Platelet-Rich Fibrin Scaffolds for Cartilage and Tendon Regenerative Medicine: From Bench to Bedside
Abstract
:1. Introduction
2. PRF-GFs in Chondrogenesis
3. PRF in Cartilage Tissue Engineering
3.1. In Vitro Studies
3.2. Pre-Clinical Implantation
3.3. Clinical Trials
4. PRF-GFs in Tenogenesis
5. PRF in Tendon Tissue Engineering
5.1. In Vitro Studies
5.2. Pre-Clinical Studies
5.3. Clinical Studies
6. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Hemocomponent/Experimental Groups | PRF Preparation Protocol | Characterization Parameters | Major Findings | Reference |
---|---|---|---|---|
- Human PRF exudates incorporated into Biodegradable Fibrin (FB) scaffolds Controls: - Bovine Biodegradable Fibrin scaffolds - Agarose scaffolds | Preparation according to Choukroun et al., 2001 [3]: - Blood collection without anticoagulant - Centrifugation (400 X g, 10 min) - Formation of a fibrin clot rich with platelets (PRF) in the middle of the tube, between the red blood cells and the acellular plasma | - Quantification of PDGF-BB, TGF-β1, IGF-1 and BMP-2 into PRF exudates - 2D and 3D cultures of human primary chondrocytes and a human chondrosarcoma cell line (SW-1353) - Proliferation studies - mRNA expression of type-II collagen and GAGs - Synthesis of GAGs and proteoglycans | When chondrocytes were cultured on FB scaffolds added with PRF exudates: - cell growth rate was significantly increased - mRNA expression of type-II collagen and GAGs was up-regulated - Synthesis of GAGs and proteoglycans was enhanced | Chien et al., 2012 [65] |
- Rabbit i-PRF Control: - Rabbit PRP | - Blood collection without anticoagulant - Centrifugation (60 X g, 3 min) with Choukroun PRF Duo Centrifuge (Process for PRF, Nice, France) - Collection of the upper plasma layer designated as i-PRF | - i-PRF- and PRP-conditioned cultures of rabbit chondrocytes in normal conditions or in the presence of IL-1β - mRNA expression of chondrogenesis-related genes (SOX9, COL2A1 and ACAN) and osteoarthritis-related markers (ADAMTS4, PTGS2 and MMP13) | i-PRF was found to be superior to PRP in: - up-regulating chondrogenesis-related genes in normal conditions - counteracting IL-1β inflammatory effects in osteoarthritis-like environment | Abd El Raouf et al., 2017 [61] |
- Rabbit PRF | Preparation according to Choukroun et al., 2001 [3] | - Quantification of PDGF, IGF-1 and TGF-β1 release - Mechanical tests - Ultrastructural morphology by SEM - In vitro and ex vivo evaluations of PRF chemotactic effect on rabbit chondrocytes - Proliferation of chondrocyte cultures - mRNA expression of cartilage markers (type-I and type-II collagen and Aggrecan) - GAG deposition | - PRF improved the chemotaxis, proliferation, and viability of the cultured chondrocytes - Chondrogenic markers were up-regulated in cell populations cultured with PRF-conditioned media - PRF increased the formation and deposition of the cartilaginous matrix produced by cultured chondrocytes | Wong et al., 2017 [66] |
- Rabbit PRF | Preparation according to Choukroun et al., 2001 [3] | - PRF chemotactic effect on rabbit meniscocytes (scratch migration and transwell migration assays) - Cell proliferation - Histological evaluation of type-I and type-II collagen, Aggrecan and GAG deposition | - PRF stimulated cellular migration and proliferation of meniscocytes - Extracellular matrix synthesis by cultured meniscocytes was enhanced by treatment with PRF releseates | Wong et al., 2017 [67] |
- Human FRP membrane | - Blood collection without anticoagulant but with a clot activator - Centrifugation (770× g, 12 min) - Pression of the fibrin clot with stainless steel plate (Box PRF BmdCon®) for exudate extraction - FRP membrane formation | - Proliferation of human ASCs - Differentiation of ASC micromass cultures towards the chondrogenic lineage | - FRP membrane eluates stimulated the proliferation of ASCs - Treatment with eluates induced mucopolysaccharide and aggrecan synthesis by differentiated ASCs | Souza et al., 2017 [68] |
End Use Destination | Hemocomponent/Experimental Groups | PRF Preparation Protocol | Characterization Parameters | Major Findings | Reference |
---|---|---|---|---|---|
Rabbits Chondral defect in the femoral condyle (diameter: 3 mm; depth: 0.5 mm) | Rabbit PRF combined with cartilage granules derived from the created defect Control: - cartilage defect with no implantation | Preparation according to Choukroun et al., 2001 [3]: - Blood collection without anticoagulant - Centrifugation (400 X g, 10 min) - Formation of a fibrin clot rich with platelets (PRF) in the middle of the tube, between the red blood cells and the acellular plasma | - 3-month implantation - MRI - ICRS Visual Histological Assessment Scale (distribution of cells, mineralization of cartilage, tissue surface and matrix, cell population viability, subchondral bone abnormalities) | - Less cartilage degradation in the PRF-treated group according to the MRI T2 values - Better histological scores in the PRF group, presenting normal cell distribution and cartilage mineralization, smooth and continuous tissue surface, hyaline cartilage-like formation and no subchondral abnormalities | Kuo et al., 2011 [69] |
Dogs Full thickness articular cartilage defect in the femoral condyle (diameter: 6 mm; depth: 5 mm) | Dog PRF Control: - cartilage defect with no implantation | Preparation according to Choukroun et al., 2001 [3] | - 4-, 16- and 24-week implantation - ICRS evaluation score for macroscopic assessment of the repaired tissue - O’Driscoll histological grading scale for microscopic investigation | - Formation of cartilage-like reparative tissue in both experimental groups, with higher number of chondrocyte-like cells and better ECM deposition in the PRF groups - Macroscopic and histological grading scores were found to be higher in the PRF-treated groups, indicating a better quality of cartilage repair | Kazemi et al., 2014 [70] |
- Dog L-PRF - Dog L-PRP Control: - cartilage defect with no implantation | Preparation according to Choukroun et al., 2001 [3] | - 4-, 16- and 24-week implantation - ICRS evaluation score for macroscopic assessment of the repaired tissue - O’Driscoll histological grading scale for microscopic investigation | - No significant difference in macroscopic scores between L-PRP and L-PRF treated defects, but lower scores in the untreated control group - High quality repair tissue in both L-PRF and L-PRP treated groups according to histological evaluations | Kazemi and Fakhrjou, 2015 [71] | |
Rabbits Subcutaneous implant to test graft viability for rhinoplasty | - Diced rabbit cartilage wrapped with rabbit PRFM - Diced rabbit cartilage wrapped with acellular dermal tissue - Diced rabbit cartilage wrapped with oxidized methylcellulose - Diced rabbit cartilage alone | Preparation according to Choukroun et al., 2001 [3] | - 10-week implantation - Histological stainings - Graft evaluated for chondrocyte viability, collagen content, ECM fibrillar structure and changes in peripheral tissues | - Better preservation of cartilage graft viability in the PRFM group - Less fibrosis, higher chondrocyte viability, better ECM deposition and less inflammation in the PRFM group | Güler et al., 2015 [78] |
Rabbits Subcutaneous implant to test graft viability for rhinoplasty | - Diced rabbit cartilage wrapped with rabbit PRF - Diced rabbit cartilage wrapped with oxidized regeneratedcellulose - Diced rabbit cartilage wrapped with fascia - Diced rabbit cartilage alone | Preparation according to Choukroun et al., 2001 [3] | - 2 month-implant - Macroscopic evaluation - Histological staining - Explants evaluated for graft viability, fibrosis, inflammation and vascularization | - Superior viability of the cartilage graft wrapped with PRF in comparison with the cartilage graft wrapped with oxidized regenerated cellulose - No significant differences among the other groups - The 4 groups were not significantly different in terms of inflammation rate, fibrosis and vascularization | Göral et al., 2016 [79] |
Rabbits Full thickness articular cartilage defect in the patellar groove (diameter: 4 mm; depth: 3 mm) | - Rabbit PRF - Rabbit PRP - Rabbit PRF + rhSDF1 - Rabbit PRP + rhSDF1 - Gelatin + rhSDF1 Control: - Untreated cartilage defect | Preparation according to Choukroun et al., 2001 [3] | - 4-week implantation - ICRS scores for macroscopic evaluations - ICRS Visual Histological Assessment Scale - Immunofluorescence analysis of type-II collagen expression - Gene expression study of cartilage markers (Aggrecan, SOX9) | - Higher ICRS macroscopic scores in the PRF + rhSDF1 group, with complete repair and good integration with the surrounding cartilage - ICRS histological scores of treated groups, except for the PRP group, were significantly higher than the untreated control - Neo-cartilages highly positive to type-II collagen in the PRF + rhSDF1, PRP + rhSDF1 and Gelatin + rhSDF1 groups - Higher expression of SOX9 in the regenerated tissue of all treated groups than the control group - Higher expression of Aggrecan in the treated groups, except for PRP group | Bahmanpour et al., 2016 [62] |
Horses Full thickness articular cartilage defect of the knee (diameter: 15 mm) | Horse APEF (Autologous Platelet-enriched Fibrin) +/− horse BMDMSCs | - Blood collection into an acid citrate dextrose bag - Isolation of fibrinogen from plasma by use of an ethanol precipitation technique - Obtainment of a fibrinogen/platelet mixture (1:1) with the thrombin solution | 1-year implantation Repair tissues were evaluated by: - Arthroscopy (ICRS scores) - Histological examination - MRI - Micro-CT - Indentation tests | - No significant differences between the two groups according to arthroscopic ICRS scores - Fair-to-good fill of chondral defects and integration with the surrounding cartilage in both groups according to histological scores - Less thick cartilaginous tissue in the repair site after the addition of BMDMSCs - No variations in the stiffness of the cartilaginous tissue between the two treatments | Goodrich et al., 2016 [72] |
Rabbits Chondral defect in the femoral condyle (diameter: 3 mm) | - Rabbit PRF + cartilage granules (PRFCG) Controls: - Rabbit PRF - Untreated cartilage defect | Preparation according to Choukroun et al., 2001 [3] | - 3-month implantation - Gross anatomy evaluation - ICRS histological scores | - Repair tissue with an intact, smooth, and hyaline-like surface resembling normal cartilage in the PRFCG group - Integration of the PRFCG implant with adjacent normal tissue, with no signs of inflammation - Histologically, better repair of the cartilage defect in the PRFCG group versus the PRF and untreated groups | Wong et al., 2017 [66] |
Rabbits 2 mm wedge shape full-thickness defect in the medial meniscus | - Rabbit PRF fragments + defect sutured with 5–0 prolene (PRF-augmented suture group) Controls: - Not sutured defects (non-suture group) - Defects sutured with 5–0 prolene (suture group) | Preparation according to Choukroun et al., 2001 [3] | - 3-month implantation - Semi-quantitative histological scores | - Better morphological integrity of the meniscus in the PRF-augmented suture group than the control groups - No signs of high-grade degeneration in the PRF-augmented suture group, but mucoid changes with clear signs of degeneration in the control groups - Better healing of the meniscal defect via PRF-augmentation according to histological scores - Better congruity of articular cartilage in the PRF treated group | Wong et al., 2017 [67] |
Rabbits osteochondral defect in the patellar groove (diameter: 5 mm; depth: 2 mm) | - Rabbit PRF + osteochondral autograft - Rabbit PRP + osteochondral autograft Control: - Osteochondral autograft | Preparation according to Choukroun et al., 2001 [3] | - 3- and 12-week implantation - ICRS macroscopic scoring system for repair evaluation - Histological examination - Immunohistochemical analysis of type-I and type-II collagen | - Macroscopical healing of the defect in the PRF group versus PRP and control groups at 3 weeks - Macroscopical healing of the defect with normal or nearly normal cartilage in all the 3 groups at 12 weeks - In the nongrafted portion of the defect, formation of hyaline-like cartilage in the PRF group and fibrocartilage in the other 2 groups | Maruyama et al., 2017 [73] |
Rabbits Full thickness osteochondral defect in the knee joint (diameter: 5 mm; depth: 5 mm) | - Rabbit i-PRF - Rabbit PRP Control: - Untreated defect | - Blood collection without anticoagulant - Centrifugation (60 X g, 3 min) with Choukroun PRF Duo Centrifuge (Process for PRF, Nice, France) - Collection of the upper plasma layer designated as i-PRF | - 4- and 12-week treatment - ICRS macroscopic scoring system - ICRS histological scoring - Safranin O/fast green staining of to assess GAG content | - At 4 weeks, higher macroscopic IRCS scores in the i-PRF group in comparison with PRP and control groups, with formation of white opaque tissue well integrated with the surrounding healthy cartilage - At 12 weeks, no significant macroscopic differences among all groups - Higher ICRS histological scores in the i-PRF group, revealing complete regeneration of the cartilage and subchondral bone, with complete integration to normal tissues and identification of normal chondrocytes | Abd El Raouf et al., 2017 [61] |
Dogs Osteochondral defect in the femoral condyle (diameter: 6 mm; depth: 5 mm) | - Dog PRF seeded with dog BM-MSCs Control: - Untreated defect | Preparation according to Choukroun et al., 2001 [3] | - 4-, 16- and 24-week implantation - ICRS evaluation score for macroscopic analysis - O’Driscoll histological grading scale for microscopic studies | - Consistently better integration of the repair tissue in the treated group versus the untreated control according to macroscopic scoring results - Formation of fibrous tissue in both experimental groups at 4 weeks - Histological detection of chondrocyte-like cells and cartilaginous ECM in the treated group at 16 and 24 weeks - Significantly higher histological scores in the treated group | Kazemi et al., 2017 [74] |
Pigs Osteochondral defect in the femoral condyle (diameter: 8 mm; depth: 5 mm) | - Pig PRF +/- autologous cartilage fragments - Autologous cartilage fragments Control: - Untreated defect | - Blood collection with clot activator and gel - Centrifugation (1,066 X g, 10 min) - Separation of the jelly-like PRF from the gel-clot without the red blood cells sinking to the bottom of the tube | - 6-month implantation - Gross appearance of coverage, tissue color, defect margins, and surface - ICRS histological grading score | - Significantly better healing and repair tissue integration in the PRF+cartilage group in comparison with other 3 groups - Significantly greater histological scores in the PRF+cartilage group, with smooth repaired hyaline-like cartilage containing columnar arrangements of chondrocytes and integration of the regenerated tissue with the normal hyaline cartilage as well as the underlying subchondral bone | Sheu et al., 2017 [75] |
Rabbits Osteochondral defect in the femoral condyle (diameter: 3 mm; length: 2 mm) | - Rabbit PRF releasates (PRFr) +/− autologous bone marrow-derived MSCs - Autologous bone marrow-derived MSCs Control: - Untreated defect | - Blood collection into a serum separation tube - Centrifugation (3,000 rpm, 10 min) - Obtainment of a fibrin clot (PRF) between a clear yellow serum layer and a coagulated red blood cell layer | - 12-week treatment - Gross assessment of shape, color, contour, and uniformity of the cartilage - Histological scoring system | - Decrease of the defect size and increase of the regenerated cartilage volume in the PRFr+MSCs group - Better histological indices (i.e., matrix deposition, cell distribution, and tissue surface) in the PRFr+MSCs group - Thicker hyaline-like cartilaginous tissue with normal GAG production in the PRFr+MSCs group in comparison with other 3 groups | Wu et al., 2017 [53] |
Rabbits Osteochondral defect in the femoral condyle (diameter: 3 mm; length: 2 mm) | - Rabbit PRF releasates (PRFr) +/− autologous ADSCs - Rabbit PRFr + chondrocytes - Autologous ADSCs Control: - Untreated defect | Preparation according to Wu et al., 2017 [53] | - 14-week treatment - Gross investigation of defect filling, integration to border zone and macroscopic appearance of the implant - ICRS histological grading score | - Decrease of the defect size and increase of the repaired cartilage volume in the PRFr+ADMSCs group - Better matrix, cell distribution, and surface indices in the PRFr+ADSCs group than other groups according to histological grading scores - Thicker hyaline cartilage-specific ECM in the PRFr+ADMSCs group - Similar histological scores for ADSCs and PRFr groups | Hsu et al., 2018 [76] |
Rabbits Full thickness cartilage defect of the ear (5 × 5 × 1 mm) | - Rabbit PRF +/- allogenic ADSCs - Allogenic ADSCs Control: - Untreated defect | Preparation according to Choukroun et al., 2001 [3] | - 1-, 2-and 3-month implantation - Macroscopic evaluation - Histological analysis - Gene/protein expression study of type-II collagen - Immune response evaluation by determining blood levels of CD4/CD8, IL-2 and IL-4 | - Best rate of repair at all observation points in the PRF+ADSCs group, with 90% greater repair rate than other groups at 3 months - More efficient repair of the cartilage defect in the PRF+ADSCs group, with the treated area almost completely filled by naïve chondrocytes. - Higher type-II collagen expression, both at the gene and protein levels, in the PRF and PRF+ADSCs groups - No significant immune response induced by allogenic ADSC transplantation | Xu et al., 2018 [77] |
End Use Destination | Hemocomponent/Experimental Groups | PRFPreparation Protocol | Characterization Parameters | Major Findings | Reference |
---|---|---|---|---|---|
Hemophilic ankle arthropathy (focal lesions) | n = 5 patients (mean age = 33 ± 6.78 years): collagen membrane loaded with BMDCs and PRF | Preparation according to the Vivostat® system | Mean follow up: 2 years The postoperative outcome was evaluated by: - AOFAS scores - radiographs - MRI and Mocart scores | - All patients showed complete filling of the talar defect - The implant borders were completely/partially integrated with the adjacent cartilage - In all patients presented inhomogeneous, hyperintense repair tissue was detected - Three patients had subchondral bone edema or cyst - Overall, the data showed good osteochondral regeneration and no progression of joint degeneration | Buda et al., 2015 [82] |
Knee cartilage focal lesions | n = 15 patients: microfractures and PRF; n = 16 patients: microfractures and PRP; n = 17 patients: microfractures alone | - | Follow up: 2, 5 years Postoperative evaluation of patients was performed by: - clinical scores (i.e., IKDC, VAS pain) - MRI and Mocart scores | - Platelet concentrates allowed to achieved better clinical results compared to microfracture alone - The PRF was more effective than the PRP at 2 years, with loss of significance at 5 years - According to Mocart score, PRF gave better results earlier than the other two treatments | Papalia et al., 2016 [84] |
Knee cartilage focal lesions | n = 25 patients (mean age = 29 ± 7.3 years): single-step AMIC procedure based on microfracture and application of autologous PRF called CLP-MB membrane, combined with an injectable collagen scaffold (Cartifill) | - Blood collection by apheresis - Separation of CLP and plasma - Cryoprecipitate formation from freeze/thawed plasma - Mixing of CLP and cryoprecipitate (CLP mix) - Activation of the CLP mix with calcium gluconate - Incubation at 37 °C for 10 min - Centrifugation (7333× g, 25 min) | Pre-implant characterization: - assessment of blood cell composition, CD34+/CD133+/VEGFR2+ cell content, fibrinogen concentration during each preparation phase - release of PDGF-AB, TGF-β1 and VEGF -mechanical tests Clinical trial: Follow-up: 1, 6 and 12 months Patients were evaluated by: - NMR and/or radiographic scans - VAS pain - IKDC scores | - Quality control tests during each phase of CLP-MB preparation assured for the obtainment of a standardized, traceable and safe product - The treatment with the hemocomponent provided short-term pain relief and functional improvement | D’Antimo et al., 2017 [85] |
Rhinoplasty (dorsal nasal augmentation) | n = 19 patients: cartilage scales-cartilage pâté compound graft with PRGF n = 21 patients: cartilage scales-cartilage pâté compound graft with i-PRF n = 8 patients: cartilage pâté graft with a-PRF | Preparation according to Choukroun et al., 2001 [3] | Follow-up controls every 3 months Medical records to assess the surgical outcome included: - follow-up notes - pre- and post-operative photographic documentation | - Satisfactory dorsal nasal augmentation in 47 patients - 1 mm-horizontal displacement of the graft in one patient 3 months after surgery, with no tendency for further displacement - No dorsal irregularities, nor signs of resorption, erythema, inflammation | Kovacevic et al., 2017 [86] |
Hemocomponent/Experimental Groups | PRF Preparation Protocol | Characterization Parameters | Major Findings | Reference |
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- Human PR-matrix - Human PP-matrix - Human purified fibrin | - Blood collection into 3.8% (wt/vol) sodium citrate - Centrifugation at 4 °C: (a) PR-plasma → 460× g, 8 min (b) PP-plasma → 4500× g, 12 min - Platelet counts before clotting - Addition of calcium chloride at a final concentration of 22.8 mM | - Proliferation of human tenocytes - Secretion of TGF-β1, VEGF and HGF (+/− cells) - Synthesis of type-I collagen (Coll-I) | - Significantly increased platelets cells proliferation - Increase in Coll-I synthesis with any difference between PR- and PP-matrices - Higher levels of TGF-β1 in PR-matrix samples (i.e., +/− tenocytes) than PP-matrices - Increased synthesis of VEGF and HGF by tenocytes on fibrin matrices - Significantly higher levels of VEGF, but not HGF, in presence of platelets | Anitua et al., 2006 [101] |
- Dog PRF matrix - Dog PRF membrane - Dog whole blood clot | a) PRF matrix - Blood collection in tube with trisodium citrate - 1st centrifugation (1100× g, 6 min) - Supernatant transfer in a tube with calcium chloride - 2nd centrifugation (1450× g, 15 min) b) PRF membran e- Blood collection in tube with trisodium citrate and the proprietary separator gel. - 1st centrifugation (1100× g, 6 min) - Supernatant transfer in a glass vial with calcium chloride - 2nd centrifugation (4500× g, 25 min) - Suspension of the resulting membrane in serum | - Quantification of eluted TGF-β1 - Evaluation of the mitogenic effect on canine tenocytes | - Both PRF constructs release significantly higher levels of TGF-β1 than blood clot, significantly increasing cell proliferation - Significantly higher levels of TGF-β1 were released from PRF membrane than PRF matrix, significantly increasing cell proliferation | Visser et al., 2010 [102] |
- Human standard/gelatinous L-PRF - Human dry/compressed L-PRF | - Blood collection (at 8.30 am.) incitrate tubes - Centrifugation for 12 min with different G-forces: (1) 200× g, (2) 400× g, (3) 1000× g - Count of platelets, leukocytes and red blood cells in extracted supernatant and “buffy coat” versus normal blood | - Leukocyte content - Release of GFs (i.e., TGF-β1, VEGF, MPO, IGF1, PDGF-AB, CXCL4) - Relationship between matrix preparation methods and GFs concentrations | - Highest concentration of platelets and leukocytes with 400× g centrifugation - L-PRF clots showed in vitro a continuous release of GFs which were significantly higher than levels expressed by normal blood at each culture time point - Higher release of GFs (i.e., CXCL4, IGF-1, PDGF-AB, and VEGF) by the standard/gelatinous- compared to the dry/compressed group | Zumstein et al., 2012 [111] |
- Human PRF-matrix - Fibrin matrix based on PRP (ViscoGel; Arthrex, Naples, FL) Controls: - Human highly cross-linked collagen membrane (Arthroflex; LifeNet Health, Virginia Beach, VA) - Porcine non-cross-linked collagen membrane (Mucograft; Geistlich Pharma, Lucerne, Switzerland) - Human fresh-frozen rotator cuff tendon (allograft) | - Blood collection - Centrifugation (3000 rpm, 10 min) | - Differentiation, proliferation of human MSCs | - MSCs successfully differentiated into all cell lines - A significantly greater number of cells adhered to both the non-cross-linked porcine collagen scaffold and PRF-matrix - Significantly higher proliferation in the non-cross-linked porcine collagen scaffold vs PRF-matrix and fibrin matrix based on platelet-rich plasma - No significant differences at the live/dead assay | Beitzel et al., 2014 [103] |
End Use Destination | Hemocomponent/Experimental Groups | PRF Preparation Protocol | Characterization Parameters | Major Findings | Reference |
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Sheeps Achilles tendon injected at 2.5 cm proximal to the bone insertion | - Injection of autologous sheep calcified PR-plasma - Injection of autologous sheep PP-plasma - Injection of saline | - Blood collection into 3.8% (wt/vol) sodium citrate - Centrifugation at 4 °C: (a) PR-plasma → 460× g, 8 min (b) PP-plasma → 4500× g, 12 min - Platelet counts before clotting - Addition of calcium chloride at a final concentration of 22.8 mM | - Cell density, morphology and distribution - Vascularization - Inflammation | - Higher increase in cell density in the fascicles treated with PR- and PP-plasma - Ovoid but aligned cells in PR- and PP- treated tendons - Neovascularization is promoted with both PR-and PP-plasma - No inflammatory cells in both PR-and PP-plasma treatment | Anitua et al., 2006 [101] |
Sheeps acute model of Achilles tendon rupture | - Re-approximation of the tendon ends with suture only - Re-approximation with suture augmented with ADP wrapped around the repair and sutured to the tendon - ADP wrapped around the proximal and distal margins of the tendon, bridging a 1.5 cm gap, with autologous PRPFM sutured in place within the gap | - PRPFM—Cascade Autologous Platelet System-4, Musculoskeletal Transplant Foundation | - Mechanical tests - Cell and tissue morphology - Vascularization - Scaffold incorporation- Inflammation | - Significant difference in elongation between the operated limb vs unoperated limb in suture only group and ADP + PRPFM group but not in suture + ADP group - No apparent fibrosis in all groups - Increased tendon thickness in suture only group - New tendon fibers without increasing tendon thickness (2/6 animals) in suture + ADP group - Complete bridging of the gap, with no change in tendon thickness in ADP + PRPFM (2/6 animals) - Peripheral integration of the APD to tendon fibers - APD +/− PRPFM augments Achilles tendon repair | Sarrafian et al., 2010 [114] |
Dogs patellar tendon; sharp incision of the central third | - Autologous dog PRF membrane to fill the injury site - Surgical closure following resection of the central third of the patellar tendon | - Blood collection in tubes with trisodium citrate and a separator gel. - 1st centrifugation (1100× g, 6 min) - Transfer of PRP supernatant in a vial containing 1.0 M calcium chloride. - 2nd centrifugation (4500× g, 25 min) while fibrin polymerization ensued | - Gross healing assessment and cross-sectional area - Cell density - Vascularization - Collagen and GAG | - Repair tissue in both groups - No histological significant difference (i.e., cellularity, vascularity, collagen organization, or GAG content) - Hypercellular fibrovascular repair tissue in defect site of both groups - Significantly greater cross-sectional area of PRF membrane–treated tendons vs the control group - PRF membrane did not enhance the rate/quality of tendon healing but it increases repair tissue surrounding the defect. | Visser et al., 2011 [117] |
Rabbits Toe flexor tendon; sharp transection between the A1 and A2 pulley and immediate surgical repair | - Allogenic PRP - Allogenic PRP-F matrix - Commercial fibrin (Beriplast P Combi Set; CSL Behing K.K., Tokyo, Japan) Control: Natural healing of the repair site | - Blood collection in syringe with acid citrate dextrose-A - 1st centrifugation (2400 rpm, 10 min at 4 °C) - 2nd centrifugation of plasma (3600 rpm, 10 min at 4 °C) - Platelets count - Addition of fibrin matrix (Beriplast P Combi-Set; CSL Behring K.K., Tokyo, Japan): liquid A (0.25 µL) + liquid B (0.25 µL) | - Edema of the toes - Adhesions extent - Mechanical tests - Histological analysis | - No significant difference in edema/adhesion scores - Significantly increased healing strength by PRP-F matrix | Sato et al., 2012 [115] |
Rabbits Experiment 1 Bone-patellar tendon-bone. Removal of the central half of each patellar tendon Experiment 2 Removal of medial collateral ligament | Experiment 1 - Allogenic rabbit CPFS; Control: untreated defect of the controlateral patella Experiment 2 Allogenic CPFS sheet Control: Insertion of rivets without reconstruction of the controlatelar medial collateral ligament | - Blood collection in tubes with a sodium citrate solution (5% wt/vol) - 1st centrifugation (3000 rpm, 15 min at 4 °C) - 2nd centrifugation of platelet poor plasma (3000 rpm, 15 min at 4 °C) - Freezing of buffy coat layer and platelet poor plasma (−80 °C) - Defrosting and enriching by ultrafiltration twice of platelet poor plasma; defrosting of buffy coat. - Blending of the two fractions and addition of calcium gluconate (final concentration 23 mM) - Incubation at 37 °C for 3 h - Pressure treatment in aqueous solution of 10 mM calcium chloride at 4 °C | - Repair tissue thickness - Mechanical tests - Inflammation | Experiment 1 - the ultimate failure load and stiffness were higher for the CPFS-treated group than untreated knee - Presence of dense and longitudinally aligned collagen bundles - No signs of immunological rejection of allogenic scaffold Experiment 2 - CPFS promoted ligament repair tissue vs the untreated side - The ultimate failure load of the CPFS repair tissue at 20 weeks was 78% of that in healthy controls of the same age CPFS enhanced/accelerated healing of tendons and ligaments | Matsunaga et al., 2013 [118] |
Rats Tendon-bone insertion site, rotator cuff. Transection and transosseous suture repair of the supraspinatus tendon | - Surgical repair + allogenic PRFM Control: - Controlateral shoulder, only surgical repair | - Blood collection in syringe with 0.5 cc of acid citrate dextrose anticoagulant solution and thixotropic polyester separator gel. - 1st centrifugation (1500 rpm, 15 min) - 2nd centrifugation of the platelet-rich layer (3000 rpm, 6 min) | - Mechanical tests - Histological analysis (i.e., collagen tissue organization/maturation; cartilage formation | - Higher ultimate load to failure, stress, and stiffness values for experimental group repairs - No differences in biomechanical testing between the groups - Less collagen organization and cartilage formation at the insertion site in the experimental group - PRF-membrane does not recapitulate the native enthesis with exuberant/disordered healing response with fibrovascular scar tissue | Hasan et al., 2016 [108] |
Rabbits Flexor digitorum profundus tendon | Part I - Autologous rabbit PRF, wrapped around the repair site, tagged with suture Part II - Autologous rabbit PRF interposed between the tendon repair ends by a 2-strand repair Control: Control tendons | - Blood collection without anticoagulant - Centrifugation (2700 rpm, 12 min at room temperature) - Compression of the PRF clot | - Range of motions analysis - Cross-sectional area - Mechanical tests | - No significant increase in range of motion - Significant increase in cross-sectional area of the tendons in the PRF group - The control had a higher load and stress to failure but similar stiffness and modulus to the PRF groups - The PRF did not have a major influence on cellular organization - Undesirable effect on the biomechanical properties of repaired flexor tendons | Liao et al., 2017 [116] |
End Use Destination | Hemocomponent/Experimental Groups | PRF Preparation Protocol | Characterization Parameters | Major Findings | Reference | |
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Full-thickness rotator cuff tear | n = 20 patients (mean age = 57.6 years): Arthroscopic single-row rotator cuff repair + 2 autologous PRP, sutured into the repair site n = 20 patients (mean age = 57.8 years; range = 44–69 years): Arthroscopic single-row rotator cuff repair | - Cascade autologous platelet system | Mean follow up and range: PRP, 28.3 (24–44) months; no PRP, 33 (24–44) months - MRI - Clinical outcome measures by ASES, Rowe, SANE, SST and Constant scores | - Retears: with PRP: 6 of 20 (30%); no PRP: 12 of 20 (60%) - Cuff tear size (no. healed): <3 cm, 7 of 14 (50%) no PRP; 12 of 14 (86%) with PRP. ≥3 cm, 1 of 6 (17%) no PRP; 2 of 6 (33%) with PRP - Significant clinical differences showing lower re-tear rates by MRI only with Rowe score | Barber et al., 2011 [104] | |
Arthroscopic rotator cuff repair | n = 43 patients (mean age = 55.5 years): Tear size (cm): small (<1); medium (1–3), PRFM n = 45 patients (mean age = 55.2 years): Tear size (cm): small (<1), medium (1–3), no PRFM | - Blood collection in a tube with trisodium citrate and a thixotropic polyester separator gel - 1st centrifugation (1100 rpm, 6 min) - Transfer of the supernatant in a bottle containing calcium chloride (1.0 M) - 2nd centrifugation (4500 RCF, 25 min) | Follow up: 16 months - Clinical outcome by Constant scores - MRI | - Statistically significant improvement in both groups but any among groups - Difference in alterations of MRI signal intensity - Re-rupture in 10.5% patients of control group and 2.5% in PRFM group but any additional treatment occurred - No difference in tendon thickness or in size of the tendon footprint tendon thickness | Castricini et al., 2011 [107] | |
Arthroscopic rotator cuff repair | n = 16 patients (mean age = 65 ± 7 years): Tear size: 3.8 ± 1.1 cm, PRFM n = 21 patients (mean age = 65 ± 9 years): Tear size: 3.9 ± 1.1 cm, no PRFM | - Blood collection in a tube with trisodium citrate - 1st centrifugation (1100 rpm, 6 min) - Transfer of supernatant into a second tube containing calcium chloride, which initiates the fibrin-clotting cascade - 2nd centrifugation (1450 rpm, 15 min) The Cascade Autologous Platelet System was used to prepare the PRFM | Mean follow-up: PRFM group, 13 ± 4 months; Untreated group, 27 ± 8 months - Operative time - MRI - Clinical outcome scores by Constant, WORC, SANE, ASES, UCL | - Retear rates: statistically significantly higher in the PRFM group (56.2%) vs. controls (38.1%) - Functional outcome scores postoperatively: not significantly improved in PRFM vs. controls - Operative time (min): 152 ± 31 in PRFM group vs 161 ± 40 in control group - 2 infections in the PRFM group - The augmentation of at-risk rotator cuff tears with PRFM did not result in improved retear rates or functional outcome scores compared with controls | Bergeson et al., 2012 [106] | |
Full-thickness rotator cuff tear | n = 40 patients (mean age = 58.90 ± 9.86 years): Tear size (nr. of patients): small: 10; medium: 20; large: 10, PRFM treatment n = 39 patients (mean age = 7.21 ± 9.42 years): Tear size (nr. of patients): small: 10; medium: 19; large: 10, No PRFM | - Cascade Membrane (Musculoskeletal Tissue Foundation, Edison, NJ, USA) | Follow-up: 6 weeks, 3 and 12 months - Power doppler ultrasound - Manual muscle testing ratio - Clinical outcome scores by ASES and l’Insalata - Strength measurements using a handheld dynamometer | - Intact repair in 24 of 36 (67%) in the PRFM group and 25 of 31 (81%) in the control group - No differences in tendon-to-bone healing - No demonstrable effect on tendon healing vascularity, manual muscle strength, or clinical rating scales by PRFM - Negative effect of PRFM on healing according to regression analysis | Rodeo et al., 2012 [109] | |
Arthroscopic rotator cuff repair | n = 30 patients (mean age = 59.67 ± 8.16 years): Tear size: 1.77 ± 0.84 cm, PRFM treatment (commercially available) n = 30 patients (mean age = 64.50 ± 8.59 years): Tear size: 1.72 ± 1.18 cm, no PRFM | - Cascade Membrane (Musculoskeletal Tissue Foundation, Edison, NJ, USA) | Follow-up: 1 h, 3, 6, 9, and 12 weeks, 1 year - Operative time - VAS pain scores, ROM, SST, FF, ER, UCLA, ASES scores - Narcotic consumption - MRI | - No complications - Longer mean surgery time for the PRFM group than control group - No significant difference in VAS, ROM, SST, FF, ER or ASES scores or narcotic use - Similar UCLA scores in both groups at baseline but statistically significantly lower in the PRFM group at follow-up - No differences in MRI - No significant improvement in perioperative morbidity, structural integrity or clinical outcome in PRFM in early follow-up | Weber et al., 2013 [110] | |
Full-thickness rotator cuff tears | n = 20 patients (mean age = 55 years): Tear size: ≤3 cm in anteroposterior length, suture-bridging double-row repair + PRPFM n = 20 patients (mean age = 57 years): Tear size: no greater than 3 cm in anteroposterior length, triple - loaded single row repair + PRPFM | - Cascade Membrane (Musculoskeletal Tissue Foundation, Edison, NJ, USA) | Mean follow-up and range: double-row group, 27 (12–46) months; single-row group, 28 (12–49) months - ASES, Rowe, SST, Constant, SANE - MRI | - No statistical difference on clinical outcome scores between groups - No MRI difference in rotator cuff tendon re-tear rate (i.e., 15% in both groups) | Barber et al., 2016 [105] | |
Arthroscopic rotator cuff repair | n = 17 patients (mean age = 65 years): Tear size (area): 322 ± 180 mm2, L-PRF n = 18 patients (mean age = 66 years): Tear size (area): 445 ± 421 mm2, No L-PRF | - Blood collection (at 8.30 am.) incitrate tubes - Centrifugation for 12 min with different G-forces: (1) 200× g, (2) 400× g and (3) 1000× g. - Count of platelets, leukocytes and red blood cells in extracted supernatant and “buffy coat” vs normal blood | - Mean follow-up: L-PRF, 14 months; Untreated group, 15 months - SSV, VAS for pain, SST, Constant-Murley | - No complications in either group - No significant differences in clinical outcome, healing rate, mean postoperative defect size, and tendon quality at 12 mo follow-up | Zumstein et al., 2016 [112] | |
Acute rupture of Achilles tendon | n = 11 patients (mean age = 32.5 ± 3.4 years): PRF augmentation n = 9 patients (mean age = 34.5 ± 3 years): No PRF n = 8 patients (mean age = 30 ± 4.4 years): Healthy | - Blood collection in a tube with sodium citrate - Centrifugation (3000 rpm, 10 min) The protocol included specific jellifying agents (i.e., calcium gluconate and batroxobin) | Follow-up: 6 months - Gait analysis | - % of the stance time of the operated leg, double-support time of the healthy leg, network of the ankle during the gait cycle showed statistically significant differences between the no-PRF and the healthy group - No differences between PRF and healthy groups - Suture + PRF augmentation shows significant functional improvements in motion efficiency | Alviti et al., 2017 [113] | |
Gluteus medius tendons | n = 18 patients (mean age = 60.26 ± 8.8 years): Tear size: small or low-grade partial tear (33.3%); large or high-grade partial tear (50.0%); large or high-grade full tear (16.7%), PRFM n = 29 patients (mean age = 63.09 ± 12.0 years): Tear size: small or low-grade partial tear (31.0%); large or high-grade partial tear (58.6%); large or high-grade full tear (10.4%), no PRFM | - | Follow-up: 1 year - Demographic variables | - No effect of PRFM on repair in terms of pain or clinical evidence of retears - PRFM may have a role in improving subjective outcomes of overall and hip-specific physical functioning | Saltzman et al., 2018 [119] |
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Barbon, S.; Stocco, E.; Macchi, V.; Contran, M.; Grandi, F.; Borean, A.; Parnigotto, P.P.; Porzionato, A.; De Caro, R. Platelet-Rich Fibrin Scaffolds for Cartilage and Tendon Regenerative Medicine: From Bench to Bedside. Int. J. Mol. Sci. 2019, 20, 1701. https://doi.org/10.3390/ijms20071701
Barbon S, Stocco E, Macchi V, Contran M, Grandi F, Borean A, Parnigotto PP, Porzionato A, De Caro R. Platelet-Rich Fibrin Scaffolds for Cartilage and Tendon Regenerative Medicine: From Bench to Bedside. International Journal of Molecular Sciences. 2019; 20(7):1701. https://doi.org/10.3390/ijms20071701
Chicago/Turabian StyleBarbon, Silvia, Elena Stocco, Veronica Macchi, Martina Contran, Francesca Grandi, Alessio Borean, Pier Paolo Parnigotto, Andrea Porzionato, and Raffaele De Caro. 2019. "Platelet-Rich Fibrin Scaffolds for Cartilage and Tendon Regenerative Medicine: From Bench to Bedside" International Journal of Molecular Sciences 20, no. 7: 1701. https://doi.org/10.3390/ijms20071701