endoret® (prgf®) technology bti implant systems scientific...

Endoret® (PRGF®) TechnologyBTI implant system

“Prince Felipe Awardfor Technological Innovation”

Scientific Dossier

Endoret® (PRGF®) Technology 3

Introduction

This scientific dossier summarises the series of indexed international articles published over the last 20 years on the range of prod-ucts and technologies developed by BTI Bi-otechnology Institute. It highlights the vast amount of scientific evidence that backs the biosafety and effectiveness of plasma rich in growth factors (Endoret® (PRGF®)) in many fields of medicine, with a particular focus on oral and maxillofacial surgery and oral im-plantology.

This autologous technology has revolution-ised the field of personalised regenerative medicine, as with the patient's blood we can obtain different therapeutic formulations rich in growth factors, the application of

which encourages healing and tissue regen-eration, reducing pain and inflammation.

Many publications show the predictability and safety of BTI dental implants and of the surgical techniques (sinus elevation, split, biological reaming, etc.) developed under a biological philosophy by Dr. Eduardo Anitua.

This dossier also reviews the therapeutic po-tential of Endoret® (PRGF®) in other fields of medicine in which our research team has been a pioneer at a worldwide level: ortho-paedic surgery, sports medicine, treatment of chronic ulcers and facial rejuvenation, among others.

4 Endoret® (PRGF®) Technology4

What are growth factors and how do they act?

Growth factors are a set of substances that carry out an important function in intercel-lular communication. They carry out a large number of biological functions among which cellular proliferation is important, though they also decisively affect cellular survival, mi-gration, differentiation and even apoptosis.

Growth factors carry out their function at very low concentrations in body fluids and tissues, in the region of pico or nanograms. They act by binding to receptors located on the cell membrane that transmit the signal from the exterior to the interior of the cell, through the coupling of different protein kinases that are phosphorylated and which regulate a signalling cascade that ends up with the activation of one or more genes.

The process of tissue regeneration includes a complex set of biological events controlled by the action and synergy of a cocktail of growth factors. There are three agents in-volved in tissue regeneration: the cellular component, a combination of multiple bio-logical mediators that include growth factors and cytokines among others and a matrix or “scaffold” that gives the new tissue under construction support.

After an injury or tissue damage, they are activated and coordinate a large number of intercellular or intracellular paths with the aim of restoring the integrity of the tissue and its haemostasis. Growth factors are also necessary to promote angiogenesis or the formation of blood vessels that will supply

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oxygen and nutrients to the damaged tissue. Another fundamental aspect to be consid-ered in the regeneration of a tissue is the de-velopment of a “scaffold” that acts as a pro-visional extracellular matrix and therefore houses the cells as well as locally presenting the biochemical, physical and structural sig-nals that allow the anchorage of the cellular motility machinery.

Werner S, Grose R. Regulation of wound healing by growth fac-tors and cytokines. Physiol. Rev. 2003;83:835-870.

Orive G, Anitua E, et al. Biomaterials for promoting brain protec-tion, repair and regeneration. Nat Rev Neurosci. 2009;9:682-692.

Over the last 20 years, the detailed study of platelets, of the biological mediators they contain and of the formulations aimed at allowing the administration and therapeutic use of growth factors and autologous biomaterials has allowed significant progress and has greatly increased the versatility and therapeutic possibilities of Plasma Rich in Growth Factors (Endoret® (PRGF®)).

Endoret® (PRGF®) technology is based on the preparation of 100% autologous platelet-rich plasma, which when applied to damaged tissue areas speeds up the regeneration of a large number of tissues without any adverse effects. Plasma rich in growth factors (Endoret® (PRGF®)) is a personalised technology that has revolutionised the field of

regenerative medicine. This article, published in one of the most prestigious journals in the field of biotechnology, summarises the most important clinical results obtained with Endoret® (PRGF®). Its application over the last decade has extended to many fields of medicine, from oral and maxillofacial surgery to dermatology, cosmetics, orthopaedic surgery and sports medicine, and more recently to ophthalmology.

Anitua E, Sánchez M, Nurden AT, Nurden P, Orive G, Andía I. Trends Biotechnol. 2006;24:227-234.

Endoret® (PRGF®): A new concept in personalised regenerative medicine

The biological activity of the dif-ferent formulations obtained with Endoret® (PRGF®) is based on two funda-mental pillars. On the one hand, the content in plasma and in particular platelet growth factors whose action regulates the main pro-cesses involved in tissue regeneration.

On the other, the fibrin matrix, which is used as a provisional structure to house the cells and control the release kinetics of the growth factors present in Endoret® (PRGF®).

This article published in the prestigious jour-nal Trends in Pharmacological Science, the most important in the field of pharmacolo-gy, talks about the therapeutic potential of Endoret® (PRGF®) and in particular describes

how the perfect synergy between growth factors and fibrin is a key aspect when ex-plaining the clinical results obtained with this autologous technology.

Anitua E, Sánchez M, Orive G, Andia I. Delivering growth factors for therapeutics. Trends Pharmacol Sci. 2008;29:37-41

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patient's blood we can obtain up to 4 bio-compatible preparations:

a. Endoret® (PRGF®) supernatant: used to cultivate primary cells and stem cells in the laboratory; it is also the base of new eye drops for treating a large number of patholo-gies of the ocular surface.

b. Liquid Endoret® (PRGF®) : Ideal for skin infiltrations, tissues of the musculoskeletal system, TMJ, etc. It is the perfect tool to bi-oactivate dental implants and prostheses of all types with the aim of accelerating their os-seointegration.

c. Endoret® (PRGF®) clot or “scaffold”: Ide-al for filling in defects and promoting tissue

The set of therapeutic preparations of En-doret® (PRGF®) are obtained by means of a simple protocol based on a tiny volume of the patient's blood. The blood is centrifuged separating the erythrocytes and white cells from platelet-rich plasma. The two fractions of Endoret® (PRGF®) are separated from the rest of the blood components by means of aspiration using the Plasma Transfer Device (PTD). Later, and prior to its therapeutic ap-plication, the fractions of Endoret® (PRGF®) are activated, leading to a series of therapeu-tic formulations.

This article, published in one of the most important scientific journals in the field of biomaterials, focuses on the enormous ver-satility of Endoret® (PRGF®), as by using the

How is Endoret® (PRGF®) obtained?


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DEMONSTRATION VIDEO Scan this code with your

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regeneration: post-extraction sockets, treat-ment of ulcers, tissue engineering, etc.

d. Fibrin membrane: due to its haemostatic properties it is the best biomaterial for seal-ing defects and stimulating epithelisation.

Anitua E. Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. Int J Oral Maxillo-fac Implants. 1999;14:529-535.

Anitua E, Sánchez M, Orive G, Andía I. The potential impact of the preparation rich in growth factors (PRGF) in different medi-cal fields. Biomaterials. 2007;28:4551-4560.


Endoret® (PRGF®) is the first 100% autolo-gous platelet-rich plasma to be described in literature worldwide. It is, likewise, a pio-neering technology in translational regen-erative medicine. Over 20 years of research, added to its exclusive properties, make En-doret® (PRGF®) a unique technique. Endoret® (PRGF®) is prepared with small volumes of the patient's blood and does not require the use of thrombin or chemical agents for its ac-tivation. Unlike other products, it does not include white blood cells (leukocytes) in its composition, which gives it more effective anti-inflammatory properties. It is the most versatile technology, as its multiple formula-tions offer a large number of therapeutic ap-plications.

In short, as shown by the series of letters to the editor published during recent years, we can define Endoret® (PRGF®) as a platelet-rich autologous plasma whose effectiveness and safety have been widely proven. However, it is important to remember that not all plate-let-rich plasmas are Endoret® (PRGF®).



What makes the Endoret® (PRGF®) system different from other platelet-rich plasmas?


Anitua E, Sánchez M, Orive G, Andía I. Shedding light in the controversial terminology for platelet rich products. J Biomed Mater Res A. 2009;90:1262-1263.

Sánchez M, Anitua E, Andia I. Poor standardization in platelet-rich therapies hampers advancement. Arthroscopy. 2010;26:725-726.

Anitua E, Sánchez M, Orive G. The importance of understanding what is platelet-rich growth factor (PRGF) and what is not. J Shoulder Elbow Surg. 2011;20:23-24.

Anitua E, Sánchez M, Prado R, Orive G. Plasma rich in growth factors: the pioneering autologous technology for tissue regeneration. J Biomed Mater Res A. 2011;97:536.

Anitua E, Sánchez M, Prado R, Orive G. The P makes the difference in plasma rich in growth factors (PRGF) technology. Platelets. 2011;22:473-474.

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Endoret® (PRGF®) contains a cocktail of autol-ogous growth factors that come from both the plasma and the platelets. In fact, the platelets have a complex storage system in the form of intracellular granules that allow them to transport a large number of biolog-ically active molecules. According to some authors, this list of proteins and peptides can come close to 500 molecules. Alpha (α) granules are the most abundant as there are around 40 to 80 alpha granules per platelet, but they are also the ones with the greatest retention capacity. In addition, they contain a series of antibacterial proteins that are ge-nerically called thrombocidines and are le-thal to a large variety of bacterial species.However, it is important to remember that the plasma contains important growth fac-

tors and that the combination of the plasma and platelet factors is a key element in the bi-ological action of Endoret® (PRGF®).

In a couple of revision articles, our research team along with the Nurden Doctors from the Reference Centre for Platelet Disorders in France have characterised the protein con-tent of platelets in order to learn about the set of molecules present in Endoret® (PRGF®) formulations.

Platelets release substances that promote tissue regeneration and modulate both an-giogenesis and inflammation. Important fac-tors include platelet-derived growth factor (PGSF), transforming growth factor ß (TGF-ß), basic fibroblast growth factor (bFGF), vascu-

The pillars of Endoret® (PRGF®): growth factors


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lar endothelial growth factor (VEGF), epider-mal growth factor (EGF) and angiopoietin-1. They release in parallel antibacterial mole-cules and specific growth factors that act on the mobilisation of progenitor cells from the bone marrow or from peripheral niches.

Calcium acts as a cofactor in the activation process of Endoret® (PRGF®), which allows the conversion of the fibrinogen of the plas-ma into fibrin, generating a gel or clot with important biological functions. On the one hand, fibrin is an excellent matrix to maintain and house the cells, it acts as a provisional scaffold while the definitive tissue is regener-ated and acts as a continuous growth factor release system. It is therefore a biocompatible and autologous sponge full of growth factors

and cytokines that will permit a progressive release of them during several weeks.

Anitua E, Andia I, Ardanza B, Nurden P, Nurden AT. Autologous platelets as a source of proteins for healing and tissue regenera-tion. Thromb Haemost. 2004;91:4-15.

Nurden AT, Nurden P, Sanchez M, Andia I, Anitua E. Platelets and wound healing. Front Biosci. 2008;13:3532-3548.

Anitua E, Sanchez M, Nurden AT, Zalduendo M, de la Fuente M, Orive G, Azofra J, Andia I. Autologous fibrin matrices: a potential source of biological mediators that modulate tendon cell activi-ties. J Biomed Mater Res A. 2006;77:285-293.

In over a decade of preclinical research, dur-ing which tens of cellular phenotypes were studied, we have managed to discover and understand the multiple biological functions that the set of therapeutic formulations of Endoret® (PRGF®) carry out. The biological mediators of Endoret® (PRGF®) stimulate and encourage such important processes for tis-sue regeneration as cellular proliferation and migration, chemotaxis (or the call from a dis-tance for cells to go to the injury site), inflam-mation and the auto/paracrine synthesis of new molecules with biological activity.

Anitua E, Sanchez M, Merayo-Lloves J, De la Fuente M, Muru-zabal F, Orive G. Plasma rich in growth factors (PRGF-Endoret) stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodifferentiation. Invest Ophthalmol Vis Sci. 2011;52: 6066-6073.

Anitua E, Prado R, Orive G. Bilateral sinus elevation evaluating plasma rich in growth factors technology: a report of five cases. Clin Implant Dent Relat Res. 2012;14:51-60

Bendinelli P, Matteucci E, Dogliotti G, Corsi MM, Banfi G, Maroni P, Desiderio MA. Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-κB inhibition via HGF. J Cell Physiol. 2012;225:757-766.



Biological and regenerative potential of Endoret® (PRGF®)

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The growing interest in the range of biolog-ical options that Endoret® (PRGF®) offers has even reached the field of stem cells. Stem or progenitor cells are characterised on the one hand by their unlimited capacity for prolifer-ation, and on the other by the possibility of undergoing asymmetrical division (that is, self-renovation) maintaining their stemness while at the same time they can differentiate to diverse types of cells. There are different types of stem cells depending on their origin and their anatomical location. There is evidence that the content of bio-logically active agents in Endoret® (PRGF®) affects the mobilisation, adhesion, prolifera-tion, survival, activation and differentiation of mesenchymal stem cells and other sub-types of precursor cells.

In addition, the cocktail of growth factors of Endoret® (PRGF®) is an ideal resource for cul-turing and expansion of stem cells in the lab-oratory.

de Boer HC, Verseyden C, Ulfman LH, Zwaginga JJ, Bot I, Biessen EA, Rabelink TJ, van Zonneveld AJ. Fibrin and activated platelets cooperatively guide stem cells to a vascular injury and promote differentiation towards an endothelial cell phenotype. Arterioscler Thromb Vasc Biol. 2006;26:1653-1659.

Kajikawa Y, Morihara T, Sakamoto H, Matsuda KI, Oshima Y, Yoshida A, Nagae M, Arai Y, Kawata M, Kubo T. Platelet-rich plasma enhances the initial mobilization of circulation-derived cells for tendon healing. J Cell Physiol. 2008;215:837-845.

Zhang J, Wang JH. Platelet-rich plasma releasate promotes differentiation of tendon stem cells into active tenocytes. Am J Sports Med. 2010;38:2477-2486.

Cenni E, Avnet S, Fotia C, Salerno M, Baldini N. Platelet-rich plasma impairs osteoclast generation from human precursors of peripheral blood. J Orthop Res. 2010;28:792-797.

Chen L, Dong SW, Liu JP, Tao X, Tang KL, Xu JZ. Synergy of tendon stem cells and platelet-rich plasma in tendon healing. J Orthop Res. 2012;30:991-997


The use of growth factors and autologous fi-brin for regenerative purposes represents a new approach to personalised medicine that a large number of patients could benefit from.

In this paper, published in one of the most important journals of drug delivery, they discuss the mechanisms of action through which Endoret® (PRGF®) produces its multi-ple therapeutic effects.

The stimulation of cell proliferation and mi-gration along with the call to circulating cells to come to the location of the injury are ba-sic aspects of the action of Endoret® (PRGF®). Likewise, also important is the angiogenic action of the growth factors which is crucial to start regeneration. Last of all, though no

less important, its anti-inflammatory and an-tibacterial properties are a key element.

Our research team has proven that Endoret® (PRGF®) presents bacteriostatic activity with a large number of bacterial and fungal strains. This is because the platelets contain a series of antibacterial proteins called throm-bocidines. These proteins are part of a wider family known as defensins, and they are of a cationic nature, which will allow them to bind to and alter bacterial membranes. In ad-dition to thrombocidines, platelets transport and release other antimicrobial peptides among which we should mention platelet factor 4, RANTES, connective tissue activat-ing peptide 3, the basic protein of platelets, thymosin β-4, and fibrinopeptides A and B.

How does Endoret® (PRGF®) act?


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In a recent paper we could see that the bac-teriostatic potential of platelet-rich growth factors is due both to the antimicrobial pep-tides and to the fibrin, and not to the pres-ence of leukocytes in their composition. In fact, the bacteriostatic effect of Endoret® (PRGF®) is identical to that of a platelet and leukocyte-rich plasma. Another important conclusion of this study was to confirm how the inclusion of leukocytes notably alters the structure and uniformity of the fibrin matrix.

Anitua E, Orive G. Endogenous regenerative technology using plasma- and platelet-derived growth factors. J Control Release. 2012;157:317-320.

Anitua E, Alonso R, Girbau C, Aguirre JJ, Muruzabal F, Orive G. An-tibacterial effect of plasma rich in growth factors (PRGF) against Staphylococcus aureus and epidermidis strains. Clin Exp Derma-tol. 2012;37:652-657.


Therapeutic applications of Endoret® (PRGF®)

This revision article is a reference in interna-tional bibliography as it is the journal with the greatest scientific impact. It is about the therapeutic potential of platelet-rich plasma and, in this specific case, Endoret® (PRGF®). The use of growth factors and autologous fibrin for regenerative purposes represents a new approach to personalised medicine that a large number of patients could benefit from.

Anitua E, Sánchez M, Orive G, Andia I. Delivering growth factors for therapeutics. Trends Pharmacol Sci. 2008;29:37-41

This dossier summarises the preclinical and clinical scientific articles that endorse the bi-osafety and efficacy of Endoret® (PRGF®) in many fields of medicine.


The fibrin obtained with Endoret® (PRGF®) is probably the best biomaterial for encouraging

tissue regeneration.


The objective of this study was to character-ise for the first time the proteins existing in the Endoret® (PRGF®) clot, which are in con-tact with the fibrin network. The technology of proteomics was used to identify proteins, their gene ontology, and network mapping of these proteins.

The results confirmed that Endoret® (PRGF®) is a clot composed primarily of fibrin proteins, forming a macroscopic three-dimensional (3D) network. In addition to the results ob-tained, they provide a description of the cat-alogue of key proteins that are in close con-tact with the fibrin matrix. The lists of proteins obtained are grouped into families and net-works according to the gene ontology. An en-richment can be seen in certain proteins that

are key to tissue regeneration, such as throm-bospondin 1, fibronectin and vitronectin.

The most relevant channels involved were also catalogued for the proteins identified, finding an enrichment in canonical channels important for tissue regeneration, such as acute phase proteins.

Lipid metabolism proteins presented a high level of enrichment (13 times that of the con-trol). Thus, a basic catalogue of proteins has been established that may be used as ba-sis for future research. Taking the data as a whole, an enrichment was found in the pro-teins and families of proteins that take part specifically in tissue regeneration and in wound healing.

Basic research

Regenerative Potential of Endoret® (PRGF®) in odontology


High-throughput proteomic characterization of plasma rich in growth factors (PRGF-Endoret)-derived fibrin clot interactome. Anitua E, Prado R, Azkargorta M, Rodriguez-Suárez E, Iloro I, Ca-sado-Vela J, Elortza F, Orive G. J Tissue Eng Regen Med. 2013 Mar 18. doi: 10.1002/term.1721.

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The objective of this study was to character-ise the kinetics of the release of four growth factors (GFs) (VEGF, PDGF-AB, HGF and IGF-I) from matrices of Endoret® (PRGF®) fibrin. Sim-ilarly, a comparison was made with those ob-tained using a PRP with leukocytes (L-PRP) to determine the effect of the inclusion of said cells on the release of the aforementioned morphogens, including an inflammatory cy-tokinin (IL-1beta) in this analysis.

The results showed that both prepara-tions differed only in the leukocyte content (0.3x103/µl in the Endoret® (PRGF®) as op-posed to 5.7x103/µl in the L-PRP); the en-richment in platelets was similar. The mor-phological analysis of the Endoret® (PRGF®) matrix demonstrated its fibrillar composi-

tion. The interweaving of the fibres give this matrix a high porosity. Regarding the GF re-lease kinetics, 70% of PDGF-AB is released during the first three days, while in the case of the other GF analysed, there is a quicker initial release (60-70%) during the first 24 hours. In all cases there is then a stage of slow sustained release. The release kinetics in all cases comply with a diffusion model apply-ing the Korsemeyer-Peppas equation. After eight days, a significant percentage of these GF were retained inside the matrix (approxi-mately 20-30%). The effect of the presence of leukocytes in the platelet-rich plasma was as-sessed at 24 hours. With the exception of one of the donors, no significant alterations were evident in the concentration of GF released by both matrices. Nevertheless, a drastic in-

Basic research



Release kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors. Ani-tua E, Zalduendo MM, Alkhraisat MH, Orive G. Ann Anat 2013 Oct;195(5):461-6.

crease in the concentration of IL-1beta was detected in the incubation medium. The En-doret® (PRGF®) matrices release approximate-ly 70% of the GF they contain during the first 3 days, and 30% is retained a week after the formation of the clot. Therefore, the use of Endoret® (PRGF®) ensures the availability of this GF during the different stages of the tis-sue regeneration process, thus backing the effectiveness of this autologous therapy. Fur-thermore, the addition of leukocytes would drastically increase the concentration of IL-1beta at the injury site, which could favour inflammatory processes, as this cytokinin is one of the main cytokinins responsible for mediating the pro-inflammatory effects.

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The objective of this in vitro study was to determine the potential of different for-mulations obtained with Endoret® (PRGF®) Technology to stimulate cell proliferation, migration and adhesion, and the synthesis of angiogenic factors and various compo-nents of the extracellular matrix. In addition, the ability of this autologous technology to impede and inhibit the myo-differentiation induced by the transforming growth factor beta 1 (TGF-β1) was evaluated. The primary cultures of human gingival fibroblasts were characterised by specific markers (vimentin, CD90 and type I collagen) using immunoflu-orescence. The results obtained showed that Endoret® (PRGF®) significantly increases the cell proliferation and migration. In addition this technology significantly stimulated the

cell adhesion of the gingival fibroblasts to a matrix of collagen I. This autologous technol-ogy also stimulates the synthesis of vascular endothelial growth factors (VEGF), hepato-cyte growth factors (HGF), and hyaluronic acid (HA). The results obtained in this study confirmed that Endoret® (PRGF®) is able to inhibit and reverse the myofibroblast pheno-type. The persistence of this biological phe-notype can severely affect tissue function, giving rise to a fibrotic tissue that impedes its normal functioning.

Thus, we can conclude, that Endoret® (PRGF®) technology effectively promotes the regeneration of the gingival connective tis-sue, stimulating the main biological process-es involved in the repair and providing an

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interesting focus for gingival situations char-acterised by chronic persistent inflammation and elevated levels of TGF-β1.

Plasma rich in growth factors promote gingival tissue rege-neration by stimulating fibroblast proliferation and migra-tion and by blocking transforming growth factor-β1-induced myodifferentiation. Anitua E, Troya M, Orive G. J. Periodontol. 2012;83(8):1028-37.


The loss of alveolar bone can affect both function and aesthetics for the patient. The osteoblasts are the main cells involved in the repair and regeneration of bone tissue. This study evaluated the stimulatory effect of En-doret® (PRGF®) on the alveolar osteoblasts. For this purpose primary cultures of alveolar osteoblasts were used. They were previous-ly characterised by immunofluorescence re-vealing markers of bone origin (osteopontin, osteocalcin and alkaline phosphatase). The effect of different formulations of Endoret® (PRGF®) on aspects of cells such as prolifer-ation, migration and protein synthesis, in-volved in the most important processes of tissue regeneration. The results showed that the treatment with Endoret® (PRGF®) increased the proliferative capacity of the

alveolar osteoblasts. Similarly, the different formulations tested significantly increased the cell migration process and chemotaxis. In addition, a stimulating effect of Endoret® (PRGF®) on the synthesis of the angiogenic growth factors analysed was quantified. Re-garding the formation of extracellular matrix, again the different formulations stimulated the synthesis of procollagen I and osteocal-cin, principal components in the bone ma-trix. Endoret® (PRGF®) also stimulated the en-zyme alkaline phosphatase, involved in the mineralisation of said matrix, in particular af-ter 11 days of treatment. All of the findings of this study indicate the safety and efficacy of Endoret® (PRGF®) technology in bone regen-eration, by the stimulation of key processes such as proliferation, migration, chemotaxis

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and the synthesis of molecules with an angi-ogenic and antiinflammatory effect as well as extracellular matrix components.

Plasma Rich in Growth Factors (PRGF-Endoret) Promotes Bone Tissue Regeneration by Stimulating Proliferation, Migration and Autocrine Secretion on Primary Human Osteoblasts. Ani-tua E, Tejero R, Zalduendo MM, Orive G. J Periodontol. 2013 Aug;84(8):1180-90.


The regeneration of the periodontal tissue is one of the most important goals in treating periodontal disease. The purpose of this in vitro study was to evaluate the biological ef-fects of Endoret® (PRGF®) technology on hu-man fibroblasts of the periodontal ligament. To do so, primary cultures were obtained of fibroblasts from the human periodontal lig-ament, characterised by immunofluores-cence with connective tissue markers (type I collagen, fibronectin and periostin) and an osteogenic marker (osteopontin). The cell re-sponse to treatment with Endoret® (PRGF®) in different biological processes, such as cell proliferation, migration and adhesion, was studied, as well as its effect on the stimula-tion of the secretion of different biomole-cules and the expression of integrin α2 by

periodontal ligament fibroblasts cultured on type I collagen.

The results obtained showed that Endoret® (PRGF®) significantly stimulates the prolifer-ation and migration of periodontal ligament fibroblasts. In addition, the cells treated with this biological therapy adhered significantly earlier. Moreover, the cell synthesis of differ-ent key proteins involved in tissue regener-ation, such as vascular endothelial growth factors (VEGF), thrombospondin 1 (TSP-1), connective tissue growth factors (CTGF), hepatocyte growth factors (HGF) and type I pro-collagen were stimulated significantly after treatment with Endoret® (PRGF®). Final-ly, when the cells were treated with this tech-nology the expression of the integrin α2 was

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lower in comparison with the unstimulated cells. This is because the condition of the cells cultured with Endoret® (PRGF®) is more dy-namic. In fact, it has been demonstrated that cell mobility inversely correlates with the ex-pression of the integrins α1 and α2.

An Autologous Platelet Rich Plasma Stimulates Periodontal Li-gament Regeneration. Anitua E, Troya M, Orive G. J Periodontol. 2013 Nov;84(11):1556-66.


Bisphosphonate-related osteonecrosis of the jaw is a common problem in patients subject to long-term administration of highly pow-erful nitrogenous bisphosphonates. This pa-thology occurs by means of mechanisms that affect the bone and soft tissue. Zoledronic acid (ZA) is the most powerful nitrogenous bisphosphonate. The objective of this study was to evaluate the role of different concen-trations of ZA on the cells of the oral cavity as well as the potential of Endoret® (PRGF®) to overcome the negative effects of this medi-cine. Primary gingival fibroblasts and prima-ry alveolar osteoblasts were used, both of hu-man origin. To evaluate the effect of ZA, the cell proliferation, apoptosis and the expres-sion of the nuclear kappa beta factor (NF-kB) and phosphorylated nuclear kappa beta

factor (pNF-kB) were quantified. The ZA had a cytotoxic effect on the gingival fibroblasts and alveolar osteoblasts. This medicine in-hibited cell proliferation, stimulated apopto-sis, and induced inflammation. The addition of Endoret® (PRGF®) was effective in sup-pressing all of these negative effects of ZA. Endoret® (PRGF®) is a cytoprotector against the negative effects of zoledronic acid on the primary oral cells. Thus Endoret® (PRGF®) can be an effective therapy for both preventing and treating bisphosphonate-related oste-onecrosis of the jaw.

PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells. Anitua E, Zalduendo M, Troya M, Orive G. Clin Oral Investig. 2015 Jul 23. [Epub ahead of print]

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The application of Endoret® (PRGF®) inhibits the side effects of apoptosis and inflammation induced by zoledronic acid in bone and gingival cells.

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Alveolar osteoblasts


This study evaluated the antimicrobial effect of plasma rich in growth factors, Endoret® (PRGF®), on different strains of microorgan-isms from the oral cavity. After obtaining in-formed consent, blood was extracted from a total of 17 adult patients who were going to be subjected to a surgical operation in the oral cavity. The blood was extracted and cen-trifuged, then the millilitre of plasma that is just above the red fraction was collected, but without including the leukocytes. The con-centration of platelets and leukocytes was analysed in each of the samples obtained. The different microorganisms used in this study were isolated from patients with oral or dental infections. The most representative microorganisms that colonise and affect the oral cavity were selected, including E. faeca-

lis, C. albicans, S. agalactiae, S oralis and P. aeruginosa. The antimicrobial effect of En-doret® (PRGF®) was assessed by calculating the minimum inhibitory concentration (MIC). To do this, a concentration of 1x104 CFU/ml of each bacterial strain was incubated in dif-ferent wells with different seried dilutions of Endoret® (PRGF®) for each patient. These were incubated for 24 hours at 37ºC. The MIC values correspond to the concentration of Endoret® (PRGF®) present in the last well in which bacterial growth was observed. The minimum bactericidal concentration (MBC) was also assessed; this corresponds to the minimum concentration of Endoret® (PRGF®) necessary to kill a given bacterial strain. The results showed that Endoret® (PRGF®) inhib-ited the growth of all the bacterial species

Basic research



studied at platelet concentrations 3 or 4 times lower than those observed in the sam-ples of Endoret® (PRGF®), except for P. aeuro-ginosa for which an inhibitory effect was not observed. Moreover, the results obtained in this study showed that, except in C. albicans, the different samples analysed produced a bacterial effect at a platelet concentration similar to that found in the samples of En-doret® (PRGF®) in the microorganism species analysed. Endoret® (PRGF®) is a potentially useful product in the fight against post-oper-ative infection. These could represent a valu-able quality of Endoret® (PRGF®), in addition to stimulate tissue regeneration.

Antimicrobial activity of pure platelet-rich plasma against mi-croorganisms isolated from oral cavity. Drago L, Bortolin M, Vassena C, Taschieri S, Del Fabbro M. BMC Microbiol. 2013 Feb 25;13:47

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In 2009 one of the first pre-clinical exper-imental studies was performed to deter-mine the regeneration potencial of Endoret® (PRGF®). The study was carried out on goats in which cavities with a diameter of 3 mm were prepared in the tibia, simulating artificial al-veoluses that were then filled with Endoret® (PRGF®) or with a blood clot (control group). The regeneration of the defect was evalu-ated 8 weeks after the surgery, by means of histological preparations the newly formed bone was studied and a histomorphometric analysis of the tissue was performed. In the Endoret® (PRGF®) group, it was possible to histologically differentiate trabecular-type newly formed bone surrounded by densely vascularised connective tissue. In the con-trol group, the tissue found in the histolo-

gies consisted of connective tissue with a high cellularity with some small areas of in-tramembranous bone tissue. Thus, Endoret® (PRGF®) can be effective in stimulating the regeneration of bone defects.

The effects of PRGF on bone regeneration and on titanium im-plant osseointegration in goats: a histologic and histomorpho-metric study. Anitua E, Orive G, Pla R, Román P, Serrano V, Andía I. J Biomed Mat Res 2009; 91ª:158-165.

Preclinical Research



b)

a) Bone obtained from one alveolus treated with Endoret® (PRGF®). b) Bone obtained from one control alveolus

a)

The Endoret® (PRGF®) clot is ideal for filling in the post-extraction alveolus and for releasing growth factors that promote its regeneration.

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The objective of this randomised clinical trial was to evaluate the effectiveness of Endoret® (PRGF®) in tissue regeneration in the post-ex-traction alveolus and in the preparation of oral areas for the subsequent placement of dental implants.

The study included 20 patients who needed dental extractions and dental implant place-ment. These patients randomly received treatment with Endoret® (PRGF®), or the con-trol treatment without Endoret® (PRGF®). In three additional patients, a split-mouth study was performed.

Between weeks 10 and 16, the biopsies were taken and they were then analysed. The re-sults showed that the epithelisation of the 10

patients treated with Endoret® (PRGF®) was very good or excellent in comparison with the control. The regeneration of the alveolus-es treated with Endoret® (PRGF®) was almost complete in 8 of the 10 patients. The biop-sies showed an external bone regeneration, forming a compact bone with well-organised trabeculae.

In patients with severe defects that were treated with Endoret® (PRGF®) and autolo-gous bone, a greater bucco-lingual/palatal width was achieved. In the control group however, connective tissue and very lit-tle mature bone were observed. The epi-thelisation, in 100% of the cases was com-plete and significantly better than in the areas not treated with Endoret® (PRGF®).

Clinical research - post-extraction alveolus



The regeneration of mature bone was also greater in terms of amount and bone quality in the patients treated with Endoret® (PRGF®).

Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. Anitua E. Int J Oral Maxi-llofac Implants. 1999 Jul-Aug;14(4):529-35.

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To verify the efficacy and safety of treating the post-extraction alveolus with Endoret® (PRGF®), a randomised double-blind clini-cal trial was designed in which the post-ex-traction alveolus in molars of the mandible would be regenerated during a period of 12 weeks. For this purpose a total of 60 patients were recruited and divided into the Endoret® (PRGF®) treatment group (36 patients) and the control group (24 patients).

The principal variable studied was the per-centage of alveoluses that achieved 75% vol-ume of regenerated bone in the alveolus at the end of the follow up. As secondary vari-ables the following were also evaluated: the bone density (measured in Hounsfield units with a CT scan), soft tissue epithelisation in-

dex (scale from 1 to 5), thickness of kerati-nised gum, post-operative pain (on a visual analogue scale) and inflammation (scale from 0 to 3). In addition bone and soft tissue biopsies were taken in the patients in whom after the follow-up period dental implants were placed, using this surgery to take the samples.

The defects to be treated after the randomi-sation corresponded to molars with radic-ular septum in 54.16% in the control group, while only 38.9% of the defects of the treat-ment group preserved the septum. Due to this difference the defects of the Endoret® (PRGF®) group were of a greater volume than those treated in the control group. In the group treated with Endoret® (PRGF®)




by 62% in the control group with statistically significant differences in both groups. After seven days the pain had disappeared in the Endoret® (PRGF®) group, and there was pain in 15% of the control group. The pain at 15 days was absent in both groups.

In the evaluation of the inflammation index after three days, the presence of inflamma-tion was found in 18% of the cases in the Endoret® (PRGF®) group, while in 65% of the cases in the control group it was present, and these were statistically significant differenc-es. After seven days, inflammation persisted in 39% of the cases in the control group, while in the study group it had disappeared completely. These differences were statisti-cally significant.

a regeneration volume greater than or equal to 75% was achieved in 96.67% of the cases, while in the control group this percentage was only reached by 45.45%, which was a statistically significant difference (p<0.01).

The percentage of newly formed bone meas-ured in the histology was 63.08% for Endoret® (PRGF®) compared to 35.56% for the control group. The density of the newly formed bone was greater in the treatment group (average 450 UH) compared to the control group (av-erage 318 UH), and these were statistically significant differences.

In the evaluation of post-operative pain af-ter three days, pain was experienced by 18% of the patients (in the treatment group), and

The application of Endoret® (PRGF®) reduces inflammation and pain, accelerates the epithelisation of soft tissues and promotes bone regeneration.


Clinical, radiographical, and histological outcomes of plasma rich in growth factors in extraction socket: a randomized con-trolled clinical trial. Anitua E, Murias-Freijo A, Alkhraisat MH, Orive G. Clin Oral Investig. 2015 Apr;19(3):589-600. doi: 10.1007/s00784-014-1278-2014-1278-2. Epub 2014 Jul 8.

After 15 days the inflammation had disap-peared in both groups.

The epithelisation rate evaluated at three, seven and 15 days was greater with statisti-cally significant differences in the Endoret® (PRGF®) group compared to the control group. The following figure shows one of the cases included in the study in the control group compared to another case included in the Endoret® (PRGF®) group.

The thickness of the keratinised gum ob-served in the case of Endoret® (PRGF®) was the double that of the control cases, and the epithelial crests were thicker.




2 weeks

12 weeks

2 weeks 2 weeks

Clinical efficacy of Endoret® (PRGF®) promoting the regeneration of the post-extraction alveolus.

2 weeks

Control Endoret® (PRGF®)

12 weeks12 weeks12 weeks

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In this study the efficacy of Endoret® (PRGF®) in improving the healing of the post-extrac-tion alveolus was evaluated in diabetic insu-lin-dependent patients.

A split-mouth clinical trial was performed: The post-extraction alveolus was treated with En-doret® (PRGF®), while the other acted as a con-trol and was subject to natural healing without treatment. The selection of each treatment was randomised. A total of 34 patients subject to bilateral extractions of homologous teeth were included. In general, for both treatment types, no surgical complications such as ex-cessive bleeding, infection or alveolar ostei-tis were observed. The value observed on the tissue healing index was always ≤ 8, and the complete closure of the alveolus was of on

average on day 21, for approximately 50% of the patients. The comparison between the relative values, in the experimental and con-trol areas, showed better healing and quick-er closure for the area treated with Endoret® (PRGF®), with statistically significant differenc-es on days three and seven and the limit of the difference at 14 days . The pain score on the VAS was practically equal on both sides, reaching zero after four days for the area treat-ed with Endoret® (PRGF®) and after the sixth day for the control area without Endoret® (PRGF®). The results of patient questionnaire were unanimously in favour of treatment with Endoret® (PRGF®). The small samples of pa-tients with blood sugar values of at least 240 mg/dl showed a poorer healing score and less reduction in the alveolus volume. The authors




Efficacy of Plasma-Rich Growth Factor in the Healing of Postex-traction Sockets in Patients Affected by Insulin-Dependent Dia-betes Mellitus. Mozzati M, Gallesio G, di Romana S, Bergamasco L, Pol R. J Oral Maxillofac Surg. 2014 Mar;72(3):456-62

concluded that the application of Endoret® (PRGF®) after dental extractions improves the healing process in the diabetic patients, accel-erating the final closure of the alveolus (epi-thelisation) and the maturation of the tissue, which proves the link between the use of En-doret® (PRGF®) and improved wound healing in diabetic patients.

The efficacy is assessed

according to the soft tis-

sue duration index and

the residual defect of the

mucous membranes. 0.003 7 14 21

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Control

p= 0.04

p= 0.10


The extraction of teeth is the main cause of bisphosphonate-related osteonecrosis of the jaw (BRONJ). This evidence has led to the study of Endoret® (PRGF®) in preventing the development of BRONJ after a dental extraction. To study this, 176 patients were recruited who took zoledronic acid and re-quired the extraction of teeth. The patients were randomised in two groups: the first (91 patients) received the Endoret® (PRGF®) treatment while the second (85 patients) were used as the control group. The En-doret® (PRGF®) treatment includes filling in the post-extraction alveolus with a clot rich in growth factors and covering the surgical area with a fibrin membrane before closing the flap. X-rays and CT scans were taken be-fore surgery and 60 months after. No intra-

operatory complications were observed in either of the two treatment groups.

Endoret® (PRGF®) was shown to be effective in preventing the development of BRONJ in 542 extractions. There were no clinical or x-ray signs of any BRONJ lesions. On the other hand, in the control group 5 out of 267 extrac-tions developed a BRONJ lesion as indicated by the presence of a bone exposure. The aver-age period for the development of this lesion is 91.6 days after the tooth extraction. All of the patients who showed these osteonecrot-ic wounds had multiple myeloma, and they were all taking zoledronic acid (for more than 12 months). At the same time, at the time of diagnosis of BRONJ in the control group, the five patients had not yet completed




The application of Endoret® (PRGF®) in the treatment of the post-extraction alveolus prevents the development of BRONJ in patients treated with bisphosphonates.

b)

d)

a)

c)

their cycles of chemotherapy with vincris-tine. All of the cases of BRONJ were treated surgically and, during the bone extirpation surgery, Endoret® (PRGF®) was used with ex-cellent results.

Tooth extraction in patients on zoledronic acid therapy. Mozzati M, Arata V, Gallesio G. Oral Oncol. 2012 Sep;48(9):817-21.


The objective of this study was to identify the surgical protocols that can improve the regeneration of the post-extraction alveolus in patients who have received radiotherapy in the head or neck.

The study was designed as prospective split-mouth study. A total of 20 patients who needed a bilateral extraction of paired teeth were included. The post-extraction alveolus of the side that received the radiotherapy was the experimental group. This alveolus was treated with Endoret® (PRGF®) while the alveolus on the other side acted as the con-trol (blood clot). The study variables were the residual volume of the alveolus, the healing index, pain, and surgical complications. The variables were evaluated in 4 sessions until

30 days after the surgery and were analysed statistically.

The group of the alveoluses treated with En-doret® (PRGF®) showed better values of the residual alveolus volume and healing index in all of the follow-up sessions (statistically significant differences). Thus the regener-ation of the mucous membranes in the En-doret® (PRGF®) group was quicker than in the control group. No complications were observed in the experimental group while in the control group two cases of bone expo-sure were observed. This bone exposure was treated successfully with Endoret® (PRGF®).

A correlation was observed between the re-sidual volume of the alveolus and the dose




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of radiation received but not with the time passed since the radiotherapy.

It has been tested that Endoret® (PRGF®) is effective in the treatment of the patients who have received radiotherapy in the head and neck, accelerating the regeneration of the mucous membranes and preventing post-operative bone exposure.

Can plasma rich in growth factors improve healing in patients who underwent radiotherapy for head and neck cancer? A split-mouth study. Mozzati M, Gallesio G, Gassino G, Palomba A, Ber-gamasco L. J Craniofac Surg. 2014 May;25(3):938-43.


The aim of this study was to evaluate the po-tential effect of Endoret® (PRGF®) in the later-al approach for sinus elevation.

Five patients were included who required bi-lateral sinus elevations with a residual bone height of 1-3 mm. On one of the quadrants Endoret® (PRGF®) was used along with in-organic bovine bone, while only biomate-rial was used on the other side. The use of Endoret® (PRGF®) doubled the volume of the graft thanks to the action of the fibrin. Post-operative pain and inflammation were greater on the control side (without En-doret® (PRGF®)). The sinuses treated with En-doret® (PRGF®) presented a larger amount of new vital bone than in the control area. The immunohistochemistry of the biopsies

revealed that the number of blood vessels per square millimetre of connective tissue was 116 vessels as opposed to 7 in the control areas. These results showed the therapeutic potential of Endoret® (PRGF®) for reducing inflammation, increasing new bone formed and generating blood vessels in these sinus elevation procedures.

Anitua E, Prado R, Orive G. Bilateral Sinus Elevation Evaluating Plasma Rich in Growth Factors Technology: A Report of Five Ca-ses. Clin Implant Dent Relat Res. 2012; 14:51-60.

Clinical Research - Quality of life and post-operative recovery



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Endoret® (PRGF®) Control

The effectiveness of Endoret® (PRGF®) in reducing tissue inflammation (anti-inflammatory properties) and improve bone formation in maxillary sinus elevations.



Endoret® (PRGF®)

Control


The objective of this clinical trial was to evalu-ate whether the use of Endoret® (PRGF®) dur-ing maxillary sinus elevations could have a favourable impact on the pain and other fac-tors related to the patient's quality of life in the first week after surgery. A total of 30 pa-tients (18 women and 12 men) were includ-ed in the study, 15 in the experimental group and 15 in the control group. There were no significant differences with regard to the age, gender distribution and smoking habits be-tween the two groups. The height of the re-sidual crest was similar in the two groups (3.9 ± 1.3 mm and 4.1 ± 1.1 mm in the experimen-tal and control groups, respectively). In the Endoret® (PRGF®) group one intraoperative perforation of less than 5 mm was made in the Schneider membrane and in two cases in

the control group. In the case of the Endoret® (PRGF®) group, the perforation was resolved using an Endoret® (PRGF®) membrane. The use of Endoret® (PRGF®) responded with a significant reduction of perceived pain dur-ing the second and third day post-op, in comparison with the control group. The patients in the group treated with Endoret® (PRGF®) presented significantly less inflam-mation, fewer haematomas and less discom-fort when chewing and speaking throughout the assessment period. Opening the mouth and sleeping were better in the patients treated with Endoret® (PRGF®) for the first 3 to 4 days. Regarding absence from work, no differences were detected between the two groups. Bleeding was significantly less in the first 2 days in the Endoret® (PRGF®) group.

Clinical Research - Post-operative recovery and quality of life



Moreover, significantly fewer analgesics were taken in the Endoret® (PRGF®) group in comparison with the control in the first three days. The authors concluded that adding the application of Endoret® (PRGF®) to the proce-dure for maxillary sinus augmentation had a beneficial effect on the patients' quality of life in the early post-surgical stage.

Plasma Rich in Growth Factors Improves Patients’ Postoperative Quality of Life in Maxillary Sinus Floor Augmentation: Prelimi-nary Results of a Randomized Clinical Study. Del Fabbro M, Cor-bella S, Ceresoli V, Ceci C, Taschieri S. Clin Implant Dent Relat Res. 2015 Aug;17(4):708-16.

Pain evaluation during

the first week after sur-

gery. The asterisks indicate

significant differences (p

<0.05).

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Endoret® (PRGF®)Control

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The objective of this study was to describe a minimally invasive technique for the restora-tion of rear atrophic maxillae with a bone re-sidual height < 5 mm. The transalveolar sinus elevation was per-formed using sequential drilling in which the last mm of bone above the Schneider mem-brane was prepared with a front cutting drill. For the elevation of the membrane and its protection, an Endoret® (PRGF®) fibrin plug (very well retracted fibrin membrane) was inserted upon creating a window of 50% in the base of the alveolus. The results indicat-ed that the bone residual height was 4.04 ± 0.09 mm. The treatment protocol described significantly increased the residual bone height to an average of 8.86 ± 1.60 mm. These indicates a bone gain of 4.82 mm. The

bone height data was analysed according to the type of graft: Endoret® (PRGF®) alone or Endoret® (PRGF®) + bone graft. The bone gain was similar in both groups (statistically non-significant differences). Thus, Endoret® (PRGF®) is an effective biomaterial as a bone graft.

The post-operative period of the patient was good, without major surgical complications, indicating the efficacy and safety of Endoret® (PRGF®). This technique can constitute a min-imally invasive alternative for treating the atrophic posterior maxillae.

Association of transalveolar sinus floor elevation, platelet rich plasma and short implants for the treatment of atrophied pos-terior maxilla. Anitua E, Alkhraisat MH, Piñas L, Orive G. Clin Oral Imp Res 2015; 26: 69-76.

Clinical Research - Endoret®: the 100% autologous biomaterial



No inflammation or infection was reported or observed. Neither the donor not the re-ceiving area displayed any dehiscence of the incision.

X-ray analysis showed an initial crest width of 3.57 ± 0.46 mm (range 1.96-6.05 mm). The use of block grafts from the lateral wall of the maxillary sinus was effective in achieving a statistically significant gain of 5.34 ± 1.59 mm (range 2.56-8.10 mm) in the horizontal dimension of the area restored. The total in-crease percentage achieved was between 42% and 200%, with a mean value of 180.6%.

Surgical correction of horizontal bone defect utilizing the late-ral maxillary wall: outcomes of a retrospective study. Anitua E, Alkhraisat MH, Miguel-Sánchez A, Orive G. J Oral Maxillofac Surg 2014 Apr;72(4):683-93.

The objective of this study was to evaluate the effectiveness of Endoret® (PRGF®) in a new surgical technique for restoring narrow alveolar crests in the anterior of the maxilla. The use of Endoret® (PRGF®) was also assayed as a biomaterial for bone regeneration. The study included 11 patients who needed a si-nus elevation and also presented a horizon-tal loss at anterior level that would require an increase.

In this area, the window obtained from the sinus (after performing the lateral sinus ele-vation) was positioned and secured using BTI microscrews. The space between the graft and the alveolar process was sealed with au-tologous bone (obtained by means of bio-logical drilling) mixed with Endoret® (PRGF®) or with the Endoret® (PRGF®) clot. This was all covered with an autologous fibrin membrane from the patient before closing the flap.

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Minimally invasive surgery with Endoret® (PRGF®) minimises the surgical complications and improves the predictability of treatment.


The objective of this study was to evaluate the use of extra-short implants in conjunc-tion with Endoret® (PRGF®) to treat severe atrophy in the mandible. Ten patients pre-senting severe reabsorption in the posterior sectors of the mandible were recruited. The treatment plan included covering the ex-posed surface of the implant that exceeded the upper edge of the jaw with a hybrid bio-material composed of Endoret® (PRGF®) and autologous bone. This combination stabilises the graft and creates a bell shape around the implant to favour vertical bone growth. As a result, the residual height from the bone crest and the mandibular canal was 4.19 ± 0.97 mm. The application of Endoret® (PRGF®) favoured the stability of the bone graft around the implant and induced a ver-

tical bone gain of 1.6 ± 0.5 mm around the implant. The post-operative period for pa-tients was favourable as no surgical compli-cations were reported. After five months, a provisional implant-mounted prosthesis was fitted following a progressive-load protocol. None of the extra-short implants failed. The surgical technique used in conjunction with the application of Endoret® (PRGF®) may be a minimally invasive alternative to bone in-crease surgery (block graft).

Implant-guided vertical bone augmentation around extra-short implants for the management of severe bone atrophy. Anitua E, Murias-Freijo A, Alkhraist MH, Orive G. J Oral Implantol 2015 Oct;41(5):563-9.




b)

d)

The application of autologous bone graft + Endoret® (PRGF®) to cover the exposed surface of extra-short implants induced the vertical bone growth around the implant. This technique may be an alternative to the use of block grafts to increase bone in severely atrophic maxillae.

a)

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The objective of this randomised clinical trial was to evaluate the effectiveness of Endoret® (PRGF®) in preventing the exposure of the ti-tanium mesh in bone increase surgery.The inclusion criteria were the presence of a bone height ≤ 7mm, a thickness of the alve-olar process ≤ 3 mm or both, in the maxilla or the mandible. The patients were random-ly assigned to receive the treatment with or without Endoret® (PRGF®). The Endoret® (PRGF®) membrane was placed over the tita-nium mesh before closing the flap. In total, 43 alveolar bone increases were performed, placing 97 implants using ABB as the graft material in all of them. Approx-imately 15 patients received treatment with Endoret® (PRGF®), while the other 15 acted as a control.

Significant differences were found between the two groups, in terms of complications and amount of bone formed. In the control group, 28.5% of the cases suffered exposure of the mesh, while in the Endoret® (PRGF®) group, no exposure was recorded. The bone increase was greater in the Endoret® (PRGF®) group than in the control. 97.3% of the im-plants placed in the control group and 100% of those placed in the Endoret® (PRGF®) group were successful for 24 months.

Platelet-rich plasma may prevent titanium-mesh exposure in al-veolar ridge augmentation with anorganic bovine bone. Torres J, Tamimi F, Alkhraisat MH, Manchón A, Linares R, Prados-Frutos JC, Hernández G, López Cabarcos E. J Clin Periodontol. 2010 Oct;37(10):943-51.




tion with Endoret® (PRGF®) indicates that is a safe biomaterial, effective in the manage-ment of the perforation of this membrane. The survival rate of the implants was 96.2% and 98.6% for ABB and ABB + Endoret® (PRGF®) respectively.

In addition, a split-mouth comparison was performed in five patients with bilateral max-illary atrophy. The histological and histomor-phometric analysis revealed that the forma-tion of new bone was significantly greater in the group ABB + Endoret® (PRGF®).

Effect of platelet-rich plasma on sinus lifting: a randomized-controlled clinical trial. Torres J, Tamimi F, Martinez PP, Alkhraisat MH, Linares R, Hernández G, Torres-Macho J, López-Cabarcos E. J Clin Periodontol. 2009 Aug;36(8):677-87.

The objective of this study was to evaluate the efficacy of Endoret® (PRGF®) in improving the bone regeneration around the ABB in lat-eral elevations of the maxillary sinus. Approximately 87 patients (residual bone height < 7 mm) were recruited for this ran-domised clinical trial. The study groups were ABB and ABB plus Endoret® (PRGF®) (ABB + PRGF). A total of 286 implants were placed in the increased bone, and were monitored for 24 months. The perforation of the Schneider membrane was reported in 5 patients (2 in the control group and 3 in the experimental group). This perforation was treated with Endoret® (PRGF®) or with a collagen membrane de-pending on the treatment group. The effec-tiveness of treating the membrane perfora-

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The aim of this study was to clinically evalu-ate the ridge expansion technique with ul-trasonics called the Split-Crest technique, for the placement of dental implants in patients with narrow ridges, together with the appli-cation of Endoret® (PRGF®) in tissue regen-eration. At least 6 months after loading the implants, the state of the hard and soft tis-sues and the expansion achieved were eval-uated, as well as the survival rate of the im-plants. Fifteen patients were included whose previous average ridge width was 4.29 mm and who received a total of 37 BTI implants. In surgery, Endoret® (PRGF®) was applied to aid the regeneration of the tissues and the implants were humected with Endoret® (PRGF®) to accelerate osseointegration. The results showed that the state of the soft tis-

sues was very good with adequate values of plaque index, bleeding and probing depth. The survival rates of the implants between 11 and 28 months after insertion was 100%. The average bone expansion achieved was 3.35 mm. These results showed how the Split-Crest technique with ultrasonics along with the application of Endoret® (PRGF®) can be considered an effective and safe technique for bone expansion in narrow ridges.

Clinical evaluation of split-crest technique with ultrasonic bone surgery for narrow ridge expansion: status of soft and hard tis-sues and implant success. Anitua E, Begoña L, Orive G.Clin Im-plant Dent Relat Res. 2013 Apr;15(2):176-87.




The new two-stage Split-Crest technique using transitional BTI implants allows an expansion of the ridge of 7 - 8 mm.

This paper describes an innovative ridge ex-pansion technique called Split-Crest in 2 stag-es, indicated for patients with extremely reab-sorbed ridges (3-4 mm) in conjunction with the application of Endoret® (PRGF®) to aid the regeneration of the bone and soft tissue. It consists of an expansion carried out in 2 con-secutive stages using transitional implants. Three patients received 4 implants with this technique. To do so, surgery was performed with ultrasound and transitional implants (2.5 and 3.0 mm in diameter) were used and replaced, 5-7 months after its placement, by implants with larger diameters. The average follow-up period was 20.5 months. During the surgery Endoret® (PRGF®) was used. The state of the soft tissues was good with ade-quate probing depth values (average value

was 3.06 mm). The average bone expansion achieved after the procedure was 8.49 mm apical and 7.10 mm occlusal. There were no implant failures during the follow-up period. These preliminary results prove the predicta-bility and safety of the two-stage Split-Crest technique combined with the application of Endoret® (PRGF®) and its potential use in pa-tients with severely resorbed ridges, as well as avoiding the use of other more aggressive techniques such as bone grafts.

Two-stage split-crest technique with ultrasonic bone surgery for controlled ridge expansion: a novel modified technique. Anitua E, Begoña L, Orive G. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Dec;112(6):708-10.


The objective of this study was to evaluate the effect of plasma rich in growth factors (PRGF) on pulp regeneration and apex for-mation in necrosed teeth with an open apex.After accessing and cleaning the root canal, the triple antibiotic paste was inserted into the canal to disinfect it. After 2 weeks, apical bleeding was caused manually using a file with a diameter of 80. The rich part of the PRGF was activated and injected to fill the canal up to the level of the enamel-cement joint. The tooth was temporarily restored. The patients were revaluated after 2 weeks. If the tooth was now asymptomatic, the ca-nal would be sealed with MTA and the tooth restored with composite. At 22 months post-op, total closure of the apex was observed in two teeth. In another two teeth a closure of

the apex and an increase in the thickness of the root wall were observed.

Thus, the protocol described in this study has shown that PRGF may be a suitable scaffold for pulp regeneration. Clinical trials are nec-essary to evaluate the effectiveness of PRGF in pulp regeneration.

The plasma-rich in growth factor as a suitable matrix in regene-rative endodontics: a case series. Bakhtiar H, Vatanpour M, Ra-yani A, Navi F, Asna-Ashari E, Ahmadi A, Jafarzadeh H. N Y State Dent J. 2014 Jun-Jul;80(4):49-53.




The objective of this study was to evaluate the effectiveness of Endoret® (PRGF®) in the treatment of osteoarthritis of the temporo-mandibular joint. Thirteen patients (mean age: 47.64 ±7.51 years, 11 were women) who suffered osteoarthrosis of the temporoman-dibular joint (TMJ) were selected. The var-iables studied were the maximum mouth opening (in mm) and the pain (visual ana-logue scale). The data was gathered before treatment (t0), after 30 days (t1) and after 6 months (t2). The data was analysed statisti-cally (the Student t-test for paired variables). The pain evaluation indicated a reduction from 7.69 ± 1.9 (t0) to 1.54 ± 1.74 (t1) and 0.23 ± 0.65 (t2). This reduction was statistically sig-nificant. The maximum mouth opening ex-perienced an increase of 7.38 mm in t1 (from

30.15 ± 4.44 mm (t0) to 37.54 ± 5.10 mm (t1). This increase was statistically significant. At t2, the maximum mouth opening was 39.54 ± 4.55 with an increase of 9.38 ±2.21 since t0 and 2 mm since t1. Both differences were sta-tistically significant.

Thus, the intra-articular use of Endoret® (PRGF®) is an effective procedure for con-trolling pain and improves the mobility of the TMJ in patients with osteoarthrosis of this joint.

Temporomandibular joint disorders treated with articular injec-tion: the effectiveness of plasma rich in growth factors-Endoret.Giacomello M, Giacomello A, Mortellaro C, Gallesio G, Mozzati M. J Craniofac Surg. 2015 May;26(3):709-13.

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The objective of this pilot clinical trial was to evaluate the use of Endoret® (PRGF®) in the management of the Schneider membrane during maxillary sinus elevations. Eight maxillary sinus elevations were carried out in eight patients.

In the sinus elevation procedure, there were two perforations of the Schneider membrane during the procedure, which were effectively resolved using a clot of Endoret® (PRGF®). The post-operative quality of life of the patient was generally good.

Use of plasma rich in growth factor for schneiderian membrane management during maxillary sinus augmentation procedu-re. Taschieri S, Corbella S, Del Fabbro M. J Oral Implantol. 2012 Oct;38(5):621-7. doi: 10.1563/AAID-JOI-D-12-00009.

Biphosphonates are a group of drugs that reduce the rate of bone turnover, mainly through the inhibition of the action of osteo-clasts, and they are administered both orally and intravenously in patients with oncologi-cal or rheumatic treatments.

A side effect of these medicinal products is the development of exposed bone that does not heal in the maxillofacial region in pa-tients treated with bisphosphonates. For this reason this pathology was named bisphos-phonate-related osteonecrosis of the jaw (BRONJ).

Recently, the use of Endoret® (PRGF®) has been proposed for the treatment of BRONJ as part of a preventive and therapeutic approach.

Clinical Research - Management of clinical complications



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Osteoradionecrosis (ORN) is the worst long-term complication of radiotherapy in the head and neck. This study evaluates the safety and the effectiveness of Endoret® (PRGF®) in the treatment of ORN.

A series of 10 patients with ORN were treated with the excision of necrotic bone and the application of Endoret® (PRGF®) to improve and accelerate the regeneration of the soft tissues. A clinical and x-ray evaluation of the patient was performed up to 12 months after the surgery. The pain was evaluated during the first week after surgery. The maturation and quality of the regeneration of the tissues were evaluated according to the modified healing index.

All of the patients were successfully treated with Endoret® (PRGF®). No intra or post-op complications were observed. The clinical and x-ray evaluation revealed the absence of signs of infection or exposed bone up to 12 months after surgery. The maturation and quality of the regenerated tissue was excellent. Complete closure of the defects was obtained in all the patients. The pain and muscular trismus was low in all of the patients despite all of the patients stopping taking analgesics from third day after surgery.

Conservative treatment with plasma rich in growth factors-Endoret for osteoradionecrosis. Gallesio G, Del Fabbro M, Pol R, Mortellaro C, Mozzati M. J Craniofac Surg. 2015 May;26(3):731-6.




The Endoret® (PRGF®) clot is an autologous haemostatic agent that improves tissue regeneration and reduces surgical morbidity.

The objective of this clinical trial is to com-pare the fibrin adhesive and Endoret® (PRGF®) as haemostatic agents. Approximately 120 patients with different blood disorders were randomised to receive out-patient dental ex-tractions. Before the surgery, the patients re-ceived systemic haematological treatment. In the control group (fibrin adhesive) 106 ex-tractions were carried out (7 were for impact-ed third molars). Secondary bleeding was ob-served in 3/60 patients (5%) on the third day after surgery, and an additional surgical op-eration and systemic treatment were neces-sary. These additional measures were repeat-ed on day 7, after the surgery, in one of the three cases. In the Endoret® (PRGF®) group there were 98 dental extractions (23 were impacted third molars). Secondary bleeding

was observed in two patients (3.3%) on the first day after the extraction. Homeostasis was reestablished with surgery but without systemic treatment. Four of the five second-ary bleeds were in patients with haemophilia A. Thus, Endoret® (PRGF®) was as effective as the fibrin adhesive. Nevertheless, Endoret® (PRGF®) is of autologous origin, does not re-quire additional systemic treatment when treating the post-extraction alveolus, im-proves the neo-angiogenesis, reduces mor-bidity and also the cost for the health system.

Autologous plasma rich in growth factors in the prevention of se-vere bleeding after teeth extractions in patients with bleeding di-sorders: a controlled comparison with fibrin glue. Cocero N, Pucci F, Messina M, Pollio B, Mozzati M, Bergamasco L. Blood Transfus. 2015 Apr;13(2):287-94.


In this article a patient developed a BRONJ le-sion after being treated for several years with zoledronic acid (IV) and after a tooth extrac-tion. Their symptomatology included severe pain and hemimandibular paraesthesia due to affectation of the dental nerve. The treat-ment consisted of surgical resection of the necrotic bone area combined with the appli-cation of Endoret® (PRGF®).

One month after surgery, total closure of the ulcerous lesion in the mucous membrane was observed without the presence of ne-crotic bone. Six months later, a significant im-provement of the pain and paresthesia was observed. After a year, the patient had total-ly recovered sensitivity and the absence of necrotic bone was confirmed. These clinical

results support the use of Endoret® (PRGF®) as an adjuvant treatment for patients with BRONJ. The use of this autologous technol-ogy is based on the potential effects of the growth factors released and the fibrin on bone remodelling and on angiogenesis.

Treatment of hemimandibular paraesthesia in a patient with bisphosphonate-related osteonecrosis of the jaw (BRONJ) by combining surgical resection and Endoret® (PRGF®). Anitua E, Be-goña L, Orive G. Br J Oral Maxillofac Surg. 2013 Dec;51(8):e272-4.




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The application of Endoret® (PRGF®) in the treatment of BRONJ improves the closure of soft tissues and the regeneration of the bone defect.

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The chemistry and the topography of the surface are of the utmost importance for the osseointegration of dental and orthopedic implants inserted in load-bearing areas. This study evaluated in vitro and in vivo titanium implants whose surface was modified with calcium ions (UnicCa® surface). The calcium ions have caused a long-lasting chemical and nano-topographic modification of the titani-um oxide. The analysis of the composition of the most superficial UnicCa® layer with the secondary ion mass spectrometry technique indicated that the calcium ions protected the implant surface from the passivation of tita-nium oxide with hydrocarbons. The release of calcium ions from the UnicCa® surface was also studied. Two thirds of the calcium was released during the first minute. The rest of

the calcium ions were released over 85 days. In cell cultures, the surface modified with cal-cium ions significantly increased the adhe-sion, proliferation and differentiation of the osteoblasts. The insertion of the implants in the tibia of ewes showed that the Unic-Ca® surface very significantly increased the bone-implant contact and the bone density in an area of 1 mm around the implant. Thus, the UnicCa® surface represents an instru-ment for improving and accelerating the os-seointegration of dental implants.

Effects of calcium ions on titanium surfaces for bone regenera-tion. Anitua E, Piñas L, Murias A, Prado R, Tejero R. Colloids Surf B Biointerfaces. 2015 Jun 1;130:173-81

Basic research

BTI dental implants


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This paper presents the results of research carried out on the release of growth factors using surfaces bioactivated with Endoret® (PRGF®).

The principal result of this study was that to achieve a sustained release and, therefore, better regeneration around the implant, Endoret® (PRGF®) must be activated. Two activators of the coagulation cascade were tested: calcium and thrombin ions. Calcium, in addition to avoiding a potential immune response, allows a greater release of platelet growth factors. In short, this paper indicates the importance of the bioactivation of the implant with Endoret® (PRGF®) in improving osseointegration.

Time-dependent release of growth factors from implant surfaces treated with plasma rich in growth factors. Sánchez-Ilárduya MB, Trouche E, Tejero R, Orive G, Reviakine I, Anitua E. J Biomed Mater Res A. 2013 May;101(5):1478-88.


This biomechanical study was carried out with the aim of evaluating the influence of distal offset on the stress distribution that the bone around the implant sustains. A me-sial force of 200 N and a distal force of 230 N were applied to the prosthesis. The results showed that the fact that there is a limited offset (of up to 2.5 mm) of the prosthesis on the implant does not increase stress on the adjacent bone.

A controlled offsetting of the implant on the prosthesis, in addition to allowing an optimal aesthetic restoration and reducing the emer-gence profile, does not increase bone stress and a possible risk of implant failure.

The use of larger diameter implants will re-duce even further the stress in the bone ad-jacent to the implant.

Finite element analysis of the influence of the offset placement of an implant-supported prosthesis on bone stress distribution. Anitua E, Orive G. J Biomed Mater Res B Appl Biomater. 2009 May;89(2):275-81.

Basic research

BTI dental implants


The aim of this biomechanical study was to evaluate the influence of the length, diam-eter and geometry of BTI implants on bone stress distribution. 3D finite element models were created and a load of 150 N was applied at an angle of 30 degrees. Different diam-eters (3.5 to 5.0 mm) and lengths (8.5 to 15 mm) were evaluated. The results showed that the effect of the implant diameter on bone stress distribution was more significant than the effect of the length or geometry. On the other hand the maximum stress was located around the implant neck and most of it in the bone adjacent to the first threads. According to the results observed, the use of greater diameter implants can be beneficial to re-duce stress around them, meaning that the use of short implants with a greater diameter

could be a reasonable alternative in locations where residual bone height is limited.

Influence of implant length, diameter, and geometry on tress dis-tribution: a finite element analysis. Anitua E, Tapia R, Luzuriaga F, Orive G. Int J Periodontics Restorative Dent. 2010 Feb;30(1):89-95.

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The objective of this study is to evaluate the se-quential regeneration around dental implants with different configurations and surfaces.

Approximately 12 Beagle dogs were subject-ed to the extraction of all teeth, from the sec-ond premolar to the first molar, on both sides of the mandible. After 3 months a full-thick-ness flap was raised and two implants of dif-ferent systems and different surfaces were inserted in the premolar area on one side of the mandible. The two surfaces evaluated in this study were unicCa® by BTI and T3® by 3i. The surgery on the other side of the mandi-ble and the slaughter of the animals was or-ganised in order to obtain biopsies that rep-resent the regeneration at 2, 4 and 8 weeks (6 biopsies for each time).

The results indicated that the sequential re-generation patterns around the surfaces unicCa® by BTI and T3® by 3i were similar. Nevertheless, a greater percentage of newly formed bone was stimulated by the UnicCa® surface by BTI than by the surface T3® by 3i. The differences were statistically significant at 2 and 4 weeks.

Sequential healing at calcium- versus calcium phosphate-mo-dified titanium implant surfaces: An experimental study in dogs. Favero R, Botticelli D, Antunes AA, Martinez Sanchez R, Caro-prese M, Salata LA. Clin Implant Dent Relat Res 2015 Mar 2. doi: 10.1111/cid.12311.


BTI dental implants


The osseointegration of dental and orthope-dic implants is the reason for their success in clinical practice. Titanium is the material of choice for the manufacture of these implants due to its favourable properties. After the placement of the implant, the titanium sur-face establishes an ionic balance with the ad-jacent tissues. In this balance, calcium plays a fundamental role since it is a co-factor in the coagulation cascade, intermediating in the adsorption of plasma proteins and interven-ing in numerous processes at an intra- and extracellular level relevant for bone regener-ation. In this trial the objective was to study the modification of the titanium surface with calcium ions (the UnicCa® surface). The UnicCa® surface was characterised in both in vitro and in vivo models. Compared with the unmodified surface, the UnicCa® surface was super-hydrophilic and was capable of inducing platelet activation and adsorption and clot formation upon contact with plas-ma. In an in vivo model, the UnicCa® surface

had significantly improved the peri-implant bone volume and bone density at 2 weeks and the implant-bone contact at 8 weeks af-ter insertion, in comparison with the unmod-ified surface. Furthermore, the combination of the UnicCa® surface with Endoret® (PRGF®) produced significantly greater bone-implant contact at 2 weeks after implantation. These findings suggest the importance of the for-mation of a provisional matrix in osseoin-tegration and reinforce the potential of the UnicCa® surface for improving the osseointe-gration of the implant.

Effects of calcium-modified titanium implant surfaces on platelet activation, clot formation, and osseointegration. Anitua E, Prado R, Orive G, Tejero R. J Biomed Mater Res A. 2015 Mar;103(3):969-80.

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In this study carried out with research ani-mals the aim was to determine whether the humectation of the implant surfaces with Endoret® (PRGF®) encouraged their osseoin-tegration. To this end a total of 23 implants were inserted in the tibia/radius of 3 goats; 13 of them were previously humected with Endoret® (PRGF®) while the other 10 were not (control). Eight weeks later, a histomorpho-metric analysis was carried out on the bone biopsies of the sacrificed animals and we ob-served that the value of the bone-implant contact (BIC) was 51.28% in the animals hu-mected with Endoret® (PRGF®), as opposed to 21.89% in the implants that were not hu-mected, generating a significantly greater area in the former (p<0.01).

These results prove how the humecta-tion of implants with Endoret® (PRGF®) en-courages their faster osseointegration.

The effects of PRGF on bone regeneration and on titanium im-plant osseointegration in goats: a histologic and histomorpho-metric study. Anitua E, Orive G, Pla R, Román P, Serrano V, Andía I. J Biomed Mat Res 2009; 91ª:158-165.


BTI dental implants


Humectation of BTI implants with Endoret® (PRGF®) encourages faster osseointegration.

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This study carried out on research animals evaluated the effect of humectation of dental implants with Endoret® (PRGF®) to encourage and accelerate their osseointegration. To this end, two dogs were used in which 12 implants were inserted, 6 on each side of the mandible, humecting the implants of one side with Endoret® (PRGF®), and placing the implants of the opposite side without humectation (control). After 12 weeks, the implants were extracted along with the adjacent bone for a histological-histomorphometric analysis. The results showed that the implants humected with Endoret® (PRGF®) presented higher levels of BIC (bone-implant contact). We also observed higher values of trabecular bone thickness and bone maturity in the areas treated with Endoret® (PRGF®).

Birang R, Tavakoli M, Shahabouei M, Torabi A, Dargahi A, Soolari A. Investigation of peri-implant bone healing using autologous plasma rich in growth factors in the canine mandible after 12 weeks: a pilot study. Open Dent J. 2011;5:168-173.


BTI dental implants


protein elements different to those of other surfaces assessed. The specificity of both the morphology and the composition of the interfaces formed with implants bioactivated with Endoret® (PRGF®) is very possibly the reason behind its beneficial clinical results.

Tejero R, Rossbach P, Keller B, Anitua E, Reviakine I. Time of flight secondary ion mass spectrometry with principal com-ponent analysis of titania-blood plasma interfaces. Langmuir. 2013;29:902-912.

The aim of this study was to assess both the morphology and the composition of the interface formed by the implants activated with Endoret® (PRGF®). Both features are of capital importance for later regenerative events as both the morphology and the composition of the interface allow the modulation, among other aspects, of the balance between inflammation and regeneration around the implant. In this article we could see through electron, atomic and confocal microscopy that the bioactivation of implants with Endoret® (PRGF®) generates a three-dimensional network with a multitude of platelets, proteins and growth factors. In addition, the composition of the interface of the surfaces bioactivated with Endoret® (PRGF®) is specific, containing platelet and

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The aim of this randomised clinical trial was to assess the need or not to administer an an-tibiotic prophylaxis with 2 g of oral amoxicil-lin one hour before the single dental implant insertion surgery to avoid post-op infections. Twelve private centres which recruited a total of 105 patients took part; 52 received amoxi-cillin and 53 received the placebo.

After 6 months, there were 6 infections and 2 implant failures in each group. No statisti-cally significant differences were found for post-op infections, adverse events or implant failures between both groups. Observing the results of this study, antibiotic prophylaxis for single implants may not be necessary.

A multicentre placebo-controlled randomised clinical trial of antibiotic prophylaxis for placement of single dental implants. Anitua E, Aguirre JJ, Gorosabel A, Barrio P, Errazquin JM, Román P, Pla R, Carrete J, de Petro J, Orive G. Eur J Oral Implantol. 2009 Winter;2(4):283-92.

Clinical research - Planning the treatment protocol



BTI dental implants


The objective of this study was to describe and compare the conventional drilling sys-tem at high revolutions (1200 rpm with ex-ternal irrigation) to a biological drilling sys-tem at low revolutions (50-100 rpm) that allows recovery of the autologous bone for use as a bone graft. In the protocol of biologi-cal drilling: except the initial drilling (800 rpm with irrigation), the preparation of the im-plant site was carried out at low revolutions without irrigation. The design of the diame-ter drills generates retentive turns able to re-trieve the bone particles during drilling. The microscopic examination showed that the bone structure and the presence of live cells was preserved in all the samples collected with low-revolution drilling while these qual-ities were not maintained with conventional

drilling. The drilling temperature, working at 50 rpm without irrigation, was approximate-ly 28ºC indicating the safety of this new drill-ing protocol. In the clinical trial, the optimum stability of the implants after 4 months in the bone with a graft of autologous bone from drilling + Endoret® (PRGF®) indicates the good regenerative quality of this graft. Bio-logical drilling at low revolutions can reduce damage to the host tissue and can be used to obtain a mass of live bone ideal for carry-ing out bone grafts associated with Endoret® (PRGF®).

A novel drilling procedure and subsequent bone autograft pre-paration: a technical note. Anitua E, Carda C, Andia I. Int J Oral Maxillofac Implants. 2007 Jan-Feb;22(1):138-45. Erratum in: Int J Oral Maxillofac Implants. 2007 Mar-Apr;22(2):309

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The quality of receiving bone is one of the most decisive factors for the osseointegration of the implant. In this paper, the bone density and the cortical bone thickness were the two parameters used to classify the bone type into five categories. The bone type was used to decide the drilling protocol with the aim of ensuring a suitable level of primary stability. The study included 295 implants with a length of 8.5 mm inserted in 192 patients. The results indicated that the insertion torque was of 59.29 ± 7.27, 56.51 ± 1.62, 46.40 ± 1.60, and 34.84 ± 2.38 Ncm for bone type I, type II, type III and type IV, respectively. Thus, we can see that the insertion torque varies depending on the bone type; it is greater for bone with a higher density. The drilling protocol of this study was effective in obtaining an insertion

torque greater than 30 Ncm in the low-density bone (bone type IV). In addition, we observed that bone with a density below 400 Ncm is different from the rest in bone type IV. In fact, the resistance of the bone to drilling was notably lower and the insertion torque was only 5 Ncm. The x-ray analysis indicates the absence of cortical bone and that it was present in the posterior area of the maxilla. Therefore, we have named this bone type V.

Efficacy of biologically-guided implant site preparation to obtain adequate implant’s primary stability. Anitua E, Alkhraisat MH, Orive G. Annals of Anatomy 2014

Clinical research - Planning the treatment protocol

BTI dental implants


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Maxillary sinus elevation by means of osteotomy with ultrasound.

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hand it improves the vision and hygiene of the surgical area and provides a more conservative and controlled bone incision.

Ultrasonic ostectomy for the surgical approach of the maxillary sinus: a technical note. Torrella F, Pitarch J, Cabanes G, Anitua E. Int J Oral Maxillofac Implants. 1998 Sep-Oct;13(5):697-700.

This article describes the sinus elevation technique with the use of an osteotomy with ultrasonics. This is the first job that uses surgical ultrasonics. This technique offers important advantages over a conventional osteotomy that uses diamond tool bits. In addition, it reduces the risk of perforating Schneider's membrane. On the other

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When there is a limited mesio-distal space, the distal offset of the implant position to re-place a single tooth in the posterior area may be an option. The objective of this study is to evaluate it in the long term in the posterior area.

Approximately 31 patients were treated with a single implant inserted in an off-centre po-sition in the posterior area. The prosthetic restoration was performed in using the Bio-pilar® by BTI and a cemented prosthesis.

Some 34 implants were placed in this study. In the study group 20 patients were women and the average age was 56 ± 12 years. The follow-up period for the implants, from load-ing, was up to 10 years (Average: 4 ± 3 years).

The majority of the implants were placed in bone type II in the molar area (85%). The adoption of an off-centre configuration and an implant with a greater diameter resulted in a mesial bone loss of 0.85 ± 0.57 mm and a distal loss of 0.83 ± 0.68 mm. There was only one implant that failed, 4 months after inser-tion. Thus survival rate of the implants was 97.1%. No prosthetic complications were ob-served.

Replacement of missing posterior tooth with off-centre placed single implant: Long-term follow-up outcomes.Anitua E, Murias-Freijo A, Flores J, Alkhraisat MH. J Prosthet Dent. 2015 Jul;114(1):27-33.

Clinical research - Standard BTI implants

BTI dental implants


The aim of this study was to analyse the factors that affect the stability of dental im-plants at 12 weeks after insertion, measured by means of resonance frequency analysis using the Osstell system.

In this prospective clinical trial, 235 implants were inserted in 93 patients. The prediction variables collected were grouped into varia-bles patient, implant and operative variables, and the baseline implant stability quotient (ISQ). They were analysed in a multivariate model to determine its influence on the ISQ score 12 weeks after insertion (result varia-ble). No link was found between the patient variables and the ISQ values at 12 weeks. Among the implant variables, it was ob-served that the ISQ value at 12 weeks was lower for the implant with a narrow diame-ter (P <0.001) and the dental implants in the superior maxilla (P = 0.006). Among the var-iables of the surgical technique, the use of Endoret® (PRGF®) (P = 0.011) gave the best ISQ values at 12 weeks. Thus, the implant di-ameter, its location and the application of En-doret® (PRGF®) significantly affect the stabili-ty of the implants.

Dental implant stability is influenced by implant diameter and localization and by the use of plasma rich in growth factors.Quesada-García MP, Prados-Sánchez E, Olmedo-Gaya MV, Mu-ñoz-Soto E, Vallecillo-Capilla M, Bravo M. J Oral Maxillofac Surg. 2012 Dec;70(12):2761-7.

The aim of this study was to evaluate the long-term survival of BTI implants and to identify the possible risk factors associated with im-plant failures. A total of 5787 BTI implants of different diameters and lengths were includ-ed in the study. The results showed that the implant survival rate was 99.2%, 96.4% and 96.0% for the analysis based on the implant, on the surgery and on the patient, respec-tively. The risk factors that could be related to a higher implant failure rate were two-stage surgery and the use of special surgery-re-lated techniques. These results attest to the predictability and safety of BTI's range of im-plants.

5-year clinical experience with BTI dental implants: risk factors for implant failure. Anitua E, Orive G, Aguirre JJ, Ardanza B, Andía I. J Clin Periodontol. 2008 Aug;35(8):724-32.

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This study was carried out with the aim of describing the immediate-load dental im-plant insertion technique and to evaluate the long-term survival, as well as the possible risk factors related to its failure. A total of 1139 implants were included and a survival rate of 99.3%, 96.8% and 96.9% was observed for the analysis based on the implant, on the sur-gery and on the patient, respectively. Only 5 of the implants failed during the follow-up period and no failure-related risk factors were found.

These results showed the predictability of the immediate load technique described provid-ed it is used with appropriate insertion tor-ques and following strict clinical protocols.

Clinical outcome of immediately loaded dental implants bioac-tivated with plasma rich in growth factors: a 5-year retrospective study. Anitua E, Orive G, Aguirre JJ, Andía I. J Periodontol. 2008 Jul;79(7):1168-76.

Clinical research - Standard BTI implants

BTI dental implants


The aim of this study is to describe a regenera-tion technique using Endoret® (PRGF®) to pre-serve the architecture of the soft tissue around the immediate post-extraction implant.

A 30-year-old woman come to the clinic with clinical symptoms that worsen when chew-ing in the area of the second right premolar. After creating a flap without relieving inci-sions, the presence of a vertical fracture was confirmed. After the tooth was extracted, a BTI dental implant was inserted immediately.

The space between the bone and the im-plant was filled with a graft of Bio-Oss® and Endoret® (PRGF®). Then the implant was cov-ered with a dense fibrin matrix and it was su-tured and left exposed.

This technique enabled guided bone regen-eration, without the need for vertical reliev-ing incisions, thus avoiding the emergence of gingival scarring. The appearance of the gingival edge was aesthetically acceptable. Thus, it was possible to satisfy the aesthetic needs without the need for more surgery or grafts. The integration of this technique into clinical practice will aid the achievement of ideal aesthetic results.

Immediate postextraction implant placement using plasma rich in growth factors technology in maxillary premolar region: a new strategy for soft tissue management. Rosano G, Taschieri S, Del Fabbro M. J Oral Implantol 2013 Feb;39(1):98-102.

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The objective of this clinical trial was to eval-uate short implants in posterior areas of the superior maxilla and mandible area in the long term.

The patients included in this retrospective study had received one or more short im-plants (≤ 8.5 mm long) in posterior areas, at least 10 years earlier. All the implants were previously humected with plasma rich in growth factors (Endoret® (PRGF®)). The accu-mulated success rate was the primary study variable. The crestal bone loss and the influ-ence of different variables were evaluated as secondary results of the study. A total of 111 short implants (7.0 , 7.5 and 8.5 mm long) were evaluated, placed in 75 patients. Some 94 implants were spliced to other longer im-

plants. The average follow-up time was 123.3 months (SD = 10.4 months) . The average crown-implant ratio was 1.4 (SD = 0.3). The average MBL was of 1.0 mm in the mesial (SD = 0.7) and 0.9 mm (SD = 0.6) in the dis-tal. One short implant failed during the study follow-up period. The success rate was 98.9% and 98.2% for the implants and the patients, respectively. Thus, the use of short implants is a safe and effective long-term option.

Long-term retrospective evaluation of short implants in the pos-terior areas: clinical results after 10-12 years. Anitua E, Piñas L, Begoña L, Orive G. J Clin Periodontol. 2013 Dec 18. doi: 10.1111/jcpe.12222.

Clinical research - Short and extra-short implants

BTI dental implants


follow-up period was 26 months from im-plant insertion. No signs of impaired nerve function were observed in the lower dental nerve. The implant survival rate was 98.4%. The peri-implant bone loss was 1 mm. No prosthetic complications were observed dur-ing the observation period.

Thus, the extra-short implants humectated with Endoret® (PRGF®) are an effective min-imally invasive alternative in the prosthetic restoration of atrophic inferior maxillae.

Novel technique for the treatment of the severely atrophied pos-terior mandible. Anitua E, Alkhraisat MH, Orive G. Int J Oral Maxi-llofac Implants. 2013 Sep-Oct;28(5):1338-46.

The objective of this clinical trial was to eval-uate a new minimally invasive surgical tech-nique for the restoration of the mandible with severe atrophy, avoiding the need for a major surgical restoration.

In this technique, the biological drilling pro-tocol was carried out in two stages: the first phase with conventional drills, limiting the working length to 1 mm less than the length of the alveolus to prepare. In the second phase, a front cutting drill was used to pre-pare the last 1 mm of the alveolus to avoid damaging the inferior dental nerve.

With this technique, 114 extra-short im-plants humectated with Endoret® (PRGF®) were inserted into 72 patients. The average

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The objective of this prospective study was to evaluate the clinical success of placing short implants in combination with a transcrestal sinus elevation, complemented with plate-let-rich plasma without leucocytes. Endoret® (PRGF®) was used to reduce the risk of per-forating the Schneider membrane and oth-er possible surgical complications. A total of 65 implants were placed in 25 patients. The short implants were spliced to one or more standard implants.

After a mean follow-up time of 14.4 months, 60 implants in 23 patients were evaluated. The success and survival rates of the implant were 100%.There were no failures in any of the pros-thetic restorations performed. The bone loss

around the implant (a year after loading) was 0.34 ± 0.21 mm for short implants of 8.5 mm (n=25) and 0.36 ± 0.30 mm for the longest implants (n=35). There were no significant differences between the two groups (p=23).

Thus, the treatment protocol proposed is a viable option for the restoration of posterior atrophic maxillae.

Mini-Invasive Osteotome Sinus Floor Elevation in Partially Eden-tulous Atrophic Maxilla Using Reduced Length Dental Implants: Interim Results of a Prospective Study. Taschieri S, Corbella S, Del Fabbro M. Clin Implant Dent Relat Res. 2012 Aug 9. doi: 10.1111/j.1708-8208.2012.00483.x.


BTI dental implants


These results showed that treatment with short and extra-short implants can be con-sidered a safe and predictable technique if used following strict clinical protocols.

Short implants in maxillae and mandibles: a retrospective study with 1 to 8 years of follow-up. Anitua E, Orive G. J Periodontol. 2010 Jun;81(6):819-26.

The aim of these studies was to evaluate the long-term survival (up to 8 years of fol-low-up) of short and extra-short BTI implants (≤ 8.5 mm) in posterior areas of the superior maxilla and the mandible. In the first of them, a total of 1287 short implants placed in 661 patients were included. The results showed a survival rate of 99.3% and 98.8% for the anal-ysis based on the implant and on the patient, respectively. Nine of the implants failed due to different causes. No risk factors related to the failure of the short implants could be identified.

In the second study the extra-short implants (≤6.5) were also studied separately, showing survival rates of 97.9% and 97.1% for the im-plants and patients, respectively.

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This study was carried out with the aim of evaluating the influence of an unfavourable crown/implant ratio (≥1) and other variables of the implant, be they surgical, prosthetic or biomechanical, on Marginal Bone Loss and on the survival of short implants in posterior areas. A total of 128 implants placed in 63 patients were evaluated. The average follow-up period was 22 months. The average C/I ratio of the implants was 1.82. In 86 of them it was <2 and in 42 implants ≥2. The marginal bone loss observed was 0.35 mm during the first year post-load and 0.45 mm after the first year post-load. The implant and prosthesis survival rate was 100 %. The unfavourable C/I ratio did not show any relationship with the marginal bone loss of the implants. Of the remaining variables studied, the only one

that showed a negative influence was the use of cantilevers in prosthetic rehabilitations.

Retrospective Study of Short and Extra-Short Implants Placed in Posterior Regions: Influence of Crown-to-Implant Ratio on Margi-nal Bone Loss. Anitua E, Piñas L, Orive G. Clin Implant Dent Relat Res. 2015 Feb;17(1):102-110.


BTI dental implants


The use of short and extra-short implants is generating prosthetic restorations with un-favourable implant-crown proportions. This study evaluates the repercussions that this unfavourable crown-implant proportion may have on the marginal bone loss. It also identi-fies possible ratios that endanger the success of implant-mounted restorations.

This study included 34 patients with 45 ex-tra-short implants (length of 5.5 or 6.5 mm). The follow-up time was up to 4 years with an average of 2 years. The crown-implant ratio was 2.4 (range: 1.5-3.69). The crown height space (CHS), defined as the distance from the bone crest to the occlusion plane, was 17.05 ± 3.05 mm. None of the extra-short implants failed.

The results indicate that the type of antago-nist significantly affected the marginal bone loss. This was greater when the antagonist is a fixed bridge (1.28 ± 1.09 mm) and lower when the antagonist is a natural tooth (0.73 ± 0.60 mm) or complete prosthesis (0.89 ± 0.60 mm). Nevertheless, the crown-implant ratio does not significantly influence the marginal bone loss. A significant correlation was observed between the CSH and the mar-ginal bone loss.

Implant survival and crestal bone loss around extra-short im-plants supporting a fixed denture: the effect of crown height spa-ce, crown to implant ratio and offset placement of the prosthesis. Anitua E, Alkhraisat MH, Piñas L, Begoña L, Orive G. Int J Oral Maxillofac Impl 2014 May-Jun;29(3):682-689.

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Clinical evaluation of Tiny® 2.5- and 3.0-mm narrow-diameter implants as definitive implants in different clinical situations: a retrospective cohort study. Anitua E, Errazquin JM, de Pedro J, Barrio P, Begoña L, Orive G. Eur J Oral Implantol. 2010 Win-ter;3(4):315-22.

Clinical research - BTI narrow implants (Tiny®)

This study was carried out to evaluate the long-term survival and clinical effectiveness of narrow-diameter (2.5 and 3.0 mm) BTI Tiny® implants in patients with an insufficient ridge (2.5 to 4.0 mm) to allow the placement of standard-diameter implants. 51 patients were included who received a total of 89 implants. The results showed a survival rate of 98.9% and 98.0% for the analysis based on the implant and on the patient, respectively. Only one implant failed 12 months after its placement. Average bone loss after 2 years of implant load was 1.26 mm. These results showed that 2.5 and 3.0 mm Tiny® implants can be used effectively and safely for the treatment of narrow and severely resorbed ridges.

BTI dental implants


The use of implants with a small diameter (<3.75 mm) are a minimally invasive alter-native to procedures of horizontal bone in-crease. The objective of this study is to analyse the long-term results of the Tiny® 2.5 mm im-plant in a restoration with a fixed prosthesis.

The patient records were analysed retrospec-tively to select those who had at least one Tiny® 2.5 mm implant before July 2005. The variables studied were the demographic pa-rameters, the peri-implant bone loss, the sur-vival of the implants and the prosthetic com-plications. Thirty-seven implants were placed in 20 patients (mean age: 54.05 ± 9.7 years). The follow-up time of the implants was 6.5 ± 3.2 years (range from 0 to 9.7 years). This fol-low-up time was greater than 7 years for 22

implants. Only one implant failed due to the lack of osseointegration. Only two prosthetic complications were observed (fracture of the connector and porcelain). Thus, the survival rate was 97.3% for the implants and 92.0% for the prostheses. The peri-implant bone loss was <1 mm.

Thus, the use of the Tiny® implant to support a fixed prosthesis obtains favourable long-term results.

Long-term follow-up of 2.5-mm narrow-diameter implants sup-porting fixed prostheses. Anitua E, Saracho J, Begoña L, Alkhrai-sat MH. Clin Implant Dent Relat Res. 2015 Apr 27. doi:10.1111/cid.12350.

“The many clinical studies carried out with BTI implants prove their versatility, safety and predictability”


This study aims to describe a protocol and analyse the results of the immediate replace-ment of the implant that has failed due to periimplantitis.

The BTI atraumatic implant extraction kit was used. All of the implants were extracted by applying a countertorque with the specif-ic wrench designed for this purpose. Then a new implant was placed in the same socket and in the same surgical intervention after the application of Endoret® (PRGF®). The new implants were monitored to evaluate their survival and the crestal bone loss.

Seventeen patients (mean age 58 ± 10 years) were included for the replacement of 22 im-plants. Of the new implants, one failed 16

months after insertion, which resulted in a survival rate of 94.7%. The average follow-up time was 40 ± 16 months after insertion. The mesial and distal bone loss was 0.89 ± 0.62 mm and 0.97 ± 0.66 mm, respectively.

Thus, the use of the implant extraction kit is minimally invasive so it is possible to insert the new implant immediately. The results of this study enable us to recommend this pro-tocol in the treatment of failed implants.

Prognosis of dental implants immediately placed in sockets affected by periimplantitis: A retrospective pilot study. Eduar-do Anitua, Laura Piñas, Leire Begoña, Mohammad Hamdan Alkhraisat. Int J Periodontics Restorative Dent. Date accepted: 2014-12-25

Clinical research - Treatment of periimplantitis

BTI dental implants


Preclinical Research was carried out to eval-uate the mechanisms of the atraumatic ex-plantation of dental implants. which can make it possible to place a new one in the bone socket.

Twelve dental implants were placed in the diaphysis of the tibia and, once osseointe-grated, they were explanted using the BTI of implant extraction kit. The osseointegration and explantation of the implant were eval-uated using the value of the implant stabil-ity quotient, the extraction torque and the angular offset. The bone walls of the alveo-lus and the surface of the extracted implant were analysed under a conventional micro-scope and a scanning electron microscope. The osseointegration of the implant broke

with an angular offset of less than 20º. The value of the implant stability quotient after breaking the osseointegration was similar to its value when the implant was inserted. At the same time, the explantation technique was minimally invasive, causing minimal damage to the bone structure and its cellu-larity.

Thus, the atraumatic extraction of the dental implant and the maintenance of the viability and structure of bone socket resulting from the explantation make it possible to achieve optimum conditions for the osseointegra-tion of a new implant inserted in this socket.

Non-traumatic implant explantation: a biomechanical and bio-logical analysis in sheep tibia. Anitua E, Murias-Feijo A, Piñas L, Prado R, Tejero R, Orive G. J Oral Implantol. 2014 Dec 23. [Epub ahead of print]

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The objective of this study is to evaluate the effectiveness of BTI implant extraction kit in the treatment of failed implants.

The implant was extracted by applying a counter-torque to the implant-bone inter-face. The post-explantation socket was in-spected and cleaned to remove the gran-ulation tissue. The immediate insertion of a new implant was carried out when suitable primary stability could be achieved.

Some 81 patients were treated to remove 158 failed implants in the maxilla and man-dible. The average age of the candidates was 62 ± 11 years. The principal cause of the im-plant removal was periimplantitis (131 im-plants; 82.9%) followed by poor positioning

of the implant (22 implants; 13.9%). The ex-plantation of 139 implants was achieved at a torque of 146 ± 5 Ncm without the need to use trephine drills. Nevertheless, the use of these drills was necessary to extract 19 im-plants and the explantation torque was 161 ± 13 Ncm.

All of the implants with a titanium plasma spray (TPS) surface treatment were extracted due to periimplantitis and the explantation torque was less than the implants treated using acid-etching, blasting with particles or oxidisation. The post-operative period of the patients presented no complications. The ex-plantation technique used in this study was effective in preserving and not damaging the oral tissues.


BTI dental implants


Thus, the protocol described in this study could constitute a real alternative to other traumatic techniques of extracting dental implants. The type of surface treatment of the implant could influence the value of the extraction torque and the periimplantitis.

Conservative implant removal for the analysis of the cause, re-moval torque and surface treatments of failed nonmobile dental implants. Anitua E, Murias-Freijo A, Alkhraisat MH. J Oral Implan-tol. 2014 Dec 1. [Epub ahead of print]

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Anitua et al. Atraumatic Implant Explantation, is it Possible? Description of a Novel Technique and a Case Series Study. JIACD. 2010;2:65-71.



This article describes for the first time the concept of “de-osseointegration” of implants. For this purpose a new technique has been developed that uses the BTI Explantation Kit, which facilitates an easy and atraumatic ex-plantation while keeping the walls of the al-veolar socket intact to allow the placement of a new implant. In this study a total of 58 explantation cases of different implants were included using the BTI Explantation Kit. The removal torque var-ied between 80 and 200 Ncm. In 20 cases a new implant was placed. This article shows how the possibility of explanting dental im-plants atraumatically opens new doors in oral implantology.


BTI dental implants


This study was carried out with the aim of de-scribing and evaluating the new technique for the atraumatic explantation of implants. This new technique facilitates a fast explan-tation, keeping the alveolar socket walls in-tact and at the same time facilitating the insertion of a new implant during the same surgical operation.

In this study 91 implants explanted from a to-tal of 42 patients were included. The remov-al torques varied between 80 and 200 Ncm. In those cases where the implant removal torque exceeded 200 Ncm, 2-3 mm incisions were carried out with a set of atraumatic tre-phines to avoid excessively high torques. These results showed how the possibility of explanting implants atraumatically can be

considered a viable alternative to replace failed implants.

A new approach for atraumatic implant explantation and imme-diate implant installation. Anitua E, Orive G. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Mar;113(3):e19-25.

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Oral and maxillofacial surgery

Publications

• Anitua E, Piñas L, Murias-Freijo A, Alkhraisat MH. Re-habilitation of Atrophied Low-Density Posterior Maxi-lla by Implant-Supported Prosthesis. J Craniofac Surg. 2016 Jan;27(1):e1-2.

• Anitua E, Alkhraisat MH, Piñas L, Orive G. Association of transalveolar sinus floor elevation, platelet rich plasma and short implants for the treatment of atrophied pos-terior maxilla. Clin Oral Imp Res 2015;26(1):69-76.

• Anitua E, Piñas L, Orive G. Retrospective Study of Short and Extra-Short Implants Placed in Posterior Regions: Influence of Crown-to-Implant Ratio on Marginal Bone Loss. Clin Implant Dent Relat Res. 2015;17(1):102-10.

• Anitua E, Pinas L. Pyogenic granuloma in relation to dental implants: Clinical and histopathological fin-dings. J Clin Exp Dent. 2015 Oct 1;7(4):e447-50.

• Anitua E, Flores J, Alkhraisat MH. Transcrestal Sinus Lift Using Platelet Concentrates in Association to Short Im-plant Placement: A Retrospective Study of Augmented Bone Height Remodeling. Clin Implant Dent Relat Res. 2015 Oct 20. doi: 10.1111/cid.12383.

• Del Fabbro M, Corbella S, Ceresoli V, Ceci C, Taschieri S. Plasma Rich in Growth Factors Improves Patients’ Posto-perative Quality of Life in Maxillary Sinus Floor Augmen-tation: Preliminary Results of a Randomized Clinical Stu-dy. Clin Implant Dent Relat Res. 2015 Aug;17(4):708-16.

• Taschieri S, Corbella S, Molinari R, Saita M, Del Fabbro M. Short implants in maxillary and mandibular rehabili-tations: interim results (6 to 42 months) of a prospecti-ve study. J Oral Implantol. 2015 Feb;41(1):50-5.

• Durán-Cantolla J, Crovetto-Martínez R, Alkhraisat MH, Crovetto M, Municio A, Kutz R, Aizpuru F, Miranda E, Anitua E. Efficacy of mandibular advancement device in the treatment of obstructive sleep apnea syndrome: A randomized controlled crossover clinical trial. Med Oral Patol Oral Cir Bucal. 2015 Sep 1;20(5):e605-15.

• Anitua E, Murias-Freijo A, Alkhraisat MH. Implant Site Under-Preparation to Compensate the Remodeling of an Autologous Bone Block Graft. J Craniofac Surg. 2015 Jul;26(5):e374-7.

• Anitua E, Piñas L, Murias A, Prado R, Tejero R. Effects of calcium ions on titanium surfaces for bone regeneration. Colloids Surf B Biointerfaces. 2015 Jun 1;130:173-81.

• Anitua E, Prado R, Orive G, Tejero R. Effects of calcium-modified titanium implant surfaces on platelet activa-tion, clot formation, and osseointegration. J Biomed Mater Res A. 2015 Mar;103(3):969-80.

• Anitua E, Murias-Freijo A, Flores J, Alkhraisat MH. Re-placement of missing posterior tooth with off-center placed single implant: Long-term follow-up outcomes. J Prosthet Dent. 2015 Jul;114(1):27-33.


• Mozzati M, Mortellaro C, Gallesio G, Ruggiero T, Pol R. Surgical treatment of denture-induced fibrous hyper-plasia with plasma rich in growth factors. J Craniofac Surg. 2015 May;26(3):772-5.

• Del Fabbro M, Gallesio G, Mozzati M. Autologous pla-telet concentrates for bisphosphonate-related os-teonecrosis of the jaw treatment and prevention. A systematic review of the literature. Eur J Cancer. 2015 Jan;51(1):62-74.

• Cocero N, Pucci F, Messina M, Pollio B, Mozzati M, Ber-gamasco L. Autologous plasma rich in growth factors in the prevention of severe bleeding after teeth ex-tractions in patients with bleeding disorders: a contro-lled comparison with fibrin glue. Blood Transfus. 2015 Apr;13(2):287-94.

• Anitua E, Zalduendo MM, Prado R, Alkhraisat MH, Orive G. Morphogen and proinflammatory cytokine release kinetics from PRGF-Endoret fibrin scaffolds: evaluation of the effect of leukocyte inclusion. J Biomed Mater Res A. 2015 Mar;103(3):1011-20.

• Anitua E, Zalduendo M, Troya M, Padilla S, Orive G. Leu-kocyte inclusion within a platelet rich plasma-derived fibrin scaffold stimulates a more pro-inflammatory en-vironment and alters fibrin properties. PLoS One. 2015 Mar 30;10(3):e0121713.

• Anitua E, Troya M, Zalduendo M, Orive G. Effects of anti-aggregant, anti-inflammatory and anti-coagulant drug consumption on the preparation and therapeutic po-tential of plasma rich in growth factors (PRGF). Growth Factors. 2015 Feb;33(1):57-64.

• Anitua E, Zalduendo MM, Troya M, Orive G. Ozone dosing alters the biological potential and therapeutic outcomes of plasma rich in growth factors. J Periodon-tal Res. 2015 Apr;50(2):240-7.

• Taschieri S, Testori T, Corbella S, Weinstein R, Francetti L, Di Giancamillo A, Del Fabbro M. Platelet-Rich Plasma and Deproteinized Bovine Bone Matrix in Maxillary Sinus Lift Surgery: A Split-Mouth Histomorphometric Evaluation. Implant Dent. 2015 Oct;24(5):592-7.

• Drago L, Bortolin M, Vassena C, Romanò CL, Taschieri S, Del Fabbro M. Plasma components and platelet acti-vation are essential for the antimicrobial properties of autologous platelet-rich plasma: an in vitro study. PLoS One. 2014 Sep 18;9(9):e107813.

• Anitua E, Alkhraisat MH, Orive G. Long-term outcome of transosteotomy bone augmentation of the inferior border of the severely resorbed mandible. Implant Dent. 2015 Apr;24(2):236-9.

• Durán-Cantolla J, Alkhraisat MH, Martínez-Null C, Agui-rre JJ, Guinea ER, Anitua E. Frequency of obstructive sleep apnea syndrome in dental patients with tooth wear. J Clin Sleep Med. 2015 Apr 15;11(4):445-50.

• Anitua E, Zalduendo MM, Prado R, Alkhraisat MH, Orive G. Morphogen and proinflammatory cytokine release kinetics from PRGF-Endoret fibrin scaffolds: evaluation of the effect of leukocyte inclusion. J Biomed Mater Res A. 2015 Mar;103(3):1011-20.

• Anitua E, Alkhraisat MH, Piñas L, Orive G. Efficacy of biologically guided implant site preparation to obtain adequate primary implant stability. Ann Anat. 2015 May;199:9-15.

• Anitua E, Murias-Freijo A, Alkhraisat MH, Orive G. Im-plant-Guided Vertical Bone Augmentation Around Ex-tra-Short Implants for the Management of Severe Bone Atrophy. J Oral Implantol. 2015 Oct;41(5):563-9.

• Anitua E, Murias-Freijo A, Alkhraisat MH, Orive G. Clini-cal, radiographical, and histological outcomes of plas-ma rich in growth factors in extraction socket: a rando-mized controlled clinical trial. Clin Oral Investig. 2015 Apr;19(3):589-600.

• Anitua E, Zalduendo M, Troya M, Orive G. PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells. Clin Oral Investig. 2015 Jul 23. [Epub ahead of print]

• Mozzati M, Arata V, Giacomello M, Del Fabbro M, Galle-sio G, Mortellaro C, Bergamasco L. Failure risk estimates after dental implants placement associated with plas-ma rich in growth factor-Endoret in osteoporotic wo-men under bisphosphonate therapy. J Craniofac Surg. 2015 May;26(3):749-55.

• Gallesio G, Del Fabbro M, Pol R, Mortellaro C, Mozzati M. Conservative treatment with plasma rich in growth factors-Endoret for osteoradionecrosis. J Craniofac Surg. 2015 May;26(3):731-6.

• Giacomello M, Giacomello A, Mortellaro C, Gallesio G, Mozzati M. Temporomandibular joint disorders trea-ted with articular injection: the effectiveness of plasma rich in growth factors-Endoret. J Craniofac Surg. 2015 May;26(3):709-13.


• Anitua E, Alkhraist MH, Piñas L, Begoña L, Orive G. Im-plant survival and crestal bone loss around extra-short implants supporting a fixed denture: the effect of crown height space, crown-to-implant ratio, and offset placement of the prosthesis. Int J Oral Maxillofac Im-plants. 2014 May-Jun;29(3):682-9.

• Anitua E, Alkhraisat MH, Miguel-Sánchez A, Orive G. Surgical correction of horizontal bone defect using the lateral maxillary wall: outcomes of a retrospective stu-dy. J Oral Maxillofac Surg. 2014 Apr;72(4):683-93.

• Anitua E, Piñas L, Begoña L, Orive G. Long-term retros-pective evaluation of short implants in the posterior areas: clinical results after 10-12 years. J Clin Periodon-tol. 2014 Apr;41(4):404-11.

• Anitua E, Zalduendo MM, Alkhraisat MH, Orive G. Re-lease kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors. Ann Anat. 2013 Oct;195(5):461-6.

• Scoletta M, Arata V, Arduino PG, Lerda E, Chiecchio A, Gallesio G, Scully C, Mozzati M. Tooth extractions in in-travenous bisphosphonate-treated patients: a refined protocol. J Oral Maxillofac Surg. 2013 Jun;71(6):994-9.

• Anitua E, Alkhraisat MH, Orive G. Novel technique for the treatment of the severely atrophied posterior mandible. Int J Oral Maxillofac Implants. 2013 Sep-Oct;28(5):1338-46.

• Rosano G, Taschieri S, Del Fabbro M. Immediate pos-textraction implant placement using plasma rich in growth factors technology in maxillary premolar re-gion: a new strategy for soft tissue management. J Oral Implantol. 2013 Feb;39(1):98-102.

• Anitua E, Alkhraisat MH, Orive G. Rigorous methodolo-gy is the school of coherent conclusions in science. Eur J Oral Implantol. 2013 Spring;6(1):9-11.

• Anitua E, Begoña L, Orive G. Clinical evaluation of split-crest technique with ultrasonic bone surgery for na-rrow ridge expansion: status of soft and hard tissues

• Taschieri S, Corbella S, Del Fabbro M. Mini-invasive os-teotome sinus floor elevation in partially edentulous atrophic maxilla using reduced length dentalimplants: interim results of a prospective study. Clin Implant Dent Relat Res.2014 Apr;16(2):185-93.

• Anitua E, Troya M, Zalduendo MM, Orive G. The effect of different drugs on the preparation and biological outcomes of plasma rich in growth factors. Ann Anat. 2014 Dec;196(6):423-9.

• Mogharehabed A, Birang R, Torabinia N, Nasiri S, Be-hfarnia P. Socket preservation using demineralized freezed dried bone allograft with and without plasma rich in growth factor: A canine study. Dent Res J (Isfa-han). 2014 Jul;11(4):460-8.

• Bakhtiar H, Vatanpour M, Rayani A, Navi F, Asna-Ashari E, Ahmadi A, Jafarzadeh H. The plasma-rich in growth factor as a suitable matrix in regenerative endodontics: a case series. N Y State Dent J. 2014 Jun-Jul;80(4):49-53.

• Mozzati M, Gallesio G, Gassino G, Palomba A, Berga-masco L. Can plasma rich in growth factors improve healing in patients who underwent radiotherapy for head and neck cancer? A split-mouth study. J Craniofac Surg. 2014 May;25(3):938-43.

• Mozzati M, Gallesio G, di Romana S, Bergamasco L, Pol R. Efficacy of plasma-rich growth factor in the healing of postextraction sockets in patients affected by insu-lin-dependent diabetes mellitus. J Oral Maxillofac Surg. 2014 Mar;72(3):456-62.

• Taschieri S, Corbella S, Tsesis I, Del Fabbro M. Impact of the use of plasma rich in growth factors (PRGF) on the quality of life of patients treated with endodontic surgery when a perforation of sinus membrane occu-rred. A comparative study. Oral Maxillofac Surg. 2014 Mar;18(1):43-52.

• Anitua E, Murias-Feijo A, Piñas L, Prado R, Tejero R, Ori-ve G. Non-traumatic implant explantation: a biome-chanical and biological analysis in sheep tibia. J Oral Implantol. 2014 Dec 23. [Epub ahead of print]


• Anitua E, Alonso R, Girbau C, Aguirre JJ, Muruzabal F, Orive G. Antibacterial effect of plasma rich in growth factors (PRGF®-Endoret®) against Staphylococcus au-reus and Staphylococcus epidermidis strains. Clin Exp Dermatol. 2012 Aug;37(6):652-7.

• Anitua E, Troya M, Orive G. Plasma rich in growth fac-tors promote gingival tissue regeneration by stimu-lating fibroblast proliferation and migration and by blocking transforming growth factor-β1-induced myo-differentiation. J Periodontol. 2012 Aug;83(8):1028-37.

• Anitua E, Begoña L, Orive G. Controlled ridge expansion using a two-stage split-crest technique with ultrasonic bone surgery. Implant Dent. 2012 Jun;21(3):163-70.

• Taschieri S, Corbella S, Del Fabbro M. Use of plasma rich in growth factor for schneiderian membrane manage-ment during maxillary sinus augmentation procedure. J Oral Implantol. 2012 Oct;38(5):621-7.

• Taschieri S, Rosano G, Weinstein T, Bortolin M, Del Fab-bro M. Treatment of through-and-through bone le-sion using autologous growth factors and xenogeneic bone graft: a case report. Oral Maxillofac Surg. 2012 Mar;16(1):57-64.

• Nóbrega AR, Norton A, Silva JA, Silva JP, Branco FM, Anitua E. Osteotome versus conventional drilling tech-nique for implant site preparation: a comparative study in the rabbit. Int J Periodontics Restorative Dent. 2012 Jun;32(3):e109-15.

• Nóbrega AR, Norton A, Silva JA, Silva JP, Branco FM, Anitua E. Osteotome versus conventional drilling tech-nique for implant site preparation: a comparative study in the rabbit. Int J Periodontics Restorative Dent. 2012 Jun;32(3):e109-15.

• . Anitua E, Prado R, Orive G. Bilateral sinus elevation evaluating plasma rich in growth factors technology: a report of five cases. Clin Implant Dent Relat Res. 2012 Mar;14(1):51-60.

• Anitua E, Orive G. A new approach for atraumatic im-plant explantation and immediate implant installa-tion. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Mar;113(3):e19-25.

• Mozzati M, Arata V, Gallesio G. Tooth extraction in patients on zoledronic acid therapy. Oral Oncol. 2012 Sep;48(9):817-21.

and implant success. Clin Implant Dent Relat Res. 2013 Apr;15(2):176-87.

• Drago L, Bortolin M, Vassena C, Taschieri S, Del Fabbro M. Antimicrobial activity of pure platelet-rich plasma against microorganisms isolated from oral cavity. BMC Microbiol. 2013 Feb 25;13:47.

• Anitua E, Begoña L, Orive G. Treatment of hemiman-dibular paresthesia in a patient with bisphosphonate-related osteonecrosis of the jaw (BRONJ) by combining surgical resection and PRGF-Endoret. Br J Oral Maxillo-fac Surg. 2013;51(8):e272-4.

• Serrano AJ, Begoña L, Anitua E, Cobos R, Orive G. Syste-matic review and meta-analysis of the efficacy and sa-fety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis. Gynecol Endocrinol. 2013;29(12):1005-14.

• Tejero R, Alkhraisat MH, Orive G. Platelet-rich plasma to improve the bio-functionality of biomaterials. Anitua E, BioDrugs. 2013 Apr;27(2):97-111.

• Tejero R, Rossbach P, Keller B, Anitua E, Reviakine I. Time-of-flight secondary ion mass spectrometry with principal component analysis of titania-blood plasma interfaces. Langmuir. 2013 Jan 22;29(3):902-12.

• Sánchez-Ilárduya MB, Trouche E, Tejero R, Orive G, Re-viakine I, Anitua E. Time-dependent release of growth factors from implant surfaces treated with plasma rich in growth factors. J Biomed Mater Res A. 2013 May;101(5):1478-88.

• Anitua E, Troya M, Orive G. An Autologous Platelet Rich Plasma Stimulates Periodontal Ligament Regeneration. J Periodontol. 2013;84(11):1556-66.

• Anitua E, Tejero R, Zalduendo MM, Orive G. Plasma rich in growth factors promotes bone tissue regeneration by stimulating proliferation, migration, and autocrine secretion in primary human osteoblasts. J Periodontol. 2013 Aug;84(8):1180-90.

• González MC, García A, Anitua E, Martínez R, Aguirre JM. Orthokeratinized odontogenic cyst: a report of three clinical cases. Case Reports in dentistry. 2013.1-4.

• Anitua E, Alkhraisat MH, Orive G. Perspectives and challenges in regenerative medicine using plasma rich in growth factors. J Control Release. 2012 Jan 10;157(1):29-38.


Advanced clinical dentistry.2010;2(5):19-29.

• Anitua E, Orive G. Short implants in maxillae and man-dibles: a retrospective study with 1 to 8 years of follow-up. J Periodontol. 2010 Jun;81(6):819-26.

• Anitua E, Tapia R, Luzuriaga F, Orive G. Influence of implant length, diameter, and geometry on stress dis-tribution: a finite element analysis. Int J Periodontics Restorative Dent. 2010 Feb;30(1):89-95.

• Anitua E, Errazquin JM, de Pedro J, Barrio P, Begoña L, Orive G. Clinical evaluation of Tiny® 2.5- and 3.0-mm narrow-diameter implants as definitive implants in di-fferent clinical situations: a retrospective cohort study. Eur J Oral Implantol. 2010 Winter;3(4):315-22.

• Torres J, Tamimi F, Alkhraisat MH, Manchón A, Linares R, Prados-Frutos JC, Hernández G, López Cabarcos E. Platelet-rich plasma may prevent titanium-mesh expo-sure in alveolar ridge augmentation with anorganic bo-vine bone. J Clin Periodontol. 2010 Oct;37(10):943-51.

• Torres J, Tamimi F, Martinez PP, Alkhraisat MH, Lina-res R, Hernández G,Torres-Macho J, López-Cabarcos E. Effect of platelet-rich plasma on sinus lifting: a rando-mized-controlled clinical trial. J Clin Periodontol. 2009 Aug;36(8):677-87.

• Del Fabbro M, Boggian C, Taschieri S. Immediate im-plant placement into fresh extraction sites with chro-nic periapical pathologic features combined with plasma rich in growth factors: preliminary results of single-cohort study. J Oral Maxillofac Surg. 2009 Nov;67(11):2476-84.

• Anitua E, Orive G. Treatment of post-extraction defects using PRGF-technology: case-series study. Italian Oral Surgery.2010;9(3):115-129.

• Anitua E, Orive G, Pla R, Roman P, Serrano V, Andía I. The effects of PRGF on bone regeneration and on tita-nium implant osseointegration in goats: a histologic and histomorphometric study. J Biomed Mater Res A. 2009 Oct;91(1):158-65.

• Mozzati M, Gallesio G, Arata V, Pol R, Scoletta M. Plate-let-rich therapies in the treatment of intravenous bis-phosphonate-related osteonecrosis of the jaw: a report of 32 cases. Oral Oncol. 2012 May;48(5):469-74.

• Del Fabbro M, Ceresoli V, Lolato A, Taschieri S. Effect of platelet concentrate on quality of life after periradicu-lar surgery: a randomized clinical study. J Endod. 2012 Jun;38(6):733-9.

• Taschieri S, Del Fabbro M. Postextraction osteoto-me sinus floor elevation technique using plasma-rich growth factors. Implant Dent. 2011 Dec;20(6):418-24.

• Mozzati M, Arata V, Gallesio G, Carossa S. A dental ex-traction protocol with plasma rich in growth factors (PRGF) in patients on intravenous bisphosphonate therapy: a case-control study. Joint Bone Spine. 2011 Dec;78(6):648-9.

• Anitua E, Begoña L, Orive G. Two-stage split-crest te-chnique with ultrasonic bone surgery for controlled ridge expansion: a novel modified technique. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Dec;112(6):708-10.

• Scoletta M, Arduino PG, Pol R, Arata V, Silvestri S, Chiec-chio A, Mozzati M.Initial experience on the outcome of teeth extractions in intravenous bisphosphonate-treated patients: a cautionary report. J Oral Maxillofac Surg.2011 Feb;69(2):456-62.

• Mozzati M, Martinasso G, Pol R, Polastri C, Cristiano A, Muzio G, Canuto R. The impact of plasma rich in growth factors on clinical and biological factors involved in healing processes after third molar extraction. J Bio-med Mater Res A. 2010 Dec 1;95(3):741-6.

• Anitua E. Atraumatic implant explantation, is it possi-ble? Description of a novel technique and a case series study. The Journal of implant & advanced clinical den-tistry.2010;2(7):65-71.

• Anitua E. The use of short and extra-short BTI implants in the daily clinical practice. The Journal of implant &


plant site preparation with motorized bone expanders. Pract Proced Aesthet Dent. 2006 Jan-Feb;18(1):17-22.

• Anitua EA. Enhancement of osseointegration by ge-nerating a dynamic implant surface. J Oral Implantol. 2006;32(2):72-6.

• Anitua E. The use of plasma-rich growth factors (PRGF) in oral surgery. Pract Proced Aesthet Dent. 2001 Aug;13(6):487-93; quiz 487-93.

• Anitua E. Plasma rich in growth factors: preliminary results of use in the preparation of future sites for implants. Int J Oral Maxillofac Implants. 1999 Jul-Aug;14(4):529-35.

• Torrella F, Pitarch J, Cabanes G, Anitua E. Ultrasonic ostectomy for the surgical approach of the maxillary sinus: a technical note. Int J Oral Maxillofac Implants. 1998 Sep-Oct;13(5):697-700.

• Anitua E, Gascón F, Gil J. Sedation and analgesia with ni-trous oxide. Av Odontoestomatol. 1990 Nov;6(9):561-5.

• Anitua E, Zabalegui B, Gil J, Gascon F. Internal bleaching of severe tetracycline discolorations: four-year clinical evaluation. Quintessence Int. 1990 Oct;21(10):783-8.

• Anitua E, Orive G. Finite element analysis of the influen-ce of the offset placement of an implant-supported prosthesis on bone stress distribution. J Biomed Mater Res B Appl Biomater. 2009 May;89(2):275-81.

• Anitua E, Aguirre JJ, Gorosabel A, Barrio P, Errazquin JM, Román P, Pla R, Carrete J, de Petro J, Orive G. A mul-ticentre placebo-controlled randomised clinical trial of antibiotic prophylaxis for placement of single dental implants. Eur J Oral Implantol. 2009 Winter;2(4):283-92.

• Anitua E, Orive G, Pla R, Roman P, Serrano V, Andía I. The effects of PRGF on bone regeneration and on tita-nium implant osseointegration in goats: a histologic and histomorphometric study. J Biomed Mater Res A. 2009 Oct;91(1):158-65.

• Del Fabbro M, Boggian C, Taschieri S. Immediate im-plant placement into fresh extraction sites with chro-nic periapical pathologic features combined with plasma rich in growth factors: preliminary results of single-cohort study. J Oral Maxillofac Surg. 2009 Nov;67(11):2476-84.

• Anitua E, Prado R, Orive G. A lateral approach for sinus elevation using PRGF technology. Clin Implant Dent Relat Res. 2009 Oct;11 Suppl 1:e23-31.

• Anitua E, Orive G, Aguirre JJ, Ardanza B, Andía I. 5-year clinical experience with BTI dental implants: risk factors for implant failure. J Clin Periodontol. 2008 Aug;35(8):724-32.

• Anitua E, Orive G, Aguirre JJ, Andía I. Clinical outcome of immediately loaded dental implants bioactivated with plasma rich in growth factors: a 5-year retrospecti-ve study. J Periodontol. 2008 Jul;79(7):1168-76.

• Anitua E, Orive G, Aguirre JJ, Andía I. Five-year clinical evaluation of short dental implants placed in poste-rior areas: a retrospective study. J Periodontol. 2008 Jan;79(1):42-8.

• Anitua E. Novel protocols for predictable implantology. Pract Proced Aesthet Dent. 2008 Mar;20(2):123-8.

• Anitua E, Carda C, Andia I. A novel drilling procedure and subsequent bone autograft preparation: a tech-nical note. Int J Oral Maxillofac Implants. 2007 Jan-Feb;22(1):138-45. Erratum in: Int J Oral Maxillofac Im-plants. 2007 Mar-Apr;22(2):309.

• Lee EA, Anitua E. Atraumatic ridge expansion and im-


Revision articles

• Sánchez M, Anitua E, Orive G, Mujika I, Andia I. Platelet-rich therapies in the treatment of orthopaedic sport injuries. Sports Med. 2009;39:345-354.

• Engebretsen L, Steffen K, Alsousou J, Anitua E, Bachl N, Devilee R, Everts P, Hamilton B, Huard J, Jenoure P, Kelberine F, Kon E, Maffulli N, Matheson G, Mei-Dan O, Menetrey J, Philippon M, Randelli P, Schamasch P, Schwellnus M, Vernec A, Verrall G. IOC consensus paper on the use of platelet-rich plasma in sports medicine. Br J Sports Med. 2010;44:1072-1081.

• Sánchez M, Anitua E, Lopez-Vidriero E, Andía I. The fu-ture: optimizing the healing environment in anterior cruciate ligament reconstruction. Sports Med Arthrosc. 2010;18:48-53.

• Andia I, Sanchez M, Maffulli N. Tendon healing and platelet-rich plasma therapies. Expert Opin Biol Ther. 2010;10:1415-1426.

• Mei-Dan O, Lippi G, Sánchez M, Andia I, Maffulli N. Autologous platelet-rich plasma: a revolution in soft tissue sports injury management? Phys Sportsmed. 2010;38:127-135

• Andia I, Sánchez M, Maffulli N. Platelet rich plasma the-

rapies for sports muscle injuries: any evidence behind clinical practice? Expert Opin Biol Ther. 2011;11:509-518.

• Andia I, Sánchez M, Maffulli N. Joint pathology and platelet-rich plasma therapies. Expert Opin Biol Ther. 2012;12:7-22.

• E. Anitua, R. Prado, M. Sánchez, G. Orive. Platelet-Rich Plasma: Preparation and Formulation. Oper Tech Or-thop 22 (2012) 25-32.

• Anitua E, Sánchez M, Orive G, Padilla S. A biological therapy to osteoarthritis treatment using platelet-rich plasma. Expert Opin Biol Ther. 2013 Aug;13(8):1161-72.

• Padilla S, Orive G, Sanchez M, Anitua E, Hsu WK. Plate-let-rich plasma in orthopaedic applications: evidence-based recommendations for treatment. J Am Acad Or-thop Surg. 2014 Aug;22(8):469-70.

• Sánchez M, Anitua E, Delgado D, Sánchez P, Orive G, Pa-dilla S. Muscle repair: platelet-rich plasma derivates as a bridge from spontaneity to intervention. Injury. 2014 Oct;45 Suppl 4:S7-14.

• Sánchez M, Delgado D, Sánchez P, Fiz N, Azofra J, Orive G, Anitua E, Padilla S. Platelet rich plasma and knee sur-gery. Biomed Res Int. 2014;2014.

• Vaquerizo V, Sánchez M, Padilla S, Orive G, Anitua E.

Traumatology, orthopaedic surgery and sports medicine

Publications


Should your algorithm include plasma rich in growth factors in the light of its clinical efficacy and safety? Se-min Arthritis Rheum. 2015 Feb;44(4):e10-1.

• Padilla S, Sánchez M, Orive G, Anitua E. Towards a co-rrect timing and dosage in PRP applications. Injury. 2015 Aug;46(8):1697-8.

Preclinic Research

• Anitua E, Andía I, Sanchez M, Azofra J, del Mar Zalduen-do M, de la Fuente M, Nurden P, Nurden AT. Autologous preparations rich in growth factors promote prolifera-tion and induce VEGF and HGF production by human tendon cells in culture. J Orthop Res. 2005;23:281-286.

• Anitua E, Sanchez M, Nurden AT, Zalduendo M, de la Fuente M, Orive G, Azofra J, Andia I. Autologous fibrin matrices: a potential source of biological mediators that modulate tendon cell activities. J Biomed Mater Res A. 2006;77:285-293.

• Sánchez M, Anitua E, Azofra J, Andía I, Padilla S, Mujika I. Comparison of surgically repaired Achilles tendon tears using platelet-rich fibrin matrices. Am J Sports Med. 2007;35:245-251.

• Anitua E, Sanchez M, Nurden AT, Zalduendo M, de la Fuente M, Azofra J, Andia I. Reciprocal actions of pla-telet-secreted TGF-beta1 on the production of VEGF and HGF by human tendon cells. Plast Reconstr Surg. 2007;119:950-959.

• Anitua E, Sánchez M, Nurden AT, Zalduendo MM, de la Fuente M, Azofra J, Andía I. Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by syno-vial fibroblasts from arthritic patients. Rheumatology (Oxford). 2007;46:1769-1772.

• Anitua E, Sánchez M, Zalduendo MM, de la Fuente M, Prado R, Orive G, Andía I. Fibroblastic response to treatment with different preparations rich in growth factors. Cell Prolif. 2009;42:162-170.

• Gallo I, Sáenz A, Artiñano E, Esquide J. Autologous plate-let-rich plasma: effect on sternal healing in the sheep mo-del. Interact Cardiovasc Thorac Surg. 2010;11:223-225.

• Anitua E, Sanchez M, De la Fuente M, Zalduendo MM, Orive G. Plasma rich in growth factors (PRGF-Endoret)

stimulates tendon and synovial fibroblasts migra-tion and improves the biological properties of hya-luronic acid. Knee Surg Sports Traumatol Arthrosc. 2012;20:1657-1665.

• Rodríguez-Jiménez FJ, Valdes-Sánchez T, Carrillo JM, Rubio M, Monleon-Prades M, García-Cruz DM, García M, Cugat R, Moreno-Manzano V. Platelet-rich plasma favors proliferation of canine adipose-derived mes-enchymal stem cells in methacrylate-endcapped ca-prolactone porous scaffold niches. J Funct Biomater. 2012 Aug 9;3(3):556-68.

• Fernández-Sarmiento JA, Domínguez JM, Granados MM, Morgaz J, Navarrete R, Carrillo JM, Gómez-Villa-mandos RJ, Muñoz-Rascón P, Martín de Las Mulas J, Millán Y, García-Balletbó M, Cugat R. Histological study of the influence of plasma rich in growth factors (PRGF) on the healing of divided Achilles tendons in sheep. J Bone Joint Surg Am. 2013 Feb 6;95(3):246-55.

• Serra CI, Soler C, Carrillo JM, Sopena JJ, Redondo JI, Cu-gat R. Effect of autologous platelet-rich plasma on the repair of full-thickness articular defects in rabbits. Knee Surg Sports Traumatol Arthrosc. 2013 Aug;21(8):1730-6.

• Vilar JM, Morales M, Santana A, Spinella G, Rubio M, Cuervo B, Cugat R, Carrillo JM. Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC Vet Res. 2013 Jul 2;9:131.

• Yoshioka T, Kanamori A, Washio T, Aoto K, Uemura K, Sakane M, Ochiai N. The effects of plasma rich in growth factors (PRGF-Endoret) on healing of medial collateral ligament of the knee. Knee Surg Sports Trau-matol Arthrosc. 2013 Aug;21(8):1763-9.

• Vilar JM, Batista M, Morales M, Santana A, Cuervo B, Ru-bio M, Cugat R, Sopena J, Carrillo JM. Assessment of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells in osteoarthritic dogs using a double blinded force platform analysis. BMC Vet Res. 2014 Jul 1;10:143.

• Cuervo B, Rubio M, Sopena J, Dominguez JM, Vilar J, Morales M, Cugat R, Carrillo. Hip osteoarthritis in dogs: a randomized study using mesenchymal stem cells from adipose tissue and plasma rich in growth factors. JM.Int J Mol Sci. 2014 Jul 31;15(8):13437-60.


• M. Sánchez, E. Anitua, D. Delgado, R. Prado, P. Sánchez, N. Fiz, J. Guadilla, J. Azofra, O. Pompei, G. Orive, M. Or-tega, T. Yoshioka, S. Padilla. Ultrasound-guided plasma rich in growth factors injections and scaffolds hasten motor nerve functional recovery in an ovine model of nerve crush injury. J Tissue Eng Regen Med (2015) Article first published online: 7 SEP 2015 DOI: 10.1002/term.2079

• Anitua E, Pelacho B, Prado R, Aguirre JJ, Sánchez M, Padilla S, Aranguren XL, Abizanda G, Collantes M, Her-nandez M, Perez-Ruiz A, Peñuelas I, Orive G, Prosper F. Infiltration of plasma rich in growth factors enhances in vivo angiogenesis and improves reperfusion and tissue remodeling after severe hind limb ischemia. J Control Release. 2015 Mar 28;202:31-9.

• Anitua E, Prado R, Orive G. Platelet-rich plasma and myofibroblasts: is the composition the key to success? Adv Skin Wound Care. 2015 May;28(5):198-9.

• Assirelli E, Filardo G, Mariani E, Kon E, Roffi A, Vaccaro F, Marcacci M, Facchini A, Pulsatelli L. Effect of two di-fferent preparations of platelet-rich plasma on syno-viocytes. Knee Surg Sports Traumatol Arthrosc. 2015 Sep;23(9):2690-703.

• Emilov-Velev K, Clemente-de-Arriba C, Alobera-García MÁ, Moreno-Sansalvador EM, Campo-Loarte J. Bone regeneration in experimental animals using calcium

phosphate cement combined with platelet growth factors and human growth hormone. Rev Esp Cir Ortop Traumatol. 2015 May-Jun;59(3):200-10.

• López-Nájera D, Rubio-Zaragoza M, Sopena-Juncosa JJ, Alentorn-Geli E, Cugat-Bertomeu R, Fernández-Sar-miento JA, Domínguez-Pérez JM, García-Balletbó M, Primo-Capella VJ, Carrillo-Poveda JM. Effects of plasma rich in growth factors (PRGF) on biomechanical proper-ties of Achilles tendon repair. Knee Surg Sports Trau-matol Arthrosc. 2015 Aug 14.

Clinical Research

• Sánchez M, Azofra J, Aizpurúa B, Elorriaga R, Anitua E, Andía I. Aplicación de plasma autólogo rico en factores de crecimiento en cirugía artroscópica - Use of autolo-gous plasma rich in growth factors in Arthroscopic sur-gery. Cuadernos de Artroscopia 2003;10:12-19.

• Sánchez M, Azofra J, Anitua E, Andía I, Padilla S, Santis-teban J, Mujika I. Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc. 2003;35:1648-1652.

• Sanchez M, Anitua E, Andia I. Application of Autolo-gous Growth Factors on Skeletal Muscle Healing. 2nd World Congress on Regenerative Medicine, May 18-20, 2005, Leipzig, Germany

Publications



Endoret® (PRGF®) technology has been a pioneer proving its effectiveness in the treatment of os-teoarthritis and tendinopathies.

• Sánchez M, Anitua E, Azofra J, Aguirre JJ, Andia I. Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retros-pective cohort study. Clin Exp Rheumatol. 2008;26:910-913.

• Sánchez M, Anitua E, Cole A, Da Silva A, Azofra J, Andia I. Management of post-surgical Achilles tendon com-plications with a preparation rich in growth factors: A study of two-cases. Injury Extra. 2009;40:11-15.

• Jiménez-Martin A, Angulo-Gutiérrez J, González-Herranz J, Rodriguez-De La Cueva JM, Lara-Bullón J, Vázquez-Garcia R. Surgery of subacromial syndrome with application of plasma rich in growth factors. Int J Shoulder Surg. 2009;3:28-33.

• Anitua E, Sánchez M, de la Fuente M, Azofra J, Zal-duendo M, Aguirre JJ, Andía I. Relationship between Investigative Biomarkers and Radiographic Grading in Patients with Knee Osteoarthritis. Int J Rheumatol. 2009;2009:747432.

• Sanchez M, Anitua E, Cugat R, Azofra J, Guadilla J, Seijas R, Andia I. Nonunions treated with autologous preparation rich in growth factors. J Orthop Trauma. 2009;23:52-59.

• Seijas R, Santana-Suarez RY, Garcia-Balletbo M, Cuscó X, Ares O, Cugat R. Delayed union of the clavicle treated

with plasma rich in growth factors. Acta Orthop Belg. 2010;76:689-693.

• Sánchez M, Anitua E, Azofra J, Prado R, Muruzabal F, An-dia I. Ligamentization of tendon grafts treated with an endogenous preparation rich in growth factors: gross morphology and histology. Arthroscopy. 2010;26:470-480.

• Mei-Dan O, Carmont M, Kots E, Barchilon V, Nyska M, Mann G. Early return to play following complete rup-ture of the medial collateral ligament of the elbow using preparation rich in growth factors: a case report. J Shoulder Elbow Surg. 2010;19:e1-e5.

• Wang-Saegusa A, Cugat R, Ares O, Seijas R, Cuscó X, Garcia-Balletbó M. Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. Arch Orthop Trauma Surg. 2011;131:311-317.

• Sánchez M, Guadilla J, Fiz N, Andia I. Ultrasound-gui-ded platelet-rich plasma injections for the treatment of osteoarthritis of the hip. Rheumatology (Oxford). 2012;51:144-150.

• Guadilla J, Fiz N, Andia I, Sánchez M. Arthroscopic ma-nagement and platelet-rich plasma therapy for avas-cular necrosis of the hip. Knee Surg Sports Traumatol Arthrosc. 2012 ;20:393-398.


• Mei-Dan O, Carmont MR, Laver L, Mann G, Maffulli N, Nyska M. Platelet-Rich Plasma or Hyaluronate in the Management of Osteochondral Lesions of the Talus. Am J Sports Med. 2012 ;40:534-541.

• Filardo G, Kon E, Pereira Ruiz MT, Vaccaro F, Guitaldi R, Di Martino A, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich plasma intra-articular injections for car-tilage degeneration and osteoarthritis: single- versus double-spinning approach. Knee Surg Sports Trauma-tol Arthrosc. 2012;20:2082-2091.

• Sánchez M, Fiz N, Azofra J, Usabiaga J, Aduriz E, Gar-cia A, Albillos J, Garate R, Aguirre JJ, Padilla S, Orive G, Anitua E. A Randomized Clinical Trial evaluating Plasma Rich in Growth Factors (PRGF-Endoret) versus hyaluro-nic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28(8):1070-1078.

• Seijas R, Ares O, Alvarez P, Cusco X, Garcia-Balletbo M, Cugat R. Platelet-rich plasma for calcific tendinitis of the shoulder: a case report. J Orthop Surg (Hong Kong). 2012 Apr;20(1):126-30.

• Sánchez M, Anitua E, Orive G, Padilla S. A biological approach to orthopaedic surgery: are they lost in translation? Arthroscopy. 2013 Jun;29(6):969-70. doi: 10.1016/j.arthro.2013.02.017

• Say F, Gürler D, Yener K, Bülbül M, Malkoc M. Platelet-

rich plasma injection is more effective than hyaluronic acid in the treatment of knee osteoarthritis. Acta Chir Orthop Traumatol Cech. 2013;80(4):278-83

• Seijas R, Ares O, Catala J, Alvarez-Diaz P, Cusco X, Cugat R. Magnetic resonance imaging evaluation of patellar tendon graft remodelling after anterior cruciate liga-ment reconstruction with or without platelet-rich plas-ma. J Orthop Surg (Hong Kong). 2013 Apr;21(1):10-4.

• Ruiz-Moneo P, Molano-Muñoz J, Prieto E, Algorta J. Plasma rich in growth factors in arthroscopic rotator cuff repair: a randomized, double-blind, controlled cli-nical trial. Arthroscopy. 2013 Jan;29(1):2-9.

• Vaquerizo V, Plasencia MÁ, Arribas I, Seijas R, Padilla S, Orive G, Anitua E. Comparison of intra-articular injec-tions of plasma rich in growth factors (PRGF-Endoret) versus Durolane hyaluronic acid in the treatment of pa-tients with symptomatic osteoarthritis: a randomized controlled trial. Arthroscopy. 2013 Oct;29(10):1635-43.

• Anitua E, Sánchez M, Aguirre JJ, Prado R, Padilla S, Orive G. Efficacy and safety of plasma rich in growth factors intra-articular infiltrations in the treatment of knee os-teoarthritis. Arthroscopy. 2014 Aug;30(8):1006-17.

• Anitua E, Sánchez M, Padilla S. More on platelet-rich plasma injections in acute muscle injury. N Engl J Med. 2014 Sep 25;371(13):1264.

Publications



• Sánchez M, Fiz N, Guadilla J, Padilla S, Anitua E, Sánchez P, Delgado D. Intraosseous infiltration of platelet-rich plasma for severe knee osteoarthritis. Arthrosc Tech. 2014 Dec 15;3(6):e713-7.

• Valentí Azcárate A, Lamo-Espinosa J, Aquerreta Beola JD, Hernandez Gonzalez M, Mora Gasque G, Valentí Nin JR. Comparison between two different platelet-rich plasma preparations and control applied during ante-rior cruciate ligament reconstruction. Is there any evi-dence to support their use? Injury. 2014 Oct;45 Suppl 4:S36-41.

• Seijas R, Ares O, Cuscó X, Alvarez P, Steinbacher G, Cu-gat R. Partial anterior cruciate ligament tears treated with intraligamentary plasma rich in growth factors. World J Orthop. 2014 Jul 18;5(3):373-8.

• Galán M, Seijas R, Ares O, Cuscó X, Rius M, Cugat R. [Ad-juvant administration of plasma rich in growth factors for bilateral quadriceps tendon tear]. Acta Ortop Mex. 2014 Sep-Oct;28(5):310-4.

• Seijas R, Ares O, Álvarez-Díaz P, Sallent A, Cuscó X, Te-jedor R, Cugat R. Arthroscopic Treatment and Injection of Plasma Rich in Growth Factors in the Treatment Fe-moroacetabular Impingement of the Hip: Results with Two Years of Follow-up. Int J Orthopaedics 2 (2015) 182-187.

• Cugat R, Cuscó X, Seijas R, Álvarez P, Steinbacher G, Ares O, Wang-Saegusa A, García-Balletbó M. Biologic enhancement of cartilage repair: the role of platelet-rich plasma and other commercially available growth factors. Arthroscopy. 2015 Apr;31(4):777-83.

• Cuervo B, Rubio B, Cugat R, García-Balletbó M, Da-miá E, Sopena JJ, Carrillo JM. New Approaches in the Treatment of Osteoarthritis. Int J Orthopaedics 2 (2015) 210-218.

• Seijas R, Rius M, Ares O, García-Balletbó M, Serra I, Cu-gat R. Healing of donor site in bone-tendon-bone ACL reconstruction accelerated with plasma rich in growth factors: a randomized clinical trial. Knee Surg Sports Traumatol Arthrosc. 2015 Apr;23(4):991-7.

• Laver L, Carmont MR, McConkey MO, Palmanovich E, Yaacobi E, Mann G, Nyska M, Kots E, Mei-Dan O. Plas-ma rich in growth factors (PRGF) as a treatment for high ankle sprain in elite athletes: a randomized con-trol trial. Knee Surg Sports Traumatol Arthrosc. 2015 Nov;23(11):3383-92.

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• Anitua E, Sánchez M, Nurden AT, Nurden P, Orive G, Andía I. New insights into and novel applications for platelet-rich fibrin therapies. Trends Biotechnol 2006;24:227-34.

• Anitua E, Sánchez M, Orive G, Andía I. The potential impact of the preparation rich in growth factors (PRGF) in different medical fields. Biomaterials 2007;28:4551-4560.

• Anitua E, Sánchez M, Orive G, Andia I. Delivering growth factors for therapeutics. Trends Pharmacol Sci. 2008;29:37-41

• Anitua E, Sánchez M, Orive G. Potential of endogenous regenerative technology for in situ regenerative medi-cine. Adv Drug Deliv Rev 2010;62:741-752.


• Anitua E, Sanchez M, Zalduendo MM, de la Fuente M, Prado R, Orive G, Andía I. Fibroblastic response to treatment with different preparations rich in growth factors. Cell Prolif. 2009;42:162-170.

• Molina F, Lopez P, Camacho F, Vicente V. The use of plasma rich in growth factors on wound healing in the skin: experimental study in rabbits. Int Wound J. 2009;6:145-148.

• Anitua E, Alonso R, Girbau C, Aguirre JJ, Muruzabal F, Orive G. Antibacterial effect of plasma rich in growth factors (PRGF-Endoret) against Staphylococcus aureus and Staphylococcus epidermidis strains. Clin Exp Der-matol. 2012;37:652-657.

• Anitua E, Pino A, Orive G. Plasma rich in growth factors promotes (PRGF) promotes skin regeneration by sti-mulating dermal fibroblast proliferation, migration and biosynthetic activity regardless the age of the patient. JWC. 2016

Clinical Research

• Anitua E, Aguirre JJ, Algorta J, Ayerdi E, Cabezas A, Ori-ve G, Andia I. Effectiveness of autologous preparation rich in growth factors for the treatment of chronic cuta-neous ulcers. JBMR-B. 2008;84:415-421.

• Anitua E, Sanchez M, Sarabia R, Sanz J, Aguirre JJ, Orive G. Eficacia y seguridad del PRGF (plasma rico en facto-res de crecimiento) en la regeneración cutánea facial. Ensayo clínico, randomizado y controlado con ácido hialurónico. Revista de la AECEP. 2011;23-33.

• Orcajo B, Muruzabal F, Isasmendi MC, Gutierrez N, Sanchez M, Orive G, Anitua E. The use of plasma rich in growth factors (PRGF-Endoret) in the treatment of a severe mal perforant ulcer in the foot of a person with

Dermatology

Publications


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diabetes. Diabetes Res Clin Pract. 2011;93:65-67.

• Ramos J, de Luna E, García O, Diaz L, Ruiz C. Use of pla-telet rich plasma to treat pressure ulcers. J Wound Os-tomy Continence Nurs. 2013;40:198-202.

• Ramos J, García O, de Luna E, Ocaña FM, Ruiz C. Effec-tiveness of platelet rich plasma and hyaluronic acid for the treatment and care of pressure ulcers. Biol Res Nurs. 2014;17:152-158.

• Aguirre JJ, Anitua E, Francisco S, Cabezas AI, Orive G, Algorta J. Efficacy and safety of plasma rich in growth factors in the treatment of venous ulcers: a randomized clinical trial controlled with conventional treatment. Clin Dermatol. 2015;3:13-20.

• Díaz B, Cuevas J, Alonso L, Calvo MI, Ríos L, Orive G, Ani-tua E, Jaén P. Benefits of plasma rich in growth factors (PRGF) in skin photodamage: clinical response and his-tological assessment. Dermatol Ther. 2015;28:258-263.

• Navarro MR, Asín M, Martinez AM, Molina C, Navarro V, Pino A, Orive G, Anitua E. Plasma rich in growth factors (PRGF) for the treatment of androgenetic alopecia. Eur J Plast Surg. 2015;38:437-442.

• Navarro MR, Asín M, Martinez MA, Martinez AM, Molina C, Moscoso L, Pino A, Orive G, Anitua E. Management of androgenetic alopecia: a comparative clinical study

between plasma rich in growth factors and topical mi-noxidil. Eur J Plast Surg. 2015.

• Navarro MR, Asin M, Martinez MA, Martinez AM, Rami-rez A, Pino A, Orive G, Anitua E. Plasma rich in growth factors promotes hair growth on female androgenetic alopecia. J Dermatolog Clin Res. 2015.

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• Anitua E, Muruzabal F, Tayebba A, Riestra A, Perez VL, Merayo-Lloves J, Orive G. Autologous serum and plasma rich in growth factors in ophthalmology: pre-clinical and clinical studies. Acta Ophthalmol. 2015 Dec;93(8):e605-14.


• Anitua E, Sanchez M, Merayo-Lloves J, De la Fuente M, Muruzabal F, Orive G. Plasma rich in growth factors (PRGF-Endoret) stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodi-fferentiation. Invest Ophthalmol Vis Sci. 2011 Aug 1;52(9):6066-73.

• Freire V, Andollo N, Etxebarria J, Durán JA, Morales MC. In vitro effects of three blood derivatives on human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2012 Aug 15;53(9):5571-8.

• Anitua E, Muruzabal F, Pino A, Merayo-Lloves J, Orive G. Biological Stability of Plasma Rich in Growth Factors Eye Drops After Storage of 3 Months. Cornea. 2013 Oct;32(10):1380-6.

• Anitua E, Muruzabal F, Alcalde I, Merayo-Lloves J, Orive G. Plasma rich in growth factors (PRGF-Endoret) stimula-tes corneal wound healing and reduces haze formation

after PRK surgery. Exp Eye Res. 2013 Oct;115:153-61.

• Anitua E, Muruzabal F, De la Fuente M, Merayo-Lloves J, Orive G. Effects of heat-treatment on plasma rich in growth factors-derived autologous eye drop. Exp Eye Res. 2014 Feb;119:27-34.

• Freire V, Andollo N, Etxebarria J, Hernáez-Moya R, Du-rán JA, Morales MC. Corneal wound healing promoted by 3 blood derivatives: an in vitro and in vivo compara-tive study. Cornea. 2014 Jun;33(6):614-20.

• Anitua E, de la Fuente M, Muruzabal F, Riestra A, Me-rayo-Lloves J, Orive G. Plasma rich in growth factors (PRGF) eye drops stimulates scarless regeneration compared to autologous serum in the ocular surface stromal fibroblasts. Exp Eye Res. 2015 Jun;135:118-26.

• Anitua E, de la Fuente M, Riestra A, Merayo-Lloves J, Muruzábal F, Orive G. Preservation of Biological Activi-ty of Plasma and Platelet-Derived Eye Drops After Their Different Time and Temperature Conditions of Storage. Cornea. 2015 Sep;34(9):1144-8.

Clinical Research

• López-Plandolit S, Morales MC, Freire V, Grau AE, Du-rán JA. Efficacy of plasma rich in growth factors for the treatment of dry eye. Cornea. 2011 Dec;30(12):1312-7.

Ophthalmology

Publications


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• Merayo-Lloves J, Sanchez RM, Riestra AC, Anitua E, Be-goña L, Orive G, Fernandez-Vega L. Autologous Plasma Rich in Growth Factors Eyedrops in Refractory Cases of Ocular Surface Disorders. Ophthalmic Res. 2015 Dec;55(2):53-61.

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