EUROPEAN  TISSUE  REPAIR  SOCIETY

THE IMPACT OF AGEING

CLINICAL ASPECTS OF AGEING
Professor K.W. Woodhouse, Dean of Medicine & Professor of Geriatric Medicine, University of Wales College of Medicine, Cardiff, UK

The tendency to emphasise the 'holistic' nature of health care for the elderly, focusing on rehabilitation and support, whilst in many ways laudable, has tended to obscure the major advances which have occurred in the prevention, diagnosis and treatment of many acute and chronic disabling diseases. This talk focuses on several areas where recent advances have made significant improvements in elderly care:-

• Stroke prevention
• Management of ischaemic heart disease
• Management of heart failure
• Osteoporosis/orthogeriatric care
• Management of neurodegenerative disease, especially Parkinsons Disease and Alzheimers Disease

PROBLEMS OF HEALING IN DIFFERENT TISSUES

SKIN
Phil Stephens, Department of Oral Surgery, Medicine & Pathology, Dental School, University of Wales College of Medicine, Cardiff, UK

Disordered skin healing occurs in a spectrum of forms: from a failure of wounds to re-epithelialise and remodel (i.e. chronic wounds in the elderly) to wounds which heal with deposition of excessive extracellular matrix and scar formation (e.g., hypertrophic and keloid scars). Today, with the increasing age of the population and the rise of interpersonal violence, these problems represent important surgical, psychological and resource problems. In chronic wounds in the elderly population, wound healing is affected by systemic (e.g., contemporaneous disease, medication or non-specific alterations in immune status) and local factors (e.g., pressure, vascular supply, bacterial colonisation). In acute wounding whilst genetic factors may be important in mediating keloid scarring, local factors (e.g., skin tension, infection etc.) are the most important pre-determinants of clinical outcome. Investigation of the underlying processes of normal wound healing has given us valuable insight into the mechanisms underlying these problematic patterns of wound healing.

EYE
Mike Boulton, Department of Optometry & Vision Science, Cardiff University, Cardiff, UK

The eye presents many problems from a wound healing perspective due to its diversity of tissue types. First, maintenance of transparency is essential for certain tissues to ensure that light can reach the retina and evoke a visual response. Second, many ocular structures are avascular. Third, damage to neural retinal tissue is irreversible. Lastly, incomplete healing is the preferred outcome for many surgical procedures.
The cornea has recently received considerable attention due to its being amenable to surgical changes in curvature to overcome long and short sightedness. While reported outcomes are good, complications such as regression and stromal haze are not uncommon. Age-related opacification of the lens (cataract) is now treated by removal of the lens capsule and insertion of an intraocular lens. However, in up to 50% of patients growth of remnant epithelial cells over the posterior lens capsule results in deterioration of vision and requires laser surgery. In glaucoma, increased intraocular pressure can be lowered by creating a drainage channel through the sclera which, due to normal wound healing processes, attempts to heal and close the fistula thus re-establishing high intraocular pressure. Selective damage to the retina activates a cascade of cellular events which inhibit aberrant neovascularisation associated with the complications of diabetes mellitus. In addition, excessive idiopathic wound healing in the form of fibrous vascular membranes on the surface of the retina are not uncommon and can result in retinal detachment. In conclusion, the eye provides an excellent paradigm for the investigation of wound healing and the identification of both positive and negative regulators.

REPAIR IN THE EYE

MOLECULAR APPROACHES TO REGULATING OCULAR WOUND HEALING
Greg Schultz, Institute of Wound Research, University of Florida, USA

Corneal scarring following infection, trauma, or surgery can lead to impaired vision, yet relatively little is known about which genes contribute to corneal scarring. Using excimer laser ablation of rat corneas as a model for corneal scarring, we found that levels mRNAs for TGF_ iso-forms and receptors increased dramatically and remained elevated for several months after ablation. Furthermore, we determined that connective tissue growth factor (CTGF) mediated the effects of TGF_ on synthesis of collagen in cultured corneal fibroblasts and on contraction of fibro-blast populated collagen matrix. Levels of CTGF mRNA and protein also significantly increased in rat corneas after ablation, and CTGF protein was localized to corneal fibroblasts and epithelial cells. Hierarchical clustering of changes in gene expression determined by microarray analysis at 12 times during healing of rat corneal wounds revealed large changes in expression of other genes including corneal crystallins, MMPs, growth factors and extracellular matrix proteins. Antisense oligonucleotides and ribozymes can be effectively delivered to the cornea by plasmids or viral vectors suggesting that selectively target therapies can be developed to control corneal scarring.

CORNEAL WOUND HEALING FOLLOWING REFRACTIVE SURGICAL TRAUMA-EVALUATION USING IN VIVO CONFOCAL MICROSCOPY
Torben Moller-Pedersen, Arhus University Hospital, Denmark

Myopia represents the most common refractive disorder with a prevalence of app. 25% for Europeans. The idea of obtaining maximal visual acuity without corrective eyewear has motivated a search for surgical alternatives to manipulate the ocular refraction. The prime focus has been on the cornea that represents the main refractive element of the eye. With the introduction of non-thermal, 193 nm excimer laser photoablation, the field of refractive corneal surgery has widely expanded. However, two major drawbacks concerning the predictability and safety have hindered a universal acceptance and use of laser vision correction. Firstly, the refraction typically undergo a 0.8 to 2.0 D my-opic regression (gradually becomes less hyperopic and more myopic) during the first year. Secondly, the majority of the patients experience a transient loss of corneal transparency, a phenomenon termed haze, which disturbs the quality of vision and may persist in about 5% of all patients. Although the exact mechanisms are unknown, it is generally suspected that the uncontrolled nature (and high inter-individual variability) of the corneal wound healing response plays a direct and important role for the development of these complications. This presentation will summarize a series of clinical and experimental studies that were conducted (using in vivo confocal microscopy and conventional laboratory techniques) to investigate and identify the underlying biological mechanisms responsible for loss of corneal transparency and refractive instability following excimer laser refractive surgery.

FROM MOLECULAR BIOLOGY TO INTERNATIONAL CLINICAL TRIALS: NEW METHODS FOR THE PREVENTION OF CONJUNCTIVAL SCARRING
Professor P.T. Khaw, PhD FRCS (Eng) & (Glasg) FRCOphth PRCP FIBiol, Professor of Wound Healing and Glaucoma Studies, Moorfields Eye Hospital and Institute of Ophthalmology, University College, London

Ocular scarring plays a part in the pathogenesis or failure of treatment of virtually every major blinding condition. In one particular disease, glaucoma, the level of surgical success if largely determined by the degree of subconjunctival scarring after surgery. We previously discovered that prolonged growth arrest of the scar Making fibroblast cell could be induced with extremely short (five minute) single applications of a variety of inexpensive, commonly used anti-cancer agents such as 5-fluorouracil. Cell culture and experimental Model have led to an eight-year clinical trial of this regimen to determine if it is appropriate for all patients. There are now collaborative clinical trials underway in the Far East and Africa. A similar regimen to prevent scarring of the retina has also been tested which has just shown for the first time a reduction in blinding rental scarring. Our group has established that transforming growth factor beta stimulates more scarring than other ocular growth factors. A new humanised antibody to transforming growth factor beta has been tested in cell culture, is effective in an experimental model, and is now undergoing multicentre trials in the UK and shortly in Europe.
We have also discovered that matrix metalloproteinases (MMPs) are essential for the process of cell mediated tissue contraction, and contraction can be inhibited if these enzymes are neutralised. This phenomenon appears to be ubiquitous in mammalian cells, and may allow us to predict and modulate disabling contractile scarring.