The purpose of this article was to review and critically assess the use of platelet rich plasma, recombinant human bone morphogenetic protein-2 and different scaffolds (i.e. tricalciumphosphate, polycaprolactone, demineralized bone matrix and anorganic bovine bone mineral) in oral and maxillofacial surgery comparing the relevant literature and own clinical experience.
A literature review was conducted using MEDLINE, MEDPILOT and COCHRANE DATABASE OF SYSTEMATIC REVIEWS. It concentrated on manuscripts and overviews published in the last five years (2006-2010). The key terms employed were platelet rich plasma, bone morphogenetic proteins and their combinations with the above mentioned scaffolds. The results of clinical studies and animal trials were especially emphasized. The statements from the literature were compared with authors’ own clinical data.
New publications and overviews demonstrate the advantages of platelet rich plasma in bone regeneration. The results from the literature review were discussed and compared with the publications detailing authors' own experiences.
A favourable outcome concerning newly grown bone was achieved combining platelet rich plasma in addition to optimal matrices with or without recombinant human bone morphogenetic protein-2, depending on the clinical case. As a consequence, the paradigm shift from transplantation of autogenous bone to bone tissue engineering appears promising.
Traditionally, the augmentation of bony defects in humans is carried out using
allografts, xenografts, autogenous bone, and synthetic biomaterials. The
transplantation of autogenous bone is regarded as the "gold standard". Globally,
there are more than 2 million autogenous bone transplantations in humans each year
in all parts of bone surgery [
1. In most cases, two surgical procedures are necessary: one for bone harvesting (e.g., from the iliac crest) and the other for implantation. This can cause suffering in some patients due to complications associated with the donor site (e.g. wound infection, chronic pain, nerve injuries, functional complications, bone fractures);
2. The risks in bone transplantation in the recipient site include wound infection,
necrosis, and resorption, representing up to 30% of the transplanted material [
Therefore the use of growth factors such as recombinant human bone morphogenetic protein-2 (rhBMP-2) and platelet rich plasma (PRP) has broken new ground in bone tissue engineering.
The purpose of this article was to review and critically assess the use of platelet rich plasma and recombinant human bone morphogenetic protein-2 combined with different scaffolds in oral and maxillofacial surgery comparing the relevant literature and own clinical experience.
A literature review was conducted using MEDLINE, MEDPILOT and COCHRANE DATABASE OF SYSTEMATIC REVIEWS. It concentrated on manuscripts and overviews published in the last five years (2006-2010). The key terms employed were platelet rich plasma (PRP), bone morphogenetic proteins (BMPs) and scaffolds used in combination. The results of clinical studies and animal trials were especially emphasised. We compared the statements from the literature with our own publications.
The use of PRP therapy was introduced in the late 1990s. PRP offers an easy and
cost-effective way to obtain high concentrations of growths factors for tissue
healing and regeneration. It is a volume of plasma fraction of autologous blood
having platelet concentrations above baseline (concentration in blood) obtained by
two different steps of centrifugation. The concentration of PRP as well as the total
amount that is inserted in the defect play an important role in the efficiency. In
the published literature, there seems to be controversial discussion regarding the
use of PRP and whether or not it favours bone regeneration [
However, all authors agree on the fact that platelets are the main regulators of the
inflammatory phase and play an essential role in the proliferation and
differentiation phase [
Amongst others, transforming growth factor (TGF-β), epidermal growth factor
(EGF), insulin-like growth factor-1 (IGF-1) and platelet-derived growth factor
(PDGF) are very important in bone regeneration [
In addition, vascular endothelial growth factor (VEGF), basic fibroblast growth
factor (bFGF), and platelet-derived endothelial cell growth factor (PDECGF) play an
essential role in angiogenesis, which is most important for nutrition of cells
[
Most publications and overviews demonstrate the advantages of PRP in bone
regeneration [
1.The acute inflammatory phase which includes platelet aggregation and activation and the migration of granulocytes and macrophages;
2. The mesenchymal cell proliferation and differentiation phase;
3. The phase of regeneration of the missing tissue by tissue-specific cells.
Marx et al. stated that monoclonal antibody assessment of cancellous cellular marrow
grafts demonstrate cells that were capable of responding to the growth factors by
bearing cell membrane receptors [
Current publications which support the positive effect of PRP to bone regeneration concentrate on the following facts and influence concerning PRP:
1.Importance of controlled release systems of growth and differentiation factors
using biomaterials in combination with PRP [
2.Enhancement of osteogenesis and angiogenesis [
3.Inhibition of osteoclast activation [
4.The enhancement of bone density adding PRP to a suboptimal doses of rhBMP-2 [
5.The activation of PRP using calcium chloride or/and thromboplastin solution [
6.A significant increase of early bone marrow stromal cells (BMSCs) proliferation and
differentiation using the combination of rhBMP-2 and bFGB (one of the signaling
molecules of PRP) [
7.Positive effect of PRP in bone regeneration in animal trials and clinical studies
in humans [
8.Relevance of PDGF and transforming growth factors (TGF-al and TGF32) for bone
regeneration [
The publications which point out negative results over the last years can be summarized in four groups:
1. The use of PRP in combination with anorganic bovine bone mineral (ABBM): several
authors did not find any advantage in using PRP in addition to ABBM in bone
development [
2. The second group combined PRP with autogenous bone, but could not improve the results by adding PRP to the autogenous bone.
Schaaf et al. used PRP for sinus lift augmentation with 11 - 12 fold concentration to
baseline [
Luaces-Rey et al. used only 10ml of venous blood to obtain PRP for alveolar cleft
reconstruction [
Soaking 1 cm3 of TCP (Vitoss Micro-Morsels®, Orthovita, PA, US) needs approximately 0.3 ml of PRP.
The same volume of polycaprolactone (PCL) (OsteoMesh®, Osteopore, Singapore) is able
to absorb approximately 0.7 ml of PRP. The needed quantity of augmentation material
and PRP depends on the volume that has to be augmented [
Nagata et al. [
The critical size defect model (CSD) is often used to study augmentation materials.
It has been defined as the smallest in situ bone defect that could not heal
spontaneously by bone formation during the lifespan of the animal. The CSD created
on the bony vault of the cranium (calvaria) represents a severe test for bone graft
substitutes. Compared with long bones, the skull is biologically rather inert due to
a poor blood supply and a relative deficiency of bone marrow. CSDs in the calvaria
have been established for different animal species [
In addition, investigators should remove the periosteum instead of preserving it
during the bone formation in the bone graft model [
Other authors increased the bone level by combining autogenous bone and PRP [
3. The third group, Gürbüzer et al. [
4. The fourth group representing Piemontese et al. [
Modern bone regeneration in periodontology using PRP or/and BMPs requires a totally
different surgical procedure. We have presented the bridge flap technique as a new
approach to avoid wound healing disturbances and to increase the clinical outcome
[
Bone tissue engineering can be described in three different models:
1. CSD-model in cranial bone;
2. CSD-model in long bone;
3. Vertical bone development (onlay technique).
1. A great number of publications using PRP in combination with different scaffolds
or in combination with autogenous bone could be found reporting on critical sized
calvarial bone defects in rats and other animals. They all proved better results in
the combination with PRP than without PRP [
A totally different treatment is required in the regeneration of human cranial bone
defects. Spector pointed out the advantage of regenerating tissues
Model of bone regeneration in critical sized defects of cranial bone in humans (vertical and lateral view), augmentation material containing cells matrices and signaling molecules, surrounding bone and periosteum, nutrition is predominantly carried out by the periosteum.
2.
Model of bone regeneration in critical sized defects of long bone defects in humans, augmentation material containing cells matrices and signaling molecules, surrounding bone and periosteum, nutrition is predominantly carried out by the periosteum.
3. A totally different issue appears in the model for bone tissue engineering in the
vertical dimension using onlay technique (
Model of vertical bone tissue engineering in humans, augmentation material containing cells matrices and signaling molecules, bone and periosteum only at one side, nutrition is predominantly carried out by the periosteum.
No publication was found representing vertical bone development using PRP and
scaffolds without adding signalling molecules in animal trials or clinical use in
humans. Literature research presented a huge number of publications concerning
autogenous bone grafting in onlay technique [
In cases of alveolar ridge atrophy, in addition to bone transplantation, a special
technique (called distraction osteogenesis) is employed. In this treatment, the
alveolar ridge is split horizontally into two parts. Osteodistraction devices are
fixed on both sides. The gap between both parts of the bone is filled with
autogenous bone or this gap regenerates through osteogenesis by distracting both
sides at a rate of 0.5 to 1 mm a day. This treatment is carried out for one to two
weeks followed by a period of consolidation of two to three months. Due to this,
patients have to wear this osteodistractor for several months, which means a severe
impairment of their quality of life [
In those cases, where the fixation of screws for the stabilization of the transplantation material is impossible and no osteodistraction devices can be fixed, traditional surgical treatments are unable to help. Here, only bone regeneration by means of tissue engineering techniques seems to provide a solution for the patients.
Without bone grafting, concentrated growth factors must be added to scaffolds in
order to obtain vertical development of a newly grown bone. This was proved by
Polimeni et al. using dental implants covered with growth factors [
A variety of different techniques have been developed in bone tissue engineering
during the last 20 years. In 1965, Urist wrote about bone growth by induction [
Zheng et al. reported at an early stage that rhBMP-2 induces endochondral
ossification [
1. Proliferation and differentiation of mesenchymal cells into chondroblasts and osteoblasts;
2. Production and maturation of cartilage and bone matrix;
3. Differentiation of circulating osteoclast precursor cells into osteoclasts.
Furthermore, Raida et al. [
In the field of oral and maxillofacial surgery, different authors have reported about
newly regenerated bone in animal models using growth factors [
We have demonstrated the advantages of combining rhBMP-2 with other carrier materials
such as demineralised bone matrix (DBM - Grafton®, Osteotech, NJ, US) which is
allogenic material and scaffolds instead of absorbable collagen sponge [
Although most of the authors present favourable results using BMPs the disadvantages have to be mentioned. One of them is high cost. Furthermore, BMPs induce the development of osteoblasts and osteoclasts, which means that a contrary development to the main target is also initiated. This negative effect can be partly counteracted by combining the BMPs with PRP.
Cenni et al. proved the inhibition of osteoclast activation using PRP [
Demineralized bone matrix (DBM), a form of allograft, possesses the properties of
osteoinductivity [
In
The augmentation of bone defects in the oral cavity using DBM exclusively was
reported by Kuvat et al. [
While Lin et al. [
Hutmacher [
Tricalcium phosphate (TCP) is an established anorganic augmentation material in bone
surgery throughout the world [
The combination of TCP, rhBMP-2 and PRP enables us not only to regenerate bone in
defects but also to recreate bone in a vertical direction. Compared with PCL,
combinations of PRP, rhBMP-2 and TCP can be shaped easily during the surgical
treatment. TCP is available as blocks and strips, which are flexible, and in form of
granules. PCL, however, is not provided as small shaped particles. In 2010, we
published a case where we regenerated a complete alveolar ridge in the maxilla of a
woman, who suffered from alveolar ridge atrophy due to a long time of wearing a
denture [
To our knowledge this is the first case which could be treated successfully this way.
It is not possible to compare the published clinical studies and animal trials concerning PRP and/or BMPs against each other due to the varying methodologies applied. However, single results especially in their summation could be evaluated.
From our point of view, comparable multicenter clinical studies should be carried out in the future.
Our critical assessment of the literature seems to emphasise, that bone tissue engineering techniques using suitable scaffolds combined with PRP and rhBMP-2 offer new options in reconstructive bone surgery. Current publications point out advantages in the bone regeneration using PRP combined with suitable scaffolds in comparison to the use without PRP. This was proved in critical sized defects in animals as well as in the treatment of humans and depends on signalling molecules released through the platelets. The induction of angiogenesis plays an important role concerning bone regeneration.
In cases of vertical bone development, the transplantation of autogenous bone is regarded as the "gold standard" till today. Due to the background of inevitable risks on the harvesting as well as on the recipient site, the transplantation of autogenous bone must be considered critically. Especially in the surgical treatment of multimorbid old patients the minimisation of risks has to be taken into account. Here, the new bone tissue engineering techniques offer alternatives. Cases, in which the residual bone does not allow to fix screws, can only be treated by means of tissue engineering techniques.
Adding PRP to BMPs suppresses the osteoclast induction of BMPs which counteracts to the development of newly grown bone. Thus, the amount of added signalling molecules can be reduced. Therefore, the clinical results can be improved and the costs decrease.
In the field of oral and maxillofacial surgery, where surgeons deal with well vascularised soft tissue, conditions for bone regeneration appear better than in trauma surgery. In addition, most interventions are performed as elective surgery. Thus the approach can be prepared precisely and performed with greater care. Hence, surgeons are able to preserve the covering periosteum which is necessary for nutrition and therefore for bone regeneration.
As a consequence, the paradigm shift from transplantation of autogenous bone to bone tissue engineering appears promising.
The authors wish to thank Ms. Conny Helbling for her linguistic review as a native speaker certified as English teacher.