Inflammation and Tissue Repair Flashcards

• Saint Joseph's University presents DPT 581: Medical Management 1, Spring 2025 on the topic of Tissue Healing.

Pathology

• Pathology involves structural or functional changes in response to disease or trauma.
• The results cause cell injury, inflammation, and tissue healing.

Physical Stress Theory

• Tissue adaptation to physical stress guides physical therapist practice, education, and research.
• The adaptation continuum includes atrophy, maintenance, hypertrophy, injury, and death.
• Injury is split into trauma and cumulative damage.
• Exposure to stress includes the magnitude of force, time, and direction of the force.
• Other factors influencing response to stress include age, PMH, medications, activity level, obesity, nutrition, and body mechanics.
• High-magnitude stress over a short duration may cause injury.
• Low-magnitude stress over a long duration may cause injury.
• Moderate-magnitude stress applied frequently may also cause injury.

Cell Injury

• Cell injury can occur in the body because of infection, ischemia, immune response, genetic factors, nutritional factors, temperature, chemical factors, trauma, and physical factors.
• The injury can be reversible or irreversible, contingent on mechanism, severity, and intervention timeline.

Reversible Cell Injury

• Reversible cell injury is a sublethal-transient alteration, and the cell can adapt to chronic sublethal injury.
• Removal of the stressor leads to a return of normal structure or function.
• Acute Reversible Cell Injury:
  • Intracellular Na and Ca increase.
  • Intracellular swelling occurs
  • Cytosol, mitochondria, and endoplasmic reticulum swell.
  • Lowered pH
• Removal of the stressor reverses the process.
• Chronic Sublethal Cell Injury:
  • Stress leads to altered functional demand, adaptations, and return to normal after stress is removed.
  • Possible adaptations include hypertrophy, hyperplasia, metaplasia, and dysplasia.

Irreversible Cell Injury

• Irreversible cell injury leads to cell death.
• Hallmarks include alterations in the nucleus, mitochondria, and lysosomes.
• Other hallmarks are rupture of the cell membrane and necrosis.
• Byproducts are released into circulation and measurable with blood tests.

Inflammation

• Inflammation is the body's response to cell injury, with functions to inactivate the cause of cell injury, break down and remove dead cells and debris, and initiate tissue healing.
• Response is dependent on amount, type, and severity. Inflammation initiates a healing response and causes innate immune responses (neutrophils, macrophages) and pro-inflammatory mediators.
  • Pro-inflammatory mediators include cytokines like interleukins (IL), tumor necrosis factor (TNF), and growth factors (GF).

Acute vs. Chronic Inflammation

• Acute:
  • Fast onset, short duration.
  • Hallmarks include edema from exudate, erythema, warm to touch, and pain.
• Chronic:
  • Prolonged duration.
  • Hallmarks include accumulation of macrophages and lymphocytes, hypervascularity and fibrosis, and tissue necrosis.
• Injury can lead to acute inflammation.
• Injurious agents removed can resolve with labile or stable cells.
• Injurious agents that persist can lead to chronic inflammation.
• Organization and scarring can take place in chronic inflammation.
• All of these paths will result in a persistent abnormal structure.

Causes for Chronic Inflammation

• Injurious agent not addressed
• Extensive necrosis:
  • Burns
  • Wide wound edges (e.g., road rash)
• Regeneration of parenchymal cells not possible
• Repeated episodes of acute inflammation
• Pt noncompliance
• Faulty movement mechanics not corrected

Chemical Mediators of Inflammation

• Histamine is stored in mast cells, basophils, & platelets.
  • Increases vascular permeability.
  • Acts as a vasodilator and bronchoconstrictor.
• Platelet Activating Factor is derived from phospholipids of the cell membrane.
  • Causes platelet aggregation & secretion.
  • Increases leukocyte concentration & other inflammatory mediators.
• Arachidonic Acid Derivatives include Cyclooxygenase pathway and Lipoxygenase pathway.
  • Cyclooxygenase promotes prostaglandins, increase platelet aggregation, mediate fever and pain.
  • Lipoxygenase promotes leukotrienes, increase vascular permeability, chemotaxis of leukocytes to injury and bronchoconstriction
• Medications that can block inflammatory responses include Corticosteroids and NSAIDs.
• Cytokines:
  • Interleukin-1 (IL-1)
  • Tumor Necrosis Factor (TNF)
  • Produced by leukocytes
  • Can produce local & systemic effects and induce fervor
  • Also increases metabolism and cause hemodynamic changes

Components of Tissue Healing

• Collagen supplies the most important structural support and tensile strength for all tissues.
  • Organization determines structural properties.
  • Tendons: parallel bundle
  • Skin, bone: random
  • Type I collagen is the most common, thick bundle, very strong (ie. Scar, tendon, bone)
  • Type II collagen is thin, growth plate
  • Type III collagen is thin, supple, elastic (skin/wound healing); it is present in children.
• During Repair: Type III collagen is secreted in large amounts
  • It is degraded and replaced by Type I during maturation
  • Fibronectin forms a scaffold for repair and is an early stabilizer of healing tissue.
  • It helps fibrin form a clot and attracts fibroblasts and macrophages to healing tissue.
• Proteoglycans & Elastin are secreted by fibroblasts, bind to fibronectin and collagen, and hydrate tissue.

Factors Affecting Tissue Healing

• Factors impacting tissue healing include age, co-morbidities, medications, infection, activity level, local blood supply, nutrition, smoking, stress, and exercise.

Causes of Tissue Damage

• Repetitive pathologic movement
• Overuse
• Trauma
• Surgery

Stages of Tissue Healing

• Hemostasis & Degeneration
• Inflammation
• Proliferation & Migration
• Maturation/Remodeling

Hemostasis & Degeneration

• This stage occurs immediately post injury up to 24 hours.
• This limits blood loss by closing off the affected area.
• Damage impacts the endothelial cells of vessels and activates a cascade of coagulation pathways.
• Platelets
  • Adhere to the subendothelial layer to for a clot.
  • They release growth factors to summon inflammatory cells.

Plasma Protein Systems.

• Blood Coagulation forms a clot to stop bleeding and prevents the spread of infection.
  • Thrombin activates additional platelets, strengthening the clot. Fibrin increases the tensile strength of the clot.
  • The Intrinsic pathway is for endothelial injury.
  • Extrinsic pathways are for tissue injury.
  • Hageman Factor XII becomes prothrombin, then is thrombin.
  • Fibrinogen becomes Fibrin, creating a clot.
• Fibrinolytic System
  • It lyses the blood clot via Plasmin
• Kinin Enzymatic System
  • This system produces Bradykinin.
  • Bradykinin causes vasodilation and induces pain.
• Complement System
  • This system promotes:
    • Vasodilation.
    • Chemotaxis of leukocytes.
    • Opsonization of microbes.
    • MAC

Inflammation

• This occurs up to 5 days post injury.
• It clears the wound site of foreign bodies & harmful substances like leukocytes and plasma proteins. It summons cells that will form new tissue:
• Fibroblasts
• Epithelial cells
• Vascular endothelial cells

Vascular Response

• An increase in local vasodilation.
• There's increased capillary permeability
• Exudation
  • Plasma proteins and WBCs move from the intravascular space to the site of injury.

Inflammatory Response

• Leukocytes
  • Margination, WBCs attach to endothelial cells of blood vessels.
  • Diapedesis
    • WBCs move from the intravascular space to the interstitial space.
  • Chemotaxis
  • Follow the injury.
• Diagnostic of inflammation

Role of Leukocytes

• Neutrophils perform phagocytization and digest bacteria.
  • They release enzymes to break down ECM of damaged tissue.
  • They can also effect production of new ECM
• Neutrophils undergo apoptosis and are ingested by Macrophages.
• These stimulates a the release of anti-inflammatory mediators.
• Monocytes/Macrophages arrive 72 hours after injury.
• This Shifts phenotypic expression of Macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory)
• This promotes Angiogenesis, Scar Formation, and Matrix Production

Proliferation & Migration

• Tissue Repair Phase
  • Days 4-21.
  • A fibrin clot is then replaced with disorganized ECM
• Fibroblasts are attracted to the area.
  • They are stimulated by growth factors like
    • Platelet-Derived Growth Factor (PDGF),
    • Transforming Growth Factor Beta (TGF-B),
    • Fibroblast Growth Factor (FGF),
    • Insulin-like Growth Factor-1
  • Fibroblasts synthesize Type III collagen.
  • They create a temporary scaffold for tissue repair (Fibroplasia) with Fibrin
• Platelets are critical for angiogenesis.
• Alpha granules release PDGF and Vascular Endothelial Growth Factor (VEGF) during the inflammatory phase.
  • They Interact with local endothelial cells to form new vessels around the injury
  • They provide nutrient supply to the tissue

Granulation Tissue

• This involves the process of Granulation consisting of fibroblasts and new blood vessels within disorganized ECM
• Fibroblasts convert to myofibroblasts, causing contractile characteristics, and draw edges of wound closer together The end result is scar.

Maturation & Remodeling

• This phase lasts for 21 days up to 1-2 years.
• Scar matures.
• Type I collagen is a major extracellular component Well organized with parallel fiber orientation.
• Mechanical strength of scar increases.
  • Increased collagen diameter and cross-linking

Results

Results of Tissue Healing:

• Repair Scarring occurs and restores structural integrity.
• However mechanical and physiological tissue properties are impaired vs. pre-injury levels, with Final structures at 80% of pre-injury strength at best

Regeneration

• Tissue is restored to a pre-injury state with a result of new cells

Rehabilitation Considerations, Inflammatory and Acute Stage

• Protection
• Elevation
• Avoid Anti-Inflammatories and Avoid stretch
• Compression
• Education
• Control edema and Minimumize pain Promote PROM of involved tissue
• Grade I/ll mobilizations
• Promote AROM of surrounding tissues
• Introduce sub-max isometrics

Rehabilitation Considerations, Proliferation, Subacute Stage

• Stress the tissue to help influence collagen alignment and prevent scar contracture. Promote AROM of involved tissue.
• Grade III/IV mobilizations
• Stretching.
• Sub-max isometrics
• Introduce resistance
• Neuromuscular re-education

Rehabilitation Considerations, Maturation of Chronic Stage

• The main Goal is a return to full function.

• Regain full, pain-free motion

• Promote Grade III and IV mobilizations. Stretching and Progress resistance training. Support sports or occupation specific training.

• Perform agility exercises and Plyometrics.

Skeletal Muscle Repair

• Tissue Repair and injury can result from intrinsic or extrinsic forces.
• Intrinsic forces come from Strain.
• Extrinsic forces come from contusion or laceration.
• Overall there is excellent healing potential, but this can be hampered by re-injury of fibrosis.

Fibrosis

• Excess ECM material at the site of repair. Continued myofibroblast activity due to prolonged inflammation and a continued release of cytokines.
• Disorganized collagen is continually deposited. Causes Altereations biomechanical qualities of muscle and limits regeneration. Can occur with re-injury, prolonged immobilization, and excess force production. Can be limited by graded mobilization of the muscle

Soft Tissue Injury Classification:

• Grade l- Little to no structural damage with minimal swelling and pain

  • There's some minor or no loss of function. Treat with conservative care. Edema on imaging.

• Grade ll- Structural tearing of ≤50% of fibers, with moderate swelling and hemorrhage

  • There's difficult muscle contraction. Promote conservative are and use Surgery. This can result in issues with Edema on imaging

• Grade lll and Defect is a 100% structural tear with or without retraction and major swelling and major hemorrhage.

  • Unable to contract. A surgical intervention is necessary.

• There is a potential for regeneration due to Satellite Cells. Repair occurs with connective tissue in the form of a scar.

  • A scar initially weak and there'sa higher higher chance of reinjury. and strengthens around 2 weeks.
  • Carefully guided motion is necessary to optimize healing and tissue alignment.

• Myofibers will connect to scar as well.

Rhabdomyolysis

• This is a severe, rapid breakdown of muscle cells with a release of contents into circulation .
• S ymptoms Muscle pain and weakness. Dark urine (cola colored due to proteins) Dehydration resulting in renal failure plus Arhythmia due to high levels of potassium in the blood. Lab values will show blood in the urine and will require lV fluids and likely dialysis

Tendon/Ligament Repair:

• This is the result of Desne bands of fibrous connective tissue, primarily Type I collagen, this sustsins high levels of tensile loads transferring forces providing flexible support under significant deformation.. With that said the MOl (Rapid Force) can be dervied from a oblique direction
• Low in vascularity promoting the healing process via facilitation of healing and a slower healing process.

Tendon Injuries

• Ruptures involving a macroscopic failure from forces exceeding physiologic capacity in an often rapid force and oblique direction.
• Lacerations are often involved in wrist or hand injuries .
• Tendinopthy can can occur.

Tendon Tissue Repair:

• Three phases exist.
• Stage 1: Hemostasis, immediate through 72 hours. Hematoma is the primary symptom, resulting in fibrin and fibronectin forming cross links with collagen. Resulting in localized edema.
• Inflammatory Proliferative is the second phase, lasting 2 to 3 week,s and contains granulation tissue for fibroblasts and Tenocytes.
• Type lll is a thick collagen with disorganized immature bundles. These need. immobilzation to prevent reinjury (2 weeks)
• Stage 3: Maturation 3 weeks. , Type lll is replaced by Type 1 collagen. It's important to limit stress to the tendon for 12 to 16 weeks.

Chronic Type of Tendinopathy

• Disordeded with disoredered helaing resulting with generation of tissue and accumulation of macrophages. Includes Collagen: with degeneration and necrosis.
• lIrregular in the collagens orientiation. Resulting in Neovascularization There will be increased ground subtances.

Ligament Repair:

Sprain or Tears can contribute to laxitity. Extra-articular ligaments repair to be similar to a tendon taking 3 years.. Limited blood supply results in in poor chance of non-surgical repair.

• The synovial sheath ruptures with blood that travels without hamatomas leading to re-modelign and collagen synthsizing.

Cartlage Repair

Avacular with alympahtic capabilities and anural with Receives nutrition through diffusion of synovial fluid. and Poor healing capabilities, can occur with

• Articular surfaces
• Fibrocatilage- tendon or lignment insertion.
• Elastic- earlobe

Explore key concepts of inflammation, tissue repair, and factors influencing healing. Questions cover histamine, leukotrienes, collagen organization, and rehabilitation stages. Test your knowledge of tissue injury grades and healing.