OST 521 Lecture 5: Wound Healing

Regeneration

this process occurs in tissues with labile or stable cells and is the complete resolution of a wound, replacing the same tissue and restoring normal structure/function

Repair

this process occurs in tissues with permanent cells, replacing them with connective scar tissue

Extracellular matrix components

•collagens

•elastins

•proteoglycans, PGs

•glycosaminoglycans, GAGs

•fibers

•ground substance

Extracellular matrix functions

this structure acts as a scaffold for migrating cells, a microenvironment for signaling, and support for the basement membrane

Provisional matrix components

•fibrinogen

•fibronectin

•hyaluronan

Provisional matrix functions

this structure acts as a temporary matrix, accumulates at the site of injury, binds stroma to reduce blood loss, and provides support for migrating cells to repair site

Growth factors

these proteins stimulate proliferation and support survival and are expressed during tissue injury/inflammation

VEGF

this growth factor is involved in angiogenesis

PDGF

this growth factor is involved in cell proliferation and ECM deposition

FGF and TGFbeta

these growth factors are involved in chemotaxis

EGF

this growth factor is involved in granulation tissue formation

Neutrophils

these cells migrate to wound site within the first 24h and release mediators

Monocytes/macrophages

these cells arrive after neutrophils to phagocytose debris, release chemo attractants, and coordinate the development of granulation tissue

Fibroblasts/myofibroblasts

these cells generate PM and ECM, change vasculature, and are responsible for contraction of wound edges

Endothelial cells

these cells move across surfaces during re-epithelialization

Stem cells

these cells regenerate tissue elements

Factors favoring complete regeneration

these factors include proteolytic digestion and resorption of exudates and the absence of necrosis

Exudates

presence of this substance in large volumes will lead to a persistent wound with hyper-granulation, causing scarring, no matter the tissue type

Severe injury

this type of injury damages the ECM and will cause scarring no matter the tissue type

Tissues favoring regeneration

these tissues include fetal tissue, bone, superficial skin abrasions, kidney/liver/embryonic stem cells, spleen tissue, lymphoid tissue, hematopoietic tissue, and GI mucosa

Fibrosis

scar tissue formation

Labile cells

these cells have a high turn over rate, dividing almost continuously

Stable cells

these cells re-enter the cell cycle and proliferate when prompted to regenerate

Permanent cells

these terminally differentiated cells are unlikely to enter the cell cycle and proliferate

Labile tissue injury

this type of injury results in rapid tissue replacement and restoration of structure

Stable tissue injury

this type of injury prompts cellular regeneration, resulting in restoration of structure as long as ECM is intact

Permanent tissue injury

this type of injury is less likely to undergo regeneration

CNS neuron injury

injury to this cell type results in repair by replacement with other cells, like glial cells

PNS neuron injury

this type of injury can trigger axonal regrowth

Neuroma

formation of this structure can occur if axonal fibers get caught in neuronal scar tissue

Cardiac tissue injury

this type of injury almost exclusively results in granulation tissue formation followed by fibrous scar tissue replacement

Healing by primary union

small, surgical cut, clean and well-apposed edges with a narrow wound space that fills in easily

Healing by secondary union

wound with jagged edges, non-apposable sides, haven't/can't be sutured, intense inflammation, necrotic debris, granulation tissue required for wound contraction

Granulation tissue formation

this specialized vascular repair tissue forms on the healing surface and involves angiogenesis, provisional matrix formation, and wound contraction

Wound contraction

this process occurs when myofibroblasts bind collagen fibrils

Angiogenesis

formation of new leaky blood vessels or capillary buds

Fibroblasts

these cells are located between blood vessels, synthesize collagen, and differentiate into myofibroblasts

Chronic inflammatory cell infiltrates

these cell types include lymphocytes, macrophages, and plasma cells

Granulation tissue appearance (histo)

blood vessels that are vertical, edematous and leaky, and have a wet, red, and bumpy appearance

Healthy granulation tissue appearance (gross)

this tissue is pink, soft, bumpy, moist, painless, and bleeds easily

Unhealthy granulation tissue appearance (gross)

this tissue is shiny, dark red, bloody, and painful

Phases of wound healing

this process involves hemostasis, inflammation, proliferation, and remodeling phases

Hemostasis

this process involves vasoconstriction, platelet aggregation, and clot formation

Inflammation phase

this process involves neutrophil/monocyte/macrophage infiltration, wound sterilization, debris phagocytosis and GF recruitment

Proliferation phase

this process involves cell proliferation and migration across the wound surface, formation of granulation tissue, provisional matrix, blood vessels, fibroblasts, and wound contraction

Remodeling phase

this process involves removal of provisional matrix, granulation tissue, and myofibroblasts and replacement with collagen III, breakdown of collagen III, and replacement with collagen I

Superficial mucosal wound outcome

healing by regeneration

Superficial mucosal wound healing

the process begins 1-2 days after injury, with rapid repair and scarless regeneration driven stem cells

Superficial mucosal wound inflammatory phase

this phase is short

Superficial mucosal wound proliferative phase

this phase involves rapid, efficient epithelialization, where cells migrate from both wound edges toward the center and proliferate to cover the lost tissue, quickly filling in the defect

Superficial mucosal wound regeneration

this phase involves replacement with a tissue that is identical to the original

Deep mucosal wound outcome

healing by extensive scarring/fibrosis

Deep mucosal wound restoration

this process depends on stem cell differentiation into specialized tissue, restoration of glandular and villi tissue, epithelial cell migration and proliferation from edges toward the center

Deep mucosal wound angiogenesis

a greater amount of granulation tissue with new blood vessels forms at ulcer base in this type of wound

Deep mucosal wound fibrosis

granulation tissue is removed and the provisional matrix is formed then replaced by overproduction of ECM, resulting in scarring

Bone fracture hemostasis

bleeding at this site leads to clot formation and development of a fracture hematoma

Bone fracture granulation tissue

this tissue type forms at the fracture ends

Procallus formation

macrophages remove debris and the clot is replaced with this structure, made of collagen and fibroblasts

Bone fracture angiogenesis

mesenchymal stem cells are recruited from the periosteum and endosteum, causing blood vessels invasion into the procallus

Bony callus formation

osteoblasts lay down bone to form primary trabeculae, creating this structure

Bony callus removal

osteoclasts and osteoblasts remodel this structure into spongy and compact bone, and a functional blood supply is re-established

Torn tendon inflammatory phase

requiring days, this process begins when vasoactive cytokines and growth factors increase vascular permeability, recruiting inflammatory neutrophils, monocytes, and macrophages, which produce pro-fibrotic cytokines

Torn tendon proliferation/repair phase

requiring weeks, tenocytes produce glycoproteins and provisional matrix before differentiating into myofibroblasts, granulation tissue links ends of the severed tendon, and a scaffold is formed for migration of cells and GFs to wound site

Tenocytes

tendon fibroblasts

Tendon remodeling phase

requiring months/years, granulation tissue is degraded quickly but myofibroblasts are unable to fully remodel the provisional matrix, resulting in fibrous scar tissue replacement

Remodeled tendon characteristics

this structure has decreased cellularity and vascularity, less tensile strength, and greater stiffness than original tissue