Podcast
Questions and Answers
What role do macrophages play in granulation tissue formation?
What role do macrophages play in granulation tissue formation?
Which of the following growth factors is NOT typically involved in ECM deposition and scar formation?
Which of the following growth factors is NOT typically involved in ECM deposition and scar formation?
What occurs during the remodeling phase of wound healing?
What occurs during the remodeling phase of wound healing?
Which type of matrix metalloproteinases (MMPs) is primarily responsible for degrading amorphous collagen and fibronectin?
Which type of matrix metalloproteinases (MMPs) is primarily responsible for degrading amorphous collagen and fibronectin?
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In which phase does collagen synthesis by fibroblasts begin after injury?
In which phase does collagen synthesis by fibroblasts begin after injury?
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Which growth factor is known to play a significant role in tissue repair and is secreted into the extracellular matrix?
Which growth factor is known to play a significant role in tissue repair and is secreted into the extracellular matrix?
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What is the primary function of collagen in the extracellular matrix?
What is the primary function of collagen in the extracellular matrix?
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Which phase of cutaneous wound healing is characterized by the formation of granulation tissue?
Which phase of cutaneous wound healing is characterized by the formation of granulation tissue?
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In healing by first intention, which factor is NOT typically involved?
In healing by first intention, which factor is NOT typically involved?
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What is the role of matrix metalloproteinases (MMPs) in tissue repair?
What is the role of matrix metalloproteinases (MMPs) in tissue repair?
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Which component of the extracellular matrix provides resilience and lubrication to tissues?
Which component of the extracellular matrix provides resilience and lubrication to tissues?
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Which of the following types of collagen primarily forms the dermal-epidermal junction?
Which of the following types of collagen primarily forms the dermal-epidermal junction?
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What is the primary characteristic of elastin in the extracellular matrix?
What is the primary characteristic of elastin in the extracellular matrix?
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What is the primary factor for the regulation of MMP synthesis and secretion during wound healing?
What is the primary factor for the regulation of MMP synthesis and secretion during wound healing?
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Which phase of cutaneous wound healing involves the formation of new tissue?
Which phase of cutaneous wound healing involves the formation of new tissue?
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What characterizes healing by first intention?
What characterizes healing by first intention?
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During which day of healing do neutrophils get replaced by macrophages according to the wound healing timeline?
During which day of healing do neutrophils get replaced by macrophages according to the wound healing timeline?
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What occurs in the remodeling phase of cutaneous wound healing?
What occurs in the remodeling phase of cutaneous wound healing?
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What is the role of ECM in wound healing?
What is the role of ECM in wound healing?
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What cellular activity begins within 24 to 48 hours after an incision?
What cellular activity begins within 24 to 48 hours after an incision?
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What distinguishes healing by second intention from healing by first intention?
What distinguishes healing by second intention from healing by first intention?
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Study Notes
Learning Objectives (LOs)
- Wound types and descriptions
- Healing and repair processes
- Cell and tissue regeneration
- Growth factors influencing tissue repair
- Skin wound healing examples
- Factors affecting tissue repair
Extracellular Matrix (ECM)
- Network surrounding cells
- Major component of any tissue type
- Regulates cell proliferation, movement, and differentiation
- Two basic forms: interstitial matrix and basement membrane
Interstitial Matrix
- Found in spaces between cells
- Connective tissue, vascular, and smooth muscle structures
- Synthesized by mesenchymal cells
Basement Membrane
- Organized interstitial matrix around epithelial, endothelial, and smooth muscle cells
- Lies below epithelium
- Synthesized by overlying epithelium and underlying mesenchymal cells
ECM Components
- Fibrous structural proteins: Collagens and elastins, provide tensile strength and recoil
- Water-hydrated gels: Proteoglycans and hyaluronan, provide resilience and lubrication
- Adhesive glycoproteins: Connect matrix elements and cells to each other
Basement Membrane Components
- Type IV collagen
- Laminin
- Proteoglycan
Interstitial Matrix Components
- Fibrillar collagens (types I, II, III, and V) – major components in healing wounds and scars
- Nonfibrillar collagens (type IV, IX, and VII) – basement membrane, intervertebral discs, and dermal-epidermal junctions
- Elastin – provides recoil and elasticity to tissues
Proteoglycans
- Form highly hydrated gels from glycosaminoglycans (e.g., dermatan sulfate, heparan sulfate) linked to a protein backbone
- Confer resilience, lubrication, and compressibility to tissues
- Serve as reservoirs for growth factors (e.g., FGF, HGF)
Adhesive Glycoproteins and Adhesion Receptors
- Structurally diverse molecules involved in cell-to-cell adhesion, cell-ECM linkage, and ECM component binding
- Fibronectin: Major interstitial ECM component, synthesized by fibroblasts, monocytes, and endothelium
- Laminin: Major constituent of the basement membrane, connects cells to underlying ECM components like type IV collagen and heparan sulfate
Integrins
- Transmembrane glycoproteins (α and β chains)
- Main cellular receptors for ECM components (e.g., fibronectin, laminin)
- Present in most animal cell plasma membranes (except red blood cells)
Cell and Tissue Regeneration
- Continuous cell renewal in labile tissues (e.g., bone marrow, gut epithelium, skin)
- Stem cell proliferation and differentiation correct damage to epithelia or blood cell loss
- Liver is a prime example of regenerative tissue
- Adrenal, thyroid, pancreas, and lungs have limited regenerative capacity
Repair by Connective Tissue
- Chronic tissue injury damages parenchymal cells, epithelia, and stromal framework
- Repair involves fibroblast and endothelial cell proliferation beginning within 24 hours of injury
- Granulation tissue formation (3-5 days) is characteristic of healing
- This tissue is pink, soft, and granular beneath skin wounds
Granulation Tissue Microscopically
- Characterized by fibroblast proliferation and thin-walled capillaries in a loose ECM
- Inflammatory infiltrate (mostly mononuclear cells with some PMNs) present
Granulation Tissue Progression
- Accumulates connective tissue matrix leading to scar formation, which can remodel over time
Repair by Connective Tissue - Sequential Process
- Angiogenesis: New blood vessel formation (vasculogenesis during embryonic development and angiogenesis by existing vessels)
- Fibroblast Migration/Proliferation: Movement and increase in fibroblasts
- ECM Deposition (Scar Formation): Accumulation of ECM components
- Remodeling: Maturation and reorganization of fibrous tissue
Main Steps in Angiogenesis
- Vasodilation: Nitric oxide and VEGF increase vessel permeability
- Endothelial Cell Migration: Toward the injury site
- Endothelial Cell Proliferation: Behind migrating cells
- Capillary Tube Formation/Remodeling: Endothelial cell reorganization into tubes
- Recruitment (Angiogenesis): Periendothelial cells (pericytes) and smooth muscle for small and large vessels, respectively
Growth Factors Involved in Angiogenesis
- VEGF and FGF-2 (basic fibroblast growth factor) induce angiogenesis
- Stimulate endothelial cell proliferation and motility
- VEGFR-2 is the main receptor for VEGF
- Stabilizing new vessels involves pericytes and smooth muscle cell recruitment, connective tissue deposition.
- Angiopoietins 1 and 2 (Ang 1 and Ang 2) and growth factors PDGF, TGF-β participate in vessel stabilization
Fibroblast Migration
- Driven by growth factors (PDGF, FGF-2, TGF-β) from activated endothelium and inflammatory cells
- Macrophages are crucial for clearing debris and generating mediators to induce fibroblast proliferation and ECM production for tissue repair
ECM Deposition (Scar Formation)
- Fibroblast proliferation and new vessel number decrease as healing progresses
- Collagen synthesis starts early (3-5 days) and continues for weeks, dependent on wound size
- Granulation tissue evolves into a scar of largely inactive, spindle-shaped fibroblasts, dense collagen, elastic tissue fragments, and other ECM components
- TGF-β, PDGF, and FGF are important growth factors in ECM deposition and scar formation
ECM and Tissue Remodeling
- Repair outcome depends on the balance between ECM synthesis and degradation
- Scar ECM undergoes modification and remodeling after synthesis and deposition
- Degradation of collagens and other ECM components is mediated by MMPs (matrix metalloproteinases)
ECM Degradation by MMPs
- Interstitial collagenases: Cleave fibrillar collagen (MMP-1, -2, -3)
- Gelatinases: Degrade amorphous collagen and fibronectin (MMP-2, -9)
- Stromelysins: Degrade various ECM components (MMP-3, -10, -11), including proteoglycans, laminin, and fibronectin
Cutaneous Wound Healing
- Involves both epithelial regeneration and connective tissue scar formation
- Has three main phases: inflammation, granulation tissue formation, ECM deposition and remodeling
- Healing can occur by first or second intention based on wound nature
Healing by First Intention
- Uninfected surgical incision approximated by sutures
- Focal disruption of the epithelial basement membrane
- Death of a few epithelial and connective tissue cells
- Rapid filling of the incisional space with fibrin-clotted blood, followed by granulation tissue invasion and new epithelium covering
Healing by Second Intention
- Larger tissue loss, such as wounds, abscesses, and ulcers
- Larger clot or scab (fibrin and fibronectin) on wound surface
- More intense inflammation due to necrotic debris and fibrin removal
- More granulation tissue formation leading to a larger scar size
- Includes wound contraction
Factors affecting healing
- Infections
- Nutritional deficiencies
- Mechanical variables
- Foreign bodies
- Type of tissue injured
- Keloid formation
- Exuberant granulation
- Delayed healing: prolonged inflammatory phase, infection, inflammatory diseases, chronic immune reaction, and chronic inflammation
- Systemic factors: nutrition, metabolic status, circulatory status, hormones
- Local factors: infection, mechanical issues, foreign bodies, wound size, location, and type
Wound Strength Over Time
- Sutured wounds achieve approximately 70% of baseline strength on average after suture removal
- Gradual increase in wound strength over the four weeks that follow
- Wound strength reaches approximately 70%–80% of normal strength by three months, but doesn't significantly improve beyond that point
Complications/abnormalities of scar formation
- Deficient scar formation (dehiscence, ulceration) due to mechanical factors, inadequate blood supply or neuropathy
- Excessive scar formation: hypertrophic scar, keloid, exuberant granulation tissue blocking re-epithelialization, and desmoids or aggressive fibromatoses contractures
- Delayed healing, due to prolonged inflammatory phase, infection, inflammatory diseases, chronic immune reaction.
Additional factors affecting healing
- Type of inflammation (acute or chronic)
- Extent of tissue necrosis
- Regenerative ability of damaged parenchymal cells
- Immune status
- Blood glucose levels
- Hydration status
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