Book Reading Rockwood P584-588 R3 楊典育. Pathophysiology of Fracture Healing Bone heals : – Endochondral ossification : Callus – Direct osteonal healing.

Book Reading

Rockwood P584-588 R3 楊典育

Pathophysiology of Fracture Healing

• Bone heals :– Endochondral ossification : Callus – Direct osteonal healing

Stages of Fracture Healing

• Hematoma Formation• The Inflammatory Response:(first few weeks)• The Reparative Phase• Remodeling

The Inflammatory Response

• Osteoclasts remove necrotic bone• macrophages remove hematoma.• Interleukin-1 and 6• TGF-β• Platelet-derived growth factor

The Reparative Phase• BMPs :– osteoinductive

• TGF-β :– Induces mesenchymal cells to produce type II collagen

and proteoglycans. – Induces osteoblasts to produce collagen

• Vasoactive substances :– nitric oxide and endothelial stimulating angiogenesis

factor – increasing tissue vascularity and trigger neoangiogenesis

• Callus:– immature or woven bone– 8 to 12 weeks to mature

This process continues for months to years

Fracture Healing Based on Type of Stabilization

• Primary Bone Healing (Direct Bone Healing)– Anatomically reduced– stably fixed fractures

• Direct osteonal penetration• Haversian remodeling with no external bridging

callus – Revascularization of necrotic fracture ends – Reconstitution of intercortical union

• Fracture Healing in Cancellous Bone– no terminal death and no bridging callus

• Distraction Osteogenesis– described by Ilizarov– gradual controlled distraction after an interval of

induction ( after 5~7 days)

Mechanical Basis of Fracture Healing

• Each tissue type has various strain tolerances:– Granulation and fibroblastic tissue : elongate up

to 100% before failure– Cartilage and bone: tolerate much less strain,

from 2% to 10% and <2%

Delayed Union

• Incidence: 5 to 10%• Inadequate fracture reduction

Nonunion

• Failure of a fracture to heal in 6 to 8 months

• Reasons of failure:– Biology (high-energy injuries with devascularization)– Host (nicotine, vascular disease, other comorbidities)– Mechanics (improper stabilization) – Treatment failure (iatrogenic devascularization)

Classification of Nonunions• Hypertrophic Nonunions– Insufficient mechanical stability

• Atrophic Nonunions– absence of callus– avascular bone ends– poor healing potential

– Gap: avascular scar tissue

• Infected Nonunions

Textbook Reading

Rockwood 6th ed. 588-5919/5

R1 郭亮增

Nonunion Classifications

• Capable of a biologic reaction or not Weber B, 1976

Viable (Hypertrophic or vascular nonunion)Elephant footHorse hoof Oligotrophic nonunion

Nonviable (Atrophic or avascular nonunion)• Clinical mobility Paley and Herzenberg

1989Stiff (<5 degrees mobility)Partially mobile (5 to 20 degrees mobility)Flail (>20° mobility)

Hypertrophic nonunions

• Elephant foot nonunions : Rich in callus

Early weight bearing Insecure fixation in a reduced fracture

• Horse hoof nonunions : Mildly hypertrophic and less callus.

Cause: Unstable fracture fixation. • Oligotrophic nonunions : Little callus

Still demonstrate some biologic capacity

Hypertrophic nonunions

• Causes:Major displacement of a fractureInternal fixation without proper apposition of the

fragmentsPremature motion fragment distraction

• TreatmentRespond well to Stable fixation Plates 、 intramedullary nails 、 external fixation

Hypertrophic nonunions

• Infection can also mimic a vascular nonunionThe callus is infected and may be part of the

involucrumRarefactions and irregularities in the callusHardware failure.

• Laboratory and diagnostic studies should be considered

Atrophic nonunions• Characteristics:

Absence of callus Avascular bone ends Poor healing potential

Subdivisions:• Torsion wedge: the result of intercalary fragments with

poor blood supply• Comminuted: when there are multiple comminuted

devascularized fragments• Defect nonunion.

Large gaps between the bones. The gap is usually filled with an avascular scar tissue with poor

osteogenic potential.

Atrophic nonunions

• Treating these nonunions is difficult due to (1)Fracture gaps

(2)Infection (3)Poor vascularity.• Pseudoarthrosis : a fibrous capsule around a

freely mobile nonunion. This cavity is filled with a viscous fluid, creating the appearance of a joint.

Infected Nonunions• Infection always should be considered! • After adequate treatment , the infected nonunion

resembles an aseptic nonunion.• Less biologic potential due to the infection and subsequent

ablative surgery Behave more like an atrophic nonunion Segmental defects are frequent

• Common associations of Inadequate soft tissue coverage Poor vascularity Loose fixation devices

An aggressive approach is required.

Risk Factors for Nonunion

• Severity of Local injury• Type of Bone• Excessive motion• Radiation necrosis• Systemic factors

Severity of Local Injury• More extensive trauma Less biologic potential for healing• Fracture healing requires (1)Adequate vascularity (2)Differentiation of mesenchymal cells• A Wide “zone of injury” (1)Infection (2) Atrophic behavior. • Loss of bone substance or gaps between fracture fragments the

cells' ability to bridge the gap is compromised, especially when (1)Bones with less soft tissue coverage, eg.: tibia, (2)Bones with less vascular options, eg. : femoral neck.

• The normal blood flow is disrupted in fracture Fracture heading depends on the periosteal capillary plexus and muscle envelope Maintenance of soft tissue attach to bone may be crucial to

maintaining their biologic healing potential !

Type of Bone• Cancellous bone : Repair is rapid

Many points of bone contact (Rich in cells and blood supply) Gaps are filled by the spread of new bone from the points of contact.

• Cortical bone unites by two mechanisms If apposition of cortical bone ends occurs with rigid immobilization,

end-to-end healing takes place from the cortical surfaces with very little external callus.

If there are small fracture gaps or some degree of motion, repair occurs by external callus.

• Certain bones are known for a predisposition to nonunion due to their little blood supply.

(1)The femoral neck (2)Scaphoid (3)Fifth metatarsal (4)Talus

Excessive Motion

• Inadequate immobilization leads to delayed union or nonunion.

• The initial fibrin scaffolding, which is the first step in fracture repair, is disrupted if

(1)Immobilization is not adequate (2)The bony bridge of external callus fails to

form properly. • Inadequate immobilization through repair

process nonunionpseudoarthrosis.

Radiation Necrosis• Bone that has been irradiated

Heal at a slower rate Higher risk of nonunion

• The threshold for osseous radiation injury is believed to be 3,000 cGy, with cell death occurring at 5,000 cGy.

• Radiation may cause vascular and cellular damage (1)Cell death in the local region (2)Thrombosis of vessels (3)Fibrosis of the marrow (4)Reduced capillary ingrowth.

• Radiation effects in bone (1)Supress osteoblastic proliferation and neovascularization (2)Decreases chondroblastic mitotic activity (3)Reduces the size of the lacunae (4)Diminishes osteoid replacement of primary cartilage .

Green N. Radiology 1969

Risk Factors for Nonunion

• Systemic factors:Age Illness and MalnutritionAnemia HormonesSmokingNSAIDs

Age• Fractures heal very rapidly and the rapid remodeling in

young adults – Elderly animals heal at a slower rate than younger animals– Children were less likely to develop nonunions than adults

Boyd H. JBJS 1961 • (1)The thicker periosteum (2) The better vascularity of the bone the lower incidence of nonunions in children. • Nonunions in fractured tibia in children are extremely rare

except in the presence of congenital pseudarthrosis• The numbers of stem cells available for healing decrease

with age.

Illness and Malnutrion• Chronic illness and malnutrition poor fracture

healing. • Malnutrion

Phosphorus and calcium deficiencies appear to delay callus formation in rats secondary to reduced mineralization

Protein dietary deficiency has been shown to reduce callus strength Protein deprivation has shown a profound detrimental effect on

fracture healing in an experiment involving rats.

• Malnourished animals had (1)Callus composed primarily of fibrous-type tissue (2)Dcreased periosteal and external callus. (3)Reduced strength and stiffness in callus

Anemia• Anemia can delay bone healing• In a rat model, marked weakness of callus strength was identified

at 3, 6, and 8 weeks after fracture in anemic animals. • Marked retardation of fracture healing in the anemic group Nonunion rate in Anemia group vs. Control: 33% vs. 0%

• Effect of anemia on fracture healing: Bone cellular metabolism depends on the oxygen tension and

circulating blood volume . Anemia decrease both above two

• Iron could be responsible for delaying bone healing by interfering with the enzyme system responsible for transporting the cytochrome chain involving iron and copper

Hormones• Corticosteroids are powerful inhibitors of fracture healing (1) Inhibit the differentiation of osteoblasts (2) Decrease synthesis rates of bone matrix • Growth hormone is a potent stimulator of fracture healing • Sex steroids play an essential role in maintaining bone

health throughout life. Osteoblast cells appear to be stimulated by androgens in vitro. In an experiment to compare fracture healing in a rat femoral

defect model, sustained delivery of dihydrotestosterone has been shown to stimulate the osteoblastic activities, which eventually causes an increase in the cortical bone density.

Hormones• Type I diabetes is associated with a decrease in skeletal

mass and delayed fracture healing.• Diabetic patients exhibit reduced bone mineral density as

measured by dual x-ray absorptiometry of the lumbar spine and proximal femur.

• In a 12-year prospective study, bone formation was shown to be reduced in diabetic humans they have diminished osteoblastic activity

• Animal model experiments have suggested Diabetes inhibits cell proliferation during fracture healing due to

decreased platelet-derived growth factor levels Diabetic animals fail to regulate osteoblast differentiation

decreased bone formation

Smoking• Smoking, and specifically the effect of nicotine, has been

shown to be a potent inhibitor of fracture healing. Cigarette smokingHigher risk of delayed union and nonunion. Inhibitory effect on long bone fracture healing.

• The primary reason for this effect is thought to be (1)Constriction of small blood vessels caused by nicotine (2)Inhibition of growth of new blood vessels. • Adversely affect bone mineral density, lumbar disk disease,

the rate of hip fractures, and the dynamics of bone and wound healing.

• Smoking is associated with an increased risk of complications in patients with open tibial fractures .

(1)Flap failure (2)delayed union and nonunion.

NSAIDs

• Prostaglandins are known to play an important role in bone repair and normal bone homeostasis.

• Prostaglandins are released as part of the inflammatory response. They are synthesized from arachidonic acid by the cyclooxygenase enzymes, COX-1 and COX-2.

• NSAIDS inhibit COX activity and have become the primary means of alleviating chronic pain associated with rheumatoid and osteoarthritis.

• Clinical reports have been largely inconclusive concerning the effects of NSAIDs on bone healing.

Treatment of Nonunions

• Enhancement of Fixation• Bone Grafting• Osseous transplants• Use of Eletricity in treating Nonunions• Pulsed Ultrasound

Enhancement of Fixation• Excessive motion + biologic potential (e.g.,

hypertrophic nonunions) The treatment consists of enhancing stability• If deformity is not as mobile, surgical release

(e.g., osteotomy or takedown of nonunion) may be required.

• It is not always necessary to change implant types.

• Failed plating may just require revision compression plating.

Bone Grafting

• Autogenous bone was preferred to allograft, as the success rate was 88% for autogenous, compared to 70% for allograft.

• There are several elements required for the success of bone graft to obtain healing. The graft needs to be osteoconductive provides

scaffolding for new bone growthIt needs to be osteoinductiveprovides the biologic

signals to recruit and influence cellular activity of bone formation.

• In order for bone to form, there needs to be a cell with osteogenic potential.

• Pelvic autograft, only from 1/20,000 to 1/100,000 of the cells are osteogenic cells .

• These cells are living and require vascularity for oxygen and nutritionthese cells may not survive long enough when implanted into an avascular nonunion site.

• Local or systemic recruitment that takes place as well as revascularization.

• Allograft bone that was found to contain proteins from the TGF-β family of proteins that were osteoinductive.

• A number of BMPs have been identified and found to have significant potential to heal osseous defects. When processed with allograft bone, demineralized bone matrix has been applied in numerous circumstances instead of autograft bone.

• BMP-2, 6, and 9 may play an important role in inducing osteoblast differentiation of mesenchymal stem cells.

• Osteogenic Protein-1 (OP-1, Stryker, Mahwah, NJ), which is a recombinant BMP-7 has been demonstrated to be effective in nonunions and

• Infuse (Wyeth, NYSE:WYE), which is a recombinant BMP-2 has been effective in acute fractures .

Osseous Transplants

• Large-defect nonunions have been successfully treated with osseous cortical implants .

• Cortical grafts do not become fully revascularized or incorporated with host bone form junctional bone welds to host bone.

• Because the allograft bone does not remodel, it is subject to failure in the active patient.

• Vascularized cortical autograft has been attempted using fibula and iliac crest.

• Vascularized fibula transfer is a valuable technique for reconstructing extensive long bone defects in the upper extremity.

• This vascularized bone is viable bone, Osteocytes and osteoblasts survivePreservation of bone-forming capacity bone fusion occurs early.

• The fibula is similar to the shape of the forearm and does not overstuff the forearm; hence wound closure is usually not a problem.

• For low extremitydelayed stress fracturesA prologed period of protected weight bearing is

needed.

Ilizarov method

• In the lower extremity, when defects exceed 4 to 6 cm, massive grafting has been challenging,

• Distraction osteogenesis : Ilizarov method. • With this method, the defect is slowly filled in by

creating an osteotomy remote from the injury site, and in a slow and controlled manner, transporting host bone into the defect.

• The distracting osteotomy site slowly fills with “regenerate” bone that forms in a unique manner and ossifies by intramembranous ossification.

Ilizarov method

• It provides a superb method for posttraumatic reconstruction.

Advantages:• Autogenous bone formation• The patient is functional during treatment.

• The method also allows correction of deformity, treatment of infection, and it provides an alternative for hypertrophic nonunions

Use of Eletricity in Treating Nonunions

• Regulates extracellular matrix synthesis stimulating repair of fractures and nonunions• For fresh fractures, osteotomies, spinal fusions,

as well as delayed and nonunionsTypes:• Capacitative Coupling• Direct Eletrical Current• Inductive Coupling• PEMF• CMF

Capacitative coupling• Bassett developed this noninvasive technique, which requires

accurate placement of two coils around the fracture site. The limb is immobilized in plaster, and the coils are placed on the plaster around the fracture site.

• Potentials of 1 to 10 V at frequencies of 20 to 200 kHz are applied, -electrical fields in the tissue of approximately 1 to 100 mV/cm.

• Capacitative coupling promotes bone healing of fracture nonunions.

• In a study to compare healing rates employing DC, capacitive coupling, or bone graft,

(1)Bone graft surgery yielded a poorer union rate when there was a previous bone graft failure

(2)Capacitive coupling had a poorer union rate in the presence of an atrophic nonunion.

Direct Electric Current• Direct electrical current techniques stimulate osteogenesis

at the cathode at currents of 5 to 100 mA. • The semi-invasive technique is composed of (a) a power pack that supplies a current of 20 mA (b) an anode consisting of a stainless steel grid applied to

the skin, and (c) stainless cathode k wires. The tip of the cathode is

inserted through the skin into the nonunion using an image intensifier.

• The overall success rate reported by Heppenstall in 50 forearm nonunions treated with 3 months semi-invasive DC stimulation in the absence of gap or infection was 80% .

• The invasive technique involves a small operation to insert a generator that supplies a constant current of 20 mA.

• A platinized anode with a titanium cathode is made into a form of helix and placed across the site of nonunion.

• Zichner,1981 .: Implantable DC stimulation is effective in managing established nonunions of the extremities .

Inductive Coupling

• Electrical fields can be produced in bone by inductive coupling (IC) with an external time varying or pulsed electromagneticfield.

• This technique uses a single or double current-carrying coil, which is driven by an external field generator and also induces a secondary electrical field in the bone.

PEMF• It has been shown that shear stresses on bone liberate electrical

potentials on osteocyte membrane, which promote fracture healing.

• Stimulate secretion of BMP-2 and 4, TGF-β, and IGF–II of osteoblast promote fracture healing. • Pulsed electromagnetic stimulation has been shown to be an

effective modality, especially for hypertrophic nonunions• Heckman et al reported healing in 64% of 149 patients using PEMF,

and that the healing rate was higher for the tibia than for the femur or humerus.

• Also helpful for nerve regeneration, wound healing, and diabetes. • PEMF stimulating endothelial release of FGF-2angiogenesis suggest a potential role for PEMF in therapeutic angiogenesis

CMF• CMF stimulators use an external coil system with

a combination of direct and alternating currents to produce both static and alternating magnetic fields.

• The size and bulk of CMF technology coils may affect patient compliance, but the units are recommended for only 30 minutes of use per day

• CMFs, a new type of biophysical stimulus, have been shown to act by stimulating endogenous production of growth factors that regulate the healing process

Pulsed Ultrasound• Ultrasound bone growth stimulation is designed to transmit

low-density, pulsed high-frequency acoustic pressure waves

(1) to accelerate healing of fresh fractures (2)and to promote healing of delayed unions and

nonunions that are refractory to standard treatment . • There is evidence from randomized trials that low-intensity

pulsed ultrasound treatment may significantly reduce the time to fracture healing for fractures treated nonoperatively.

• Treatment with the active ultrasound device also substantially reduced the incidence of tibial delayed unions in smokers and nonsmokers.

Pulsed UltrasoundAccelerates cortical and cancellous bone fracture

healingSubstantially mitigates the delayed healing

effects of smokingSpeeds the return to normal activityReduces the long-term complication of delayed

union• There does not appear to be any additional

benefit to ultrasound treatment after intramedullary nailing with prior reaming

Chapter 18: local complication

591-595Treatment of nonunions

Osseous transplants

• Large –defect non-unions treated with osseous cortical implants

• Not mean cortical grafts• Vascularized cortical autograft1.Vascularized fibula transfer2.Iliac crest

Fibula transfer

Osseous transplantsfibula transfer

• Used more often in upper extremity than loer extremity

1.Weight bearing 2.Delay stress fracture

Osseous transplants

• Ilizarov technique1.Distracting osteotomy2.autogenous3.Ossify by intramembranous ossification4.Patient is functional during treatment5.Deformity, infection, hypertrophic non-union

Ilizarov technique

Hypoplastic ulnar and Distraction Lengthening

Electricity in treating nonunions

• In 1841, Edward Hartshorne first reported use of electricity in treating tibial nonunions

• Direct current(DC), pulsed electromagnetic fields(PEMF), combined magnetic fields(CMF), alternative current

• To treat fresh fracture, osteotomies, spinal fusions, delayed and nonunions

Electricity for treatment of non-union

• Capacitative coupling1. Two coils around fracture site2. 1-10 V, 20-200kHz, 1-100mv/cm3. Capacitative Coupling promotes bone healing of

fracture nonunions --J Orthop Trauma 19984. Capacitive coupling had a poore union rate in

arthrophic nonunion --Clin orthop 1995

Electricity for treatment of non-union

• Direct electrical current1.Osteogenesis at currents of 5 to 100 mA2.Semi-invasive or invasive method3. Success rate of union in 50 forearm

nonunions was 80% --J Trauma 1983

Electricity for treatment of non-union

• Pulsed electromagnetic fields(PEMF)electrical potentials on osteocyte membrane• In vitro, osteoblast secreted BMP-2,-4, TGF-

beta, IGF-II• Nerve regeneration, wound healing,

angiogenesis

Electricity for treatment of non-union

• Pulsed ultrasound1.Promoting healing of delayed unions and

nonunions refractory to standard treatment --CMAJ 20022. Wider acceptance and ease of use

Bleeding complications

• Unstable pelvic injuries, long bone fracture, or combination with visceral injuries

• Hemorrhage in unstable pelvic fracture1.venous 2. angiographic embolization3.Antishock pelvic clamp in ER4.Late mortality associated with sepsis-induced

multiple organ failure

Bleeding complication

• Complications in massive resuscitations1.hypothermia, coagulopathy, abdominal

compartment syndrome• DIC is one of complications of massive blood

transfusion1.Acute DIC: general bleeding, petechiae,

microcirculatory and macrocirculatory thrombosis

2.shock-like pticture

Bleeding complications

• Hematoma1. ischemia, tissue necrosis and dehiscence2. Medium for bacterial growth3. Immediate suture removal to release the tension

on the wound4. Solidified mass after several days liquefaction between 7-14 days5. It’s necessary to place drains for first 24 hrs6. Long-term no commended