Untitled Quiz

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