Biologic and Biophysical Technologies. FINAL

BIOLOGIC & BIOPHYSICAL
TECHNOLOGIES FOR THE

ENHANCEMENT OF
FRACTURE REPAIR
INTRODUCT
ION
 Fracture repair includes multiple signaling pathways and regulated by both local and systemic
factors
 Complications may occur during fracture healing
 Delayed union
 Non union
 The cause of impairment may be related to, inadequate reduction, instability, or the systemic state of
the patient
 To improve and expedite repair surgeons may use bone grafts, biologic agents, or physical
stimulation
BONE GRAFTS AND BONE GRAFT SUBSTITUTES
 Indications of use include malunions, nonunions, arthrodesis, and reconstructive procedures
 Factors that affect bone grafts incorporation:
 Osteoinductive growth factors
 Osteocunductive ECM(local blood supply, biomechanical forces on graft and tissues)
 Osteogenic pluripotent stem cells
 The main contribution of the graft is to act as an osteoinductive and osteoconductive substrate
 Types of graft
 Autologous bone graft(Gold standard)
 Allograft bone
AUTOLOGOUS BONE
 Remains the GOLD STANDARD
 Has excellent osteoinductive, osteoconductive and osteogenic potential
 Graft vs Host disease and disease transmission risk are elimainated
 Either cancellous or cortical can be harvested
 Most common sources:
 Pelvis
 Distal radius
 Fibula
 Proximal tibia
 Ribs
 Greater trochanter
 Olecranon
AUTOLOGOUS CANCELLOUS BONE GRAFT
 The most commonly used bone graft source
 Prefered used in fracture associated with bone loss, nonunions, small bone defect
 May be used for fractures that do not require immediate structural support
 Provides osteoconductive and osteoinductive
 Main advantage lies in its tremendous biologic activity
 Serves as a scaffold to be resorbed as the mature osteogenic cells lays down new osteoid matrix
 Does not provide structural support by itself, it must be aided by internal fixation
 It is used for areas of bone loss.
AUTOLOGOUS CORTICAL BONE
GRAFT
 Provide good structural support, but weaker osteoconductive and osteoinductive

 May be used in fractures that require immediated structural support
 Remodeling proceeds and creeping substitution can require upto 2 years
 Ribs, fibula, crest of the illium, with or without a vascular pedicle
VASCULARIZED CORTICAL BONE
GRAFT
 Harvested from
 Iliac crest with deep circumflex artery
 Fibula with peroneal artery branches
 Medial femoral condyle with descending genicular artery branches
 Ribs with the posterior intercostal artery
 Retention upto 90% of the grafts osteocyte

 Indicated in >12cm bone loss
 Indicated for reconstruction of defects where the host microenvironment is inadequate to initiate
effective biologic response.
NON – VASCULARIZED CORTICAL BONE
GRAFT
 For defect of 6cm in length
 Incorporated to creeping substitution
 Immediate structural support
COMPLICATIONS:
 The morbidity associated with longer operative time of harvesting
 Superficial hematomas and infection( iliac crest bone graft)
 Deep hematomas and infection, joint compromise, proximal tibial fracture(proximal and distal tibial)
 De Quervain’s tenosynovitis, superficial radial nerve injury, and fx at the donor site(distal radius)
 the Reamer Irrigator Aspirator lessens the postoperative pain in harvesting autologous graft
ALLOGENIC
BONE
 Best used in combination with autologous graft
 Harvested sites: pelvis, ribs, and fibula
 Used in spinal surgery, joint arthroplasty, and upper and lower extremity(e.g total wrist
arthrodesis)
 Limitations associated with its preparation:
 Prepared and sterilized via freeze – drying, freezing, or irradiation
 Grafts incorporation may be impaired with poor vascularization

DEMINIRALIZED BONE
MATRIX
 Produced by acid extraction of allograft bone
 Contains type 1 collagen, noncollagenous proteins and osteoinductive growth factors( BMPs and
TGF – betas).
 Has more osteoinductive potential than allografts
 Available as freeze dried powder, granules, a gel, a putty or strips
 No sufficient evidence demonstrating its efficacy when used alone in the treatment of fresh fractures
or nonunions or in the reconstruction of bone defects.
BONE GRAFT SUBSTITUTES
 Calcium Phosphate Ceramics

 Hydroxyapatite
 Tricalcium Phosphate
 Calcium Phosphate Cements
 Calcium Sulfate
CALCIUM PHOSPHATE
CERAMICS
 Osteoconductive materials produced by sintering
 Its osteoconductive potential is dependent on porosity and pore size
 Examples of CPC include HA, TCP, and Calcium phosphate – collagen composite
 Best used as bone void fillers, especially when supplemented with autologous bone
 Preferable to use them in parts of the skeleton where tensile strains are low or nonexistentt
HYDROXYAPATITE
 A slow resorbing compound that is derived from several sources, both animal and synthetic
 Degraded by osteoclast in 2 – 5 years
 Interpore – a coralline HA and was the first calcium phosphate based bone graft substitute approve
by the FDA.
 Apapore 60 – is also a commercial HA, that has shown promise in impaction grafting for
acetabular defects.
TRICALCIUM
PHOSPHATE
 It undergoes partial resorption and some of it may be converted to HA once implanted to the body.
 Its composition is similar to calcium and phosphate phase of human bone
 Shown promise in acetabular grafting for revision hip surgery
 BoneSave – is a biphasic ceramic composed of 80% of TCP and 20% of HA
CALCIUM PHOSPHATE CEMENTS
 Used in bone void fillers in the treatment of bony associated with acute fractures
 It hardens within minutes, achieving its maximum compressive strength after 4 hrs
 It is used as adjunct, rather than as the primary method of fixation
 Norian Skeletal Replacement System(Norian SRS) – a commercially available CPC, shown
promising results in treatment of distal radius and other fractures.
 Possesses the necessary compressive strength to enable early weight bearing
CALCIUM PHOSPHATE
 A.K.A plaster of paris
 Acts as osteoconductive material, completely resorbs within 6 – 12 weeks
 Also available as an injectable cement with good biocompatibility
ENHANCEMENT OF FRACTURE HEALING
WITH BIOLOGIC THERAPIES
 Mesenchymal Stem Cells and Progenitor Cells
 Bone Morphogentic Proteins
 Wnt Proteins
 Other Peptide Signaling Molecules
 TFG – B
 VEGF
 FGF
 PDGF
 Prostaglandin Modulators
 NSAID
MSC AND PROGENITOR CELLS
 Plays a critical role in fracture healing
 They have autocrine, paracrine, or endocrine effects
 A source of autologous graft material
 Produce osteoid matrix when supplemented with DBM in critical sized calvarial defects
BONE MORPHOGENIC PROTEINS
 Plays an important role in osteogenic development and bone repair
 These are non-collagenous glycoproteins that belong to the TGF – B superfamily
 BMP – 2: recommended in open tibia fractures and those with large cortical defects
 BMP – 7(OP-1): recommended in recalcitrant non-unions of long bones
 BMP – 2 must be administered in children with caution
WNT
PROTEINS
 Critical in the regulation of osteogenesis and bone formation.
 Regulated by Dkkl and Sclerostin
 Studies shows that these antibodies to both Dkkl and Sclerostin increase bone mass, cortical and trabecular
bone formation
 However both of these proteins are still currently being evaluated in phase two clinical trials
regarding fracture and non union healing
OTHER PEPTIDE SIGNALING MOLECULES
 Transforming Growth Factor – B
 Has a similar structure and function to the BMPs
 Chemotactic factor for fibroblast and macrophage recruitment
 Dose dependent effects in influencing fracture repair
 Vascular Endothelial Growth Factor

 Promotes angiogenesis during early phase of fracture repair
 Fibroblast Growth Factor

 One of the most potent stimulator of angiogenesis
 Has mitogenic effects on osteoblast, chondrocytes and plays a role during growth, wound healing and fracture
repair
 Platelet Derived Growth Factor
 Mitogenic and chemotactic properties for osteoblast
PROSTAGLANDIN MODULATORS
 PGE and PGF has osteogenic effects when implanted into skeletal sites or infused
systematically
 Prostaglandin E2 caused a dose dependent stimulation of callus formation and
increase total bone mineral content.
 Inhibition of lipoxygenase may enhance bone healing
NONSTEROIDAL ANTI-
INFLAMMATORY DRUGS
 Effective and commonly used analgesics
 Act by binding and blocking COX enzymes
 Dose dependent and reversible
 Safe to be used an analgesic in short durations(10-14days)
SYSTEMICS ENHANCEMENT OF FRACTURE
HEALING
 Parathyroid Hormone
 Major regulator of mineral homeostasis exerting its effect by binding to a receptor on osteoblast
 Acts both stimulatory and inhibitory in bone metabolism
 Teraparatide (PTH 1-34): FDA approved treatment for osteoporosis.
 Growth Hormone and Insulin Like Growth factor 1

 Play an important role in skeletal development and remodeling
 Stimulates endochondral ossification, periosteal bone formation and linear growth.
 IGF -1(somatomedin C) and IGF II
 Statins
 HMG-COA reductase inhibitors – lipid lowering drugs that blocks cholesterol synthesis through inhibition of
mevalonic acid production.
 Inhibits osteoclast maturation
 Stimulates the BMP-2
 Bisphosphonates and Osteoclast Inhibitors

 Used for the treatment of osteoporosis
 Act by binding to hyaluronic Acid and inhibiting osteoclast mediated bone resorption by inducing
osteoclast apoptosis
MECHANICAL AND BIOPHYSICAL STIMULATION
 Plays a crucial role in the healing process.
 Early weight bearing accelerates the fracture healing process
 Compression plating – enhanced bone formation 120 post injury when compared to external fixation
 Micromotion as seen with compression plating actually modulates fracture healing
 Distraction Osteogenesis
 Enhances bone regeneration in both orthopedic and maxillofacial operations
 Three phases: Latency phase, Distraction phase, Consolidation phase
 There is an established risk of fracture after removal of external fixators
PHYSICAL ENHANCEMENT OF SKELETAL REPAIR
 Electrical Stimulation
 Stimulates the production of osteogenic and mitogenic growth factors(BMP-2,BMP-4,TGF-B)
 Three methods: Constant Direct Current, Capacitive Coupling, Time varying inductive coupling
 Used together with cast immobilization will increase the rate of bone union comparable with bone graft surgery.
 Ultrasound Stimulation
 LIPUS – promotes fracture repair and increase mechanical strength of fracture callus
 Act as onsteoinduction modulator
 Studies shown with LIPUS substantially reduced the incidence of delayed union in smokers and non smokers
 Extracorporeal Shock Waver Therapy

 Stimulates bone formation by increasing local and systemic inflammatory and osteogenic GF
 Works well for hypertrophic non unions but was less optimal for atrophic non union
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Biologic and Biophysical Technologies. FINAL

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BIOLOGIC & BIOPHYSICAL

TECHNOLOGIES FOR THE

 Provide good structural support, but weaker osteoconductive and osteoinductive

 Retention upto 90% of the grafts osteocyte

 Grafts incorporation may be impaired with poor vascularization

 Calcium Phosphate Ceramics

 Vascular Endothelial Growth Factor

 Fibroblast Growth Factor

 Growth Hormone and Insulin Like Growth factor 1

 Bisphosphonates and Osteoclast Inhibitors

 Extracorporeal Shock Waver Therapy

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