Regeneration vs. Repair:
Regeneration: Replacement with the same tissue, restoring appearance and function.
Repair: Replacement with scar (connective tissue), which does not restore appearance and function.

Extra: Scar Tissue: Scar tissue is a type of dense connective tissue. It primarily consists of collagen fibers that are densely packed together, which form a scaffold for healing in response to injury. This tissue is formed during the repair process and lacks the same elasticity and functionality as the original tissue, typically resulting in a different appearance and reduced function compared to normal tissue.

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Case Study: Herpes simplex virus - Cold sore:
Predict whether the healing process will involve regeneration or repair.

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Case Study: Aphthous ulcer:
Predict the healing outcome similar to above.

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Impact of Skin Function:
Consider what functions of skin may be impaired post-healing (e.g., sensation, barrier effectiveness).

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Types of Injury:
Normal, Mild, superficial injury leads to Regeneration.
Severe injury leads to SCAR FORMATION.

Process of Healing from Mild/Superficial Injury to Severe Injury

1. Mild/Superficial Injury (Regeneration)

Initial Injury:
The skin or tissue experiences a mild, superficial injury (e.g., abrasion or a small cut).
Immediate Response:
Blood vessels constrict to minimize bleeding and a haemostatic plug forms at the injury site.
Platelets aggregate and release growth factors and signaling molecules.
Inflammation Phase:
Small inflammatory response occurs. Immune cells, particularly macrophages and neutrophils, migrate to clear debris and pathogens, but the response stays localized and controlled.
Cellular Proliferation:
Epithelial cells at the edges of the wound proliferate and migrate to cover the wound area.
Keratinocytes (skin cells) divide rapidly to regenerate the top layer of skin.
Granulation Tissue Formation:
Granulation tissue develops beneath the new epithelium; it contains new blood vessels, collagen, and various cell types that assist in healing.
Remodeling Phase:
The newly formed tissue undergoes remodeling as collagen fibers are rearranged.
The regeneration process restores both function and appearance of the tissue with minimal intrusion from scar tissue.

2. Severe Injury (Scar Formation)

Initial Injury:
A severe injury occurs, such as a deep laceration or a traumatic wound, affecting deeper tissues beyond the skin.
Immediate Response:
Blood vessels quickly constrict, a larger haemostatic plug forms to stop bleeding, but a significant amount of blood may be lost.
Inflammation Phase:
A more extensive inflammatory response occurs, with increased recruitment of immune cells to manage the injury and prevent infection.
The inflammatory response can lead to swelling, redness, and heat in the affected area.
Cellular Response:
Large amounts of growth factors and cytokines are released to promote healing.
While some epithelial cells proliferate, deeper layers (muscle or connective tissue) may experience cell death (necrosis) due to the extensive damage.
Granulation Tissue Formation:
In response to the injury and cell death, granulation tissue forms as immune cells, endothelial cells, and fibroblasts migrate into the damaged area.
This tissue is characterized by a rich vascular network, providing nutrients to support healing but begins to form a scaffold for future scar tissue.
Fibrosis/Scar Formation:
The granulation tissue is gradually replaced by dense connective tissue, primarily composed of collagen.
This collagen is laid down in an organized manner; however, it does not restore the original architecture of the tissue.
The final scar is less elastic and differs in appearance and function compared to healthy tissue.
Maturation Phase:
The scar undergoes constant remodeling and maturation over months to years.
Although it may improve in appearance over time, it will never fully regain the full function or aesthetics of the original tissue.

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Heart Function Impairment Post-Injury:
Loss of contractility.
Altered conduction.
Altered antithrombotic endocardial surface molecules.

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Healing Mechanisms:
Organs/tissues may undergo either repair or regeneration based on the extent of injury.
Some may exhibit both simultaneously due to varying types of cells.
This may happen, for instance, when some cells are capable of regeneration while others are primarily involved in repair, leading to a hybrid healing response.
Factors influencing healing:
Type of tissue affected (e.g., epithelial vs. connective tissues)
Severity and duration of the injury
Presence of infection or foreign bodies
Age and overall health of the individual

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Regeneration Requirements:

Cells capable of replication (mature survivor, progenitor, or stem cells).
Intact extracellular matrix (ECM).

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Cell Types for Regeneration:
Continuous (labile) cells: e.g., surface epithelium (epidermis, GIT).
Conditional (stable) cells: e.g., liver, kidney.
Non-renewing (permanent) cells: e.g., nerve cells, myocardium.

Continuous (Labile) Cells:

These cells are constantly dividing and can rapidly regenerate.
Examples include the surface epithelium, such as the epidermis of the skin and the gastrointestinal tract (GIT).
They are crucial for healing and maintaining the integrity of tissues that are frequently damaged or undergo wear and tear.

Conditional (Stable) Cells:

These cells normally have a low level of replication but can proliferate in response to injury or loss of tissue.
Examples include parenchymal cells of the liver and kidney, which can regenerate effectively if injured, although they do not do so regularly in a healthy state.

Non-Renewing (Permanent) Cells:

These cells do not divide and are replaced primarily through scar formation following injury.
Examples include nerve cells (neurons) and cardiac muscle cells (myocardium).
In the event of damage, the loss of these cells can lead to permanent functional impairment, as they do not regenerate effectively.

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Cirrhosis of the Liver:
Characterized by nodular regenerative liver tissue and presence of scar.

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Visuals: Images of liver cirrhosis and regeneration of hepatocytes.

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Scar Formation:
Composition: Collagen and other ECM proteins, specifically arranged in parallel bundles.
Scar tissue, also referred to as fibrosis, differs from normal tissue's meshwork arrangement.

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Granulation Tissue:
Includes macrophages, blood vessels, myofibroblasts, and serves as a critical component in healing.

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Scar Formation Mechanism:
Granulation tissue grows into the injured area, remodels over time into a scar with defined phases:
1. Inflammation
2. Proliferation
3. Remodeling

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Initiating Repair Process:
Traumatic injuries create a haemostatic plug, triggering inflammation and growth factors for repair.
Non-traumatic injuries may not present blood clots but can have chronic inflammation affecting growth factor outcomes.

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Factors Impairing Healing:
Local Factors: Vascularity, infection, mechanical trauma, chemical injury, foreign bodies, irradiation, neoplasia.
Systemic Factors: Age, nutritional status, systemic diseases, hormonal status, smoking.

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Abnormal Healing:
Examples of chronic wounds: venous leg ulcers, arterial ulcers, diabetic ulcers, pressure sores, excessive granulation tissue (keloids, hypertrophic scars).

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Macrophage Function:
Two main phenotypes:
- M1: Pro-inflammatory, responsible for early wound response and debris clearance.
- M2: Anti-inflammatory, promotes healing and granulation tissue formation.

Macrophage Functions in Healing

M1 Macrophages:
Function: M1 macrophages are primarily pro-inflammatory cells that play a crucial role in the early stages of the wound healing response.
Responsibilities:
- Debris Clearance: They are involved in clearing cellular debris, pathogens, and dead cells from the injury site.
- Cytokine Production: M1 macrophages produce pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, which help recruit additional immune cells to the site of injury.
- Activation of Immune Response: These macrophages can activate neutrophils and other immune cells, amplifying the local inflammatory response to fight infections.
M2 Macrophages:
Function: M2 macrophages are characterized by their anti-inflammatory properties and play a significant role in promoting healing and tissue repair.
Responsibilities:
- Tissue Repair: They facilitate tissue repair by producing growth factors, such as TGF-β and VEGF, which are essential for angiogenesis (formation of new blood vessels) and the formation of granulation tissue.
- Resolution of Inflammation: M2 macrophages help resolve inflammation by secreting anti-inflammatory cytokines and enzymes that inhibit further immune responses, thus promoting a peaceful environment for healing.
- Collagen Synthesis: They aid in the deposition of collagen and other extracellular matrix components, crucial for the formation of scar tissue and functional restoration of the injured area.

Overall, the balance between M1 and M2 macrophages is critical for a successful healing process, as M1 macrophages initiate the inflammatory response, while M2 macrophages facilitate recovery and repair.

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Angiogenesis Overview:
Describes how new blood vessels migrate from existing capillaries, requiring ECM scaffolding.
Stimulated by factors like VEGF due to hypoxia.
Consequence: New blood vessels are always leaky.

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Wound Healing Phases:

Inflammation: Remove irritants.
Proliferation: New tissue is generated.

Proliferation Process in Healing

Definition: Proliferation is the phase in the wound healing process where new tissue is generated to fill in the wound area following the initial inflammatory response.
Key Steps in Proliferation:

Cell Migration: After inflammation, cells such as fibroblasts and keratinocytes migrate into the wound area. This migration is stimulated by various growth factors released during the inflammatory phase.
Cell Proliferation: Once in the wound area, these cells begin to proliferate. Keratinocytes replicate to reform the epithelial layer, while fibroblasts multiply and play a vital role in laying down new extracellular matrix (ECM) components.
Granulation Tissue Formation: As fibroblasts proliferate, they produce collagen and other ECM proteins that form granulation tissue. This newly formed tissue is a pinkish, soft tissue that consists of new blood vessels (angiogenesis), collagen, and inflammatory cells, providing a scaffold for healing.
Angiogenesis: Blood vessels grow into the granulation tissue to provide oxygen and nutrients essential for the healing process. This process is vital for supporting the metabolic demands of the rapidly proliferating cells in the wound.
Extracellular Matrix Production: Fibroblasts synthesize collagen (especially type III collagen initially), proteoglycans, and glycoproteins that constitute the ECM. The ECM serves as a support structure for the new tissue and plays a role in signaling to cells to direct further proliferation and differentiation.
Epithelium Reformation: As keratinocytes proliferate, they migrate over the granulation tissue, covering the wound and establishing a new layer of epithelial cells. Growth factors and cytokines are crucial in regulating this process, promoting keratinocyte migration and proliferation.
Matrix Remodeling: The granulation tissue is gradually remodeled as collagen is cross-linked and organized more effectively, transitioning to a more mature scar tissue.

Duration: The proliferation phase typically lasts for several days to weeks, depending on the size and severity of the wound and the overall health of the individual.
Conclusion: The proliferation process is critical for effective wound healing, enabling significant tissue regeneration and the restoration of integrity and function to the injured site.

Remodeling: Final scar tissue maturation.

Remodeling Process:

Definition: Remodeling refers to the maturation of the final scar tissue following the initial stages of healing. It is the final phase of the wound healing process where new tissue is restructured and gains strength over time.
Phases of Remodeling:

Collagen Remodeling: During this phase, collagen fibers in the scar tissue are reorganized, cross-linked, and aligned along tension lines to enhance the mechanical strength of the newly formed tissue.
Reduction of Vascularity: Initially, granulation tissue is highly vascularized; however, during remodeling, the number of blood vessels in the scar tissue decreases as the need for nutrients and oxygen diminishes.
Decreased Cellularity: The number of cells, including fibroblasts and inflammatory cells, diminishes as the tissue matures. This leads to a less cellular scar that is ultimately more similar in composition to normal tissue.
Improvement in Function and Appearance: Over time, the appearance and function of the scar may improve, becoming less noticeable than during the earlier stages of healing, although it will never fully regain the original tissue's characteristics.

Timeframe: The remodeling phase can last from months to years, depending on the extent of the injury and individual healing responses.

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Summary of Healing Mechanisms:
Regeneration: Complete restoration with the same tissue.
Repair: Scarring with collagen deposition, resulting in varied aesthetic and functional outcomes.

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Healing By Intention:
First intention: Healing occurs when skin edges are apposed.
Second intention: When skin edges do not touch, leading to more complex scarring.