Healing and Repair Flashcards
what is healing?
Replacement of destroyed or lost tissue by a viable tissue
what is the primary wound closure?
- -Usually a small, straight, and clean incision
- -Primary approximation of the wound edges without irregularities
- -Minimal inflammation
- -Minimal to no granulation tissue
- -Organ-specific tissue forms at the site of healing
- -Hairline scar or no scar formation
- -eg surgical wound
what is the secondary wound closure?
–Usually larger open wounds with irregular edges (most common type of wound)
–Irregular wound edges that cannot be perfectly approximated
–Pronounced inflammation
–Requires the formation of granulation tissue (increase the length of healing)
–Wound replaced with increased proliferation of fibroblasts
Scar formation
what is the tertiary wound closure (also called delayed primary closure)
- -Due to an interruption in normal wound healing
- -Combination of primary closure and secondary closure
- -Results in a larger scar than with primary or secondary closure
- -Wounds created by specialists
- -Wounds that are at high risk for contamination are cleaned and left open to assess the risk of infection. They are surgically closed a few days later; e.g., animal bites and lacerations with foreign bodies.
what are the responses of tissue to injury?
- The initial response of damaged tissue is to an acute inflammation
- Resolution
- Regeneration
- Repair by fibrosis
resolution is characterized by?
• No tissue destruction
• Damaging agent and cell debris are removed
• Tissue returned to its pre-injury state
e.g., mild heat injury
what is the difference between regeneration and repair?
- Regeneration is the replacement of the lost tissue by a tissue of the same type
- Repair is the replacement of the destroyed tissue by a fibrous scar
list the factors that affect the healing process
- The ability to remove the causative agent
- The ability to clear the inflammatory debris
- The degree of architectural damage
- The ability of the cell to proliferate
- The extent of extracellular matrix damage
what are the labile cells?
- -Continuously dividing cells,
- -Epidermis, mucosal epithelium, GI tract epithelium, etc.
- -Cells are derived from stem cells
- -injury to such tissue can easily heal by regeneration if the supporting stroma is intact
injury to tissue with labile cells leads to repair. Truer/False
False
Regeneration
what are the stable cells?
- -Normally low level of replication
- -Hepatocytes, renal tubular epithelium, pancreatic acini
- -Cells can be stimulated to divide
- -Healing by regeneration if the supporting stroma and the regenerative stem cells are intact
healing of tissue with stable cells can be done by regeneration. True/False
True
if the supporting stroma and the regenerative stem cells are intact
liver cirrosis is due to regeneration. True/False
False.
It is repaired, in cirrhosis tissue architecture and stroma are disrupted so regeneration cannot take place vs in liver resection architecture is intact, so remaining tissue is regenerated and grows.
what are the permanent cells?
- Nondividing cells
- Neurons, cardiac myocytes, skeletal muscle
- No regeneration
- Replaced by connective tissue
list the phases of the cell cycle
- -G1
- -S (DNA synthesis)
- -G2
- -M (Mitosis)
- -G0 (resting)
labile cells always remain in the G1 phase. True/False
True
They never go to G0
stable cells can enter both G1 and G0. True/False.
True
Enter G1 from G0 when stimulated.
Permanent cells can enter G1. True/False
False
Remain in G0, regenerate from stem cells.
what are the polypeptide growth factors?
- -Most Important Mediators affecting Cell Growth
- -Present in serum or produced locally
- -Exert pleiotropic effects; proliferation, cell migration, differentiation, tissue remodeling
- -Regulate growth of cells by controlling the expression of genes that regulate cell proliferation
what is the pleiotropic effect of growth factors
Growth factors exert different effects on target cells–proliferation, cell migration, differentiation, tissue remodeling
stroma is composed of?
- Extra-cellular matrix
- -Interstitial matrix
- -Basement membranes - Mesenchymal cells
- Vessels
what is the extracellular matrix?
An organized, mesh-like structure formed by glycosaminoglycans, proteoglycans, glycoproteins, amino sugars, laminin, fibronectin, other molecules. It provides structure and supports cell growth and function.
what is the basement membrane?
A thin layer of extracellular matrix to which cells can anchor. Separates epithelium from underlying connective tissue. Composed of the basal lamina adherent to the epithelium and the reticular lamina, which is beneath the basal lamina and adheres to underlying connective tissue.
The extracellular matrix is just a scaffold for cells to grow on. true/False
False
what are the functions of the extracellular matrix?
Regulates cell growth, motility, and differentiation
the extracellular matrix is composed of?
1)Fibrous structural proteins • Collagens • Elastin 2)Adhesive glycoproteins that link ECM component to one another and to cells 3)Proteoglycans
what are the proteoglycans?
Proteins with numerous covalently linked GAG side chains. Proteoglycans have multiple functions, e.g., shock absorption and supportive function for cartilage.
what is the elastin vs collagen?
1) A highly elastic protein, encoded by the ELN gene, that is a component of elastic fibers. Allows tissues to reassume their original shape after exposure to mechanical strain, stretching, or contracting (e.g., skin smoothing out after being pinched).
2) An abundant protein that organizes and strengthens the extracellular matrix. Undergoes extensive posttranslational modification. Includes several subtypes of collagen (e.g., type I collagen, the most common type that is found in bone, skin, and tendons).
how cells interact with each other?
1) Growth factors
- -EGF, PDGF, FGF, VEGF, TGFβ
2) Cytokines
3) Growth inhibitors
how cells interact with the extracellular matrix?
- -Integrins
1) Cell surface receptors that mediate cellular attachment to the extracellular matrix
2) Transduction of signals from ECM to cells
what are the integrins?
family of transmembrane receptor proteins that facilitate stable cellular adhesion to the basement membrane by binding to collagen, laminin, and fibronectin. Integrins also establish intercellular junctions in the immune system (e.g., for leukocyte extravasation).
define complete vs incomplete regenration
1) complete: Tissue loss is both homogeneously functionally and structurally replaced
- only possible in labile and minimally damaged stable tissue (e.g., regeneration of skin without scarring).
2) Tissue loss is replaced by a tissue of inferior quality.
- occurs in permanent tissue and stable tissue with pronounced damage (e.g., healing of skin with scar formation)
define regeneration
- -Replacement of lost cells by cells of the same type through cell division
- -The supporting framework must be intact
- -The tissue is returned to its pre-injury state
- -The process is controlled by stimulatory and inhibitory factors and interactions between cells and extracellular matrix
define repair by connective tissue
1)Healing by fibrosis
2) Occurs when there is-
- -Destruction to both parenchymal cells and stromal framework
- -Death of permanent cells
- -Organisation of inflammation
3) Involves the production of Granulation Tissue
- -Granulation tissue is Fibroblasts and capillary buds and myofibroblasts)
- -Angiogenesis - New vessels budding from old
- -Fibrosis, consisting of emigration and proliferation of fibroblasts and deposition of ECM (type III collagen)
4) Scar remodeling type III collagen is replaced by type I collagen (collagenase- requires zinc)
what is the fibrosis?
the proliferation of fibroblasts and deposition of collagen in tissues as a result of a reparative process (e.g., following injury, inflammation, and/or necrosis) or as part of a reaction to chronic irritants (e.g., pneumoconiosis, chronic lymphedema).
when does repair happen?
- -Destruction to both parenchymal cells and stromal framework
- -Death of permanent cells
- -Organisation of inflammation
what is the granulation tissue?
A type of connective tissue generated by fibroblasts during wound healing. Initially, it is composed of type III collagen, which is then replaced by type I collagen to create a stronger extracellular matrix.
what is the fibroblast?
A type of cell present in connective tissue that produces collagen and other components of the extracellular matrix. Fibroblasts play an important role in the wound healing process.
what is the myofibroblast
A cell that differentiates from fibroblasts in response to tissue injury. Synthesizes components of the extracellular matrix during wound healing. It can cause pathologic fibrosis.
contractile hybrid cells with features of both fibroblasts and smooth muscle cells
fibroblasts are contractile?
Yes
but they need to differentiate into myofibroblast
what is the angiogenesis?
The normal physiological development of new blood vessels. Not to be confused with neovascularization, which refers to the pathological formation of new blood vessels (e.g., in abnormal tissue or in abnormal locations).
what is type 3 collagen?
A protein encoded by the COL3A1 gene that is found in extensible connective tissue (e.g., skin, lungs, vessels), bones, cartilage, dentin, and the lens of the eye, granulation tissue. Mutations in the COL3A1 gene cause type III and IV Ehlers-Danlos syndrome (predominantly cardiovascular manifestations).
what are the collagenases?
A matrix metalloproteinase involved in several physiologic functions, including immunity, wound healing, and scar formation. Dysregulation of collagenase results in the destruction of the extracellular matrix (e.g., in gas gangrene). It can be used in the treatment of Dupuytren contracture and to promote wound healing.
collagenases require what to function?
Collagenases are zinc-dependent proteinases that belong to the family of matrix metalloproteinases.
what are the phases of wound healing?
- Inflammatory phase
- Proliferative phase
- -Epidermal re-growth
- -Dermal repair - Remodeling phase
- -Restoration of elasticity
describe the inflammatory phase of wound healing
–Induction of acute inflammatory response by an initial injury
• Hematoma formation
• Infiltration by neutrophils
• Infiltration by macrophages
–days 1-3
–Inflammatory cells (i.e., neutrophils, macrophages, lymphocytes) migrate to the site of injury
–Macrophages release growth factors and cytokines that recruit other immune cells and stimulate fibroblast proliferation (fibrosis).
–Lymphocytes migrate to injury approx. 72 hours after the injury to promote cellular immunity.
–Continued vasodilation
–Epithelium at the wound margins begins to proliferate.
what is the proliferative phase of wound healing?
1) Epithelial cell proliferation
2) Granulation tissue
- -Formation of new vessels
- -Proliferation of fibroblasts
- -Synthesis of ECM proteins
- -Days 3–7
what is the remodeling phase of wound healing?
- -Replacement of the granulation tissue by a fibrous tissue
- -Remodeling of parenchymal elements to restore tissue function
- -Remodeling of connective tissue to achieve wound strength
- -Degradation of excessive extracellular matrix (metalloproteinase)
- -Macrophages release matrix metalloproteinases and collagenases that facilitate the final remodeling of the collagen. Collagen becomes more organized, returning strength to the region of injury.
- -Peak tensile strength (approx. 80% of original strength) is reached after approx. 60 days after injury.
- -Sweat and sebaceous glands do not regenerate.
what are the stages of wound healing by primary intention?
1) Day 1
- -Wound filled with blood clot
- -Acute inflammation in the surrounding tissue
- -Proliferation of epithelial cells
2) Day 2
- -Macrophages
- -Epithelial cells cover the surface
3) Day 3
- -Granulation tissue formation
4) Day 5
- -Collagen deposition
5) Day 7
- -Sutured removed
at what day granulation tissue forms?
Day 3
at what they collagen deposition starts?
day 5
after 1 week, what is the strength of the wound?
1) After sutures are removed at one week, wound strength is only 10% of unwounded skin (Walker’ Law)
2) By 3-4 months, wound strength is about 80% of unwounded skin (Walker’s Law)
do wound issue returns its previous strength?
No
By 3-4 months, wound strength is about 80% of unwounded skin (Walker’s Law)
what are the pathologic aspects of wound healing?
1) Deficient scar formation
- Wound rupture
2) Excessive scar formation
- Keloid- Type III collagen. Genetic predisposition
3) Contracture deformity
4) Malignant transformation (v. very rare)
what are the types of excessive scar?
Dysregulation of the wound healing process during the proliferative stage and maturation stage leads to excess fibroblast replication and collagen deposition.
1) Hypertrophic scar: Increased collagen deposition leading to a scar that protrudes from the surface of the skin. The scar remains confined within the original wound margins.
2) Keloid: Increased collagen deposition and fibroblast proliferation where tissue expands beyond the original wound margins.
what is the keloid?
A scar that extends beyond the original margins of a wound. Consists of disorganized collagen (types I and III) and is usually seen 3-12 months after injury. Recurrence after resection is common.
which race is predisposed to keloid formation?
Increased incidence in patients with a family history of keloids and in African Americans
what is the difference between a keloid and hypertrophic scar?
expands beyond the wound margins vs confined to the wound margins
what is the contracture?
1) Excessive proliferation in myofibroblasts during proliferative and maturation phases leads to contraction of the wound.
2) Excessive contraction can reduce the functionality of the injured limbs or organs.
3) Wounds that cross a joint (e.g., on the hands and fingers) are at high risk for causing functional deficits from contracture. Periodic exercise of the involved limb can help preserve normal function.
collagen in keloid vs hypertrophic scars
1) disorganized, type 1 and 3
2) parallel organization, type 3
do chronic wounds can transform into malignancy?
Yes
rarely into SCC
how wounds on mucosal surface healed?
1) Erosion is healed by regeneration
2) Ulceration by regeneration and fibrosis
how liver injury is healed?
1) A single short-lived injury is healed by regeneration
2) Chronic injury by cirrhosis (due to disruption of tissue architecture)
how the central nervous system is injured?
1) Central nervous systemà–Gliosis
2) Peripheral nerves–Regeneration
how injured muscle tissue is healed?
1) Cardiac muscleà Fibrosis
2) Skeletal muscleà Fibrosis
what factors influence healing?
- -Local factors
- -Systemic factors
what are the local factors that influence healing?
- Poor vascular supply
- Infection
- Foreign material
- Excessive movement
- Poor approximation
- Size, size, and type of injury
what are the systemic factors that influence healing?
1) Age
2) Nutrition (proteins, Vitamin C- collagen formation, copper- cross linking of collagen, Zinc- conversion of type III to type I collagen)
3) Metabolic status (DM)
4) Hormones (steroids)
5) Malignancy
6) Chemotherapy
7) Radiotherapy
why Zinc deficiency results in delayed wound healing
cause it is a cofactor of collagenases which play an important role in wound healing during the remodeling phase.
why vitamin C deficiency results in delayed wound healing?
cause it is a coenzyme for Collagen synthesis: hydroxylation of proline and lysine
what is the role of Vit C in collagen synthesis?
1) Hydroxylation of proline residue to hydroxyproline and of lysine residue to hydroxylysine
2) Enzymes: prolyl hydroxylase and lysyl hydroxylase: vitamin C-dependent hydroxylases (additional cofactors are α-ketoglutarate, Fe2+, and O2)
3) Function: a prerequisite for the formation of stable triple helices
why copper deficiency results in delayed wound healing?
1) Formation of collagen fibrils: cross-linking of hydroxylysine residues in adjacent tropocollagens
2) Enzyme: copper-dependent lysyl oxidase
3) Function: requirement for subsequent fiber formation
