Mandibular reconstruction / oral surgery courses

MANDIBULAR RECONSTRUCTION
WITH BMP & PRP

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INDIAN DENTAL ACADEMY
Leader in continuing dental education


INTRODUCTION
 Mandibular defects in OMFS are common.
 Mandibular reconstruction in OMFS is a major challenge.
 Gold standard for reconstruction
 Newer techniques.


DEFINITION OF RECONSTRUCTION :
 Reconstruction refers to the rebuilding or the restoration
of original form and function that have been lost owing to
disease or treatment of disease.
CLASSIFICATION OF BONY DEFECTS
 Cantor and curtis
 HCL classification


MANDIBULAR RECONSTRUCTION
a. Immediate
 Inability to detect recurrence
 Increased risk of graft rejection
b. Delayed
 Late covering of primary site
 Increase in complication
 Increased hospital stay
 Cost


GOALS OF RECONSTRUCTION :

 Restore maxillofacial form
 Maintain quality of tissues
 Maintain oral competence
 Maintain oral cavity function
 Achieve coverage of soft tissue defect


RECONSTRUCTION TECHNIQUES :
Free bone grafts

Poor tolerance to infection

‘K’ Wires

Failure rate of 70%

Stainless steel intra
meduallary pins

Scarring & Contracture

AO plates

Excellent cosmetic result

Titanium, Vitallium

Good outcome

Stainless steel wire mesh

Good outcome

Allo plast + Free bone grafts

Greater
potential
neovascularization


for

Osteomyocutaneous flaps :
 Pec. major flap with 5th and 6th rib
 Trapezius flap with scapular spine
 Sternocleido mastoid flap with clavicle
 Latissmus dorsi flap with iliac crest

Distraction osteogenesis


LIMITATION OF CONTEMPORARY TECHNIQUES :
 Limited application
 Short supply of graft material
 Risk of disease transmission
 Potential morbidity at donor site


TISSUE ENGINEERING
Definition :
Construction of a device in the laboratory containing
viable cells and biological mediators in a synthetic or biologic
matrix that could be implanted in patients to facilitate
regeneration of particular tissues.
 Bone morphogenic protein - BMP
 Platlet rich plasma – PRP


BONE MORPHOGENIC PROTEIN
History :


Neuhof in 1917 and Huggisn in 1930 demosntrate

“Heterotropic osteogenesis”.
 In 1965 Urist unveils the concept of auto induction –
Ectopic bone formation.
 In 1971 the term osteoinduction was coined.


In

1988

Wozney

and

Colleagues

clones

morphogeneic protein using recombinant technology.


bone

PRINCIPLES OF BONE REGENERATION

 OSTEOINDUCTION
 OSTEOCONDUCTION
 OSTEOGENESIS


SOURCE OF BMP :
CYTOKINES
PDGF ; TGFb; FGF; IGF
TGFb1 ; TGFb2
BMP
BMP 1 - 15

BMP

- Present

in high concentration in bone matrix,

osteosarcoma tissue, dentin matrix.
TGFb – Found in high concentration in platlets about 50ng /
ml of whole blood, sequestred within platlets.

PERIOSTEUM – Source of Osteoprogenitor cells in bone


TYPES OF BMP
BMP1 -

Regulatory molecule; activates BMP

BMP2 -

Ectopic bone formation; OI ; present in bone
spleen, liver, brain, kidney, heart, placenta.

BMP3 -

OI ; Present in lung, kidney, brain, interstine.

BMP4&5 -

OI ; Embryogenesis

BMP6 -

Not Osteoinductive

BMP7 -

OI ; Bone differentiation

BMP8&9 -

OI ; Bone formation

BMP 12&13- Inhibition of terminal differentiation of
myoblast.

STEPS IN OSTEOINDUCTION :
 Chemotaxis of osteoprogenitor cells.
 Synthesis of Type III collagen.
 Differentiation of chondroblasts.
 Conversion of connective tissue into cartilage.
 Invasion by capillaries.
 Calcification
 Synthesis of Type IV collagen
 Synthesis of Type I collagen
 Ossification

FUNCTIONS :
Growth factors

-

Cell to cell interaction in skeletal
tissue.

BMP Type 2

-

a. Acts on immature
osteoprogenitor cells.
b. Differentiate them into
osteoblasts and chondroblasts
for bone formation.

TGFb2

-

Stimulates proliferation of
osteoprogenitor cells and also
chemotactically attracts
osteoprogenitor cells to sites of
bony defects.

BMP in mandibular reconstruction
 Pleiotropy
 Bone graft
- Cortical, cancellous or both
 Scaffolds ;
-They are the supporting or carrier materials.
-They are rigid, solid, gel, paste or injectible fluid.
-They can be absorbable, resorbable,
osteoconductive or osteoinductive.
 Matrix metallo proteinases
- Biodegrades matrices and hydrogels.

biodegradable,

FORMS OF BMP :
 Bovine BMP – bBMP
 Recombinant human BMP – rhBMP
-‘K. Bessho’ advocates rhBMP due to consistency of safety
and quality for clinical application.
-rhBMP is not fully characterized
-Activity of rhBMP is 1/10th of bBMP.
-Synthesis of bBMP is very minimal 10 – 20mg / kg dry bone


APPLICATION OF BMP :
-

In clinical surgery BMP is applied as a paste.

-

It contains 1mg of purified BMP per cm3.

-

BMP action is decreased on sterilization by irradation

-

BMP is sterilized by defatting via chloroform /
ehtanoland freezing to -70º.


LIMITATION OF BMP :
- Bone inducing capacity is unpredictable
- Pathologic expression of BMP
(Yashika & Colleagues in CANCER in 1994) revealed 40%
of osteosarcoma or osteoinductive
- Osteoblast and fibrohistio cytic types account for highest
level of BMP
- No evidence to support BMP causes oncogenesis.
- Researchers in 10 years of animal studies in rhBMP has
reported no evidence of oncogenesis.
- In 2004, FDA cancels sanction for use of rhBMP for clinical
use in OMFS

CLINICAL RESEARCH :
1. Reconstruction of primate mandible with rhBMP2 and
bone marrow.
(Ichiro, Izumi, Shoji)
JOMS, 2001
University of Japan.
- Implantation of bone marrow alone, rhBMP + bone
marrow and rhBMP alone in mandible of Japanese
Monkey after creating segmental mandibular defects.
Carrier – PGLA.
- Results : rhBMP + BM > BM > rhBMP.

2. Reconstruction of mandibular defects with autologous
tissue engineered bone.
(Bradford, B. Kaban, Maria)
JOMS, 2004
University of Boston.
- MSC isolated from ilium of porcine were expanded in
culture and seaded to PGLA & Scaffolds. Four defects of
2x 2 cm was created and filled with autogeneous graft,
only scaffold, empty as control.
- Results
:
Mandibular defects can be successfully
regenerated by MSC on polymer scaffold with penetration
of bone and vessels.

3. Mandibular defects repair by TGFb and IGF1 released
from osteoconductive gel.
(Rachmiel ; Blumenfeld, Liune)
JCFS, 2005
University of Japan.
- Mandibular defects in rat mandible was filled with TGFb,
IGF1, both hydrogel and control and tested after 3rd and 6th
weeks
- Results : Defects filled with TGFb and TGFb + IGF1
showed greater bone formation with hydrogel scaffold.


PLATLET RICH PLASMA
Definition :
PRP is an autologous concentration of human platlets in a
small volume of plasma.
History :
1997– PRP was first introduced in OMFS by Whitman.
1998 – PRP’s role in bone formation with autogeneous bone
by Marx et al.


COMPONENTS OF PRP :
 IGF1
 PGDF
 TGF – b
 VEGF
 EGF
 Cell adheshion molecules


FUNCTIONS :


PGDF

–

Mitosis

of

healing

cells,

angiogenesis,

macrophage activation.
 IGF – Secreted by osteoblast, mytogenic to osteoblast line
of cells.
 PRP – Increases the number of growth factors in the graft


PROCUREMENT OF PRP :
 Withdraws 400 – 450ml of whole blood, 50ml per minute
with a speed of 5000 rpm.
 Citrate phosphate dextrose 1 : 5 for anticoagulation
Layers of PRP
 PPP – 200 ml
 PRP – 70 ml
 RBC – 180 ml
 1 to 3 ml of RBC layer is also added to PRP.

APPLICATION OF PRP :
 Initiation of clotting process
 PRP is mixed with PCBM
 10 ml of CaCl2 and 10,000 units of topical bovine thrombin
 In 10 ml syringe 6ml of PRP + 1ml of CaCl2 + 1ml of air is
added to form a gelatin mass.
 A PRP count of 1 million per micro litre is the benchmark
for “therapeutic dose of PRP”.


ROLE OF GROWTH FACTRORS IN PRP :
 Stimulation of cellular activity
 Release of PGDF, TGFb and IGF from platlets in the graft
 PDGF stimulates mitogenesis of marrow stem cells.
 Angiogenesis

of capillary
endothelial mitosis.

budding

by

inducing

 TGFb activates fibroblast and preosteoblast to initiate
mitosis and lay down bone matrix and collagen matrix to
support capillary in growth.
 By day 3, capilliaries penetrate the graft
 By day 14, complete permeation of capillaries takes place

 Life span of platlets in a site is 5 days.
 Aftermath, bone regeneration is by macrophages.
 Phase I Bone :
a. Formed in the first four weeks
b. Bone formed is disorganized woven bone
c. Little structural integrity present.
 Phase II Bone :
a. Mature lamellar bone
b. Presence of Haversion system
c. Presence of structural integrity
d. Formation of periosteum and endosteum

USES OF PRP :
 Accelerated rate of bone formation was demonstrated on
plain radiograph using PRP.
 Rate of bone generation is not only faster but also greater,
verified by histiodensitometric study.


CLINICAL RESEARCH :
1. PRP : Evidence to support its use
(Richard E. Marx)
JOMS, 2004
University of Miami
Clinical Contraversy
- Failures are due to inappropriate sequestration of platlets,
less therapeutic platelet level, inappropriate preparation of
PRP.
- Benefits are continuity defects, sinus lift augmentation
grafting, ridge preservation grafting, periodontal /
perioimplant defects
- Autologous PRP is the safest
- PRP does not promote infection, pH is 6.5

2. Differential growth factor retention by platlet rich
plasma.
(Rick ; Jenifer, Sidney)
JOMS, 2005
- To evaluate an optimal substrate for extended growth
factor retention.
- PRP + TRAP ; PRP + Bovine thrombin ; PRP + bone
substitues.
- PRP + bovine thrombin results in large immediate release
of growth factors which is lost via interstitium.
- PRP + TRAP – release of growth factor at a slow and
sustained rate for longer period

3. Effect of PRP with autogeneous bone graft for maxillary
sinus augmentation in a rabbit model
(Kevin ; Jeffry ; Gloria)
JOMS, 2005
- This study fails to find a direct stimulatory effect of PRP
on healing of autogeneous bone graft using static and
dynamic histomorphometric analysis.


SUMMARY :
 Tissue engineering methods in bone regeneration is
promising based on the scientific studies carried out in
animals.
 The hurdles of large bone reconstruction by tissue
engineering has yet to be explored especially in in
humans.
 With strides of advancement in technology and global
research there is little down that reconstruction of bony
defect will be a reality.


REFERENCE :
 Tissue engineering – Richard E Marx ; Lynch
 Bone morphogenic protein – Lindholm
 JOMS ; 2001, 2004, 2005
 JCFS ; 2005
 IJOMS ; 2004


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Mandibular reconstruction / oral surgery courses

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