Orthobiologics

J. Tracy Watson, MD
Professor of Orthopaedic Surgery Chief,
Division of Orthopaedic Traumatology
St. Louis University School of Medicine

Created February 2007

Orthobiologics:
Common Sense Approach for
Orthopaedics and Traumatology

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?

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)

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

COMPOSITION OF BONE GRAFT

ORGANIC 30%
MATRIX 98%
HYDROXYAPPETITE 95%

plus
MAGNESIUM
SODIUM
FLOURIDE
POTASSIUM
CHLORIDE

MINERAL
MINERAL70%
70%

CELLS 2%

COMPOSITION OF BONE GRAFT

CELLS 2%

COLLAGEN 95%
NON-COLLAGENOUS
PROTIENS 5%

MATRIX
MATRIX 98%
98%

OSTEOBLASTS
OSTEOCYTES
OSTEOCLASTS

CATEGORIES OF INTERVENTION

CURRENTLY AVAILABLE
INTERVENTIONS

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

CURRENTLY AVAILABLE
INTERVENTIONS
CONDUCTIVE
SUBSTRATES
A-CELLULAR
BIOACTIVE
MEMBRANES
SOFT TISSUE
SCAFFOLDING

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

OSTEOINDUCTION
CELLULAR ELEMENTS
CELLULAR
ENVIRONMENT
CELLULAR INDUCTIVE
SUBSTANCES

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

MOTHER CELL

Mother cell will give rise to daughter cells which then can
differentiate into many potential tissue types

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

TGF- /Inhibin-Activinlike 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-13

BMP-12
BMP-11

BMP 7
BMP 2
P 8- 9

GROWTH &
DIFFERENTIATION BMPS

BMP 4
BMP 5

OSTEOGENIC
BMPS

IGF-I

EGF

FGF

OTHER PEPTIDE
SIGNALING
MOLECULE
FAMILIES

PDGF

VEGF

LIMP
1

HEALING CASCADE
Binding of
plasma
fibronectin to
Demin.Bone
Matrix.MSC
attachment and
proliferation

BONE MORPHOGENESIS
CASCADE
BINDING OF PLASMA FIBRONECTIN TO
IMPLANTED DEMIN. MATRIX
FACILITATES MESENCHYMAL CELL
ATTACHMENT AND PROLIFERATION

DAY 1-3

CHONDROBLAST DIFFERENTIATION
AND CHONDROGENESIS
DAY 5-9
ANGIOGENESIS &VASCULAR INVASION
ENDOCHONDRAL BONE REMODELED
DAY 10-11

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

DAY 1-3

PDGF-FGF-TGF-

FACTORS ACTIVATE MACROPHAGE ACTIVITY

SURFACE KENETICS TO
FACILITATE ATTACHMENT
AND PROLIFERATION OF
MSC

3-D ARCHITECTURE
OF CONDUCTIVE
SUBSTRATES
IMPORTANT

THROUGH
CHEMOTAXIS,
STEM CELL
MIGRATION AND
IMPLANTATION
ONTO THIS
SPECIFIC
CONDUCTIVE
SUBSTRATE
SURFACE

CELLULAR DIFFERENTIATION

OSTEOCLAST

OSTEOBLAST

TWO CATEGORIES OF CONDUCTIVE

SUBSTRATES
CALCIUM
CERAMICS
CaPO4
CaSO4

CONDUCTIVE SUBSTRATES

VOID
FILLERS

METAPHYSEAL DEFECTS
VASCULAR
REGION
BIOLOGICALLY
COMPETENT
SOLITARY VOID
LARGE /
CONTAINED

REQUIRES + /MECHANICAL
SUPPORT

METAPHYSEAL
REQUIREMENTS
CONDUCTIVE
SUBSTRATE ONLY
RELIABLE
SUBCHONDRAL
SUPPORT
(+HARDWARE)
INDUCTIVE
FACTORS NOT
NEEDED

METAPHYSEAL DEFECTS
SURGEON NEEDS
TO KNOW THE
RATE OF
INCORPORATION

SIMPLE
SUBSTITUE
ONLY!!!!

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

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

POROSITY OF MATERIAL
CaPO4
POROSITY OF MATERIAL
FACILITATES CELLULAR
PENETRATION
INCREASED SURFACE
AREA
RESORBED MATERIAL OR
OSTEOINTEGRATION
.CELLULAR MEDIATED
EVENT

3-D ARCHITECHTURE
IMPORTANCE OF POROSITY
ABILITY TO
FOSTER CELLULAR
INTERACTIONS
BETWEEN THE
INTERSTICIES OF
THE CONDUCTIVE
MATERIALS

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

-TCP

EXAMPLES OF CALCIUM
PHOSPHATE MATERIALS

VITOSS

PORE SIZE APPROX. CANCELLOUS

BONE

-TCP

CALCIUM PHOSPHATE

CONDUIT

PORE SIZE APPROX. CANCELLOUS

BONE

-TCP

CALCIUM PHOSPHATE

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

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.

HA

ProOsteon

ProOsteon
LONG INCORPORATION TIME
> 36-48 MONTHS..(NEVER)
Bucholz RW et al, Clin Orthop. 240: 53 - 62, 1989.

CONDUCTIVE SUBSTRATES

CEMENTS

CONDUCTIVE SUBSTRATES
CEMENTS
DELIVERY AND
CONTAINMENT
MAY BE
PROBLEMATIC

Norian SRS

Norian patients had less pain and earlier

restoration of motion

At 1 year follow-up:
Satisfactory result
Malunion

SRS
82 %
18 %

Control
56 %
42 %

Sanchez-Sotelo J, et al. J Bone Joint Surg Br. 2000

Aug;82(6):856-63.

MATERIAL STILL PRESENT 28-30mo.

POST-OP.LONG RESORBTION TIME
M. TYLLIANAKIS,et.al.OTHOP. (25, 3; 2002)
GREECE

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

Self setting paste into hardened

crystalline form

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

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

CaSO4 CERAMICS
CRYSTALLINE INDEPENDENT
RATE OF INCORPORATION
CONSISTENT THROUGHOUT
WIDE RANGE OF MATERIAL
PROPERTIES
LOW COMPRESSIVE STRENGTH
10-25 MPa
GRAFT EXTENDER

CaSO4 CERAMICS
PELLETS
BEAD KITS
INJECTABLE

POROSITY OF
MATERIAL CaSO4
VERY LITTLE INITIAL POROSITIY ON
IMPLANTATION DURING
DISSOLUTION INCREASED SURFACE
AREA EXPOSED
RESORBED MATERIAL OR
OSTEOINTEGRATION .CHEMICAL
DISSOLUTION MEDIATED EVENT

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

CaSO4 PELLET
IMPLANTATION

3 months resorbtion
time

CANCELLOUS VOID FILLED WITH RESORBABLE

4
CaSO

GRADUAL OSTEOINTEGRATION WITH

4
CONDUCTIVE RESORBABLE CaSO

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

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

INJECTABLE
SELF
SETTTING
CEMENTS

18 MONTHS POST OP
WITH COMPLETE
INCORPORATION

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: 1:103-107, 2004.

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

PO & SO CEMENTS
4

POOR TENSION RESISTANCE

WEAK IN SHEAR STRESS
AVOID DIAPHYSEAL REGIONS

PHOSPHATES MAY FRAGMENT AND

DEGRADATE WHEN
INSTRUMENTED WITHOUT
APPROPRIATE CURING OF
MATERIAL

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)

BONE MORPHOGENESIS
CASCADE
BINDING OF PLASMA FIBRONECTIN TO
IMPLANTED DEMIN. MATRIX
FACILITATES MESENCHYMAL CELL
ATTACHMENT AND PROLIFERATION

DAY 1-3

CHONDRO/OSTEOBLAST DIFFERENTIATION
AND CHONDRO/OSTEOGENESIS
DAY 5-9
ANGIOGENESIS &VASCULAR INVASION
ENDOCHONDRAL BONE REMODELED

BONE MORPHOGENESIS
CASCADE
CHONDRO/OSTEOBLAST
DIFFERENTIATION AND
CHONDRO/OSTEOGENESIS

DAY 5-9

MACROPHAGES DEGRADE BONE

SUBSTRATE WITH RELEASE OF INHERENT
FACTORS FROM BONE MATRIX

RELEASE OF AUTOGENOUS GROWTH

FACTORS FROM MACROPHAGE ACTIVATION
EARLY FACTORS

RELEASE OF EARLY
GROWTH FACTORS
PEPTIDE SIGNALING MOLECULES
FGF, TGF-, PDGF, IGF, VEGF

LOCATION
SPECIFIC

STIMULATE ACTIVITY OF
CHONDROPROGENITOR AND
OSTEOPROGENITOR CELLS AND
MATURE CONDRO- AND
OSTEOBLASTS

OSTEO-PROMOTIVE

BONE MORPHOGENESIS
CASCADE
BINDING OF PLASMA FIBRONECTIN TO
IMPLANTED DEMIN. MATRIX

DAY 1-3

FACILITATES MESENCHYMAL CELL

ATTACHMENT AND PROLIFERATION

CHONDROBLAST DIFFERENTIATION AND

DAY 5-9
CHONDROGENESIS
ANGIOGENESIS &VASCULAR INVASION
(INFLAMMATORY PHASE)
DAY 10-11
ENDOCHONDRAL BONE REMODELED

IMPORTANCE OF SOFT
TISSUE COVERAGE TO
INFLAMMATORY
PHASE OF HEALING
(REQUIRES VASCULAR INGROWTH FROM
SURROUNDING TISSUES)

DEMINERLIZED BONE
MATRIX (DBM) in theory contains
MANY components of TGF- superfamily
TGF B
SUPERFAMILY

BMP 3

BMP- 7
BMP- 2
BMP-14
12
BMP-13

BMP-

P 8- 9

BMP-4
BMP -5

OSTEOGENIC
BMPS

BMP-11

GROWTH &
DIFFERENTIATION
BMPS

ANGIOGENESIS, INFLAMMATION,
CHONDROGENIC, CHEMOTAXIC

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

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

DBM

VIAGRAF
DYNAGRAFT
ORTHOBLAST
ACCELL
OPTIFORM
OPTIUM
INTERGRO

DBX
GRAFT
CHAMBER
OSTEOSET2-DBM
ALLOMATRIX
OSTEOFIL
GRAFTON
ORTHOBLAST II

MANY COMMERCIAL BRANDS AVAILABLE

(PARTIAL LIST)

BIOACTIVITY ASSAY
IN VIVO
MEASURE ALK.
PHOSPHOTASE ACTIVITY

IN VITRO
STIMULATION OF HUMAN
OSTEOBLAST CULTURE
HOW TO TEST EFFECTIVENESS OF DBM

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

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

Han B et al. J Orthop Res. 21(4):648-54, 2003.

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

DEMINERALIZED BONE
MATRIX (DBM)

Putty

Paste

Gel

Paste

Putty

Strips

Combination products with:

DBM chips
Cancellous bone
Synthetic bone graft
substitutes

MORE
EXPENSIVE
THAN JUST
PARTICULATE
ALONE

DBM

10cc

DBM WITH CARRIER COMPOSITE.

AIDS IN HANDLING, DELIVERY AND
IMPLANTATION CHARACTERISTICS

$1100
DBM PARTICULATE WITHOUT CARRIER

$400

2007 PRICE

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

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

PLATELETS: A SOURCE OF GROWTH FACTORS

PLATELETS IN RESTING STATE

RELEASED GROWTH FACTORS:

Discoid shape

PLATELETS IN ACTIVATED
STATE
Psuedopod formation

PLATELET DERIVED GROWTH

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

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

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

: Osteopromotion for
accelerated bone growth

PLATELET CONCENTRATE

Rate

Accelerated Healing Rate

Normal Healing Rate

ENHANCE BONE HEALING

Clotting and
inflammation

Soft callus
formation

Hard callus
formation

Remodeling

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

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.

IF
YOUR
LOOKING
FOR
A
Need for well-controlled
MULTICENTER,
randomized
clinical
studies
to
PROSPECTIVE,
assesRANDOMIZED,
ideal concentration
of
the
DOUBLE
differentBLIND
factorsPLACEBO
and to determine
CONTROLLED
CLINICAL
which
auto/alloplastic
graft
STUDY
ON
EFFICACY
OF
materials provides the greatest
PLATLET GEL..

effect

CLINICAL DATA ON
EFFECT / EFFICACY

..in progress

PLATLET GELS FUNCTION AS

AN EXCELLENT (BEST)
CARRIER FOR GRAFT
MATERIALS

435 lb Pt with non-union and

broken hardware

Marrow Aspirate + DBM + Platelet Gel

13 months

BIOLOGIC ENHANCEMENT
CASCADE
OSTEOINDUCTION WITH BONE
MORPHOGENES BMPs
MITOGENESIS OF
Tissue specific effect
UNDIFFERENTIATED
PERIVASCULAR MESENCHYMAL
CELLS (STEM CELLS) LEADING TO
THE FORMATION OF
OSTEOPROGENITOR CELLS
EFFECT OCCURS LATER IN THE HEALING CASCADE

BONE MORPHOGENESIS
CASCADE
DAY 10-11
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

ACTION OF
EXOGENOUS BMPS

BIOLOGIC ENHANCEMENT
CASCADE
OSTEOINDUCTIVE FACTORS
BMP-2 (rhBMP-2)
INFUSE (BMP-2 + TYPE 1
COLLAGEN)
BMP-7
OP-1 (BMP-7 + BOVINE
COLLAGEN)

Tibial Nonunion Study

IM NAILING WITH.Autograft vs. BMP-7
Implant
Study Population
Tibial Nonunions (challenging ) n=122 (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)

BMP-7 Implant WITH IM NAIL

FOR NONUNION
Clinical problem:
Bone loss
Nonunion
Loss of function
Pain

Goal:
Bridge Defect
Restore function
Relieve pain
Post-op

9 Months Post-op 24 Months Post-op

CLINICAL RESULTS
BMP-7
MULTICENTER TRIAL
> 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

CLINICAL RESULTS
BMP-2
MULTICENTER TRIAL
> 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

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

Gd IIIa OPEN TIBIA IMPLANTED WITH BMP-2 AT

SECONDARY WOUND CLOSURE

13 WEEKS POST OP
DEMONSTRATES
COMPLETE HEALING
COST VERY
EXPENSIVE $$$$

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

CLINICAL RESULTS BMP-2

RECONSTRUCTION TIBIAL DEFECTS
(ave. 4 cm)
Autograft vs. BMP-2 + allograft
RECOMBINANT HUMAN BMP-2 AND ALLOGRAFT
COMPARED WITH AUTOGENOUS BONE GRAFT FOR
RECONSTRUCTION OF DIAPHYSEAL TIBIAL FRACTURES
WITH CORTICAL DEFECTS. A RANDOMIZED, CONTROLLED
TRAIL
JONES AL, BUCHOLZ RW et.al. J.BONE JOINT SURG.88(7):143141.2006

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
JONES AL, BUCHOLZ RW etal.

22 y/o s/p MCCrash gdIIIA , 3 cm defect

BMP-2 implant at definitive wound

closure

Frame off 7 months

AUTOGENOUS
CELLULAR THERAPIES

PROPOSED CELLULAR HARVEST

EXPANSION/ IMPLANTATION SCHEME
EXTRACT

CULTURE
EXPANDED
MESENCYMAL
CELLS

CELLS

LOADED ON
CONDUCTIVE
SURFACE

UILD
BONE

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

ASPIRATE INJECTION
PERCUTANEOUS INJECTION OF
MARROW ASPIRATE (NONCONCENTRATED) + DBM IN CANINE
DEFECTS (COMPOSTIE GRAFT)
COMBINATION OF DBM + MARROW
ASPIRATE SYNERGISTIC RESPONSE > 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.268:294,1991

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)

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

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

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.

 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

74 y/o 2nd exchange nail

AUTOGRAFT + DBM

13 MONTHS POST GRAFT

REVISION WITH ILIAC ASPIRATE CONCENTRATE +

DEMIN ALLOGRAFT + BMP-7

RECOMBINANT BMP-s

$4-$5000.00
per dose

HOLD IN RESERVE
FOR
TGF B
SUPERFAMILY
RECALCITRANT NON-UNION.>5
FAILED INTERVENTIONS OR
SIGNIFICANT RISK FACTORS..
BMP- 7

BMP-2

OSTEOGENIC
BMPS
GROWTH &
DIFFERENTIATIO
N BMPS

ANGIOGENESIS, INFLAMMATION,
CHONDROGENIC, CHEMOTAXIC

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

CELL BASED THERAPIES

SUBSTITUTES/EXPANDERS/
INDUCTIVE 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

ASK BEFORE you Use the

Technology?

(HOW) DOES IT WORK???????

IS IT SAFE?
IS IT COST EFFECTIVE????

DIVISION OF ORTHOPAEDIC
TRAUMATOLOGY
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