Tissue Healing (DPT 581) Spring 2025 Lecture Notes PDF

Tissue Healing DPT 581: Medical Management I Spring 2025 At the conclusion of this lecture students will be able to: Describe the Physical Stress Theory & the body’s adaptive responses to stress Compare the effects of reversible vs irreversible cell injury, & cellular adaptations to stress...

Tissue Healing DPT 581: Medical Management I Spring 2025 At the conclusion of this lecture students will be able to: Describe the Physical Stress Theory & the body’s adaptive responses to stress Compare the effects of reversible vs irreversible cell injury, & cellular adaptations to stress Describe the stages of tissue healing Describe appropriate physical therapy interventions as they relate to stages of tissue healing Compare & contrast tissue healing times in muscle, tendon, ligament, & cartilage Apply concepts of tissue healing to develop interventions that optimize tissue healing & repair in the management of musculoskeletal conditions Pathology Structural or functional changes in the body caused by disease or trauma Tissue Cell Injury Inflammation Healing  Physical Stress Theory Atrophy Maintenance Hypertrophy Injury Death Trauma Cumulative Damage Mueller MJ, Maluf KS. Phys Ther. 2002; 82: 383-403.  Physical Stress Theory Exposure to stress is a composite of: Magnitude of force Time Direction of force Mueller MJ, Maluf KS. Phys Ther. 2002; 82: 383-403. Other Factors Influencing Response to Stress Age PMH Medications Activity level Obesity Nutrition Body mechanics How Does Stress Cause Injury? High-magnitude stress over a short duration Low-magnitude stress over a long duration Moderate-magnitude stress applied frequently How Does Cell Injury Occur in the Body? Infection Ischemia Immune response Genetic factors Nutritional factors Chemical factors Physical factors ○ Trauma ○ Temperature 2 Types of Cell Injury 1. Reversible Type of injury depends on: 2. Irreversible Mechanism Severity Timeline of intervention Reversible Cell Injury Sublethal- transient alteration Removal of stressor à return of normal structure or function Cell can adapt to chronic sublethal injury Acute Reversible Cell Injury ↑ intracellular Na, Ca Intracellular swelling ○ Cytosol ○ Mitochondria ○ Endoplasmic Reticulum Lowers pH of cell Removal of stressor à process reverses Chronic Sublethal Cell Injury Irreversible Cell Injury Lethal à Cell death Hallmarks: ○ Alterations in nucleus ○ Mitochondria ○ Lysosomes ○ Rupture of cell membrane ○ Necrosis Byproducts released into circulation ○ Can be measured with blood tests What is the Body’s Response to Cell Injury? Functions of the Inflammatory Response Inactivate cause of cell injury ○ Trauma, bacteria, toxins Break down and remove dead cells & debris Initiate tissue healing  Inflammatory Reaction Response dependent on: ○ Amount ○ Type Initiates healing response ○ Severity ○ Innate immune response (neutrophils, macrophages) ○ Pro-inflammatory mediators Cytokines- interleukins (IL), tumor necrosis factor (TNF), growth factors (GF) Acute vs Chronic Inflammation Acute Chronic Fast onset, short duration Prolonged duration Hallmarks: Hallmarks: ○ Edema from exudate ○ Accumulation of macrophages & lymphocytes ○ Erythema ○ Hypervascularity & fibrosis ○ Warm to touch ○ Tissue necrosis ○ Pain Causes of 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 Arachidonic Acid Derivatives ○ Stored in mast cells, basophils, & ○ Cyclooxygenase pathway: Prostaglandins platelets Increase platelet aggregation ○ Increase vascular permeability Mediate fever, pain ○ Vasodilator, bronchoconstrictor ○ Lipoxygenase pathway: Leukotrienes Platelet Activating Factor Increase vascular permeability ○ Derived from phospholipids of Chemotaxis of leukocytes to injury cell membrane Bronchoconstriction ○ Causes platelet aggregation & secretion ○ Medications: can block inflammatory responses ○ Increase leukocyte concentration Corticosteroids & other inflammatory mediators NSAIDs Chemical Mediators of Inflammation: Cytokines Interleukin-1 (IL-1) Produce local & systemic effects Tumor Necrosis Factor (TNF) Induce fever Produced by leukocytes Increase metabolism Hemodynamic changes See Box 6.2 in Goodman text Components of Tissue Healing Collagen- Most important structural support & tensile strength for all tissues ○ Organization: determine structural properties Tendons: parallel bundle Skin, bone: random ○ Types: I: most common, thick bundle, very strong (ie. Scar, tendon, bone) II: thin, growth plate III: thin, supple, elastic (skin/wound healing); children During Repair: Type III collagen is secreted in large amounts ○ Degraded & replaced by Type I during maturation Components of Tissue Healing Fibronectin- forms scaffold for repair, “glue” ○ Early stabilizer of healing tissue ○ Helps fibrin form clot ○ Chemotaxis for fibroblasts and macrophages to healing tissue Proteoglycans & Elastin ○ Secreted by fibroblasts ○ Bind to fibronectin and collagen ○ Hydrate tissue Factors Affecting Tissue Healing Age Local Blood Supply Co-morbidities Nutrition Medications Smoking Infection Stress Activity level Exercise Causes of Tissue Damage Repetitive pathologic movement ○ Overuse Trauma Surgery Stages of Tissue Healing 1. Hemostasis & Degeneration 2. Inflammation 3. Proliferation & Migration 4. Maturation/Remodeling Hemostasis & Degeneration Immediately post injury up to 24 hours Limits blood loss by closing off area ○ Damage to endothelial cells of vessels Activates cascade of coagulation pathways ○ Platelets Adhere to subendothelial layer of vessels- Form clot Release growth factors that summon inflammatory cells Plasma Protein Systems Blood Coagulation System ○ Forms clot- stops bleeding and prevents spread of infection ○ Thrombin- activates additional platelets- strengthens clot ○ Fibrin- increases tensile strength of clot Plasma Protein Systems Fibrinolytic System ○ Lyses blood clot via Plasmin Kinin Enzymatic System ○ Produces Bradykinin causes vasodilation, induces pain Complement System ○ Vasodilation ○ Chemotaxis of leukocytes ○ Opsonization of microbes ○ MAC Inflammation Up to 5 days post injury Clears wound site of foreign bodies & harmful substances ○ Leukocytes ○ Plasma proteins Summons cells that will form new tissue ○ Fibroblasts ○ Epithelial cells ○ Vascular endothelial cells Inflammation & Vascular Response Local vasodilation Increased capillary permeability Exudation: plasma proteins and WBCs move from intravascular space to injury site Inflammatory Response Leukocytes ○ Margination: WBC attach to endothelial cells of blood vessels ○ Diapedesis: WBC move from intravascular space to interstitial space ○ Chemotaxis: follow the injury ○ Diagnostic of inflammation Inflammation: Role of Leukocytes Neutrophils- initial immune cells Neutrophils undergo apoptosis and are ingested by Macrophages ○ Phagocytize debris, digest bacteria ○ Stimulates release of anti-inflammatory ○ Release enzymes that break down mediators ECM of damaged tissue ○ Shifts phenotypic expression of Can also effect production of new Macrophages from M1 (pro-inflammatory) ECM to M2 (anti-inflammatory) Monocytes/Macrophages- primary immune cells Promotes Angiogenesis, Scar Formation, and Matrix Production ○ Arrive 72 hours after injury Proliferation & Migration Tissue Repair Phase- Days 4-21 Fibrin clot replaced with disorganized ECM Fibroblasts attracted to area- stimulated by growth factors ○ Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor Beta (TGF-B), Fibroblast Growth Factor (FGF), Insulin-like Growth Factor-1 ○ Synthesize Type III collagen ○ With Fibrin forms temporary scaffold for tissue repair (Fibroplasia) Platelets- important for angiogenesis ○ Alpha granules release PDGF and Vascular Endothelial Growth Factor (VEGF) during inflammatory phase Interact with local endothelial cells to form new vessels around injury Provides nutrient supply to tissue Proliferation: Granulation Tissue Consists of fibroblasts and new blood vessels within disorganized ECM Fibroblasts convert to myofibroblasts ○ Contractile characteristics- draw edges of wound closer together End result is scar Maturation/Remodeling Day 21 up to 1-2 years Scar matures Type I collagen is major extracellular component ○ Well organized parallel fiber orientation Mechanical strength of scar increases ○ Increased collagen diameter and cross-linking  Results of Tissue Healing Repair Regeneration Scarring Tissue restored to pre-injury state Restores structural integrity Result of new cells Mechanical &/or physiological tissue properties impaired vs. pre- injury levels Final structure is never as strong as original tissue ○ 80% of pre-injury strength at best Rehabilitation Considerations: Inflammatory/Acute Stage Control edema Minimize pain PROM of involved tissue ○ Avoid stretch Grade I/II mobilizations AROM of surrounding tissues Introduce sub-max isometrics Dubois B, Esculier JF. Br J Sports Med. 2020;54:72-73. Rehabilitation Considerations: Proliferation/Subacute Stage Stress to tissue to influence collagen alignment Prevent scar contracture AROM of involved tissue Grade III/IV mobilizations Stretching Sub-max isometrics Introduce resistance Neuromuscular re-education Dubois B, Esculier JF. Br J Sports Med.2020;54:72-73. Rehabilitation Considerations: Maturation/Chronic Stage Goal is return to function Sport/occupation-specific tasks Regain full, pain-free motion Agility exercises Grade III/IV mobilizations Plyometrics Stretching Progress resistance training Tissue Repair Tissue Repair: Skeletal Muscle Injury can result from: ○ Intrinsic forces: Strain ○ Extrinsic forces: Contusion, Laceration Excellent healing potential Can be hampered by: ○ Re-injury ○ Fibrosis  Fibrosis Excess ECM material at site of repair Continued myofibroblast activity due to prolonged inflammation and continued release of cytokines Disorganized collagen continually deposited Alters biomechanical qualities of muscle & limits regeneration Can occur with re-injury, prolonged immobilization, excess force production Can be limited by graded mobilization of the muscle  Soft Tissue Injury Classification Grade I Grade II Grade III Little to no structural damage Structural tearing ≤50% of fibers 100% structural tear with/without retraction Minimal swelling, pain Moderate swelling, hemorrhage, pain Major swelling, hemorrhage, pain Min/No loss of function Muscle contraction difficult Unable to contract Conservative care Conservative care vs. Surgery Surgery Edema on imaging Possible defect or partial retraction on imaging Defect &/or retraction on imaging Muscle Retraction Tissue Repair: Skeletal Muscle Potential for regeneration due to Satellite Cells ○ Myogenous stem cells Repair occurs as well- connective tissue scar ○ Scar initially weak- chance of reinjury ○ Strengthens around 2 weeks Myofibers connect to scar Carefully guided motion necessary to optimize healing and tissue alignment Skeletal Muscle: Rhabdomyolysis Severe, rapid breakdown of Symptoms: muscle cells with release of ○ Muscle pain and weakness: mild to contents into circulation severe ○ Creatinephosphokinase ○ Tea or cola colored urine (proteins) ○ Myoglobin ○ Dehydration, renal failure Can lead to renal failure ○ Arrhythmia- high levels of K in blood Risk Factors: Dx: lab values, (+) blood in urine ○ Ephedra Tx: IV fluids, dialysis ○ High dose statins ○ High levels of strenuous exercise Tissue Repair: Tendon/Ligament Dense bands of fibrous connective tissue ○ Primarily Type I collagen Sustain high tensile loads, transfer forces, provide flexible support all without significant deformation MOI: rapid force in oblique direction OR degenerative changes Low vascularity ○ Allows function with low metabolic demand under normal conditions ○ Facilitates slower healing process Increased risk of adhesions due to healing via migration of fibroblasts from neighboring tissues Tendon Injuries Rupture ○ Macroscopic failure from forces exceeding physiologic capacity ○ Often rapid force in oblique direction https://www.youtube.com/watch?v=-kbzZbQR0IY Lacerations ○ Common in wrist and hand Tendinopathy ○ Often result of overuse/repeated stress Potential for non-surgical repair varies by location Tissue Repair: Tendon Hemostasis (immediately -72 hours): ○ Hematoma ○ Fibrin & fibronectin form cross links with collagen ○ Localized edema Inflammatory/Proliferative (2-3 weeks) ○ Granulation tissue from fibroblasts, tenocytes ○ Type III collagen, angiogenesis ○ 2 weeks: collagen thick, disorganized immature bundles BUT need immobilization to prevent reinjury Maturation (3 weeks) ○ Type III replaced by Type I collagen ○ Limit stress to tendon until 12-16 weeks; only 40-60% recovery Chronic Tendinopathy Disordered healing of tendon tissue that results in degeneration of tissue Accumulation of macrophages ○ Collagen degeneration and necrosis ○ Irregular collagen orientation ○ Neovascularization ○ Increased ground substance Tissue Repair: Ligament Sprains/tears near joint can contribute to laxity Extra-articular ligaments heal similar to tendon ○ Can take up to 3 years to achieve near-normal tensile strength Intra-articular (e.g. ACL) ○ Limited blood supply- poor chance of non-surgical repair ○ Synovial sheath ruptures and blood travels; no hematoma; no inflammatory response ○ Remodeling: collagen synthesis and degradation (months-years) but does not return to normal tissue ○ Net effect is decreased stability of joint Tissue Repair: Cartilage Composed of chondrocytes and ECM (proteoglycans and collagen) Types of Cartilage: ○ Articular (Hyaline)- joint surfaces ○ Fibrocartilage- tendon/ligament insertion, menisci, annulus fibrosis of IVD ○ Elastic- earlobe, trachea ○ Fibroelastic- meniscus Avascular, Alymphatic & Aneural ○ Receives nutrition through diffusion of synovial fluid ○ Poor healing capabilities