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This document discusses concepts related to tissue repair and regeneration. It defines regeneration as the complete renewal of lost tissue architecture and function, while repair involves restoration of tissue continuity through scar formation. The key processes involved in repair are cell proliferation, growth factor signaling, stem cell differentiation, angiogenesis, connective tissue deposition, and remodeling. Growth factors stimulate cell growth and migration to form new tissue, while stem cells develop into specialized cells that repopulate injured areas. Overall repair restores structure, but regeneration fully restores the original tissue.

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REPAIR AND REGENERATION- BASIC CONCEPTS DEPARTMENT OF PERIODONTICS
CONTENTS • Introduction • Definition • Cell and Tissue regeneration • Repair by connective tissue deposition • Factors that influence tissue repair • Abnormalities in tissue repair • Wound strength • Healing of epithelial injury • Conclusion • Reference 2
INTRODUCTION • The survival of an organism depends on its ability to heal after damage caused by toxic insults and inflammation. • Healing is the body’s response to injury in an attempt to restore normal structure and function. • It involves two processes: 1. Repair 2. Regeneration 3 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Melcher 1969 • Regeneration  Biologic process by which the architecture and function of lost tissue is completely renewed. • Repair Continuity of disrupted tissue is restored by new tissues which do not replicate the structure and function of the lost tissues 4 DEFINITION Repair or regeneration following periodontal therapy? Sigmund Stahl, J Clin Periodontol, 1979
5 Regeneration • Reproduction or reconstitution of a lost or injured part Periodontal regeneration • Restoration of lost periodontium Repair • Healing of a wound by tissue that does not fully restore the architecture or the function of the part. - Glossary of Periodontal Terms (2001) DEFINITION
Regeneration • Some tissues are able to replace the damaged components and essentially return to a normal state; this process is called regeneration Repair • Sometimes called healing, refers to the restoration of tissue 6 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
• Regeneration: When healing takes place by proliferation of parenchymal cells and usually results in complete restoration of the original tissues. • Repair: When healing takes place by proliferation of connective tissue resulting in fibrosis and scarring. 7 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
8 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION MECHANISM OF TISSUE REPAIR
CELLAND TISSUE REGENERATION • The regeneration of injured cells and tissues involve:  Cell proliferation  Growth factors  Development of mature cells from stem cells 9 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
CELL PROLIFERATION • Cell proliferation is fundamental to development, maintenance of steady-state tissue homeostasis, and replacement of dead or damaged cells. • Sequence of events that result in cell division is called cell cycle. 10 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
• The ability of tissues to repair themselves is determined by their intrinsic proliferative capacity. • Based on intrinsic proliferative capacity cells are divided into: 11 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION LABILE CELLS STABLE CELLS PERMANENT CELLS
12
CELL CYCLE 13 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION G1 phase S Phase G2 Phase M Phase
• G1 phase cell grows in size and synthesize mRNA and protein that are required for DNA synthesis. • S Phase DNA is replicated; occurring between G1 and G2 phase • G2 Phase Rapid cell growth and protein synthesis during which the cell prepares itself for mitosis • M Phase Involves nuclear division and cytokinesis, where two identical daughter cells are produced. 14
15 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION CELL CYCLE
EXTRACELLULAR MATRIX • Extracellular matrix is assembled from components synthesized and deposited outside the cell surface that provide structural and functional integrity. • Major extracellular matrix involved in wound healing process are – Structural proteins – Glycosaminoglycans – Matricellular proteins – Multi-domain adhesive glycoproteins 16 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
Structural proteins • Contribute to the structural integrity during repair • They involve – Collagen – Elastin – Fibrin 17 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
Glycosaminoglycans • Glycosaminoglycans are proteins that are deposited around other ECM proteins such as collagen and elastin. • They are hydrophilic substances which absorb upto 1000 times their volume in water to form a gel-like material called the ground substance. • They include – Hyaluronan – Proteoglycans such as versican, syndecan, glypicans, perlecans 18 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
Matricellular proteins • Matricellular proteins are associated with ECM but do not perform a structural role within tissues. • They act temporarily and spatially to provide signals that trigger specific cell activities. • They are a group of proteins including Galectin Tenascins Thrombospondins Osteopontin Secreted protein acidic Vitronectin and rich in cysteine (SPARC) 19 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
Multi-domain adhesive glycoproteins • These are biological glue that mediates interaction between cells and other ECM proteins. • They include – Fibronectin – Vitronectin – Laminin 20 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
21 • High molecular weight glycoprotein • Produced by endothelial cells, fibroblasts, epithelial cells • Primary matrix in the organization of collagenous tissue during the repair process FIBRONECTIN • Component of platelets • Contain receptors which act as binding site for membrane bound integrins and provide anchor to extracellular matrix VITRONECTIN • Most abundant glycoprotein in basement membrane • Binds cells to basal lamina of epithelial and connective tissue LAMININ Caffesse, Quliiones. Polypeptide growth factors and attachment proteins in periodontal wound healing and regeneration .Periodontology 2000.1999 ; I:69-79
GROWTH FACTORS • Major role of growth factors is to stimulate the activity of genes that are required for cell growth and cell division. • Source: – Macrophages activated by tissue injury – Stromal cells – Epithelial cells – Endothelial cells – Platelets – Mesenchymal cells 22 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Role of growth factors in wound healing • Promotes cell proliferation and metabolism through interaction with specific cell membrane bound receptors. • Induce migration of cells into the wound space. • Serve as chemoattractants to recruit leucocytes and fibroblasts into the wound space. 23
Some of the important growth factors involved in cell proliferation • Epidermal growth factor (EGF) • Transforming growth factor-α (TGF-α) • Transforming growth factor-β (TGF-β) • Vascular endothelial growth factor (VEGF) • Platelet derived growth factor (PDGF) • Fibroblast growth factors (FGF) • Keratinocyte growth factor (KGF) 24
Epidermal growth factor(EGF) • Sources: – Activated macrophages – Salivary glands – Keratinocytes • Functions: – Mitogenic for keratinocytes and fibroblasts – Stimulates keratinocyte migration – Stimulates formation of granulation tissue 25 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Transforming growth factor-α(TGF-α) • Sources: – Activated macrophages – Keratinocytes • Functions: – Stimulates proliferation of hepatocytes and many other epithelial cells 26 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Transforming growth factor-β(TGF-β) • Sources: – Platelets – T-lymphocytes – Macrophages – Endothelial cells – Keratinocytes – Fibroblasts – Smooth muscle cells • Functions: • Chemotactic for leucocytes and fibroblasts • Stimulates ECM protein synthesis • Suppresses acute inflammation 27 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Vascular endothelial growth factor(VEGF) • Sources: – Mesenchymal cells • Functions: – Stimulates proliferation of endothelial cells – Increases vascular permeability 28 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Platelet derived growth factor(PDGF) • Sources: – Platelets – Macrophages – Endothelial cells – Smooth muscle cells – Keratinocytes • Functions: – Chemotactic for neutrophils, macrophages, fibroblasts and smooth muscle cells – Stimulates ECM protein synthesis – Activates and stimulates proliferation of fibroblasts, endothelial cells and other cells 29 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Fibroblast growth factor(FGF) • Sources: – Macrophages – Mast cells – Endothelial cells • Functions: – Chemotactic and mitogenic for fibroblasts – Stimulates angiogenesis and ECM protein synthesis 30 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Keratinocyte growth factor(KGF) • Sources: – Fibroblasts • Functions: – Stimulates keratinocyte migration, proliferation and differentiation 31 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Types of ECM - Growth factor interactions TYPES EXAMPLES Growth factor binding to ECM FGF-2 must be bound to heparan sulfate chains of proteoglycan to act as a mitogen Integrin mediated interactions Integrins-α1 and α2 necessary for VEGF- induced angiogenesis Matrikine ligand presentation by ECM components Tenascin-C and laminin bind to epidermal growth factor receptors where they act to enhance fibroblast migration Growth factor regulation of ECM TGF-β controls ECM production and degradation 32 Christopher P, Role of Growth Factors in Cutaneous Wound Healing: A Review; Critical Reviews in Oral Biology and Medicine, 1993
DEVELOPMENT OF MATURE CELLS FROM STEM CELLS • In adults, the most important stem cells for regeneration after injury are tissue stem cells. • These stem cells live in specialized niches, and it is believed that injury triggers signals in these niches that activate quiescent stem cells to proliferate and differentiate into mature cells that repopulate the injured tissue 33 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
STEM CELLS • Stem cells are the primitive cells having capacity for self renewal and that they can be modulated into multilineage differentiation. • Types (based on differentiation) 34 Totipotent stem cell Pluripotent stem cell Multipotent stem cell Unipotent stem cell Oligopotent stem cell ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
TOTIPOTENT STEM CELL • Ability to differentiate into all cell types and an entire functional organism • Eg Zygote PLURIPOTENT STEM CELL • Ability to differentiate into all cell types but cannot form a functional organism • Eg Embryonic stem cells 35 Bhattacharyya et al. The voyage of stem cell toward terminal differentiation: a brief overview, Acta Biochim Biophys Sin.2012;44(6):463
MULTIPOTENT STEM CELL • Ability to differentiate into closely related family of cells • Eg Hematopoietic stem cell UNIPOTENT STEM CELL • Ability to differentiate into single cell type • Eg Muscle cells OLIGOPOTENT STEM CELL • Ability to differentiate into a few cell types • Eg Lymphoid or myeloid stem cells 36 Bhattacharyya et al. The voyage of stem cell toward terminal differentiation: a brief overview, Acta Biochim Biophys Sin.2012;44(6):463
37 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION STEM CELL LINEAGE
REPAIR BY CONNECTIVE TISSUE DEPOSITION • If repair cannot be accomplished by regeneration alone it occurs by replacement of the injured cells with connective tissue. • Steps in Scar formation: – Tissue injury – Inflammatory responses – Angiogenesis – Deposition of connective tissue – Remodelling of connective tissue 38
• Inflammation is one of the body’s first reaction to injury. • Release of damaged cells and tissue debris occurs upon injury • These expelled particles act as antigens to stimulate a non specific immune response and cause proliferation of leukocytes • Resulting infiltration of tissues by leukocytes, plasma proteins and fluid causes redness, swelling and pain. 39 TISSUE INJURY
INFLAMMATORY RESPONSES Acute inflammation has 3 major components: • Dilation of small vessels leading to an increase in blood flow • Increased permeability of microvasculature enabling plasma proteins and leucocytes to leave the circulation • Emigration of leucocytes from the microcirculation, their accumulation in the focus of injury 40
ACUTE INFLAMMATORY REACTIONS HAVE ONE OF THREE OUTCOMES • Complete resolution • Healing by connective tissue replacement (scarring, or fibrosis) • Progression of the response to chronic inflammation 41 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
ANGIOGENESIS • Formation of new blood vessels which supply nutrients and oxygen needed to support the repair process. • Angiogenesis involves several signaling pathways, cell-cell interactions, ECM proteins and tissue enzymes • Angiopoetin 1 & 2 play a vital role in angiogenesis and structural maturation of new vessels. 42 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
STEPS IN ANGIOGENESIS Vasodilation and increased vascular permeability by VEGF Separation of pericytes and breakdown of basement membrane to allow formation of vessel sprout Migration and proliferation of endothelial cells Remodelling into capillary tubes Formation of mature vessels by periendothelial cells 43 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
44 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION ANGIOGENESIS
DEPOSITION OF CONNECTIVE TISSUE • The laying down of connective tissue occurs in two steps: – Migration and proliferation of fibroblasts into the site of injury – Deposition of extracellular matrix • Transforming growth factor-β (TGF-β) is the most important cytokine for the synthesis of connective tissue proteins 45 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
STEPS IN CONNECTIVE TISSUE DEPOSITION Proliferating fibroblasts and new vessels decreases Increased deposition of ECM Fibroblasts begin collagen synthesis(3-5 days) Progressive vascular regression which transforms highly vascular granulation tissue into pale avascular scar 46 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
REMODELLING OF CONNECTIVE TISSUE • After its deposition, the connective tissue in the scar gets modified and remodelled. • The degradation of collagens and other ECM components is accomplished by a family of Matrix Metalloproteinases(MMPs). • MMPs are activated by proteases to remodel the deposited ECM and inhibited by Tissue inhibitors of metalloproteinases(TIMP) produced by mesenchymal cells. 47 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
Common MMPs involved in remodelling of connective tissue MMP NAME FUNCTION MMP-1 Collagenases Cleaves fibrillar collagen MMP-2, MMP-9 Gelatinases Degrades amorphous collagen and fibronectin MMP-3, MMP-10, MMP-11 Stromelysins Degrades proteoglycans, laminins, fibronectin and amorphous collagen MMP-7 Matrilysin Disrupted cell aggregation, increased cell invasion 48
FACTORS THAT INFLUENCE TISSUE REPAIR • Infection • Diabetes • Nutrition • Glucocorticoids • Mechanical factors • Poor perfusion • Foreign bodies • Type, extent and location of the injury 49 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
50 Infection prolongs inflammation and potentially increases the local tissue injury Diabetes is a metabolic disease that compromises tissue repair, systemic causes of abnormal wound healing ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION Prolonged inflammatory reaction Increase in no of neutrophils Secrete pro inflammatory cytokines TNFα, IL-1β Disruption in wound healing MMP’S synthesised and degrade proteins and growth factors
51 Nutrition particularly vitamin C deficiency, inhibits collagen synthesis and retards healing Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart, or dehisce. Glucocorticoids (steroids) have anti inflammatory effects, and their administration may result in weakness of the scar due to inhibition of TGFβ production and diminished fibrosis
52 Type, size and location of injury determines whether healing takes place by resolution or organisation ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION Poor perfusion, due either to arteriosclerosis and diabetes or to obstructed venous drainage also impairs healing Foreign bodies including sutures interfere with healing and cause intense inflammatory reaction and infection.
53 SIZE OF WOUND • Small wound heal faster than larger wound LOCATION OF WOUND • Wound in increased vascularised area can heal faster TYPE OF TISSUE • Complete restoration of tissues to normal (stable or labile cells) • Replacement of damaged tissue by granulation tissue is organisation (permanent cells)
ABNORMALITIES IN TISSUE REPAIR 1. Inadequate formation of granulation tissue 2. Excessive formation of the components of the repair process 3. Exuberant granulation 4. Wound contracture 54 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
1. Inadequate formation of granulation tissue – Wound dehiscence: Rupture of the wound, occurs most frequently due to increased pressure. – Wound ulceration: Occurs as a result of inadequate vascularization during healing. 55 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
2. Excessive formation of the components of the repair process KELOID HYPERTROPHIC SCAR Accumulation of excessive amounts of collagen which extends beyond the wound margin Accumulation of excessive amounts of collagen confined within the borders of the wound margin More common in African- American population No racial predilection 56
3. EXUBERANT GRANULATION • Excessive formation of granulation tissue that protrudes above the level of surrounding skin and blocks re-epithelialization. • Excessive granulation tissue must be removed by cautery or surgical excision to permit restoration of continuity of epithelium. 57 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
4. WOUND CONTRACTURE • Wound contraction is an important part of the healing process. • An exaggeration of this process gives rise to contracture and results in deformities of the wound and the surrounding tissues. 58 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
WOUND STRENGTH • Carefully sutured wounds have approximately 70% of the strength of normal skin. • 1 week after removal of suture wound strength is approximately 10% of that of the normal skin. • After 4 weeks, wound strength rapidly increases due to increased collagen production and decreased collagen degradation. • Wound strength reaches approximately 70% to 80% of normal by 3 months but never improves beyond that point. 59 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
HEALING OF EPITHELIAL INJURY • This is a process that involves both epithelial regeneration and formation of connective tissue scar. • Based on the nature and size of the wound the healing occurs by: – Primary union or Healing by first intention – Secondary union or Healing by second intention 60 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
PRIMARY UNION VS SECONDARY UNION FEATURE PRIMARY UNION SECONDARY UNION Cleanliness of wound Clean Unclean Infection Generally uninfected May be infected Margins Surgical clean Irregular Sutures Used Not used Granulation tissue Scanty granulation tissue at the incised gap and along suture tracks Exuberant granulation tissue to fill the gaps Outcome Neat linear scar Contracted irregular wound Complications Infrequent, epidermal inclusion cyst formation Suppuration, may require debridement 61 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
HEALING BY FIRST INTENTION • When the injury involves only the epithelial layer, the principle mechanism of repair is epithelial regeneration. • Example: Clean, uninfected surgical incision approximated by sutures. • The repair consists of three connected processes: – Inflammation – Proliferation of epithelial and other cells – Maturation of connective tissue scar 62 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
Sequence of events in healing by first intention • Immediate  Wounding activates the coagulation pathways and leads to formation of clot.  Clot formed stops bleeding and acts as a scaffold for migrating cells activated by chemokines released by damaged tissue.  Dehydration of the external surface of the clot leads to formation of a scab covering the wound 63 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
• Within 24 hours to 48 hours:  Neutrophils migrate towards the clot and release proteolytic enzymes that clear the debris.  Basal cells at the cut margins show increased mitotic activity.  Epithelial cells from cut margins proliferate and migrate along the dermis and meet in the middle beneath the scab  This yields a thin but continuous epithelial layer covering the wound. 64 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
65 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
• By day 3:  Neutrophils are largely replaced by macrophages.  Granulation tissue invades the incision space.  Collagen fibers are now evident at incision margins.  Epithelial proliferation continues and forms a covering approaching the normal thickness. 66 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
• By day 5:  Neovascularization reaches its peak as granulation tissue fills the incision space.  Fibroblasts produce extracellular matrix proteins and collagen fibrils which become abundant and begin to bridge the incision.  Epithelium recovers its normal thickness as differentiation of surface cells yields a mature epithelial architecture. 67 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
• During 2nd week:  Leucocyte infiltration, edema and increased vascularity are substantially diminished.  The process of blanching begins due to increased collagen deposition and regression of vascular channels. • By the end of first month:  Scar comprises a cellular connective tissue largely devoid of inflammatory cells and covered by an normal epithelium. 68 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
Healing by Second intention • When cell or tissue loss is extensive, such as in large wounds, abscesses, ulceration healing occurs by secondary union or healing by second intention. • This involves both the combination of regeneration and scarring. • The inflammatory reaction is more intense and there is development of abundant granulation tissue, formation of a large scar and wound contraction by myofibroblasts. 69 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
Sequence of events in healing by second intention Wounds have large tissue deficits which are filled by large fibrin clots and there is more exudate and necrotic debris. Neutrophils accumulate initially which are then replaced by macrophages which clear the necrotic debris. Epithelial cells from both the wound margins proliferate and migrate until they meet each other in the middle. 70
Proliferation of fibroblasts and neovascularization forms a larger granulation tissue. With time, the scar on maturation becomes pale and white which is due to increase in collagen and decrease in vascularity. Wound contracts to one-third to one-fourth of its original size. 71
72 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
CONCLUSION • The goal of regenerative medicine is to restore the cells, tissues and structures that are lost or damaged after disease or injury. • The understanding of these mechanisms can facilitate highly relevant therapeutic strategies in regenerative medicine. 92
REFERENCE • Robbins and Cotran Pathologic Basis of Disease, 9th edition • Textbook of pathology, Harsh Mohan, 7th edition • Carranza’s clinical periodontology, 11th edition • Sigmund Stahl. Repair or regeneration following periodontal therapy?, J Clin Periodontol.1969 93
• Christopher P. Role of Growth Factors in Cutaneous Wound Healing: A Review; Critical Reviews in Oral Biology and Medicine.1993 • Schultz and Wysocki. Interactions between extracellular matrix and growth factors in wound healing. Wound Rep Reg. 2009;17:153–162 • Bhattacharyya et al. The voyage of stem cell toward terminal differentiation: a brief overview. Acta Biochim Biophys Sin. 2012;44(6):463 94 REFERENCE

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Repair and Regeneration.pptx

  • 1.
    REPAIR AND REGENERATION- BASICCONCEPTS DEPARTMENT OF PERIODONTICS
  • 2.
    CONTENTS • Introduction • Definition •Cell and Tissue regeneration • Repair by connective tissue deposition • Factors that influence tissue repair • Abnormalities in tissue repair • Wound strength • Healing of epithelial injury • Conclusion • Reference 2
  • 3.
    INTRODUCTION • The survivalof an organism depends on its ability to heal after damage caused by toxic insults and inflammation. • Healing is the body’s response to injury in an attempt to restore normal structure and function. • It involves two processes: 1. Repair 2. Regeneration 3 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 4.
    Melcher 1969 • Regeneration Biologic process by which the architecture and function of lost tissue is completely renewed. • Repair Continuity of disrupted tissue is restored by new tissues which do not replicate the structure and function of the lost tissues 4 DEFINITION Repair or regeneration following periodontal therapy? Sigmund Stahl, J Clin Periodontol, 1979
  • 5.
    5 Regeneration • Reproduction orreconstitution of a lost or injured part Periodontal regeneration • Restoration of lost periodontium Repair • Healing of a wound by tissue that does not fully restore the architecture or the function of the part. - Glossary of Periodontal Terms (2001) DEFINITION
  • 6.
    Regeneration • Some tissuesare able to replace the damaged components and essentially return to a normal state; this process is called regeneration Repair • Sometimes called healing, refers to the restoration of tissue 6 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 7.
    • Regeneration: Whenhealing takes place by proliferation of parenchymal cells and usually results in complete restoration of the original tissues. • Repair: When healing takes place by proliferation of connective tissue resulting in fibrosis and scarring. 7 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 8.
    8 ROBBINS PATHOLOGIC BASICSOF DISEASE – 9TH EDITION MECHANISM OF TISSUE REPAIR
  • 9.
    CELLAND TISSUE REGENERATION •The regeneration of injured cells and tissues involve:  Cell proliferation  Growth factors  Development of mature cells from stem cells 9 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 10.
    CELL PROLIFERATION • Cellproliferation is fundamental to development, maintenance of steady-state tissue homeostasis, and replacement of dead or damaged cells. • Sequence of events that result in cell division is called cell cycle. 10 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 11.
    • The abilityof tissues to repair themselves is determined by their intrinsic proliferative capacity. • Based on intrinsic proliferative capacity cells are divided into: 11 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION LABILE CELLS STABLE CELLS PERMANENT CELLS
  • 12.
  • 13.
    CELL CYCLE 13 HARSH MOHANTEXTBOOK OF PATHOLOGY – 7TH EDITION G1 phase S Phase G2 Phase M Phase
  • 14.
    • G1 phasecell grows in size and synthesize mRNA and protein that are required for DNA synthesis. • S Phase DNA is replicated; occurring between G1 and G2 phase • G2 Phase Rapid cell growth and protein synthesis during which the cell prepares itself for mitosis • M Phase Involves nuclear division and cytokinesis, where two identical daughter cells are produced. 14
  • 15.
    15 HARSH MOHAN TEXTBOOKOF PATHOLOGY – 7TH EDITION CELL CYCLE
  • 16.
    EXTRACELLULAR MATRIX • Extracellularmatrix is assembled from components synthesized and deposited outside the cell surface that provide structural and functional integrity. • Major extracellular matrix involved in wound healing process are – Structural proteins – Glycosaminoglycans – Matricellular proteins – Multi-domain adhesive glycoproteins 16 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
  • 17.
    Structural proteins • Contributeto the structural integrity during repair • They involve – Collagen – Elastin – Fibrin 17 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
  • 18.
    Glycosaminoglycans • Glycosaminoglycans areproteins that are deposited around other ECM proteins such as collagen and elastin. • They are hydrophilic substances which absorb upto 1000 times their volume in water to form a gel-like material called the ground substance. • They include – Hyaluronan – Proteoglycans such as versican, syndecan, glypicans, perlecans 18 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
  • 19.
    Matricellular proteins • Matricellularproteins are associated with ECM but do not perform a structural role within tissues. • They act temporarily and spatially to provide signals that trigger specific cell activities. • They are a group of proteins including Galectin Tenascins Thrombospondins Osteopontin Secreted protein acidic Vitronectin and rich in cysteine (SPARC) 19 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
  • 20.
    Multi-domain adhesive glycoproteins •These are biological glue that mediates interaction between cells and other ECM proteins. • They include – Fibronectin – Vitronectin – Laminin 20 Schultz and Wysocki, Interactions between extracellular matrix and growth factors in wound healing, Wound Rep Reg (2009) 17 153–162
  • 21.
    21 • High molecularweight glycoprotein • Produced by endothelial cells, fibroblasts, epithelial cells • Primary matrix in the organization of collagenous tissue during the repair process FIBRONECTIN • Component of platelets • Contain receptors which act as binding site for membrane bound integrins and provide anchor to extracellular matrix VITRONECTIN • Most abundant glycoprotein in basement membrane • Binds cells to basal lamina of epithelial and connective tissue LAMININ Caffesse, Quliiones. Polypeptide growth factors and attachment proteins in periodontal wound healing and regeneration .Periodontology 2000.1999 ; I:69-79
  • 22.
    GROWTH FACTORS • Majorrole of growth factors is to stimulate the activity of genes that are required for cell growth and cell division. • Source: – Macrophages activated by tissue injury – Stromal cells – Epithelial cells – Endothelial cells – Platelets – Mesenchymal cells 22 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 23.
    Role of growthfactors in wound healing • Promotes cell proliferation and metabolism through interaction with specific cell membrane bound receptors. • Induce migration of cells into the wound space. • Serve as chemoattractants to recruit leucocytes and fibroblasts into the wound space. 23
  • 24.
    Some of theimportant growth factors involved in cell proliferation • Epidermal growth factor (EGF) • Transforming growth factor-α (TGF-α) • Transforming growth factor-β (TGF-β) • Vascular endothelial growth factor (VEGF) • Platelet derived growth factor (PDGF) • Fibroblast growth factors (FGF) • Keratinocyte growth factor (KGF) 24
  • 25.
    Epidermal growth factor(EGF) •Sources: – Activated macrophages – Salivary glands – Keratinocytes • Functions: – Mitogenic for keratinocytes and fibroblasts – Stimulates keratinocyte migration – Stimulates formation of granulation tissue 25 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 26.
    Transforming growth factor-α(TGF-α) •Sources: – Activated macrophages – Keratinocytes • Functions: – Stimulates proliferation of hepatocytes and many other epithelial cells 26 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 27.
    Transforming growth factor-β(TGF-β) •Sources: – Platelets – T-lymphocytes – Macrophages – Endothelial cells – Keratinocytes – Fibroblasts – Smooth muscle cells • Functions: • Chemotactic for leucocytes and fibroblasts • Stimulates ECM protein synthesis • Suppresses acute inflammation 27 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 28.
    Vascular endothelial growthfactor(VEGF) • Sources: – Mesenchymal cells • Functions: – Stimulates proliferation of endothelial cells – Increases vascular permeability 28 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 29.
    Platelet derived growthfactor(PDGF) • Sources: – Platelets – Macrophages – Endothelial cells – Smooth muscle cells – Keratinocytes • Functions: – Chemotactic for neutrophils, macrophages, fibroblasts and smooth muscle cells – Stimulates ECM protein synthesis – Activates and stimulates proliferation of fibroblasts, endothelial cells and other cells 29 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 30.
    Fibroblast growth factor(FGF) •Sources: – Macrophages – Mast cells – Endothelial cells • Functions: – Chemotactic and mitogenic for fibroblasts – Stimulates angiogenesis and ECM protein synthesis 30 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 31.
    Keratinocyte growth factor(KGF) •Sources: – Fibroblasts • Functions: – Stimulates keratinocyte migration, proliferation and differentiation 31 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 32.
    Types of ECM- Growth factor interactions TYPES EXAMPLES Growth factor binding to ECM FGF-2 must be bound to heparan sulfate chains of proteoglycan to act as a mitogen Integrin mediated interactions Integrins-α1 and α2 necessary for VEGF- induced angiogenesis Matrikine ligand presentation by ECM components Tenascin-C and laminin bind to epidermal growth factor receptors where they act to enhance fibroblast migration Growth factor regulation of ECM TGF-β controls ECM production and degradation 32 Christopher P, Role of Growth Factors in Cutaneous Wound Healing: A Review; Critical Reviews in Oral Biology and Medicine, 1993
  • 33.
    DEVELOPMENT OF MATURECELLS FROM STEM CELLS • In adults, the most important stem cells for regeneration after injury are tissue stem cells. • These stem cells live in specialized niches, and it is believed that injury triggers signals in these niches that activate quiescent stem cells to proliferate and differentiate into mature cells that repopulate the injured tissue 33 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 34.
    STEM CELLS • Stemcells are the primitive cells having capacity for self renewal and that they can be modulated into multilineage differentiation. • Types (based on differentiation) 34 Totipotent stem cell Pluripotent stem cell Multipotent stem cell Unipotent stem cell Oligopotent stem cell ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 35.
    TOTIPOTENT STEM CELL •Ability to differentiate into all cell types and an entire functional organism • Eg Zygote PLURIPOTENT STEM CELL • Ability to differentiate into all cell types but cannot form a functional organism • Eg Embryonic stem cells 35 Bhattacharyya et al. The voyage of stem cell toward terminal differentiation: a brief overview, Acta Biochim Biophys Sin.2012;44(6):463
  • 36.
    MULTIPOTENT STEM CELL •Ability to differentiate into closely related family of cells • Eg Hematopoietic stem cell UNIPOTENT STEM CELL • Ability to differentiate into single cell type • Eg Muscle cells OLIGOPOTENT STEM CELL • Ability to differentiate into a few cell types • Eg Lymphoid or myeloid stem cells 36 Bhattacharyya et al. The voyage of stem cell toward terminal differentiation: a brief overview, Acta Biochim Biophys Sin.2012;44(6):463
  • 37.
    37 ROBBINS PATHOLOGIC BASICSOF DISEASE – 9TH EDITION STEM CELL LINEAGE
  • 38.
    REPAIR BY CONNECTIVETISSUE DEPOSITION • If repair cannot be accomplished by regeneration alone it occurs by replacement of the injured cells with connective tissue. • Steps in Scar formation: – Tissue injury – Inflammatory responses – Angiogenesis – Deposition of connective tissue – Remodelling of connective tissue 38
  • 39.
    • Inflammation isone of the body’s first reaction to injury. • Release of damaged cells and tissue debris occurs upon injury • These expelled particles act as antigens to stimulate a non specific immune response and cause proliferation of leukocytes • Resulting infiltration of tissues by leukocytes, plasma proteins and fluid causes redness, swelling and pain. 39 TISSUE INJURY
  • 40.
    INFLAMMATORY RESPONSES Acute inflammationhas 3 major components: • Dilation of small vessels leading to an increase in blood flow • Increased permeability of microvasculature enabling plasma proteins and leucocytes to leave the circulation • Emigration of leucocytes from the microcirculation, their accumulation in the focus of injury 40
  • 41.
    ACUTE INFLAMMATORY REACTIONSHAVE ONE OF THREE OUTCOMES • Complete resolution • Healing by connective tissue replacement (scarring, or fibrosis) • Progression of the response to chronic inflammation 41 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 42.
    ANGIOGENESIS • Formation ofnew blood vessels which supply nutrients and oxygen needed to support the repair process. • Angiogenesis involves several signaling pathways, cell-cell interactions, ECM proteins and tissue enzymes • Angiopoetin 1 & 2 play a vital role in angiogenesis and structural maturation of new vessels. 42 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 43.
    STEPS IN ANGIOGENESIS Vasodilationand increased vascular permeability by VEGF Separation of pericytes and breakdown of basement membrane to allow formation of vessel sprout Migration and proliferation of endothelial cells Remodelling into capillary tubes Formation of mature vessels by periendothelial cells 43 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 44.
    44 ROBBINS PATHOLOGIC BASICSOF DISEASE – 9TH EDITION ANGIOGENESIS
  • 45.
    DEPOSITION OF CONNECTIVETISSUE • The laying down of connective tissue occurs in two steps: – Migration and proliferation of fibroblasts into the site of injury – Deposition of extracellular matrix • Transforming growth factor-β (TGF-β) is the most important cytokine for the synthesis of connective tissue proteins 45 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 46.
    STEPS IN CONNECTIVETISSUE DEPOSITION Proliferating fibroblasts and new vessels decreases Increased deposition of ECM Fibroblasts begin collagen synthesis(3-5 days) Progressive vascular regression which transforms highly vascular granulation tissue into pale avascular scar 46 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 47.
    REMODELLING OF CONNECTIVETISSUE • After its deposition, the connective tissue in the scar gets modified and remodelled. • The degradation of collagens and other ECM components is accomplished by a family of Matrix Metalloproteinases(MMPs). • MMPs are activated by proteases to remodel the deposited ECM and inhibited by Tissue inhibitors of metalloproteinases(TIMP) produced by mesenchymal cells. 47 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 48.
    Common MMPs involvedin remodelling of connective tissue MMP NAME FUNCTION MMP-1 Collagenases Cleaves fibrillar collagen MMP-2, MMP-9 Gelatinases Degrades amorphous collagen and fibronectin MMP-3, MMP-10, MMP-11 Stromelysins Degrades proteoglycans, laminins, fibronectin and amorphous collagen MMP-7 Matrilysin Disrupted cell aggregation, increased cell invasion 48
  • 49.
    FACTORS THAT INFLUENCETISSUE REPAIR • Infection • Diabetes • Nutrition • Glucocorticoids • Mechanical factors • Poor perfusion • Foreign bodies • Type, extent and location of the injury 49 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 50.
    50 Infection prolongs inflammationand potentially increases the local tissue injury Diabetes is a metabolic disease that compromises tissue repair, systemic causes of abnormal wound healing ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION Prolonged inflammatory reaction Increase in no of neutrophils Secrete pro inflammatory cytokines TNFα, IL-1β Disruption in wound healing MMP’S synthesised and degrade proteins and growth factors
  • 51.
    51 Nutrition particularly vitaminC deficiency, inhibits collagen synthesis and retards healing Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart, or dehisce. Glucocorticoids (steroids) have anti inflammatory effects, and their administration may result in weakness of the scar due to inhibition of TGFβ production and diminished fibrosis
  • 52.
    52 Type, size andlocation of injury determines whether healing takes place by resolution or organisation ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION Poor perfusion, due either to arteriosclerosis and diabetes or to obstructed venous drainage also impairs healing Foreign bodies including sutures interfere with healing and cause intense inflammatory reaction and infection.
  • 53.
    53 SIZE OF WOUND •Small wound heal faster than larger wound LOCATION OF WOUND • Wound in increased vascularised area can heal faster TYPE OF TISSUE • Complete restoration of tissues to normal (stable or labile cells) • Replacement of damaged tissue by granulation tissue is organisation (permanent cells)
  • 54.
    ABNORMALITIES IN TISSUEREPAIR 1. Inadequate formation of granulation tissue 2. Excessive formation of the components of the repair process 3. Exuberant granulation 4. Wound contracture 54 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 55.
    1. Inadequate formationof granulation tissue – Wound dehiscence: Rupture of the wound, occurs most frequently due to increased pressure. – Wound ulceration: Occurs as a result of inadequate vascularization during healing. 55 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 56.
    2. Excessive formationof the components of the repair process KELOID HYPERTROPHIC SCAR Accumulation of excessive amounts of collagen which extends beyond the wound margin Accumulation of excessive amounts of collagen confined within the borders of the wound margin More common in African- American population No racial predilection 56
  • 57.
    3. EXUBERANT GRANULATION •Excessive formation of granulation tissue that protrudes above the level of surrounding skin and blocks re-epithelialization. • Excessive granulation tissue must be removed by cautery or surgical excision to permit restoration of continuity of epithelium. 57 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 58.
    4. WOUND CONTRACTURE •Wound contraction is an important part of the healing process. • An exaggeration of this process gives rise to contracture and results in deformities of the wound and the surrounding tissues. 58 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 59.
    WOUND STRENGTH • Carefullysutured wounds have approximately 70% of the strength of normal skin. • 1 week after removal of suture wound strength is approximately 10% of that of the normal skin. • After 4 weeks, wound strength rapidly increases due to increased collagen production and decreased collagen degradation. • Wound strength reaches approximately 70% to 80% of normal by 3 months but never improves beyond that point. 59 ROBBINS PATHOLOGIC BASICS OF DISEASE – 9TH EDITION
  • 60.
    HEALING OF EPITHELIALINJURY • This is a process that involves both epithelial regeneration and formation of connective tissue scar. • Based on the nature and size of the wound the healing occurs by: – Primary union or Healing by first intention – Secondary union or Healing by second intention 60 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 61.
    PRIMARY UNION VSSECONDARY UNION FEATURE PRIMARY UNION SECONDARY UNION Cleanliness of wound Clean Unclean Infection Generally uninfected May be infected Margins Surgical clean Irregular Sutures Used Not used Granulation tissue Scanty granulation tissue at the incised gap and along suture tracks Exuberant granulation tissue to fill the gaps Outcome Neat linear scar Contracted irregular wound Complications Infrequent, epidermal inclusion cyst formation Suppuration, may require debridement 61 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 62.
    HEALING BY FIRSTINTENTION • When the injury involves only the epithelial layer, the principle mechanism of repair is epithelial regeneration. • Example: Clean, uninfected surgical incision approximated by sutures. • The repair consists of three connected processes: – Inflammation – Proliferation of epithelial and other cells – Maturation of connective tissue scar 62 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 63.
    Sequence of eventsin healing by first intention • Immediate  Wounding activates the coagulation pathways and leads to formation of clot.  Clot formed stops bleeding and acts as a scaffold for migrating cells activated by chemokines released by damaged tissue.  Dehydration of the external surface of the clot leads to formation of a scab covering the wound 63 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 64.
    • Within 24hours to 48 hours:  Neutrophils migrate towards the clot and release proteolytic enzymes that clear the debris.  Basal cells at the cut margins show increased mitotic activity.  Epithelial cells from cut margins proliferate and migrate along the dermis and meet in the middle beneath the scab  This yields a thin but continuous epithelial layer covering the wound. 64 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 65.
    65 ROBBINS PATHOLOGIC BASICSOF DISEASE – 9TH EDITION
  • 66.
    • By day3:  Neutrophils are largely replaced by macrophages.  Granulation tissue invades the incision space.  Collagen fibers are now evident at incision margins.  Epithelial proliferation continues and forms a covering approaching the normal thickness. 66 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 67.
    • By day5:  Neovascularization reaches its peak as granulation tissue fills the incision space.  Fibroblasts produce extracellular matrix proteins and collagen fibrils which become abundant and begin to bridge the incision.  Epithelium recovers its normal thickness as differentiation of surface cells yields a mature epithelial architecture. 67 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 68.
    • During 2ndweek:  Leucocyte infiltration, edema and increased vascularity are substantially diminished.  The process of blanching begins due to increased collagen deposition and regression of vascular channels. • By the end of first month:  Scar comprises a cellular connective tissue largely devoid of inflammatory cells and covered by an normal epithelium. 68 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 69.
    Healing by Secondintention • When cell or tissue loss is extensive, such as in large wounds, abscesses, ulceration healing occurs by secondary union or healing by second intention. • This involves both the combination of regeneration and scarring. • The inflammatory reaction is more intense and there is development of abundant granulation tissue, formation of a large scar and wound contraction by myofibroblasts. 69 HARSH MOHAN TEXTBOOK OF PATHOLOGY – 7TH EDITION
  • 70.
    Sequence of eventsin healing by second intention Wounds have large tissue deficits which are filled by large fibrin clots and there is more exudate and necrotic debris. Neutrophils accumulate initially which are then replaced by macrophages which clear the necrotic debris. Epithelial cells from both the wound margins proliferate and migrate until they meet each other in the middle. 70
  • 71.
    Proliferation of fibroblastsand neovascularization forms a larger granulation tissue. With time, the scar on maturation becomes pale and white which is due to increase in collagen and decrease in vascularity. Wound contracts to one-third to one-fourth of its original size. 71
  • 72.
    72 ROBBINS PATHOLOGIC BASICSOF DISEASE – 9TH EDITION
  • 73.
    CONCLUSION • The goalof regenerative medicine is to restore the cells, tissues and structures that are lost or damaged after disease or injury. • The understanding of these mechanisms can facilitate highly relevant therapeutic strategies in regenerative medicine. 92
  • 74.
    REFERENCE • Robbins andCotran Pathologic Basis of Disease, 9th edition • Textbook of pathology, Harsh Mohan, 7th edition • Carranza’s clinical periodontology, 11th edition • Sigmund Stahl. Repair or regeneration following periodontal therapy?, J Clin Periodontol.1969 93
  • 75.
    • Christopher P.Role of Growth Factors in Cutaneous Wound Healing: A Review; Critical Reviews in Oral Biology and Medicine.1993 • Schultz and Wysocki. Interactions between extracellular matrix and growth factors in wound healing. Wound Rep Reg. 2009;17:153–162 • Bhattacharyya et al. The voyage of stem cell toward terminal differentiation: a brief overview. Acta Biochim Biophys Sin. 2012;44(6):463 94 REFERENCE