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

6 Biomaterials and regenerative medicine in ophthalmology

The origin of the term ‘tissue engineering’ as such is controversial. It is worth discussing the issue here, not only because it involves the activity of an ophthalmologist, but also considering that Charles Vacanti has recently dismissed as invalid any recorded use of the term tissue engineering prior to that in one of his articles published in 1991 in a surgical magazine

(Vacanti and Vacanti, 1991), because – in his opinion – these earlier uses of the term do not reflect the meaning of the discipline ‘as it is currently understood’ (Vacanti, 2006). This statement not only disregards the fact that the term was already in correct use in 1987, as there is evidence that NSF was running at that time a ‘Panel on Tissue Engineering’, but also ignores the Lake Tahoe meeting and the communications presented there (Skalak et al., 1988). Furthermore, as shown below, there is documented evidence that an ophthalmologist was in fact the first to use this term in a publication pre-dating these events.

J. Reimer Wolter (1924–2003) was a highly respected ophthalmologist, both as an educator and clinician, and an outstanding histologist and pathologist.

He was educated in Germany but spent most of his career at the University of Michigan. He was the first to show in scientific detail how the eye tissue responds to implanted IOLs (Wolter, 1985) and other foreign materials, and he is regarded as the founder of modern ophthalmic cytopathology. Wolter was also an expert in retinal and orbital surgery, a pioneer of laser ophthalmic surgery, and he made contributions to paediatric ophthalmology and ophthalmic neuropathology. In 1984, he reported in detail the cytopathological findings of a keratoprosthesis explanted from a patient almost 20 years after implantation (Wolter and Meyer, 1984), an extraordinarily long retention for an artificial cornea, by any standard. The prosthesis was of the ‘through-and- through’ type, with a fenestrated skirt of Teflon and an optical zone made

(probably) from PMMA. Wolter’s analysis demonstrated that the skirt was embedded in the corneal stroma without inflammatory reaction. He also detected two transparent membranes: an acellular membrane formed on the anterior prosthetic surface and a cellular membrane on the posterior surface generated by macrophages that differentiated into fibroblasts. Remarkably, both membranes were transparent. Wolter hypothesized that the eye was able to produce membranes to separate the implant from the anterior chamber, and interpreted the formation of the retroprosthetic membrane as a cellular response to prevent light scattering induced by the abnormal presence of the foreign material; in other words, as if the presence of the keratoprosthesis ‘engineered’ the formation of the membranes. As a concluding remark, the paper contains (Wolter and Meyer, 1984, p. 198) the following statements.

This membrane took the place of the endothelium and it remained clear for 20 years. Nature impresses us with a great variety of reactive possibilities in the adaptation of its tissues to new conditions and substances. Sound

progress in medicine is easiest when we work along with the physiological currents of beneficial reaction and adaptation. To understand the direction and the limits of nature’s reactions is always the first step toward progress in tissue engineering.

The term ‘tissue engineering’ was used again on the same page, in the summary section of the article, where it was emphasized that the study revealed the ‘significance of the successful adaptation of the plastic materials of the prosthesis to the tissues of the cornea and the fluids of the inner eye for the future of tissue engineering in the region of the eye […]’ (Wolter and Meyer, 1984). There is no doubt in my mind that – considering Wolter’s erudition and integrity, as well as the diversity of his research interests – he used the term precisely to describe a field as he comprehended it, and there is no reason to doubt that his understanding of the term coincided with, or at least was very close to, the current meaning. Whether this will be accepted or not by the tissue engineering community is irrelevant, but it is reassuring that some leading investigators have acknowledged Wolter’s first use of the term (Godbey and Atala, 2002).

In a thought-provoking essay (Williams, 2006), which perhaps should be read by all those working in the field, David Williams made a critical analysis of the current central tissue engineering paradigm. He concluded that a reason why tissue engineering has yet to deliver the expected clinical outcomes is that not only the paradigm, but also some concepts and the definition itself, might be wrong, and suggested that a combination of systems engineering and systems biology approaches will provide the conditions for cells to generate the required tissue in circumstances that are not normal. He went further and proposed a more adequate definition of tissue engineering (Williams, 2006): ‘Tissue engineering is the creation of new tissue for the therapeutic reconstruction of the human body, by the deliberate and controlled stimulation of selected target cells, through a systematic combination of molecular and mechanical signals.’

Tissue engineering should be regarded as ‘a major part of regenerative medicine’ (Atala, 2007). The term ‘regenerative medicine’ is currently described by even more definitions than the terms ‘biomaterials’ and ‘tissue engineering’ put together, which is obviously suggestive of the variety of interpretations resulting from different opinions on both the aim of this discipline and the contributing disciplines. Consequently, many prominent investigators, including William Haseltine, who introduced the term (Haseltine,

2001), have made commendable efforts to formulate a consensus definition that would adequately and correctly incorporate the whole diversity of this emerging medical field (Haseltine, 2003; Mironov et al., 2004; Greenwood et al., 2006; Daar and Greenwood, 2007; Ingber and Levin, 2007; Mason and

Dunnill, 2008). In the most thorough analysis to date, Daar and Greenwood

8 Biomaterials and regenerative medicine in ophthalmology

critically and objectively discussed a range of existing definitions, and proposed a definition that captures the essence of regenerative medicine

(Daar and Greenwood, 2007), a part of which is reproduced below.

Regenerative medicine is an interdisciplinary field of research and clinical applications focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function resulting from any cause, including congenital defects, diseases, trauma and ageing. It uses a combination of several converging technological approaches, both existing and newly emerging, that moves it beyond traditional transplantation and replacement therapies.

The definition is actually longer, further disclosing that the main role of these approaches is to trigger self-healing processes, for which bioactive molecules, stem/progenitor cell therapy, gene therapy and tissue engineering can be used (Daar and Greenwood, 2007). Aiming at formulating a more convenient definition for communications between scientists and public, other researchers processed the above definition and provided a much abbreviated version (Mason and Dunnill, 2008): ‘Regenerative medicine replaces or regenerates human cells, tissue or organs, to restore or establish normal function’.

Prosthetics and transplantation are not generally regarded as valid approaches in regenerative medicine, since ‘replacement’ is fundamentally different from ‘regeneration’. Essential to regenerative medicine is also the distinction between ‘repair’ and ‘regeneration’ (Yannas, 2001; Yannas, 2005; Mason and

Dunnill, 2008), in other words the response of adult mammals to any injury that causes loss of tissue or organs. While the spontaneous repair process can accomplish the healing of a wound through contraction and formation of scar tissue, but cannot restore the original integrity and function, the process of regeneration performs full healing by synthesizing the missing tissue or organs and recovering normal structure and function. There is, however, an insurmountable problem: true regeneration never occurs in adult mammalian organisms. In humans, it only occurs in the foetus during the first 6 months of gestation. In adults, the only alternative to replacement or repair is

‘induced regeneration’, a process defined by Yannas as ‘the synthesis of non- regenerative tissues in a severely injured adult organ that leads to, at least partial, recovery of physiological structure and function’ (Yannas, 2005). To achieve induced regeneration is the cornerstone of regenerative medicine. In attempting this process, the investigators frequently use scaffolds, which in most cases have a biomaterial component, and cellular therapies. Episodes of induced regeneration have been reported so far in skin, peripheral nerves, bone, heart valves, articular cartilage, urological organs and spinal cord. It is important to note, in the context of this book, that induced regeneration has been also reported in conjunctiva (Hatton and Rubin, 2005) and cornea

(Kinoshita and Nakamura, 2005).

Haseltine predicted an ongoing role for biomaterials in regenerative medicine, but he emphasized that they should fully integrate with the living cells (Haseltine, 2001). He also included the use of electronic devices to replace sensory functions (Haseltine, 2003); at least formally, the materials of such devices should be regarded as biomaterials. It is accepted (Mironov et al., 2004; Daar and Greenwood, 2007) that biomaterials can be involved in regenerative medicine in a variety of ways, for instance as components of delivery systems for bioactive molecules, as nanostructured materials developed to provide new regenerative strategies, or as constituents of tissue-engineered constructs involved in certain approaches to induced regeneration.

The translation from the laboratory to the clinical setting of tissue engineering and regenerative medicine procedures has begun in respect to many specific organs (Atala, 2007; Furth and Atala, 2008; Tubo, 2008). However, in spite of occasional sensationalization in the press of laboratory-scale achievements, only a few products are commercially available and approved for clinical use; and these are almost entirely limited to the regeneration of skin (Mansbridge,

2006; Russell and Bertram, 2007; Tubo, 2008) or cartilage (Russell and Bertram, 2007; Tubo, 2008). In the eye, examples of tissue engineering applications have been reported mainly in the anterior segment (cornea, conjunctiva). As it is accepted that the scaffolds can be either biodegradable or non-biodegradable (Langer and Vacanti, 1993; Williams, 2008), the ‘core- and-skirt’ keratoprostheses with a porous skirt (Chirila, 1994; Chirila, 1997; Chirila et al., 1998; Chirila, 2001; Duan et al., 2006; Sheardown and Griffith,

2008) may be legitimately regarded as an early example of ophthalmic tissue engineering. One such artificial cornea (Chirila et al., 1994; Crawford et al.,

2002; Hicks et al., 2003), available commercially as AlphaCor™, is in routine clinical use in humans in a number of countries. Current tissue engineering and regenerative medicine applications in the ocular field include constructs to replace damaged full-thickness cornea (tissue-engineered corneal equivalents) (Germain et al., 2004; Duan et al., 2006; Ruberti et al., 2007), which will obviate the need for keratoprostheses, and constructs for the restoration of ocular surfaces that have been damaged as a result of pathological disorders or trauma leading to the loss of epithelial stem cells (Nishida, 2003; Selvam et al., 2006; Boulton et al., 2007). Significant advances have been made in cellular therapies for treating retinal degenerative conditions (Lund et al.,

2001; Klassen, 2006; Lamba and Reh, 2008). Some progress has been made in the field of visual prostheses for restoration of vision in retina-blind people (Maynard, 2001; Weiland and Humayun, 2003; Dagnelie, 2007); although these developments involve biomaterials and elements of tissue engineering, they are essentially based on electronic engineering and neurostimulation techniques. In recent years, some efforts have been made to understand the mechanism of regeneration of the eye’s crystalline lens and to investigate the possibility of creating such lenses by tissue engineering/regenerative

10 Biomaterials and regenerative medicine in ophthalmology

medicine approaches (Sommer et al., 2006; Tsonis, 2006). Some preliminary investigations of the regeneration of the retina have also been reported (Sommer et al., 2006).

1.4References

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2

Advances in intraocular lens development

D. Morrison, B. Klenkler, D. Morarescu and H. Sheardown, McMaster University, Canada

Abstract: While cataracts are relatively easily treated by removal of the existing lens and its replacement with a synthetic lens, problems remain. These lenses are subject to a high incidence of secondary complications including the formation of secondary cataracts in as many as 40% of patients. Furthermore, the majority of existing intraocular lenses are unable to accommodate for vision. However, there have been a number of improvements to the materials and the lens design which have been demonstrated to and which have the potential to decrease the incidence of secondary cataracts. Additionally, new developments in the field of lens

design have led to lenses that show some degree of accommodation. These are discussed in the current chapter. The chapter also highlights the results of research that may lead to truly accommodating systems in the future.

Key words: intraocular lens, posterior capsule opacification, silicone, acrylic, accommodation.

2.1Introduction

Cataracts, responsible for the majority of blindness worldwide, and an evitable consequence of the ageing process, lead to changes in the structure of the lens resulting in the formation of opacities. However, cataracts are relatively easily treated, particularly in the developed world, by the replacement of the diseased lens with a synthetic replacement. These intraocular lenses (IOLs) have been highly successful at restoring the vision of millions of patients worldwide. However, the formation of secondary cataracts or posterior capsule opacification (PCO) remains a significant problem, occurring in as many as 40% of adult patients and a considerably greater fraction of paediatric patients. These secondary cataracts require subsequent treatment, are a burden to the healthcare system and an inconvenience to the patient.

However, significant materials and manufacturing developments have resulted in a decrease in the incidence of PCO. Furthermore, current IOLs are unable to provide accommodative vision. Ongoing work aimed at further improving the success of IOL materials, including surface modifications and new materials, are highlighted in this chapter.

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2.2Native lens structure

The lens, a biconvex crystalline structure located behind the iris, is responsible for approximately 30% of the refractive power of the eye (Andley, 2007). It is generally considered to be composed of three layers: the nucleus, cortex and epithelium (Fig. 2.1); these layers are housed within the lens capsule, a bag-like structure approximately 10 mm in diameter with an axial length of 4 mm. The lens is suspended within the eye by zonular fibres which act to attach the lens capsule to the ciliary body.

The lens epithelium consists of cuboidal cells that differentiate into the cortical fibres that constitute the bulk of the lens. These lens fibres are tightly packed and contain no organelles or nuclei; they do contain proteins called lens crystallins. Lens fibres are continually added throughout life, thereby causing the lens to increase in size, eventually becoming denser, and more convex and less elastic, all of which contribute to an eventual decrease in the ability to focus light adequately.

2.3Cataracts

Lens transparency is regulated in vivo by physical and chemical processes that, when disturbed, result in lens damage and opacification. The term ‘cataract’ has been traditionally used in a broad sense to mean any opacity or loss of transparency of the lens. Typically, cataracts are defined as lens opacities that cause some degree of visual impairment. Age-related cataracts are the most common type of cataracts; however, cataracts result from several different promoting factors including direct trauma to the eye, diabetes mellitus, heavy smoking and exposure to ultraviolet (UV) radiation. Regardless, the physiological factor leading to cataract formation appears to be the insufficient supply of nutrients to deep lens fibres (Marieb, 2001). This lack of nutrients promotes the clumping of crystalline proteins within the lens fibres. Cataracts are the leading cause of blindness worldwide, accounting for nearly 48%

Cortical fibres

Nuclear fibres

Posterior