Platelet-rich brin: Its role in periodontalregeneration

Preeja Chandran a,*, A

a Department of Periodontics, PMSThiruvananthapuram 695028, Kera

b Scienc

R ed 7 SeA 2013

KEYWORDS

Tissue engineering;

Abstract Platelets can play a crucial role in periodontal regeneration as they are reservoirs of

opment of therapeutic alternatives which are easy to prepare, non-toxic or biocompatible to living

membranes enriched with platelets and growth factors. Evidence from the literature suggests the

potential role of PRF in periodontal regeneration and tissue engineering. The slow polymerization

concentrate PRF and its potential role in periodontal regeneration.g Saud University.

3. What is PRF? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

* Corresponding author. Tel.: +91 9447492992; fax: +91 472 258

7874.

E-mail address: drpreeja@gmail.com (Preeja C.).

Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

The Saudi Journal for Dental Research (2014) 5, 117122

King Saud University

The Saudi Journal for Dental Research

www.ksu.edu.sawww.sciencedirect.com1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

2. Role of platelets in periodontal wound healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 2013 Production and hosting by Elsevier B.V. on behalf of Kin

Contents2352-0035 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.http://dx.doi.org/10.1016/j.ksujds.2013.09.001during centrifugation and brin-based structure makes PRF a better healing biomaterial than PRP

and other brin adhesives. The main aim of this review article is to briey describe the novel plateletGrowth factors tissues and economically cheap that might result in the local release of growth factors accelerating

hard and soft tissue healing. PRF is a natural brin-based biomaterial prepared from an anticoag-

ulant-free blood harvest without any articial biochemical modication that allows obtaining brinPlatelet-rich brin;

Platelet-rich plasma;

Regeneration;

growth factors and cytokines which are the key factors for regeneration of the bone and maturation

of the soft tissue. Platelet-rich plasma (PRP) and platelet-rich brin (PRF) are autologous platelet

concentrates prepared from patients own blood. Recent researches are being focused on the devel-Kerala Institute of Medical

eceived 18 June 2013; revisvailable online 20 Octoberrun Sivadas b

College of Dental Science & Research, Golden Hills, Vattappara, Venkode (PO),la, India

es, Thiruvananthapuram 695029, Kerala, India

ptember 2013; accepted 7 September 2013REVIEW ARTICLE

4. Historical background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

5. Potential benets of using PRF in periodontal regeneration6. Protocol for preparation of PRF . . . . . . . . . . . . . . . . . . .7. Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8. Evidence for the role of PRF in periodontal regeneration . .9. Evidence for the role of PRF in tissue engineering . . . . . . .10. Drawbacks of PRF . . . . . . . . . . . . . . . . . . . . . . . . . . . .11. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

Periodontal disease is dened as a complex, multifactorial dis-ease characterized by the loss of connective tissue attachment

with destruction of periodontal tissues. The aim of periodontaltherapy is to eliminate inammatory process, prevent the pro-gression of periodontal disease and also to regenerate the lostperiodontal tissues. Periodontal regeneration is a complex

multifactorial process involving biologic events like cell adhe-

118 Preeja C, Arun SPlatelets play a key role in wound healing and hence wound

healing after periodontal treatment can be accelerated by theuse of platelet concentrates. The wound healing process initi-ated by the formation of blood clot and after tissue injury inperiodontal surgery causes adherence and aggregation of

platelets favoring the formation of thrombin and brin. Inaddition, there is release of certain substances from plateletsthat promote tissue repair, angiogenesis, inammation and im-

mune response. Platelets also contain biologically activeproteins and the binding of these secreted proteins within aFigure 1 Test tube showing platelet-rich brin after centrifuga-

tion of blood.2. Role of platelets in periodontal wound healingsion, migration, proliferation, and differentiation in an orches-trated sequence.1 Periodontal regenerative procedures include

soft tissue grafts, bone grafts, root biomodications, guidedtissue regeneration, and combinations of these procedures.2

The current perspective is that regenerative periodontal thera-

pies to date can only restore a fraction of the original tissuevolume 2 and have a limited potential in attaining completeperiodontal restoration.3 Various biomaterials have been usedfor periodontal tissue regeneration in addition to autogenous

and allogenic bone grafts but not a single graft material is con-sidered as gold standard for the treatment of intrabony defects.

Periodontal wound healing requires a sequence of interac-

tions between epithelial cells, gingival broblasts, periodontalligament cells, and osteoblasts. The disruption of vasculature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

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during wound healing leads to brin formation, platelet aggre-

gation, and release of several growth factors into tissues fromplatelets4 through molecular signals which are primarily med-iated by cytokines and growth factors. There is evidence that

the presence of growth factors and cytokines in platelets playkey roles in inammation and wound healing.5 Platelets alsosecrete brin, bronectin, and vitronectin, which act as a ma-

trix for the connective tissue and as adhesion molecules formore efcient cell migration.6 This has led to the idea of usingplatelets as therapeutic tools to improve tissue repair particu-

larly in periodontal wound healing.Platelet-rich brin (PRF) described by Choukroun et al.7 is

a second-generation platelet concentrate which contains plate-lets and growth factors in the form of brin membranes pre-

pared from the patients own blood free of any anticoagulantor other articial biochemical modications. The PRF clotforms a strong natural brin matrix, which concentrates al-

most all the platelets and growth factors of the blood harvest8,9

and shows a complex architecture as a healing matrix with un-ique mechanical properties which makes it distinct from other

platelet concentrates. PRF enhances wound healing and regen-eration and several studies show rapid and accelerated woundhealing with the use of PRF than without it.10,11 PRF is supe-rior to other platelet concentrates like PRP due to its ease and

inexpensive method of preparation and also it does not needany addition of exogenous compounds like bovine thrombinand calcium chloride. It is advantageous than autogenous graft

also because an autograft requires a second surgical site andprocedure. Thus PRF has emerged as one of the promisingregenerative materials in the eld of periodontics. This review

article explains the novel platelet concentrate PRF, its prepara-tion, clinical applications and benets and drawbacks overother biomaterials.

developing brin mesh or to the extracellular matrix can createchemotactic gradients favoring the recruitment of the stemcells, stimulating cell migration, differentiation, and promoting

repair. Thus the use of autologous platelet concentrates is apromising application in the eld of periodontal regenerationand can be used in clinical situations requiring rapid healing.

3. What is PRF?

PRF (platelet rich brin) was rst developed in France for use

in the eld of oral and maxillofacial surgery.7 Choukrounsplatelet-rich brin (PRF) is a leukocyte and platelet rich brinbiomaterial12 with a specic composition and three-dimen-

sional architecture. PRF is classied as a second generationplatelet concentrate as it is prepared as a natural concentratewithout the addition of any anticoagulants.13,14 PRF is often

called Choukrouns PRF as there are other platelet concen-trates with similar names such as Vivostat PRF (considereda pure platelet-rich plasma) or Fibrinet PRF (without leuko-cytes). PRF has a dense brin network with leukocytes, cyto-

kines, structural glycoproteins15 and also growth factors suchas transforming growth factor b1, platelet-derived growth fac-tor, vascular endothelial growth factor and glycoproteins such

as thrombospondin-1 during P7 day.16 Leukocytes that areconcentrated in PRF scaffold play an important role in growth

due to the complexity in preparation and risk of cross-infection.After that concentrated platelet-rich plasma (cPRP) was devel-oped with a less complex production protocol. It is prepared

from the patients own blood and is activated by the additionof thrombin and calcium. The structure consists of a threedimensional biocompatible brin scaffold with a limited volume

of plasma enriched in platelets. When PRP is activated thegrowth factors and proteins are released to the local environ-ment accelerating postoperative wound healing and tissue re-

pair.18 But the disadvantage of using PRP is that its propertiescan vary depending on the concentration of platelets, amountof leukocytes, the type of activator used and time of placementof brin scaffold after clotting. But there are certain risks asso-

ciated with the use of PRP.21 The presence of bovine thrombininPRPcan result in the development of antibodies to the clottingfactors V, XI and thrombin which can adversely affect the coag-

ulation process. In addition, bovine thrombin preparations con-tain clotting factor V which can result in immune systemactivation when challenged with a foreign protein. Other draw-

backs about the use of PRP include legal restrictions onhandling

Platelet-rich brin: Its role in periodontal regeneration 119factor release,16 immune regulation,9 anti-infectious activi-

ties,17 and matrix remodeling during wound healing. The slowpolymerization mode of PRF and cicatricial capacity creates aphysiologic architecture favorable for wound healing.18

4. Historical background

Platelets are used as powerful tools for periodontal regeneration

for the past two decades due to the key role of platelets in woundhealing process. Although the use of brin adhesives is well doc-umented from the past 30 years19,20 their use is still controversial

Figure 2 Platelet-rich brin after centrifugation.the blood and also controversies in the literature regarding thebenets and clinical outcome of use of PRP. All these have led

to the generation of a new family of platelet concentrate calledplatelet-rich brin which overcomes many of the limitations ofPRP. PRF is a potent autologous regenerative material withmany clinical applications in the eld of periodontics as it accel-

erates both soft tissue and hard tissue healing.

5. Potential benets of using PRF in periodontal regeneration

Platelet-rich brin is a second generation platelet concentratewhich can enhance both soft and hard tissue healing. Its advanta-ges over platelet-rich plasma include ease of preparation, ease of

application, minimal expense, and lack of biochemical modica-tion (no bovine thrombin or anticoagulant is required). This con-siderably reduces the biochemical handling of blood as well as

risks associated with the use of bovine-derived thrombin. PRFalso contains physiologically available thrombin that results inslow polymerization of brinogen into brin which results in a

physiologic architecture that is favorable to wound healing.The cytokines which are present in platelet concentrates

play an important role in wound healing. The structural

Figure 3 Platelet-rich brin after collection.

Dr. Choukroun7 in 2000. It is the current PRF technique

120 Preeja C, Arun Sauthorized by the French Health Ministry in which PRF isprepared without using an anticoagulant during blood harvest-ing or bovine thrombin during gelling.6

A standard protocol for PRF preparation should befollowed to obtain proper quantity and quality of the brinmatrix, leukocytes, platelets, and growth factors. The equip-

ment required for PRF preparation includes a PC-02 table cen-trifuge and a blood collection kit consisting of a 24 gaugebuttery needle and 9 ml blood collection tubes. A sample ofblood is collected from patient without anticoagulant in

10 ml tubes which are immediately centrifuged at a rate of3000 rpm for 10 min. During the centrifugation process, whenthe blood gets in contact with the test tube wall the platelet gets

activated leading to the initiation of coagulation cascade. Aftercentrifugation, the resultant product consists of three layers.The topmost layer consisting of acellular PPP (platelet poor

plasma), PRF clot in the middle and RBCs at the bottom ofthe test tube (see Fig. 1). The brin clot obtained after centri-fugation is removed from the tube and the attached red bloodcells scraped off from it and discarded (see Fig. 2). PRF can

also be prepared in the form of a membrane by squeezingout the uids present in the brin clot.

The duration of time between blood collection and centrifu-

gation process is an important parameter affecting the successand clinical outcome of this procedure. The slow handling ofblood to centrifugation process will result in diffuse polymeriza-

tion of brin leading to the formation of a small blood clot withirregular consistency. Hence a reproducible protocol for PRFconguration of PRF with respect to cytokine incorporation inbrin meshes is different from that present in PRP. The naturalpolymerization in PRF results in increased incorporation of the

circulating cytokines in the brin meshes (intrinsic cytokines).These intrinsic cytokines will be having an increased lifespanand they will be released and used only at the time of initial cic-

atricial matrix remodeling which creates a long term effect. InPRP and other brin adhesives the presence of articial addi-tives like bovine thrombin and calciumchloride results in sudden

brin polymerization causing loss of synergy between cytokinesand brin with faster physiologic elimination of these cytokines.

The threedimensionalorganizationofabrinnetwork inPRFand PRP affects the biologic and mechanical properties of these

platelet concentrates. During gelling of these brin structures,the brin brillae can be assembled in 2 ways, bilateral junctionsor equilateral junctions. In PRP there are bilateral junctions with

strong thrombin concentrations that allow thickening of brinpolymer with a rigid network resulting in poor cytokine entrap-ment and cellularmigration. But in PRF the equilateral junctions

are present with weak thrombin concentrations forming a neandexiblebrinnetworkwhich ismore elastic innature favoringcytokine entrapment and cellular migration.8 All these compara-

tive parametersmake PRF a better healing biomaterial than PRPand other brin adhesives.

Another added advantage of PRF is the presence of naturalbrin network in PRF which protects the growth factors from

proteolysis.12,22 PRF also favors the development of microvas-cularization leading to a more efcient cell migration.

6. Protocol for preparation of PRF

The classical technique for PRF preparation was invented byproduction should be followed to obtain a clinically usable brinclot with massive enmeshment of platelets (see Fig. 3).

7. Clinical applications

PRF is a powerful healing biomaterial with inherent regenera-tive capacity and can be used in various procedures such as for

the treatment of periodontal intrabony defects,10,11 treatmentof furcation,23 sinus lift procedures24 and as a scaffold for hu-man periosteal cells in vitro, which nds application in the eld

of tissue engineering.25

8. Evidence for the role of PRF in periodontal regeneration

PRF is enriched with platelets, growth factors and cytokinesincreasing the healing potential of both hard and soft tissue.4,5

There are only a few references in the literature about the biologic

properties of PRFwhen compared to other platelet concentrates.The literature mostly contains animal and human studies of theexperimental use of PRF and only limited in vitro studies have

been carriedouton the effectsofPRFoncell proliferation. Inspiteof the lack of scientically proven clinical benets, PRF is consid-ered as a healing biomaterial and is commonly used in implantand plastic periodontal surgery procedures to enhance bone

regeneration and soft-tissue wound healing.26,27 According toChoukron et al. PRF was initially used in implant surgery to en-hance the healing properties of the bone.7 PRF can promote the

healing of osseous defects by the following mechanisms. Accord-ing to Chang et al. PRF promotes the expression of phosphory-lated extracellular signal-regulated protein kinase (p-ERK) and

stimulates the production of osteoprotegerin (OPG)which inturncauses proliferation of osteoblasts.28 Another study by Huanget al. reported that PRF stimulates the osteogenic differentiation

of the human dental pulp cells by upregulating osteoprotegerinand alkaline phosphatase expression.29 PRF also releases growthfactors such as platelet-derived growth factor and transforminggrowth factorwhich promote periodontal regeneration.8,9 Chang

et al. in a study reported thatPRF stimulates cell proliferation in aspecic manner.30 PRF induces cell proliferation of osteoblasts,periodontal ligament cells and growth factors during a 3-day cul-

ture period and suppressed oral epithelial cell growth. These celltype-specic actions may be benecial for periodontal regenera-tion. Diss et al. in a 1 year prospective study on osteotome sinus

oor elevation using Choukrouns platelet-rich brin graftingmaterial clearly demonstrated that brin matrix of PRF directlypromotes angiogenesis.31 PRF when used as a membrane forguided tissue regeneration as a grafting material creates an im-

proved spacemaking effect which facilitates cell events that arefavorable for periodontal regeneration leading tomineralized tis-sue formation. PRF is having an inherent osteoconductive and/or

osteoinductive propertywhich is benecial for regenerationof thebone. Sanchez et al. in an experimental study compared the inu-ence ofPRPandPRFonproliferation anddifferentiationof oste-

oblasts and he reported that the afnity of osteoblasts to the PRFmembrane appeared tobe superior than the afnityof osteoblaststo PRP.21 Sharma et al. conducted a randomized controlled clin-

ical trial for the treatment of 3-wall intrabony defects in chronicperiodontitis patientswithplateletrichbrinandreporteda statis-tically signicant improvement in pocket depth reduction andbone ll in test group than in controls.10 A similar study was con-

ducted for the treatmentofmandibulardegree II furcationdefects

with plateletrich brin and showed a signicant improvement in Thus PRF is a potential tool in tissue engineering but clinical

Platelet-rich brin: Its role in periodontal regeneration 121pocket depth reduction, gain in clinical attachment level andbonell in test groupwhen compared to controls.23 Thorat et al. inves-

tigated the clinical and radiological effectiveness of autologousPRF in the treatmentof intrabonydefectsof chronicperiodontitispatients and reported a greater reduction in pocket depth, more

gain in clinical attachment level and greater intrabony defect llat sites treated with PRF than those treated with open apdebridement alone.11 Another randomized controlled clinical

trial was done in three treatment groups comprising of OFD(open ap debridement) + PRF, OFD+ PRF+HA (poroushydroxyapatite graft) and OFD alone as control. This studyshowed a signicant bone ll in plateletrich brin treated group

than in controls and a signicant bone ll and gain in clinicalattachment level in plateletrich brin combined with poroushydroxyapatitegraft than incontrolgroup.32Acomparative eval-

uationbetweenplatelet-richbrinandplatelet-richplasma for thetreatment of three-wall intrabony defects was done and showed agreater bone ll in PRF treated group than in PRP treated

group.33 The effect of platelet-rich brin on human periodontalligament broblasts and application in periodontal infrabony de-fects was studied by Chang et al. and reported that PRF was

found to increase extracellular signal-regulated protein kinasephosphorylation and osteoprotegerin in periodontal ligamentbroblasts and upregulation of alkaline phosphatase activity.Also, infrabony defects exhibited pocket reduction and clinical

attachment gain after six months with bone ll in defects.34

9. Evidence for the role of PRF in tissue engineering

The a-granules present in platelets contain growth factors likeplatelet derived factor (PDGF), transforming growth factor-b(TGF-b), vascular endothelial growth factor (VEGF), and epi-dermal growth factor (EGF).35 Platelet derived growth factor(PDGF) has an important role in periodontal regenerationand wound healing36 and receptor for PDGF is present on gin-

giva, periodontal ligament and cementum and it activates bro-blasts and osteoblasts promoting protein synthesis37 PDGF alsofunctions as a chemoattractant for broblasts and osteoblasts in

gingiva and periodontal ligament resulting in their activation.38

PRF promotes angiogenesis because as it has low thrombin le-vel optimal for the migration of endothelial cells and broblasts.PRF entraps circulating stem cells due to its unique brin struc-

ture. This property of PRF nds application in healing of largeosseous defects where there is migration of stem cells differenti-ating into osteoblast phenotype.26 PRF also helps in facilitating

adhesion and spreading of cells, regulates gene expression ofgrowth factors, growth factor receptors, proteins, and deter-mines the outcome of a cells response to growth factors due

to the presence of collagen, bronectin, elastin, other non-col-lagenous proteins, and proteoglycan in the extracellulat matrixof PRF.39 The use of PRF as a tissue engineering scaffoldwas investigated by many researchers for the past few years.

In a study by Gassling et al. reported that PRF appears to besuperior to collagen as a scaffold for human periosteal cell pro-liferation and PRF membranes can be used for in vitro cultiva-

tion of periosteal cells for bone tissue engineering.25 PRF hasimmune functions like chemotaxis as leukocytes present inPRF degranulates during activation and releases cytokines like

IL-1, IL-4, IL-6 and TNF-a. PRF also contains anti-inamma-tory cykokine such as IL-4 which requires further research.9aspects of PRF in this eld requires further investigation.

10. Drawbacks of PRF

The main shortcoming of PRF is its preparation and storage.The clinical benet of PRF depends on time interval between

speed of handling between blood collection and centrifugationas PRF is prepared without any addition anticoagulants.Another main disadvantage of PRF is its storage after

preparation.40 Also PRF membranes should be used immedi-ately after preparation as it will shrink resulting in dehydrationaltering the structural integrity of PRF.Dehydration also results

in the decreased growth factor content in PRF16 and leukocyteviability will be adversely affected altering its biologic proper-ties. PRF when stored in refrigerator can result in risk of bacte-

rial contamination of themembranes. These limitations with theuse of PRFcanbe circumvented by sticking onto a standard pro-tocol for preparation and preservation.

11. Future directions

In the future more studies should be carried out to correlatethe clinical outcome of PRF with its biologic mechanisms

which opens novel applications of this autologous plateletconcentrate. There are only limited studies in the literatureon the effect of PRF on cell proliferation and other biologic

effects. Therefore, more studies should be conducted whichopen newer strategies for the use of this platelet concentrate.

12. Conclusion

PRF by Choukrouns technique is a simple and inexpensivetechnique for the successful regeneration of periodontal

tissues. The main advantage is that PRF preparation utilizesthe patients own blood reducing or eliminating diseasetransmission through blood. In the future more studies and

clinical trials are needed to investigate potential applicationsof PRF in the eld of periodontal regeneration and tissueengineering and to extend its clinical applications.

Conict of interest

The author declared that there is no conict of interest.

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Platelet-rich fibrin: Its role in periodontal regeneration1 Introduction2 Role of platelets in periodontal wound healing3 What is PRF?4 Historical background5 Potential benefits of using PRF in periodontal regeneration6 Protocol for preparation of PRF7 Clinical applications8 Evidence for the role of PRF in periodontal regeneration9 Evidence for the role of PRF in tissue engineering10 Drawbacks of PRF11 Future directions12 ConclusionConflict of interestReferences