Advanced Wound Repair Therapies

David Farrar

• Publisher: Woodhead Publishing
• Year: 2011
• ISBN:
  9780857093301
• Topic: Medicine
• Subtopic: Medical Technology & Supplies

Wound repair is an important and growing sector of the medical industry with increasingly sophisticated biomaterials and strategies being developed to treat wounds. Advanced wound repair therapies provides readers with up-to-date information on current and emerging biomaterials and advanced therapies concerned with healing surgical and chronic wounds.Part one provides an introduction to chronic wounds, with chapters covering dysfunctional wound healing, scarring and scarless wound healing and monitoring of wounds. Part two covers biomaterial therapies for chronic wounds, including chapters on functional requirements of wound repair biomaterials, polymeric materials for wound dressings and interfacial phenomena in wound healing. In part three, molecular therapies for chronic wounds are discussed, with chapters on topics such as drug delivery, molecular and gene therapies and antimicrobial dressings. Part four focuses on biologically-derived and cell-based therapies for chronic wounds, including engineered tissues, biologically-derived scaffolds and stem cell therapies for wound repair. Finally, part five covers physical stimulation therapies for chronic wounds, including electrical stimulation, negative pressure therapy and mechanical debriding devices.With its distinguished editor and international team of contributors, Advanced wound repair therapies is an essential reference for researchers and materials scientists in the wound repair industry, as well as clinicians and those with an academic research interest in the subject.

• Provides readers with up-to-date information on current and emerging biomaterials and advanced therapies concerned with healing surgical and chronic wounds
• Chapters include the role of micro-organisms and biofilms in dysfunctional wound healing, tissue-biomaterial interaction and electrical stimulation for wound healing
• Covers biologically-derived and cell-based therapies for chronic wounds, including engineered tissues, biologically-derived scaffolds and stem cell therapies for wound repair

Part I

Introduction to chronic wounds

1

Dysfunctional wound healing in chronic wounds

P. Stephens, Cardiff University, UK

Abstract:

This chapter discusses the normal wound healing process and how this is dysfunctional within chronic skin wounds in aged individuals. Skin ageing in relation to changes in cellular responses and composition of the extracellular matrix is described and introduced as a pre-cursor to aberrant wound repair. Theories for the development of these chronic wounds are suggested and the dysfunctional response is described in detail with respect to altered immune/inflammatory responses, re-epithelialisation, dermal repair and angiogenesis.

Key words

chronic skin wound

ageing

dysfunctional cell response

altered extracellular matrix

1.1 Normal skin wound healing

The wound healing process is a highly ordered and extremely complex process which, for the purpose of convenience, can be considered to consist of three successive but overlapping phases (for review see Clark (1996) and references therein and Table 1.1 for a general timescale for a normal wound healing process).

Table 1.1

The time course of wound healing (for a simple, uncomplicated wound) – the individual processes of wound healing do not occur in isolation but overlap to varying degrees

Time	Biological/cellular response
0 Hours	Vascular response initiated and blood coagulation begins.
10–12 Hours	Initiation of new connective tissue formation.
1 Day	Fibrin network formed. Commencement of re-epithelialisation.
3–7 Days	Vascular response has peaked and started to subside. Peak of inflammatory response has been reached.
12 Days	Re-epithelialisation of superficial wounds completed (longer in more extensive wounds).
14 Days	Inflammatory response completed.
6–16 Days	Peak of formation of connective tissue.
> 16 Days	Maturation of collagen and remodelling of connective tissue.

1.1.1 The vascular and inflammatory responses

The loss of blood from a fresh wound has the effect of cleansing the wound of some of the invading foreign bodies and debris. Within seconds, vasocon-striction, platelet adhesion and aggregation, along with blood coagulation, result in the formation of a thrombus which encourages haemostasis. Coagulation proceeds via the two major enzymatic cascades and the resulting fibrin clot not only establishes haemostasis but also, in conjunction with fibronectin, provides a provisional matrix for the migration of many cell types into the wound space. The migration of initially neutrophils, and subsequently, monocytes into the injured tissue site is stimulated by a variety of chemotactic factors (e.g. fibrin degradation products, growth factors released from platelets). The neutrophils, via phagocytosis and by cellular killing, clear contaminating bacteria from the injured tissue site. On arriving at the wound site, the monocytes undergo a phenotypic metamorphosis to macrophages which phagocytose and digest pathogenic organisms and scavenge tissue debris. Macrophages continue to accumulate after neutrophil influx has ceased and release a number of growth and chemotactic factors that are necessary for the initiation and propagation of subsequent new tissue formation.

1.1.2 New tissue formation

Re-epithelialisation

Within hours after injury, movement of epidermal cells from the cut edges of the wound begins the process of re-epithelialisation. On completion of re-epithelialisation the keratinocytes revert to a normal phenotype and the basement membrane becomes reconstituted. The signals that drive this process involve the local presence of growth factors (e.g. Transforming Growth Factor-alpha (TGF-α), Transforming Growth Factor-beta (TGF-β), Keratinocyte Growth Factor (KGF) and Epidermal Growth Factor (EGF)), changes in keratinocyte exposure to extracellular matrix (ECM) molecules and changes in ECM tension.

Fibroplasia and wound contraction

After a lag of several days, fibroblasts migrate into the wound space, whence proliferation begins, stimulated by a number of fibroblast growth and chemotactic factors emanating from both the platelets and the macrophages and from the fibroblasts themselves. During fibroplasia, the fibroblasts change from having a migratory phenotype, to an ECM-producing phenotype and finally to a myofibroblast phenotype when the cells have characteristics common to both fibroblasts and smooth muscle cells. The loose deposit of ECM initially produced by the fibroblasts is composed of large quantities of fibronectin and hyaluronic acid and is termed granulation tissue. These ECM components, along with tenascin, act as a scaffold for fibroblast migration throughout the wound space. Over the following few days the composition of the granulation tissue changes such that the collagen becomes the major component, with the fibronectin matrix acting as a scaffold for its fibrillogenesis. Early collagen deposition is highly disorganised but its subsequent organisation is primarily achieved by wound/matrix contraction involving the action of myofibroblasts.

Angiogenesis

This process is vital for successful wound healing and its initiation occurs within days of injury. Stimulated by numerous angiogenic factors the endothelial cells from venules closest to the site of injury migrate through enzymatically fragmented basement membranes into the affected area. Endothelial cells within the parent vessel begin to proliferate (giving rise to capillary sprouts) and join the migrating population. When they meet the capillary, sprouts branch at their tips, join with the migrating cells and form capillary loops through which blood can flow. Activated endothelial cells then form further sprouts and loops giving rise to a capillary plexus.

1.1.3 Tissue remodelling

The composition and structure of the continuously changing granulation tissue depends on both the time elapsed since injury and the distance from the wound margin. Initially the matrix contains components such as fibrin, fibronectin, vitronectin, types I and III collagen, tenascin and hyaluronic acid. This provides a suitable framework for the migration and influx of many cell types with fibronectin also possibly serving as a nidus for collagen fibrillogenesis. Over the following weeks, maturation of the matrix results in a great reduction of the fibronectin and hyaluronic acid content within the granulation tissue, but an increase in the amounts of collagen bundles and proteoglycans such as chondroitin sulphate and dermatan sulphate. Matrix metalloproteinases (MMPs) as well as the plasminogen activator/plasmin system and hyaluronidase play an important role in this remodelling process as are tissue inhibitors of metalloproteinases (TIMPs). The result of all this tissue remodelling is mature scar tissue, which is, however, mechanically weaker than non-wounded tissue.

1.2 Ageing skin and the onset of chronic, dysfunctional wound healing

Chronic skin wounds are more often than not found in the aged population and it is no coincidence that associated with the aged are changes in the structure and function of their skin. The typical signs of ageing such as wrinkling and sagging of the skin are all too permanent reminders of the encroachment of time or of too much time spent in the sun without the appropriate protection. So exactly what does ageing do to the largest organ of our bodies?

1.2.1 Skin ageing

Ageing of the skin has been described in detail elsewhere (Stephens 2003); however, a brief overview will be given to set the scene for later sections concerning chronic wound healing (see also Table 1.2). Ageing is a basic biological process characteristic of all living organisms (Yaar & Gilchrest 2001). Inevitably it leads to reductions in maximal function and reserve capacity in all organ systems rendering the individual more susceptible to injury, disease and eventually death. Intrinsic or innate skin ageing (the skin becomes thin, pale and finely wrinkled) refers to the slow, but irreversible, degeneration of the s...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributor contact details
• Introduction
• Part I: Introduction to chronic wounds
• Part II: Biomaterial therapies for chronic wounds
• Part III: Molecular therapies for chronic wounds
• Part IV: Biologically derived and cell-based therapies for chronic wounds
• Part V: Physical stimulation therapies for chronic wounds
• Index