Unit 5 Repair and Regeneration

Tissue Repair How do we fix the damage (healing)? 1. Regeneration تجديد Restoration of original tissue architecture and function 2. Repair Replacement by connective tissue (scarring) There will be alterations in both architecture and function

Regeneration: Cell requirements CELLULAR PROLIFERATION Tissues of the body are divided into three groups: Continuously dividing (labile) tissues Stable tissues Permanent tissues

CELLULAR PROLIFERATION Tissues of the body are divided into three groups: Continuously dividing (labile) tissues cells are continuously proliferating can easily regenerate after injury contain a pool of stem cells examples: bone marrow, skin, GI epithelium

CELLULAR PROLIFERATION Stable tissues cells have limited ability to proliferate limited ability to regenerate (except liver!) normally in G0, but can proliferate if injured examples: liver, kidney, pancreas

CELLULAR PROLIFERATION Permanent tissues cells can’t proliferate can’t regenerate (so injury always leads to scar) examples: neurons, cardiac muscle

The Cell Cycle and Different Cell Populations

The parenchyma are the functional parts of an organ in the body The parenchyma are the functional parts of an organ in the body. This is in contrast to the stroma, which refers to the structural tissue of organs, namely, the connective tissues. Organ Parenchyma brain neurons and glial cells heart myocyte kidney nephron liver hepatocyte lungs Lung parenchyma pancreas Islets of Langerhans and Pancreatic acini spleen white pulp and red pulp

Regeneration Regeneration results in the replacement of lost cells by their own kind, thereby returning the tissue to normal structure and function Labile or stable cells Intact stroma سدى (connective tissue) and basement membranes Parenchymal cells (functional cells) migrate across existing stromal framework الإطار and multiply to restore tissue integrity سلامة

Regeneration: Hindrances العوائق Destruction of stroma Chaotic فوضوي proliferation الانتشار of parenchymal cells Replacement of stroma Excessive exudation/infection PMNs secrete numerous proteases (collagenases, elastases) which digest the basement membrane and supporting connective tissues Bacteria often have similar enzymes and/or toxins which may kill the parenchymal or inflammatory cells Excessively large defects Permanent cells

Repair When the requirements for regeneration are not met, then the gaps produced by lost cells heal by connective tissue replacement Repair by fibrous tissue/connective tissue/ granulation tissue Wound healing

Repair by Connective Tissue Conditions for regeneration are not met Four components to this process: Formation of new blood vessels (angiogenesis) Migration and proliferation of fibroblasts (fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework ) Deposition of Extracellular matrix, synthesis of collagen (scar formation) Maturation, contraction, and organization of fibrous tissue (remodeling of scar)

Angiogenesis

Role of (Fibrosis) Fibroplasia Fibroblasts proliferate replace fibronectin-fibrin with collagen contribute ECM Fibroplasia – fibrous repair Formulation of Granulation tissue Infiltration of fibroblasts Collagen laid down in random pattern Scar tissues excessive if inflammation re-initiated

3. Role of extracellular matrix in wound healing and scar formation Extracellular matrix (ECM) is formed by specific secreted macromolecules that form a network on which cells grow and migrate along ECM proteins assemble into two general organizations Interstitial matrix (present between cells) Basement membrane [BM] (produced by epithelial and mesenchymal cells and is closely associated with the cell surface)

Three groups of macromolecules constitute the ECM Fibrous structural proteins Collagen Fibrillins Adhesive glycoproteins Cadherin Integrins Immunoglobulin family Selectins Proteoglycans and Hyaluronic Acid

Maturation & Remodeling Initial scar formation takes weeks Scar matures Longest part of inflammation (over 1 yr) Re-absorb temporary vasculature Scar shrinks (contraction) & changes color Scar remodels Collagen fibers re-align with stress (SAID) Less tensile strength than tissue it replaces

The phases of cutaneous wound healing Injury leads to accumulation of platelets and coagulation factors. Coagulation results in fibrin formation and release of PDGF and TGF-b and other inflammatory mediators by activated platelets. This leads to more Neutrophil recruitment which signals the beginning of inflammation (24 h). After 48 h macrophages replace neutrophils. Neutrophils and macrophages are responsible for removal of cellular debris and release growth factors to reorganize the cellular matrix. At 72 hours the proliferation phase begins as recruited fibroblasts stimulated by FGF and TFG-b begin to synthesize collagen. Previously formed fibrin forms initial matrix for fibroblasts Collagen cross-linking and reorganization occurs following months after injury in the remodeling phase of repair. Wound contraction follows in large surface wounds and is facilitated by actin-containing fibroblasts (myofibroblasts)

Skin Wound healing First intention healing Second intention healing Skin wounds are classically described to heal by either primary or secondary intention and the distinction is made by the nature and extent of the wound wounds with clean opposing edges (surgical incision, should form a narrow scar due to small amount of granulation tissue required to fill the gap) First intention healing wounds with separated edges (trauma that requires abundance of granulation tissue for wound closure) Second intention healing

Complications of wound healing Deficient scar formation Wound dehiscence (premature "bursting" open of a wound along surgical suture) Ulceration Excessive formation of scar tissue Keloid (excessive collagen deposition) Desmoid (aggressive fibromatosis, semi-malignant) Contraction

Wound ulceration Wound dehiscence Contracture Keloid

Keloids: Beyond the Borders Excess Deposition of Collagen Causes Scar Growth Beyond the Border of the Original wound XRT=radiation Tx Tx: XRT, steroids, silicone sheeting, pressure, excise. often Refractory to Tx & not preventable

Factors that influence wound healing I. Systemic factors Malnutrition Protein deficiency Vitamin C deficiency (inhibition of collagen synthesis) Metabolic status e.g Diabetes mellitus Consequence of microangiopathy Cortison treatment inhibits inflammation and collagen synthesis Circulatory status Inadequate blood supply due to ateriosclerosis Varicose veins (retarded venous drainage)

Factors that influence wound healing II. Local Factors Infection (single most important reason for delayed wound healing) Foreign bodies suture material, bone and wood splinters …. Mechanical factors Early movement Pressure