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Improvising PRP for use in osteoarthritis knee- upcoming trends and futuristic view

Published:October 20, 2018DOI:https://doi.org/10.1016/j.jcot.2018.10.005

      Abstrac

      Platelet rich plasma (PRP) has clearly emerged offering a possible solution that could modify the disease process and offer symptomatic relief in early osteoarthritis of knee. Great efforts are underway to improve PRP products for use in knee osteoarthritis (OA). Upcoming research is focused on the ideal PRP type, dose, frequency of injection and mode of injection. The combination of PRP with biocompatible carriers/scaffolds like gelatin hydrogel and chitosan appear to be promising based on early in vitro and animal studies. PRP in combination with hyaluronate has also emerged to have synergistic and additive effects. This article intends to review the recent trends and advancing ideas for improvising PRP for use in early knee OA treatment.

      Keywords

      1. Introduction

      Platelet Rich plasma is being widely used by orthopaedic surgeons for varying conditions throughout the world owing to its healing potential contained within the platelets. Positive results have been uniformly observed by various researchers for Early Knee OA in the past few years.
      • Filardo G.
      • Kon E.
      • Buda R.
      • et al.
      Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis.
      ,
      • Patel S.
      • Dhillon M.S.
      • Aggarwal S.
      • Marwaha N.
      • Jain A.
      Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial.
      OA knee is a heterogenous disease wherein the dynamic equilibrium between the breakdown and repair of joint tissues becomes unbalanced. There is marked interactions between synoviocytes, cartilage matrix, Hyaluronate with changes in chemical and biological properties. PRP has clearly demonstrated its supremacy in comparison to Hyaluronic acid and placebo in various clinical trials and is undoubtedly the best option available that could modify the disease process in early Osteoarthritis of knee.
      • Filardo G.
      • Kon E.
      • Buda R.
      • et al.
      Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis.
      • Patel S.
      • Dhillon M.S.
      • Aggarwal S.
      • Marwaha N.
      • Jain A.
      Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial.
      • Spaková T.
      • Rosocha J.
      • Lacko M.
      • Harvanová D.
      • Gharaibeh A.
      Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid.
      • Cerza F.
      • Carnì S.
      • Carcangiu A.
      • et al.
      Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis.
      The release of growth factors from PRP occurs immediately upon injection into an arthritic joint, and the effects can last upwards of a year.
      • Filardo G.
      • Kon E.
      • Buda R.
      • et al.
      Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis.
      ,
      • Patel S.
      • Dhillon M.S.
      • Aggarwal S.
      • Marwaha N.
      • Jain A.
      Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial.
      PRP in combination with biocompatible carriers/scaffolds or with hyaluronate appear to be a way of prolonging the effects of PRP in the arthritic joint. With its safety and efficacy clearly being established, we review advances in PRP use, and new methods of harnessing the power of regenerative medicine in research, and clinical translation in the future.

      1.1 Ideal PRP composition and volume

      Parameters which define PRP type are the presence of leukocytes, volume, concentration, and activation. . There are various classifications
      • Mishra A.
      • Harmon K.
      • Woodall J.
      • et al.
      Sports medicine applications of platelet rich plasma.
      ,
      • DeLong J.M.
      • Russell R.P.
      • Mazzocca A.D.
      Platelet-rich plasma: the PAW classification system.
      which classify PRP type based on the above factors. Different preparation methods are known to yield different PRP product in the same donor.
      • Magalon J.
      • Bausset O.
      • Serratrice N.
      • et al.
      Characterization and comparison of 5 platelet-rich plasma preparations in a single-donor model.
      Intra-individual variation in the PRP product with the same technique at different time frames is also noted.
      • Mazzocca A.D.
      • McCarthy M.B.R.
      • Chowaniec D.M.
      • et al.
      Platelet-rich plasma differs according to preparation method and human variability.
      The ideal PRP needed for treatment of knee osteoarthritis is not clearly defined and requires further standardization. Additionally, all PRP preparations are not the same and the following are some of the parameters which define clinical use and our understanding.

      1.1.1 Leucocyte rich versus leucocyte poor PRP

      This was a hot topic of research 7–8 years back and the studies so far suggest that both are clinically effective and safe, however the minor adverse reactions like pain and effusion were less with leucocyte poor PRP and it appears to be slightly better. Recent clinical studies by Riboh et al.
      • Riboh J.C.
      • Saltzman B.M.
      • Yanke A.B.
      • et al.
      Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis.
      and Filardo et al.
      • Filardo G.
      • Kon E.
      • Pereira Ruiz M.T.
      • et al.
      Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double- spinning approach.
      support the use of Leucocyte free PRP for knee OA.

      1.1.2 Volume of PRP required for knee OA

      It is suggested by some, that PRP refers to a product of at least 4 x baseline concentration of platelets (1.5–4.5 × 10⁵/lL) in order to label the product as PRP. What has not been studied is the ideal volume to be injected. Most of the clinical studies have used 4–5 ml PRP.
      • Filardo G.
      • Kon E.
      • Buda R.
      • et al.
      Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis.
      ,
      • Spaková T.
      • Rosocha J.
      • Lacko M.
      • Harvanová D.
      • Gharaibeh A.
      Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid.
      ,
      • Cerza F.
      • Carnì S.
      • Carcangiu A.
      • et al.
      Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis.
      Spakova et al.,
      • Spaková T.
      • Rosocha J.
      • Lacko M.
      • Harvanová D.
      • Gharaibeh A.
      Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid.
      and Paterson et al.,
      • Paterson K.L.
      • Nicholls M.
      • Bennell K.L.
      • Bates D.
      Intra-articular injection of photo-activated platelet-rich plasma in patients with knee osteoarthritis: a double-blind, randomized controlled pilot study.
      have used 3 ml PRP; Li et al.,
      • Li M.
      • Zhang C.
      • Ai Z.
      • Yuan T.
      • Feng Y.
      • Jia W.
      [Therapeutic effectiveness of intra-knee-articular injection of platelet-rich plasma on knee articular cartilage degeneration].
      has used 3.5 ml. In contrast, Patel et al.,
      • Patel S.
      • Dhillon M.S.
      • Aggarwal S.
      • Marwaha N.
      • Jain A.
      Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial.
      and Sanchez et al.,
      • Sanchez M.
      • Anitua E.
      • Azofra J.
      • et al.
      Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retrospective cohort study.
      have used 8 ml PRP. Various commercial PRP kits usually focus on taking minimal patient blood ranging from 20 ml to 30 ml and the final product is usually 3–4 ml. Our experience is that for adequate treatment of osteoarthritic knees, volumes of at least 8 ml of PRP should be injected and this has been confirmed by randomized controlled studies.
      • Patel S.
      • Dhillon M.S.
      • Aggarwal S.
      • Marwaha N.
      • Jain A.
      Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial.
      ,
      • Sanchez M.
      • Anitua E.
      • Azofra J.
      • et al.
      Intra-articular injection of an autologous preparation rich in growth factors for the treatment of knee OA: a retrospective cohort study.
      The rationale is to ensure that platelets as well as plasma in the final PRP product can diffuse throughout the joint reaching all areas of the synovium. When PRP is activated, the plasma in the product forms a clot which traps the platelets thereby creating a biologic scaffold. We routinely use 8 ml PRP for knee joints and we refer to this as SuperdosePRP”. Additionally the absolute number of platelets is also more and hence more growth factors. Producing 8 ml PRP would mean drawing more blood and hence a burden for the current commercial kits available as they have to recalibrate and update the kits. This is a major clinical implication as most of the clinicians have been using less volume PRP into Knee joints. We feel the present kits which yield 3–4 ml PRP is ideal for tendinopathies where we usually need less volume.

      1.1.3 Activated versus non activated PRP

      The term “activation of PRP” refers to 2 key processes that are initiated during PRP preparation: Firstly, degranulation of platelets to release growth factors (GFs) from α-granules followed by fibrinogen cleavage to initiate matrix formation, a clotting process which allows the formation of a platelet gel, and therefore to confine the secretion of molecules to the chosen site. It can be done by using 10% CaCl2, 10% autologous thrombin or mixture of 10% CaCl2 +10% autologous thrombin or 10% calcium gluconate. Cavallo et al.,
      • Cavallo C.
      • Roffi A.
      • Grigolo B.
      • et al.
      Platelet-rich plasma: the choice of activation method affects the release of bioactive molecules.
      has compared the amount of growth factor released from PRP with and without activator, and concluded that there was an increased concentration of growth factor release when PRP was used with activator, and the effects were immediate and sustained for up to 24 h. Proponents of activator believe that the main role of activator is to increase growth factor release and further augment PRP. Those who don't use activator argue that PRP once given gets activated endogenously as it comes in contact with the tissue.
      • Spaková T.
      • Rosocha J.
      • Lacko M.
      • Harvanová D.
      • Gharaibeh A.
      Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid.
      ,
      • Duymus T.M.
      • Mutlu S.
      • Dernek B.
      • Komur B.
      • Aydogmus S.
      • Kesiktas F.N.
      Choice of intra-articular injection in treatment of knee osteoarthritis: platelet-rich plasma, hyaluronic acid or ozone options.
      Multiple studies have been conducted investigating the clinical outcomes of use of PRP in knee OA with activation
      • Filardo G.
      • Kon E.
      • Buda R.
      • et al.
      Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis.
      ,
      • Patel S.
      • Dhillon M.S.
      • Aggarwal S.
      • Marwaha N.
      • Jain A.
      Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial.
      ,
      • Filardo G.
      • Kon E.
      • Pereira Ruiz M.T.
      • et al.
      Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double- spinning approach.
      ,
      • Li M.
      • Zhang C.
      • Ai Z.
      • Yuan T.
      • Feng Y.
      • Jia W.
      [Therapeutic effectiveness of intra-knee-articular injection of platelet-rich plasma on knee articular cartilage degeneration].
      and without activation
      • Spaková T.
      • Rosocha J.
      • Lacko M.
      • Harvanová D.
      • Gharaibeh A.
      Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid.
      ,
      • Duymus T.M.
      • Mutlu S.
      • Dernek B.
      • Komur B.
      • Aydogmus S.
      • Kesiktas F.N.
      Choice of intra-articular injection in treatment of knee osteoarthritis: platelet-rich plasma, hyaluronic acid or ozone options.
      however, no head-to-head comparison has been published. This is a likely area for future investigation.

      1.2 Platelet rich plasma and hyaluronic acid

      Platelet rich plasma and hyaluronic acid are two current options that have been shown to have a disease modifying effect in early osteoarthritis of knee.
      • Di Y.
      • Han C.
      • Zhao L.
      • Ren Y.
      Is local platelet-rich plasma injection clinically superior to hyaluronic acid for treatment of knee osteoarthritis? A systematic review of randomized controlled trials.
      ,
      • Zhang H.F.
      • Wang C.G.
      • Li H.
      • Huang Y.T.
      • Li Z.J.
      Intra-articular platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: a meta-analysis.
      PRP and hyaluronic acid (HA) have been shown to act on the disease milieu by different mechanisms with some overlap and may have an anabolic and synergistic effect. HA acts through not only its viscoelastic and lubrication properties but also by anti-inflammatory, anti-fibrotic and chondro-protective effects.
      • Musumeci G.
      • Loreto C.
      • Carnazza M.L.
      • et al.
      Acute injury affects lubricin expression in knee menisci: an immunohistochemical study.
      ,
      • Abate M.
      • Pulcini D.
      • Di Iorio A.
      • Schiavone C.
      Viscosupplementation with intra-articular hyaluronic acid for treatment of osteoarthritis in the elderly.
      PRP also exerts a chondro-protective effects on cartilage,
      • Sundman E.A.
      • Cole B.J.
      • Karas V.
      • et al.
      The anti-inflammatory and matrix restorative mechanisms of platelet-rich plasma in osteoarthritis.
      anti-inflammatory effect on synovium
      • Anitua E.
      • Sánchez M.
      • Nurden A.T.
      • et al.
      Platelet-released growth factors enhance the secretion of hyaluronic acid and induce hepatocyte growth factor production by synovial fibroblasts from arthritic patients.
      and regulates the apoptotic pathway.
      • Bendinelli P.
      • Matteucci E.
      • Dogliotti G.
      • et al.
      Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-κB inhibition via HGF.
      It has been shown in a few in vitro as well as clinical studies that combination of PRP with HA may exert a synergistic effect. Torrecillas et al.,
      • Ramos-Torrecillas J.
      • García-Martínez O.
      • De Luna-Bertos E.
      • Ocaña-Peinado F.M.
      • Ruiz C.
      Effectiveness of platelet-rich plasma and hyaluronic acid for the treatment and care of pressure ulcers.
      in their study to the effects on wound healing showed that platelet rich in growth factors PRGF with HA was better than PRGF alone in reducing ulcerated wounds in 36 days. Anitua et al., and Marmotti et al.,
      • Anitua E.
      • Sanchez M.
      • De la Fuente M.
      • et al.
      Plasma rich in growth factors (PRGF-Endoret) stimulates tendon and synovial fibroblasts migration and improves the biological properties of hyaluronic acid.
      ,
      • Marmotti A.
      • Bruzzone M.
      • Bonasia D.E.
      • et al.
      One-step osteochondral repair with cartilage fragments in a composite scaffold.
      have recently postulated that PRP in combination with HA may be synergistic, by enhancing the migratory potential of fibroblasts in in vitro studies. Both HA and PRP are biological approaches and their use together may be critical in the initial phases of the OA, modifying the environment through immunomodulation and improved joint hemostasis, Andia et al.,
      • Andia I.
      • Abate M.
      Knee osteoarthritis: hyaluronic acid, platelet-rich plasma or both in association?.
      confirm these findings. Chen et al.
      • Chen W.H.
      • Lo W.C.
      • Hsu W.C.
      • et al.
      Synergistic anabolic actions of hyaluronic acid and platelet-rich plasma on cartilage regeneration in osteoarthritis therapy.
      have demonstrated that combination may increase cartilage growth apart from the anti inflamatory effect in their in vitro study. Inhibition of cytokines and adipokines was the postulated mechanism for their antiinflamatory effect as per another study by the same authors.
      • Chen W.H.
      • Lin C.M.
      • Huang C.F.
      • et al.
      Functional recovery in osteoarthritic chondrocytes through hyaluronic acid and platelet-rich plasma–inhibited infrapatellar fat pad adipocytes.
      Better chondrocyte survival, cell count and cell proliferation were also noted in PRP encapsulated in Gelatin-HA polymer loaded in biphasic calcium phosphate scaffold by Son et al.
      • Son S.R.
      • Sarkar S.K.
      • Linh N.T.
      • et al.
      Platelet-rich plasma encapsulation in hyaluronic acid/gelatin-BCP hydrogel for growth factor delivery in BCP sponge scaffold for bone regeneration.
      In contrast, Russo et al.
      • Russo F.
      • D'Este M.
      • Vadalà G.
      • et al.
      Platelet rich plasma and hyaluronic acid blend for the treatment of osteoarthritis: rheological and biological evaluation.
      in their in vitro study wherein they assessed the viscoelastic and biological properties of different combinations of PRP and HA found that addition of PRP to HA exerts a dilutional effect on HA leading to poor viscoelastic and lubrication properties. They also noted higher proliferation rates of chondrocytes in cultures with PRP alone as compared to PRP + HA blend.
      Dalllari et al.
      • Dallari D.
      • Stagni C.
      • Rani N.
      • et al.
      Ultrasound-guided injection of platelet-rich plasma and hyaluronic acid, separately and in combination, for hip osteoarthritis a randomized controlled study.
      in their hip OA RCT compared PRP, HA and PRP + HA and concluded that PRP + HA did not offer any additional benefit over PRP alone at 2, 6 and 12 months. However, Lana et al.
      • Lana J.F.
      • Weglein A.
      • Sampson S.E.
      • et al.
      Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee.
      in their RCT on early OA of knee compared PRP, HA and HA + PRP. They observed better results in combination group. So the above two clinical studies suggest conflicting evidence of efficacy of PRP and HA combination. However, it should be kept in mind that these studies may not have used the ideal combination of PRP and HA as suggested by Russo et al.
      • Russo F.
      • D'Este M.
      • Vadalà G.
      • et al.
      Platelet rich plasma and hyaluronic acid blend for the treatment of osteoarthritis: rheological and biological evaluation.
      Loss of viscoelastic properties due to dilution or lower concentration of HA may be some contributing factors which may have given suboptimal results in the above studies. To counter this problem it has been suggested by some authors to use PRP and HA one after the other at a gap of few weeks and not simultaneously.
      • Patel S.
      • Dhillon M.S.
      • Bansal T.
      Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee-Letter to the Editor & Author Response.
      Combination of PRP and HA appear promising due to different mechanism of actions which appear to be synergistic, but further studies are needed to define the schedule, dosage and ideal concentration of PRP and HA.

      1.3 Biomaterial, scaffolds and PRP

      The primary effects of platelet growth factors occur during approximately 8 days (the half-life of platelets). It has led many authors to use multiple PRP injections at varying frequencies like weekly, biweekly, every-3-week, or monthly intervals to maximize effects. Due to the short term efficacy and non-sustained release of growth factors from PRP used alone, there has been increasing interest in using bio degradable materials as a carrier vehicle for PRP.
      PRP has been used with many different biomaterials like gelatin hydrogels, chitosan, polylactic-co-glycolic acid (PLGA) mesh and β-tricalcium phosphate scaffolds for a prolonged and sustained release of growth factors with success. The combination of PRP with these different biomaterials, have been shown in various in vitro and in vivo studies to be significantly better than PRP alone for osteoarthritis knee.
      • Saito M.
      • Takahashi K.A.
      • Arai Y.
      • et al.
      Intra-articular administration of plateletrich plasma with biodegradable gelatin hydrogel microspheres prevents osteoarthritis progression in the rabbit knee.
      • Busilacchi A.
      • Gigante A.
      • Mattioli-Belmonte M.
      • Manzotti S.
      • Muzzarelli R.A.
      Chitosan stabilizes platelet growth factors and modulates stem cell differentiation toward tissue regeneration.
      • Kurita J.
      • Miyamoto M.
      • Ishii Y.
      • et al.
      Enhanced vascularization by controlled release of platelet-rich plasma impregnated in biodegradable gelatin hydrogel.
      Saito et al.,
      • Saito M.
      • Takahashi K.A.
      • Arai Y.
      • et al.
      Intra-articular administration of plateletrich plasma with biodegradable gelatin hydrogel microspheres prevents osteoarthritis progression in the rabbit knee.
      in a rabbit model of knee osteoarthritis noted that PRP impregnated gelatin hydrogel resulted in sustained release of growth factors contained in PRP and had preventive effects against OA when compared to PRP alone both morphologically and histologically. It also resulted in increase in chondrocyte GAG synthesis.
      Chitosan has been of particular interest and have been used widely with PRP for various applications. Various in vitro studies have shown chitosan to enhance the effect when combined with PRP. Depres-Tremblay et al.
      • Deprés-Tremblay G.
      • Chevrier A.
      • Tran-Khanh N.
      • Nelea M.
      • Buschsaitomann M.
      Chitosan inhibits platelet-mediated clot retraction, increases platelet-derived growth factor release, and increases residence time and bioactivity of platelet-rich plasma in vivo.
      noted Chitosan PRP hybrid clots to have decreased retraction, higher cumulative release of PDGF and EGF and higher cell recruitment and granulation tissue synthesis compared to PRP clots. Chitosan also helps in better platelet adhesion and aggregation. It also increases expression of glycoprotein IIIa expression and increases release of growth factors.
      • Shen E.
      • Chou T.C.
      • Gau C.H.
      • Tu H.P.
      • Chen Y.T.
      • Fu E.
      Releasing growth factors from activated human platelets after Chitosan stimulation: a possible biomaterial for platelet rich plasma preparation.
      Chitosan has some role in increasing the efficacy of PRP by providing an increased and controlled release profile of growth factors. Dwivedi et al.
      • Dwivedi G.
      • Chevrier A.
      • Hoemann C.D.
      • Buschmann M.D.
      Freeze Dried Chitosan/platelet-rich-plasma Implants Improve Marrow Stimulated Cartilage Repair in Rabbit Chronic Defect Model.
      in their study on rabbit model surgically created chronic defects in cartilage and used bone marrow stimulation (BMS) with PRP in one group and freeze dried Chitosan with PRP in the other. They noted that animals treated with BMS + Chitosan PRP had better articular scores at 8 weeks than BMS + PRP. They hypothesized that Chitosan/PRP reside for several weeks in vivo, in contrast to PRP which is quickly degraded. Segundo et al.
      • Segundo F.A.
      • Costa E.I.
      • Azevedo A.S.
      • et al.
      Platelet-rich plasma, hydroxyapatite, and chitosan in the bone and cartilaginous regeneration of femoral trochlea in rabbits: clinical, radiographic, and histomorphometric evaluations.
      in their study on surgically created cartilage defects in rabbit knees noted that composite base of PRP, hydroxyapatite and chitosan promoted better bone healing and cartilage healing compared to control. There is encouraging in vitro and in vivo evidence that PRP can be used with biomaterials to enhance their effect, however whether this can be translated to actual clinical scenarios remains to be seen.

      2. Conclusion

      PRP is cementing its place in the symptomatic treatment of early knee OA. It is clear that all PRP products are not the same and hence more research into defining the ideal PRP preparation, dose, concentration, number of injections, activation status and if PRP should be ideally combined with other substances and/or engineered biomaterials. The common aim is improving the present day PRP to make it more effective, compliant and long acting for the treatment of early knee OA.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

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