Analyze Diet
Cartilage2022; 14(1); 59-66; doi: 10.1177/19476035221142010

Preclinical Use of FGF-18 Augmentation for Improving Cartilage Healing Following Surgical Repair: A Systematic Review.

Abstract: To evaluate the efficacy of fibroblast growth factor-18 (FGF-18) augmentation for improving articular cartilage healing following surgical repair in preclinical () animal models. A systematic review was performed evaluating the efficacy of FGF-18 augmentation with cartilage surgery compared with cartilage surgery without FGF-18 augmentation in living animal models. Eligible intervention groups were FGF-18 treatment in conjunction with orthopedic procedures, including microfracture, osteochondral auto/allograft transplantation, and cellular-based repair. Outcome variables were: International Cartilage Repair Society (ICRS) score, modified O'Driscoll histology score, tissue infill score, qualitative histology, and adverse events. Descriptive statistics were recorded and summarized for each included study. In total, 493 studies were identified and 4 studies were included in the final analysis. All studies were randomized controlled trials evaluating use of recombinant human FGF-18 (rhFGF-18). Animal models included ovine ( = 3) and equine ( = 1), with rhFGF-18 use following microfracture ( = 3) or osteochondral defect repair ( = 1). The rhFGF-18 was delivered via intra-articular injection ( = 2), collagen membrane scaffold ( = 1), or both ( = 1). All studies reported significant, positive improvements in cartilage defect repair with rhFGF-18 compared with controls based on ICRS score ( = 4), modified O'Driscoll score ( = 4), tissue infill ( = 3), and expression of collagen type II ( = 4) ( < 0.05). No adverse events were reported with the intra-articular administration of this growth factor, indicating short-term safety and efficacy of rhFGF-18 . This systematic review provides evidence that rhFGF-18 significantly improves cartilage healing at 6 months postoperatively following microfracture or osteochondral defect repair in preclinical randomized controlled trials.
Publication Date: 2022-12-21 PubMed ID: 36541606PubMed Central: PMC10076894DOI: 10.1177/19476035221142010Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
  • Systematic Review
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article discusses the effectiveness of a protein called fibroblast growth factor-18 (FGF-18) in enhancing the healing process of articular cartilage after surgical repair, specifically in animal models. The results show that FGF-18 substantially improves the repair of cartilage defects when administered postoperatively.

Research Methodology

  • The research conducted a systematic review to evaluate the efficacy of FGF-18 augmentation with cartilage surgery in comparison with cartilage surgery without FGF-18 augmentation. The test subjects used in the study were living animal models.
  • The interventions applicable for review were instances in which FGF-18 treatment was applied in conjunction with orthopedic procedures. These procedures include microfracture, osteochondral auto/allograft transplantation, and cellular-based repair.
  • The outcomes of the interventions were assessed using several variables. These include International Cartilage Repair Society (ICRS) score, modified O’Driscoll histology score, tissue infill score, qualitative histology, and any adverse events.

Data Collection and Analysis

  • From a total of 493 studies, only 4 were included in the final analysis. The criteria for inclusion required the studies to be randomized controlled trials specifically evaluating the use of recombinant human FGF-18 (rhFGF-18).
  • The animal models used in the studies were sheep (ovine) and horse (equine). The experiments utilizing rhFGF-18 were conducted following microfracture in 3 instances, or osteochondral defect repair in 1 instance.
  • The administration of rhFGF-18 was executed via intra-articular injection, collagen membrane scaffold, or a combination of both, depending on the individual study.

Results

  • All the studies that were reviewed reported significant positive improvements in the repair of cartilage defects with the use of rhFGF-18 compared to controls. This was based on several scoring systems including ICRS score, modified O’Driscoll score, tissue infill, and expression of collagen type II.
  • Importantly, the application of rhFGF-18 did not cause any adverse events, demonstrating its short-term safety and efficacy.

Conclusion

  • This study concludes that rhFGF-18 significantly improves the healing of cartilage at 6 months postoperatively following microfracture or osteochondral defect repair based on evidence gathered from preclinical randomized controlled trials.

Cite This Article

APA
DePhillipo NN, Hendesi H, Aman ZS, Lind DRG, Smith J, Dodge GR. (2022). Preclinical Use of FGF-18 Augmentation for Improving Cartilage Healing Following Surgical Repair: A Systematic Review. Cartilage, 14(1), 59-66. https://doi.org/10.1177/19476035221142010

Publication

ISSN: 1947-6043
NlmUniqueID: 101518378
Country: United States
Language: English
Volume: 14
Issue: 1
Pages: 59-66

Researcher Affiliations

DePhillipo, Nicholas N
  • McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.
  • Mechano-Therapeutics LLC, Philadelphia, PA, USA.
Hendesi, Honey
  • Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Aman, Zachary S
  • Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
Lind, Dane R G
  • McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.
Smith, Joseph
  • Department of Health, Nutrition, and Exercise Sciences, North Dakota State University, Fargo, ND, USA.
Dodge, George R
  • McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.
  • Mechano-Therapeutics LLC, Philadelphia, PA, USA.

MeSH Terms

  • Animals
  • Humans
  • Sheep
  • Horses
  • Fractures, Stress
  • Cartilage, Articular / surgery
  • Cartilage, Articular / pathology
  • Fibroblast Growth Factors / pharmacology
  • Fibroblast Growth Factors / therapeutic use
  • Collagen

Conflict of Interest Statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

This article includes 33 references
  1. Dekker TJ, Aman ZS, DePhillipo NN, Dickens JF, Anz AW, LaPrade RF. Chondral Lesions of the Knee: An Evidence-Based Approach.. J Bone Joint Surg Am 2021 Apr 7;103(7):629-645.
    pubmed: 33470591doi: 10.2106/JBJS.20.01161google scholar: lookup
  2. Di Martino A, Perdisa F, Filardo G, Busacca M, Kon E, Marcacci M, Zaffagnini S. Cell-Free Biomimetic Osteochondral Scaffold for the Treatment of Knee Lesions: Clinical and Imaging Results at 10-Year Follow-up.. Am J Sports Med 2021 Aug;49(10):2645-2650.
    pubmed: 34283948doi: 10.1177/03635465211029292google scholar: lookup
  3. Ibarra C, Villalobos E, Madrazo-Ibarra A, Velasquillo C, Martinez-Lopez V, Izaguirre A, Olivos-Meza A, Cortes-Gonzalez S, Perez-Jimenez FJ, Vargas-Ramirez A, Franco-Sanchez G, Ibarra-Ibarra LG, Sierra-Suarez L, Almazan A, Ortega-Sanchez C, Trueba C, Martin FB, Arredondo-Valdes R, Chavez-Arias D. Arthroscopic Matrix-Assisted Autologous Chondrocyte Transplantation Versus Microfracture: A 6-Year Follow-up of a Prospective Randomized Trial.. Am J Sports Med 2021 Jul;49(8):2165-2176.
    pubmed: 34048286doi: 10.1177/03635465211010487google scholar: lookup
  4. Familiari F, Cinque ME, Chahla J, Godin JA, Olesen ML, Moatshe G, LaPrade RF. Clinical Outcomes and Failure Rates of Osteochondral Allograft Transplantation in the Knee: A Systematic Review.. Am J Sports Med 2018 Dec;46(14):3541-3549.
    pubmed: 29039969doi: 10.1177/0363546517732531google scholar: lookup
  5. Zanotto GM, Liesbeny P, Barrett M, Zlotnick H, Frank E, Grodzinsky AJ, Frisbie DD. Microfracture Augmentation With Trypsin Pretreatment and Growth Factor-Functionalized Self-assembling Peptide Hydrogel Scaffold in an Equine Model.. Am J Sports Med 2021 Jul;49(9):2498-2508.
    pubmed: 34161182doi: 10.1177/03635465211021798google scholar: lookup
  6. DePhillipo NN, Aman ZS, Dekker TJ, Moatshe G, Chahla J, LaPrade RF. Preventative and Disease-Modifying Investigations for Osteoarthritis Management Are Significantly Under-represented in the Clinical Trial Pipeline: A 2020 Review.. Arthroscopy 2021 Aug;37(8):2627-2639.
    pubmed: 33812028doi: 10.1016/j.arthro.2021.03.050google scholar: lookup
  7. Müller S, Lindemann S, Gigout A. Effects of Sprifermin, IGF1, IGF2, BMP7, or CNP on Bovine Chondrocytes in Monolayer and 3D Culture.. J Orthop Res 2020 Mar;38(3):653-662.
    pmc: PMC7065224pubmed: 31608492doi: 10.1002/jor.24491google scholar: lookup
  8. Behrendt P, Ladner Y, Stoddart MJ, Lippross S, Alini M, Eglin D, Armiento AR. Articular Joint-Simulating Mechanical Load Activates Endogenous TGF-β in a Highly Cellularized Bioadhesive Hydrogel for Cartilage Repair.. Am J Sports Med 2020 Jan;48(1):210-221.
    pubmed: 31877102doi: 10.1177/0363546519887909google scholar: lookup
  9. Ruan S, Deng J, Yan L, Huang W. Evaluation of the effects of the combination of BMP-2-modified BMSCs and PRP on cartilage defects.. Exp Ther Med 2018 Dec;16(6):4569-4577.
    pmc: PMC6257496pubmed: 30542406doi: 10.3892/etm.2018.6776google scholar: lookup
  10. Sennett ML, Meloni GR, Farran AJE, Guehring H, Mauck RL, Dodge GR. Sprifermin treatment enhances cartilage integration in an in vitro repair model.. J Orthop Res 2018 Oct;36(10):2648-2656.
    pmc: PMC7241943pubmed: 29761549doi: 10.1002/jor.24048google scholar: lookup
  11. Ellsworth JL, Berry J, Bukowski T, Claus J, Feldhaus A, Holderman S, Holdren MS, Lum KD, Moore EE, Raymond F, Ren H, Shea P, Sprecher C, Storey H, Thompson DL, Waggie K, Yao L, Fernandes RJ, Eyre DR, Hughes SD. Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors.. Osteoarthritis Cartilage 2002 Apr;10(4):308-20.
    pubmed: 11950254doi: 10.1053/joca.2002.0514google scholar: lookup
  12. Reker D, Kjelgaard-Petersen CF, Siebuhr AS, Michaelis M, Gigout A, Karsdal MA, Ladel C, Bay-Jensen AC. Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo.. J Transl Med 2017 Dec 12;15(1):250.
    pmc: PMC5727954pubmed: 29233174doi: 10.1186/s12967-017-1356-8google scholar: lookup
  13. Reker D, Siebuhr AS, Thudium CS, Gantzel T, Ladel C, Michaelis M, Aspberg A, Berchtold MW, Karsdal MA, Gigout A, Bay-Jensen AC. Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo.. Sci Rep 2020 Apr 7;10(1):6011.
    pmc: PMC7138815pubmed: 32265494doi: 10.1038/s41598-020-63216-zgoogle scholar: lookup
  14. Antunes BP, Vainieri ML, Alini M, Monsonego-Ornan E, Grad S, Yayon A. Enhanced chondrogenic phenotype of primary bovine articular chondrocytes in Fibrin-Hyaluronan hydrogel by multi-axial mechanical loading and FGF18.. Acta Biomater 2020 Mar 15;105:170-179.
    pubmed: 31982592doi: 10.1016/j.actbio.2020.01.032google scholar: lookup
  15. Gigout A, Guehring H, Froemel D, Meurer A, Ladel C, Reker D, Bay-Jensen AC, Karsdal MA, Lindemann S. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix.. Osteoarthritis Cartilage 2017 Nov;25(11):1858-1867.
    pubmed: 28823647doi: 10.1016/j.joca.2017.08.004google scholar: lookup
  16. Liu Z, Lavine KJ, Hung IH, Ornitz DM. FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate.. Dev Biol 2007 Feb 1;302(1):80-91.
    pubmed: 17014841doi: 10.1016/j.ydbio.2006.08.071google scholar: lookup
  17. Meloni GR, Farran A, Mohanraj B, Guehring H, Cocca R, Rabut E, Mauck RL, Dodge GR. Recombinant human FGF18 preserves depth-dependent mechanical inhomogeneity in articular cartilage.. Eur Cell Mater 2019 Aug 8;38:23-34.
    pmc: PMC7273689pubmed: 31393594doi: 10.22203/eCM.v038a03google scholar: lookup
  18. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.. BMJ 2009 Jul 21;339:b2535.
    pmc: PMC2714657pubmed: 19622551doi: 10.1136/bmj.b2535google scholar: lookup
  19. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies.. BMC Med Res Methodol 2014 Mar 26;14:43.
    pmc: PMC4230647pubmed: 24667063doi: 10.1186/1471-2288-14-43google scholar: lookup
  20. Getgood A, Henson F, Skelton C, Brooks R, Guehring H, Fortier LA, Rushton N. Osteochondral tissue engineering using a biphasic collagen/GAG scaffold containing rhFGF18 or BMP-7 in an ovine model.. J Exp Orthop 2014 Dec;1(1):13.
    pmc: PMC4545804pubmed: 26914758doi: 10.1186/s40634-014-0013-xgoogle scholar: lookup
  21. Hendesi H, Stewart S, Gibison ML, Guehring H, Richardson DW, Dodge GR. Recombinant fibroblast growth factor-18 (sprifermin) enhances microfracture-induced cartilage healing.. J Orthop Res 2022 Mar;40(3):553-564.
    pmc: PMC8560655pubmed: 33934397doi: 10.1002/jor.25063google scholar: lookup
  22. Howard D, Wardale J, Guehring H, Henson F. Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model.. J Orthop Res 2015 Aug;33(8):1120-7.
    pubmed: 25721940doi: 10.1002/jor.22882google scholar: lookup
  23. Power J, Hernandez P, Guehring H, Getgood A, Henson F. Intra-articular injection of rhFGF-18 improves the healing in microfracture treated chondral defects in an ovine model.. J Orthop Res 2014 May;32(5):669-76.
    pubmed: 24436147doi: 10.1002/jor.22580google scholar: lookup
  24. Dahlberg LE, Aydemir A, Muurahainen N, Gühring H, Fredberg Edebo H, Krarup-Jensen N, Ladel CH, Jurvelin JS. A first-in-human, double-blind, randomised, placebo-controlled, dose ascending study of intra-articular rhFGF18 (sprifermin) in patients with advanced knee osteoarthritis.. Clin Exp Rheumatol 2016 May-Jun;34(3):445-50.
    pubmed: 27050139
  25. Hochberg MC, Guermazi A, Guehring H, Aydemir A, Wax S, Fleuranceau-Morel P, Reinstrup Bihlet A, Byrjalsen I, Ragnar Andersen J, Eckstein F. Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis: The FORWARD Randomized Clinical Trial.. JAMA 2019 Oct 8;322(14):1360-1370.
    pmc: PMC6784851pubmed: 31593273doi: 10.1001/jama.2019.14735google scholar: lookup
  26. Lohmander LS, Hellot S, Dreher D, Krantz EF, Kruger DS, Guermazi A, Eckstein F. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial.. Arthritis Rheumatol 2014 Jul;66(7):1820-31.
    pubmed: 24740822doi: 10.1002/art.38614google scholar: lookup
  27. Onuora S. Osteoarthritis: Sprifermin shows cartilage-protective effects in knee OA.. Nat Rev Rheumatol 2014 Jun;10(6):322.
    pubmed: 24798571doi: 10.1038/nrrheum.2014.68google scholar: lookup
  28. Onuora S. Sprifermin benefits maintained at 5 years.. Nat Rev Rheumatol 2021 Jul;17(7):378.
    pubmed: 34075240doi: 10.1038/s41584-021-00643-wgoogle scholar: lookup
  29. Rai MF, Pham CT. Intra-articular drug delivery systems for joint diseases.. Curr Opin Pharmacol 2018 Jun;40:67-73.
    pmc: PMC6015522pubmed: 29625332doi: 10.1016/j.coph.2018.03.013google scholar: lookup
  30. Siegel RA. Stimuli sensitive polymers and self regulated drug delivery systems: a very partial review.. J Control Release 2014 Sep 28;190:337-51.
  31. Chung MF, Chia WT, Wan WL, Lin YJ, Sung HW. Controlled Release of an Anti-inflammatory Drug Using an Ultrasensitive ROS-Responsive Gas-Generating Carrier for Localized Inflammation Inhibition.. J Am Chem Soc 2015 Oct 7;137(39):12462-5.
    pubmed: 26391111doi: 10.1021/jacs.5b08057google scholar: lookup
  32. Mohanraj B, Duan G, Peredo A, Kim M, Tu F, Lee D, Dodge GR, Mauck RL. Mechanically-Activated Microcapsules for 'On-Demand' Drug Delivery in Dynamically Loaded Musculoskeletal Tissues.. Adv Funct Mater 2019 Apr 11;29(15).
    pmc: PMC7351315pubmed: 32655335doi: 10.1002/adfm.201807909google scholar: lookup
  33. Peredo AP, Jo YK, Duan G, Dodge GR, Lee D, Mauck RL. Mechano-activated biomolecule release in regenerating load-bearing tissue microenvironments.. Biomaterials 2021 Jan;265:120255.

Citations

This article has been cited 6 times.
  1. Migliorini F, Simeone F, Bardazzi T, Memminger MK, Pipino G, Vaishya R, Maffulli N. Regenerative Cartilage Treatment for Focal Chondral Defects in the Knee: Focus on Marrow-Stimulating and Cell-Based Scaffold Approaches. Cells 2025 Aug 7;14(15).
    doi: 10.3390/cells14151217pubmed: 40801648google scholar: lookup
  2. Liu J, Zhai L, Xu Z, Wu A, Zhou D, He Y, Liu Q, Tang Q, Zhu W. [Early effectiveness of transosseous suture fixation in treatment of recurrent acute patellar dislocation with patellar osteochondral fractures]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2025 Jul 15;39(7):831-836.
    doi: 10.7507/1002-1892.202504009pubmed: 40659585google scholar: lookup
  3. Gomes Velasque Gama F, Casciani C, Dutra EH. FGF18 induces chondrogenesis and anti-osteoarthritic effects in a mouse model for TMJ degeneration. PLoS One 2025;20(4):e0317816.
    doi: 10.1371/journal.pone.0317816pubmed: 40273050google scholar: lookup
  4. Shanto PC, Park S, Fahad MAA, Park M, Lee BT. 3D bio-printed proteinaceous bioactive scaffold loaded with dual growth factor enhanced chondrogenesis and in situ cartilage regeneration. Bioact Mater 2025 Apr;46:365-385.
  5. Lane NE, Simon LS, Tambiah J. Slow acting medications for progressive and painful knee osteoarthritis. How do we assess the benefit to risk of these potentially novel therapies?. Osteoarthr Cartil Open 2025 Mar;7(1):100546.
    doi: 10.1016/j.ocarto.2024.100546pubmed: 39737142google scholar: lookup
  6. Chen M, Jiang Z, Zou X, You X, Cai Z, Huang J. Advancements in tissue engineering for articular cartilage regeneration. Heliyon 2024 Feb 15;10(3):e25400.
    doi: 10.1016/j.heliyon.2024.e25400pubmed: 38352769google scholar: lookup