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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