Wound Healing and Tissue Repair Friday, January 31, 2003

1. RBC “The Point of Pain” Platelets “Nature of My Disease” Wound Healing and Tissue RepairFriday, January 31, 2003

2. “Response to Injury”

3. Wound Healing and Repair Scenario combines 3 important processes: hemostasis, because blood vessels are open; inflammation, because there has been an injury and possible infection; and regeneration, because cellular/tissue structures have been severed or destroyed. Plan of wound healing/repair is always the same-- to close the gap and seal it up with normal tissue or a scar.

4. Wound Healing and Repair (cont’d) The ultimate result vary depending upon: --presence or absence of bacteria; --the nature of the wound (open or closed); --the blood supply; --the amount of dead tissue to be eliminated; --the type of wounded tissue, and many other factors!

5. Healing and Repair- Distinguishing Them Following tissue damage and/or loss from any cause, including damage due to the inflammatory process, there may be a number of different “solutions to the problem”: Resolution- Dead cellular material and debris are removed by phagocytosis (macrophages) and tissue is left with its original architecture. Regeneration- Lost tissue is replaced by proliferation of cells of the same type, which reconstruct the normal architecture.

6. Healing and Repair- Distinguishing Them Repair- A fibrous scar that is produced from granulation tissuereplaces lost tissue. All of these processes may occur in the same tissue, and begin as soon as there is significant tissue damage. Healing reactions do not wait for inflammation or other damaging processes to subside, but take place at the same time.

7. The Outcome of Healing and Repair The outcome in any situation depends on which of the three processes predominates, and depends on a number of factors: Resolution- --This tends to occur when there is little tissue destruction. --A good example is lobar pneumonia. In the earlier stages of lobar pneumonia the alveolar spaces fill with pus but the alveolar walls remain intact. --If the infecting organism is destroyed then the purulent material may be completely scavenged by macrophages, leaving the original lung structure intact.

8. The Outcome of Healing and Repair (cont’d) Regeneration- The cells of the body are divided into 3 groups: 1. Continuously dividing (also called labile cells) follow cell cycle from one mitosis to the next, and continue to proliferate, replacing cells that are continuously destroyed. --surface epithelia such as skin, oral cavity, vagina and cervix; liningmucosa of all of the excretory ducts; --columnar epithelium of the GI tract, uterus, and fallopian tubes; the transitional epithelium of the urinary tract and cells of the splenic, lymphoid and hematopoietic tissues.

9. The Outcome of Healing and Repair (cont’d) 2. Quiescent (or stable) cells usually demonstrate a low normal level of replication. These cells can undergo rapid division in response to a variety of stimuli and help reconstitute the tissue or origin. --this would be parenchymal cells(“functional”) in virtually all of the glandular organs of the body, liver, kidney, and pancreas; --mesenchymal cells(“stromal”) such as fibroblasts and smooth muscle cells; and vascular endothelial cells.

10. The Outcome of Healing and Repair (cont’d) 3. Non-dividing (permanent) cells have left the cell cycle and cannot undergo mitotic division in postnatal life. --the nerve cells and cardiac muscle cells.

11. Cell Groups Based on “Capacity to Regenerate” Cells are usually classified into these three groups depending on their capacity for regeneration: --Labile (continuously dividing) cells are those that normally have a high rate of loss and replacement and therefore have a high capacity for regeneration. --Stable (quiescent) cells do not normally proliferate to a significant extent but can be stimulated to do so after damage. --Permanent (non-dividing) cells are unable to divide after initial development and therefore cannot regenerate.

12. Tissue Architecture • Simple structures are easier to reconstruct following damage than complex • ones, e.g., a flat surface such as epidermis regenerates very successfully, but dermal sweat glands do not. • An imperfect attempt at regeneration of tissue architecture may have important clinical consequences: • --chronic inflammatory liver disease regenerative proliferation of hepatocytes is vigorous; • --damage to the connective tissue framework results in an abnormal nodular architecture- cirrhosis; • --abnormal liver architecture can lead to portal hypertension that may result in death due to uncontrollable hemorrhage.

13. Steps to Achieving Repair or Regeneration Amount of Tissue Loss- Regeneration implies that there are cells left to regenerate. If there is large loss of area of tissue, it will heal by scar formationrather than regeneration.

14. Steps to Achieving Repair or Regeneration Repair- The repair process results in formation of a fibrous scar from granulation tissue. The steps in this process are as follows: --Phagocytosis of necrotic debris by macrophages. --Proliferation of blood vessel endothelial cells and fibroblasts at the edges of the damaged area.

15. Steps to Achieving Repair or Regeneration --Endothelial cells grow into the damaged area, initially as solid buds from adjacent blood vessels, to form an abundant network of delicate, thin-walled capillaries. --Fibroblasts migrate into the damaged area along with the capillaries to form a loose connective tissue framework. This delicate fibrovascular tissue is granulation tissue. --The new capillary vessels establish a blood circulation in the healing area and differentiate towards arterial and venous types as necessary.

16. Steps to Achieving Repair or Regeneration The steps in this process are as follows (continues): --Fibroblasts produce collagen, giving the healing tissue mechanical strength. --Eventually a mature scar consisting almost entirely of dense collagen is produced.

17. Histology of Wound Healing and Repair At high magnification, granulation tissue has capillaries,fibroblasts, and a variable amount of inflammatory cells (mostly mononuclear).

18. Gross of Wound Healing and Repair Chronic inflammation can be seen in conjunction with some degree of scarring. Here, chronic inflammation of the bronchi has led to dilation and scarring with increased tan to white collagenous tissue.

19. Histology of Wound Healing and Repair The end result of inflammation can be scarring. The alveolar walls are thickened and filled with pink collagen following an autoimmune disease lasting for decades.

20. Primary and Secondary Intention Wound Healing- Time course of healing by repair and the amount of scar tissue formed depend on factors such as the extent of tissue damage, presence of persisting infection, inflammation, etc. Simple, rapid process of healing in a clean skin wound which has been closed promptly and where tissue damage is minimal (e.g., surgical incision) is termed healing by first or primary intention. Epidermis regenerates across the gap quickly and successfully, the volume of tissue into which granulation tissue has to grow is small, and the amount of fibrous scar produced is minimal.

22. Histology of Wound Healing and Repair This is a healing biopsy site on skin a week after the excision. The skin surface has re-epithelialized, and below this is granulation tissue with small capillaries and fibroblasts forming collagen. After a month, just a small collagenous scar will remain.

23. Histology of Wound Healing and Repair This is a healing biopsy site on skin a week after the excision. The skin surface has re-epithelialized, and below this is granulation tissue with small capillaries and fibroblasts forming collagen. After a month, just a small collagenous scar will remain. Healing of an open wound where there is significant tissue loss or where there is ongoing tissue damage from infection is termed “healing by secondary intention”.

24. Outcome of Healing and Repair A recently severely burnt hand. Much of the skin has been completely destroyed and the underlying tissue is undergoing repair. The damaged area is being replaced by granulation tissue, which will undergo further organization to form dense fibrous scar.

25. Outcome of Healing and Repair A recently severely burnt hand. Much of the skin has been completely destroyed and the underlying tissue is undergoing repair. The damaged area is being replaced by granulation tissue, which will undergo further organization to form dense fibrous scar. In this situation, the amount of granulation tissue formed is substantial, scar contraction greater, and re-epithelialization less complete.

26. Granulomatous Inflammation(Chronic Inflammation) vs. Granulation Tissue (Wound Healing/Tissue Repair) This photomicrograph shows several thin-walled capillary blood vessels growing into damaged tissue associated with a perforation of the large intestine. Red blood cells can be seen within the vessels and also extravasated in the tissue. The elongated cells with plump, oval nuclei and pink cytoplasm are fibroblasts.

27. Granulation Tissue (Wound Healing/Tissue Repair) This area of granulation tissue contains chronic inflammatory cells, illustrating that inflammation and healing can happen concurrently.

28. Granulation Tissue (Wound Healing/Tissue Repair) The wall of an abscess has granulation tissue, shown on the left. The purulent exudate with some hemorrhage is shown on the right in the abscess center.