EUROPEAN  TISSUE  REPAIR  SOCIETY

CHRONIC WOUNDS
R.G. Sibbald, Toronto, Canada

Patients with chronic wounds need treatment of the underlying cause and the recognition of patient-centered concerns before the local wound bed preparation can be optimized. Three factors are key to local wound bed preparation: debridement, moisture balance and bacterial balance.
The wound bacterial interphase is complex. All chronic wounds are contaminated with bacteria. Colonization or the attachment of bacteria to the surface may result in partial or complete biofilm formation. Biofilms can favour organism survival and decrease the effectiveness of topical and systemic antibacterial therapy. Bacteria can also injure tissue by released toxins and protolytic enzymes leading to delayed healing. This stage of critical colonization (increased bacterial burden) may precede the usual clinical signs of infection.
Chronic wounds also have superficial and deep compartments. The superficial wound bed can be treated with topical agents such as ionized silver and cadexomer iodine. These advanced agents have deceased tissue toxicity compared to traditional antiseptics and facilitate moisture balance. Deep compartment bacterial imbalance (critical colonization or infection) necessitates the use of systemic antimicrobial agents.
The achievement of bacterial balance on the superficial and deep wound bed compartments can facilitate healing or prepare the wound bed for biological agent stimulation.

MEASUREMENT AND ASSESSMENT OF HEALING

THE NEED FOR MEASUREMENT AND ASSESSMENT OF HEALING
Tom Hunt, University of California San Francisco, USA

Human healing differs from animals, and is not as accessible to measurement. This is our greatest obstacle. We need human methods. Even more, we must learn to accept and distill meaning from those measures that we have. For instance, implanted sampling devices are pertinent to all wound types, though superficially, they may not appear to represent one's speciality interests. Stubborn insistence on full healing as the only acceptable endpoint has restricted the use of much useful information. For instance, reduced pain is a victory even without reduced wound size. Is preventing amputation without healing the index wound a victory? If not, the problem is us.
We must construct and believe in surrogates for individual healing components in humans. Take, for instance, a treatment that elevates wound PO2. Any means that relieves hypoxia reduces infection, raises collagen deposition and increases angiogenesis. Relieving hypoxia won't heal all wounds. But we cannot heal hypoxic wounds without doing it!
We will never have a fully representative, chronic wound model. We need models of healing components. Among other needs, a quantifiable, reproducible measure of angiogenesis would satisfy many current needs.

PHYSICAL METHODS OF MEASUREMENT
Raj Mani, Vascular Group, Medical Physics & Bioengineering, Southampton University Hospitals Trust, Southampton, UK

Objective measurements are aimed to provide diagnosis, confirm efficacy of clinical management, and to predict treatment outcomes. The growing literature on wound measurements testifies to the importance of the subject; have reached that stage at which the laboratory can safely guide the clinical management of wounds?
Tests of vascular supply and function have gained acceptance in leg ulcer management. Transcutaneous measurements of skin oxygen may be used reliably to measure viability of peripheral tissues in the diabetic patient whose limb is threatened by worsening arterial supply.
Wound size measured easily and with accuracy, has the potential to forecast treatment outcomes but in doing so we need to have a clear understanding of the common complications oedema, infection and pain. In practice, wound exudate needs to be well managed. Measurements in exudates have yielded data of the composition but much ground needs covering before the clinical significance is discovered. Are exudates related to wound complications?
We must persevere with measurements in the milieu of wounds defining end points in order to achieve our measurement objectives.

BIOCHEMICAL METHODS OF MEASUREMENT
Tim James, Department of Clinical Biochemistry, Oxford Radcliffe Hospital, UK

The clinical evaluation of chronic wounds would be improved if indicators were available which could either predict, or monitor progress towards, healing. Recent studies of wound fluid composition have identified several biochemical components that could provide suitable candidate markers.
Important characteristics of an ideal biochemical marker include a method of analysis that is simple, robust, sensitive and specific using a specimen that is easy to collect in a reproducible manner. A highly stable biochemical marker is also preferred. The candidate markers of healing need evaluation against these criteria.
Potential markers of healing include components of the extracellular matrix (fibronectin degradation products or markers of collagen synthesis), cytokines and proteolytic enzymes (including matrix metalloproteases). Wound fluid albumin and total protein could provide simple alternatives.
Marker validation studies to date have been on small numbers of patients and larger studies are needed. A primary objective should be to identify factors that could affect result interpretation. For example pre-analytical factors, such as period and technique used for collection may have profound effects on the measured level of the potential markers.

THE FUTURE POTENTIAL
Bob Williams, Dean of Learning and Teaching, University of Glamorgan, Pontypridd, UK

A key role for engineers is the translation of methodologies developed in carefully controlled clinical settings, often using cutting edge technologies, into devices and systems for use in routine clinical practice. The design challenge almost universally demands robust, de-skilled, non-invasive techniques. Biological and Biochemical measurements have a significant role to play in this but it is, perhaps, physical measures, which offer the best scope for immediate indicators. Wound appearance and metrics, temperature, microcirculation and tissue oxygenation are obvious targets. Much has been reported in recent years on the underlying measurement philosophies, for example the adaptation of 'Laser Doppler' to imaging techniques for blood perfusion studies. There are increasing reports of new sensor technologies such as 'electronic noses'. Fibre optics may be treated in a manner, which makes their light transmission characteristics a function of a parameter to be measured such as pH or minute magnetic fields. Electronic device technologies are also strongly influential on possible design solutions. Transistors capable of operation at 200GHz and cheap credit card size memories having capacities of 10.8TB (terabytes) are currently being announced. Such technologies will enable vast amounts of data, such as digital images, to be acquired and processed in handheld devices. Consumer devices such as 'Palm' based PDA's with plug-in CCD image sensors are already showing the way.
In the medical arena, hand-held host computers with personality modules are beginning to appear; the Huntleigh Assist vascular laboratory is a good example. Further developments in communications technologies will make the transmission of data from treatment sites to central hubs faster, cheaper, and easier. The concerted interaction of clinicians and designers, however, is vital to maximise the potential for assessment systems, which can genuinely influence wound management.

AGEING AND TISSUE REPAIR

AGEING AND CUTANEOUS WOUND HEALING
Gillian Ashcroft, School of Biological Sciences, University of Manchester, UK

Impaired wound healing states cost the NHS over £1 billion per year, and this figure is likely to increase with the rapid expansion of the elderly population in the UK. Ageing influences all spatial and temporal components of the wound healing response, including re-epithelialization, matrix deposition and the inflammatory cell profile. Intriguingly, marked gender differences have also been observed in the wound healing response, however the cellular and molecular mechanisms underlying such changes are only now being investigated. Estrogen has been recently implicated as a major regulator of wound repair, and both systemic and topical estrogen can reverse age-related impaired wound healing in human and animal models. A number of potential mechanisms associated with estrogen's beneficial effects have been recently identified, including direct and indirect modulation of the local neutrophil response, with downstream effects on protease levels and subsequent matrix deposition. We have identified potential candidate genes with estrogen binding sites in their promoter regions and which appear to be regulated by estrogen. Deletion of one such specific gene, known as SLPI (secretory leukocyte protease inhibitor) results in a wound healing phenotype which parallels age-related changes in human and murine models of repair. Increased understanding of the specific mechanisms, and signaling pathways, through which estrogen acts will allow a more focused approach to therapeutic manipulation of age-related impaired healing.
Dr Ashcroft is funded by the Wellcome Trust.

INJURY AND REPAIR IN THE CENTRAL NERVOUS SYSTEM FOLLOWING STROKE
Nancy Rothwell, School of Biological Sciences University of Manchester, UK

Injury and repair in the CNS has until recently, been thought to be very different to processes in other tissues. The brain has been considered as an 'immune privileged' organ, which fails to show a classical inflammatory response or normal repair process.
Recent advances have changed this view significantly, and it is now recognised that inflammatory mediators contribute directly to injury and repair. In particular, specific cytokines such as IL-1 are primary mediators of CNS injury while others (e.g., IL-10, TGFb) are neuroprotective. Glia, the primary source and target for cytokines, are activated rapidly in response to stroke or other injury and also participate in repair and recovery. We have identified IL-1 as a potential therapeutic target in stroke and are currently undertaking a double blind trial of IL-1 receptor antagonist. Scarring is a major problem in the CNS since it can impair function, and is mediated by a number of growth factors. Thus, for example, while TGFb is neuro-protective probably via inhibition of IL-1, it can increase scarring and limit neorite extension after injury. Further evidence suggests that neurogenesis can occur in some areas of the CNS.

CALORIC RESTRICTION AND CALORIC RESTRICTION MIMETICS; IMPLICATIONS FOR HUMANS
George Roth, National Institute on Ageing, Baltimore, USA

Dietary caloric restriction (CR) is the most robust intervention for slowing aging and extending lifespan and healthspan in animals. Recent studies in monkeys suggest that humans might also benefit from CR, but most would be unwilling to practice it for the bulk of their adult life-spans. Thus, we are introducing a new approach, termed CR mimetics, which will allow individuals to obtain the positive health and longevity effects of CR without dieting. Potential CR mimetics include synthetic compounds, as well as naturally occurring nutraceuticals that elicit at least some of the biological effects of CR without supressing appetite or food intake.
Literature on a number of such agents, such as Gym-nema sylvestre, phenformin, and Garcinia cambogia already exist to support the feasibility of our approach. However, in order to verify our hypothesis that such agents can mimic CR in a controlled study, we employed the glucose analog, 2-deoxyglucose (2DG), in rats. Our initial objectives were to determine whether long-term 2DG feeding could effect some of the key metabolic responses linked to the anti-aging mechanisms of CR.
Others have already shown that short-term 2DG treatment can reduce tumor formation and neurotoxicity, as well as other effects similar to those resulting from CR.
After six months, 2DG fed animals in our study had slightly lower body weights, but ate essentially the same amounts of chow as pair-fed controls. More important, the treated rats had lower body temperatures and plasma insulin levels (two of the most important metabolic effects of CR) than controls. A second study was, therefore, initiated to determine whether 2DG fed rats actually live longer than pair-fed controls. A progress report on this newer experiment will be presented. In summary, results to date, from our laboratory and others, strongly suggest that the CR mimetic approach is indeed feasible and could potentially result in significant healthspan (and possibly lifespan) extension in humans.