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口 腔 病 理 科 Wound Healing 傷口癒合 陳玉昆教授: 高雄醫學大學 口腔病理科 07-3121101~2755 [email protected] 學 習 目 標 1. Regeneration & repair 2. Epithelium & connective tissue 3. Tooth extraction wound 4. Bone fracture References 參考資料 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/ 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: 1 1. Complete removal of all cells, by-products inflammatory exudate that enter2 the tissue 2. Return of microcirculation to its preinflammatory state 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 Brushingcervical 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 Sharp edge of a tooth Fungus infection Tumor Traumatic ulcer Repair process cannot be completed until the source of injury is removed or the injurious agents are destroyed Refs. 1, 7 Wound Healing Repair Epithelium and connective tissue Tooth extraction wound Bone fracture Wound Healing Repair Events of wound healing Injury Small injury involving epithelium and connective tissue Clot forms 1. Inflammation 2. Epithelization 3. Neurovascularization Migrating epithelial cells from a new surface layer Granulation 4. Granulation tissue tissue forms 5. Contraction 6. Collagen formation Tissue remodeling forms scar tissue 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 injury source 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(成塊) red blood cells and platelets (thrombocytes) Platelets are found in blood are important in the formation of a clot Wound Healing Repair Clot Clotting mechanism Blood (Factor XII) 4 1 3 2 Ref. 2 Wound Healing Repair One Day After Injury. Acute inflammation takes place in the area of repair Neutrophils emigrate(攅入)from microcirculation into the injured tissue, phagocytosis of foreign substance & necrotic tissues Neutrophil Neutrophil Ref. 1 Wound Healing Phagosome Engulf Repair www.sumanasinc.com/webcontent/animations/biology.html Blood Neutrophil Phagolysome Blood Stem cell Monocyte Tissue Excretion Macrophage Mast cell Eosinophil Refs. 1, 2 Lymphoid tissue B lymphocyte Thymus T lymphocyte Plasma cell T helper T suppressor T killer Memory cell Wound Healing Repair Stem Cell Differentiation Wound Healing Repair Lysosomes containing lysosomal enzymes Monocyte (Blood) Nucleus Macrophage (Tissue) Phagocytosis of bacterium Ref. 1 Wound Healing Repair Macrophage Foot Bacterium Outside of Macrophage Surface of Macrophage a) b) Phagosome Lysosome c) d) “So long, bacterium” Bacterium Refs. 8, 15 Wound Healing Repair Wound Healing Repair 2 Days After Injury. Monocytes emigrate from microcirculation into the injured area as macrophage Macrophages continue phagocytosis Neutrophils 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 Epithelial new surface Repair Granulation tissue 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. Guide for migrating epithelial cells 2. Scaffold for forming connective tissue 3. Protect the two newly formed tissues Clot remains in place is important: 1. Allow optimal repair in both tissues 2. Dressing placed over the clot may be beneficial to healing process Wound Healing Repair Inflammatory phase Ref. 6 Wound Healing http://multimedia.mcb.harvard.edu/media.html Repair A: Cell Adheres Resting ICAM: Intercellular adhesion molecules Neutrophil C: Cell stops & flattens ICAM B: Cell rolls Activated Detressing signals D: Cell emigrates Infection or injury From one selectin to adjacent selectin Wound Healing Repair Reepithelization & neovascularization 1. Guide for migrating epithelial cells 2. Scaffold for collagen 3. Protection Ref. 6 Wound Healing Repair Clot Epithelium Epithelium Granulation tissue Ref. 4 Wound Healing Repair Clot 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 PMN Lymphocyte and plasma cell Amount 多形核白血球 (polymorphonuclear granulocyte, PMN)又 叫顆粒白血球 (granulocytes),它是 由骨髓產生,人體每分 鐘產生 80×106 個,壽 命只有2~3天。 (單核血球 則有幾個月 到幾年),它構成體內 白血球(leukocytes) 的 60~70%。 Macrophage Two Days Time Acute --- Chronic Inflammation --- Immune ----------------------------------response 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 Lymphocyte and plasma cell Amount PMN Macrophage Two Days Time Acute --- Chronic Inflammation --- Immune ----------------------------------response Seven Days Ref. 1 Wound Healing Repair Contraction 2 Wks After Injury. The initial granulation tissue & its fibers have been remodeled, giving the tissue its full strength 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 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 Sutured injury (Primary wound healing) Small clot Less scar Decreased granulation tissue tissue Ref. 1 Wound Healing Repair When the needle is held upside down & the wrist pronated(前旋),the needle tip moves farther away from the laceration & penetrates deeply. Thus, there is more tissue at the depth of the wound, causing eversion of the wound. The needle should enter the skin at 90 degrees. Simple Needle holder Needle rolled in arc Needle holder rolled Suture Needle tip grasped parallel to skin Skin edge retracted More tissue in depth than at surface Ref. 4 Wound Healing Repair Skin edge retracted The needle is first inserted at the depth of the wound and removed closer to the skin surface. The needle is then inserted superficially into the opposite side of the wound & exists deeply so that the knot is buried deep within the wound Needle holder Deep Suture Ref. 4 Wound Healing Repair Common techniques of wound closure Treatment Sutures (釘書釘) Staples Advantage Time-honored method Meticulous closure Greatest tensile strength Lowest dehiscence rate Rapidity of application Low tissue reactivity Low cost Low risk of needle stick Disadvantage Removal required Anesthesia required Greatest tissue reactivity Highest cost Slowest of application Less meticulous closure than with sutures May interfere with computed tomography And magnetic resonance imaging Tissues Adhesives Rapidity of application Patient comfort Resistance to bacterial growth No need for removal Low cost No risk of needle stick Lower tensile strength than sutures Dehiscence over high-tension areas (joints) Surgical Tapes Least tissue reactivity Lowest infection rates Rapidity of application Patient comfort Low cost No risk of needle stick Lower tensile strength than sutures Highest rate of dehiscence Use of toxic adjuncts required Cannot be used in hairy areas Must remain dry 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. tooth 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 Wound Tertiary Intention Increased granulation tissue 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 Wound closure Necessary for survival – reduces risk of infection etc. (REVIEW) Scarring Unnecessary for wound closure – may simply be a side-effect. Ref. 10 Wound Healing Repair (REVIEW) HEALING PROGRESS: ACUTE WOUNDS Sequence completed in continuous and expected time frame Usually achieved with few or no complications Overreaction in acute wound healing - Keloids - Hypertrophic scars Ref. 10 Wound Healing (REVIEW) Repair Phases of Wound Healing Hemostasis & Inflammation Fibroplasia 0 Injury 2 4 6 8 Maturation 365 Days after injury Ref. 10 Wound Healing Repair (REVIEW) Scar Maturation Collagen Fibril Crosslinking REMODELING W O U N D I N G Endothelial Cells Epithelial Cells Collagen Fibroblasts PROLIFERATION Lymphocytes Macrophages Neutrophils INFLAMMATION Proteoglycans Fibrins Platelets HEMOSTASIS Time from Injury Ref. 10 Wound Healing (REVIEW) Repair COMPONENTS OF WOUND HEALING Cell Types Involved Coagulation Process Platelets Platelet Macrophages Neutrophils Inflammation Process Migratory Proliferative Process Macrophages Lymphocytes Fibroblasts Epithelial cells Endothelial cells Remodeling Process Fibroblasts Injury Hours Days Weeks Ref. 10 Wound Healing Repair (REVIEW) HEALING RETARDED BY SEVERAL FACTORS Ischemia Dry wound environment Infection Foreign bodies Anti-inflammatory therapy Nutritional deficiency 維他命C 高壓氧 Refs. 10, 13, 16 Wound Healing Repair (REVIEW) EFFECTS OF BACTERIA ON WOUND HEALING Quantitative bacterial cultures: >106 per gm Presence of significant organisms - Staphylococcus aureus - Pseudomonas species - Streptococcus species Ref. 10 Wound Healing Repair (REVIEW) FUTURE OF WOUND HEALING Continued research - Elucidation of signals/growth factors involved in: * Epithelization * Wound contraction and scarring * Angiogenesis Tissue engineering Gene therapy Ref. 10 Wound Healing Repair Tooth Extraction Wound Wound Healing Repair Tooth Extraction Wound 拔牙後,齒槽癒合的程序:一、血塊之形成 ,二、血塊 之有機化,血管之再生,三、肉芽組織出現,四、噬骨細 胞(osteoclast)的出現、造骨細胞(osteoblast)的出現,五、 硬組織修補。 在這癒合過程中除上述之機轉,許多局部因子與全身因子 亦參與調節傷口之癒合。如PTH、Vitamin D、Calcitonin、 Glucocorticoid、Sex steroid (Estrogen、Androgen)、 Progestins.、Thyroid hormone、Retinoids、GH、IGF、 IGG、IGF、TGFB I.II.III.、BMP等cytokine。上述這些局部 因子或全身因子以局部癒合加速現象RAP(regional accelerate phenomenon)(Frost,1983),或全身癒合加速現 象SAP(systemic accelerate phenomenon),局部或全身, 直接或間接的方式影響拔牙傷口之癒合。 Ref. 18 Wound Healing Repair Tooth Extraction Wound 關於齒槽骨於拔牙後傷口之癒合,Mangos(1941)曾於 人類身上對拔牙傷口癒合做組織學的研究,觀察到之變化: 術後3天,成纖維細胞(fibroblast)出現於血塊邊緣。 術後7天,血管開始有機化。 上皮幾乎覆蓋拔牙傷口。 術後14天,上皮已覆蓋拔牙傷口,並有骨小樑 (trabeculae)出現。 術後40天,拔牙槽之上半部有明顯的纖維組織。 術後72天,上皮組織已很完整,皮下肉芽組織已不復見, 且已被緻密結締組織取代。 Ref. 18 Wound Healing Repair Tooth Extraction Wound Amler(1960)亦有類似發表,特別是在術後7天的拔牙傷 口有所謂造骨纖維(osteogenic fiber)出現。 Amler的觀點被Carter等人(1991)所證實,並說明此類造 骨纖維即是新生骨(woven bone or immature bone)生成 時的模板(template)架構,日後此骨塑形(bone modeling) 所生成的新生骨經過骨重塑形(bone remodeling)的過程轉 為成熟的板狀骨(lamellar bone)。 Ref. 18 Wound Healing Repair Tooth Extraction Wound 除了上面三篇外,Boyne(1996)以四環素(tetracycline) 作為骨骼螢光標記(Fluorochrome bone labels),認為拔牙 傷口內新生骨出現於術後10天,並且先出現於拔牙槽的側 壁(socket wall)上,而非過去認為的齒槽底部(socket fundas)。 除了人類外,其他動物拔牙傷口之癒合過程也有大量研 究及文獻報告,例如:Eyler(1920)、Dalogh(1932)、 Meyer(1935)、Claflin(1930)等人用狗;Huebsch(1952)、 Smith(1974)、Hsieh等人(1994, 1995)用大白鼠; Simpson(1958)、Radden(1959)等人用猴子做拔牙傷口癒 合之研究,基本癒合模式(healing pattern)均類似,只因物 種(species)間不同,其生長代謝速率不同而有時間上快慢 之別。 Wound Healing Repair Tooth Extraction Wound Comparison of Repair Responses in Skin and Teeth Repair Response In skin Epithelial response Proliferation and migration of cells to cover the defect Connective tissue response Polymorph response Macrophage response Fibroblast response from undifferentiated perivascular cells & undamaged fibroblasts New fibroblasts form collagen In teeth No epithelial response because ameloblasts are lost at time of tooth extraction Polymorph response Macrophage response Fibroblast response by division of undamaged pulpal & perivascular cells New fibroblasts form collagen, which mineralizes to form dentin Ref. 21 Wound Healing Repair Tooth Extraction Wound Repair response after tooth extraction The tooth in situ Hemostatic response: The socket fills with clot Ref. 21 Wound Healing Repair Tooth 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) 1 2 3 4 Ref. 21 Wound Healing Repair Tooth Extraction Wound New osteoblasts differentiate and proliferate, and form new bone to fill the extraction (10-12 weeks) Proliferative and synthesizing phase Ref. 21 Wound Healing Repair Tooth Extraction Wound Normal Healing Extraction wound Delayed Healing (dry socket) Ref. 17 Wound Healing Repair Bone Tissue 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 Bridging callus Anchoring callus Uniting callus Sealing callus 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 It has 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, remodeling & invasion of connective tissue, and in ability to induce angiogenesis. Wound healing genes promote cancer progression 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. Ref. 7 口 腔 病 理 科 SUMMARIES 1. Regeneration & repair 2. Epithelium & connective tissue 3. Tooth extraction wound 4. Bone fracture Processes, types, characteristics