegelaar BW,

Fitton JH, Platten S, Crawford GJ and Constable IJ (1998), ‘Artificial cornea’, Prog Polym Sci, 23, 447–73.

Chirila TV and Hicks CR (1999), ‘The origins of the artificial cornea: Pellier de Quengsy and his contribution to the modern concept of keratoprosthesis’, Gesnerus, 56, 96–106.

Choi CY, Kim JY, Kim MJ and Tchah H (2008a), ‘Transmission electron microscopy study of corneal epithelial flaps following removal using mechanical scraping, alcohol, and epikeratome techniques’, J Refract Surg, 24, 667–70.

118 Biomaterials and regenerative medicine in ophthalmology

Choi SK, Kim JH, Lee D, Lee JB, Kim HM, Tchah HW, Hahn TW, Joo M and Ha CI (2008b), ‘Different epithelial cleavage planes produced by various epikeratomes in epithelial laser in situ keratomileusis’, J Cataract Refract Surg, 34, 2079–84.

Choyce DP (1968), ‘The present status of intracameral and intra-corneal implants’, Canad J Ophthalmol, 3, 295–311.

Choyce DP (1982) ‘Semi-rigid corneal inlays in the management of albinism, aniridia and ametropia’, in Henkind P (Ed.), Proceedings of the 24th International Congress of Ophthalmology. San Francisco, Lippincott.

Choyce DP (1985), ‘The correction of refractive errors with polysulfone corneal inlays’,

Trans Ophthalmol Soc UK, 104, 332.

Climenhaga H, Macdonald JM, McCarey BE and Waring GO (1988), ‘Effect of diameter and depth on the response to solid polysulphone intracorneal lenses in cats’, Arch Ophthalmol, 106, 818–24.

Coassin M, Zhang C, Green WR, Aquavella JV and Akpek EK (2007), ‘Histopathologic and immunologic aspects of AlphaCor artificial cornea failure’, Am J Ophthalmol, 144, 699–704.

Colin J (2008) ‘Expert shows intracorneal rings stable over 10 years’, OSN SuperSite Top Story, http.www.osnsupersite.com/view.aspx?rid = 31222 jump.

Coskunseven E, Kymionis GD, Tsiklis NS, Atun S, Arslan E, Jankov MR and Pallikaris IG (2008), ‘One-year results of intrastromal corneal ring segment implantation (KeraRing) using femtosecond laser in patients with keratoconus’, Am J Ophthalmol,

145, 775–79.

Cotlier E (1975), ‘The lens’, in Moses RA (Ed.), Adler’s Physiology of the Eye; Clinical Applications. Saint Louis, USA, C.V. Mosby Company, pp. 275–97.

Cotsarelis G, Cheng S-Z, Dong G, Sun T-T and Lavker RM (1989), ‘Existence of slowcycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells’, Cell, 57, 201–09.

Coury AJ, Levy RJ, McMillin CR, Pathak Y, Ratner BD, Schoen FJ, Williams DF and

Williams RL (1996), ‘Degradation of materials in the biological environment’, in

Rattner BD, Hoffman AS, Schoen FJ and Lemon JE (Eds), Biomaterials Science: An Introduction to Materials in Medicine. San Diego, Academic Press, pp. 243–60.

Coutinho P, Qiu C, Frank S, Wang CM, Brown T, Green CR and Becker DL (2005), ‘Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury’, Br J Plast Surg, 58, 658–67.

Crosson CE, Klyce SD and Beuerman RW (1986), ‘Epithelial wound closure in the rabbit cornea: a biphasic process’, Invest Ophthalmol Vis Sci, 27, 464–73.

Dalton BA, Evans MDM, McFarland GA and Steele JG (1999), ‘Modulation of corneal epithelial stratification by polymer surface topography’, J Biomed Mater Res, 45, 384–94.

Dalton BA, McFarland GA and Steele JG (2001), ‘Stimulation of epithelial tissue migration by certain porous topographies is independent of fluid flux’, J Biomed Mater Res, 56, 83–92.

Dalton M (2008), ‘Presbyopia – Corneal inlays: the next big thing?’, Eyeworld News Mag, http.//www.eyeworld.orlarticle.php?sid = 4286.

Darwish T, Brahma A, Efron N and O’Donnell C (2007), ‘Subbasal nerve regeneration after LASEK measured by confocal microscopy’, J Refract Surg, 23, 709–15.

Davanger M and Evensen A (1971), ‘Role of pericorneal papillary structure in renewal of corneal epithelium’, Nature, 229, 560–61.

Dawson DG, Holley GP, Geroski DH, Waring GO 3rd, Grossniklaus HE and Edelhauser