INJURY, INFLAMMATION �& HEALING

[Insert Name]

PTA Instructor

[Insert office phone number]

[Insert email address]

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INJURY, INFLAMMATION, & HEALING

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Objectives

• Distinguish theories & pathologic processes associated with aging, & how PT can affect outcomes
• Delineate mechanisms of cell injury & how the body reacts
• Distinguish the reversible & irreversible mechanisms of cell injury
• Explain the process for specific phases of healing, inflammation & tissue repair

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INJURY, INFLAMMATION, & HEALING

Objectives

• Recognize an inflammation response from cell injury & tissue healing restores homeostasis
• Recognize the principles of tissue healing
• Distinguish the differences between anatomic structures

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INJURY, INFLAMMATION, & HEALING

Key Terms

• Age associated cell damage
• Wear & tear
• Free radical
• Telomere aging
• Ischemia
• Comorbidities
• Contracture
• Effusion
• Exudate

INJURY, INFLAMMATION, & HEALING

Key Terms

• Hypertrophy
• Metaplasia
• Senescence
• Tetany
• Sepsis
• SAID principle
• Virus & methods of killing cells
• Homeostasis
• Reversible/Irreversible cell injury

INJURY, INFLAMMATION, & HEALING

Key Terms

• Components of tissue healing
• Factors influencing healing
• Phases of healing
• Hemostasis & degeneration
• Inflammation
• Proliferation & migration
• Remodeling & maturation
• Inflammatory Exudates

INJURY, INFLAMMATION, & HEALING

Key Terms

• Wallerian degeneration
• Skeletal muscle
• Tendon
• Ligament
• Articular & fibrocartilage
• Intervertebral disk
• Articular cartilage
• Fibrocartilage

INJURY, INFLAMMATION, & HEALING

Clinical Application

• You have a patient who is 4 weeks s/p rotator cuff repair.
• Is it safe to:
• Stretch?
• Do active exercises?
• Do resistive exercises?
• Why?

(A Guide To Rotator Cuff Surgery, 2022)

INJURY, INFLAMMATION, & HEALING

CELL INJURY

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CELL INJURY

Telomere

Normal Cell

Aging Cell

(Ehrenberg, 2015)

Aging: Pathological Changes

• Reduced functional reserve
• Reduction caused by atrophy of tissues/organs
• Atherosclerosis result in ⭡ CV and cerebrovascular injuries or death
• Decline in resistance to infection

CELL INJURY

Aging: Pathological Changes

• Can PT interventions make improvements in these declines?
• Have any effect?
• What would you include in a program?
• How would you monitor progress?
• Factors: nutritional; physical; mechanical; chemical; psychosocial

CELL INJURY

Mechanisms of Cell Tissue Injury

• Each leads to reversible/irreversible injury
• Ischemia
• Decreased blood flow
• Reduced O₂/nutrient delivery, waste removal🡪 decreased APT & increase fluid in cell

CELL INJURY

Mechanisms of Cell Tissue Injury

• Infectious agents
• Tetany
• Sepsis
• When chemicals released into bloodstream to fight infection trigger inflammatory response
• Immune reactions
• System usually defensive
• Has ability to increase metabolic output

CELL INJURY

Mechanisms of Cell Tissue Injury

• Factors
• Genetic alterations
• Nutritional factors
• Physical factors
• Mechanical factors
• Chemical factors

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CELL INJURY

(Pye, 2012)

CELL INJURY

Viruses

• Kill cells by 2 methods
• Complete redirection of cells
• Biosynthesis towards viral replication
• Direct cytopathic effect
• RNA-kills from within
• Disturbs cellular processes
• Indirect cytopathic effect
• DNA-type viruses
• Integrate into genome

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CELL INJURY

Risk Factors: Vitamin C Deficiency

• Inadequate food intake
• Malabsorption syndromes
• Physical injury/emotional stress
• Moderate-severe
• Pregnancy & lactation
• Tobacco products
• Obesity
• Alcoholism

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CELL INJURY

Risk Factors: Vitamin C Deficiency

• Rheumatoid arthritis
• Kidney dialysis
• Diabetes mellitus
• Oral contraceptives
• Drugs/medication
• IE: salicylates; corticosteroids; tetracycline

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CELL INJURY

Free Radicals: Oxidative Process & Formation

• O₂ atoms lose of four paired electrons
• Unstable atom “steals” electron from healthy cell
• Creates another unstable atom (free radical)
• Sets off chain reaction (oxidation)

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CELL INJURY

Free Radicals

• Integral part of metabolism
• Can exert positive or negative effects
• Help fight inflammation, kill bacteria, regulate ANS
• In excess - damage cells
• Degenerative conditions
• Free radical toxicity causes degeneration of neurons in substantia nigra
• Endogenous vs. exogenous antioxidant

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(Shelat, 2018)

CELL INJURY

Reversible Cell Injury

• Adaptation
• Extent which cell can alter mechanisms and regain homeostasis
• Atrophy
• Hypertrophy
• Hyperplasia
• Increased # of cells in tissue

(Hoffmann, 2018)

CELL INJURY

Reversible Cell Injury

• Adaptation
• Dysplasia
• Increased # of cells with �altered/loss of cell organization
• Metaplasia
• First level of dysplasia
• Storage or accumulations
• Increases in lipids, proteins, carbohydrates or pigment in cell from overload of metabolites/exogenous material

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CELL INJURY

Irreversible Cell Injury

• Injury of sufficient magnitude/duration
• Cell unable to adapt
• Necrosis
• Active process-degradation of dead cells
• Types: coagulative; caseous; Liquefactive: fatty necrosis; Fibrinoid

(Cell Injury, 2022)

CELL INJURY

Irreversible Cell Injury

• Necrosis
• Once in blood stream: measured with blood tests
• Aspartate aminotranserase, creatine kinase, lacatate dehdrogenase elevated in blood serum with MI/viral hepatitis

CELL INJURY

Irreversible Cell Injury

• Calcification
• Dystrophic calcification
• Deposition of Ca salts in damaged tissue
• Metastatic calcification
• Hypercalcemia (increased blood Ca levels) in living tissue. (HO)

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(IP Lab, 2020)

CELL INJURY

Coagulative Necrosis

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CELL INJURY

Lung: Caseous Necrosis

(Cell Injury, 2022)

CELL INJURY

Histology

Extensive Appearance

Initial Appearance

Brain Tissue: Liquefactive Necrosis

(Kendall, 2022)

CELL INJURY

Fat Necrosis

(Cell Injury, 2022)

CELL INJURY

Fibrinoid Necrosis

• Limited to small muscular arteries, arterioles, venules, & glomerular capillaries
• In connective tissue disease
• Immune vasculitis
• Malignant hypertension

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(Vasculitis, 2022)

CELL INJURY

Pathogenesis: Myocardial Infarction

• Reduced coronary artery blood flow (CABF) - Ischemia
• Coronary artery bursts – not clogged
• Irreversible cell injury
• Intracellular enzymes released from dead heart tissue
• S&S – angina – SOB – sweating, nausea

CELL INJURY

Pathogenesis: Myocardial Infarction

• Electrocardiogram = ST segment elevation
• Cytoplasmic enzymes released from dead cells CK
• PTA understands the healing of the tissue

CELL INJURY

ST Elevation: Myocardial Infarction

CELL INJURY

CELL INJURY

“The doctor wants me to run a few more blood tests.”

Components

• Fibronectin
• Structural support to stabilize healing tissue
• Binds to & stabilizes fibrin->blood clots
• Attracts fibroblasts + macrophages

CELL INJURY

(Crampton, 2022)

Components

• Proteoglycans and elastin
• Secreted by fibroblasts
• Retain water->hydration of tissue for healing
• Organize collagen

CELL INJURY

(Crampton, 2022)

Components

• Collagen – structural support and tensile strength
• Type 1 – most common, mature scars
• Type 2 – cartilaginous tissues
• Type 3 – fresh scars, newborns
• Type 4 – basement membranes
• Types 5 through 27 reviewed in Table 3.2

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CELL INJURY

Structure of Collagen

• Physical
• Collagen fiber
• Fibrils
• Polypeptide chains that wrap around one another in a triple helix

CELL INJURY

Ehlers-Danlos

Osteogenesis Imperfect�(The Editors of Encyclopedia Britannica, 2019)

CELL INJURY

HEALING

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Factors Influencing Healing

• Physiologic variables - growth factors vascular supply
• General health of individual
• Presence of co-morbidities
• Tobacco, alcohol, caffeine
• Nutrition
• Local or systemic infection; immune system

HEALING

Factors Influencing Healing

• Type of tissue
• Medical treatment
• Ability or willingness to follow a Plan of Care

HEALING

HEALING

Phases of Healing

• Hemostasis and degeneration
• Inflammation
• Proliferation and migration
• Remodeling and maturation

HEALING

(Maynard, 2019)

Hemostasis & Degeneration

• Hemostasis phase
• First step after tissue injury
• Blood fills gap & coagulation cascade begins
• Platelets release chemical messengers (growth factors)->inflammatory cells arrive
• Migration of epithelial cells, fibroblasts, vascular endothelial cells
• Differentiation of cells
• There is overlapping of stages

HEALING

Hemostasis & Degeneration

• Degeneration phase
• Formation of a hematoma
• Necrosis of dead cell
• Start of the inflammatory cell response.

HEALING

Overview

• Inflammation plays a vital role in healing
• Replace injured tissue with regenerated tissue, a fibrous scar, or both
• Begins as soon as the blood clot forms
• Leukocytes & macrophages get to the site – fight infection
• Growth factors, cytokines & chemokines are bioregulators – directs the process
• After 5 days the granular tissue starts to move in (tissue not strong)

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HEALING

Inflammation

• Acute – 4 cardinal signs
• Redness
• Swelling
• Increased temp
• Pain
• Pressure from edema on peripheral nerves

HEALING

Inflammation

• Chronic
• Persists, does not resolve
• Hallmark: accumulation of macrophages, lymphocytes & plasma cells.
• Assists with healing but not full restoration

HEALING

Inflammation

• Inflammatory reaction:
• Vascular alterations – redness and warmth.
• Fluid transudates from blood vessels and accumulates in anatomic space 🡪effusions
• Leukocyte accumulations
• Actively engaged in the destruction/neutralization of invading microorganisms
• Chemical mediators
• Lymphatic system for removal of waste products

HEALING

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Inflammatory Exudates (Table 3-4)

HEALING

HEALING

Wound Examples

HEALING

Wound Examples

Proliferation & Migration

• Neovascularization/Angiogenesis
• Formation of new blood vessels
• Endothelial cells
• Bring in oxygen & nutrients

HEALING

Proliferation & Migration

• Granulation tissue- visible to naked eye
• Endothelial cells & fibroblasts
• Fibroblasts synthesize new collagen, elastin, & proteoglycan
• Begin to fill in gaps
• Referred to as islands

HEALING

Remodeling & Maturation

• Contraction
• Normal process
• Approximates margins of healing tissue
• Contracture
• Undesirable
• Excessive shrinkage of healing tissue

HEALING

Remodeling & Maturation

• Regeneration
• Replacement of dead parenchymal cells �by new cells
• Original matrix is thick, but weak
• Restores normal tissue structure & function
• Thinner, but stronger tissue
• Chronic wounds
• Remain in inflammatory & �proliferative phases

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HEALING

Healing Formation of Scar Tissue

• A. Primary union
• Small scar
• B. Secondary union
• Bigger scar
• C. Infections
• Large wound
• Scarring

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HEALING

(Jorno, 2014)

HEALING

Specific Tissue/Organ Repair

• Depends on type of cell, ability to divide, type of damage incurred, & other factors
• Lung
• Digestive tract
• Peripheral nerves
• Skeletal muscle
• Bone

HEALING

Specific Tissue/Organ Repair

• Depends on type of cell, ability to divide, type of damage incurred, & other factors
• Tendon
• Ligament
• Cartilage
• Synovial membrane
• Disc

HEALING

Lung & Digestive Tract

• Lung
• Regeneration only occurs if basement membranes are intact
• If scar tissue formation, can lead to restrictive lung disease

HEALING

Lung & Digestive Tract

• Digestive Tract
• Villi
• Nutrient absorption & digestive enzyme production
• Healthy gut needed for healty immune system & serotonin function
• Normal 100% turnover of cells: �3-4 weeks
• Moderately impaired gut: 3-6 months to heal; 12-18 months for repair

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HEALING

Basement Membrane

• Basal lamina
• From epithelial cells
• Collagen fibers
• Reticular lamina
• Secreted by connective tissue cells
• Reticular fibers
• Holds cells to connective tissue
• Guide for cell migration during development

(Geary, 2022)

HEALING

Intestinal Villi

HEALING

Lungs: Exposure

HEALING

Peripheral Nerves

• Cut nerve - peripheral portion undergoes myelin degeneration & axonal fragmentation.
• Wallerian degeneration:
• Lipid debris removed by macrophages mobilized from surrounding tissues.

HEALING

(Knight, 2010)

Peripheral Nerves

• Microsurgical approximation:
• Careful microsurgical approximation of nerve may result in re-innervation
• Most important factor: maintenance of the neurotubules where new axonal sprouts can pass

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HEALING

(Knight, 2010)

Nerve Fiber Regeneration

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HEALING

MUSCULAR SKELETAL ELEMENTS

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Skeletal Muscle

• Muscle injury
• Contusion
• Strain
• Laceration
• Muscle regeneration/repair
• Muscle can repair
• Structural integrity, functional capability

MUSCULAR SKELETAL ELEMENTS

Skeletal Muscle

• Muscle regeneration/repair
• If basement membrane disrupted: no place for satellite cells to multiply
• Heals by forming connective tissue scar
• Muscle stiffness
• Micro fibrinous adhesions
• Increased collagen fibers & crosslinks
• Less water content

MUSCULAR SKELETAL ELEMENTS

Skeletal Muscle

• Motor control & muscle inhibition
• Neurophysiologic adaptation to chronic pain
• Feed forward mechanisms
• Cortical plasticity
• Task specificity
• Therapy role in chronic pain management?

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MUSCULAR SKELETAL ELEMENTS

MUSCULAR SKELETAL ELEMENTS

MUSCULAR SKELETAL ELEMENTS

MUSCULAR SKELETAL ELEMENTS

Bone

• Type
• Cortical
• 80% of skeletal tissue
• Tough, outer layer that surrounds trabecular bone
• Cancellous (trabecular)
• Spongy, intermeshing thin plates in contact with bone marrow

MUSCULAR SKELETAL ELEMENTS

Bone

• Surfaces
• Periosteal (External)
• Endosteal (internal)
• Shape & Mass
• Mechanical loading
• Mineral homeostasis
• Injury & Disease

MUSCULAR SKELETAL ELEMENTS

Bone Tissue Repair

• Stages of healing:
• Hematoma formation/inflammatory phase
• Granulation tissue & fibrocartilage formation
• Soft callus replaced by bony callus
• Remodeling phase with complete restoration of medullary canal

MUSCULAR SKELETAL ELEMENTS

Tendon Injury/Repair

• Viscoelastic characteristics
• 78% H₂O; 20% collagen; �2% glycosaminoglycan
• Handle large unidirectional forces
• Function of tendon
• Attach muscles to their osseous origins

MUSCULAR SKELETAL ELEMENTS

Tendon Injury/Repair: Healing

• Proliferation of tenoblasts
• Vascular ingrowth & proliferation of fibroblasts
• Adhesions are common
• Scar: weaker, larger, compromised biomechanical integrity
• Animal Studies: 12-16 weeks before tendon healing occurred
• Forced muscle contraction can re-tear surgical repair

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MUSCULAR SKELETAL ELEMENTS

Tendon Structure

GENETICS

MUSCULAR SKELETAL ELEMENTS

(Parmer, 2018)

Rotator Cuff Tear

MUSCULAR SKELETAL ELEMENTS

(Gayles, 2022)

(Patel & Amini, 2022)

Ligament Injury

• Viscoelastic characteristics
• Provide support to joints through bone-to-bone attachments
• Sprains & Tears
• Abnormal or excessive joint motion
• 1^st, 2^nd, 3^rd degree tears

MUSCULAR SKELETAL ELEMENTS

Ligament Injury

• Variations in healing (ex: ACL)
• After ligament ruptures, thin synovial sheath disrupted & blood dissipated
• Prevents clot & hematoma formation
• Joint effusion may take few hours
• Healing can’t take place without foundation for repair
• Surgery often indicated

MUSCULAR SKELETAL ELEMENTS

MUSCULAR SKELETAL ELEMENTS

(Hanft, 2014)

Stress & Strain

• How ligaments stretch

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MUSCULAR SKELETAL ELEMENTS

Torn ACL

MUSCULAR SKELETAL ELEMENTS

(Staff, 2020)

(ACL Injuries, 2022)

Cartilage Types

• Articular (“hyaline”)
• Aneural; avascular; alymphatic
• Does not regenerate well after adolescence
• Replaced with scar or a matrix
• Fibrocartilage (meniscus)
• Disperse compressive load

MUSCULAR SKELETAL ELEMENTS

Cartilage Types

• Annulus fibrosus
• Insertions of ligaments & tendons into bone
• Elastic
• Lig flavum
• External ear
• Epiglottis

MUSCULAR SKELETAL ELEMENTS

Menisci (Knee)

• Fibrocartilaginous structures
• Mainly collagen
• Circumferential orientation
• Heal by migration of cells from the synovial membrane
• Injury & degeneration leading to laceration

MUSCULAR SKELETAL ELEMENTS

Multiple zones make up the whole

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MUSCULAR SKELETAL ELEMENTS

Meniscus Tears

MUSCULAR SKELETAL ELEMENTS

(Meniscal Tears, 2022)

Synovial Membrane

• Lines inner surface of joint capsules & other intra-articular structures
• 2 layers
• Intimal (cellular/synoviocytes)
• Subintimal (supportive)
• 3 Functions
• Secretion of hyaluronate
• Phagocytosis of waste material
• Regulation of movement of solutes, electrolytes, proteins

MUSCULAR SKELETAL ELEMENTS

Synovial Membrane

• Acute injury
• Hemorrhage
• Hypertrophy
• Hyperplasia of cell lining in capsule
• Prolonged chronic synovitis (hemophilia)
• Joint immobilization
• Fibrous adhesions
• Progressive joint damage

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MUSCULAR SKELETAL ELEMENTS

MUSCULAR SKELETAL ELEMENTS

MUSCULAR SKELETAL ELEMENTS

Zones: Adult Human Lumbar Intervertebral Disc

MUSCULAR SKELETAL ELEMENTS

Functions of the Discs

• Held in place by the annulus
• Primarily type I collagen
• Fibers can disrupt-trauma; degenerative
• Normal blood supply to outer region
• Outer 1/3 innervated by the sinuvertebral nerve

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MUSCULAR SKELETAL ELEMENTS

Functions of the Discs

• Degeneration
• Nucleus loses ability to absorb water
• Disc becomes dehydrated
• Loss of ability to absorb shock
• Calcification of end plates
• Smoking speeds up the process

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MUSCULAR SKELETAL ELEMENTS

MUSCULAR SKELETAL ELEMENTS

Herniated Disc

MRI example

Spinal Anatomy�(Limited, 2022)

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Final Considerations

• Managing edema
• Prevention activities
• Rehabilitation post soft tissue injury
• Tendon or muscle rupture
• Muscle strain
• Ligament sprain
• Modalities

MUSCULAR SKELETAL ELEMENTS

Final Considerations

• Medications/comorbidities
• Immobilization
• Full motion always the goal?
• DVT
• Stiffness
• Low load sustained stretch principles
• Cartilage
• Biomaterials?

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MUSCULAR SKELETAL ELEMENTS

SUMMARY

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Objectives

• Distinguish the theories & pathologic processes associated with aging, and how physical therapy can affect patient outcomes
• Delineate the possible mechanisms of cell injury & how the body reacts
• Distinguish the reversible & irreversible mechanisms of cell injury
• Explain the process, including specific phases of healing, for inflammation & tissue repair

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INJURY, INFLAMMATION, & HEALING

Objectives

• Recognize that an inflammation response from cell injury & tissue healing occurs to restore homeostasis
• Recognize the principles of tissue healing
• Distinguish the differences between anatomic structures

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INJURY, INFLAMMATION, & HEALING

WORKS CITED

ACL Injuries. (n.d.). Atlanta Bone and Joint Specialists. Retrieved July 14, 2022, from https://www.atlantaboneandjoint.com/acltear.html

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Aghayev, K. (n.d.). Kamran Aghayev | Neurosurgeon | LUMBAR DISC HERNIATION. Kamranaghayev.com. Retrieved July 19, 2022, from https://kamranaghayev.com/page/lumbar-disc-herniation

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A Guide to Rotator Cuff Surgery. (n.d.). Town Center Orthopaedics. Retrieved July 8, 2022, from https://www.towncenterortho.com/blog/rotator-cuff-tear-surgery-video/

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Balfousias, T., Apostolopoulos, A. P., Angelis, S., Maris, S., & Papanikolaou, A. (2019). Spontaneous Knee Hemarthrosis Due to Hypofibrinogenemia Following Tigecycline Treatment for Periprosthetic Joint Infection. Cureus. https://doi.org/10.7759/cureus.5883

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Cell Injury. (n.d.). Webpath.med.utah.edu. Retrieved July 18, 2022, from https://webpath.med.utah.edu/CINJHTML/CINJ026.html

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Crampton, L. (2022, July 10). Fibronectin: A Cell Adhesion and Blood Clotting Protein. Owlcation. https://owlcation.com/stem/Fibronectin-A-Cell-Adhesion-and-Blood-Clotting-Protein

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Ehrenberg, R. (2015, May 20). DNA disorganization linked to aging. Science News. https://www.sciencenews.org/article/dna-disorganization-linked-aging

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Gayles, R. (n.d.). Rotator Cuff Tear - Nona Medical Arts | Shoulder Injury. Nona Medical Arts. Retrieved July 19, 2022, from https://www.nonamedicalarts.com/pain-conditions/rotator-cuff-tear/

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Geary, C. (n.d.). GoConqr - Unit 2 - Tissues. GoConqr. Retrieved July 19, 2022, from https://www.goconqr.com/mindmap/6180539/unit-2-tissues

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Hanft, A. (2014, January 20). A broken rubber band. Flickr. https://www.flickr.com/photos/foundphotography/12060410586

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Hoffman, H. (2018, March 13). Causes And Prevention Of Muscle Atrophy After Stroke. Saebo. https://www.saebo.com/blog/causes-prevention-muscle-atrophy-stroke/

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IPLab:Lab 2:Metastatic Calcification - Pathology Education Instructional Resource. (2020, June 19). Peir.path.uab.edu. https://peir.path.uab.edu/wiki/IPLab:Lab_2:Metastatic_Calcification

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Jorno, T. (2014, September 15). physical therapy billing software Archives - Page 10 of 14 - best PT Billing EHR & Practice Management Software. Bestptbilling.com. https://bestptbilling.com/tag/physical-therapy-billing-software/page/10/

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Kendall, T. (n.d.). Necrosis – Pathologia. Pathologica. Retrieved July 18, 2022, from https://pathologia.ed.ac.uk/topic/necrosis/

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WORKS CITED

Knight, J. (2010, July 30). Damaged Nerves In Hand - Treatment & Recovery. Hand and Wrist Institute. https://handandwristinstitute.com/nerve-injuries-hand/

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LIBRARY, J. C. P. (n.d.). Macro section of a normal human kidney - Stock Image - C038/3707. Science Photo Library. Retrieved July 18, 2022, from https://www.sciencephoto.com/media/908887/view/macro-section-of-a-normal-human-kidney

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Limited, A. (n.d.). Lumbar Vertebra and Nerves, illustration Stock Photo - Alamy. Www.alamy.com. Retrieved July 19, 2022, from https://www.alamy.com/lumbar-vertebra-and-nerves-illustration-image353193046.html

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Maynard, J. (2019, March 20). How Wounds Heal: The 4 Main Phases of Wound Healing. Shield HealthCare. http://www.shieldhealthcare.com/community/popular/2015/12/18/how-wounds-heal-the-4-main-phases-of-wound-healing/

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Meniscal Tears | Brisbane Knee and Shoulder Clinic | Dr Macgroarty. (n.d.). Brisbane Knee and Shoulder Clinic. Retrieved July 14, 2022, from https://kneeandshoulderclinic.com.au/knees/surgical-conditions/meniscal-tears/

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Osteoarthritis. (2016, November 3). Radiology Key. https://radiologykey.com/osteoarthritis-3/

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Parmar, K. (2018). Tendon and ligament: basic science, injury and repair. Orthopaedics and Trauma, 32(4), 241–244. https://doi.org/10.1016/j.mporth.2018.05.008

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Patel, M., & Amini, M. H. (2022). Management of Acute Rotator Cuff Tears. Orthopedic Clinics of North America, 53(1), 69–76. https://doi.org/10.1016/j.ocl.2021.08.003

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Pye, J. (2012, August 13). Runner without a country finishes marathon. San Diego Union-Tribune. https://www.sandiegouniontribune.com/sdut-runner-without-a-country-finishes-marathon-2012aug12-story.html

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Shelat, A. (2018). Substantia nigra and Parkinson disease: MedlinePlus Medical Encyclopedia Image. Medlineplus.gov. https://medlineplus.gov/ency/imagepages/19515.htm

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Staff, E. (2020, January 18). Why Are ACL Tears So Common? And How to Avoid Them. Medicalopedia. https://www.medicalopedia.org/8219/why-are-acl-tears-so-common-and-how-to-avoid-them/

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The Editors of Encyclopedia Britannica. (2019). Osteogenesis imperfecta | disease. In Encyclopædia Britannica. https://www.britannica.com/science/osteogenesis-imperfecta

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Vasculitis. (2022, June 17). Neuromuscular.wustl.edu. https://neuromuscular.wustl.edu/pathol/vascmedves.htm