ARTICULO ESPECIAL

 

Platelet –rich plasma

Plasma rico en plaquetas

 

 

J. González Lagunas

Médico Especialista.
Servicio de Cirugía Oral y Maxilofacial.
Hospital Universitari Vall d’Hebrón, Barcelona, España

Dirección para correspondencia

 

 

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ABSTRACT

Platelet-rich plasma is a by-product of centrifuged whole blood that contains high levels of thrombocytes. In the last decade, scientific and media interest has been generated by this product that apparently has the capacity of inducing and promoting tissue healing and regeneration. The premise of its use is that the large number of platelets in PRP release significant amounts of growth factors. In this paper, a critical review of the medical literature regarding PRP and bone healing will be presented. Also, the suggested clinical applications of the product will be addressed.

Key words: Platelet-rich plasma; Osteoinduction; Bone regeneration; Bone graft.

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RESUMEN

El Plasma Rico en Plaquetas es una suspensión concentrada de la sangre centrifugada que contiene elevadas concentraciones de trombocitos. Durante los últimos años, este producto ha aparecido de forma repetida en publicaciones científicas y en medios de comunicación generales como un producto que por sus características induce la curación y regeneración de los tejidos. La premisa de su uso es que las elevadas concentraciones de plaquetas en el PRP, liberan cantidades significativas de factores de crecimiento. En este artículo se van a recoger las evidencias científicas que se han presentado en la literatura médica con respecto al PRP y a la curación ósea, así como las diferentes aplicaciones clínicas que se han sugerido.

Palabras clave: Plasma rico en plaquetas; Osteoinducción; Injerto óseo; Regeración ósea.

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Introduction

Platelet-Rich Plasma or Plasma Rich in Growth Factors is a concentrated suspension from blood placed in a centrifuge machine and spun down, that contains high levels of thrombocytes. During the last few years, this product has appeared repeatedly in scientific publications and in the general media as a product that, due to its characteristics, enhances healing and tissue regeneration. In spite of the enthusiasm generated in some authors by the development of the product and the diffusion carried out by the companies that market the kits for obtaining PRP, there are still doubts as to the true effectiveness of platelet-rich plasma on skeletal regeneration. This article will gather together the scientific evidence presented in the medical literature with regard to PRP and bone healing.

 

Foundations

Platelets contain a certain number of growth factors. Growth factors are proteins that play an essential role in cellular migration, differentiation and proliferation. A large number of these proteins have been described but, in the subject that concerns us, the most important are PDGF (Plateletderived growth factor) TGF-b (Transforming growth factor beta), FGF (Fibroblast growth factor), VEGF (Vascular endothelial growth factor), and IGF (Insulin-like growth factor).¹

Growth factors are costly, and repeated doses are required in order to achieve a therapeutic effect that is clinically evident. ¹ For this reason, the work hypothesis that has led to the development of PRP is that, with a product having a larger concentration of platelets, the growth factor levels increase linearly according to the number of platelets.² The production of this gel allows a sustained release of growth factors.

With this concept in mind, the industry has launched onto the market systems designed specifically for the rapid preparation of platelet concentrate from a small sample of blood (Table 1). This supposedly permits the concentration of the natural growth factors that are to be found in platelets. These systems should comply with the following requirements: they should be viable on an outpatient basis, they should concentrate the platelets between 3-6 times their basic levels, and they should be able to retain and preserve viable platelets and release growth factors for 7-10 days.² The comparative studies presented do not reveal any significant differences in the results obtained with the different systems.^3-5

 

Historical antecedents

In 1994, a group of surgeons added an autologous fibrin adhesive to cancellous bone in mandibular reconstruction. ² For this they resorted to separating a blood sample into its components and they used the plasma fraction as cryoprecipitate. They observed early bone consolidation that was attributed to the larger number of osteo-competent cells that remained in the fibrin mesh. In 1997 Whitman presented the platelet gel as an autologous alternative to the fibrin adhesive for oral and maxillofacial surgery, using it not only as a tissue adhesive but also as a means of initiating the consolidation process of corticocancellous grafts in the maxillas.⁷ Later on, Marx and cols⁸ observed that PRP increased the concentration of platelets in the grafts, and they observed the presence of at least 3 growth factors: PDGF, TGF- ß1 and 2. They observed that spongy cells had receptors for these growth factors. Their evaluation in orthopantomographies and histomorphometries concluded that:

1. Adding PRP increased the speed at which bone was formed and the degree of bone formation during at least 6 months.

2. It was technically possible to, concentrate and add a large number of platelets (and as a result growth factors) to bone grafts.

3. Stem-cells from spongy [bone] marrow contained receptors for growth factors. (figure 1)

 

Proposed indications for Platelet-rich plasma

Not confusing the actions of growth factors or BMP with the actions of Platelet-rich plasma is fundamental.^2,6,9,10 It is also important to point out that in some of these potential applications, there is no consistent evidence as to its longterm efficiency, although the clinical "appreciation" of the authors would indicate that there are some benefits associated with its use:

1. Bone growth and maturation.

2. Graft stabilization.

3. Wound sealing (flap attachment).

4. Scar formation (soft tissue regeneration).

5. Hemostasia (cessation of capillary bleeding and potential haematomas).

6. Implantology.

7. Other applications.

a. Traumatology and orthopedics: bone and soft tissue lesions.
b. Medication carrier. (figure 2)

 

Bone regeneration studies on animals

The study hypothesis of most of the papers presented is that the addition of PRP to an autogenous or allogenic graft material has a positive effect on bone healing. This effect should be evaluated with objective parameters such as with radiologic, histologic and histomorphometric examination.

Fennis^11,12 presented two studies on goats that underwent mandibular resection and reconstruction with particulate bone from the iliac crest with and without PRP. The radiologic, histologic and histomorphometric studies revealed that the use of PRP considerably improved bone healing at 6 to 12 weeks.

Aghaloo and cols carried out studies on parietal rabbit bone, grafting surgical defects with autogenous bone, PRP or a combination of both. Radiographic, histologic and histomorphometric analysis permitted the observation of a slight tendency towards a greater bone density with the addition of PRP that without it. However, the differences were not statistically significant.¹³ In another similar study, but with demineralised bovine bone, better bone density was observed in the cases grafted with autogenous bone, than in those grafted with demineralised bovine bone and PRP.¹⁴

A canine study compared bone healing in mandibular resection defects reconstructed with isolated autogenous bone, or combined with PRP. The biopsies at 6 weeks and fluorescence microscopy revealed that PRP did not enhance new bone formation.¹⁵

Kim carried out a study placing titanium implants in the iliac crest of dogs, and filling the peri-implant defects with a combination of dentine/plaster of Paris, with and without PRP. According to the authors, osteointegration improved in the dogs treated with PRP.¹⁶ In another canine study in which demineralised bone powder was used, Kim studied osteointegration of dental implants in the iliac crest, observing that there was better osseous contact when the bone was combined with PRP.¹⁷ Furthermore, the three works mentioned are difficult to apply in customary clinical situations, given that the implants were applied on external oral cavity bone, where the bacterial contamination conditions are different.

In a study on 28 rats Winstar, Roldan and cols¹⁸ observed that the application of PRP did not enhance the formation of bone in anorganic bovine bone nor in autogenous bone grafts. In another study on porcine frontal skull bones, the preparation of the graft bed with PRP does not appear to have had any influence on the osteointegration of implants.¹⁹ Zechner, on the other hand created mandibular defects in 12 minipigs, applying PRP and placing implants He observed improved peri-implant bone regeneration in the initial phases (6 weeks), with the stimulation of osteogenic cell proliferation being comparable at 12 weeks.²⁰

Lastly, in one of the few in vitro studies presented,²¹ the stimulation is studied of cell proliferation in the bone marrow of rats. Effects comparable with BMP could not be demonstrated.

Only the study by Fennis had study conditions comparable to those that are usually [found] when using PRP in oral and maxillofacial surgery, together with a rigorous analysis of the results.^11,12 His results suggest that there is a supposed beneficial effect of PRP when added to an autologous graft in goats. The authors recognise that they lack information on the PRP dose-effect relationship, as well as of the time period during which activity is shown. (figure 3)

 

Application in dentoalveolar surgery

A Spanish study presented alveolar healing experiences with and without platelet-rich plasma. The study was based on 10 patients with only 3 "split-mouth" design patients. Epithelialization was evaluated by means of a periodontal probe with photographs, and bone healing was evaluated with a biopsy at 4 weeks. The bone characteristics at 4 weeks were better in the PRP group that in the control [group].^22,23

Recently PRP has been analysed for preventing dry socket after the extraction of third molars. A prospective study was carried out on 118 patients, that underwent the Harvest system. Improved hemostasis was observed, the flap had a better appearance, there was less pain according to the visual analogue scale, and there was reduced incidence of dry socket (3.4 versus 12.5%). It should however be pointed out that the evaluation was with non-quantifiable parameters. ²⁴

Della Valle et al²⁵ applied PRP gel in 40 patients submitted to oral surgery and anticoagulant therapies requiring mechanical heart valve replacement: 5% reported hemorrhagic complications and 40% had mild bleeding that was treated with local hemostatic agents. (figure 4)

 

Application in periodontics

Its use in periodontics is basically of a clinical nature, although there are some works of investigation in biological science. Okuda and Kawase again demonstrated the high concentration of PDGF and TGF-beta in PRP, and they observed stimulation in the ADN synthesis in gingival fibroblasts and in periodontal ligament cells, as well as its capacity for regulating collagen synthesis in the extracellular matrix.^26,27

De Obarrio incorporates PRP into a bone allograft combined with guided tissue regeneration techniques (GTR) in order to treat intrabony defects, observing a significant increase in clinical attachment and bone fill in tests two year later.²⁸

Various other studies have used PRP or fibrin gel for managing gingival recession defects.^29-32 either on its own or combined with different techniques of guided bone regeneration and with different biomaterials. The authors themselves suggest that new studies are necessary in order to establish the role played by each component in these combined therapies. (figure 5)

 

Application in sinus augmentation

The application of PRP in sinus augmentation derives from its adhesive effect on grafted material. It has not been reliably demonstrated that it has an intrinsic osteoinductive effect on synthetic biomaterials. The literature contains just a few series that mainly include "How I do it" but no consistent results in the long term.^33-37

Wallace and Froum presented in 2003 a systematic review of the literature with regard to implant survival in patients that had undergone sinus augmentation. They did not find sufficient data to be able to recommend the use of platelet-rich plasma in sinus augmentation.³⁸

In sinus augmentation with autogenous bone and PRP, Jakse et al observed an improvement of 3-4% in bone formation in a study on 12 sheep. This difference was considered clinically as insignificant and they affirmed that [the results] "show a regenerative capacity of PRP of low potency" In a study on 21 rabbits that underwent sinus augmentation with iliac crest, Butterfield obtained similar results,³⁹ concluding that they could not find a stimulatory effect of PRP on autogenous bone grafts.

In sinus augmentation with demineralised bovine bone and PRP on 12 minipigs, Fürst concluded that the combination of PRP with other biomaterials was not demonstratively superior than PRP on its own.⁴⁰

There are also various studies on bone augmentation with biomaterials in humans. Froum carried out a study on 3 patients performing a bilateral sinus augmentation (demineralised bovine bone versus demineralised bovine bone with PRP).⁴¹ The biopsy samples showed no significant differences between both sides. Wiltfang carried out a study with TCP on its own, or TCP + PRP, observing new bone formation that was 10% higher in the group in which PRP had been added.⁴² However, they were unable to demonstrate that the resorption/substitution rate with TCP was superior. Rodriguez et al⁴³ presented 24 sinus augmentations in 15 patients with demineralised bovine bone and PRP, with no control group. With a single biopsy they observed an implant integration rate of 92% and they concluded that by adding PRP implants could be loaded earlier (4 months). In another study with biopsies on sinus augmentation with "bone substitutes" and PRP, a significant improvement was not noticed in sinus bone density. Kassolis used PRP with an allograft of freeze-dried bone for sinus augmentation in 36 patients, observing in the biopsies that at 12 months there was bone formation around the allografts with no signs of inflammation.⁴⁵ (figure 6)

 

Application as a tissue adhesive

One of the applications, in which there is general unanimity, is in its use as a biological adhesive.⁷ It has been used as a cohesive in bone grafts or particulate biomaterial, such as biological membranes or in a spray form in order to increase the adhesiveness of cutaneous or mucosal flaps to the receptor bed. Matras in 1982 described these fibrin adhesives as products with a capacity for tissue sealing and hemostasis, and for promoting tissue healing.⁴⁶ It appears to act efficiently as a biological membrane.

 

Application in soft tissue surgery

PRP has been used in aesthetic surgery of the face since 1998, as a tissue adhesive in order to encourage and modulate healing in cutaneous flap reattachments. It has been used in rhytidectomy and blepharoplasty [procedures] and in other flap surgery, as well as in "laser resurfacing". The authors refer improved wound healing, and the elimination of dead space, eliminating the need to use aspiration drainage, or of using cutaneous sutures.^2,49-51 Clinical comparisons that have not been objectively contrasted refer fewer edemas during the first 72 hours, which in turn leads to less pain in the immediate postoperative period.² The incision lines show less erythema and inflammation and healing takes place faster than in the control [groups]. Marx in a study that was observational, histopathological and morphometric, observed that skin donor sites treated with PRP showed better wound healing, faster epithelization, greater skin thickness and less pain and discomfort when compared with the control [group].⁵²

Man used PRP in 20 patients that underwent aesthetic surgery including facelifts and breast surgery, observing improved hemostasis when PRP was used and fibrin gel.49

In 2003⁵¹ Hom and Manivel presented a successfully treated cutaneous neck ulcer that had been present for 12 years, which was treated with recombinant human plateletderived growth factor-BB (Becaplermin), [gel], meaning that the indications for this product can be widened, and that its use is not restricted to the chronic ulcers of the extremities of diabetics. (figure 7)

 

Application in Traumatology and Orthopedics

Again we must insist on the importance of differentiating between the functions carried out by growth factors and those that are carried out by platelet-rich plasma. In the current literature there is no scientific evidence that shows the supposed acceleration in fracture healing. There are reports on its application in muscle and tendon lesions, and its use in arthroscopic surgery, but these deal with preliminary clinical studies with no long-term follow-up.⁵³ In facial osteotomies there are several anecdotal references on the use of PRP with beta-tricalcium phosphate for the management of severe atrophy of the upper maxilla.⁵⁴

 

Conclusions

The enthusiasm generated in the media by the appearance of PRP as a biological procedure for bone regeneration does not appear to be accompanied by conclusive investigation results. A critical revision of the literature that exists on PRP and its clinical application allows drawing a series of conclusions that can be resumed in the following way.^55-57

1. There are many articles on the possible skeletal applications of PRP, but there is no solid scientific evidence as to its efficiency in bone generation.

2. There are no experimental studies on the application of PRP in humans that indicate its advantages.

3. The clinical studies that exist are limited to just a few cases: in general these are uncontrolled clinical studies, with no success parameters, nor control group.

4. It efficiency has been suggested in a series of aspects that facilitate surgery such as the reduction of intra- and postoperative bleeding, faster soft-tissue healing with reduced inflammatory reaction, and greater initial stability of the tissue grafted at the receptor site as a result of its properties as a tissue adhesive.

In short, we are able to affirm that PRP is a promising tissue-engineering product, with no side effects having been described, and that it gives the professional [using it] surgical advantages that can justify its use. However, with current scientific evidence, it would be risky to affirm that by using PRP the acceleration of bone regeneration is a reality.

 

 

Dirección para correspondencia:
Casa nova 101 Principal
08011 Barcelona, España
E-mail: glagunas@terra.es

Recibido: 25.02.2005
Aceptado: 09.03.2005

 

 

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