Effects of Platelet-Rich Plasma on the Healing of Autologous Bone Grafted Mandibular Defects in Dogs

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J Oral Maxillofac Surg64:443-451, 2006

Effects of Platelet-Rich Plasma on theHealing of Autologous Bone Grafted

Mandibular Defects in DogsDavid Gerard, PhD,* Eric R. Carlson, DMD, MD, FACS,†

Jack E. Gotcher, DMD, PhD,‡ and Mykle Jacobs, DDS§

Purpose: This study was undertaken to describe both radiographically and with histomorphometricanalysis the effect platelet-rich plasma (PRP) has on immediate autologous bone grafts in a dog model.

Materials and Methods: Thirteen dogs comprised the study. Twelve adult dogs received bilateralinferior mandibular border defect resections measuring 2 cm � 1 cm. The right defect was immediatelygrafted with milled autologous iliac corticocancellous bone along with 2 cc of PRP that was developedin a standardized fashion. The left side was immediately grafted with the same amount of autologous iliaccorticocancellous bone placed without PRP. Three animals were sacrificed at 1, 2, 3, and 6 months. Athirteenth dog underwent bilateral inferior border resections with only PRP placed in the right defect,and nothing placed in the left defect. This dog was sacrificed at 6 months. Ten and 3 days before sacrificeall animals received 10 mg/kg body weight tetracycline intravenously. At sacrifice, grafts along withadjacent native bone were harvested, fixed, radiographed, and processed for epifluorescence analysis.

Results: Analysis of digitized radiographs indicated that at 1 and 2 months the non-PRP grafts weresignificantly more dense than the PRP grafts, and at 3 and 6 months there was no significant difference.Histomorphometric analysis showed that at 1 and 2 months there was significantly less grafted bone andmore new bone in the PRP grafts than in the non-PRP grafts. At 3 and 6 months there was no differencein the amount of grafted bone or new bone between the PRP and non-PRP grafts. Histology of the controldog showed incomplete bony healing at 6 months, suggesting that this was a critical sized defect. Thebone apposition rate for all times in the PRP and non-PRP graft sites did not significantly change.

Conclusion: PRP appeared to enhance early autologous graft healing. However, after 2 months this effectis no longer significant. The early enhanced healing occurred by increasing the amount of non-viable graftedbone that was removed and increasing the amount of new bone that was formed. PRP did not change the rateat which new bone was formed, and no increase in trabecular density was realized in these grafts.© 2006 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 64:443-451, 2006
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eceived from the Department of Oral and Maxillofacial Surgery,

niversity of Tennessee Graduate School of Medicine, Knoxville, TN.

*Associate Professor, Director of Research.

†Professor and Chairman.

‡Professor.

§Chief Resident.

Presented in part at the 86th AAOMS Annual Meeting and Sci-

ntific Sessions.

Address correspondence and reprint requests to Dr Carlson:

niversity of Tennessee Medical Center, Department of Oral and

axillofacial Surgery, 1930 Alcoa Highway, Suite 335, Knoxville,

N 37920; e-mail: [email protected]

2006 American Association of Oral and Maxillofacial Surgeons

278-2391/06/6403-0015$32.00/0

toi:10.1016/j.joms.2005.11.016

443

latelet-rich plasma (PRP) was first described for useith mandibular grafts by Marx et al in 1998.1 This

tudy suggested that PRP enhanced the healing ofutologous bone grafts, and the authors attributed thiso the concentration of growth factors that wereeleased when the platelets were activated. In addi-ion, this study and others indicated an increase inrabecular density of these bone grafts as realized at 6onths. Specifically, Marx et al1 reported a greater

one density in grafts in which PRP was added (74.0%11%) than in grafts in which PRP was not added

55.1% � 8%; P � .005) at 6 months.1 The same studyndicated a radiographic maturation rate 1.62 to 2.16imes that of grafts with PRP compared with thosehat did not include PRP.1 Subsequently, a number oftudies have been published examining the use ofRP to enhance many different combinations of au-
ologous and/or exogenous graft materials.2-9 The re-

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444 EFFECT OF PRP ON AUTOLOGOUS BONE GRAFTS

ults of these studies vary widely, and many of thesetudies are anecdotal with no control data.10-16 Be-ause there are few controlled studies, and the graftaterials and sites vary, there is still some question as

o how effective PRP is in enhancing bone grafts. Theurrent study examined the effect of PRP on mandib-lar defects in a dog model. PRP and non-PRP autol-gous grafts in the same animals were directly com-ared for 1, 2, 3, and 6 months’ healing times. Theorking hypothesis was that PRP would enhance theealing process of immediate autologous bone grafts

n the mandible of dogs. Digitized radiographic dataas collected and analyzed for bone density. Histo-orphometric measurements of kinetic bone activityere analyzed using fluorochrome double labels. The

esults of this study will give valuable information onow PRP affects autologous bone graft healing in theandible in dogs.

aterials and Methods

PRP PREPARATION

PRP was prepared using a Harvest Technologiesmart Prep Centrifuge, with the PRP-20 cc prep kitHarvest Technologies, Plymouth, MA). Twenty cc oferipheral blood was drawn from each animal androcessed for PRP preparation using the manufactur-r’s instructions. An additional 2 cc was drawn at theame time to calculate peripheral platelet counts forach animal.

SURGICAL PROCEDURE

Following orotracheal intubation, the neck andight ilium regions were prepped with betadine solu-ion and sterile surgical drapes were placed at theonor and recipient sites. Simultaneous recipient sitereparation surgery was performed by 1 surgeonE.R.C.), and donor site bone harvest surgery waserformed by another surgeon (J.E.G.). This extraoralite was chosen to decrease the chance of infectionrom exposure to the oral cavity, and to limit distur-ance of the prominent mandibular neurovascularundle present in dogs.

RECIPIENT SITE PREPARATION

In the neck, a 5 cm midline incision was madehrough the skin and subcutaneous tissues with acalpel. Deeper dissection to the fascia of the midlineeniohyoid muscles took place with the electrocau-ery unit. At this point, dissection proceeded superfi-ial to the muscle fascia laterally so as to encounterhe inferior border of the mandible. The periosteumas divided sharply between the angle of the mandi-le and the mental foramen region bilaterally. A sub-
eriosteal dissection was performed with strict atten- m
ion to avoid the oral cavity. An aluminum templateas placed on the inferior border of the mandible thatutlined a 2 cm � 1 cm standardized marginal resec-ion of the inferior border of the body of the mandibleilaterally. Care was taken to protect the inferiorlveolar neurovascular bundle whenever possible.he marginal resection cortices were removed withaws and osteotomes. At this point, Vicryl mesh (Ethi-on, Somerville, NJ) was brought to the field andecured to the inferior border with 6 mm � 1.5 mmynthes screws (Synthes Maxillofacial, West Chester,A). The harvested corticocancellous bone waslaced in the Thom bone mill (Stryker-Leibinger, Por-age, MI) and particulated with 5 turns on the boneill. The milled bone was placed in 3 cc syringe and

ompressed. Half of this bone (1.5 cc) was placed inhe left marginal defect (Fig 1). The other half of thisone (1.5 cc) was mixed with 2 cc of PRP that hadeen activated with thrombin and CaCl2, per the

IGURE 1. Clinical appearance of bone graft reconstruction withoutRP (A) and with PRP (B).

erard et al. Effect of PRP on Autologous Bone Grafts. J Oralaxillofac Surg 2006.

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ith the particulate bone. This PRP-bone preparationas placed in the right marginal defect (Fig 1). Con-ensation of the bone graft was accomplished withand instrumentation. Care was taken to ensure thatRP did not saturate the left mandibular reconstruc-ion. To this end, the periosteum of the left mandib-lar recipient site was closed before placing the rightandibular bone graft. In a similar fashion, the peri-

steum of the right mandibular defect was closedfter the placement with activated PRP, followed bylosure of the subcuticular and skin surfaces in theidline of the neck with resorbable suture.

DONOR SITE SURGERY

A 4 cm incision was made with a scalpel over therominence of the right posterior iliac crest. Deepissection proceeded through underlying fascial lay-rs with the electrocautery unit. The sartorius muscleas conservatively reflected from the lateral posterior

lium. The periosteum in this area was then dividednd reflected. A rongueur was used to remove theortical bone of the iliac crest, followed by harvest ofhe cancellous bone with a curette. Approximately 15c of cancellous bone was harvested from each donorite and placed in normal saline storage medium tem-orarily. The donor site was irrigated and hemostasisas achieved. An anatomic closure was accomplished

n layers. The harvested bone was placed in the boneill and particulated, as previously described, so as to

ield approximately 3 cc of milled, compressed bone.

TISSUE PROCESSING

Ten days and 3 days prior to euthanasia, each ani-al was given tetracycline intravenously at 10 mg/kg

ody weight. Labeling at these times gave clearlyemarcated double labels as close to the time ofacrifice as possible. After euthanasia, the mandibularefects and adjacent mandible (2 to 3 mm beyond thecrews) were harvested intact and immediatelylaced into Carson’s fixative. Within the first 24 hourstandardized radiographs were taken of the samples.fter 48 hours fixation, the undercalcified samplesere dehydrated in an ethanol series over a 2 weekeriod and embedded in Spurr’s plastic. Serial, longi-udinal, 100 �m sections were cut to the center of theefects, including adjacent mandible with a Leitz600 bone saw (Ernst Leitz Wetzlar, Wetslar, Ger-any).

EPIFLUORESCENCE ANALYSIS

Two sections from the center of each defect werelued onto petrographic slides and ground to 40 �mhickness. Ten random areas from the defect of eachection were examined at 6.3� with a Zeiss epifluo-escence microscope, and digital images of these ar-
as were analyzed using IMAGE software (NIH). The t
ercent active bone surface (single or double la-eled), percent graft bone volume, percent new boneolume, and the bone apposition rates were calcu-ated for all the graft sites. The values for percentctive surface, percent graft bone volume, and per-ent new bone volume were then combined for theRP and non-PRP sites for each time (n � 6; 2 sectionsrom each site, 3 animals for each time point), andompared using ANOVA. The apposition rate wasetermined by measuring the distance between theenters of the double labels at 25 different sites forach slide totaling 50 measurements for each animal,nd 150 measurements for each time point. The av-rage distance was then used to calculate the apposi-ion rates for all graft sites.

RADIOGRAPHIC ANALYSIS

The digitized radiographs for each sample werenalyzed in a standard fashion. A field 0.1 mm squareas used for all analyses. Internal standardization of

he gray scale values used 10 fields over the screws ashe upper limiting gray scale value, and 10 fields overhe radiographic film outside the sample as the lowerimiting value. Fifteen fields were randomly analyzed

ithin the graft site, and 15 fields were randomlyelected in bone outside the graft site. The percentensity of the graft site was then compared with theercent density of the native bone using ANOVA.

esults

PRP PREPARATION

Platelet concentration averaged 388% for 1-monthnimals, 344% for 2-month animals, 386% for 3-monthnimals, and 334% for 6-month animals. Two animalst the 3-month time point did not have concentrationsalculated. Concentrations of platelets are compara-le to those described by Marx et al1,17 in their clin-

cal trials. (These data are summarized in Fig 2.)

HISTOMORPHOMETRIC ANALYSIS

At 1 month the graft sites that received PRP had atatistically significant (P � .05) lower volume ofrafted bone (non-viable) than the non-PRP graft sitesFig 3). The volume of new bone was significantlyreater in the PRP graft sites as compared with theon-PRP graft sites (Fig 4). The newly formed bone inoth the PRP and non-PRP graft sites was looselyrranged woven bone, with virtually every surfacective (Fig 5).

At 2 months there was less grafted bone in the PRPraft sites as compared with the non-PRP graft sitesFig 3). This was statistically significant at P � .05.he volume of new bone was significantly greater in

he PRP sites when compared with the non-PRP sites

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P � .05; Fig 4). There was significantly more activeurface in the new bone in the PRP sites as comparedith the non-PRP sites (P � .05; Fig 6). The newly

orming woven bone was more compact than at 1onth for both the PRP and non-PRP sites. Modeling

f the newly formed woven bone was occasionallyeen in both types of graft sites at this time (Fig 7).

At 3 months there was no statistical differenceetween the PRP and non-PRP graft sites for graftone volume (Fig 3), new bone volume (Fig 4), orercent active surface on the newly forming boneFig 6). The newly forming bone in both types of graftites was becoming further compacted, and there wasonsiderable evidence of modeling of the newlyormed woven bone (Fig 8).

At 6 months the grafted bone has been completelyemoved from both the PRP and non-PRP graft sitesFig 3). There was no difference between the PRP andon-PRP grafts new bone volume (Fig 4) or percent

IGURE 2. Figure shows the increased concentration of platelets overeripheral blood in the PRP used in this study.


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IGURE 3. At 1 and 2 months there is significantly more non-viablerafted bone in the non-PRP grafts versus the PRP grafts. *indicatestatistically significant difference.


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ctive bone surface (Fig 6). The woven bone in bothypes of grafts was dense and most of the surfacectivity was associated with modeling of the wovenone (Fig 9).The bone apposition rate was calculated for all the

raft sites (Fig 10). There was no difference in theone apposition rate for the PRP and non-PRP grafts.his value remained at 1.82 �m/day � 0.3 �m for all

imes and grafts.

RADIOGRAPHIC ANALYSIS

Image analysis of the standardized, digitized radio-raphs showed that at 1 month the non-PRP graftsere more dense than the PRP grafts (Fig 11). Thisifference was statistically significant (P � .05). At 2onths the non-PRP grafts were still more dense, but

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IGURE 4. There is significantly more newly formed bone volume inhe PRP grafts at 1 and 2 months. After 2 months the volume of newone is not significantly different for the PRP versus the non-PRP grafts.indicates statistically significant difference.


IGURE 5. Fluorescent microscopy of loosely arranged woven bonerom a non-PRP graft site at 1 month. Note that almost every new boneurface has been fluorochrome labeled. The PRP sites looked similar tohis. (Original magnification �63.)


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his difference was not statistically significant (Fig 11).t 3 and 6 months there was no statistically significantifference between the densities of the radiographsor either the PRP or non-PRP graft sites (Figs 11, 12).

iscussion

Our hypothesis that PRP enhances the healing pro-ess of fresh autologous bone grafts in the mandiblef dogs appears to be true only for the early timeoints (1 and 2 months) of this study. At the 3- and-month time points, PRP did not have any addedeneficial effect on the bone grafts from the stand-oint of bone healing, bone volume, or radiographicensity.The early enhanced healing of the bone grafts with

RP that was observed in this study resulted from 2

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IGURE 6. The percent active bone surface is significantly higher forhe PRP grafts only at the 2-month time point. *indicates statisticallyignificant difference.


IGURE 7. At 2 months the bone graft sites showed considerableew bone formation. This photograph shows activity in a PRP graft site.ote the early modeling activity with the presence of at least 1 osteon.

Original magnification, �63.)


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ifferent processes. First, there was an increase in themount of new bone that was being formed in theRP graft sites. This has been described in a numberf studies in both humans and animals.1,2,5,9,11,13,17

Marx et al1,17 first described bone activity in pa-ients with mandibular defects 5 cm or greater whoad received cancellous bone grafts with and withoutRP. The researchers found that at 2, 4, and 6 monthsost-grafting the PRP sites were more mature than theon-PRP sites. At 6 months, histology showed greaterrabecular bone area with the PRP grafts. The modelor increased bone formation that these authors pro-osed suggested that the release of transformingrowth factor-� and platelet-derived growth factor

IGURE 8. This fluorescent photograph shows woven bone in aon-PRP graft site at 3 months. The woven bone is more compact thant 1 or 2 months, but there is no difference in bone activity between theRP and non-PRP grafts at this time. (Original magnification, �63.)


IGURE 9. At 6 months the grafts from both the PRP and non-PRPrafts contained compact woven bone. Modeling osteons are therimary activity seen at this time. This fluorescent photograph is from aRP graft site at the margin. Note the organized native bone to the rightnd the newly formed woven bone to the left. (Original magnification,63.)


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esulted in the stimulation of stem cells and osteoblastrogenitor cells to divide and/or differentiate and

nitiate bone formation while also inducing endothe-ial cell mitosis and subsequent angiogenesis. Theuthors suggested that they saw this effect even out tomonths. The maturity of the bone shown by these

uthors at 4 and 6 months is striking. In contrast, ourtudy indicates that at 3 and 6 months the graft sitesor both PRP and non-PRP contained primarily denseoven bone with the primary activity at 6 monthseing modeling.A number of recent studies have examined the use

f PRP in conjunction with mandibular grafts, sinusift procedures, early implant placement, and grafts tother sites. The results of these studies have beenixed.Roldan et al3 reported on a rat study evaluating the

ffect of PRP and BMP on autologous and allograftaterial in a critical size mandibular defect. The au-

hors found no enhancement of bone formation withither autologous or allograft material with the addi-ion of PRP. Choi et al4 evaluated PRP added to autol-gous bone grafts of the mandible in dogs and found

IGURE 10. Higher magnification of a double-labeled bone surfacerom a non-PRP graft site at 6 months. The line shows the distance fromhe center of the first label (1) to the center of the second label (2). Thisistance is used to calculate the bone apposition rate. (Originalagnification, �160.)


o enhancement of new bone formation by the addi- i

ion of PRP at 6 weeks. The authors suggested thatRP might actually interfere with bone remodeling.obiony et al11 used PRP in conjunction with autolo-ous bone grafts and distraction osteogenesis of se-erely atrophic mandibles in 5 patients and suggestedhat PRP enhances healing; however, there were noontrols for this study. Fennis et al2 reported that PRPnhanced healing of autologous bone grafts in a sheepandibular continuity resection model. The benefitsere especially seen at 6 and 12 weeks.Philippart et al10 reported on the use of PRP, rhTF,

nd tetracycline in conjunction with autologous bonen sinus floor augmentation in 18 patients. The au-hors suggested that this enhanced vascularizationnd osteoblast numbers, but no controls were used inhis study. Oyama et al5 evaluated 7 cleft patientssing CT who had autologous bone grafts with PRP.he authors stated that, compared with controls, theolume of bone using PRP was significantly higher.akse et al6 reported on the use of PRP in sinus graftsn sheep using autologous bone. Histomorphometricxamination at 4 and 12 weeks indicated that PRP hadmodest but not statistically significant positive effectn new bone formation and new bone contact withrafted bone.Jensen et al7 examined the effect of PRP on implant

ite healing with allografts in the humerus of dogs.he authors reported that PRP had no significantffect on healing or implant fixation at 3 weeks. Kimt al18 reported on the use of PRP in conjunction withentin-plaster of Paris around implants placed in the

liac crest of dogs at 6 and 12 weeks. The authorseported that PRP enhanced bone contact with themplants. A meta-analysis of studies looking at the usef PRP in conjunction with implants in humans con-luded that there was a lack of scientific evidence toupport the use of PRP in combination with bonerafts during augmentation procedures.19

A number of recent studies have examined theffect of PRP on healing cranial defects. Aghaloo et al8

eported that PRP enhanced bone activity in conjunc-ion with Bio-Oss (Geistlich Biomaterials Inc, Wol-usen, Switzerland) compared with Bio-Oss alone in aon-critical size defect of the cranium of rabbits.owever, the authors also reported that autologousrafts showed more bone activity than the PRP/Bio-ss grafts at 1, 2, and 4 months. In a second study,ghaloo et al9 showed that there was no significant

ncrease in bone formation with PRP using autologousone grafts at 1, 2, and 4 months in non-critical sizeefects of the rabbit cranium. Wiltfang et al20 re-orted that PRP with an allograft did not increaseone mineralization, but PRP with an autologous graftid significantly increase bone regeneration in a crit-

cal size defect in the forehead of mini-pigs.

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A second process that appears to speed up theealing process in our model is an increase in themount of grafted, non-viable bone that was removedrom the graft site. This observation has not beeneported before, and was particularly obvious at 1 andmonths. On initial examination of the radiographic

ata it was puzzling that lower bone density was seenn the PRP-grafted sites at 1 and 2 months. Afternalyzing the histomorphometric data the apparentiscrepancy was resolved. The PRP graft sites at 1 andmonths had significantly less grafted, non-viable

one and significantly greater amounts of newlyormed bone. The grafted bone was considerablyore dense than the rapidly forming woven bone,

nd thus the radiographs showed less density for theRP grafts at 1 and 2 months. At 3 and 6 months theadiographic densities were comparable for both theRP and non-PRP grafts, and this corresponded with

IGURE 11. Matched radiographic images for each time studied. Aore dense non-PRP grafts can be observed. The 3-month grafts (E, lehe 6-month grafts (G, left graft; H, right graft) similarly showed no st

erard et al. Effect of PRP on Autologous Bone Grafts. J Oral Ma

t 1 month (A, left graft; B ,right graft) and 2 months (C, left graft; D, graft) theft graft; F, right graft) showed no statistically significant difference in density.atistically significant difference in density.

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IGURE 12. At 1 month the non-PRP grafts were significantly moreense than surrounding bone compared to the PRP grafts. There waso significant difference between the density of the grafts at any otherime. *indicates statistically significant difference.


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ifference in new bone volume for the PRP and non-RP grafts. Growth factors released by platelets thattimulate osteoblast differentiation and function alsotimulate osteoclast precursor cells to divide and dif-erentiate.21,22 The increased amounts of theserowth factors caused by the PRP may explain thearly activation of larger numbers of osteoclasts thatere then active in removal of non-viable bone from

he graft site.These results strongly suggested that in this animalodel the increase in bone formation at 1 and 2onths in the PRP grafts is caused by an increase in

he number of osteoblasts that were producing newone. Also, these results indicated that either theumber or efficiency of osteoclasts was increased inhe PRP grafts at 1 and 2 months. After 2 months theesults of this study indicated that the PRP and non-RP graft sites have similar bone forming and resorb-

ng capabilities.Interestingly, the apposition rate (or the rate athich new bone was formed) was not affected byRP. It was 1.82�0.3 �m/day for all times with orithout PRP. At this point it is important to correctlyefine the process whereby increased bone formation

s seen with PRP at 1 and 2 months. Some authorsave stated that PRP increased the rate of bone for-ation in healing grafts,1,8,9,17 but none of these stud-

es actually measured the rate of bone formation. Thepposition rate, or the rate at which new bone forms,an only be determined histologically by measuringhe distance between fluorochrome labels given atpecific intervals. The increase in the concentrationf growth factors produced by PRP did not stimulaten increase in the rate of bone formation. What theseesearchers were most likely observing was an in-reased volume of new bone due to a larger numberf osteoblasts working in the graft site. In our animalodel the increased concentration of growth factorsroduced by PRP did not stimulate an increase in theate of bone formation. This is an important distinc-ion and must be clearly stated to more clearly under-tand how PRP enhances healing in bone graft sites.onversely, osteoclast activity in the graft site cannote measured with histomorphometric means, but in-reased removal of non-viable grafted bone suggestshat an increased number of osteoclasts or more ro-ust osteoclasts with greater numbers of nuclei areorking in the graft site. To further examine therocesses by which bone is formed and removed

rom these graft sites, cell counts, along with theumber of vascular profiles, will be part of a subse-uent paper. This study will also look at the compar-tive number of remodeling profiles seen at 2, 3, andmonths.In this animal model system PRP enhanced bone

ormation and resorption at 1 and 2 months. This

enefit was no longer seen at 3 and 6 months. Thearly effects of the PRP were caused by 2 differentrocesses. First, PRP increased the amount of newone that was formed, probably by increasing theumber of osteoblasts that were active in the graftite. Second, the amount of non-viable graft bone thatas removed from the graft site increased, possiblyy increasing the number of osteoclasts active in theraft site. Finally, the rate at which bone formationccurred was not affected by the addition of PRP toutologous grafts.

The clinical correlations of this study extrapolatedo the human model may be contrary to the anecdotalnformation that has filled our specialty’s literaturever the past several years. Based on the informationleaned by this study, PRP does not create a graft ofreater trabecular density than a graft without PRP.hile new bone formation occurs at an earlier time

rame, it does not occur faster. Moreover, the finalroduct is no different from the standpoint of boneolume and mineral density between grafts supple-ented with PRP versus those grafts not supple-ented with PRP. With this information in mind,

he clinician might speculate as to the theoreticaldvantages of the addition of PRP to a cancellousellular bone graft reconstruction of the facial skel-ton, similar to those performed in the dog modelf this study. Freymiller and Aghaloo23 haveointed out that PRP is not without known bene-ts. They indicated that PRP acts as a biologicdhesive that holds the bone particles together,hereby making manipulation of the graft materialuch easier. Also, the addition of PRP invokes a

pre-consolidated” type of property to the graft thatesists movement during closure of the facial coverap over the graft and during the postoperativeourse. In the final analysis, the surgeon might wisho use PRP in patients for whom “jump starting” aone graft would be recommended. Such patients

nclude those with radiated tissue beds, where anntraoperative inadvertent perforation of mucosaccurs, or in patients with compromised systemicomorbidity, such as diabetes mellitus.

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8. Aghaloo TL, Moy PK, Freymiller EG: Investigation of platelet-rich plasma in rabbit cranial defects: An animal study. J OralMaxillofac Surg 60:1176, 2002

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0. Philippart P, Brasseur M, Hoyaux D, et al: Human recombinanttissue factor, platelet-rich plasma, and tetracycline induce ahigh-quality human bone graft: A 5-year study. Int J Oral Max-illofac Implants 18:411, 2003

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