effect of platelet-rich plasma on bone growth and ...€¦ · ""clinical instructor,...

45

Effect of Platelet-Rich Plasma onBone Growth and Osseointegrationin Human Maxillary Sinus Grafts:Three Bilateral Case Reports

Stuart J. Froum, DDS*Stephen S. Wallace, DDS**Dennis P. Tarnow, DDS***Sang-Choon Cho, DDS****

Platelet-rich plasma is an autologous product that is derived from whole bloodthrough the process of gradient density centrifugation. The proposed value of thisproduct in dental implantology and in bone augmentation procedures lies in theability to incorporate high concentrations of the growth factors PDGF, TGF-fJj,TGF-fJ,, and IGF, as well as fibrin, into the graft mixture. Research has shown anincreased bone maturation rate and improved bone density when this product, orits recombinant growth factors, is added to small bony defects or to larger defectsthat use autogenous bone as the grafting material. This study tested the efficacyof platelet-rich plasma in three bilateral sinus graft cases with grafts of anorganicbovine bone that contained minimal or no autogenous bone. Histomorphometricanalysis indicated that the addition of platelet-rich plasma to the grafts did notmake a significant difference either in vital bone production or in interfacia! bonecontact on the test implants. (Int J Periodontics Restorative Dent 2002;22:45-53.)

"Clinical Professor, Department of Surgical Services (Periodontics) andDepartment of Implant Dentistry, New York University College of Dentistry.

"Associate Clinical Professor, Ashman Department of Implant Dentistry,New York University College of Dentistry.

'"Professor and Chair, Ashman Department of Implant Dentistry, New YorkUniversity College of Dentistry

""Cl inical Instructor, Ashman Department of Implant Dentistry, New YorkUniversity College of Dentistry,

Reprint requests: Dr Stuart Froum, 17 West 54th Street, Suite 1 C/D,New York, New York 10O19.

The subantral augmentation (sinuselevation) procedure has beenshown to be a predictable methodfor increasing maxillary posteriorbone volume for the successfulplacement of load-bearing root-formimplants.1 Initial sinus elevation tech-niques relied on grafts that consistedof 100% autogenous bone har-vested from either oral (ramus, chin)or extraorai (iliac crest) donor sites,2"7

It has subsequently been found thatthe autogenous bone graft can bereplaced, in whole or in part, by avariety of allografts, xenografts, allo-plasts, and bone morphogeneticproteins with a highly predictablegraft and implant survival rate.8"20

In fact, the addition of autogenousbone to a composite graft may resultin a higher vital bone percentage atan earlier time, allowing for earlierimplant placement and subsequentloading.20-21

The sequence of treatment fordelayed implant placement with acomposite or nonautogenous graftbegins with a graft maturationperiod of 6 to 12 months. This inter-val is determined by the clinicianand is based on such factors as

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height of remaining crestal bone,quality of the remaining crestalbone, percentage of autogenousbone in the composite graft, andsurface texture of the implant(s)being placed. As early loading pro-tocols generally do not apply tografted bone, an osseointegrationperiod of approximately 6 months isallowed prior to second-stagesurgery (if applicable) and loading,Consequently, with staged implantplacement, the patient must waitbetween 12 and 18 months toreceive the implant restoration.Grafts of 100% autogenous bonemay require only 4 to 6 months formaturation, reducing the waitingperiod to 10 to 12 months.

The incorporation of platelet-rich plasma (PRP) activated withbovine thrombin (autologousplatelet gel) in a sinus graft has beenproposed as a method of creatingdense, vital bone in a shorter inter-val. If effective, this could reducethe interval from composite graftingto implant loading to one resem-bling that applicable to 100% auto-genous bone grafting (10 to 12months).

PRP is derived from wholeblood by sequestering and con-centrating the platelets via gradientdensity centnfugation. Improvedtechnology has allowed the blooddraw required for production of thefinal product to be reduced from450 mL to a much more manage-able 50 mL. This negates the needfor autotransfusion of the unusedfraction to maintain patient f uidvolume. As the growth factorsource is autologous, there is no

risk of disease transmission associ-ated with use of this technology.The proposed value of PRP in bonegrafting lies in the ability to incor-porate high concentrations of thegrowth factors PDGF, TGF-pv TGF-P2, and IGF, as well as fibrin, intothe graft mixture.

Marx et al22 used this technol-ogy in treating large mandibularcontinuity defects The increasedbone maturation rate and bone den-sity in these defects warranted a con-trolled clinical, histologic, and histo-morphometric study to evaluate thehealing response in sinus augmen-tation surgery using autologousplatelet gel (thrombin-activated PRP)with composite grafts containingminimal or no autogenous bone-

Method and materials

Three patients were selected fromthose who presented for maxillaryposterior implant therapy at the NewYork University Department ofImplant Dentistry. All were diag-nosed as requiring bilateral sinusaugmentation procedures prior tothe placement of the implants. Allpatients were advised of alternativetreatment plans and selected theplan requiring maxillary sinus eleva-tion. All patients with absolute con-traindications for this procedure,such as uncontrolled diabetes, long-term steroid usage, and blood dis-orders, were excluded. All patientswere informed of the requirementsfor participation in the study, and allhad the option of withdrawing fromthe study at any time. The nature of

the study was explained to eachpatient, and each signed an in-formed consent form that wasapproved by both the UniversityCommittee on Activities InvolvingHuman Subjects and the New YorkState Department of Health BloodResources Program.

On the day of surgery, a flip of acoin determined the experimentalside (PRP) and the control side (non-PRP). All six sinuses in this pilot studywere grafted with anorganic bovinebone (0.25 to 1 mm cancellousBioOss, Osteohealth}. All sinus graftswere performed with a lateral win-dow approach, modified from thetechnique presented by Wood andMoore.a The step-by-step surgicaltechnique and histomorphometricevaluation protocols have beendescribed in a previous article.20 PRPwas obtained from a blood draw of350 to 450 mL processed with aSequestra 1000 gradient density cellseparator (Medtronics). This yieldedapproximately 30 mL of PRP for clin-ical use. The remaining blood frac-tion was autotransfused through theclosed system to minimize bloodvolume loss. The BioOss graft mate-rial was hydrated with the PRP(experimental side only) in a dap-pen dish. Bovine thrombin wasaddedjust priorto placement of thegraft, resulting in the formation of anautologous platelet gel containingthe particulate graft material.Membranes were placed over all sixlateral windows, as this has beenshown to resuit in improved vitalbone counts/3

In case 3, miniature test implantsof 2.0 mm in diameter and 10 mm in

The International Journal of Periodontics & Restorative Dentistry

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Fig 1 (left) Panoramic view of testimplants in place in grafted sinuses in case3, Test sinus is on right, control is on left.

Fig 2 (below) Clinical view of test (PRP)sinus graft completed and test implants inplace in case 3.

length (3i/lmplant Innovations} wereplaced through the crestal bone intothe sinus grafts. Figures 1 and 2show the test implants in place incase 3. Placement of the permanentimplants was performed at 7months, 7.5 months, and 11 months,respectively, for cases 1, 2, and 3. Atthe time of implant placement,trephine cores of 3 mm in diameterand 10 mm in length were harvestedthrough the site of the former lateralwindow. The three test implantswere removed with a special guideand trephine at the same time. Thecores were fixed and sent to theHard Tissue Research Laboratory atthe University of Oklahoma Collegeof Dentistry for blinded histologicand histomorphometnc evaluation.The test implants were evaluatedfor total volume of calcifiedmaterial, percentage of vital bone,

percentage connective tissue, per-centage residual graft material, andpercentage of bone at the implant-bone interface.

Case 7

The patient was a 43-year-old non-smoking woman with an unremark-able medical history. Bilateral sinusgrafts were placed using 100%BioOss. PRP activated with bovinethrombin was used to hydrate thegraft on the experimental side priorto graft placement. A bioabsorbableBioGide membrane (Osteohealth)was placed over both lateral win-dows and stabilized in position withtitanium tacks. Cores were taken atthe time of implant placement,which occurred 7 months after sinusgrafting.

Case 2

The patient was a 35-year-oldwoman who was a light smoker(three to five cigarettes per day) withan unremarkable medical history.Bilateral sinus grafts were placedusing 95%+ BioOss and < 5% auto-genous bone harvested from thetuberosity. PRP activated with bovinethrombin was added to the graftmaterial for the left sinus prior tograft placement. BioGide mem-branes were placed over both lateralwindows and stabilized in positionwith titanium tacks. Cores weretaken at the time of implant place-ment, which occurred 7.5 monthsafter sinus grafting.


48

Case 3

The patient was a 69-year-oid non-smoking man with a history of hyper-tension. Bilateral sinus grafts wereplaced using 100% BioOss. PRP acti-vated with bovine thrombin wasadded to the graft material for theright sinus prior to graft placement.Nonabsorbable expanded polyte-trafluoroethylene (e-PTFE) mem-branes (Gore-Tex AugmentationMaterial oval-9, 3i/WL Gore) weretrimmed and placed over both fatera!windows and stabilized with titaniumtacks. Two test implants were placedin the right (test) and one in the left(control) sinus at the time of sinusgrafting. The sites chosen for theseimplants were determined to befuture final implant positions by useof computed tomographic scanningand SimPlant (Columbia Scientific)analysis with radiographic and surgi-cal templates. Cores were taken fromthe lateral window area and the testimplants were removed with sur-rounding bone cores at the time ofimplant placement, which occurred11 months after sinus grafting.

Results

Table 1 presents the vital bone con-tent of the three bilateral sinus grafts.The two test implants placed in thePRP sinus had slightly higher per-centages of imp!ant-bone contact(37.6% and 38.8%) than the testimplants placed in the contralateralnon-PRP sinus (33.8%). Figures; 3 and4 show representative histologicsamples of bone cores from case 3.

Figures 5 and 6 depict representativehistologic samples of the implant-bone interface of the test implants.

Discussion

There has been some confusion inthe literature regarding the nomen-clature of the blood productdescribed in this article. It has beenreferred to as PRP, platelet concen-trate, and autologous platelet gel.The definition of these blood prod-ucts or fractions can be found in thetechnical manual of the AmericanAssociation of Blood Banks.24 Thesedefinitions may not be applicable tothe technique that we are clinicallydescribing, as the plasma volume inwhich the sequestered platelets areultimately suspended is left to thediscretion of the clinician. Theauthors have opted for the use of theterm PRP in this article, as it is thenomenclature most often encoun-tered in the literature. In the litera-ture review, however, we have leftthe original authors' nomenclatureunchanged.

Numerous references in theperiodontal literature relate to theeffectiveness and mode of action ofPDGF, TGF-p, IGF, and fibrin in peri-odontal regeneration. These arereadily available and are beyond thescope of this article. Ross et al25 andWestermark26 have published com-prehensive reviews of the biology ofPDGF. A limited number of refer-ences, however, are found in thedental literature relating to the use ofPRP, platelet concentrate, autolo-gous platelet gel, or its recombinant

components as an adjunct to intra-oral bone grafting, implant place-ment, and/or grafting of the maxil-lary sinus.

Lynch et al27 reported on theeffects of combined recombinantPDGF-IGF on bone formationaround roughened titanium implantsin the dog model. Direct applicationto the implants stimulated the regen-eration of bone in periimplant sitesin the early phase of healing. Boththe implant-bone contact and fill ofthe periimplant spaces wereimproved. An immediate' extrac-tion-implant placement dog study28

observed a twofold increase inimplant-bone contact and in areas ofbone adjacent to the implant sur-face when using a recombinantPDGF and IGF-I gel beneath an e-PTFE membrane. Tayapongsak etal29 showed a 50% decrease in timefor remodeling and graft incorpora-tion with the addition of autologousfibrin adhesive to particulate can-cellous bone and marrow grafts inmajor mandibular reconstructionsurgery.

Marx et al22 reported on agroup of 88 cancellous cellular mar-row bone graft reconstructions of 5cm or greater mandibular continuitydefects; 44 received grafts with PRPadded, with 44 additional casesserving as a control. The grafts withPRP added showed a radiographicmaturation rate that was 1.62 to2.16 times that of the grafts withoutPRP. Histomorphometry demon-strated a greater bone density inthe PRP-added sites (74.0% + 11%)than in the sites where PRP was notadded (55.1% ± 8%). Additionally,


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Table 1 Histomorphometric analysis of vitalsinuses

TimeCase (mo)

1 72 7.5

3 11Mean

Graft

100%BioOss95%+ BioOss

% vital bonePRP (test)

1521

< 5% autogenous bone100% BioOss 34

23.3

bone in grafted

% vital bonenon-PRP (control)

1319

3221.3

Fig 3 (left) Non-demmeralized sectionfrom test (PRP) bone core (Stevenet'sblue—van Gieson's picric fuchsin stain; orig-inal magnification x 25).

Fig 4 (right) Non-demmeralized sectionfrom control (non-PRP) bone core(Stevenel's blue-van Gieson's picric fuchsinstain; original magnification x 25).

Fig 5 (left) Test implant from control(non-PRP) sinus from case 3. The superiorportion of the implant is in crestal bone.The apical portion is in the sinus graft(Stevenel's blue—van Gieson's picric fuchsinstain; original magnification x 2).

Fig 6 (right) Test implant from the test(PRP) sinus from case 3, which demonstrat-ed an overall 38.8% bone contact at theinterface (Stevenei"s blue-van Gieson's picricfuchsin stain; original magnification - W).

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the harvested cancellous marrowwas shown to have receptor sitesfor PDGF and TGF-|i. These werepredominantly centered aroundblood vessels (endosteal osteoblasts)but were also found in lesser num-bers in the marrow (marrow stemcells and osteoprogenitor cells).

Anitua30 used PRP in the prepa-ration of future implant sites. Extrac-tion sockets in 20 patients wereeither treated with PRP or left un-treated as controls. The sockets withPRP added exhibited greater buc-colmgual/palatal bone width,greater bone density, and faster softtissue coverage than the controls.

Kassolis et alJ1 recently pub-lished the results from 14 sinus graftsand three maxillary ridge augmen-tations using PRP with freeze-driedbone allografts (LifeNet). The graftswere mixed at a ratio of 0.5 g:2 mLPRP prior to insertion into the sinus.The grafts were then covered with aPRP "membrane." Histologic sec-tions revealed numerous areas ofosteoid and bone formation aroundthe freeze-dried bone allograft par-ticles, with no evidence of inflam-matory cell infiltrate. Histomorpho-metry was not performed, and therewere no controls; therefore, quanti-tative measurements could not bemade.

While the reports using auto-genous bone with PRP are promis-ing, other reports indicate that PRPmay not be effective when usedwith bone substitutes. Wironen etal32 have shown that PRP is notosteoinductive when added todemineralized bone matrix placedin pouches created in the recti

abdomini muscles of athymic nuderats. More specifically related to thepresent article, Terheyden33 com-pared rhOP-1 and PRP in bilateralsinus grafts that used 100% anor-ganic bovine bone as a graftingmaterial. The PRP was not effectivein producing bone regeneration,whereas in the contralateral sinusthe rhOP-1 was effective.

The literature appears to indi-cate that PRP may be effective in therelatively small periodontal defectand in larger bone defects whenthey are grafted wtth autologousbone. When autologous bone is notpresent in the graft, and the graft isof large volume, PRP may not pro-duce the desired stimulatoryresponse because vital bone cellsare needed for this stimulation tooccur.

Several authors22-34-35 (andRusso and Garg, unpublished data)have explained the mode of actionof platelet growth factors. In review,platelet degranulation and releaseof growth factors occurs within 3 to5 days, and the growth factor activ-ity may end in as soon as 7 to 10days. The PDGF that is released dur-ing degranulation is chemotactic formacrophages, which then maketheir own contribution to thewound-healing cascade. The com-bined roles of PDGF, TGF-p, andIGF are chemotaxis and mitogene-sis of stem cells and osteoblasts,angiogenesis for capillary ingrowth,bone matrix formation, and colla-gen synthesis. Fibrin maintains theregenerative space and provides amatrix for cell migration and prolif-eration.

The sinus model may be con-sidered to be a relatively large-volume graft- Uchida et al3* showedthat a sinus graft for multiple 15-mmimplants is likely to require 5.5 mL ofgraft material. When using a bonegraft substitute that contains neithervital celts nor bone morphogeneticproteins, bone formation must orig-inate from the bony wads (endostealosteoblasts and circulating stemcells). This healing pattern was pro-posed by Boyne and James2 andlater demonstrated in monkeys37

and humans.8

The most effective way to eval-uate the effects of PRP on the for-mation of bone in a sinus graft is tostudy the effect in bilateral sinusgrafts, with the addition of PRPbeing the only controlled variable.This is the first study to be per-formed in this manner. We chose touse a nonvital bone substitute as agraft material for two reasons. First,reports using autogenous bone inthe nonsmus model have shown PRPto have a positive effect on boneformation. Second, we felt it impor-tant to determine if PRP would havea similar positive effect on a nonm-ductive, nonvital graft material.

The above-outlined wound-healing mechanisms, coupled withthe relatively large graft size, couldexplain the minimal difference in vitalbone between test and controlsinuses in our study. With the excep-tion of case 2, which had minimalautogenous bone in the graft, therewere no cells (endosteal osteoblastsor stem cells) present in the body ofthe graft. Endothelial migration(revascularization) and migration of


cells from the bony sinus walls isunlikely to happen in an interval thatwould render the released growthfactors effective (7 to 10 days).Therefore, the stimulating effect ofthese growth factors may only occurclose to the bony wails. Each of thethree cases in this pilot study showedonly a 2% increase in vital bone onthe test (PRP) side, which is not clin-ically or statistically significant. Itwould appear that the differences invital bone formation between thethree cases relate to maturation timeof the graft and no1 to any effect ofthe PRP. The effect of time on the for-mation of vital bone in sinus graftswas demonstrated in prior articlesfrom the authors' sinus graftstudy.20'38

Our findings of similar vital boneformation in the test (PRP) and con-trol (non-PRP) sinuses are paralleledby the results seen in the cores con-taining the test implants that wereplaced bilaterally in case 3. The twotest implants placed in the PRP sinushad slightly higher percentages ofimplant-bone contact (37.6% and38.8%) than the test implant placedin the contralateral non-PRP sinus(33.8%). Considering that the nativecrestal bone above both sinuses wasapproximately 5 mm, the above val-ues represent an accurate reflectionof the healing response of the graftmaterials. As all three test implantswere well-integrated, it seems thatthe difference in implant-bone con-tact was not significant to implantsuccess. Of course, these valuesshould be viewed in light of the 11-month implant and graft healingperiod.

Aside from any effect that PRPmight have on wound healing, thehandling properties of the particu-late graft material were dramaticallyimproved by the addition of thethrombin-activated PRP. The resul-tant fibrin formation consolidatedthe graft, allowing it to be cut intoconveniently sized blocks that couldbe easily carried to and inserted intothe lateral window. These soft blockscould then be moved to any desiredlocation, such as the narrow andoften hard-to-reach anterior region,where they couid be molded intoposition. Additionally, graft place-ment can be accomplished withoutthe inadvertent spillage of graftmaterial into the buccal flap area.Tayapongsak et al29 reported similarhandling qualities when addingautologous fibrin adhesive activatedwith bovine thrombin to cancellousbone and marrow grafts.

Marx et al22 showed a meanincrease in platelet concentration of338% using an Electro Medics 500(Medtronics) gradient density cellseparator with a 400- to 450-mLwhole blood sample. Other cen-trifuge units, which require a wholeblood sample approximating 50 ml_,are the Platelet ConcentrateCollection System (3i/lmplantInnovations) and the SmartPReP(Harvest Technologies}. Both of theabove small-draw units report higherplatelet concentrations than thelarge-draw Medtronics unit.

It is of interest to note that themanufacturers of platelet sequestra-tion and concentration systems givevarying values for the final plateletconcentration achieved. This may

vary from three to eight times theplatelet concentration in thepatient's blood. Additionally, theoperator may alter the final concen-tration by increasing or decreasingthe volume into which the plateletbutton is suspended. It thenbecomes obvious that the finalplatelet concentration will dependupon three factors: fJJthe total num-ber of platelets in the original sam-ple; 0 t h e recovery rate of the sys-tem used; and (3) the final volume ofplasma into which the platelets aresuspended. For purposes of factor-ing in the actual platelet concentra-tion used in our future cases, we pro-pose to obtain platelet counts fromthe initial blood sample and alsofrom the harvested PRP. A standard-ized technique should be devisedthat includes dilution of the concen-trated platelets, resuspension, andmultiple sampling to ensure an accu-rate platelet count.

Volume 22. Number 1, 2002

Conclusions

The following conclusions may bedrawn from these three case reports:

1. Platelet-rich-plasma did notmake a significant difference inthe production of vital bone insinuses grafted with BioOss.

2. Platelet-rich plasma did notmake a significant difference inbone contact at the implant-bone interface.

3. The use of platelet-rich plasmawith grafts consisting of 100%BioOss should be consideredonly in respect to the improvedhandling quality (containment) ofthe particulate graft material thatcan be achieved through theactivation of the platelet-richplasma with thrombin.

Acknowledgments

The authors wish to acknowledge the contri-butions of M. D. Rohrer, DDS and Han Passad,PhD for their assistance wilh the histologicpreparation and histomorphometric analysis

References

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3- Tatum OH. Maxilla'y and sinus implantreconstruction Dent Clin North Am 1986;30:207-229.

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14. Wheeler SL, Holmes RE, Calhoun CJ. Six-year clinical and histologic study of sinuslift grafts. Int J Oral Maxillofac Implants1996:11:26-34,

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