Kyle%20F.%20Dickson,%20M.D.%20M.B.A.

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Kyle F. Dickson, M.D. M.B.A.
Professor Baylor College of Medicine Southwest
Orthopaedic Group, Houston, Texas
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Nonunions

• Kyle Dickson MD, MBA
• Professor of Orthopaedics Baylor College of
  Medicine
• Southwest Orthopaedic Group

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LECTURE GOALS

• Understand the factors that lead to nonunion
• Be able to avoid these factors in fracture
  treatment
• Understand how to apply the principles of
  nonunion surgery

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G.R.75 y.o. male with L subtroch femur fracture
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G.R.
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G.R.
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G.R.
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Nonunion

• A fracture that has lost the potential to heal ,
  typically 6-9 mos from injury (FDA 9 months)
• no progress in healing documented on serial
  radiographs
• typically healing stalled at soft callus phase

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Delayed Unions and Nonunions in Open Tibia
Fractures with Angiogram Proven Single or Double
Vessel Injury

• Dickson
  CORR 1994

-Delayed union 4 months with two month of no
clinical or radiographic healing -Nonunions 6
months with 3 months without healing
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CM-11-30-00
Instant nonunion
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Major bone defects

• Stability
• Restore integrity
• cancellous grafting
• free vascularized bone transplant
• transport or lengthening (Ilizarov)
• BMPs ?

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CM-4-11-02
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CM-4-11-02
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CM-11-7-02
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• ETIOLOGY
• MECHANICS
• Inadequate stability
• Patient cooperation
• BIOLOGY
• ? Blood supply either traumatic or surgical
• Infection
• Patient factors e.g. Nutrition,smoking,NSAID
• Combination

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Krettek, JBJS 1991

• External fixation with lag screws 2x the
  refracture rate and bone graft rate versus
  external fixation alone

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BR 5-17-01
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BR 1-3-02
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BR 1-3-02
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BR 1-17-02
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BR 1-17-02
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• fracture manipulated with bone-holding forceps or
  levers
• negative biologic impact

Choke Kill
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INFECTED NONUNION

• Diagnosis culture all nonunions
• Debridement
• 1 or 2 stage
• Bone reconstruction
• Bone graft timing
• Soft tissue reconstruction
• Antibiotics

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TECHNIQUE OF ABX ROD
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Etiology

• Patient factors (systemic)
• Extremity factors
• Surgeon factors

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Etiology

• Obesity
• Infection
• Anemia
• Smoking
• Diabetes

• Old age
• Malnutrition
• Steroids
• NSAIDS
• Radiation

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NONUNION-RISK FACTORS

• INJURY
• SURGEON
• PATIENT/HOST
• LIFE STYLE
• SMOKING, NICOTINE
• NONCOMPLIANT WITH WEIGHT BEARING STATUS

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Etiology Extremity Factors

• High energy trauma
• Open fractures

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Etiology Surgeon Factors

• Wrong surgery
• Wrong implants
• Poor technique
• Bad decisions

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Fracture healingWhat does nature do with a
broken bone?

• It will heal by callus formation, if there is
  motion between fragments!

Indirect healing
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Fracture healing

• Inflammation
• 2. Soft callus
• 3. Hard callus
• 4. Remodeling

Hematoma Mesenchymal cells Granulation
tissue Intramembranous bone formation Enchondral
ossification

bony bridging
Excessive motion(gt10)
Failure in bridging
Nonunion
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HYPERTROPHIC NONUNION

• MECHANICAL INSTABILITY
• VASCULARITY PRESERVED
• HORSES HOOF OR ELEPHANT FOOT (ABUNDANT CALLUS)

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Hypertrophic Nonunion
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ATROPHIC NONUNION

• BIOLOGICAL CAUSE
• NO CALLUS

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Oligotrophic Nonunion
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• Pseudoarthrosis
• Formation of a false joint where a
  fibro-cartilaginous cavity is lined with synovial
  membrane

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Classification

• Location
• Diaphyseal, metaphyseal, intra-articular
• Etiology
• Mechanical (hypertrophic), biological (atrophic)
• Infection
• Currently infected, previously infected, never
  infected

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DIAGNOSIS OF NONUNION

• Symptoms
• Pain
• Swelling
• Instability
• Deformity
• Loss of function

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DIAGNOSIS OF NONUNION

• Signs
• Swelling
• Local tenderness
• Pain on stressing the fracture site
• Instability
• Deformity

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DIAGNOSIS OF NONUNION

• Imaging
• Plain radiographs
• CT scan

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DIAGNOSIS OF NONUNION

• Blood work
• CBC and differential
• ESR and CRP
• Aspiration of nonunion site rarely necessary

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Principles of Treatment

• Deformity correction (reduction)(plate ilizarov
  vs nail)
• Adequate stabilization (fixation)
• Preserve/stimulate the biology of fracture repair
  
• Early ROM rehabilitation

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DECISION PROCESS

• IS THERE INFECTION ?
• WHAT HARDWARE PRESENT ?
• HYPERTROPHIC vs ATROPHIC ?

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General Treatment

• Hypertrophic
• correct deformity and stabilization
• Atrophic
• biological and mechanical
• Infection
• debridement, bone reconstruction, soft tissue
  reconstruction, antibiotics

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MANAGEMENT

• PREOPERATIVE PLANNING IS MANDATORY (surgical
  tactic, template, equipment)
• positioning
• skin incisions
• deformity correction
• fixation
• grafting
• soft tissue coverage

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• MANAGEMENT
• OPTIMIZE MECHANICS (ALIGNMENT AND STABILITY)
• PRESERVE /- ENHANCE BIOLOGY
• COMBINATION

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Surgical Technique

• Prevention (no gaps tibia or humerus)
• Maintain vascularity
• Optimize the mechanical environment

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Operative protocol

• Remove hardware
• Create bleeding bone on both sides of the
  nonunion
• Correct deformity
• Perform stable fixation
• Addition of autologus bone graft bmp

What not to do!
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Bone Preparation

• Maintain vascularity limited stripping and
  fracture take down
• Sclerotic bone ends removed
• Bleeding ends vs. soft tissue bleeding

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Nonunions
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IM nailing

• advantages
• load sharing vs. load bearing ? less stress on
  implant less risk of implant failure
• insertion friendlier on soft tissues
• reinjures nonunion site ? reinitiates healing
  cascade
• reaming stimulates increased periosteal blood
  flow

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AH-12/13/02
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AH-12/13/02
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AH-12/15/02
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AH-12/15/02
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AH-5/22/03
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AH-5/22/03
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JP-3/28/02
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JP-3/28/02
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JP-4/17/03
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JP-4/17/03
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JP-4/17/03
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Plate Fixation

• advantages
• fixation rigid ? compression
• malalignment associated with nonunion can be
  addressed
• access for bone grafting
• can be used for most long bones regardless of
  location

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BR 1-17-02
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External Fixation

• can be used for stabilization
• osteogenesis occurs during distraction
• half pin frame
• ring fixator
• over a nail

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JC

• 58 yo male
• Shotgun blast to distal left femur 1975

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JC (cont.)

• Initially treated with casting, braces, and
  intramedullary rodding
• Presented with broken rod, nonunion, and 13 cm
  shortening
• 21 year nonunion with 17 previous surgeries

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JC (cont.)

• Ilizarov placement 10/17/96 no corticotomy
• EUA healed fracture and began lengthening 3/6/97

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Healing Characteristics Role of BMPs
Matrix Osteoconductive void fillers/DBM
Structure Cement, Support Fixation
GROWTH FACTORS Osteoinductive (BMPs)
Cells Osteopromotive/ Osteogenic factors (BMA,
platelets, osteoblasts, etc.)
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OSTEOINDUCTION

• The ability of a substance to stimulate new bone
  formation by recruitment of pluripotential
  mesenchymal cells from the host bed

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OSTEOCONDUCTION

• The ability of a substance to act as a passive
  scaffold for the ingrowth of perivascular tissue
  and the orderly proliferation of osteoprogenitor
  cells

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OSTEOGENIC

• Cellular elements which survive transplantation
  and synthesize new bone at the recipient site.

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BIOLOGIC STIMULUS

• Ideal Bone Graft Substitute
• Biocompatable
• Bioresorbable
• Osteoconductive
• Osteoinductive
• Structural
• Easy to use
• Cost effective

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AUTOGENOUS BONE GRAFT

• GOLD STANDARD
• Osteoconductive
• Hydroxyapatite ,
  Collagen
• Osteoinductive
• BMP, TGF-B, ect
• Osteogenic
• Osteoprogenitor cells

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Purpose of Graft

• Heal fractures
• Maintain reduction (calcium phosphates)
• Fill defects (prevent fractures)

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Alternatives to Bone Grafting

• Allograft (DBMs)
• Biomaterials
• Bone marrow
• Growth factors (bmps)

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DBM Competitive Landscape

• Examples
• Grafton/DBM (Osteotech)
• Optium (Depuy)
• DBX (Synthes)
• Dynagraft II (GenSci)
• Orthoblast II (GenSci)
• Accell II (GenSci)
• Regenafil (RTI)
• Allomatrix (Wright Medical)
• Ignite (Wright Medical)
• Collagraft (Zimmer)

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Cocktail

• DBM - Whats in there?
• 1 part per 100 million OP-1?
• 1 part per million BMP-3?
• BMP-3 shown to inhibit bone formation
• Creutzfeldt-Jakob disease 3 cases in Britain
  (central body) prions

ORS-1998 Anaheim, CA
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BMP-7 in DBM
Bae, H., Inter and Intravariability of BMPs in
Commercially Available Demineralized Bone
Matrice, NASS 2003
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Han 2003

• Acid extraction of cadaveric human bone leaving
  collagen, noncollagenous proteins, and BMPs
• Growth factor activity is variable between tissue
  banks and between donors
• Some products terminally sterilized which may
  further decrease BMP availability

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Carriers

• DBX synthetic neutral hyaluronic acid
• Grafton glycerol (doesnt stay around)
• AlloMatrix CaSO4 timed release (?drainage)
• Osteofil porcelline gel (?immune reaction)
• Accell no carrier, Ortholast reverse thermal
  synthetic carrier (?DBMs activity at body
  temperature), Dynagraft synthetic pluronic acid
  (?immune reaction)

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Medicare Advisory MeetingSeptember 2005

• DBM is not directly cleared for use in nonunion
  fractures
• 54 and 75 healing (Ziran 2004, Coupe 2003)
• 34 deep infection rate (Ziran 2004)
• 498 studies 0 comparing prospective human
  defects or nonunions

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Allograft

• Osteoconductive
• Clinical data (bulk allograft)
• Disease transmission low
• Plenty available

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Problems with Allografts

• 3 - 7mm incorporation
• Minimally osteoinductive
• No osteogenic capabilities
• Cost

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Allograft Use

• Graft extender
• Not used for articular reductions

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Titanium Cage Reconstruction
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Technique Titanium Cage
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Technique Titanium Cage

• Cancellous bone packed posteriorly and around
  proximal distal bone-cage junctions

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Osteoconductive Biomaterials

• Interpore, collagraft, hydroxyapatite cement,
  grafton, jax (calcium sulfate), bonesource
  (calcium phosphate), norian

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Biomaterials

• Calcium sulfate (synthetic biomaterials) quickly
  resorbable ?abx
• Calcium phosphate (hydroxyapatite cement and
  tricalcium phosphates)

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Trauma Uses

• Bone defects under articular impactions
• Fracture fixation stability (osteoporosis)

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Problems

• Not osteoinductive
• Not osteogenic
• Resorption

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Problems (cont.)

• No weight bearing
• Success?
• Required?

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Injectable Calcium Phosphate

• Stronger than cancellous bone (croutons
  nonconforming to articular reduction)
• Maintain articular reductions

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Bone Source Hydroxyapatite Cement (HAC) for
Traumatic Metaphyseal Bone Void Filling
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Osteogenics Bonesource HAC

• Tetracalcium Phosphate Dicalcium Phosphate
• (TTCP) (DCPA)
• Ca4(PO4)2O CaHPO4
• Water ? H2O
• HYDROXYAPATITE
• Ca5(PO4)3OH

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Materials Methods

• 28 patients (29 defects) 85 follow-up
• 13 Bonesource group 15 (16) autograft

Dickson 2002
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Results

• Maintenance of Reduction
• 10/12 (83) bone source
• 10/15 (68) autograft

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Defects

• Maintain reduction (distal radius, tibial
  plateau, actabulum, tibial plafonds, etc)

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Bone Marrow Aspirations

• Osteogenic
• Minimally osteoinductive
• Small donor site
• ? Mixed with osteoconductive

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Proteins for Enhanced Bony Healing

• Osteoinductive
• No shortage

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Problems with Proteins

• Which protein to use?
• Required?
• Expensive
• Carrier (localize and immunogenicity)

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Osteogenic Proteins

• OP - 1 (BMP 7)
• BMP - 2 (BMP 2A)
• BMP - 4 (BMP 2B)
• ?PDGF

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Fibula Defect Study
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Commercially Approved
Infuse (BMP-2) OP-1 (BMP-7)
INFUSE Bone Graft is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound management. INFUSE Bone Graft must be applied within 14 days after the initial fracture. Prospective patients should be skeletally mature. OP-1 Implant is indicated for use as an alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed.
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INDICATION
OP-1 Implant (BMP-7) is indicated for use as an
alternative to autograft in recalcitrant long
bone non-unions where use of autograft is
unfeasible and alternative treatments have
failed. H01002, 10/17/01
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BMP 7 vs. BMP - 2

• Similar mechanisms except VEGF
• Similar cell line culture bone stimulation
• Less published literature on dosing and acute
  fractures

• Compressibility of sponge poor fusions
• Less difficult cases tested - nonunions
• Better dosing studies
• Carriers binding bone vs tendon

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Tibial Nonunion Study (TNS)
OP-1 (BMP-7) in the Treatment of Tibial
Nonunions Friedlaender et al., JBJS, 2001
Objective Establish safety and efficacy of OP-1
in a challenging tibial nonunion
model. Methods

• 122 patients with 124 recalcitrant nonunions were
  enrolled between 1992 and 1996. Each patient was
  treated with an intramedullary rod and OP-1
  Implant or fresh bone autograft.
• Assessment criteria included
• the severity of pain at the fracture site
• the ability to walk with full weight-bearing
• the need for surgical retreatment
• radiographic success in ¾ views
• Physician assessment of clinical outcome

Friedlaender, G.E. et al. Osteogenic Protein-1
(Bone Morphogenetic Protein-7) in the Treatment
of Tibial Nonunions. JBJS. 2001 Apr 83-A S1-151.
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Tibial Nonunion Study

• Controlled, randomized prospective human clinical
  trial, initiated in 1991
• Treatment of nonunions which have persisted for a
  minimum of 9 months
• 122 Patients, 18 US sites
• Autograft and OP-1 are Equivalent

Friedlaender et. al, JBJS, Vol. 83-A, No. 4,
April, 2001.
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TNS Clinical Success
Clinical Success
Friedlaender et. al, JBJS, Vol. 83-A, No. 4,
April 2001.
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TNS Patient Demographics
Patient Demographics
OP-1 IMPLANT
AUTOGRAFT
P VALUE
Duration (mean)
17 months
0.858
17 months
Atrophic Nonunion
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25
0.048
Grade III (a-c)
0.480
30
36
0.876
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Comminuted Fracture
0.177
31
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Failed Prior Autograft
0.280
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Failed Prior IM Rod
0.057
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Tobacco Use
statistically significant
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Summary of Safety
Friedlaender et. al, JBJS, Vol. 83-A, No. 4,
April 2001.
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D.L. 5 months post-op
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Preliminary Data 2002

• 98 cases 95 nonunions
• 90 unions
• 5 failures 2 OP-1 alone, 3 OP-1 with autologus
  bone graft

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Data cont.

• Tibia 53
• Femur 17
• Humerus 9
• Fibula 5

• Acetabulum 4
• Forearm 4
• Pelvis 3
• THA - 3

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Data cont.

• 67 cases with autograft
• 25 OP-1 alone
• 6 with aspiration

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Indications for OP-1

• Failed ICBG
• Failed prior bone graft substitutes
• ICBG impractical
• Diabetes
• Morbid obesity
• Poor nutrition
• osteopenia

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Indications cont.

• ? Segmental defects
• ? Hip revisions
• ? Acute fractures

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Problems

• Carrier (physiologic release of bmp vs. 10
  minutes)
• Limited dosage studies
• Antibodies (38) pregnancy (transient and
  towards bmp or collagen carrier)
• Cost
• BMP preferentially stimulate periosteum vs bone
  marrow cells

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Bone Stimulators Electricity, Pulse
Electromagnetic Field (PEMF), and Ultrasound
Its Effects on Fracture Healing
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Types of Electricity

• PEMF (inductive coupling)
• Capacitive coupled electrical stimulation
• Direct current (20 µA 1.0V)

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May have limited use in atrophic nonunions
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Sharrard, JBJS Br 1990

• Double blind, placebo controlled randomized, cast
  treatment
• 45 unions vs. 14

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Indications for PEMF

• Delayed unions with medical comorbidites
• My bone grafting and stabilization has failed
• Infected nonunions (unable to bone graft
  initially i.e. Ilizarov)

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Indications

• None
• Tibia and radius treated in cast
• Bones close to the skin treated without internal
  fixation

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G.R.
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Summary

• DBMs allograft as as graft extender
• Ca Biomaterials CaPh under articular reductions
  (plafond, plateau, acetabulum, distal radius)
• Bmps and ICBG- nonunions
• Biophysical- PEMF rarely nonunions

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SUMMARY

• Etiology
• Mechanical and biological
• Principles of treatment
• Correct the deformity reduction
• Stabilize the nonunion fixation
• Preserve and enhance the biology
• Early functional rehabilitation

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• Nature has her own doctor in every limb
  therefore every surgeon should know that it is
  not he, but Nature, who heals
• Paracelsus (1493-1541)