口 腔 病 理 科 Wound Healing 傷口癒合 陳玉昆副教授: 高雄醫學大學 口腔病理科 07-3121101~2755 yukkwa@kmu.edu.tw

學 習 目 標 1. Regeneration & repair 2. Epithelium & connective tissue 3. Extraction wound 4. Bone fracture

參考資料 (1) References 1. Ibsen OAC: Oral Pathology for the dental hygienist. 4th ed., pp. 36- 52 2. Avery JK: Oral Development & Histology, pp. 192-212 3. Horwitz AF: Integrins and Health. Sci Am 1997;May, 68-75 4. Singer AF et al: Evaluation and management of traumatic lacerations. New Eng Med J 1997;337:1142-8 5. Habeck M: Wound-healing genes promote cancer progression. Lancet Oncol 2004;5:138 6. Epstein FH: Cutaneous wound healing New Eng Med J 1999;341:738-46 7. Kaohsiung Medical University, Oral Pathology Department 8. Sompayrac L. How the immune works Lecture 1. An overview 1999:p.5-16 9. www.mybiology.com/archive_movies 10. http://www.bu.edu/woundbiotech/WoundHealingProcess/

參考資料 (2) References 11. http://connection.lww.com/products/taylor/documents/cc37figure37- 1.jpg 12. http://ls.berkeley.edu/bio/gallery_mcb/wound.html 13. www.nchmd.org 14. http://www.ma.hw.ac.uk/~jas/researchinterests/scartissueformation.html 15. http://www.malp-research.de/ 16. http://www.imakenews.com/mvius/e_article000210982.cfm 17. Awang MN. The aetiology of dry socket: a review. Int Dent J 1989;39:236- 40 18. 徐博文、謝耀東 拔牙後齒槽骨傷口之癒合 中華民國口腔植體學會會訊 1997年 5月 第4期 p.27-30 19. Shafer WG. A textbook of oral pathology. 1st edition, p.609-10 20. www.unireptile.com/amphibian/newt/newt_web.htm 21. Nanci A. Ten Cate’s Oral Histology 7th ed., pp. 388-9

Wound Healing (再生) Regeneration When tissue damage is slight, the inflamed area may return completely to its normal structure and function This is the most favorable end to acute inflammation and involves: Complete removal of all cells, by-products inflammatory exudate that enter the tissue 2. Return of microcirculation to its preinflammatory state 1 2 蠑螈 Ref. 20

Wound Healing (修復) Repair Repair takes place when complete return of the tissue to normal is not possible because the damage has been too great Some tissues, such as epithelium, fibrous connective tissue, and bone have the ability to undergo repair. Other tissues, such as enamel, dentin, cementum do not Bruxism - Attrition Brushing- cervical abrasion Ref. 1

Wound Healing Repair Repair is the body’s final defense mechanism in its attempt to restore injured tissue to its original state During repair process, destroyed cells & tissue are replaced with live cells & new tissue components Traumatic ulcer Sharp edge tooth Fungus infection Tumor Repair process cannot be completed until the source of injury is removed or the injurious agents are destroyed Refs. 1, 7

Wound Healing Epithelium and connective tissue Extraction wound Repair Epithelium and connective tissue Extraction wound Bone fracture

Wound Healing Repair Events of wound healing Injury 1. Inflammation 2. Epithelization 3. Neurovascularization 4. Granulation tissue 5. Contraction 6. Collagen formation 7. Scar remodeling Ref. 1

Wound Healing Repair Microscopic events that occur during repair 1. Occurs in both epithelium & connective tissue 2. These events are different for each of these tissues but occur almost simultaneously and are dependent on each other for optimal healing If the source of injury is removed, the repair process is usually completed in 2 weeks Repair process is slightly different in mucosa than in skin because mucosal tissue are wet & a scab does not form

Wound Healing Repair Day of Injury. A clot forms as the blood flows into the injured tissue. The clot or meshwork of fibrin is produced in the area of injury as a result of activation of the clotting mechanism The clot consists of locally produced fibrin, clumped red blood cells and platelets (thrompbocytes) Platelets are found in blood are important in the formation of a clot

Wound Healing Repair Clotting mechanism Clot (Factor XII) 4 1 3 2 Blood (Factor XII) 1 2 3 4 Ref. 2

Wound Healing Repair One Day After Injury. Acute inflammation takes place in the area of repair Neurophils emigrate from microcirculation into the injured tissue, phagocytosis of foreign substance & necrotic tissues Neutrophil Ref. 1

Wound Healing Repair Phagosome Engulf Phagolysome Excretion Repair www.sumanasinc.com/webcontent/animations/biology.html Refs. 1, 2

Wound Healing Repair Ref. 1

Wound Healing Repair Stem Cell Differentiation

Wound Healing Repair Monocyte (Blood) Macrophage (Tissue) Ref. 1

Wound Healing Repair Macrophage Foot Bacterium Refs. 8, 15

Wound Healing Repair Ref. 8

Wound Healing Repair 2 Days After Injury. Monocytes emigrate from microcirculation into the injured area as macrophage Macrophages continue phagocytosis Neurophils are reduced in number as chronic inflammatory process proceeds Fibroblasts increase in number within the injured connective tissue Producing new collagen, using fibrin meshwork as a scaffold (鷹架)

Wound Healing Repair Initial tissue formed in connective tissue is called granulation tissue. It has more capillaries & fibroblasts Sometimes the growth is excessive Need to be removed for proper healing

Wound Healing Repair If the surface epithelium is destroyed by injury, Epithelial new surface Granulation tissue Repair If the surface epithelium is destroyed by injury, epithelial cells create a new surface tissue at the same time that granulation tissue forms in the injured connective tissue Epithelial cells from borders of the healing injured area lose their cell junctions and become mobile They can divide and migrate across injured tissue, using fibrin meshwork as a guide to form a new surface layer Ref. 2

Wound Healing Repair Functions of fibrin meshwork 1. As a guide for migrating epithelial cells 2. As a scaffold for forming connective tissue 3. Protect the two newly formed tissues Clot remains in place is important: Allow optimal repair in both tissues Dressing placed over the clot may be beneficial to healing process

Wound Healing Repair Inflammatory phase Ref. 6

Wound Healing Repair http://multimedia.mcb.harvard.edu/media.html C: Cell stops & flattens Repair ICAM: Intercellular adhesion molecules ICAM A: Cell Adheres Neutrophil B: Cell rolls Activated Resting Detressing signals D: Cell emigrates Infection or injury From one selectin to adjacent Ref. 3

Wound Healing Repair Reepithelization & neovascularization 1. Guide for migrating epithelial cells 2. Scaffold for collagen 3. Protection Reepithelization & neovascularization Ref. 6

Wound Healing Repair Cytokines that affect wound healing Major Sources Target Cells & Major Effects Ref. 6

Wound Healing Repair pithelium Contact inhibition Epithelium Ref. 4

Wound Healing Repair Abnormal mitosis Capillary spouts Ref. 4

Wound Healing Repair At the end of 2 days. Lymphocytes & plasma cells emigrate from surrounding blood vessels into the injured area as chronic inflammation and immune response begin Macrophages present in the area assist lymphocytes in the immune response occurring at the site injury Ref. 1

Wound Healing Repair Two Days Ref. 1

Wound Healing Repair 7 Days After Injury. Fibrin is digested by collagenase & sloughs off, and the initial repair is completed Clinically, surface of repaired injury remains redder because of the thinness of new epithelium and increased vascularity of new connective tissue

Wound Healing Repair Two Days Seven Days Ref. 1

Wound Healing Repair 2 wks After Injury. The initial granulation tissue & its fibers have been remodeled, giving the tissue its full strength Contraction The new tissue is called scar tissue and appears whiter or paler at the surface of the repaired injury due to increased collagen and decreased vascularity Refs. 2, 14

Wound Healing Repair Ref. 9

Wound Healing Repair Amount of scar tissue depends on: Heredity, strength & flexibility needed, type of repair Oral mucosa is lesser scar formation than skin

Wound Healing Repair Types of repair: Healing by primarily intention. Little loss of tissue, clean edges are joined with sutures to form a small clot, & little granulation tissue Less scar tissue & higher retention

Wound Healing Repair Decreased granulation tissue Less scar tissue Sutured injury (Primary wound healing) Decreased granulation tissue Less scar tissue Small clot Ref. 1

Wound Healing (前旋) Repair Simple Suture Ref. 4

Wound Healing Repair Deep Suture Ref. 4

Wound Healing Repair Common techniques of wound closure (釘書釘) Treatment Advantage Disadvantage (釘書釘) Ref. 4

Wound Healing Repair Healing by secondary intention: There is loss of tissue, so the edges of injury cannot be joined A large clot slowly forms, resulting increased granulation tissue (e.g. extraction site) Ref. 7

Wound Healing Repair Large injury (Secondary wound healing) Large Clot Increased granulation tissue Increased scar tissue Ref. 1

Wound Healing Repair Healing by tertiary intention (delayed primary): If infected wound left open for a few days, edges not surgically joined until infection is controlled Waiting to close as if primary until infection is resolved

Wound Healing Repair Tertiary Intention Wound Increased Late suturing granulation Late suturing with wide scar Ref. 11

Wound Healing Repair Keloid Excessive scarring in skin, sometimes need surgically removed keloid Ref. 1

Wound Healing Repair Ref. 10

Wound Healing Repair A simulation model, showing the collagen fiber network several days after injury The black dots show the cells (only 10% of the cells are shown). Note pronounced alignment of the collagen fibers orthogonal to the plane of the skin A simulation mathematical mode for scar formation Before therapy After therapy The color represents collagen density (red=high, blue=low) Ref. 14

Wound Healing Repair Ref. 10

Wound Healing Repair Ref. 10

Wound Healing Repair Ref. 10

Wound Healing Repair Ref. 10

Wound Healing Repair Ref. 10

Wound Healing Repair Refs. 10, 12

Wound Healing Repair Ref. 10

Wound Healing Repair Ref. 10

Wound Healing Repair Ref. 10

Wound Healing Repair 維他命C 高壓氧 Refs. 13, 16

Wound Healing Repair Ref. 10

Wound Healing Extraction Wound Repair

Wound Healing Extraction Wound Repair Ref. 18

Wound Healing Repair Extraction Wound Ref. 18

Wound Healing Repair Ref. 18

Wound Healing Repair Extraction Wound Ref. 18

Wound Healing Repair Extraction Wound Comparison of Repair Responses in Skin and Teeth Repair Response In skin In teeth Ref. 21

Wound Healing Repair Extraction Wound Repair response after The tooth in situ Repair response after tooth extraction Hemostatic response: The socket fills with clot Ref. 21

Wound Healing Repair Extraction Wound Epithelial response: 1. Proliferation & migration of cells to epithelialize the socket (10 days) Inflammatory response: 2. Polymorph response 3. Macrophage response 4. Cells with osteogenic potential invade the clot from adjacent bone marrow (10 days) Ref. 21

Wound Healing Repair Extraction Wound New osteoblasts differentiate Proliferative and synthesizing phase: New osteoblasts differentiate and proliferate, and form new bone to fill the extraction (10-12 weeks) Ref. 21

Wound Healing Repair Extraction Wound Normal Healing Extraction wound Delayed Healing (dry socket) Ref. 17

Wound Healing Repair Repair of a bone injury is similar to the process that takes place in fibrous connective tissue except that it involves the creation of bone tissue, produced by osteoblasts

Wound Healing Repair Mechanisms of Bone Healing: Formation of new bone at fracture site Clotting of blood and formation of hematoma; 6-8 hr Organization of hematoma: 10 days to complete a. fibrin b. phagocytic activity c. granulation tissue Formation of fibrous callus

Wound Healing Repair Formation of primary bony callus; 10-30 days to complete a. Stages of primary bony callus 1. Anchoring callus 2. Sealing callus 3. Bridging callus 4. Uniting callus b. Low calcium; no radiographic image

Wound Healing Repair Formation of Primary Callus Fracture site Anchoring callus Bridging callus Uniting callus Sealing callus Fracture site Ref. 19

Wound Healing Repair Formation of secondary bony callus 20-60 days a. Irregular bone; influx of calcium radiographic image b. Removal of cast; 4-5 week for jaw bone Reconstruction and remodeling a. Alignment to stress b. Removal of excess

Wound Healing Repair Healing of bone depends on: Interrupted by removal of osteoblast-producing tissues Increased movement of bone Presence of edema or infection

Wound Healing Repair Fixation 1 Fixation 2

Wound Healing Repair Wound healing genes promote cancer progression It has long been recognized that carcinoma cells & their surrounding stroma behave in a remarkably similar way to cells in a healing wound with characteristics such as rapid division, migration, remodelling & invasion of connective tissue, and in ability to induce angiogenesis. In 1986, Harold Dvorak (Berth Israel Deaconess Medical Center, Boston, MA, USA) made the most graphic analogy between wound healing & cancer when he said that tumors are wounds that do not heal. Wound healing genes promote cancer progression Ref. 7

口 腔 病 理 科 SUMMARIES 1. Regeneration & repair 2. Epithelium & connective tissue 3. Extraction wound 4. Bone fracture Processes, types, characteristics