Tissue Response to Bone Injury

tissue repair

a healing response to injury which forms an alternative tissue to restore function of a specific tissue

• scar tissue

• fibrosis

tissue regeneration

healing response leads to restoration of damaged tissue cells
■ Muscle healing
■ “angiogenesis”
■ Bone healing

three broad groups for tissue healing

– The Inflammatory Phase
– The Proliferation/Matrix Deposition Phase
– The Remodeling Phase

the inflammatory phase

– Occurs immediately after acute injury
– Causes pain and bleeding
■ Bleeding can be minimal
■ Do not to think of massive hemorrhaging
– Hemostasis creates fibrin clot to stop bleeding
■ Provides provisional matrix for migratory cells

– Blood clotting results in the release of pro-inflammatory molecules
■ Cytokines, growth factors
– These cells are chemotactic for WBCs , specifically neutrophils to enter the fray
– This cascade also promotes tissue mesenchymal stem cells (MSCs), and fibroblasts to proliferate and localize to the area of injury

the matrix deposition/proliferation phase

– After fibrin clot consolidates collagen will be deposited at injury site
– These deposition cells act as a bridge for local tissue to adhere to
■ Assists with local MSC differentiation
■ Orthobiologics!!!

– The early matrix deposited can have functional consequences
■ Irregular organization of cells/collagen can lead to structural and functional issue if the injury is severe enough
■ Rapid vascularization in a tissue that does not usually have abundant vascularity can lead to changes in surrounding tissue expanding outside the zone of injury
– ie: meniscus, ligaments

the remodeling phase

– SLOW process
■ Injured tissue undergoes changes in vascularity, gene expression, innervation, etc
■ Reorganization of collagen fibrils occurs over a long period of time (up to a year)
■ Initially deposited material appears to be replaced by more organized tissue that more closely resembles native tissue
– For instance: They do tend to reorganize along the long axis of the ligament
■ Injured soft tissue will never look microscopically like native healthy tissue
– But the goal is that functionally there is not a deficit
– As long as no function deficit the outcome is acceptable

skin response to injury

– Opposite of ligament healing
– New and remodeling tissue overlaps in a ”basket weave” fashion
■ This provides extra strength in multiple directions

ligament response to injury

– Not all ligaments are created equal
– Various environmental and mechanical factors influence their response to injury and healing
■ ie: MCL vs ACL healing
– Environmental factors:
■ Intra-articular (ACL)

■ Intra-articular environment without supporting soft tissue vascular supply to allow healing
■ Even partial injuries to ACL will likely not heal
■ Presence of synovial fluid also reduce the ability for intra-articular structures to heal
– Fluid becomes a barrier to new blood vessel and scar tissue formation
– Scar cannot bridge the tissue because fluid is in the way
■ Extra-articular (MCL)

■ Extra articular environment with ample surrounding microvasculature to facilitate
healing
■ Even complete transections of MCL can heal well functionally

factors that affect healing

• age (declines in inflammatory response mechanisms)

• comorbidities (diabetes, cardiovascular, etc) (latrogenic - caused by treatment)

connective tissue (collagen)

• a family of proteins containing a TRIPLE helix of peptides

• 5 types

• formed initially in endoplasmic reticulum then enters extracellular space where it is strengthened

Types of Collagen

• type 1 - bone, tendon, skin

• type 2 - cartilage, nucleus propulsus

• type 3 - blood vessels

• type 4 - basement membranes

• type 5 - minor component of bone

connective tissue (proteoglycans)

– Macromolecules that form the intracellular matrix of hyaline cartilage
– Proteins attach to glycosaminoglycans to form proteoglycans
– Proteoglycans combine with hyaluronic acid and then water to form a very elastic structure
■ Cartilage important to have this elasticity for lining joint surfaces
– Defects in the formation of proteoglycans can lead to a number of disease states

connective tissue (muscle)

– Derived from myoblasts
– Muscle fiber is a single cell
■ Made from many myofibrils
■ Smallest contractile unit
– Healing leads to regeneration of muscle tissue – Not fibrous scar tissue

muscle soreness

• caused by edema and inflammation in the connective tissue

• neutrophils are the most abundant cells early on after acute injury

• peaks at 24-48hrs

muscle strain

• occur at myotendinous junction (off during eccentric contraction which produces highest forces in skeletal muscle)

muscle atrophy

• caused by disuse or nerve injury

• leads to fatty infiltration and increased fatigability

• muscles crossing a single joint atrophy faster

• loss of cross-sectional area leads to decreased force generation

muscle injury

– Grade 1 – mild microscopic injury
– Grade 2 – partial muscle injury
■ Macroscopic injury with hematoma, temporary loss of contractile units
– Complete rupture of muscle belly
■ Muscle cannot contract
■ Treatment can be surgical unlike grades 1&2

intramembranous ossification

• osteoblast differentiate from mesenchyme and form bone directly

endochondral ossification

• During the 6th gestational week mesenchyme differentiates into chondrocytes

• These chondrocytes then group together and form the preliminary skeleton

• The chondrocytes mature, then hypertrophy and calcify, turning to bone

• In the 7th gestational week the periosteal sleeve forms over these bone

primary ossification centers start in the ________ of long bones

diaphysis

periosteum

– This is a soft tissue that surrounds bone in the developing skeleton
– It is osteogenic and helps promote appositional bone growth (growth from either end of the primary ossification center)
■ This capability allows for rapid fracture healing in young children
– “kids can heal anything”
– It is very thick in young patients and adds structure and stability to young bones

woven bone

■ Formed during the fetal period and has more collagen and flexibility than lamellar bone
■ Makes up the metaphysis of growing bones
■ Makes up the “callus” of healing fractures
■ Need flexibility for passage in birth canal

lamellar bone

■ Replaces woven bone soon after birth
■ By age 4 most woven bone has transitioned to lamellar bone

bone growth

– Cortical (outer layer) of bone increases during childhood
– Increasing thickness and lamellar structure of bone and higher proportion of calcium increase strength but reduce flexibility
– These changes are important in understanding different types of fractures/fracture patterns throughout life

closed fracture

the skin over the fracture site is intact

open fracture

If bone fragment or skin injury communicates to fracture site

fracture healing phases

inflammation, proliferation and remodeling

stage one of healing bone fracture

■ Inflammation (Week 1)
– Hematoma forms and provides a source of hematopoietic cells capable of secreting growth factors
– Fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around
fracture ends
– Osteoblasts and fibroblasts proliferate
■ Osteoblasts - bone making cells

stage two of healing bone fracture

■ Proliferation/Repair (Weeks 2-3)
■ Primary callus forms within two weeks. If the bone ends are not touching, then bridging soft callus forms.
– The mechanical environment drives differentiation of either osteoblastic (stable environment) or chondrocytic (unstable environment)
– Endochondral ossification converts soft callus to hard callus (woven bone)
– Medullary callus also supplements the bridging soft callus
– Cytokines drive chondrocytic differentiation
– Cartilage production provides provisional stabilization
■ Type II collagen (cartilage) is produced early in fracture healing and then followed by type I collagen (bone) expression
– Amount of callus is inversely proportional to extent of immobilization
• Endochondral healing with periosteal bridging occurs with closed treatment

stage three of healing bone fracture

■ Remodeling (Weeks 4-12)
– Begins in middle of repair phase and continues long after clinical union
• Chondrocytes undergo terminal differentiation
■ Wolff's law: bone remodels in response to mechanical stress
– Similar response scar tissue has as we discussed before

primary healing

– Apposition of injured tissue can heal side to side
– A laceration or incision repair by sutures

secondary healing

– Large gap or missing tissue
– Heals more slowly by granulation tissue and fibrin filling defect and remodeling more slowly over time