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Over the years, regenerative medicine has been improved thanks to new therapies and new innovative clinical protocols. The purpose of this work was to evaluate the efficacy of Platelet-rich Plasma by retracing the history of the evolution of the preparation technique, enhancing the role of platelets in tissue healing, as well as its use in various sectors of medicine. At the same time, through a critical review of recent innovations in the field of bone regeneration, was paid attention to new clinical protocols obtained from second generation platelet concentrates.
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                                                                                                               Article


Platelet-rich plasma (PRP): history of the platelets’
concentrates and current applications in medicine


M. Covelli1                                                ered the gold standard treatment1 . The biotechnologies
A. Cusanno2                                                used to recreate bone tissue and optimize the biolog-
C. Benincasa3                                              ical substrate can be identified in: bone morphogenic
R. Ruggiero3                                               proteins (rhBMP), autologous growth factors contained
C. Annichiarico3                                           in platelet-enriched plasma (PRP), mesenchymal stem
B. Marrelli3°                                              cells and scaffolds; these can be used alone and / or
G. Palumbo2°                                               in combination 2. Platelet Rich Plasma (PRP) is a blood
                                                           product and presents as an autologous concentrate of
1
  CIRPAS, University of Bari, Italy                        platelets suspended in a small volume of plasma3. The
2
  Department of Mechanics Management and Mathe-            PRP has an autologous origin 4 and exploits the biologi-
  matics (DMMM), Politecnico di Bari, Italy                cal properties of platelets5. Platelets play a fundamental
3
  Marrelli Health, Tecnologica Research Institute, Italy   role in haemostasis and have pro-inflammatory, regu-
° Co-Last Authors                                          latory and regenerative properties and release growth
                                                           factors (GFs), chemokines and other regulatory mole-
Corresponding Author:                                      cules6. Research now shows that platelets also release
Caterina Benincasa; e-mail: research@tecnologicasrl.com    many bioactive proteins responsible for the attraction of
                                                           macrophages, mesenchymal stem cells and osteoblasts
                                                           that not only promote the removal of degenerated and
                                                           necrotic tissues, but also improve tissue regeneration
Abstract                                                   and healing7-8. Numerous experimental and clinical stud-
Over the years, regenerative medicine has been im-         ies carried out in recent years have made it possible to
proved thanks to new therapies and new innovative          thoroughly investigate the effectiveness of the platelet
clinical protocols. The purpose of this work was to        concentrate and the possibility of using it frequently and
evaluate the efficacy of Platelet-rich Plasma by re-       on a daily basis as a therapeutic support for various dis-
tracing the history of the evolution of the preparation    eases of both the oral cavity and bone tissue in general9.
technique, enhancing the role of platelets in tissue       This is because the use of PRP has advantages: the su-
healing, as well as its use in various sectors of medi-    praphysiological concentration of growth factors which
cine. At the same time, through a critical review of       appears to be able to increase the speed of wound re-
recent innovations in the field of bone regeneration,      pair, reduce inflammation associated with trauma and
was paid attention to new clinical protocols obtained      minimize the production of scar tissue 10.
from second generation platelet concentrates.

Key words: Platelet-rich Plasma, Preparation Tech-         History of the Use of PRP
nique, Platelets, Regenerative Medicine, Tissue
Healing, PRF, PRGF.                                        The use of lyophilized fibrin, bank or autologous, dates
                                                           back to the seventies, in particular in orthopedic surgery
Introduction                                               where it was useful in grafts for the effect of conglobation
                                                           of the particulate bone tissue and for a better neo-osteo-
Pathologies affecting the bone tissue have always been     genesis, then attributed to a generic effect osteoconduc-
of great interest both for the high incidence with which   tor of fibrin. Tayapongsak et al11 who first adopted autol-
they occur and for the difficulty of having a complete     ogous fibrin in maxillofacial surgery (1994), adhered to
healing and therefore a full functional recovery of the    this explanation. In 1995, Slater et a 12 found that adding
structures involved. The therapeutic protocols currently   platelets to an osteoblast culture in vitro accelerated its
in use in the treatment of these diseases are far from     development. In the field of oral and maxillofacial sur-
a real returned ad integrum. Current research is there-    gery, the PRP technique has been the subject of numer-
fore converging towards the study of therapies that aim    ous publications13. In 1997, on the other hand, Whitman
to stimulate endogenous repair and the formation of a      et al14 studied the efficacy of “Platelet Gel” in accelerating
tissue with morpho-functional characteristics similar to   the wound healing process15.
those of healthy tissue. Research has increasingly al-     The use of PRP begins with the publications of Robert E.
lowed the implementation of non-surgical treatments.       Marx who in 1998 demonstrated the beneficial effects of
For this reason, scientists have focused their research    an amplification of PDGF and TGF-β on bone regenera-
on the enhancement of some biological substances           tion. Described as a quick, safe, inexpensive and easy-
active on alternative healing processes to autologous      to-obtain product, PRP is the subject of ever-increasing
bone transplantation, which for many years was consid-     clinical interest16-17.


Annali di Stomatologia 2022; XIII (1-4): 27-32                                                                              27
     Platelet-rich plasma (PRP): history of the platelets’ concentrates and current applications in medicine

     Marx et al16 in their work dated 1998, compared, in 88             of myoblasts. The increase of all parameters survival,
     cases in which mandibular restriction occurred, the re-            proliferation and differentiation also occurred in C2C12
     generative and maturative results obtained by doing a              / BM-MSC co-cultures in the presence of PRP compared
     regenerative with ground bone taken from the iliac crest           to treatment with PRP alone22.
     with those deriving from bone grafting iliac creast added          However, the use of PRP in long bones seems to be
     with PRP. The results obtained showed that in the cases            somewhat controversial. In a randomized clinical study
     treated with bone graft added with PRP there was a fast-           carried out in 2007, a lower healing capacity was shown
     er bone regeneration and maturation and, consequent-               in subjects treated with PRP, about 60% of the testers,
     ly, a better quality and quantity of bone trabeculae with          both against BMP-7 and autograft transplant23.
     the higher density of the regenerated bone tissue. they
     were also evaluated through histological examinations
                                                                        PRP in Plastic Surgery
     and histomorphometric data showed a greater exten-
     sion of the bone trabeculae in cases with bone and PRP             In recent years, the use of treatment in cosmetic surgery
     compared to that found in samples with only bone grafts.           has also grown considerably. The use of platelet concen-
     Another confirmation came from immunohistochemical                 trate for non-transfusional use, in particular in regenera-
     examinations: by treating the samples with monoclonal              tive medicine or dermatology, is an internationally estab-
     antibodies for the growth factors PRGF and TGF-R, their            lished practice. The PRP is, in fact, indicated for these
     presence was detected in the platelets of the PRP and              applications as a facilitator in the biorevitalization treat-
     in numerous cells of the bone tissue taken for grafting 16 .       ment. Numerous clinical studies have been conducted to
     The first studies were carried out in the field of maxillofa-      evaluate its application in the field of aesthetic medicine
     cial surgery, however the most sensational results were            in particular for hair loss conditions, skin rejuvenation,
     obtained first on experiments on the jaw of goats and              scarring and dispigmentation conditions24.
     then on the vertebral column in humans. Fennis et al17             A meta-analysis and randomized clinical trials aimed at
     reports in its article dated 2002 how the use of PRP im-           quantifying hair density in subjects with androgenic alo-
     proves healing in physiological and timing terms; in fact,         pecia show a hair density of 0.58 with a 95% confidence
     in 28 goats mandibular defects were created, 14 goats              interval in subjects treated with PRP compared to pla-
     were treated with only bone graft while the remaining              cebo25.
     with PRP added with particulate bone. The latter showed
     excellent healing in a short time. Lowery et al18 demon-
                                                                        PRP in Uro-Gynecological Disorders
     strates a percentage of positive results of 30% of the
     use of PRP in lumbar spinal fusions. PRP was used with             A search of the literature, carried out in 2021, also re-
     hydroxyapatite. The results obtained in the 39 treated             vealed an excellent use with excellent results in the
     patients confirmed the excellent properties: chemotac-             treatment of uro-gynecological disorders26: PRP could
     tic and mitogenic effect on mesenchymal stem cells and             be used in alternative protocols for the management of
     osteoblasts.                                                       vaginal atrophy, in some subjects it also led to an im-
     Even more recent studies confirm the efficacy of PRP in            provement in the symptoms of stress urinary inconti-
     vertebral and non-vertebral surgery. In fact, from a sys-          nence27.
     tematic review on PUBMED, in 2020, considered 274
     patients undergoing meniscus reconstruction, it stated             PRP in Gynecology
     a lower failure rate in subjects treated with PRP than in
     those cases treated without PRP19. By recreating critical          The use of PRP in gynecology and in particular in assist-
     size defects in rabbits, Leng et al20 believes that PRP            ed fertilization techniques is also spreading to address
     can compensate for the porous DBM deficiency. In fact,             both the problem of thin endometrium and to improve
     the radiographic evaluation and the histological analysis          implantation rates in women with previous failures. Im-
     revealed a greater formation of new bone after implan-             portant scientific works report interesting success rates
     tation in the DBM group added with PRP at 6 and 12                 in patients treated with PRP and with previous repeat-
     weeks compared to the DBM group without PRP.                       ed embryonic implantation failures, due to insufficient
                                                                        endometrial growth. In a recent publication, dated July
                                                                        2022, the net increase in implantation rates in participat-
     PRP in Muscle Tissue Repair
                                                                        ing women undergoing PRP treatment is confirmed, but
     Recent studies are trying to identify strategies aimed             no efficacy on abortion rates28. Another study conduct-
     at improving endogenous muscle repair potential. The               ed by Tremellen et al29 considered 20 female patients
     administration of bone marrow-derived mesenchymal                  under the age of 45, with severe decreases in ovarian
     stromal cells (BM-MSC) together with the effect of PRP             reserves. Treatment with PRP showed an increase in
     represents a very promising strategy. Although there are           the number of embryos generated but an insignificant in-
     clinical results, they are very controversial for therapeu-        crease in the number of oocytes generated. The results
     tic application in skeletal muscle injuries21. Vallone et          are to be considered excellent compared to the results
     al22, in their study, evaluated the viability, survival, prolif-   obtained in untreated women.
     eration and myogenic differentiation induced by PRP on
     C2C12 and BM-MSC myoblasts and at the same time                    Evolution of Technique
     also the effect of PRP in combination with BM-MSC in
     the induce myogenic differentiation. Assays of incorpo-            The mode of action of the PRP exploits the role of action
     ration of MTS and EdU, expression of Ki67 and signaling            of platelets. The preparation techniques of the product,
     of Akt and Notch-1 have decreed how the treatment with             therefore, must keep the platelets unaltered and intact30.
     PRP increased the survival, viability and proliferation            It is during the inflammatory phase that platelets play



28                                                                                        Annali di Stomatologia 2022; XIII (1-4): 27-32
M. Covelli et al.

different roles: antimicrobial effect, induces the coagu-     bone regeneration before dental implant rehabilitation, in
lation cascade and retroactive the clot, releases growth      liquid form in order to soak sponges of fibrin and implant
factors and cytokines. The secretion of growth factors is     wires15.
stimulated by the coagulation cascade, therefore PRP          However, in a recent study there is talk of lyophilized
must be obtained from blood treated with anticoagulant,       PRP. Such platelet concentrate in titanium scaffolds
so that the platelets remain viable long enough to allow      most strongly promoted cell viability and osteogenic dif-
treatment31.                                                  ferentiation of BMSCs39.
PRP treated with anticoagulant lasts for about eight
hours. The preparation of the PRP must take place in
such a way as to effectively separate the platelets from      PRP vs PRF
the erythrocytes and concentrate them without dam-
                                                              PRP represents a source of bioactive growth factors,
aging the platelets themselves. The method chosen is
                                                              however optimal preparation, activation, as well as
important since the growth factors contained within the
                                                              quantification of the various growth factors present is a
alpha granules are activated when the granules them-
                                                              controversial and still unclear topic40.
selves merge with the platelet membrane31-32.
                                                              Recently, it has attracted widespread attention for its
According to Marx’s protocol, the one described above
                                                              regenerative potential in soft tissues, however, the in-
and the one used to date, the PRP is prepared from au-
                                                              fluence on bone healing and dental tissue regeneration
tologous blood starting from a centrifugation which, us-
                                                              is still unclear41. In fact, the literature reports the use of
ing the different density gradients, can collect and con-
                                                              fibrin as an osteonic material, to be used alone or to be
centrate platelets during surgery. The collection of PRP
                                                              compacted with bone grafts: the importance of growth
is done in 20-30 minutes through a gradient density cell
                                                              aids in the process of tissue repair, cell proliferation and
separator (Medtronics). This cell separator draws 400 to
                                                              chemotaxis is emphasized42. The protocol for the reali-
450 mL of autologous whole blood through a central ve-
                                                              zation of the PRF is a single centrifugation of the tubes
nous catheter placed during surgery. With a spin speed
                                                              without coagulant. The absence of the coagulant allows
of 5600 RPM, whole blood is drawn at a rate of 50ml /
                                                              the activation of coagulation and therefore the formation
min. Citrate phosphate dextrose (CPD) is then added to
                                                              of a fibrin clot is expected that contains all the platelets
the centrifugate in a ratio of 1 ml of CPD to 5 ml of blood
                                                              and leukocytes. While PRP is considered a plasma de-
to achieve anticoagulation. The PRP is then activated
                                                              rivative with two consecutive centrifuges and can be
with calcium chloride and bovine thrombin in order to
                                                              cryopreserved, PRF is an autologous scar that cannot
have a platelet gel then added with both spongy and cor-
                                                              be preserved43.
tical autogenous bone and with synthetic bone matrix32.
                                                              Several studies have analyzed how osteoid tissue is
In fact, literature data have shown that when calcium and
                                                              present in the PRF graft area for 4 months and the ab-
thrombin are added to PRP, platelets are activated and
                                                              sence of anticoagulant means that the platelets are fully
can thus release the content of their granules a, which
                                                              activated and used for a long-term effect44.
include both PDGF and TGF-ß33-34.
                                                              The fibrin network that forms after the PRF protocol is
Over the years have been examined different methods
                                                              three-dimensionally more homogeneous than the one
for the preparation of PRP, starting in 1994 when Tay-
                                                              that forms with the PRP protocol; in fact, in the PRP
apongsak et al35 produced an autologous fibrin adhe-
                                                              protocol, the addition of bovine thrombin and calcium
sive, from a whole blood unit with its plasma fraction, to
                                                              chloride determines a more rapid polymerization of fibrin
be used in the following 2 -3 weeks.
                                                              with a three-dimensional structure that is less elastin and
In 1999, Anitua studied an open cycle technique of sin-
                                                              more disordered45. The absence of manipulations during
gle centrifugation for the preparation of PRP in order to
                                                              the PRF preparatory phase and a front of a greater num-
obtain a platelet concentration 2-3 times higher than the
                                                              ber of intrinsic growth factors makes the PRF protocol
classic one: it used a protocol characterized by a 160 g
                                                              safer than the old PRP preparation protocols46.
centrifugation for 6 minutes , subsequently changed to
270 g for 7 minutes36. The author suggests the use of
calcium chloride to activate the product with the possibil-
ity of accelerating the gelling process by also associating
                                                              PRP vs PRGF
autologous bone36.                                            The evolution of platelet concentrates is aimed at pro-
In 2000, Sacchi et al37 Described a double centrifugation     moting the regeneration process. Today we talk about
technique, respectively at 180 rpm and 580 rpm for a du-      PRGF, plasma rich in growth factors, growth factors that
ration of 20 minutes each in open cycle and for outpatient    initiate the migration of undifferentiated stem cells to-
use, involving an enrichment of the PRP of 3.57 times         wards the site and to induce their differentiation as well
compared to the basal concentration. subsequently to be       as their growth47-48 .
activated with calcium chloride and Botropase.                For the realization of the product only one centrifugation
Landesberg et al38, in 2005, proposed an alternative          of 8 minutes is foreseen. From centrifugation there will
protocol for the preparation of PRP: compares samples         be two fractions. Fraction 2 (F2) is defined as the 2 mL of
with the addition of the classic bovine thrombin used as      plasma just above the Buffy coat and Fraction 1 (F1) is
anticoagulant to the thrombin receptor agonist peptide-6      the plasma column above F2. Adding 10% calcium chlo-
(TRAP) samples. Thrombin caused rapid clotting of the         ride to F1 can form a fibrin barrier membrane to acceler-
PRP with clot formation within 3.25 minutes. Adding           ate soft tissue healing and adding to F2 can form a fibrin
TRAP at 100 μmol / L took 9.25 minutes for the clot to so-    clot. F2 can also be mixed with bone graft materials in
lidify completely. The author himself therefore proposes      order to accelerate the healing processes and resorption
the use of TRAP as a valid alternative to bovine thrombin.    of degradable bone graft materials.
In 2012 Inchingolo et al15 shows the effectiveness of a       A study from 2022 confirms its use in in vitro regenera-
method that involves the use of PRP as graft material in      tive medicine. In this study, were evaluated the chromo-


Annali di Stomatologia 2022; XIII (1-4): 27-32                                                                                 29
     Platelet-rich plasma (PRP): history of the platelets’ concentrates and current applications in medicine

     somal stability of the gingival and fibroblasts at the same             blood. Am J Vet Res 2004 ;65: :924-930.
     time alveolar osteoblasts after long-term culture. Cul-          4.     Giusti I, Rughetti A, D’Ascenzo S. Identification of
     tured cells were expanded with PRGF or fetal bovine se-                 an optimal concentration of platelet gel for promot-
     rum (FBS) as a culture medium supplement. The results                   ing angiogenesis in human endothelial cells. Trans-
     showed a higher cell proliferation rate in PRGF-treated                 fusion 2009;49:771-778.
     cells. Analysis of the CGH array (Genomic Hybridization          5.     Maia L., de Souza M.V., Ribeiro J.I., de Oliveira
     Assay) to consider chromosomal stability did not reveal                 A.C., Silveira Alves G.E., Benjamin L., Silva Y.F.R.,
     genetic instability. The autologous PRGF technology, ac-                Zandim B.M., Moreira J. 2009 Platelet-rich plasma
     cording to Anitua et al., Preserves the genomic stability               in the treatment of induced tendinopathy in horses:
     of the cells and represents a valid alternative to the FBS              histologic evaluation Journal of Equine Veterinary
     culture medium and therefore a good supplement for cell                 Science 29(8), 618-626
     therapy49.                                                       6.     Haigler MC, Abdulrehman E, Siddappa S, Kishore
                                                                             R, Padilla M, Enciso R. Use of platelet-rich plasma,
                                                                             platelet-rich growth factor with arthrocentesis or ar-
     Conclusions                                                             throscopy to treat temporomandibular joint osteoar-
                                                                             thritis: Systematic review with meta-analyses. J Am
     The mechanisms of bone formation and repair have                        Dent Assoc 2018; 149:940-952.
     been rapidly investigated and elucidated over the past           7.     Sampson S, Gerhardt M, Mandelbaum B. Platelet
     decade. Although many problems still remain open, it is                 rich plasma injection grafts for mu-sculoskeletal in-
     clear for now what the gold standard is for tissue restitu-             juries: a review. Curr Rev Musculoskelet Med 2008;
     tion ad integrum but it is only clear that numerous cyto-               1: 165-174.
     kines and GFs as well as polypeptides play an essential          8.     Cieslik-Bielecka A, Bielecki T, Gazdzik TS, Arendt
     role in these processes. . The GFs and BMPs regulate                    J, Król W, Szczepanski T. Autologous platelets and
     the proliferation and differentiation of mesenchymal cells              leukocytes can improve healing of infected high-en-
     and play a role of primary importance in the remodel-                   ergy soft tissue injury. Transfus Apher Sci 2009;
     ing, regeneration and healing phases of both tissues.                   41:9-12.
     A prospect that has become interesting in the last de-           9.     Rose LF, Rosenberg E. Bone grafts and growth and
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