I. Overview（概観）
Wound healing is a phenomenon in which regeneration or wound repair reactions take place in tissues where cells have been injured by trauma or surgery. The types of trauma covered here include incised wounds, skin defects, burns, chemical injuries and ultraviolet injury, as well as surgical treatment. The series of strategies by which human body attempts to repair and reconstruct the tissues themselves and regain lost functions is called wound healing.
1. Regeneration（再生） is a reaction in which the injured part is replaced by normally functioning cells to regain previous functions that have been lost.
2. Repair（修復） is a reaction accompanied by fibrosis following inflammatory reactions on which various cells play roles. This can be regarded as a response in which the injured part is replaced by scar tissue after the tissue defect has been repaired.
3. Wound contraction（創収縮） The mechanism also acts at this time to close the wound rapidly, and may lead to scar contracture.
4. 皮膚の創傷治癒
In this chapter, wound healing in the skin is discussed. In the wound healing process, except in very superficial wounds where the proportion of repaired cells is high, that is, the healing mechanism is seen in the epidermis, leaving scar tissue to a greater or lesser extent. So it is very important to understand the mechanism of wound healing and to conduct treatment from the viewpoint of achieving as close to normal regeneration of skin as possible while preventing scarring and scar contracture.
5. Basic concept（基本的な考え方）of conventional wound treatment has also changed from the use of antimicrobial drugs and disinfectants to prevent infection of the wound surface to occlusive therapy using dressings to optimize the body’s repair processes.
II. The mechanism of wound healing in the skin and the actions of growth factors and cytokines
（創傷治癒における増殖因子とサイトカインの働き）
Human keratinocytes and the liver can be replaced with new tissue if they are injured or removed. This phenomenon is called regeneration. Repair, on the other hand, is a phenomenon in which the injured tissues are usually replaced by fibrous scar tissue, but in fact all wound healing in humans can be regarded as repair because scars remained to some extent in most cases. If the repair process does not progress smoothly for a certain reason, excessive collagen accumulates in the scar, creating a hypertrophic scar or keloid, which can be regarded as a kind of overreaction as well as scar contracture. It is evident that those outcomes are troublesome from aesthetically and functionally. The substances that have been observed to promote and control the series of mechanisms we call wound healing are growth factors, or more specifically, cytokines.
1. Wound healing process（創傷治癒のプロセス）
The wound healing process is roughly divided into a) the bleeding/hemostasis phase, b) the inflammation phase, c-1) the epithelization phase, c-2) the granulation phase, c-3) the collagenization phase and 4) the scar maturation phase. These processes are described below. Phases of c-1), c-2), c-3) are sometimes called proliferation phase (Table 1).
a) Bleeding/hemostasis phase（出血凝固期）
Platelets adhere to and aggregate in the injured vascular endothelium and activate the coagulation system. At that time, various important mediators, growth factors and cytokines, such as PDGF and TGF-β, are secreted from the platelets and trigger the subsequent progress of the inflammation, epithelization, granulation and collagenization phases.
b) inflammation phase（炎症期）
From the neutrophils that appear early on in the inflammation phase, various cytokines and growth factors are also released that play a role in leading monocytes and macrophages to the wound. It is known that TGF-β, TGF-a and FGF are secreted abundantly from monocytes and macrophages in this phase. It has recently been found that these growth factors play a crucial role in controlling the proliferation and differentiation of fibroblasts and keratinocytes in wound healing.
c) epithelization, granulation and collagenization phase（増殖期）
Subsequently, the keratinocytes at the margin of the wound and in the appendages of the skin divide and extend to form a layer on the upper surface of the wound (Fig. 1). It is known that the proliferation and differentiation of these keratinocytes is accelerated by the TGF-a, EGF and FGF secreted from fibroblasts and macrophages. In the dermis, on the other hand, fibroblasts, mast cells, plasma cells and reticular cells start to act, but the first action defining this phase is active cell proliferation, and generally, the substances controlling this phenomenon are cytokines and growth factors such as TGF-β, PDGF and IGF-1, plus the active synthesis of intercellular substances, collagen, elastic fibers and proteoglycan, in so called granulation tissues. The second phenomenon is the building up of new vasculature（血管新生）, and it is believed that VEGF, HGF and FGF are largely involved in this phenomenon. The characteristic phenomenon at this point time is wound contraction. Because TGF-β, particularly TGF-β1, is closely involved in this phenomenon, it is believed that the contraction and hypertrophic change of scars can be prevented by controlling this wound contraction process. In addition, one growth factor that has recently been identified is HGF, a substance believed to act antagonistically on TGF-βto prevent fibrosis of the lungs, heart and kidney and to accelerate the regeneration of such organs. The active responses of cells and collagen production will be attenuated in due course, cross-links will be formed in the collagen fibers, and remodeling, during which the physical strength of wound increases, will progress.
d) scar maturation phase（瘢痕成熟期）
As a result of this process, the vascular system finally regresses substantially, and dense and robust mature scar tissues that differ from the surrounding normal tissues now occupy the wound. It is thought that TGF-β provoked apoptosis is involved in this type of control. In this manner, under the control of cytokines and growth factors, the body repairs the injured part and finally regains its integrity (Fig. 2).
2. まとめ
To summarize the above, Various cells are mobilized to the wound site as a part of the self-repair function of the body,
1) Cell proliferation is controlled by cytokines and growth factors.
2) Mechanisms are activated for controlling the production of extracellular matrices and collagen.
3) There is potential for modification of these series of phenomena. In short, the details of wound healing have been clarified by biochemical methods and it now appears possible to achieve faster and better therapeutic results by modifying the process using cytokines and growth factors produced artificially by genetic engineering methods.
With a focus on these four points, active research into the challenge of clinical application has been begun. It already appears that wound healing methods will change significantly in the future. I believe that we have to change our viewpoint radically from
a. the assumption that the self-repair function of the body can be relied on by simply controlling infection, to
b. the realization that these biological reactions can be controlled more actively by administration of recombinant cytokines and growth factors to facilitate and control a more planned and directed form of healing in the future.
III. Future perspectives for wound treatment（展望）
1. Biomaterialと増殖因子の併用:The recombinant human growth factors are thought to be able to achieve unprecedented and remarkable effects, alone or in combination with the use of biomaterials such as collagen sponge.
2. Biomaterialと増殖因子と細胞治療:In the future, it is expected that elucidation of the mechanism of wound healing process will provide a major contribution to future clinical practice in the form of combination of cytokines and growth factors prepared by molecular biological methods, new biomaterials and genetic engineering with cultured cells isolated from the body, so-called advanced tissue engineering（組織工学）.
3. 速度のみでなく質の向上:The results of innovative studies have been showing that prevention of scarring in sutured wounds will become possible by using growth factors such as bFGF and HGF. As already described, it goes without saying that it would not be practical to treat all wounds with one drug or a wound-dressing materials. However, physicians engaged in wound treatment should realize that it is very important to learn how wounds actually behave by extensive observation over a long period.
4. 増殖因子による創傷治癒の制御:They should also realize that the wound healing processes could be controlled with growth factors in ways far more sophisticated than simply speeding up the healing process.
List of abbreviations
PDGF（platelet−derived growth factor）
TGF-α（transforming growth factor α）
TGF-β（transforming growth factor β）
EGF（epidermal growth factor）
TNF-α（tumor necrosis factor α）
IGF（insulin-like growth factor）
FGF（fibroblast growth factor、acidic FGF（aFGF）とbasic FGF（bFGF)
INF-α（tumor necrosis factor-α）
IL-1（Interleukin-1）
lL-6（Interleukin-6）
lL-8（Interleukin-8）
VEGF（vascular endothelial growth factor）
HGF（hepatocyte growth factor)
Table 1: Phases of wound healing.
1) the bleeding/hemostasis phase（出血止血期）
2) the inflammation phase（炎症期）
3) the epithelization phase（表皮化期）
4) the granulation phase（肉芽形成期）
5) the collagenization phase（膠原形成期）
6) the scar maturation phase（瘢痕成熟期）
3), 4), 5) are called proliferation phase（増殖期）.
Fig. 1: Mechanisms of epithelization.
Fig. 2: Flowchart of wound healing process.
参考文献
1、小野一郎: 損傷、創傷治癒総論. 標準形成外科学、第4版. 医学書院. 東京. 92-102, 2000.
2、Ferguson, MWJ, Leigh, IM: Wound healing. In Textbook of Dermatology, Sixth edition, Vol. 1. Edited by RH Champion, LH Burton, DA Burns, SM Breathnach, Blackwell Science Ltd., Edinburgh, 1998, pp 337-356.