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

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5.1The cornea

The cornea is a transparent tissue, acting not only as the eye’s main refractive constituent, but also as a physical barrier to protect the interior ocular elements.1 It consists of three cellular layers – the epithelium, the stroma and the endothelium – which are in turn separated by discrete layers, namely Bowman’s layer and Descemet’s membrane. The epithelium mainly contains three cell types that are tightly organized into five to seven layers, providing much of the cornea’s protective barrier functions. The stroma is the thickest and strongest part of the cornea, consisting mostly of water and collagen fibrils, with keratocyte cells found within the fibril network. The endothelium is a single layer of cells, organized hexagonally, and regulates corneal hydration. As the cornea reflects light on to the retina, any damage or opacification of the organ will result in vision impairment or blindness.2

5.2The need for an artificial cornea

According to the World Health Organization, vision loss due to corneal disease, trauma, scarring or ulceration constitutes to the second leading cause of blindness,3 roughly affecting 10 million people worldwide4. In fact, 1.5–2 million new cases of corneal blindness occur annually as a result of corneal trauma or ulceration.4

The most successful and accepted treatment for corneal blindness is corneal allograft surgery, also known as penetrating keratoplasty, whereby donor tissue is implanted into the host cornea. Although 80% success rates are achieved within the first 2 years,4 this rate falls to 65% 5 years post-surgery,5 and is further complicated by underlying corneal damage or disease.1 There are also disease transmission risks associated with allograph surgeries, primarily HIV and hepatitis.6 Furthermore, there is a shortage of donor tissue, with surgery wait times averaging 2 years in North America; these wait times are only expected to lengthen due to an ageing population4 and the increased popularity of laser in situ keratomileusis (LASIK) surgery, which renders the cornea unsuitable for transplantation.6 An attractive alternative is therefore artificial replacement of the cornea, either with a keratoprosthesis or a tissue -engineered corneal equivalent (TECE).2

5.3Artificial cornea

The artificial cornea must be non-toxic and able to interact well with surrounding corneal cells and tissue, transparent with a refractive index similar to the native cornea, be strong enough to withstand intraocular

pressure, and allow for oxygen and nutrient diffusion to keep remaining corneal cells viable.1,2,6,7 Current artificial corneal devices can be considered

as keratoprostheses, which are made from synthetic polymers, or as tissueengineered corneal equivalents, which are typically made from natural polymers combined with a biological component.7

5.4Keratoprostheses

Keratoprostheses (KPros) are typically designed as a collar button device, also referred to as the optical stem with skirt implant, or as a core and skirt device.8 The former design has two plates joined by an optical core, while the latter design has an optical core surrounded by a skirt used to anchor the device into the stroma. The optical core in both designs should be transparent and as a short as possible to avoid anterior chamber penetration,9 while device segments intended for anchorage must be flexible but durable to withstand placement and suturing.8 In many designs, the skirt is porous to allow for nutrient and oxygen diffusion and for device integration with the host’s tissue,4 with pore sizes being able to accommodate cell–cell interactions and extracellular matrix deposition.6 The anterior surface of the KPro should encourage epithelialization to promote tear interactions, but avoid epithelial downgrowth to avoid device extrusion.7 Furthermore, the posterior should inhibit cell integration to maintain device clarity on the optical core.

Early KPros fabricated from gold, quartz, and glass were met with a high incidence of device extrusion.9,10 In the late 1940s, the second generation of

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KPros were fabricated from synthetic polymers, the first being composed of poly(methyl methacrylate) (PMMA).10 However, a variety of polymer materials have been examined in this application including polytetrafluoroethylene (PTFE),polybutylene:polypropylene,polyurethane,Dacron,poly(2-hydroxyethyl methacylate) (PHEMA) and poly(dimethyl siloxane) (PDMS).2,10

Synthetic KPro devices are advantageous owing to their potential for off-the-shelf availability, their durability in the prevention of postoperative remodeling, and a reduction in the risk of disease transmission that is associated with allograft surgeries.2 However, KPros often fail to interact sufficiently with host tissue which results in device extrusion, tissue rejection (in the form of stromal melting and epithelial thinning), aqueous humour

leakage, infection, retroprosthetic membrane formation, retinal detachment and glaucoma.6,7,11

5.4.1Dohlman–Doane Keratoprosthesis

The Dohlman–Doane KPro (D-KPro) is a PMMA collar button device that sandwiches the corneal tissue between 2 plates.12,13 It has been approved by

the United States Food and Drug Administration and has been implanted in over 190 eyes since the 1990s.12,13 There are 2 PMMA prototypes: type I

is utilized for patients with good ocular surface hydration, while type II is intended for patients with ocular surface disease – such as dry eye, ocular

mucous membrane pemphigoid, or Stevens–Johnson syndrome – who thus can not support the type I device.12,13 A third prototype has been created

with a titanium ring to enhance mechanical stability.12

Following implantation in 63 eyes between 1990 and 1997, 6 devices required replacement, while 10 devices were permanently removed.14 Complications associated with the D-KPro were glaucoma (46%), retroprosthetic membrane (37%), tissue melting (29%), retinal detachment (19%) and endophthalmitis (8%). Although visual acuities between 20/20 and 20/200 were initially achieved, 42% of patients lost vision improvements because of device complications. Preoperative conditions were attributed to complications, with non-cicatrizing conditions, such as graft failure, having the best outcomes, while the Stevens–Johnson syndrome group had the worst outcomes. Elsewhere, histological analysis revealed epithelial downgrowth.13

Further development of both the design and surgical and postoperative techniques (anti-inflammatory agents, contact lens bandages, antibiotics, shunts, etc.) resulted in no device extrusion and improved visual acuity.15,16 Furthermore, no occurrences of endophthalmitis, reoperations, dislocations or extrusions of 25 implanted D-KPros have been reported as of 2005.17

5.4.2Osteo-odonto keratoprosthesis

The osteo-odonto KPro (OOKP) has a PMMA optic, which is secured to a haptic made from a tooth root, containing its alveolar ligament, belonging to the patient or a compatible donor.18 Long-term studies of 224 eyes beween 1973 and 1999 demonstrated 85% retention over 18 years with fewer instances of complications;18 however, there are concerns regarding increased intraocular

pressure and resorption of the bone, owing to chronic inflammation, which loosens and leads to the eventual failure of the device.19,20 Synthetic OOKP

devices have been fabricated from aluminum oxide, hydroxyapatite (HA) ceramic and glass ceramic.20 However, degradation of corals, HA-based materials, tooth and bone was rapid and may not be suitable for the ocular environment; hence more chemically stable materials are necessary.20

5.4.3Seoul-type keratoprosthesis

The Seoul-type KPro (S-KPro) consists of a PMMA optic, of the collar button design, surrounded by a polyurethane or polypropylene skirt, which is secured to the cornea, with monofilament polypropylene haptics that are secured to the sclera for enhanced mechanical stability.21 Preliminary animal in vivo studies with both prototypes demonstrated fibroblast integration, collagen deposition and corneal neovascularization, and only mild tissue necrosis and inflammation, with the polypropylene device performing best.22 However, short-term human trials using the polypropylene prototype demonstrated tissue melting around the skirt, which may have been related to preoperative conditions.21 Other complications included retroprosthetic membrane formation, retinal detachment, glaucoma and endophthalmitis.21 Long-term usage of S-KPro, resulted in visual rehabilitation for about 32 months; however, instances of tissue melting and exposure of the skirt after approximately 13 months and retinal detachment following S-KPro exchange, which was attributable to poor vitrectomy techniques, were also evident.23 Further in vivo animal research to improve vitrectomy techniques following device exchange resulted in a decrease in retinal detachment and may enhance the long-term success of the S-KPro.24

5.4.4AlphaCor keratoprosthesis

Previously referred to as the Chirila KPro, the AlphaCor KPro, is a core and porous skirt design, all composed of PHEMA.9 Initially there were two prototypes: type I is intended for patients with an intact conjuctival flap and is no longer available; type II, which has a smaller diameter, is less invasive, does not require a healthy conjuctiva and can be reversed if required.

As of February 2006, 322 AlphaCor KPro devices have been implanted in

138 Biomaterials and regenerative medicine in ophthalmology

the United States, Europe and Australia with 416 patient years of experience.25 Retention of this device after 1 year is high, approximately 80%, as a result of stromal fibroblast integration into the porous skirt; however, tissue melting, retroprosthetic membrane formation, optic damage and in some cases opacification due to calcification of the KPro can occur.25,26 Extracted devices have provided evidence of stromal cell integration, along with chronic inflammation.27–29 Omitting the second-stage surgical procedure, whereby the implant is exposed to the external surface of the eye, resulted in improved KPro outcomes, including longer device (14–38 months) tolerance, despite having a non-functioning endothelium; however, it is unknown how this will affect corneal hydration.30

5.4.5BIOKPro device

There are three prototypes of the BIOKPro device: type I has a PMMA optic core while types II and III are composed of silicone with a polyvinylpyrrolidone coating; all have porous PTFE haptics.31 Following implantation, the BIOKPro I demonstrated tissue integration through keratocyte migration and collagen production.32 Clinical trials with 11 devices implanted for 5 years were less successful, with evidence of glaucoma, tissue necrosis, device extrusion, endophothalmitis, lens dislocation and retroprosthetic membrane formation.33 Only 36% were retained, with 8 cases of melting, 10 cases of retroprosthetic membrane formation, 5 cases of endophthalmitis and 4 cases of device extrusion33. BIOKPro II had increased short-term clinical success with increased keratocyte integration and few corneal complications34. Although long-term studies with this KPro were more successful than those for type I (38% failure), there were still instances of skirt exposure, retroprosthetic membrane formation, endophthalmitis and device extrusion.31 Further design led to the development of the BIOKPro III, which has a smaller optic and larger skirt, in comparison with BIOKPro II.35 However, long-term human implantation results were disappointing, with only 1 of 7 devices remaining intact.

5.4.6SupraDescemetic keratoprosthesis

The SupraDescemetic KPro (SDKP) can be fabricated from PMMA, or copolymers of PHEMA with MMA (PHEMA-MMA) or N-vinylpyrrolidinone (PHEMA-NVP).36 Following implantation into seven rabbit corneas, these KPros were well tolerated after 8 weeks, and there was no evidence of inflammation in five eyes, with mild inflammation in the remaining two eyes, and no cases of retinal detachment.36 Subsequent long-term studies in rabbits revealed 100% of the PHEMA-MMA, 80% of the PMMA and 60% of the PHEMA-NVP devices retained transparency.37 Furthermore,