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BMC veterinary research2026; doi: 10.1186/s12917-026-05368-0

Long term safety and efficacy of a functionalized nanogel with endothelin-1 and bradykinin receptor antagonist peptides for treatment of osteoarthritis of the metacarpophalangeal and distal interphalangeal joints in horses: a descriptive clinical pilot study.

Abstract: Intra-articular drug delivery systems (DDS) are emerging as promising therapies for osteoarthritis (OA), yet their efficacy in spontaneous clinical cases remains largely untested. This uncontrolled, descriptive pilot study was designed to provide a proof of concept for the feasibility, safety, and preliminary clinical effects of intra-articular administration in sport horses with naturally occurring OA. The study involved a peptide-functionalized nanogel composed of chitosan and hyaluronic acid, delivering endothelin type A (BQ-123) and bradykinin B1 (R-954) receptor antagonists, which have previously demonstrated anti-inflammatory and chondroprotective properties in preclinical models. Results: Eight client-owned sport horses with moderate OA of the metacarpophalangeal (MCPJ) or distal interphalangeal joint (DIPJ) received a single intra-articular injection of 2.4 mL nanogel and were followed for 12 months. No major adverse events were observed. Two horses developed mild, transient joint swelling that resolved within three days. Seven of eight horses showed improvement in lameness scores by week 12, although complete resolution on hard ground circles was observed in only two horses. All horses were sound on soft ground and returned to competition, with a median time of 128 days post-treatment. Six horses remained in active competition at one year without additional intervention. Four horses (50%) met the predefined primary outcome of return to the same level and frequency of competition as before lameness onset. Horses treated for DIPJ OA and those showing radiographic joint space narrowing were overrepresented among treatment failures. Conclusions: Intra-articular administration of a peptide-functionalized nanogel was feasible and well tolerated in sport horses with naturally occurring OA and was associated with partial but prolonged clinical improvement. Although only half of the horses achieved full return to pre-lameness performance, most showed sustained clinical benefit without additional treatment over one year. These findings support further investigation of this drug delivery system in larger, randomized controlled trials to better define its therapeutic efficacy and optimal indications.
Publication Date: 2026-03-03 PubMed ID: 41776496DOI: 10.1186/s12917-026-05368-0Google Scholar: Lookup
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APA
Terlinden A, Jacquet S, Manivong S, Coudry V, Tallaj A, Cullier A, Legendre F, Garcia AA, Moldovan F, Sirois P, Banquy X, Galéra P, Audigié F, Roullin G, Demoor M, Bertoni L. (2026). Long term safety and efficacy of a functionalized nanogel with endothelin-1 and bradykinin receptor antagonist peptides for treatment of osteoarthritis of the metacarpophalangeal and distal interphalangeal joints in horses: a descriptive clinical pilot study. BMC Vet Res. https://doi.org/10.1186/s12917-026-05368-0

Publication

ISSN: 1746-6148
NlmUniqueID: 101249759
Country: England
Language: English

Researcher Affiliations

Terlinden, Antoinette
  • Ecole Nationale Vétérinaire d'Alfort, ACAP3, Goustranville, F-14430, France.
  • Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94700, France.
Jacquet, Sandrine
  • Ecole Nationale Vétérinaire d'Alfort, ACAP3, Goustranville, F-14430, France.
  • Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94700, France.
Manivong, Seng
  • Centre Hospitalier Universitaire Sainte Justine, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
  • Faculty of Dentistry, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
  • Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
Coudry, Virginie
  • Ecole Nationale Vétérinaire d'Alfort, ACAP3, Goustranville, F-14430, France.
  • Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94700, France.
Tallaj, Amelie
  • Ecole Nationale Vétérinaire d'Alfort, ACAP3, Goustranville, F-14430, France.
  • Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94700, France.
Cullier, Aurélie
  • Université Caen Normandie, Normandie Univ, BIOTARGEN UR7450, Normandie Equine Vallée, GIS CENTAURE, Caen, F-14000, France.
Legendre, Florence
  • Université Caen Normandie, Normandie Univ, BIOTARGEN UR7450, Normandie Equine Vallée, GIS CENTAURE, Caen, F-14000, France.
Garcia, Araceli Ac
  • Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
  • TransMedTech Institute (NanoBio Technology Platform), Montréal, QC, H3T 1J4, Canada.
Moldovan, Florina
  • Centre Hospitalier Universitaire Sainte Justine, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
  • Faculty of Dentistry, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
Sirois, Pierre
  • Faculty of Medicine, Université Laval, Quebec City, QC, G1V 4G2, Canada.
Banquy, Xavier
  • Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
Galéra, Philippe
  • Université Caen Normandie, Normandie Univ, BIOTARGEN UR7450, Normandie Equine Vallée, GIS CENTAURE, Caen, F-14000, France.
Audigié, Fabrice
  • Ecole Nationale Vétérinaire d'Alfort, ACAP3, Goustranville, F-14430, France.
  • Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94700, France.
Roullin, Gaëlle
  • Faculty of Pharmacy, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
Demoor, Magali
  • Université Caen Normandie, Normandie Univ, BIOTARGEN UR7450, Normandie Equine Vallée, GIS CENTAURE, Caen, F-14000, France.
Bertoni, Lélia
  • Ecole Nationale Vétérinaire d'Alfort, ACAP3, Goustranville, F-14430, France. lelia.bertoni@vet-alfort.fr.
  • Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, 94700, France. lelia.bertoni@vet-alfort.fr.

Grant Funding

  • ESF 2014-2020 / Operational Program ERDF (European Regional Development Funds)/ESF 2014-2020 and by an ERDF and Regional Council of Normandie (France) grant in the CPER Centaure program (2014-2020)
  • Ph.D. scholarship / Arthritis Society
  • Ph.D. scholarship / Institut TransMedTech
  • Ph.D. scholarship CARTnGEL project / Région Normandie
  • FQR-NT (2018-PR-205644) and CIHR grants (#186079 and #189175) / Canadian funding

Conflict of Interest Statement

Declarations. Ethics approval and consent to participate: The study protocol was approved by the ComERC/ENVA Ethical Committee (Permit No. 2022–01–11–1) and written informed consent was obtained from all owners prior to inclusion. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

References

This article includes 67 references
  1. Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072.
  2. Oke SL, McIlwraith CW. Review of the economic impact of osteoarthritis and oral joint-health supplements in horses. Proc Am Assoc Equine Pract. 2010;56:12–6.
  3. McIlwraith CW, Frisbie DD, Kawcak CE. The horse as a model of naturally occurring osteoarthritis. Bone Joint Res. 2012;1(11):297–309.
  4. Contino EK. Management and rehabilitation of joint disease in sport horses. Vet Clin North Am Equine Pract. 2018;34(2):345–58.
  5. Knott LE, Fonseca-Martinez BA, O’Connor AM, Goodrich LR, McIlwraith CW, Colbath AC. Current use of biologic therapies for musculoskeletal disease: a survey of board-certified equine specialists. Vet Surg. 2022;51(4):557–67.
  6. Katz JN, Neogi T, Callahan LF, Block JA, Conaghan PG, Simon LS, et al. Disease modification in osteoarthritis: pathways to drug approval. Osteoarthritis Cartilage Open. 2020;2(2):100059.
  7. Oo WM, Little C, Duong V, Hunter DJ. The development of disease-modifying therapies for osteoarthritis (DMOADs): the evidence to date. Drug Des Devel Ther. 2021;15:2921–45.
  8. Jacobs CC, Schnabel LV, McIlwraith CW, Blikslager AT. Non-steroidal anti-inflammatory drugs in equine orthopaedics. Equine Vet J. 2022;54(4):636–48.
  9. De Falco L, Fioravanti A, Galeazzi M, Tenti S. Bradykinin and its role in osteoarthritis. Reumatismo. 2013;65(3):97–104.
  10. Kaufman GN, Zaouter C, Valteau B, Sirois P, Moldovan F. Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis. Arthritis Res Ther. 2011;13(3):R76.
  11. Manivong S, Ac Garcia A, Mahrouche L, Guerra F, Séguy L, Sirois P, et al. Peptide-grafted nanogels for sustained endothelin and bradykinin blockade in osteoarthritis. Int J Pharm. 2025;667:126089.
  12. DeJulius CR, Gulati S, Hasty KA, Crofford LJ, Duvall CL. Recent advances in clinical translation of intra-articular osteoarthritis drug delivery systems. Adv Ther. 2021;4(1):2000088.
  13. Zhang S, Xing M, Li B. Recent advances in musculoskeletal local drug delivery. Acta Biomater. 2019;93:135–51.
  14. Manivong S, Cullier A, Audigié F, Banquy X, Moldovan F, Demoor M, et al. New trends for osteoarthritis: biomaterials, models and modeling. Drug Discov Today. 2023;28(3):103488.
  15. Lu KY, Lin YC, Lu HT, Ho YC, Weng SC, Tsai ML, et al. A novel injectable in situ forming gel based on carboxymethyl hexanoyl chitosan/hyaluronic acid polymer blending for sustained release of berberine. Carbohydr Polym. 2019;206:664–73.
  16. Manivong S, Garcia Ac A, Patten SA, Fernandes JC, Benderdour M, Banquy X, et al. Chitosan-based nanogels: synthesis and toxicity profile for drug delivery to articular joints. Nanomaterials (Basel). 2022;12(8):1337.
  17. Kaderli S, Boulocher C, Pillet E, Watrelot-Virieux D, Rougemont AL, Roger T, et al. A novel biocompatible hyaluronic acid–chitosan hybrid hydrogel for osteoarthrosis therapy. Int J Pharm. 2015;483(1–2):158–68.
  18. Demoor M, Ollitrault D, Gomez-Leduc T, Bouyoucef M, Hervieu M, Fabre H, et al. Cartilage tissue engineering: molecular control of chondrocyte differentiation for proper cartilage matrix reconstruction. Biochim Biophys Acta. 2014;1840(8):2414–40.
  19. Zhang L, Hu J, Athanasiou KA. The role of tissue engineering in articular cartilage repair and regeneration. Crit Rev Biomed Eng. 2009;37(1–2):1–57.
  20. Yang J, Zhang YS, Yue K, Khademhosseini A. Cell-laden hydrogels for osteochondral and cartilage tissue engineering. Acta Biomater. 2017;57:1–25.
  21. Cullier A, Cassé F, Manivong S, Contentin R, Legendre F, Garcia Ac A, et al. Functionalized nanogels with endothelin-1 and bradykinin receptor antagonist peptides decrease inflammatory and cartilage degradation markers of osteoarthritis in a horse organoid model of cartilage. Int J Mol Sci. 2022;23(16):8949.
  22. Terlinden A, Jacquet S, Manivong S, Cullier A, Cassé F, Legendre F, et al. Double-blinded randomized tolerance study of a biologically enhanced nanogel with endothelin-1 and bradykinin receptor antagonist peptides via intra-articular injection for osteoarthritis treatment in horses. BMC Vet Res. 2024;20:547.
  23. Mayet A, Zablotski Y, Roth SP, Brehm W, Troillet A. Systematic review and meta-analysis of positive long-term effects after intra-articular administration of orthobiologic therapeutics in horses with naturally occurring osteoarthritis. Front Vet Sci. 2023;10:1125695.
  24. da Silva Xavier AA, da Rosa PP, de Brum Mackmill L, Roll VFB. Effectiveness of hyaluronic acid and polyacrylamide hydrogel in horses with osteoarthritis: systematic review and network meta-analysis. Res Vet Sci. 2021;134:42–50.
  25. Bliddal H, Beier J, Hartkopp A, Conaghan PG, Henriksen M. Polyacrylamide gel versus hyaluronic acid for the treatment of knee osteoarthritis: a randomized controlled study. Clin Exp Rheumatol. 2024;42(9):1729–35.
  26. Tnibar A, Persson AB, Jensen HE. Mechanisms of action of an intraarticular 2.5% polyacrylamide hydrogel (Arthramid Vet) in a goat model of osteoarthritis: preliminary observations. J Biomed Eng. 2017;3(3):1022.
  27. Tnibar A, Schougaard H, Camitz L, Rasmussen J, Koene M, Jahn W, et al. Efficacy of intra-articular polyacrylamide hydrogel in horses with osteoarthritis: a 24-month follow-up. Acta Vet Scand. 2015;57:20.
  28. Broeckx SY, Seys B, Suls M, Vandenberghe A, Mariën T, Adriaensen E, et al. Equine allogeneic chondrogenic induced mesenchymal stem cells are an effective treatment for degenerative joint disease in horses. Stem Cells Dev. 2019;28(6):410–22.
  29. Magri C, Schramme M, Febre M, Cauvin E, Labadie F, Saulnier N, et al. Single versus repeated intra-articular injection of allogeneic neonatal mesenchymal stem cells for osteoarthritis in horses: a pilot study. PLoS ONE. 2019;14(8):e0219761.
  30. Pichereau F, Décory M, Ramos GC. Autologous platelet concentrate for refractory fetlock osteoarthritis in horses. J Equine Vet Sci. 2014;34(4):489–93.
  31. Bembo F, Eraud J, Philandrianos C, Bertrand B, Silvestre A, Veran J, et al. Combined platelet-rich plasma and micro-fat therapy in sport and race horses with degenerative joint disease. Muscles Ligaments Tendons J. 2016;6(2):198–204.
  32. Warner K, Schulze T, Lischer CJ. Treatment of osteoarthritis with ACS (IRAP®) in 26 horses: a retrospective study. Pferdeheilkunde. 2016;32:241–8.
  33. Fürst A, Veith G, Eisenreich J. GOLDIC® technique versus corticosteroid and hyaluronic acid injections for arthrogenic lameness in horses. Pferdeheilkunde. 2020;36(3):196–204.
  34. Rhodin M, Roepstorff L, French A, Keegan KG, Pfau T, Egenvall A. Head and pelvic movement asymmetry during lungeing in horses with symmetrical movement on the straight. Equine Vet J. 2016;48(3):315–20.
  35. Zetterberg E, Persson-Sjodin E, Lundblad J, Hernlund E, Rhodin M. Prevalence of movement asymmetries in high-performing riding horses perceived as free from lameness. PLoS ONE. 2024;19(7):e0308061.
  36. Dyson S, Greve L. Subjective gait assessment of 57 sports horses in normal work. J Equine Vet Sci. 2016;38:1–7.
  37. Mallen CD, Peat G, Thomas E, Lacey R, Croft P. Predicting poor functional outcome in older adults with knee pain. Ann Rheum Dis. 2007;66(11):1456–61.
  38. Rovel T, Audigié F, Coudry V, Jacquet-Guibon S, Bertoni L, Denoix JM. Standing low-field MRI for diagnosis of advanced distal interphalangeal joint osteoarthritis in horses. J Am Vet Med Assoc. 2019;254(2):257–65.
  39. Kawcak CE, Frisbie DD, Werpy NM, Park RD, McIlwraith CW. Effects of exercise versus experimental osteoarthritis on imaging outcomes. Osteoarthritis Cartilage. 2008;16(12):1519–25.
  40. Olive J, D’Anjou MA, Alexander K, Laverty S, Théoret C. Comparison of magnetic resonance imaging, computed tomography and radiography for assessment of non-cartilaginous changes in equine metacarpophalangeal osteoarthritis. Vet Radiol Ultrasound. 2010;51(3):267–79.
  41. Maninchedda U, Lepage OM, Gangl M, Hilairet S, Remandet B, Meot F, et al. Development of an equine groove model to induce metacarpophalangeal osteoarthritis: a pilot study on six horses. PLoS ONE. 2015;10(2):e0115089.
  42. Bertoni L, Jacquet-Guibon S, Branly T, Legendre F, Desancé M, Mespoulhes C, et al. An experimentally induced osteoarthritis model in horses performed on both metacarpophalangeal and metatarsophalangeal joints. PLoS ONE. 2020;15(6):e0235251.
  43. Suarez Sanchez-Andrade J, Richter H, Kuhn K, Bischofberger AS, Kircher PR, Hoey S. Comparison between magnetic resonance imaging, computed tomography, and arthrography to identify artificially induced cartilage defects of the equine carpal joints. Vet Radiol Ultrasound. 2018;59(3):312–25.
  44. Nagy A, Dyson SJ. Combined standing low-field magnetic resonance imaging and fan-beam computed tomographic diagnosis of fetlock region pain in sports horses. Equine Vet J. 2025;57(5):1313-27.
  45. Mathiessen A, Haugen IK, Slatkowsky-Christensen B, Bøyesen P, Kvien TK, Hammer HB. Ultrasonographic assessment of osteophytes in hand osteoarthritis: reliability and associations with MRI, radiographs and clinical findings. Ann Rheum Dis. 2013;72(1):51–6.
  46. Schumacher J, Steiger R, Schumacher J, De Graves F, Schramme M, Smith R, et al. Effects of analgesia of the distal interphalangeal joint or palmar digital nerves on lameness caused by solar pain in horses. Vet Surg. 2000;29(1):54–8.
  47. Wise BL, Seidel MF, Lane NE. The evolution of nerve growth factor inhibition in clinical medicine. Nat Rev Rheumatol. 2021;17(1):34–46.
  48. van Weeren PR. General anatomy and physiology of joints. In: McIlwraith CW, Frisbie DD, Kawcak CE, editors. Joint disease in the horse. Philadelphia: Elsevier; 2016. p. 1–24.
  49. Sun Y, Ding SL, Zhao X, Sun D, Yang Y, Chen M, et al. Self-reinforced MOF-based nanogel alleviates osteoarthritis by long-acting drug release. Adv Mater. 2024;36:e2401094.
  50. Tu C, Gao X, Zheng H, Huang R, Yang F, Dong Y, et al. Injectable self-healing exosome cross-linked biomimetic hydrogel for cartilage regeneration. J Control Release. 2025;381:113608.
  51. Hwang HS, Lee CS. Exosome-integrated hydrogels for bone tissue engineering. Gels. 2024;10(12):762.
  52. Wan J, He Z, Peng R, Wu X, Zhu Z, Cui J, et al. Injectable photocrosslinking spherical hydrogel-encapsulated targeting peptide-modified engineered exosomes for osteoarthritis therapy. J Nanobiotechnology. 2023;21(1):284.
  53. US Food and Drug Administration. Osteoarthritis: structural endpoints for the development of drugs, devices, and biological products for treatment—guidance for industry. 2018.
  54. Gómez Álvarez CB, Oosterlinck M. The ongoing quest for a validated, universally accepted visual lameness grading scale. Equine Vet J. 2023;55(1):5–8.
  55. Dyson S. Can lameness be graded reliably? Equine Vet J. 2011;43(4):379–82.
  56. Keegan KG, Wilson DA, Kramer J, Reed SK, Yonezawa Y, Maki H, et al. Comparison of a body-mounted inertial sensor system with subjective evaluation for detection of lameness in horses. Am J Vet Res. 2013;74(1):17–24.
  57. McCracken MJ, Kramer J, Keegan KG, Lopes M, Wilson DA, Reed SK, et al. Comparison of an inertial sensor system of lameness quantification with subjective lameness evaluation. Equine Vet J. 2012;44(6):652–6.
  58. Pfau T, Stubbs NC, Kaiser LJ, Brown LEA, Clayton HM. Effect of trotting speed and circle radius on movement symmetry in horses during lunging. Am J Vet Res. 2012;73(12):1890–9.
  59. Greve L, Dyson SJ. The interrelationship of lameness, saddle slip and back shape in sports horses. Equine Vet J. 2014;46(6):687–94.
  60. American Association of Equine Practitioners. Guide for veterinary service and judging of equestrian events. Lexington: AAEP; 1991. p. 19.
  61. Dupays AG, Coudry V, Denoix JM. Ultrasonographic examination of the dorsal aspect of the distal interphalangeal joint of the horse. Equine Vet Educ. 2012;24(1):38–44.
  62. Denoix JM, Bertoni L, Heitzmann AG, Werpy N, Audigié F. Ultrasonographic examination of the collateral ligaments of the distal interphalangeal joint in horses. Part A: technique and normal images. Equine Vet Educ. 2011;23(11):574–80.
  63. Seignour M, Pasquet H, Coudry V, Denoix JM. Ultrasonographic diagnosis of injuries to the deep digital flexor tendon and associated structures in the equine foot. Equine Vet Educ. 2011;23(7):369–76.
  64. Denoix JM, Jacot S, Bousseau B, Perrot P. Ultrasonographic anatomy of the dorsal and abaxial aspects of the equine fetlock. Equine Vet J. 1996;28(1):54–62.
  65. Denoix JM. Ultrasound examination of joints and miscellaneous tendons. In: Rantanen NW, McKinnon AO, editors. Equine diagnostic ultrasonography. Baltimore: Williams & Wilkins; 1998. p. 475–514.
  66. Bertoni L, Branly T, Jacquet-Guibon S, Desancé M, Desquilbet L, Rivory P, et al. Intra-articular injection of different dosages of autologous and allogeneic mesenchymal stem cells triggers variable inflammatory responses in the equine fetlock joint. Stem Cell Int. 2019;2019:1–17.
  67. Bertoni L, Jacquet-Guibon S, Branly T, Desancé M, Legendre F, Melin M, et al. Evaluation of allogeneic bone marrow-derived and umbilical cord blood-derived mesenchymal stem cells to prevent osteoarthritis development in an equine model. Int J Mol Sci. 2021;22(5):2499.

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