The clot thickens: Autologous and allogeneic fibrin sealants are mechanically equivalent in an ex vivo model of cartilage repair

Autoři: Rebecca M. Irwin aff001;  Lawrence J. Bonassar aff001;  Itai Cohen aff003;  Andrea M. Matuska aff004;  Jacqueline Commins aff001;  Brian Cole aff005;  Lisa A. Fortier aff006
Působiště autorů: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America aff001;  Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York, United States of America aff002;  Department of Physics, Cornell University, Ithaca, New York, United States of America aff003;  Research and Development, Arthrex Inc., Naples, Florida, United States of America aff004;  Midwest Orthopedics at Rush, Rush University Medical Center, Chicago, Illinois, United States of America aff005;  College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224756


Fibrin sealants are commonly used in cartilage repair surgeries to adhere cells or grafts into a cartilage defect. Both autologous and commercial allogeneic fibrin sealants are used in cartilage repair surgeries, yet there are no studies characterizing and comparing the mechanical properties of fibrin sealants from all-autologous sources. The objectives of this study were to investigate (i) the effect of fibrinogen and thrombin sources on failure mechanics of sealants, and (ii) how sealants affect the adhesion of particulated cartilage graft material (BioCartilage) to surrounding cartilage under physiological loading. Allogeneic thrombin and fibrinogen were purchased (Tisseel), and autologous sources were prepared from platelet-rich plasma (PRP) and platelet-poor plasma (PPP) generated from human blood. To compare failure characteristics, sealants were sandwiched between cartilage explants and pulled to failure. The effect of sealant on the adhesion of BioCartilage graft to cartilage was determined by quantifying microscale strains at the graft-cartilage interface using an in vitro cartilage defect model subjected to shear loading at physiological strains well below failure thresholds. Fibrinogen sources were not equivalent; PRP fibrinogen created sealants that were more brittle, failed at lower strains, and resulted in sustained higher strains through the graft-cartilage interface depth compared to PPP and allogeneic sources. PPP clotted slower compared to PRP, suggesting PPP may percolate deeper into the repair to provide more stability through the tissue depth. There was no difference in bulk failure properties or microscale strains at the graft-cartilage interface between the purely autologous sealant (autologous thrombin + PPP fibrinogen) and the commercial allogeneic sealant. Clinical Significance: All-autologous fibrin sealants fabricated with PPP have comparable adhesion strength as commercial allogeneic sealants in vitro, whereas PRP creates an inferior all-autologous sealant that sustains higher strains through the graft-cartilage interface depth.

Klíčová slova:

Articular cartilage – Cartilage – Deformation – Fibrinogen – Surgical repair – Thrombin – Tissue repair – Fibrin


1. Sameem M, Wood TJ, Bain JR. A Systematic Review on the Use of Fibrin Glue for Peripheral Nerve Repair. Plast Reconstr Surg. 2011;127: 2381–2390. doi: 10.1097/PRS.0b013e3182131cf5 21311390

2. Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty hepatic resections: Evolution of technique towards bloodless surgery. Br J Surg. John Wiley & Sons, Ltd; 1996;83: 1526–1529. doi: 10.1002/bjs.1800831110 9014666

3. Currie LJ, Sharpe JR, Martin R. The use of fibrin glue in skin grafts and tissue-engineered skin replacements: a review. Plast Reconstr Surg. 2001;108: 1713–26. Available: doi: 10.1097/00006534-200111000-00045 11711954

4. Hohendorff B, Siepen W, Staub L. Treatment of Acute Achilles Tendon Rupture: Fibrin Glue versus Fibrin Glue Augmented with the Plantaris Longus Tendon. J Foot Ankle Surg. 2009;48: 439–446. doi: 10.1053/j.jfas.2009.04.005 19577719

5. Verra WC, van Hilten JA, Honohan Á, van Zwet EW, van der Bom JG, Nelissen RGHH, et al. The effect of a fibrin sealant on knee function after total knee replacement surgery. Results from the FIRST trial. A multicenter randomized controlled trial. Paschos NK, editor. PLoS One. 2018;13: e0200804. doi: 10.1371/journal.pone.0200804 30044846

6. Mccormick F, Harris JD, Abrams GD, Frank R, Gupta A, Hussey K, et al. Trends in the Surgical Treatment of Articular Cartilage Lesions in the United States: An Analysis of a Large Private-Payer Database Over a Period of 8 Years. Arthroscopy. 2014;30: 222–6. doi: 10.1016/j.arthro.2013.11.001 24485115

7. Choi N-Y, Kim B-W, Yeo W-J, Kim H-B, Suh D-S, Kim J-S, et al. Gel-type autologous chondrocyte (ChondronTM) implantation for treatment of articular cartilage defects of the knee. BMC Musculoskelet Disord. BioMed Central; 2010;11: 103. doi: 10.1186/1471-2474-11-103 20507640

8. Farr J, Tabet SK, Margerrison E, Cole BJ. Clinical, Radiographic, and Histological Outcomes After Cartilage Repair With Particulated Juvenile Articular Cartilage A 2-Year Prospective Study. Am J Sports Med. 2014;42: 1417–1425. doi: 10.1177/0363546514528671 24718790

9. Wang KC, Frank RM, Cotter EJ, Christian DR, Cole BJ. Arthroscopic Management of Isolated Tibial Plateau Defect With Microfracture and Micronized Allogeneic Cartilage–Platelet-Rich Plasma Adjunct. Arthrosc Tech. 2017;6: e1613–e1618. doi: 10.1016/j.eats.2017.06.018 29399444

10. Christensen BB, Foldager CB, Jensen J, Lind M. Autologous Dual-Tissue Transplantation for Osteochondral Repair. Cartilage. SAGE PublicationsSage CA: Los Angeles, CA; 2015;6: 166–173. doi: 10.1177/1947603515580983 26175862

11. Baxter Healthcare Corporation. Tisseel (Fibrin Sealant) [Package Insert]. 2013.

12. Castillo TN, Pouliot MA, Kim HJ, Dragoo JL. Comparison of Growth Factor and Platelet Concentration From Commercial Platelet-Rich Plasma Separation Systems. Am J Sports Med. 2011;39: 266–271. doi: 10.1177/0363546510387517 21051428

13. Fortier LA, Brofman PJ, Nixon AJ, Mohammed HO. Disparate chondrocyte metabolism in three-dimensional fibrin cultures derived from autogenous or commercially manufactured fibrinogen. Am J Vet Res. 1998;59: 514–20. Available: 9563640

14. Hale BW, Goodrich LR, Frisbie DD, McIlwraith CW, Kisiday JD. Effect of scaffold dilution on migration of mesenchymal stem cells from fibrin hydrogels. Am J Vet Res. American Veterinary Medical Association; 2012;73: 313–318. doi: 10.2460/ajvr.73.2.313 22280396

15. Salamanna F, Veronesi F, Maglio M, Della Bella E, Sartori M, Fini M. New and emerging strategies in platelet-rich plasma application in musculoskeletal regenerative procedures: general overview on still open questions and outlook. Biomed Res Int. Hindawi; 2015;2015: 1–24. doi: 10.1155/2015/846045 26075269

16. Man D, Plosker H, Winland-Brown JE. The use of autologous platelet-rich plasma (platelet gel) and autologous platelet-poor plasma (fibrin glue) in cosmetic surgery. Plast Reconstr Surg. 2001;107: 229–37; discussion 238–9. Available: doi: 10.1097/00006534-200101000-00037 11176628

17. Nurden AT, Nurden P, Sanchez M, Andia I, Anitua E. Platelets and wound healing. Front Biosci. 2008;13: 3532–48. Available: 18508453

18. Qureshi AH, Chaoji V, Maiguel D, Faridi MH, Barth CJ, Salem SM, et al. Proteomic and phospho-proteomic profile of human platelets in basal, resting state: insights into integrin signaling. PLoS One. Public Library of Science; 2009;4: e7627. doi: 10.1371/journal.pone.0007627 19859549

19. Goodrich LR, Chen AC, Werpy NM, Williams AA, Kisiday JD, Su AW, et al. Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects. J Bone Jt Surg. 2016;98: 23–34. doi: 10.2106/JBJS.O.00407 26738900

20. Fortier L, Brofman P, Nixon A, Mohammed H. Disparate chondrocyte metabolism in three-dimensional fibrin cultures derived from autogenous or commercially manufactured fibrinogen. Am J Vet Res. 1998;59: 514–20. Available: 9563640

21. Dickneite G, Metzner H, Pfeifer T, Kroez M, Witzke G. A comparison of fibrin sealants in relation to their in vitro and in vivo properties. Thromb Res. 2003;112: 73–82. doi: 10.1016/j.thromres.2003.10.010 15013277

22. Lämsä T, Jin H-T, Sand J, Nordback I. Tissue adhesives and the pancreas: biocompatibility and adhesive properties of 6 preparations. Pancreas. 2008;36: 261–6. doi: 10.1097/MPA.0b013e31816714a2 18362839

23. Lacaze L, Le Dem N, Bubenheim M, Tsilividis B, Mezghani J, Schwartz L, et al. Tensile Strength of Biological Fibrin Sealants: A Comparative Study. J Surg Res. Academic Press; 2012;176: 455–459. doi: 10.1016/j.jss.2011.11.1017 22341344

24. Azadani AN, Matthews PB, Ge L, Shen Y, Jhun C-S, Guy TS, et al. Mechanical Properties of Surgical Glues Used in Aortic Root Replacement. Ann Thorac Surg. 2009;87: 1154–1160. doi: 10.1016/j.athoracsur.2008.12.072 19324142

25. Hickerson WL, Nur I, Meidler R. A comparison of the mechanical, kinetic, and biochemical properties of fibrin clots formed with two different fibrin sealants. Blood Coagul Fibrinolysis. 2011;22: 19–23. doi: 10.1097/MBC.0b013e32833fcbfb 21150581

26. Glidden PF, Malaska C, Herring SW. Thromboelastograph assay for measuring the mechanical strength of fibrin sealant clots. Clin Appl Thromb Hemost. 2000;6: 226–33. Available: 11030529

27. Isaacs JE, McDaniel CO, Owen JR, Wayne JS. Comparative analysis of biomechanical performance of available “nerve glues.” J Hand Surg Am. 2008;33: 893–9. doi: 10.1016/j.jhsa.2008.02.009 18656762

28. Cravens MG, Behn AW, Dragoo JL. Comparison of mechanical compressive properties of commercial and autologous fibrin glues for tissue engineering applications. Clin Biomech. 2017;49: 34–39. doi: 10.1016/j.clinbiomech.2017.08.004 28863319

29. Hunter CJ, Levenston ME. Maturation and Integration of Tissue-Engineered Cartilages within an in Vitro Defect Repair Model. Tissue Eng. Mary Ann Liebert, Inc.; 2004;10: 736–746. doi: 10.1089/1076327041348310 15265290

30. Scotti C, Mangiavini L, Boschetti F, Vitari F, Domeneghini C, Fraschini G, et al. Effect of in vitro culture on a chondrocyte-fibrin glue hydrogel for cartilage repair. Knee Surgery, Sport Traumatol Arthrosc. Springer-Verlag; 2010;18: 1400–1406. doi: 10.1007/s00167-009-1014-7 20033674

31. Peretti GM, Bonassar LJ, Caruso EM, Randolph MA, Trahan CA, Zaleske DJ. Biomechanical Analysis of a Chondrocyte-Based Repair Model of Articular Cartilage. Tissue Eng. 1999;5: 317–326. doi: 10.1089/ten.1999.5.317 10477854

32. Peretti GM, Xu J-W, Bonassar LJ, Kirchhoff CH, Yaremchuk MJ, Randolph MA. Review of Injectable Cartilage Engineering Using Fibrin Gel in Mice and Swine Models. Tissue Eng. Mary Ann Liebert, Inc.; 2006;12: 1151–1168. doi: 10.1089/ten.2006.12.1151 16771631

33. Meppelink AM, Zhao X, Griffin DJ, Erali R, Gill TJ, Bonassar LJ, et al. Hyaline Articular Matrix Formed by Dynamic Self-Regenerating Cartilage and Hydrogels. Tissue Eng Part A. 2016;22: 962–970. doi: 10.1089/ten.TEA.2015.0577 27324118

34. Johnson TS, Xu J-W, Zaporojan V V., Mesa JM, Weinand C, Randolph MA, et al. Integrative Repair of Cartilage with Articular and Nonarticular Chondrocytes. Tissue Eng. Mary Ann Liebert, Inc.; 2004;10: 1308–1315. doi: 10.1089/ten.2004.10.1308 15588391

35. Gaffney PJ, Wong MY. Collaborative study of a proposed international standard for plasma fibrinogen measurement. Thromb Haemost. 1992;68: 428–32. Available: 1448775

36. Epstein KL, Brainard BM, Gomez-Ibanez SE, Lopes MAF, Barton MH, Moore JN. Thrombelastography in Horses with Acute Gastrointestinal Disease. J Vet Intern Med. John Wiley & Sons, Ltd (10.1111); 2011;25: 307–314. doi: 10.1111/j.1939-1676.2010.0673.x 21314719

37. Epstein KL, Brainard BM, Lopes MAF, Barton MH, Moore JN. Thrombelastography in 26 healthy horses with and without activation by recombinant human tissue factor. J Vet Emerg Crit Care. John Wiley & Sons, Ltd (10.1111); 2009;19: 96–101. doi: 10.1111/j.1476-4431.2008.00381.x 19691590

38. Triplett DA, Harms CS. Thrombin clotting time. In: DA T, CS H, editors. Procedures for the coagulation laboratory. Chicago: American Society of Clinical Pathologists Press; 1981. pp. 38–41.

39. Fortier LA, Chapman HS, Pownder SL, Roller BL, Cross JA, Cook JL, et al. BioCartilage Improves Cartilage Repair Compared With Microfracture Alone in an Equine Model of Full-Thickness Cartilage Loss. Am J Sports Med. SAGE Publications; 2016;44: 2366–2374. doi: 10.1177/0363546516648644 27298478

40. Hirahara AM, Mueller KW. BioCartilage: A New Biomaterial to Treat Chondral Lesions. Sports Med Arthrosc. 2015;23: 143–8. Available: doi: 10.1097/JSA.0000000000000071 26225574

41. Buckley MR, Gleghorn JP, Bonassar LJ, Cohen I. Mapping the depth dependence of shear properties in articular cartilage. J Biomech. 2008;41: 2430–2437. doi: 10.1016/j.jbiomech.2008.05.021 18619596

42. Buckley MR, Bergou AJ, Fouchard J, Bonassar LJ, Cohen I. High-resolution spatial mapping of shear properties in cartilage. J Biomech. 2010;43: 796–800. doi: 10.1016/j.jbiomech.2009.10.012 19896130

43. Middendorf JM, Shortkroff S, Dugopolski C, Kennedy S, Siemiatkoski J, Bartell LR, et al. In vitro culture increases mechanical stability of human tissue engineered cartilage constructs by prevention of microscale scaffold buckling. J Biomech. Elsevier; 2017;64: 77–84. doi: 10.1016/j.jbiomech.2017.09.007 28964498

44. Herberhold C, Faber S, Stammberger T, Steinlechner M, Putz R, Englmeier KH, et al. In situ measurement of articular cartilage deformation in intact femoropatellar joints under static loading. J Biomech. 1999;32: 1287–95. Available: doi: 10.1016/s0021-9290(99)00130-x 10569707

45. Blaber J, Adair B, Antoniou A. Ncorr: Open-Source 2D Digital Image Correlation Matlab Software. Exp Mech. 2015;55: 1105–1122. Available:

46. Hale BW, Goodrich LR, Frisbie DD, McIlwraith CW, Kisiday JD. Effect of scaffold dilution on migration of mesenchymal stem cells from fibrin hydrogels. Am J Vet Res. American Veterinary Medical Association; 2012;73: 313–318. doi: 10.2460/ajvr.73.2.313 22280396

47. Hanson AJ, Quinn MT. Effect of fibrin sealant composition on human neutrophil chemotaxis. J Biomed Mater Res. 2002;61: 474–81. doi: 10.1002/jbm.10196 12115473

48. Bensaïd W, Triffitt JT, Blanchat C, Oudina K, Sedel L, Petite H. A biodegradable fibrin scaffold for mesenchymal stem cell transplantation. Biomaterials. 2003;24: 2497–502. Available: doi: 10.1016/s0142-9612(02)00618-x 12695076

49. Ho W, Tawil B, Dunn JCY, Wu BM. The Behavior of Human Mesenchymal Stem Cells in 3D Fibrin Clots: Dependence on Fibrinogen Concentration and Clot Structure. Tissue Eng. 2006;12: 1587–1595. doi: 10.1089/ten.2006.12.1587 16846354

50. Gugerell A, Pasteiner W, Nürnberger S, Kober J, Meinl A, Pfeifer S, et al. Thrombin as important factor for cutaneous wound healing: Comparison of fibrin biomatrices in vitro and in a rat excisional wound healing model. Wound Repair Regen. Wiley/Blackwell (10.1111); 2014;22: 740–748. doi: 10.1111/wrr.12234 25231003

51. Khan IM, Gilbert SJ, Singhrao SK, Duance VC, Archer CW. Cartilage integration: evaluation of the reasons for failure of integration during cartilage repair. A review. Eur Cell Mater. 2008;16: 26–39. Available: 18770504

52. Chan DD, Cai L, Butz KD, Trippel SB, Nauman EA, Neu CP. In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee. Sci Rep. Nature Publishing Group; 2016;6: 19220. doi: 10.1038/srep19220 26752228

53. Hanson AJ, Quinn MT. Effect of fibrin sealant composition on human neutrophil chemotaxis. J Biomed Mater Res. 2002;61: 474–481. doi: 10.1002/jbm.10196 12115473

54. Henak CR, Ross KA, Bonnevie ED, Fortier LA, Cohen I, Kennedy JG, et al. Human talar and femoral cartilage have distinct mechanical properties near the articular surface. J Biomech. Elsevier; 2016;49: 3320–3327. doi: 10.1016/j.jbiomech.2016.08.016 27589932

55. Bonnevie ED, Galesso D, Secchieri C, Cohen I, Bonassar LJ. Elastoviscous Transitions of Articular Cartilage Reveal a Mechanism of Synergy between Lubricin and Hyaluronic Acid. PLoS One. 2015;10: e0143415. doi: 10.1371/journal.pone.0143415 26599797

56. Bonnevie ED, Galesso D, Secchieri C, Bonassar LJ. Frictional characterization of injectable hyaluronic acids is more predictive of clinical outcomes than traditional rheological or viscoelastic characterization. Awad HA, editor. PLoS One. Public Library of Science; 2019;14: e0216702. doi: 10.1371/journal.pone.0216702 31075142

57. Spotnitz WD. Fibrin Sealant: The Only Approved Hemostat, Sealant, and Adhesive-a Laboratory and Clinical Perspective. ISRN Surg. Hindawi Limited; 2014; 1–28. doi: 10.1155/2014/203943 24729902

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