Gorka Orive

Platelet-rich therapies in the treatment of orthopaedic sport injuries.

Biomedical sciences have made major advances in understanding how tissues repair, and the signalling mechanisms required to achieve this goal are progressively being dissected. Advances in the understanding of tissue repair mechanisms and the pivotal role of growth factors have stimulated the use of platelet-rich therapies by orthopaedic surgeons and sports physicians, mainly with the aim of stimulating and enhancing tissue healing. Autologous activated platelets retained in fibrin matrices are used as a source of molecular signals that control cell fate, including cell growth, cell differentiation and the synthesis of diverse functional proteins. Thus far, platelet-rich technologies have spawned additional ambitious endeavours, including surgical and nonsurgical treatments in sports orthopaedics. Reconstruction of anterior cruciate ligament and tendon surgery and treatment of joint injuries, tendinopathy or muscle tears are but a few examples of the potential applications of this technology in the field of orthopaedic sports medicine. In the present article, some of the most important therapeutic applications using these approaches–especially preparation rich in growth factor (PRGF) technology–are presented, as are some of the limitations, anti-doping concerns and future challenges in the field. In view of a general state of confusion, the concept of platelet-rich plasma needs rigorous definition associated with well characterized products and re-administration procedures. There is evidence that reconstruction of anterior cruciate ligament and tendon surgery combined with PRGF enhances healing and functional recovery; clinical evidence is also appearing in the literature regarding treatment of tendinopathies and osteoarthritis. Currently, the challenge lies in conducting randomized, controlled clinical trials to determine the essential qualities of these technologies. If anti-doping agencies clarify their regulatory guidelines, robust studies in athletes are expected to emerge. Although much research work lies ahead, the current knowledge points to a future in which platelet-rich therapies will continue improving existing conventional approaches to treatment of sports injuries.

A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis.

PURPOSE This multicenter, double-blind clinical trial evaluated and compared the efficacy and safety of PRGF-Endoret (BTI Biotechnology Institute, Vitoria-Gasteiz, Spain), an autologous biological therapy for regenerative purposes, versus hyaluronic acid (HA) as a short-term treatment for knee pain from osteoarthritis. METHODS We randomly assigned 176 patients with symptomatic knee osteoarthritis to receive infiltrations with PRGF-Endoret or with HA (3 injections on a weekly basis). The primary outcome measure was a 50% decrease in knee pain from baseline to week 24. As secondary outcomes, we also assessed pain, stiffness, and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index; the rate of response using the criteria of the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI); and safety. RESULTS The mean age of the patients was 59.8 years, and 52% were women. Compared with the rate of response to HA, the rate of response to PRGF-Endoret was 14.1 percentage points higher (95% confidence interval, 0.5 to 27.6; P = .044). Regarding the secondary outcome measures, the rate of response to PRGF-Endoret was higher in all cases, although no significant differences were reached. Adverse events were mild and evenly distributed between the groups. CONCLUSIONS Plasma rich in growth factors showed superior short-term results when compared with HA in a randomized controlled trial, with a comparable safety profile, in alleviating symptoms of mild to moderate osteoarthritis of the knee. LEVEL OF EVIDENCE Level I, randomized controlled multicenter trial.

Fibroblastic response to treatment with different preparations rich in growth factors

Objectives:  Preparations rich in growth factors (PRGF) release them plus bioactive proteins at localized sites, with the aim of triggering healing and regenerative processes. The prevailing paradigm suggests that their influence on proliferation, angiogenesis and the extracellular matrix synthesis is minimal. However, variations in their composition and impact on different cell phenotypes have not been examined.

Potential of endogenous regenerative technology for in situ regenerative medicine

Endogenous regenerative technology (Endoret) involves the use of patients own biologically active proteins, growth factors and biomaterial scaffolds for therapeutic purposes. This technology provides a new approach for the stimulation and acceleration of tissue healing and bone regeneration. The versatility and biocompatibility of using patient-derived fibrin scaffold as an autologous, biocompatible and biodegradable drug delivery system open the door to a personalized medicine that is currently being used in numerous medical and scientific fields including dentistry, oral implantology, orthopaedics, ulcer treatment, sports medicine and tissue engineering among others. This review discusses the state of the art and new directions in the use of endogenous technology in the repair and regeneration of injured tissues by means of a controlled and local protein and growth factor delivery. The next generations of engineering strategies together with some of the most interesting therapeutic applications are discussed together with the future challenges in the field.

Perspectives and challenges in regenerative medicine using plasma rich in growth factors.

Plasma rich in growth factors (PRGF-Endoret) is an endogenous therapeutic technology that is gaining interest in regenerative medicine due to its potential to stimulate and accelerate tissue healing and bone regeneration. This autologous biotechnology is designed for the in situ delivery of multiple cellular modulators and the formation of a fibrin scaffold, thereby providing different formulations that can be widely used in numerous medical and scientific fields including dentistry, oral implantology, orthopedics, ulcer treatment and tissue engineering among others. Here we discuss the important progress that has been accomplished in this field. Furthermore, a comprehensive outlook of the intriguing therapeutic applications of this technology is presented.

Antibacterial effect of plasma rich in growth factors (PRGF®-Endoret®) against Staphylococcus aureus and Staphylococcus epidermidis strains.

Background.  Formulations containing plasma rich in growth factors (PRGF) are opening new avenues in the field of regenerative medicine.

The effects of PRGF on bone regeneration and on titanium implant osseointegration in goats: A histologic and histomorphometric study

The effect of local application of scaffold-like preparation rich in growth factors (PRGF) on bone regeneration in artificial defects and the potential effect of humidifying titanium dental implants with liquid PRGF on their osseointegration were investigated. The PRGF formulations were obtained from venous blood of three goats and applied either as a 3D fibrin scaffold (scaffold-like PRGF) in the regeneration of artificial defects or as liquid PRGF via humidifying the implants before their insertion. Initially, 12 defects were filled with scaffold-like PRGF and another 12 were used as controls. The histological analysis at 8 weeks revealed mature bone trabeculae when PRGF was used, whereas the control samples showed mainly connective tissue with incipient signs of bone formation. For the second set of experiments, 26 implants (13 humidified with liquid PRGF) were placed in the tibiae of goats. Histological and histomorphometric results demonstrated that application of liquid PRGF increased the percentage of bone-implant contact in 84.7%. The whole surface of the PRGF-treated implants was covered by newly formed bone, whereas only the upper half was surrounded in control implants. In summary, PRGF can accelerate bone regeneration in artificial defects and improve the osseointegration of titanium dental implants.

5-year clinical experience with BTI® dental implants: risk factors for implant failure

OBJECTIVES The aims of this study were to identify with appropriate statistical tests the risk factors associated with implant failure and to evaluate the long-term survival of dental implants using implant loss as an outcome variable and performing an implant-, surgery- and patient-based analysis of failures. MATERIAL AND METHODS A retrospective cohort study design was used. One thousand sixty patients received 5787 BTI implants during the years of 2001-2005 in Vitoria, Spain. The potential influence of demographic items, clinical items, surgery-dependent items and prosthetic variables on implant survival was studied. Implant survival was analysed using a life-table analysis. Cox proportional hazards regression was used to identify risk factors related to implant failure. RESULTS Smoking habits, implant position, implant staging (two-stage implants) and the implementation of special techniques were statistically correlated with lower implant survival rates. Two risk factors associated with implant failure were detected in this study: implant staging (two-stage implants) and the use of special techniques. Additionally, the overall survival rates of BTI implants were 99.2%, 96.4% and 96% for the implant-, surgery- and patient-based analysis, respectively. Totally, 28 out from 5787 implants (0.48%) were lost during the observation period. Most of the patients with implant failure (69.6%) presented chronic or aggressive periodontitis. CONCLUSIONS Implant staging and the use of special techniques are risk factors for implant failure.

Morphogen and proinflammatory cytokine release kinetics from PRGF-Endoret fibrin scaffolds: Evaluation of the effect of leukocyte inclusion

The potential influence of leukocyte incorporation in the kinetic release of growth factors from platelet-rich plasma (PRP) may explain the conflicting efficiency of leukocyte platelet-rich plasma (L-PRP) scaffolds in tissue regeneration. To assess this hypothesis, leukocyte-free (PRGF-Endoret) and L-PRP fibrin scaffolds were prepared, and both morphogen and proinflammatory cytokine release kinetics were analyzed. Clots were incubated with culture medium to monitor protein release over 8 days. Furthermore, the different fibrin scaffolds were morphologically characterized. Results show that leukocyte-free fibrin matrices were homogenous while leukocyte-containing ones were heterogeneous, loose and cellular. Leukocyte incorporation produced a significant increase in the contents of proinflammatory cytokines interleukin (IL)-1β and IL-16 but not in the platelet-derived growth factors release (<1.5-fold). Surprisingly, the availability of vascular endothelial growth factor suffered an important decrease after 3 days of incubation in the case of L-PRP matrices. While the release of proinflammatory cytokines was almost absent or very low from PRGF-Endoret, the inclusion of leukocytes induced a major increase in these cytokines, which was characterized by the presence of a latent period. The PRGF-Endoret matrices were stable during the 8 days of incubation. The inclusion of leukocytes alters the growth factors release profile and also increased the dose of proinflammatory cytokines.

Bilateral sinus elevation evaluating plasma rich in growth factors technology: a report of five cases.

PURPOSE The purpose of this study was to evaluate the potential effects of plasma rich in growth factors (PRGF) technology and its autologous formulations in five consecutive patients in which bilateral sinus lift augmentation was carried out. MATERIAL AND METHODS Five consecutive patients received bilateral sinus floor augmentation. All patients presented a residual bone height of class D (1-3 mm). The effects of PRGF combined with bovine anorganic bone (one side) were compared with the biomaterial alone (contralateral side). The effects of using liquid PRGF to maintain the bone window and autologous fibrin membrane to seal the defect were evaluated. A complete histological and histomorphometrical analysis was performed 5 months after surgery. RESULTS One patient was excluded from the study as the Schneiderian membrane of the control side was perforated during the surgery. In two patients, the biopsies obtained from the control sides 5 months postsurgery were not acceptable for processing. PRGF technology facilitated the surgical approach of sinus floor elevation. The control area was more inflamed than the area treated with PRGF technology. Patients referred also to an increased sensation of pain in the control area. PRGF-treated samples had more new vital bone than controls. In patient number 1, image processing revealed 21.4% new vital bone in the PRGF area versus 8.4% in the control area, whereas in patient number 2, 28.4% new vital bone was quantified in the PRGF area compared with the 8.2% of the control side. The immunohistochemical processing of the biopsies revealed that the number of blood vessels per square millimeter of connective tissue was 116 vessels in the PRGF sample versus 7 in the control biopsy. CONCLUSIONS These preliminary results suggest that from a practical point of view, PRGF may present a role in reducing tissue inflammation after surgery, increasing new bone formation and promoting the vascularization of bone tissue.