Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010
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the book, deal with the present status of ophthalmic biomaterials and their physicochemical and biological properties. This book also includes the more recent areas of biomedical investigation, tissue engineering and regenerative medicine, which aim to make or reproduce living tissues by combining materials science and cell biology.
Among the early investigators who made fundamental contributions to biomaterials, especially in ophthalmology, were Wichterle and Lim, in what was then Czechoslovakia, with their work in acrylic hydrogels, and in particularly with their invention of the hydrogel (soft) contact lenses, made of poly(2-hydroxyethyl methacrylate) (PHEMA) incorporating 38% water, an invention that was eventually refined in the USA and in other countries with great clinical and commercial success. The PHEMA hydrogel contact lens was the beginning of a series of hydrogel lenses, mostly made of HEMA copolymers, but also of hydrogels from copolymers of other hydrophilic monomers, with improved physiological properties due to improved oxygen transmissibility to the cornea, mainly a result of the higher water content and/ or lower lens thickness, compared with the original PHEMA lenses. At about the same time, several companies in the USA, France and Japan, introduced the silicone rubber contact lenses that provided optimal oxygen transmissibility to the cornea. Nevertheless, as a result of some unfavorable physical and mechanical properties of the silicone lenses, even after hydrophilic surface treatments and despite changes in lens design, their use was essentially terminated because they were too uncomfortable.
Another fundamental contribution to contact lens materials, in this case in order to improve the original oxygen-impermeable rigid PMMA lenses, was that of Gaylord and Seidner, in the USA; they developed the first rigid oxygen-permeable contact lens, made from a copolymer of MMA and methacryloxypropyl-tris(trimethylsiloxy) silane (TRIS). This material was followed by a series of rigid contact lens materials based on the same idea. The rigid gas-permeable lenses are very good as far as oxygen permeability and optical correction are concerned, but they are less comfortable, at least initially, than the hydrogel lenses. The last important development in contact lens materials has been the siloxane–hydrogel lenses that aim to have the comfort of the conventional hydrogel lenses and the oxygen permeability of the siliconeand/or TRIS-containing lenses. The priority of the invention of the siloxane–hydrogel family of contact lens materials is contentious. Nevertheless, a patent with such a claim, one of the two first generation siloxane–hydrogel contact lenses approved by the US Food and Drug Administration (FDA), is credited to 18 inventors from 3 continents. As far as nomenclature is concerned, in my opinion, silicone–hydrogel is correct when the material contains polysiloxane (silicone) moieties. However, if the hydrogel contains only TRIS or TRIS-like moieties, instead of silicone, the siloxane–hydrogel nomenclature is the correct one. Furthermore, the name
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siloxane–hydrogel is correct for both kinds of hydrogels, with silicone and/ or TRIS moieties.
In this book, there are chapters dealing with aspects of contact lens materials. Although corneal contact lenses are not surgical devices, but medical devices used on the ocular surface for optical correction or for therapeutic or cosmetic use, they must be approved, as must all medical devices, by the proper governmental agencies, such as the FDA in the USA. Some biomaterial devices are implanted into transparent corneas for optical correction. On the other hand, artificial corneas (keratoprostheses) are implanted in opaque corneas to restore vision to eyes that would not tolerate corneal tissue transplanted from donor eyes.
Eyes with cataract recover vision after the surgical extraction of the opaque crystalline lens, vision that is highly improved after the implantation of an intraocular lens (IOL) made of biomaterials. The original IOLs were made of PMMA, and were implanted in the eye through the relative large incision required for the extraction of the crystalline lens. However, a new cataract surgical procedure (phacoemulsification) was conceived in the late 1960s by Kelman, an ophthalmologist in New York, a procedure that emulsifies and removes the cataractous lens through a small incision. Then, new IOLs were developed made of hydrogels, silicone rubber or novel acrylic polymers that can be folded in such a way that they can be introduced into the eye through a small incision, and then unfold into the eye. In special cases of phakic eyes in need of a special optical correction, IOLs are implanted in eyes without removing the transparent crystalline lens. IOLs, as well as contact lenses, are among the biomedical devices most frequently used all over the world, and their present status and related research activities are dealt with in this book.
Other applications of polymeric biomaterials in the eye are as glaucoma implants that are used to lower the intraocular pressure by draining aqueous humor from the anterior chamber of the eye into the tissues of the external periphery of the eyeball where the aqueous is reabsorbed.
Biomaterials are used for the reattachment of detached retinas, by means of scleral buckling implants that restore the contact between the retina and the subretinal tissues, by neutralizing the traction of the shrinking vitreous on the retina. For some complicated cases of giant retinal detachment, a vitreous substitute is the only alternative to restore some degree of vision to such blind eyes. The objective in this procedure is to inject intravitreously a substance that will push the detached retina into its normal position, over the choroid, and retain it there. This procedure is currently performed with injections of gases or low viscosity perfluorocarbon liquids that are reabsorbed or removed from the eye in a relatively short postoperative time. These gases or liquids are exchanged in most cases by a vitreous substitute that will maintain the retina in its normal place for a longer time. Despite many
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attempts with biological polymers, such as the viscoelastic gel hyaluronan, and diverse viscous solutions of other biopolymers or synthetic hydrophilic polymers, and high water content hydrogels, the only long-lasting vitreous substitute actually in use is the hydrophobic silicone oil, with a viscosity that is 1000–2000 times higher than water. Silicone oils act as a good tamponade against the effusion of subretinal fluid in to the vitreous cavity and support the detached retina onto the choroid. Nevertheless, silicone oil is far from an ideal vitreous substitute, and new directions of research are presented in this book.
Surgicaladhesives,suchasthemonomerbutylcyanoacrylatethatpolymerizes in situ in the presence of moisture, have been used in ophthalmology, mainly for closing corneal leaking wounds or ulcers while they heal. Other synthetic or biological polymeric adhesives for ophthalmic use have been investigated or are under investigation, as shown in this book. Polymeric biomaterials, biodegradable or non-biodegradable, are used also in devices for sustained delivery of drugs on and into the eye.
Up to this point, my comments have dealt essentially with the past and present of ophthalmic biomedical materials and devices that are most familiar to me. A number of chapters in the book deal with relatively new fields of research, tissue engineering and regenerative medicine, which are, somewhat, related to biomaterials, and aim to create a fantastic future for ophthalmology. I do not have personal experience in these fields of research, but I am aware of the excellent work of some of the authors, and I expect that the interested reader will find this portion of the book very enlightening.
In my opinion, this book can be highly recommeneded to scientists, engineers, ophthalmologists and optometrists, in academia or industry, in laboratory or clinic, who are interested in any aspect of biomaterials and regenerative medicine as applied to ophthalmology.
Miguel F. Refojo, D.Sc. Senior Scientist Emeritus, Schepens Eye Research Institute Associate Professor of Ophthalmology (Ret.), Harvard Medical School Boston, MA, USA
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Preface
This is the first book dedicated to ophthalmic biomaterials and ophthalmic tissue engineering and regenerative medicine. Strictly speaking, about a decade ago there was an attempt to publish such a book, following an invitation that I received from the editors of the journal Progress in Polymer Science to guest-edit a special issue. The result appeared in 1998 as issue number 3 of volume 23, having the additional title ‘Polymer Science and the Eye’ on the title page (but not on the cover). It contained eight contributions covering not only ocular biomaterials but also the macromolecular structure of ocular tissues. I was fortunate in securing the participation of some high-calibre contributors such as Miguel Refojo, Jorge Heller, Simon Ross-Murphy, Robert Gurny, Robert Augusteyn and Vickery Trinkaus-Randall. However, a subscription-restricted circulation (it was not marketed as a book) and a rather small number of chapters dedicated specifically to biomaterials could not make that journal issue into a representative multi-author textbook in the field of ophthalmic biomaterials. I hope that the present book will be regarded and employed in such a capacity, providing a comprehensive coverage of these materials and their use for the repair and regeneration of eye structures through the techniques of tissue engineering and regenerative medicine. To this end, a collection of chapters was assembled that focuses on the materials used in ophthalmic surgery, with emphasis on certain applications and advanced methodologies for the reconstruction of ocular elements. We did not intend to have a collection of unrelated chapters, and have made efforts to achieve, at least in part, a coordinated general outlook.
I feel privileged to propose this book as a tribute to Miguel Refojo. Although I have not asked them, I am sure that the other contributors will give their consent. Miguel is the scientist who established the macromolecular basis of ophthalmic biomaterials. He did this at a time when most of the
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few clinicians who manifested any interest for ocular prosthetic materials were using the word ‘plastic’ in their reports to denote PMMA exclusively, as they were not aware that other polymers may also exist.
Miguel was born in 1928 in Santiago de Compostela, Spain. He studied at the University of Santiago where he obtained a doctorate in organic chemistry in 1956. After a 3-year postdoctoral stint at Yale University and a few years as a senior research chemist at DuPont Canada in Ontario, Miguel became a researcher at the Retina Foundation (now Schepens Eye Research Institute, SERI) in Boston, Massachusetts, where he stayed for the next 35 years. He retired in 1998 as the head of the Biomedical Polymers Laboratory at SERI and an associate professor at Harvard Medical School. Between 1965 and 1968, Miguel published a series of about ten articles regarding the synthesis, structure, properties and characterization of acrylic hydrogels and their applications in ophthalmology. These papers stood the test of time. They contributed essentially to the progress of hydrogels research, while also providing a scientific foundation for the emerging field of ophthalmic biomaterials. Subsequently, Miguel’s interests expanded, and during his career he investigated almost all aspects of ophthalmic biomaterials, including: vitreous substitutes (c. 30 papers); materials for episcleral buckling in the treatment of retinal detachment (c. 20 papers); contact lens materials (c. 50 papers); controlled release of ocular drugs (c. 20 papers); ocular adhesives; corneal implants; IOLs; ocular pharmacology; and tear film physiology. He also wrote five general reviews on ophthalmic biomaterials and 32 book chapters, most of them regarded as standard references in our field, and obtained ten US patents for his inventions. Miguel’s achievements were recognized through many awards and honours, and I shall mention here the prestigious Ruben Medal from the International Society for Contact Lens Research (1997), the Clemson Award from the Society for Biomaterials (2000) and the Wichterle Medal from the Czech Contactology Society (2002). Miguel accepted the invitation to write a foreword to this book with grace, and I cannot think of anyone more appropriate to do so.
I am grateful for the confidence and support from Woodhead Publishing Limited who invited me to edit this book. Special thanks are due to Laura Overend (née Bunney), the Commissioning Editor, who first approached me on behalf of the publisher – we worked together to select and recruit potential contributors; and to Lucy Cornwell, Publications Co-ordinator, who ensured that the processing of submissions became a pleasant activity. I am enormously indebted to those who agreed to contribute and write the chapters that form this book. Finally, I thank the management of the Queensland Eye Institute in Brisbane, Australia, for allowing me to carry out much of my editorial work during working hours.
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An introduction to ophthalmic biomaterials and their application through tissue engineering and regenerative medicine
T. V. Chirila, Queensland Eye Institute, Australia
Abstract: This chapter presents a brief history of the development of ophthalmic biomaterials. Particularities in the development of ophthalmic biomaterials are discussed and some of their historic priorities within the general field of biomaterials are revealed or emphasized. The chapter then discusses the role and integration of ophthalmic biomaterials in tissue engineering and regenerative medicine applications.
Key words: ophthalmic biomaterials, polymers, tissue engineering, repair, regenerative medicine.
1.1Introduction
The ultimate goal of the research and development of materials (other than drugs) for applications in medicine, which we call biomaterials, has always been to emulate natural materials. Since the natural target for biomaterials, i.e. our body’s tissues and organs, is exceedingly complex, it is not surprising that in many instances the laboratory-made materials cannot match in their performance the natural entities they are meant to augment or replace. This is obviously different from the development of materials for industrial applications, which usually perform better than their natural counterparts (if the latter exist), and also evolve relatively fast, unhindered by biological constraints. For too long, an acceptable end-performance in the short term was the main requirement from a biomaterial, with little attention paid to changing its bulk and/or surface properties through the manipulation of composition and/or structure, in order to maximize the clinical outcome. Over the past six decades or so, however, the progress in bringing the properties and functionality of biomaterials close to those of their biological targets has been remarkable. While the above statements are also valid for ophthalmic biomaterials, their development has shown some particular features. The general developments in the field of biomaterials have customarily been gauged through the achievements in the branches of orthopaedic biomaterials and – to a lesser extent – biomaterials for cardiology while the progress of ophthalmic biomaterials has usually been ignored or seldom presented.
There are many definitions of the concept of ‘biomaterials’, all conveying
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essentially the same message (Ratner et al., 2004). Nevertheless, the term can also be used for ‘biological materials’, and attempts have been made to reconcile such dual meaning (Nerem and Sambanis, 1995). I shall not delve further into terminological aspects except for warning against some unacceptable inconsistencies such as: the use of ‘biopolymer’ instead of ‘biomaterial’; using the term ‘biomaterials’ exclusively for natural biological materials or, worse, to describe specifically biological matter deposited on non-biological substrata; and the more recent use of the qualifier ‘biosynthetic’ to designate a biomaterial resulting from the combination of a biopolymer with a synthetic polymer. In my role as an editor, I devoted much attention to avoiding such ambiguities throughout this book.
During the last two centuries, a large variety of biomaterials have been reported including metals, minerals, ceramics, wood, biopolymers and synthetic polymers. Most materials to be placed in the eye must be transparent, and this prerequisite is indeed unique to the ophthalmic biomaterials. Consequently, the focus of this book will be synthetic polymers, biopolymers (as such or modified), and combinations of the two, as the other materials are not normally transparent. Although no longer in use today, glass and quartz were the biomaterials of choice for ophthalmic applications before polymers became available, for instance in artificial corneas (Chirila et al., 1998; Chirila and Hicks, 1999; Chirila et al., 2005) and contact lenses (Feinbloom,
1932; Dallos, 1936; Heitz, 1984; Barr and Bailey, 1991). Opaque materials, such as ceramics, may still have minor uses in the eye, but only at locations outside the vision pathway.
1.2Development of ophthalmic biomaterials: a brief history
In discussing here the evolution of ophthalmic biomaterials I will avoid the rather disconcerting trend of regarding, and even formally citing, biblical stories and anecdotal sources involving saints or other mythical characters, as scientific literature allegedly documenting some sort of respectable antiquity of the disciplines of biomaterials and tissue engineering. With all due respect to anyone’s personal beliefs, these sources clearly do not constitute scientific evidence.
The eye is an organ of great complexity, yet it is more accessible to medical observation and surgical manipulation than most of our organs. This probably explains why the eye was the organ in which the first transplantation of donor tissue was successfully performed in humans (Zirm, 1906). Rather inexplicably, Zirm’s transplantation of a donor cornea is still not recognized as being the first organ transplantation from a human donor to a human recipient. This accolade is usually reserved for the kidney transplantation reported much later (Murray et al., 1955), even though the latter was performed in identical
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twins, while the former involved non-related human subjects. However, prior to the episode of corneal transplantation, the eye was also the organ where foreign materials were implanted for the first time with the purpose of fulfilling, in today’s terms, a role as biomaterials. In 1862, Onofrio Abbate, an
Italian ophthalmologist practising in Cairo (Hirschberg, 1991), presented his experiments with an artificial cornea at the Periodical International Congress of Ophthalmology in Paris. This report was published in the following year in the congress proceedings, a publication that is virtually impossible to obtain nowadays. Fortunately, details of Abbate’s work are available in one of the early reviews on artificial cornea (Forster, 1923). His keratoprosthesis was made from a glass disk encased within a skirt of two successive rings, the first made of gutta-percha and the second of casein. Both are natural polymers: gutta-percha is the trans-isomer of natural rubber isolated from trees of the genera Palaquium and Payena (Malaya), and casein is a mixture of phosphoproteins precipitated from milk or cheese. The concept of this device illustrates Abbate’s remarkable anticipation of the need for a skirt made from a material different from that used in the central zone (in this case, glass), in order to promote biointegration. His choice of the skirt materials was, however, not the most appropriate, as casein is brittle and gutta-percha becomes so on exposure to air and light. The device was maintained in animal corneas for no longer than one week. At the end of the same century,
Lang implanted spheres fabricated from an artificial material (celluloid) as replacements for the enucleated eye globes (Lang, 1887). Strictly speaking, the socket implant is a cosmetic prosthesis. Soon afterwards, however, the first attempt ever to use a man-made material as a functional prosthesis took place in Germany, when – unaware of Lang’s work – Dimmer made an artificial cornea (or keratoprosthesis) from celluloid and implanted it in four human patients (Dimmer, 1889; Dimmer, 1891). Celluloid, the first commercial plastic developed in the world, is a blend of nitrocellulose (a modified biopolymer), camphor, and certain stabilizing agents, therefore not actually a fully synthetic polymer. Regardless, this material was not a fortunate choice, as Dimmer’s keratoprostheses were rejected within a few months.
The use of fully synthetic polymers as implantable ophthalmic biomaterials eventually occurred about half a century later, starting with poly(vinyl alcohol) gels inserted as socket implants (Thiel, 1939; Beyer, 1941), followed by the first artificial corneas made of poly(methyl methacrylate) (PMMA) (Wünsche, 1947; Franceschetti, 1949; Kuwahara, 1950; Györffy, 1951), a landmark not exempted from some controversy regarding priority (Chirila and
Crawford, 1996), and culminating with the much better known and undisputed development of Ridley’s PMMA intraocular lens (IOL) (Ridley, 1951; Ridley, 1952a; Ridley, 1952b). A few years later, poly(1-vinyl-2-pyrrolidinone) became the first synthetic polymer to be implanted in the vitreous cavity as a vitreous substitute (Scuderi, 1954; Hayano and Yoshino, 1959). In parallel
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developments, synthetic polymers also aroused the interest of the contact lens manufacturers. Feinbloom was the first to use glass (central part) in combination with commercially available synthetic polymers (peripheral part) in scleral contact lenses, and PMMA was among the polymers he proposed
(Feinbloom, 1937; Feinbloom, 1940). It is not known with certainty who introduced the first scleral contact lenses made entirely from PMMA, as the unfolding of the subsequent events becomes blurred, an unfortunate result of the fact that the contact lens was perceived from the very beginning as a fast-profit-generating device. As a consequence, the research and development activities were generally carried out in the laboratories of the manufacturers, and the field became contaminated with an excessive amount of patents and litigations between competing manufacturers, while being depleted of valid scientific publications in peer-reviewed journals due to exaggerated trade secret policies. It is believed that Mullen, Obrig or Györffy were perhaps among the first to make scleral contact lenses totally from PMMA (Barr and Bailey, 1991). It is also generally accepted that around 1947, Tuohy made the first corneal contact lenses from PMMA (Barr and Bailey, 1991; Goodlaw, 2000), although he did not report it in a scientific journal. His famous patent (Tuohy, 1950) is notoriously ambiguous about what polymers are claimed for manufacture. The contact lens has a rather particular position among ophthalmic biomaterials. The device involves intimate contact with some components of the ocular surface, especially the corneal epithelium, a circumstance that is essentially different from the situation of implanting polymer devices into the eye. However, biocompatibility remains the fundamental issue for both ocular implants and contact lens materials. The latter should be, and usually are, treated as ophthalmic biomaterials – as is the case in this book. We should, however, acknowledge that the research and development of contact lenses is a discipline on its own.
The range of ophthalmic biomaterials has subsequently expanded significantly, particularly after the introduction of synthetic hydrogels (i.e. polymers that absorb and retain water without dissolving in aqueous media) by Otto Wichterle’s group in Czechoslovakia (Dreifus et al., 1960; Wichterle, 1960; Wichterle and Lím, 1960; Wichterle et al., 1961).
Through the remarkable activity of Miguel Refojo at the Retina Foundation
(now Schepens Eye Research Institute) in Boston, Massachusetts, by the mid 1970s the field of ophthalmic biomaterials became an established discipline. Brian Tighe at Aston University in Birmingham, UK, further contributed to the development of this field through fundamental studies on hydrogels and contact lens materials. The number of scientists involved in ophthalmic biomaterials worldwide increased steadily, although not to the same extent as in other branches of biomaterials. Research groups or departments dedicated to ophthalmic biomaterials and established by non-profit institutions and universities are still relatively few in number.
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1.3Tissue engineering and regenerative medicine in ophthalmology
Tissue engineering should be regarded as the next evolutionary step in the development of biomaterials. Going beyond prostheses or devices, tissue engineering aims at developing truly functional substitutes able to compensate for tissue loss or to restore failed organs. Basically, this is achievable through the ex-vivo manipulation of cells and tissues, and employing growth factors, angiogenic or anti-angiogenic agents, signalling molecules or other bioactive agents, and their combination with the biomaterial scaffolds. This was ideally expressed by David Williams when he defined tissue engineering as ‘the persuasion of the body to heal itself, through the delivery to the appropriate sites of molecular signals, cells and supporting structures’ (Williams, 1999).
As cogently stated later by Linda Griffith, ‘coaxing cells to form tissue is inherently an engineering process as they need physical support […] as well as chemical and mechanical signals […] to form the intricate hierarchical structures that characterize native tissue’ (Griffith, 2002). Clearly, the field of tissue engineering involves methodologies and techniques that are much more complex than the placement of a contact lens on to the cornea or the insertion of an IOL in the anterior segment of the eye.
This multidisciplinary field probably has more definitions* than the biomaterials field has, but most are variations of the definition that appeared in the preface of the proceedings book of a tissue engineering workshop held at Granlibakken, Lake Tahoe, California in February 1988 (Skalak et al.,
1988), sponsored by the National Science Foundation (NSF) (USA). This definition revealed the essence of tissue engineering as ‘the development of biological substitutes to restore, maintain, or improve tissue functions’, and the accompanying commentary unambiguously identifies the field as it is understood today. This definition was adopted by leading researchers in the field (Nerem and Sambanis, 1995; Godbey and Atala, 2002). A popular opinion is, however, that tissue engineering was born in the late 1980s in the laboratories of Robert Langer, Joseph Vacanti, Charles Vacanti and their colleagues at Massachusetts Institute of Technology (MIT) and Harvard Medical School. In a much-cited paper from this group (Langer and Vacanti, 1993), the definition of tissue engineering was a modification of that mentioned above, a fact acknowledged by the authors.
* It has recently come to my attention that other investigators have been more thorough than me in searching for the origins of the term ‘tissue engineering’. In an editorial (Lysaght and Crager, 2009) published in July 2009 in Tissue Engineering Part A, it is asserted that the very first use of the term was actually in two press releases distributed in 1982 and
1983 by a commercial information service known as PR Newswire. The releases, obviously not peer-reviewed publications, heralded the funding by two US medical companies of research undertaken at MIT by the late Eugene Bell, a pioneer in the field.