J' Tracy Watson, MD

1
Orthobiologics
J. Tracy Watson, MD Professor of Orthopaedic
Surgery Chief, Division of Orthopaedic
Traumatology St. Louis University School of
Medicine Created February 2007
2
Orthobiologics Common Sense Approach for
Orthopaedics and Traumatology
3
BONE GRAFT SUBSTITUTES HOW TO CHOOSE???

• Is the specific clinical need for
• Structural support?
• Ease and method of application?
• Placement before or after internal fixation?
• Speed of resorption/incorporation?
• Improved healing?
• AUGMENT HEALING???BONE LOSS??
• Is efficacy proven by scientific studies?
• Cost effectiveness?

4
CLINICAL RESULTS

• IS AUTOGRAFT THAT BAD???
• 5-7 COMPLICATION RATES AT DONOR SITE
• HEMATOMA
• WOUND BREAKDOWN
• Fx
• INTANGEBLES??? PAIN, 30
• DELAY TO FULL AMBULATION, HOSPITAL STAY (
  LOS)

5
CLINICAL RESULTS

• AUTOGRAFT
• HOW GOOD IS IT?????
• FEW (NONE) STUDIES EVALUATING AUTOGRAFT vs
  PREPPING THE RECIPIENT BED ONLY
• (INCREASING LOCAL INFLAMMATORY RESPONSE..VASCULAR
  INGROWTH etc.)

WE DONT REALLY KNOW HOW GOOD AUTOGRAFT IS
6
COMPOSITION OF BONE GRAFT
ORGANIC 30
MATRIX 98
CELLS 2
HYDROXYAPPETITE 95
plus
MAGNESIUM SODIUM FLOURIDE POTASSIUM
CHLORIDE
MINERAL 70
7
COMPOSITION OF BONE GRAFT
CELLS 2
OSTEOBLASTSOSTEOCYTES OSTEOCLASTS
COLLAGEN 95
NON-COLLAGENOUS PROTIENS 5
MATRIX 98
8
CATEGORIES OF INTERVENTION
9
CURRENTLY AVAILABLE INTERVENTIONS

• ALLO/AUTOGRAFT
• DBM
• PLATELET GELS
• BMPs
• MARROW ELEMENTS (MSC)
• HARVEST
• CONCENTRATION
• APPLICATION

10
CURRENTLY AVAILABLE INTERVENTIONS

• CONDUCTIVE SUBSTRATES
• A-CELLULAR BIOACTIVE MEMBRANES
• SOFT TISSUE SCAFFOLDING

11
THREE MECHANISMS OF AUGMENTING BONE HEALING

• OSTEOGENESIS New Bone Formed From
  Live Cells (Autograft)
• OSTEOINDUCTION New Bone Formed by
  Active Recruitment of host
  Cells with the potential for
  osseous repair
• OSTEOCONDUCTION Inert Scaffolding Which
  Passive Permits
  Ingrowth of New Host Bone

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OSTEOINDUCTION

• CELLULAR ELEMENTS
• CELLULAR ENVIRONMENT
• CELLULAR INDUCTIVE SUBSTANCES

13
CRITICAL CELLS

• MESENCHYMAL STEM CELLS (MSC)
• SELF-RENEWING STEM CELLS (mother cells) THAT CAN
  BE ACTIVATED TO FORM PROGENY (daughter
  cells).PLURI-POTENTIAL
• DIFFERENTIATE INTO MULTIPLE TISSUE TYPES

14
MOTHER CELL
Mother cell will give rise to daughter cells
which then can differentiate into many potential
tissue types
15
INDUCTIVE FACTORS

• MULTIPLE POLYPEPTIDES
• CHEMOTACTIC / MITOGENIC TO FIBROBLASTS,
  MONOCYTES, MESENCHYMAL CELLS, OSTEOBLAST
  PRECURSORS
• 20 FAMILIES AND SUPERFAMILIES
• MOST COMMON IS THE TGF-ß SUPERFAMILY
• MOST COMMONLY USED MORPHOGENES BELONG TO THIS
  FAMILY

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TGF-? /Inhibin-Activin-like molecules
INHB ?B INHB ?A Act ?B INHB ?
TGF ?1 TGF ?2 TGF ?3
Nodal
xNR2

EBAF
xNR1 Lefty
TGF ? SUPERFAMILY
BMP3
BMP-14 BMP-12 BMP-13
BMP-11
BMP 7
BMP 4 BMP 2
OSTEOGENIC BMPS
BMP 8- 9
BMP 5
GROWTH DIFFERENTIATION BMPS
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EGF
IGF-I
FGF
OTHER PEPTIDE SIGNALING MOLECULE FAMILIES
PDGF
LIMP1
VEGF
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HEALING CASCADE
Binding of plasma fibronectin to Demin.Bone
Matrix.MSC attachment and proliferation
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BONE MORPHOGENESIS CASCADE

• BINDING OF PLASMA FIBRONECTIN TO IMPLANTED DEMIN.
  MATRIX
• FACILITATES MESENCHYMAL CELL ATTACHMENT AND
  PROLIFERATION
• CHONDROBLAST DIFFERENTIATION AND CHONDROGENESIS
• ANGIOGENESIS VASCULAR INVASION
• ENDOCHONDRAL BONE REMODELED

DAY 1-3
DAY 5-9
DAY 10-11
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BONE MORPHOGENESIS CASCADE

• BINDING OF PLASMA FIBRONECTIN TO IMPLANTED DEMIN.
  MATRIX
• FACILITATES MESENCHYMAL CELL ATTACHMENT AND
  PROLIFERATION
• PLATELET ACTIVATION OCCURS WITH RELEASE OF
  PLATELET GRANULES WHICH CONTAIN ADDITIONAL
  FACTORS
• PDGF-FGF-TGF-ß
• FACTORS ACTIVATE MACROPHAGE ACTIVITY

DAY 1-3
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SURFACE KENETICS TO FACILITATE ATTACHMENT AND
PROLIFERATION OF MSC
3-D ARCHITECTURE OF CONDUCTIVE SUBSTRATES
IMPORTANT
24
THROUGH CHEMOTAXIS, STEM CELL MIGRATION AND
IMPLANTATION ONTO THIS SPECIFIC CONDUCTIVE
SUBSTRATE SURFACE
25
CELLULAR DIFFERENTIATION
OSTEOCLAST
OSTEOBLAST
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TWO CATEGORIES OF CONDUCTIVE SUBSTRATES
CALCIUM CERAMICS

CaPO4 CaSO4
27
CONDUCTIVE SUBSTRATES

• VOID FILLERS

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METAPHYSEAL DEFECTS

• VASCULAR REGION
• BIOLOGICALLY COMPETENT
• SOLITARY VOID
• LARGE / CONTAINED
• REQUIRES /- MECHANICAL SUPPORT

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METAPHYSEAL REQUIREMENTS

• CONDUCTIVE SUBSTRATE ONLY
• RELIABLE SUBCHONDRAL SUPPORT (HARDWARE)
• INDUCTIVE FACTORS NOT NEEDED

30
METAPHYSEAL DEFECTS

• SURGEON NEEDS TO KNOW THE RATE OF INCORPORATION
• SIMPLE SUBSTITUE ONLY!!!!

31
CONTAINED DEFECTS

• CERAMICS EFFECTIVE AS SOLITARY MATERIAL WHEN
  CONTACT IS MAXIMIZED BETWEEN GRAFT AND
  SURROUNDING BONE .i.e. METAPHYSEAL DEFECT

32
UNCONTAINED DEFECTS

• WHEN CONTACT IS LIMITED (UNCONTAINED DEFECT.).
• .DIA-METAPHYSEAL DEFECT
• LARGE SEGMENTAL DEFECT, SPINAL APPLICATIONS
• HEALING SHOWN TO BE IMPROVED WITH ADDITION OF BMA
  (BONE MARROW ASPIRATE) SEEDING THE GRAFT,
  i.e.COMPOSITE GRAFT

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POROSITY OF MATERIAL CaPO4

• POROSITY OF MATERIAL FACILITATES CELLULAR
  PENETRATION
• INCREASED SURFACE AREA
• RESORBED MATERIAL OR OSTEOINTEGRATION .CELLULAR
  MEDIATED EVENT

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3-D ARCHITECHTURE IMPORTANCE OF POROSITY

• ABILITY TO FOSTER CELLULAR INTERACTIONS BETWEEN
  THE INTERSTICIES OF THE CONDUCTIVE MATERIALS

35
CaPO4 CERAMICS (PARTICULATE)

• CRYSTALLINE DEPENDENT RATE OF INCORPORATION
• BEHAVES AS A TRUE CERAMIC IN A FLUID DYNAMIC
• TRUE CERAMIC WILL NOT OR VERY SLOW TO DISSOLVE IN
  JOINT OR AT IMPLANT SITE
• CELL MEDIATED EVENT.THUS SLOW INCORPORATION

36
EXAMPLES OF CALCIUM PHOSPHATE MATERIALS
?-TCP

• VITOSS

PORE SIZE APPROX. CANCELLOUS BONE
37
CALCIUM PHOSPHATE
?-TCP

• CONDUIT

PORE SIZE APPROX. CANCELLOUS BONE
38
CALCIUM PHOSPHATE
?-TCP
chronOS

• Osteoconductive
• Resorbs in 6-18 months
• Granules, blocks, cylinders, wedges

39
ProOsteon Indications

• Repair of metaphyseal defects, long bone cysts
  and tumor defects
• A safe, effective alternative to autologous
  cancellous bone when used to fill bone voids when
  repairing tibial plateau fractures

Bucholz RW et al, Clin Orthop. 240 53 - 62, 1989.
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ProOsteon
HA
LONG INCORPORATION TIME gt 36-48 MONTHS..(NEVER)
Bucholz RW et al, Clin Orthop. 240 53 - 62, 1989.
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CONDUCTIVE SUBSTRATES

• CEMENTS

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CONDUCTIVE SUBSTRATES CEMENTS

• DELIVERY AND CONTAINMENTMAY BE PROBLEMATIC

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Norian SRS

• Norian patients had less pain and earlier
  restoration of motion

• At 1 year follow-up SRS Control
• Satisfactory result 82 56
• Malunion 18 42

Sanchez-Sotelo J, et al. J Bone Joint Surg Br.
2000 Aug82(6)856-63.
44
MATERIAL STILL PRESENT 28-30mo. POST-OP.LONG
RESORBTION TIME
M. TYLLIANAKIS,et.al.OTHOP. (25, 3 2002) GREECE
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PHOSPHATE PUTTY

• SOLUBLE CALCIUM PHOSPHATE PUTTY CaPO4
• PORE SIZE APPROXIMATES CANCELLOUS BONE
• COMPOSITE WITH MARROW ASPIRATE

Self setting paste into hardened crystalline form
46
PROSPECTIVE MULTICENTER RANDOMIZED STUDY OF AIBG
(Autograft) vs. ?-BSM

• SIG. RATE OF ADVERSE EVENTS USING AUTOGRAFT
• SIG. HIGHER INCIDENCE OF ARTICULAR SUBSIDENCE
  WITH AUTOGRAFT
• RANDOMIZED STUDIES USING AUTOGRAFT AS CONTROL
  GROUP SEEM UNJUSTIFIED STUDY STOPPED

RUSSELL, LEIGHTON, et.al..OTA 2004
47
CONDUCTIVE SUBSTANCES

• CALCIUM PHOSPHATE CERAMICS
• PROVIDE STRUCTURAL SUPPORT
• COMPRESSIVE STRENGTH VARIES GREATLY BETWEEN
  PRODUCTS
• CANCELLOUS BONE 5-15 MP a
• CORTICAL BONE..110-200 MP a
• NORIAN 55 MP a
• ? BSM 12 MP a
• CORTOSS 110-211MP a
• BONESOURCE.. 66MP a

HIGHER COMPRESSIVE STRENGTH COMPARED TO CaSO4
48
CaSO4 CERAMICS

• CRYSTALLINE INDEPENDENT RATE OF INCORPORATION
• CONSISTENT THROUGHOUT WIDE RANGE OF MATERIAL
  PROPERTIES
• LOW COMPRESSIVE STRENGTH 10-25 MPa
• GRAFT EXTENDER

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CaSO4 CERAMICS

• PELLETS
• BEAD KITS
• INJECTABLE

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POROSITY OF MATERIAL CaSO4

• VERY LITTLE INITIAL POROSITIY ON IMPLANTATION
  DURING DISSOLUTION INCREASED SURFACE AREA EXPOSED
• RESORBED MATERIAL OR OSTEOINTEGRATION .CHEMICAL
  DISSOLUTION MEDIATED EVENT

51
CaSO4 CERAMICS

• BEHAVES AS A TRUE SALT IN A FLUID DYNAMIC
• A SALT WILL DISSOLVE IN THE JOINT.INTO
  RESPECTIVE IONS (Ca AND SO4) AND ABSORBED INTO
  SYNOVIAL TISSUES WITHOUT SEQUELLA

52
CaSO4 PELLET IMPLANTATION
53
3 months resorbtion time
54
CANCELLOUS VOID FILLED WITH RESORBABLE CaSO4
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GRADUAL OSTEOINTEGRATION WITH CONDUCTIVE
RESORBABLE CaSO4
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COMPLETE INCORPORATION OF MATERIAL WITH
MAINTENANCE OF ARTICULAR REDUCTION
MOED, WATSON,et al Calcium sulfate used as bone
graft substitute in acetabular fracture fixation
.CLIN ORTHOP 410 303-309 2003
57
SELF SETTING Ca SO4 CEMENTS

• Ca SO4 INJECTABLE
• PERCUTANEOUS APPLICATION WITH MECHANICAL
  SUPPORT
• THE COMPRESSIVE STRENGTH HAS A RANGE
  BETWEEN..10 MP and 48 MPa

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INJECTABLE SELF SETTTING CEMENTS
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18 MONTHS POST OP WITH COMPLETE INCORPORATION
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INJECTABLE Ca SO4 CEMENTS RESULTS

• SPECIFIC INDICATIONS
• MAINTAIN ARTICULAR REDUCTIONS IN CONJUNCTION WITH
  K-WIRE PRIOR TO DEFINITIVE STABILLIZATION
• SIMILAR INCORPORATION KENETICS
• CaSO4 PELLETS
• PREDICTABLE RESULTS WITH MAINTENENCE OF ARTICULAR
  REDUCTION

WATSON JT USE OF AN INJECTABLE BONE GRAFT
SUBSTITUE IN TIBIAL METPHYSEAL FRACTURES.
ORTHOPAEDICS 27 1103-107, 2004.
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CONDUCTIVE SUBSTANCES

• TIMING OF APPLICATION OF ADJUNCTIVE HARDWARE
  CRYSTALLINE DEPENDENT
• INCORPORATION AND OSTEOINTEGRATION OF MATERIALS
  IS VARIABLE..CRYSTALLINE DEPENDENT

64
PO4 SO4 CEMENTS

• POOR TENSION RESISTANCE
• WEAK IN SHEAR STRESS
• AVOID DIAPHYSEAL REGIONS
• PHOSPHATES MAY FRAGMENT AND DEGRADATE WHEN
  INSTRUMENTED WITHOUT APPROPRIATE CURING OF
  MATERIAL

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CONDUCTIVE SUBSTANCES

• HANDLING, APPLICATION, DELIVERY SYSTEMS AT ISSUE
• MULTIPLE PROSPECTIVE RANDOMIZED STUDIES
  DEMONSTRATE THE EFFICACY OF THESE MATERIALS
  PRIMARILY FOR METAPHYSEAL DEFECTS(GOOD LEVEL 1
  EVIDENCE). CAUTION FOR SOLITARY USE IN DIAPHYSEAL
  DEFECTS (BONE GRAFT EXTENDER ONLY)

66
BONE MORPHOGENESIS CASCADE

• BINDING OF PLASMA FIBRONECTIN TO IMPLANTED DEMIN.
  MATRIX
• FACILITATES MESENCHYMAL CELL ATTACHMENT AND
  PROLIFERATION
• CHONDRO/OSTEOBLAST DIFFERENTIATION AND
  CHONDRO/OSTEOGENESIS
• ANGIOGENESIS VASCULAR INVASION
• ENDOCHONDRAL BONE REMODELED

DAY 1-3
DAY 5-9
67
BONE MORPHOGENESIS CASCADE

• CHONDRO/OSTEOBLAST DIFFERENTIATION AND
  CHONDRO/OSTEOGENESIS
• MACROPHAGES DEGRADE BONE SUBSTRATE WITH RELEASE
  OF INHERENT FACTORS FROM BONE MATRIX

DAY 5-9
68
RELEASE OF AUTOGENOUS GROWTH FACTORS FROM
MACROPHAGE ACTIVATION EARLY FACTORS
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RELEASE OF EARLY GROWTH FACTORS

• PEPTIDE SIGNALING MOLECULES
• FGF, TGF-ß, PDGF, IGF, VEGF
• STIMULATE ACTIVITY OF CHONDROPROGENITOR AND
  OSTEOPROGENITOR CELLS AND MATURE CONDRO- AND
  OSTEOBLASTS

LOCATION SPECIFIC
OSTEO-PROMOTIVE
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BONE MORPHOGENESIS CASCADE

• BINDING OF PLASMA FIBRONECTIN TO IMPLANTED DEMIN.
  MATRIX
• FACILITATES MESENCHYMAL CELL ATTACHMENT AND
  PROLIFERATION
• CHONDROBLAST DIFFERENTIATION AND CHONDROGENESIS
• ANGIOGENESIS VASCULAR INVASION (INFLAMMATORY
  PHASE)
• ENDOCHONDRAL BONE REMODELED

DAY 1-3
DAY 5-9
DAY 10-11
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IMPORTANCE OF SOFT TISSUE COVERAGE TO
INFLAMMATORY PHASE OF HEALING (REQUIRES VASCULAR
INGROWTH FROM SURROUNDING TISSUES)
72
DEMINERLIZED BONE MATRIX (DBM) in theory contains
MANY components of TGF-ß superfamily
TGF B SUPERFAMILY
BMP 3
BMP- 7
BMP-4 BMP- 2
BMP -5
OSTEOGENIC BMPS
BMP 8- 9
BMP-14 BMP-12 BMP-13
BMP-11
ANGIOGENESIS, INFLAMMATION, CHONDROGENIC,
CHEMOTAXIC
GROWTH DIFFERENTIATION BMPS
73
DBM

• HOW DOES IT WORK?
• DOES IT REALLY WORK?
• WHEN SHOULD WE USE IT?

QUESTIONS AS YET UNANSWERED WITH REGARD TO DBM
ALL DBM IS NOT CREATD EQUAL
74
DEMINERALIZED BONE MATRIX (DBM)

• DBM Facilitates the Natural Processes of Bone
  Formation
• INCREASED SURFACE AREA SERVES AS CELL ATTACHMENT
  SITE
• ?VIABILITY? OR EFFECTIVENESS OF INDUCTIVE
  PROTIENS

PROPOSED MECHANISM OF ACTION
75
DBM

• DBX
• GRAFT CHAMBER
• OSTEOSET2-DBM
• ALLOMATRIX
• OSTEOFIL
• GRAFTON
• ORTHOBLAST II

• VIAGRAF
• DYNAGRAFT
• ORTHOBLAST
• ACCELL
• OPTIFORM
• OPTIUM
• INTERGRO

MANY COMMERCIAL BRANDS AVAILABLE (PARTIAL LIST)
76
BIOACTIVITY ASSAY

• IN VIVO
• MEASURE ALK. PHOSPHOTASE ACTIVITY
• IN VITRO
• STIMULATION OF HUMAN OSTEOBLAST CULTURE

HOW TO TEST EFFECTIVENESS OF DBM
77
BIOACTIVITY ASSAY

• BIOACTIVITY OF DBM VAIRES FROM DONOR TO DONOR
  (AGE RELATED ACTIVITY) (CHECK WITH THE
  INDIVIDUAL MANUFACTERER TO DETERMINE
  EFFECTIVENESS OF PARTICULAR MATERIAL

HOW TO TEST EFFECTIVENESS OF DBM
78
DEMINERALIZED BONE MATRIX (DBM)

• Growth factor activity is variable between tissue
  banks and between donors1
• Some products are terminally sterilized, which
  may further decrease BMP availability

1 Han B et al. J Orthop Res. 21(4)648-54, 2003.
79
BIOACTIVITY ASSAY

• CURRENT ASSAYS EVALUATE THE DBM WITHOUT CARRIER
  MATIRX
• ? DATA ASSAYS ON DBM ASSAY WITH CARRIER
  ADD-MIXTURE (DATA NOT AVAIL)
• MOST DBM IS COMMERCIALLY AVALABLE MIXED WITH A
  CARRIER
• INDIVIDUAL CARRIERS MAY EFFECT HANDLING AND
  APPLICATION PROPERTIES AS WELL AS EFFICACY

80
DEMINERALIZED BONE MATRIX (DBM)
Gel
Strips
Putty
Paste

• Combination products with
• DBM chips
• Cancellous bone
• Synthetic bone graft substitutes

MORE EXPENSIVE THAN JUST PARTICULATE ALONE
81
DBM 10cc

• DBM WITH CARRIER COMPOSITE.
  AIDS IN HANDLING, DELIVERY AND
  IMPLANTATION CHARACTERISTICS 1100
  
• DBM PARTICULATE WITHOUT CARRIER 400
  

2007 PRICE
82
DBM

• THERE ARE NO GOOD PROSPECTIVE RANDOMIZED TRAILS
  IN HUMANS TO DETERMINE EFFICACY OF THESE
  MATERIALS

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DBM

• OVERALL DATA IS WEAK AT BEST FOR EFFICACY IN
  SPINAL FUSIONS, NONUNIONS AS STAND ALONE GRAFT
• MOST STUDIES DOCUMENT USE AS A GRAFT
  EXTENDER.NOT A STAND ALONE PRODUCT

WHAT WE KNOW
84
PLATELETS A SOURCE OF GROWTH FACTORS
PLATELETS IN RESTING STATE
RELEASED GROWTH FACTORS

• PLATELET DERIVED GROWTH FACTOR (PDGF)
• TRANSFORMING GROWTH FACTOR- ? (TGF-?)
• VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
• EPIDERMAL GROWTH FACTOR (EGF)
• INSULIN-LIKE GROWTH FACTOR (IGF)

Discoid shape
PLATELETS IN ACTIVATED STATE
Psuedopod formation
85
WHAT DOES PLATELET GEL DO?

• PROVIDES A RICH SOURCE OF MULTIPLE GROWTH FACTORS
  THAT SERVE A CRITICAL FUNCTION IN WOUND /
  FRACTURE HEALING
• FACTORS RELEASED DIRECT CHEMOTACTIC AND
  MITOGENIC EFFECTON OSTEOBLASTS AND OSTEOBLAST
  PRECURSORS (MSC)

PRE-CLINICAL ANIMAL STUDIES
86
WHAT DOES PLATELET GEL DO?

• AUTOLOGOUS PLATELET CONCENTRATES MODULATE AND
  UPREGULATES ONE GROWTH FACTORS FUNCTION IN THE
  PRESENCE OF OF A SECOND OR THIRD.
• RECOMBINANT GROWTH FACTORS (BMPs) FOCUS ONLY ON
  A SINGLE GENERATION PATHWAY SPECIFICALLY
  FOR EXPEDITING BONE FORMATION

PRE-CLINICAL STUDIES
87
PLATELET CONCENTRATE Osteopromotion for
accelerated bone growth
Rate
ENHANCE BONE HEALING
Remodeling
Hard callus formation
Soft callus formation
Clotting and inflammation
88
PLATELET GEL PREPARATION ISSUES

• DO YOU RECEIVE INTACT PLATELETS
• DO YOU RECEIVE FUNCTIONING PLATELETS

PLATELET CONCENTATE IS VARIABLE IN ITS QUALITY
AND HOW IT IS PRODUCED AT THE TIME OF DELIVERY
89
TOTAL GROWTH FACTORS RELEASED FROM PLATELET
CONCENTRATE PREPARATIONS
60 ml preparations
2000
1500
ng
1000
500
PDGF-AB
TGF-?1
KEVY S et.al.COMPARISON OF METHODS FOR POINT OF
CARE PREPARATION OF AUTOLOGOUS PLATELT GEL JECT,
2004.
90
IF YOUR LOOKING FOR A MULTICENTER, PROSPECTIVE,
RANDOMIZED, DOUBLE BLIND PLACEBO CONTROLLED
CLINICAL STUDY ON EFFICACY OF PLATLET GEL..
Need for well-controlled randomized clinical
studies to asses ideal concentration of the
different factors and to determine which
auto/alloplastic graft materials provides the
greatest effect
91
CLINICAL DATA ON EFFECT / EFFICACY ..in progress
PLATLET GELS FUNCTION AS AN EXCELLENT (BEST)
CARRIER FOR GRAFT MATERIALS
92
435 lb Pt with non-union and broken hardware
93
Marrow Aspirate DBM Platelet Gel
94
13 months
95
BIOLOGIC ENHANCEMENT CASCADE

• OSTEOINDUCTION WITH BONE MORPHOGENES BMPs
• MITOGENESIS OF UNDIFFERENTIATED PERIVASCULAR
  MESENCHYMAL CELLS (STEM CELLS) LEADING TO THE
  FORMATION OF OSTEOPROGENITOR CELLS

Tissue specific effect
EFFECT OCCURS LATER IN THE HEALING CASCADE
96
BONE MORPHOGENESIS CASCADE

• ANGIOGENESIS VASCULAR INVASION (INFLAMMATORY
  PHASE)
• OSTEOCLAST RELEASE OF INHERENT BMP FROM HOST BONE
  ACTS SYNERGISTICALLY WITH IMPLANTED BMP TO
  STIMULATE CELLS TO DIFFENTIATE DIRECTLY INTO BONE
  FORMING UNITS

DAY 10-11
97
ACTION OF EXOGENOUS BMPS
98
BIOLOGIC ENHANCEMENT CASCADE

• OSTEOINDUCTIVE FACTORS
• BMP-2 (rhBMP-2)
• INFUSE (BMP-2 TYPE 1 COLLAGEN)
• BMP-7
• OP-1 (BMP-7 BOVINE COLLAGEN)

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Tibial Nonunion Study

• IM NAILING WITH.Autograft vs. BMP-7 Implant
• Study Population
• Tibial Nonunions (challenging ) n122 (61/grp)
• Minimum 9 month (9-285 months)
• No surgery or healing 3 months prior to treatment
• Success criteria
• Full weight-bearing
• Less than severe pain
• Radiographic bridging (3 of 4 vs any views)
• No surgical retreatment (additional criterion)

100
BMP-7 Implant WITH IM NAIL FOR NONUNION
Clinical problem Bone loss Nonunion Loss of
function Pain GoalBridge DefectRestore
functionRelieve pain
Post-op
9 Months Post-op
24 Months Post-op
101
CLINICAL RESULTSBMP-7

• MULTICENTER TRIAL
• gt 122 TIBIAL NON-UNIONS RANDOMIZED PROSPECTIVE
  TREATMENT BMP-7 vs AUTOGRAFT WITH IM NAILING
• RESULTS SIMILAR FOR BOTH GROUPS
  86 UNION
• NO BIOCOMPATABILITY ISSUES FOR OP-1
• AT ISSUE DELIVERY SYSTEMS

FRIEDLANDER. et.al..
JBJS 83-A S1-151, 2001
102
CLINICAL RESULTSBMP-2

• MULTICENTER TRIAL
• gt 450 OPEN TIBIAL Fxs RANDOMIZED PROSPECTIVE
  TREATMENT WITH IM NAIL..
• WITH BMP-2 AT WOUND CLOSURE
• 1.5 mg ml
• 0.75 mg ml
• WOUND CLOSURE ONLY

RECOMBINANT HUMAN BONE MORPHOGENIC PROTEIN-2 FOR
TREATMENT OF OPEN TIBLA FRACTURES. GOVENDER,
S.et.alJBJS..DEC 2002
103
CLINICAL RESULTS BMP-2

• MULTICENTER TRIAL
• ANALYSIS OF OPEN TIBIA FxS
• FASTER HEALING TIMES
• FEWER SECONDARY INTERVENTIONS
• FEWER HARDWARE FAILURES
• 1.5 mg/ml DOSAGE SUPERIOR TO .75mg/ml .reduced
  frequency of 2nd interventions and overall
  invasiveness of treatment

RECOMBINANT HUMAN BONE MORPHOGENIC PROTEIN-2 FOR
TREATMENT OF OPEN TIBLA FRACTURES. GOVENDER,
S.et.alJBJS..DEC 2002
104
Gd IIIa OPEN TIBIA IMPLANTED WITH BMP-2 AT
SECONDARY WOUND CLOSURE
105
13 WEEKS POST OP DEMONSTRATES COMPLETE HEALING
COST VERY EXPENSIVE
106
CLINICAL RESULTS BMP-2

• TIBIAS WITH BMP-2
• FEWER SECONDARY INTERVENTIONS
• FEWER HARDWARE FAILURES
• HIGHER COST TO HOSPITALS UP FRONT
• TIBIAS WITHOUT BMP-2
• MORE SECONDARY PROCEEDURES
• LONGER DELAY TO WORK RETURN (IF THEY WORKED)
• HIGHER COST TO SOCIETY AND HOSPITAL LONG RUN

COST EFFECTIVNESS FOR TREATMENT OF OPEN TIBLA
FRACTURES WITH BMP-2 . JONES A,
.et.alOTA..OCT, 2004
107
RECOMBINANT HUMAN BMP-2 AND ALLOGRAFT COMPARED
WITH AUTOGENOUS BONE GRAFT FOR RECONSTRUCTION OF
DIAPHYSEAL TIBIAL FRACTURES WITH CORTICAL
DEFECTS. A RANDOMIZED, CONTROLLED TRAILJONES
AL, BUCHOLZ RW et.al. J.BONE JOINT
SURG.88(7)1431-41.2006
CLINICAL RESULTS BMP-2

• RECONSTRUCTION TIBIAL DEFECTS (ave. 4 cm)
• Autograft vs. BMP-2 allograft

108
JONES AL, BUCHOLZ RW etal.
EFFECTIVE FOR DEFECT MANAGEMENT???CRITICAL SIZE???

• 15 patients in each group
• HEALED WITHOUT FURTHER INTERVENTION
• 10pts AUTOGRAFT
• 13pts BMP-2 ALLOGRAFT
• FUNCTIONAL OUTCOME SAME FOR BOTH GROUPS (SMFA)
• MAY SUBSTITUE FOR AUTOGRAFT IN THESE PATIENTS

109
22 y/o s/p MCCrash gdIIIA , 3 cm defect
110
BMP-2 implant at definitive wound closure
111
Frame off 7 months
112
AUTOGENOUS CELLULAR THERAPIES
113
PROPOSED CELLULAR HARVEST EXPANSION/ IMPLANTATION
SCHEME
EXTRACT CELLS
CULTURE EXPANDED MESENCYMAL CELLS
LOADED ON CONDUCTIVE SURFACE
BUILD BONE
114
CONCENTRATION OF MARROW DERIVED CELLS

• MULTIPLE ILIAC ASPIRATES CONCENTRATED BY SIMPLE
  CENTRIFUGATION FOLLOWED BY IMPLANTATION
• SIG. INCREASE IN BONE FORMATION IN AN ANIMAL MODEL

CONNOLLY J.F. et.al.DEVELOPMENT OF AN OSTEOGENIC
BONE-MARROW PREPARATION. JBJS71(5)684-91, 1989
115
ASPIRATE INJECTION

• PERCUTANEOUS INJECTION OF MARROW ASPIRATE
  (NON-CONCENTRATED) DBM IN CANINE DEFECTS
  (COMPOSTIE GRAFT)
• COMBINATION OF DBM MARROW ASPIRATE SYNERGISTIC
  RESPONSE gt MORE THAN DBM OR MARROW ALONE
  COMPARABLE TO AUTOGRAFT

TIEDEMAN J.J, CONNOLY J.R. et.al.TREATMENT OF
NONUNION BY PERCUTANEOUS INJECTION OF BONE MARROW
AND DBM. CLIN ORTH.268294,1991
116
HUMAN ASPIRATE INJECTION RESULTS

• THE USE OF ILIAC ASPIRATES COMBINED WITH DBM HAS
  BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF
  SPECIFIC LONG BONE CONDITIONS.
• THE USE OF ILIAC ASPIRATES WITHOUT SELECTIVELY
  CONCENTRATING THE BONE FORMING CELLS HAS BEEN
  SHOWN TO HAVE A HIGH FAILURE RATE
  (WATSON,CONNOLLY)

117
SELECTIVE RETENTION STRATEGIES NOW BEING DEVELOPED

• ABILITY TO ASPIRATE MARROW ELEMENTS THEN
  CONCENTRATE OR SELECT OUT FOR THE SPECIFIC BONE
  FORMING CELLS..
• THEN IMPLANT THEM INTO SITE OF PATHOLOGY TO USE
  AS A GRAFT SUBSTITUE MATERIAL
• TECHNOLOGIES NOW IN USE ON A SELECTIVE BASIS

118
SELECTIVE RETENTION STRATEGIES

• PRE-CLINICAL CELLULAR GRAFTS ENHANCED IN THIS WAY
  HAVE BEEN SHOWN TO HAVE GTER EFFICACY THAN
  ASPIRATES ALONE
• MANY SMALL CLINICAL SERIES REPORTED USING THIS
  TECHNIQUE
• DEMONSTRATE SATISFACTORY UNION RATES FOR SELECT
  PATIENTS
• THIS TECHNOLOGY IS CELL BASED AND HOLDS GREAT
  PROMISE FOR FUTURE GRAFT REPLACEMENT TECHNIQUES

119
HOWEVER.. THE TECHNIQUE OF ASPIRATION IS
CRUCIAL!!!!

• MULTIPLE ASPIRATION SITES ALONG CREST
• ASPIRATE SMALL QUANTITIES 2-3 cc THEN REDIRECT
  NEEDLE AND RE-ASPIRATE
• THIS TECHNIQUE SHOWN TO ACHIEVE HIGHEST ACTIVE
  AND VIABLE BONE COLONY FORMING UNITS (CFUs)

Muschler et.alJBJS 1997, 2002.
120

• HIGHER YEILD OF COLONY FORMING UNITS OBTAINED
  WITH SMALL ASPIRATE QUANTITY 3-4 cc COMPARED TO
  LARGER AMOUNTS
• WITH LARGER QUANTITIES CELL COUNTS ARE DILUTED
  WITH DECREASED CELLS AVAILABLE

121
74 y/o 2nd exchange nail
122
(No Transcript)
123
AUTOGRAFT DBM
124
13 MONTHS POST GRAFT
125
REVISION WITH ILIAC ASPIRATE CONCENTRATE DEMIN
ALLOGRAFT BMP-7
126
4-5000.00 per dose
RECOMBINANT BMP-s
HOLD IN RESERVE FOR RECALCITRANT NON-UNION.gt5
FAILED INTERVENTIONS OR SIGNIFICANT RISK
FACTORS..
TGF B SUPERFAMILY
BMP- 7
BMP-2
OSTEOGENIC BMPS
GROWTH DIFFERENTIATION BMPS
ANGIOGENESIS, INFLAMMATION, CHONDROGENIC,
CHEMOTAXIC
127
BONE GRAFT SUBSTITUE ISSUES TO CONSIDER

• DELIVERY MECHANISMS
• TIMING OF IMPLANTATION
• DOSE / RESPONSE
• CONCENTRATION OF MATERIAL vs TOTAL DOSE DELIVERY
• LOCAL HOST ENVIRONMENT
• VASCULARITY
• LOCAL SEPSIS
• MECHANICAL STABILITY REQUIREMENTS

128
CELL BASED THERAPIES SUBSTITUTES/EXPANDERS/INDUCT
IVE DEVICES SHOULD I USE THEM????

• 1. SURGEON FRIENDLY HANDLING CHARACTERISTICS ?
  CARRIER PROPERTIES
• 2. AUGMENT / DECREASE NEED FOR SIGNIFICANT
  AUTOGENOUS GRAFTING
• 3. EXPAND INDICATIONS AND EFFICACY OF BONE
  GRAFT SUBSTITUTES FOR OSTEOINTEGRATION

129
ASK BEFORE you Use the Technology?

• (HOW) DOES IT WORK???????
• IS IT SAFE?
• IS IT COST EFFECTIVE????

130
THANK-YOU
DIVISION OF ORTHOPAEDIC TRAUMATOLOGY
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