bone morphogenetic protein

8/14/2019 Bone Morphogenetic Protein

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BONE MORPHOGENETICBONE MORPHOGENETIC

PROTEINPROTEIN

JBJS-JUN 2005-BY TERMAATJBJS-JUN 2005-BY TERMAAT

DEN BOERDEN BOER

BAKKERBAKKERPATKAPATKA

HAARMANHAARMAN

Department of surgery andDepartment of surgery andtraumatology ,VU university medicaltraumatology ,VU university medical

center, Amsterdam, the Netherlandscenter, Amsterdam, the Netherlands


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The treatment of # remains the challenge for theThe treatment of # remains the challenge for the

orthopedic surgeonorthopedic surgeon

The life time risk of # is 1-2 for male &1/3 in femalesThe life time risk of # is 1-2 for male &1/3 in females The majority of # heal normally betn 5-10% of the patientsThe majority of # heal normally betn 5-10% of the patients

have impaired fracture-healing.have impaired fracture-healing.

The corner stones for successful bone healing are-The corner stones for successful bone healing are-

Biomechanical stability and biological vitality of the boneBiomechanical stability and biological vitality of the bonewhich provides the environment in which new bone canwhich provides the environment in which new bone can

formform

There are condition in which the bone formation can beThere are condition in which the bone formation can be

impaired are-vascular comprise ,infection ,mechanicalimpaired are-vascular comprise ,infection ,mechanicalinstability and systemic diseases.instability and systemic diseases.


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JBJS JUN 2005 VOL87 A PAGE 1367


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Increasing understanding of theIncreasing understanding of the

bone physiology and advancementsbone physiology and advancements

in biotechnology have led to a newin biotechnology have led to a new

surgical therapy for controling andsurgical therapy for controling and

modulating bone healing with growthmodulating bone healing with growth

factors.factors.


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HISTORYHISTORY URIST- 1965-URIST- 1965- coined the term bonecoined the term bone

morphogenetic protein and also describedmorphogenetic protein and also describedthe phenomenon of bone induction orthe phenomenon of bone induction or

osteoinduction after he did experiment inosteoinduction after he did experiment in

rodents.rodents.

1980- it was found that not a single protein1980- it was found that not a single protein

but GROUP OF PROTEINS in the bone matrixbut GROUP OF PROTEINS in the bone matrix

was responsible for osteoinduction.was responsible for osteoinduction.

At present more than 16 human BMP hasAt present more than 16 human BMP hasbeen identified with the aid of molecularbeen identified with the aid of molecular

biology techniques.biology techniques.


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PHYSIOLOGY OF BMPPHYSIOLOGY OF BMP

(OSTEOINDUCTIVE(OSTEOINDUCTIVE

ACTIVITY)ACTIVITY) CHENG et alCHENG et al demonstrated indemonstrated inmesenchymal progenitor andmesenchymal progenitor and

osteoblastic cells infected byosteoblastic cells infected byadenovirus-mediated geneadenovirus-mediated gene

transfer of BMP, the relativetransfer of BMP, the relative

osteoinductivity of different BMPosteoinductivity of different BMPat various stages of theat various stages of the

differentiation processdifferentiation process


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RECEPTORS AND INTRACELLULAR SIGNALLINGRECEPTORS AND INTRACELLULAR SIGNALLING


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PRECLINICAL RESEARCH WITHPRECLINICAL RESEARCH WITH

BMPsBMPs BIOLOGICAL ACTIVITY OF BMPs-BIOLOGICAL ACTIVITY OF BMPs-

The production of individual recombinant humanThe production of individual recombinant humanBMPs(rh-BMPs) by biotechnology companies led to twoBMPs(rh-BMPs) by biotechnology companies led to twoimportant conclusions-important conclusions-

1.Single BMPs are osteoinductive by themselves.1.Single BMPs are osteoinductive by themselves.

2.The osteoinductivity of a single BMP has a dose 2.The osteoinductivity of a single BMP has a dose

response ratio.response ratio. So the conc of BMP at the site of implantation is moreSo the conc of BMP at the site of implantation is moreimportant than the total dose of the BMP,If the dose isimportant than the total dose of the BMP,If the dose istoo low there will be inadequate bone formation and iftoo low there will be inadequate bone formation and ifits too high than there will be more bone formation.its too high than there will be more bone formation.

Local overdose of the BMP could be expected to leadLocal overdose of the BMP could be expected to leadto heterotopic ossification,but this phenomenon hasto heterotopic ossification,but this phenomenon hasbeen shown to occur under physiological conditions.been shown to occur under physiological conditions.

GLASER t lt d t t d i it t


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GLASER et al-et a - demonstrated in vivoemonstrate n v vothat heterotopic ossification inthat heterotopic ossification in

fibrodysplasia ossificans progressivafibrodysplasia ossificans progressiva

may not due to genetic overmay not due to genetic overexpression of BMP-4but due to underexpression of BMP-4but due to under

expression of the extra cellularexpression of the extra cellular

antagonist of BMP-antagonist of BMP-nogginnoggin

The dose of BMP needed for clinical efficacy must overcome aThe dose of BMP needed for clinical efficacy must overcome athreshold-threshold- Human doseHuman dose

3.5mg/4ml of sterile saline solution or 0.88mg/ml of sterile3.5mg/4ml of sterile saline solution or 0.88mg/ml of sterilesolution for rhBMP-7solution for rhBMP-7

12mg/8ml of sterile water or 1.50mg/ml of sterile water for12mg/8ml of sterile water or 1.50mg/ml of sterile water forrhBMP-2.rhBMP-2. AS the rhBMP are expensive SO this raises the imp questionAS the rhBMP are expensive SO this raises the imp question

regarding the combination therapies of BMP and theregarding the combination therapies of BMP and thedevelopment of advanced delivery systems that are moredevelopment of advanced delivery systems that are more

efficient and more cost effectiveefficient and more cost effective


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DELIVERY SYSTEM FOR BMPsDELIVERY SYSTEM FOR BMPs 19901990- BMP were isolated ,identified and- BMP were isolated ,identified and

physiological mechanism were discovered.physiological mechanism were discovered. It also become evident that local application of BMPsIt also become evident that local application of BMPs

is essential as there systemic clearance is highis essential as there systemic clearance is high The natural delivery system ie Bone matrix is highlyThe natural delivery system ie Bone matrix is highly

effective as the proteins are incorporated into matrixeffective as the proteins are incorporated into matrix

that serves as reservoir so research has beenthat serves as reservoir so research has beenconcentrated on how to deliver these proteinsconcentrated on how to deliver these proteinsefficiently at the site of implantation by varying theefficiently at the site of implantation by varying thedelivery systemsdelivery systems

There are two approaches-There are two approaches-

1 .Protien therapy1 .Protien therapy - recombinant protein is delivered- recombinant protein is delivereddirectly to the regeneration site with or withoutdirectly to the regeneration site with or withoutcarrier matrixcarrier matrix

2. Gene therapy2. Gene therapy - protein is delivered indirectly by- protein is delivered indirectly by

its encoding geneits encoding gene


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CARRIERSCARRIERS

An ideal carrier should be biocompatibleAn ideal carrier should be biocompatible,biodegradable and osteoinductive.,biodegradable and osteoinductive.

The primary function of these delivery materials is toThe primary function of these delivery materials is toincrease the efficacy of BMPs by preventing rapidincrease the efficacy of BMPs by preventing rapid

diffusion of the inductive agent away from the implantdiffusion of the inductive agent away from the implantsite and by providing a sustained release of thesite and by providing a sustained release of theproteinprotein

With the use of buffer delivery system


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CARRIERSCARRIERS For the treatment of # - the delivery must beFor the treatment of # - the delivery must be

coupled with carrier that degrades rapidly to meetcoupled with carrier that degrades rapidly to meetthe rate of new bone formationthe rate of new bone formation

For the treatment of nonunion and for spinalFor the treatment of nonunion and for spinalfusion-the carrier characteristic have to include afusion-the carrier characteristic have to include aslow release of BMP.slow release of BMP.

Carriers material-Carriers material-

Demineralized collagenous bone matrix, collagenDemineralized collagenous bone matrix, collagenproduct, resorble polymers, gelatin hydrogels,product, resorble polymers, gelatin hydrogels,calcium phosphate ceramics such as tricalciumcalcium phosphate ceramics such as tricalcium

phosphate and hydroxyapatite, resorble calciumphosphate and hydroxyapatite, resorble calciumphosphates cement (alpha-BSM) and combinationphosphates cement (alpha-BSM) and combinationof these materialsof these materials


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CARRIERSCARRIERS

Collagen based carries posses theCollagen based carries posses the

appropriate characteristics as type Iappropriate characteristics as type I

collagen the main component of bonecollagen the main component of bone

matrix is biocompatible andmatrix is biocompatible andresorbableresorbable

The rh BMP available for the clinicalThe rh BMP available for the clinical

applications are delivered in type-Iapplications are delivered in type-Ibovine collagen carrier either collagenbovine collagen carrier either collagen

sponge or collagen particlessponge or collagen particles


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GENE THERAPYGENE THERAPY

There two ways to deliver the required the BMPThere two ways to deliver the required the BMPgene to the regeneration site-gene to the regeneration site-

In vivo transduction-direct delivery to theIn vivo transduction-direct delivery to thetissue so that host cells are transfected andtissue so that host cells are transfected and

express proteinexpress protein In vitro transduction-thro transfection ofIn vitro transduction-thro transfection of

cultured cells which are implanted at thecultured cells which are implanted at theregeneration site and subsequently expressregeneration site and subsequently express

the protein.the protein. Despite using the gene therapy to expressDespite using the gene therapy to express

growth factors precaution must be takengrowth factors precaution must be takenregarding using safe viral vectors.regarding using safe viral vectors.


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CLINICAL EFFICACY OF BMP FORCLINICAL EFFICACY OF BMP FOR

STIMULATING FRACTURE HEALINGSTIMULATING FRACTURE HEALINGAuthor Year Study design Indicati

on

No rhBMP

Riedelandvalentin

opran

1999 Feasibiltystudy

Opentibial #

12 rhBMP-2

Besttstudygroup

2002 Prospective

,controlled,ra

ndomized

Opentibia #

437 rhBMP-2


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BONE DEFECT ANDBONE DEFECT AND

NONUNIONNONUNIONAuthor Year Studydesign IndicationNo rhBMP

M keeet al 2003 Prospective

,controlled,randomized

Open tibia # 124 rhBMP-7

Geesink et al 1999 Prospective

,doubeblid,randomized

fibular bonedefect

24 rhBMP-7

Friedlaenderet al

2001 Prospective


Open tibia#nonunion

127 rhBMP-7


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CLINICAL EFFICACY IN SPINAL FUSIONCLINICAL EFFICACY IN SPINAL FUSION

Author Year Studydesign

IndicationNo rhBMP

ohnsson et al 2002 Prospective

,controlled,ran

domized

Post lat fusion 20 rhBMP-7

Burkus et al 2002 Prospective


Interbodyfusion

279 rhBMP-2

Burkus et al 2002 Prospective


Ant lumbar

fusion

42 rhBMP-2


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THANK YOUTHANK YOU

THANK YOUTHANK YOU

bone morphogenetic protein

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