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WOUND HEALING AND
REPAIR
Presenter: Nyangara Rajabu,
MMed(OBGY)
Facilitator: Dr Mgaya
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CONTENTS
History
Introduction
Types of wounds
Regeneration and Repair Phases of wound healing
Nature of wound healing
Factors influencing healing Complications of wound healing
References
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HISTORY The earliest accounts of wound healing date back
to about 2000 B.C
Galen of Pergamum emphasized the importanceof maintaining a moist environment to ensureadequate healing.
Ambriose Par found that simply dressed gunshotwounds heal faster and are less painful than whentreated with boiling oil, the previously acceptedmethod.
Ignaz Philipp Semmelweis advocated need forwashing hands
Joseph Lister began soaking his instruments inphenol and spraying the operating rooms, reducingthe mortality rates from 50 to 15%.
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INTRODUCTION
The repair of tissue damage broadly separated
into two processes, regenerationand healing Regeneration refers to growth of cells and tissues
to replace lost structures.
Wound healing is the effort of tissues to restorenormal function and structure after injury
-To reform barriers to fluid loss and infection,
-limit further entry of foreign organisms and material,-re-establish normal blood and lymphatic flow
patterns,
-restore the mechanical integrity of the injureds stem
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TYPES OF WOUND Abrasions. Also called scrapes, they occur
when the skin is rubbed away by friction against
another rough surface (e.g. rope burns andskinned knees).
Avulsions. Occur when an entire structure or
part of it is forcibly pulled away, such as theloss of a permanent tooth or an ear lobe.Animal bites may cause avulsions.
Contusions. Are also called bruises and arethe result of a forceful trauma that injures aninternal structure without breaking the skin.
Blows to the chest, abdomen, or head with ablunt instrument e. . a football or a fist can
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TYPES OF WOUND cont...
Crush wounds. Occur when a heavy object
falls onto a person, splitting the skin andshattering or tearing underlying structures.
Cuts. Slicing wounds made with a sharp
instrument, leaving even edges. They may beas minimal as a paper cut or as significant as asurgical incision.
Incised wound: Any sharp cut in which thetissues are not severed; a clean cut caused bya keen cutting instrument. The wound mayeither be aseptic or infected, depending on the
circumstances.
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TYPES OF WOUND cont...
Lacerations. Also called tears, these are
separating wounds that produce ragged edges.They are produced by a tremendous forceagainst the body, either from an internal sourceas in childbirth, or from an external source likea punch.
Open wound. A contusion, in which the skin isalso broken, such as gunshot, incised or
lacerated wound.
Penetrating wound. A wound in which the skinis broken and the agent causing wound enters
subcutaneous tissue or a deep lying structure
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REGENERATION AND REPAIR
Healing involves two processes:
1. Regeneration
2. Repair
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Regeneration
Definition: means proliferation of theparenchymal cells resulting incomplete restoration of the original
tissues. It requires cell proliferation which is
largely regulated by micro
environment that can eitherstimulateor inhibitcell growth.
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Regeneration cont...
Cell proliferation depends on the cell growthcycle which consists of 4 unequal phases:
M (mitotic) phase
G1 (pre synthetic) phase S (DNA synthesis) phase
G2 (pre mitotic) phase
Quiescent or resting cells will be in aphysiologic state called G0.
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e e yc e an eren ePopulations
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Cells of the body are usually classifiedinto three groups depending on theircapacity for regeneration:
1.Labile cells2.Stable cells
3.Permanent cells
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1. Labile cells
Also called continuously dividing cells
Follow the cell cycle from one mitosis toother
Continue to proliferate throughout life,replacing tissues that are continuouslydestroyed
These include: surface epithelial cells of
epidermis, alimentary tract , respiratorytract, urinay tract, vagina, cervix, uterineendometrium, haematopoietic cells of bone
marrow and cells of lymph node and
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2. Stable cells Also called quiescent cells
These cells lose or decrease their capacityto proliferate after adoloscene but retainthe capacity to multiply in response to
stimuli throughout adult life These include: parenchymal cells of organs
like liver, pancreas, kidney, adrenal and
thyroid ; mesenchymal cells of smoothmuscle cells , fibroblasts, vascularendothelium, bone and cartilage cells.
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3. Permanent cells
Also called non dividing cells. Have left the cell cycle and cannot
undergo mitotic division in post natal life.
These include: neurons of nervoussystem, skeletal muscle and cardiacmuscle cells.
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Repair
Is the replacement of injured tissue byfibrous tissue.
Processes involved in repair:
1. Granulation tissueformation
2. Contraction of wounds
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PHASES OF WOUND HEALING
Normal wound healing follows a predictablepattern that can be divided into overlappingphases defined by characteristic cellularpopulations and biochemical activities:
(a) Hemostasis & inflammation
(b) Proliferation
(c) Maturation and Remodeling
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HEMOSTASIS AND INFLAMMATION In the inflammatory phase clotting takes
place in order to obtain hemostasis, or stopblood loss, and various factors are releasedto attract cells that phagocytise debris,bacteria, and damaged tissue and release
factors that initiate the proliferative phase ofwound healing
The events can be divided into:
1.Vascular events
2.Cellular events
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1. Vascular events Earliest manifestation is vasodilatation, it follows a transient constrictionof
arterioles lasting a few seconds.
Wounding disrupts tissue integrity and direct exposure of extracellular
matrix to platelets
Initial contact between platelets and collagen requires the von Willebrandfactor (vWF)
Binding results in changes in platelet conformation, triggering intracellularsignal transduction pathways that result in platelet activation and the releaseof biologically active proteins.
Platelet granules are storage organelles that contain
-Platelet-derived growth factor (PDGF),
-Transforming growth factor(TGF)-,
-Insulin-like growth factor (IGF)-1,
-Fibronectin,
-Fibrinogen,
-Thrombospondin,
-vWF.
V l
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Vascular events cont... The dense bodies contain the vasoactive amines, such as serotonin, which
cause vasodilation and increased vascular permeability.
The clotting cascade is initiated through both the intrinsic and the extrinsic
pathways. Vasodilation is followed by increased permeability of the microvasculature,
followed by stasis, which leads to accumulation of leucocytes along thevascular endothelium which then migrate through the vascular wall into theinterstitial tissue.
Increased permeability is due to- formation of endothelial gaps in venules,
- direct endothelial injury,
- delayed prolonged leakage,
- leucocyte mediated endothelial injury,-increased transcytosis and leakage from new vessels
The combination of intense vasodilation and increased vascular permeabilityleads to clinical findings of inflammation,
rubor(redness), tumor(swelling),calor(heat), and dolor(pain).
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2. Cellular events1. Polymorphonuclear cells or Neutrophils First infiltrating cells to enter the wound site,
peaking at 24 to 48 hours Neutrophil migration is stimulated by
- Increased vascular permeability,- local prostaglandin release, and
- the presence of chemotactic substances, suchas complement factors, interleukin-1 (IL-1), tumornecrosis factor alpha (TNF-), TGF , plateletfactor 4, or bacterial products.
PMNs are also a major source of cytokinesearlyduring inflammation, especially TNF-, alsorelease proteases such as collagenases.
Following functional activation neutrophils
scavenge necrotic debris, foreign material, and
PMN t
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PMN cont. Stimulated neutrophils generate free oxygen
radicals with electrons donated by the reduced
form of nicotinamide adenine dinucleotidephosphate, (NADPH).
The electrons are transported across themembrane into lysosomes where superoxide anion(O2-) is formed.
This very potent free radical is bactericidal, but it isalso toxic to neutrophils and surrounding viable
tissues. Migration of PMNs stops when wound
contamination has been controlled, usually withinthe first few days after injury.
PMNs do not survive longer than 24 hours
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PMN cont. If wound contamination persists or secondary
infection occurs, continuous activation of thecomplement system and other pathwaysprovides a steady supply of chemotacticfactors, resulting in a sustained influx ofPMNs into the wound.
PMNs are not essential to wound healingbecause their role in phagocytosis andantimicrobial defense may be taken over bymacrophages.
Sterile incisions will heal normally without the
presence of PMNs
2 M h
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2. Macrophages Second population of inflammatory cells that invades the
wound.
Macrophage is the one cell that is truly central to woundhealing, serving to orchestrate the release of cytokinesand stimulate many of the subsequent processes ofwound healing
Derived from circulating monocytes, achieve significantnumbers in the wound by 48 to 96 hours post injury andremain present until wound healing is complete.
Chemotactic factors specific for monocytes include
-bacterial products,-fibronectin,
-complement degradation products (C5a),
-collagen,
-thrombin,
F ti f h
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Functions of macrophages1. Macrophages induce PMN apoptosis
2. Macrophages have specific receptors for IgG (Fc-receptor),C3b (CR1 and CR3), and fibronectin (integrin receptors),which permit surface recognition of opsonized pathogensand facilitate phagocytosis.
3. Activated wound macrophages also produce nitric oxidewhich has antimicrobial properties.
4. Phospholipase is induced, causing enzymatic degradation ofthe cell membrane phospholipids, releasing thromboxane A2and prostaglandin F2
5. Releases leukotriene B4 ,a potent neutrophilchemoattractant, and C4 and 15- and 5-
hydroxyeicosatetraenoic acid.6. Release proteinases, including matrix metalloproteinases(MMP-1, MMP-2, MMP-3, and MMP-9) which degrade theECM and are crucial for removing foreign material,promoting cell movement through tissue spaces, and
regulating ECM turnover.7. Release rowth factors that stimulate fibroblast endothelial
3 T l h t
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3. T lymphocytes
Another population of inflammatory/immune
cells that routinely invades the wound. Less numerous than macrophages, numbers
peak at about 1 week post injury
Bridge the transition from the inflammatory tothe proliferative phase of healing
Depletion of most wound T lymphocytesdecreases wound strength and collagen
content Also exert a down regulating effect on
fibroblast collagen synthesis by cell-
associated interferon-, TNF-, and IL-1.
PROLIFERATION PHASE
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PROLIFERATION PHASE Second phase of wound healing and roughly spans
days 4 through 12
It is during this phase that tissue continuity is re-established Fibroblasts and endothelial cells are the last cell
populations to infiltrate the healing wound, and thestrongest chemotactic factor for fibroblasts is PDGF.
Recruited fibroblasts first need to proliferate, and thenbecome activated, to carry out their primary function ofmatrix synthesis remodeling.
The proliferative phase is also called the reconstruction
phase. The events in this stage can be subdivided into:
Angiogenesis
Fibroplasia and granulation tissue formation
Epithelization
Contraction
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1. Angiogenesis Also called neovascularization, the process of angiogenesis
occurs concurrently with fibroblast proliferation whenendothelial cells migrate to the area of the wound.
Because the activity of fibroblasts and epithelial cellsrequires oxygen and nutrients, angiogenesis is imperative forother stages in wound healing, like epidermal and fibroblastmigration. The tissue in which angiogenesis has occurredtypically looks red (is erythematous) due to the presence ofcapillaries.
Stem cells of endothelial cells, originating from parts ofuninjured blood vessels, develop pseudopodia and pushthrough the ECM into the wound site to establish new bloodvessels.
Endothelial cells are attracted to the wound area byfibronectin found on the fibrin scab and chemotactically byangiogenic factors released by other cells, e.g. frommacrophages and platelets when in a low-oxygenenvironment. Endothelial growth and proliferation is alsodirectly stimulated by hypoxia, and presence of lactic acid in
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Angiogenesis cont..
To migrate, endothelial cells needcollagenases and plasminogen activator todegrade the clot and part of the ECM. Zinc-dependent metalloproteinases digestbasement membrane and ECM to allow cell
migration, proliferation and angiogenesis When macrophages and other growth factor-
producing cells are no longer in a hypoxic,lactic acid-filled environment, they stopproducing angiogenic factors. Thus, whentissue is adequately perfused, migration andproliferation of endothelial cells is reduced.Eventually blood vessels that are no longerneeded die by apoptosis.
2 Fibroplasia and granulation tissue
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2. Fibroplasia and granulation tissueformation
Simultaneously with angiogenesis, fibroblastsbegin accumulating in the wound site. Fibroblasts
begin entering the wound site two to five daysafter wounding as the inflammatory phase isending, and their numbers peak at one to twoweeks post-wounding.
By the end of the first week, fibroblasts are themain cells in the wound.Fibroplasia ends two tofour weeks after wounding.
In the first two or three days after injury,fibroblasts mainly proliferate and migrate, whilelater, they are the main cells that lay down thecollagen matrix in the wound site.Fibroblasts
from normal tissue migrate into the wound area
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Fibroplasia and granulation tissue formation cont....
Initially fibroblasts use the fibrin scab formed in theinflammatory phase to migrate across, adhering tofibronectin. Fibroblasts then deposit groundsubstance into the wound bed, and later collagen,which they can adhere to for migration
Granulation tissue functions as rudimentary tissue,and begins to appear in the wound already duringthe inflammatory phase, two to five days postwounding, and continues growing until the wound
bed is covered. Granulation tissue consists of new blood vessels,
fibroblasts, inflammatory cells, endothelial cells,myofibroblasts, and the components of a new,
provisional extracellular matrix (ECM)
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Extracellular Matrix
The wound is strengthened by proliferationof fibroblasts and myofibroblasts which getstructural support from the extracellularmatrix (ECM). ECM has five main
components:i. collagen
ii. adhesive glycoprotein
iii. basement membraneiv. elastic fibres
v. proteoglycans.
i C ll d iti
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i. Collagen deposition
One of fibroblasts' most important duties is theproduction of collagen.Fibroblasts begin secreting
appreciable collagen by the second or third post-wounding day, and its deposition peaks at one tothree weeks. Collagen production continuesrapidly for two to four weeks, after which its
destruction matches its production and so itsgrowth levels off. Collagen deposition is important because it
increases the strength of the wound; before it islaid down, the only thing holding the woundclosed is the fibrin-fibronectin clot, which does notprovide much resistance to traumatic injury. Also,cells involved in inflammation, angiogenesis, andconnective tissue construction attach to, grow and
differentiate on the collagen matrix laid down by
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Collagen deposition cont....
Collagen synthesis, as well as post
translational modifications, is highlydependent on systemic factors such as
an adequate oxygen supply
the presence of sufficient nutrients (aminoacids and carbohydrates)
cofactors (vitamins and trace metals)
the local wound environment (vascularsupply and lack of infection).
ii Adhesive glycoprotein
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ii. Adhesive glycoprotein
Fibronectin is the best characterised glycoproteinin ECM and has binding binding properties to other
cells and ECM. It is of 2 typesPlasma fibronectin, synthesized by the liver cells and is trapped
and is trapped in basement membrane such as in filtrationthrough the renal glomerulus.
Tissue fibronectin, is formed by fibroblasts , endothelial cells and
other mesenchymal cells. It is responsible for the primitivematrix in wound healing.
Tenascin or cytotactin is the glycoproteinassociated with fibroblasts and appears in wound
after 48 hours of injury. It disappears from maturescar tissue.
Thrombospondin is mainly synthesised bygranules of platelets. Function as adhesive protein
for keratinocytes and platelets but is inhibitory to
iii Basement membrane
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iii. Basement membrane
Flexible, thin (40- to 120-nm thick) mats of specialized ECMthat separate cells and epithelia from the underlying orsurrounding connective tissue
In the skin, the basal lamina is tethered to the underlyingconnective tissue by specialized anchoring fibrils
This composite of basal lamina and collagen is thebasement membrane
Most mature basal laminae contain type IV collagen and theglycoproteins laminin.
The basal lamina serves numerous functions1. As a molecular filter, preventing passage of
macromolecules (i.e., in kidney glomerulus)
2. As a selective barrier to certain cells (i.e., the laminabeneath the epithelium prevents fibroblasts from contactingepithelial cells, but does not stop macrophages orlymphocytes)
3. As a scaffold for regenerating cells to migrate
4. Is important in tissue regeneration where the basal lamina
iv Elastic fibres
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iv. Elastic fibres
Provide the resilience to allow for recoil after
transient stretch. Elastin is composed of hydrophobic and
alanine and lysine-rich -helical segmentsthat alternate along the polypeptide chain
Elastic fibers consist of an elastin corecovered with a sheath of microfibrils, whichare composed of several distinct
glycoproteins, such as fibrillin. Microfibrils appear before elastin in
developing tissues and seem to form a
scaffold on which the secreted elastin
v Proteoglycans
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v. Proteoglycans
These are agroup of molecules having 2components- an essential carbohydrate
polymer (called glycosaminoglycan), and aprotein bound to it, and hence the nameproteoglycan. Various proteoglycans are
distributed in different tissues as under: Chondrointin sulphate- abundant in cartilage , dermis Heperan sulphate- in basement membranes
Dermatan sulphate- in dermis
Keratan sulphate- in cartilage
Hyaluronic acid- in cartilage , dermis
In wound healing the deposition ofproteoglycans precedes collagen laying
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3. Epithelialization The formation of granulation tissue in an open
wound allows the reepithelialization phase totake place, as epithelial cells migrate acrossthe new tissue to form a barrier between thewound and the environment.
Basal keratinocytes from the wound edges anddermal appendages such as hair follicles,sweat glands and sebaceous (oil) glands arethe main cells responsible for the
epithelialization phase of wound healing. Keratinocytes migrate without first proliferating.
Migration can begin as early as a few hours
after wounding.
If the basement membrane is not breached epithelial cells
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If the basement membrane is not breached, epithelial cellsare replaced within three days by division and upwardmigration of cells in the stratum basale in the same fashionthat occurs in uninjured skin. However, if the basement
membrane is ruined at the wound site, reepithelization mustoccur from the wound margins and from skin appendagessuch as hair follicles and sweat and oil glands that enter thedermis that are lined with viable keratinocytes. If the woundis very deep, skin appendages may also be ruined andmigration can only occur from wound edges.
Migration of keratinocytes over the wound site is stimulatedby lack of contact inhibition and by chemicals such as nitricoxide. Before they begin to migrate, cells must dissolve theirdesmosomes and hemi desmosomes, which normally anchorthe cells by intermediate filaments in their cytoskeleton toother cells and to the ECM. Transmembrane receptorproteins called integrins, which are made of glycoproteinsand normally anchor the cell to the basement membrane byits cytoskeleton, are released from the cell's intermediatefilaments and relocate to actin filaments to serve as
attachments to the ECM for pseudopodia during migration.
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4. Contraction Contraction is a key phase of wound healing.
Contraction commences approximately a week afterwounding, when fibroblasts have differentiated intomyofibroblasts.
In full thickness wounds, contraction peaks at 5 to 15
days post wounding. Contraction can last for several weeks and continues
even after the wound is completely reepithelialized.
A large wound can become 40 to 80% smaller aftercontraction.
Wounds can contract at a speed of up to 0.75 mm perday, depending on how loose the tissue in the
wounded area is.
At first contraction occurs without myofibroblast
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At first, contraction occurs without myofibroblastinvolvement. Later, fibroblasts, stimulated by growthfactors, differentiate into myofibroblasts.Myofibroblasts, which are similar to smooth muscle
cells, are responsible for contraction. Myofibroblastscontain the same kind of actin as that found in smoothmuscle cells.
Myofibroblasts are attracted by fibronectin and growthfactors and they move along fibronectin linked to fibrin
in the provisional ECM in order to reach the woundedges. They form connections to the ECM at the woundedges, and they attach to each other and to the woundedges by desmosomes.
As the actin in myofibroblasts contracts, the wound
edges are pulled together. Fibroblasts lay downcollagen to reinforce the wound as myofibroblastscontract The contraction stage in proliferation ends asmyofibroblasts stop contracting and commit apoptosis. .These events signal the onset of the maturation stageof wound healing.
MATURATION AND REMODELLING PHASE
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MATURATION AND REMODELLING PHASE When the levels of collagen production and degradation equalize, the
maturation phase of tissue repair is said to have begun.
The maturation phase can last for a year or longer, depending on the
size of the wound and whether it was initially closed or left open. During maturation, type III collagen, which is prevalent during
proliferation, is gradually degraded and the stronger type I collagen islaid down in its place.
Originally disorganized collagen fibers are rearranged, cross-linked,
and aligned along tension lines. As the phase progresses, the tensilestrength of the wound increases, with the strength approaching 50%that of normal tissue by three months after injury and ultimatelybecoming as much as 80% as strong as normal tissue. Since activityat the wound site is reduced, the scar loses its red appearance asblood vessels that are no longer needed are removed by apoptosis.
The phases of wound healing normally progress in a predictable,timely manner; if they do not, healing may progress inappropriately toeither a chronic wound such as a venous ulcer or pathologicalscarring such as a keloid scar.
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Keloid scar
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NATURE OF WOUND HEALING
Accomplished by on of the following twoways:
i. Healing by primary intention
ii. Healing by secondary intention
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i. Healing by primary intention
Healing of wounds with followingcharacteristics:
-clean and uninfected
-surgically incised-without much loss of cells and tissue
-edges of wound are approximated by
surgical sutures
Sequence of events involved are:
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Initial haemorrhage
Space between approximated surfaces of the incised wound is filled with bloodwhich than clots and seals the wound against dehydration and infection.
Acute inflammatory response
Within 24hours appearance of polymorphs from the margins of incision. By the 3 rdday polymorphs are replaced by macrophages
Epithelial changes
Basal cells of epidermis from both the cut margins start proliferating and migratingtowards incisional space in the form of epithelial spurs.
The migrated epithelial cells separate the underlying viable dermis from theoverlying necrotic material and clot, forming scab which is cast off.
The basal cells from the margins continue to proliferate and by the 5th day amultilayered new epidermis is formed
Organisation
By 3rd fibroblasts also invade the wound area. By 5th day new collagen fibrils startforming which dominate till healing is completed. In 4 weeks, the scar tissue withscanty cellular and vascular elements, a few inflammatory cells and epithelialisedsurface is formed.
Suture tracks
Each suture track is a separate wound and incites the same phenomenon as in
Healing by secondary intention
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Healing by secondary intention
Healing of a wound with the followingcharacteristics:
-open with a tissue defect, at times
infected-having extensive loss of cells andtissues
-the wound is not approximated bysurgical sutures but is left open
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Sequence of events involved are:
Initial haemorrhage
As a result of injury, the wound is filled with blood and fibrin clotwhich dries.
Inflammatory phase
There is an initial acute inflammatory response followed by theappearance of macrophages which clear off the debris as inprimary union
Epithelial changes The epidermal cells from both the margins of wound proliferate and
migrate into the wound in the form of epithelial spurs till they meetin the middle and re-epithelialise the gap completely .
However the proliferating epithelial cells do not cover the surface
fully until granulation tissue from the base has started filling thewound space.
In this way, pre existing viable connective tissue is seperateed fromthe necrotic material and clot on the surface, forming scab which iscast off.
In time the regenerated epidermis becomes stratified andkeratinised.
Granulation tissueM i b lk f d h li i b l ti
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Main bulk of secondary healing is by granulations.
Granulation tissue is formed by proliferation of fibroblasts andneovascularisation from the adjoining viable elements.
The newly formed granulation tissue us deep red, granular and very
fragile . With time the scar on maturation becomes pale and white due to
increase in collagen and decrease in vascularity.
Specialised structures of skin like hair follicles and sweat glands arenot replaced unless their viable residues remain which may
regenerateWound contraction
Due to the action of myofibroblasts present in granulation tissue, thewound contracts to one-third of its original size.
Wound contraction occurs at a time when active granulation tissue is
being formed.Presence of infection
Bacterial contamination of open wounds delays th process of healingdue to release of bacterial toxins that provoke necrosis, suppurationand thrombosis.
Surgical removal of dead and necrosed tissue, debridement , helpsin preventing the bacterial infection of open wounds.
FACTORS INFLUENCING HEALING
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FACTORS INFLUENCING HEALING
LOCAL FACTORS
1. Infection single most important reason fordelayed wound healing
2. Foreign bodies
-suture material, bone and wood splinters .-interfere with healing and cause inflammatory
reaction and infection.
3. Mechanical factors
-Early movement
-Pressure
-Delays healing process
4. Ionising radiation : delays granulation tissue
SYSTEMIC FACTORS
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1. Malnutrition-Protein deficiency delays wound healing
-Vitamin C deficiency (inhibition of collagensynthesis)
2. Metabolic status-e.g. Diabetes mellitus
-Cortisone treatment.inhibits inflammation and collagen
synthesis
3. Circulatory status
-Inadequate blood supply due to arteriosclerosis-Varicose veins
4. Age : Older patient at higher risk of poor woundhealing
5. Medication: Anti-inflammator as irin
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HEALING
1.Infection
2. Pigmentation3. Implantation
4. Deficient scar formation
5. Hypertrophied scar & Keloid formation
6. Excessive contraction
7. Neoplasia
8. Incisional hernia
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REFERENCES
Robins textbook of Basic Pathology ;8thEdition
Essentials of Pathology for Dental
students; 3rd edition Harsh Mohan www.google.com
Wikipedia
http://emedicine.medscape.com