1. Unit 5 Repair and Regeneration

2. 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

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

5. 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

6. 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

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

8. The Cell Cycle and Different Cell Populations

10. 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

11. 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

12. 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

13. 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

14. 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)

15. Angiogenesis

16. 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

17. 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)

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

19. 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

20. 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)

21. 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

22. 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

23. Wound ulceration
Wound dehiscence
Contracture
Keloid

24. 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

25. 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)

26. 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