11- Tissue Repair & Regeneration

regeneration or repair

Process of tissue healing begins soon after tissue injury or death and occurs by either:

Regeneration

Regrowth of original tissue

Repair

Formation of a connective scar tissue

What affects tissue healing?

Components and factors

Components (building blocks)

-fibronectin
-proteoglycans
-elastin
-collagen

Factors (regulators)

-growth factors
-nutrition

Fibronectin

-An extracellular glycoprotein secreted by animal cells that helps them attach to the extracellular matrix.
-Tensile strength
-One of the 1st proteins to stabilize healing tissue
-Plasma proteins are first source for healing tissue

ACL reconstruction

a surgical procedure that uses a graft to replace a torn anterior cruciate ligament in the knee

Proteoglycans

-a glycoprotein consisting of a small core protein with many carbohydrate chains attached, found in the extracellular matrix of animal cells.
-binds to fibronectin and collagen to help stabilize repairing tissue
-retain water which can hydrate healing tissue
-contribute to stability of collagen

Elastin

-synthesized and secreted by fibroblasts
-protein that becomes cross-linked to form fibrils or sheets that provide elasticity to tissues

Williams syndrome

-reduced amounts of functional elastin
-Thickened arteries
-Changes in skin texture/elasticity
-Supraventricular valvular stenosis (SVAS)

Collagen

-Most important protein to provide structural protein to provide structural support and tensile strength for almost all tissues and organs of body
-Most abundant protein in the body
-"glue producer"

Type I collagen

-most common
-Thick bundle found in all body tissues
-Very strong: mature scars, tendon, bone

Type II collagen

-Thin, supporting filaments
-Predominant in cartilaginous tissue (hyaline cartilage)
-Not present in skin—outer ear, end of nose, external annulus

Type III collagen

-Thin filaments
-Strong, but supple and elastic
-Interchain disulfide bonds (not in I or II)
-First collagen deposited in wounds (granulation tissue)
-Highly soluble —> can turnover quickly
-Affords plasticity to vessels and skin
-Overexposure to sun can break down, leads to wrinkles

Type IV collagen

-Not assembled into fibers
-Forms basement membrane; base of epithelial, endothelial, mesenchymal cells in developing fetus
-Determines if tissues can be regenerated vs. repaired

What is TUBS?

Traumatic Unilateral dislocation with Bankart lesion requiring Surgery

What is AMBRI?

Atraumatic Multidirectional Bilateral (usually) Rehabilitation (first line) Inferior capsular shift (best operation choice)

What is the main collagen type making up the cartilage on the femoral condyles?

Hyaline cartilage; type II

Growth factors

-Proteins that regulate cell reactions involved in healing
-Cell proliferation, differentiation, migration
-Synthesis and degradation of proteins
-Angiogenesis
-Integrate inflammation with repair

Decreased growth factor =

Delayed healing and hypotrophic scar

Increased growth factor =

hypertrophic scar (keloid, burns)

Platelet-derived growth factor (PDGF)

stimulates division of smooth muscle cells and fibroblasts to rebuild blood vessel wall

Fibroblast Growth Factor (FGF)

Stimulates endothelial cells to form new blood vessels

Transforming growth factor-beta (TGF-beta)

Inhibits cell growth, inactivates macrophages

insulin-like growth factors (IGFs) increases _______

collagen synthesis

Platelet-Rich plasma is __________

Using blood plasma that has been enriched with platelets to stimulate healing of bone and soft tissue

Factors affecting tissue healing

Physiologic variables (e.g. age), overall health, comorbidities, substance use/abuse, nutrition, infection, type of tissue, medical Rx

How many proteins do you need for wound repair?

0.6-1.0 g/lb BW

What are the phases of healing?

-hemostasis/degeneration
-Inflammation
-proliferation and migration
-remodeling/maturation

hemostasis

-Occurs immediately after injury to stop bleeding
-Platelets clump to form loose clot
-Platelets release messengers including GF that summon inflammatory cells to wound

Degeneration

-Formation of hematoma
-Necrosis of dead cells
-Bridge from hemostasis to inflammation
-Repair begins within 24h of acute injury

Inflammation

-Response of vascularized tissue toward injury
1.) Inactive injurious agent (destroy/dilute/wall off)
2.) Break down and remove dead cells
3.) Initiate course of repair/healing

proliferation and migration phase

• Endothelial proliferation to form vascular network
  - angiogenesis starts at day 2

- Appearance of reddish layer - granulation tissue
- Removal of damaged tissue. Provisional matrix consists of fibrin and fibronectin
- New collagen, elastin and proteoglycan synthesized by fibroblasts - takes several weeks

Remodeling and maturation phase

-scar tissue is reduced and remodeled, can take up to several years
-Takes on natural skin tone
-Fibroblasts and capillaries undergo apoptosis

Parts of remodeling and maturation phase of wound healing

Tissue contraction and contracture, tissue regeneration, tissue repair

Tissue contraction and contracture

-Newly formed ECM draws together causing contraction of healing tissue
-Size of tissue defect decreases
-Some fibroblasts take on smooth muscle characteristics

Contracture

-Excessive tissue shrinkage
-Can cause disfigurement and impairment movement or organ function
-can lead to arthrofibrosis
-3-4 month window before surgical manipulation

Tissue regeneration

-Replacement of dead parenchymal cells by new cells
-Desirable as it restores normal tissue structure and function
-Can only occur if parenchymal cells undergo mitosis
-Not possible in permanent tissues (cardiac myocytes )
-Inflammatory response must be short-lived

Tissue repair

-Formation of connective tissue scar, requires removal of connective tissue matrix
-Structural integrity of parenchymal cells relies on formation of scar
-Minimizing the inflammatory reaction during closure is critical

Primary union (first intention) healing

Complete healing without granulation

Secondary intention healing

wound in which the tissue surfaces are not approximated and there is extensive tissue loss; formation of excessive granulation tissue and scarring

Tertiary intention healing

Delayed closure in contaminated wound that has filled with granulation tissue

Chronic wounds

-when a wound fails to heal normally re-epithelialization and closure do not occur
-remain in inflammatory and prolif

Type of cell and extent of damage

What does specific tissue/organ repair depend on?

Labile cells

-continuously dividing and can regenerate
-epithelium, bone marrow

Stable cells

-Normally do not divide but can with proper stimulus
-liver, skeletal muscle, kidney cells

Lung regeneration

-regen can occur when basement membrane remains intact
-adjacent epithelial cells migrate to basement membrane and differentiate into type II pneumocystis-regen can occur when basement membrane remains intact
-adjacent epithelial cells migrate to basement membrane and differentiate into type II pneumocystis
-Those cells can later differentiate into type I pneumocystis (gas exchange)
-If basement membrane is interrupted, repair must occur and can result in restrictive lung disease

Digestive tract regeneration

-villi that turns over every 3-4w
-mild to moderate injured 3-6mo to heal
-severe intestinal injury will take 12-18mo

Peripheral nerve regeneration

-distal portion undergoes rapid myelin degeneration and axonal fragmentation
-lipid debris removed by macrophages—Wallerian degeneration
-surgical approximation may result in reinnervation

Wallerian degeneration

degeneration of the distal portion of the axon and myelin sheath

Contusion

Compressive force or direct blow

Strain

-excessive tensile force
-leads to overstrain of myofiber
-more likely during ECC contraction
-2-joint muscles at high risk

Where is strain most common?

Myotendinous junction

Is tissue regeneration of skeletal muscle possible?

Yes, but depends on type of injury sustained

Severe infection

-Muscle fibers may be destroyed but basement membrane and endomysium remain intact
-Regen of muscle cells can occur

Muscle transection

-Muscle fibers may grow from undamaged stumps or from new independent fibers
-possible when basement membrane intact
-satellite cells serve as source of myoblast for fiber regen

Contused or strained muscle

-capable of self-repair, but process is slow and usually incomplete
-High rate of re-injury, loss of strength
-Follows same course of repair described previously

Bone repair

Hematoma formation, callus formation, callus ossification, bone remodeling

Phases of bone regeneration

Inflammatory phase, reparative phase, remodeling phase

Inflammatory phase of bone healing

-inflammatory cells arrive
-accompanied by vascular response and cellular proliferation
-pain, swelling, warmth
-clotting factors form a fibrin mesh work
-made up of fibroblasts and capillary buds b/w bony ends
-end of 1w: majority of hematoma cleared and initial fibrosis occurring

Reparative phase of bone healing

-fibrocartilaginous callus formation-vessels grow into hematoma and firbroblasts invade and produce collagen and develop chondroblasts and form fibrocartilagenous soft callus which repairs tissue bridging the edges of the break 3 weeks
-bony cartilage formation-areas with vascular bone tissue. Osteoblasts produce spongy trabeculae which joins the fragments and turns into a spongy bone- bony hard callus 3-4 months

Remodeling phase of bone

-Begins at clinical union and persists until bone returns to normal
-excessive callus removed
-bone remodels to imposed stress

Tendon regeneration

-may heal from proliferation of tenoblasts from cut ends of tendon or from vascular ingrowth and proliferation of fibroblasts derived from surrounding tissues injured at same time
-since surrounding tissues contribute to healing, adhesions are common
-surgical repair often needed

ligament regeneration after injury: begins at, healing ligament by 6 mon, 1 yr, 1-3 yr

-begins at 5 weeks post injury
-healing ligament is 50% its normal strength by 6 months
-80% by 1 year
-100% by 1-3 years

Cartilage Regeneration

-not good, limited, avascular
-without intervention, heals with fibrous scar or not at all
-does not function well and can affect adjacent tissues injured
-surgical options

debridement/chondroplasty

-least invasive surgical option
-similar rehab to meniscectomy

Fixation of unstable fragments

-Best option in OCD w/ open physics and >2cm
-May not heal in skeletally mature

Microfracture surgery

penetration of subchondral bone causes bleeding from underlying vessels which allows clot formation in the cartilaginous defect and subsequent formation of fibrocartilage

Osteochondral autograft transplant (OAT)

-Mosaicplasty
-Hyaline cartilage
-stable
-limited donor tissue
-limited WB x3mo

Osteochondral allograft

-Can address large defects
-grafts must be fresh
-slow healing

Autologous Chondrocyte Implantation (ACI)

Alternative to partial or total knee replacement when there is damage to articular cartilage

Meniscus repair

-more proteoglycans present in this injured tissue
-collagen fibers are circumferential IOT disperse compressive load, resist shear, aid in shock absorption
-Heal by migration of cells from synovium to meniscus
-remodeling events not well understood
-healing impeded based on location of tear, type of tear, and blood supply
-swelling, catching, locking often lead to surgical intervention

Meniscus surgery

-limited WB 2-6 weeks
-Limited flexion 6 weeks (90 deg limit)
-Can vary based on location of tear and type of tear
-6 months to maximize tissue healing