Wharton's jelly MSC-derived extracellular vehicles—loaded hyaluronic acid-alginate adhesives for treatment of osteoarthritis

doi:10.1016/j.jmst.2022.09.061

Abstract

Abstract: The repair of cartilage injury caused by osteoarthritis (OA) has long plagued clinicians. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) show great potential in cartilage regeneration and immunoregulation to realise cell-free therapy. However, unprotected sEVs are prone to be washed away by the flow of fluids and degraded in vivo. In this work, we successfully revealed that human Wharton's jelly of umbilical cord-derived MSC (hWJMSC) sEVs promote proliferation, inhibit apoptosis, and attenuate the inflammation of chondrocytes in vitro. In light of the long period required for cartilage regeneration, we synthesised an injectable and adhesive aldehyded sodium alginate crosslinked acylhydrazide-modified hyaluronic acid (ALG-CHO/HHA) hydrogel loaded with sEVs to boost the reparative effect of the sEVs. The hydrogel-bearing sEVs was injected into cartilage defects where they adhered to the cartilage surface. In this configuration, the sEVs were delivered in a sustainable manner with the degradation of the hydrogel at the injury sites, thus contributing to highly efficient cartilage repair by regulating the regenerative and immune microenvironment. The ALG-CHO/HHA-sEV platform meets the clinical demand for long-lasting repair with a single injection. Thus, this work provides a new idea and theoretical basis for the clinical application of sEVs in the treatment of OA.

Key words: Extracellular vesicles, Hydrogel, Osteoarthritis, Cartilage regeneration

Yanhong Zhao, Xige Zhao, Hainan Xu, Yi Xing, Tengling Wu, Xun Sun, Mingjie Kuang, Xinlong Ma, Wenguang Liu, Qiang Yang. Wharton's jelly MSC-derived extracellular vehicles—loaded hyaluronic acid-alginate adhesives for treatment of osteoarthritis[J]. J. Mater. Sci. Technol., 2023, 142: 240-252.

References

[1] J. Martel-Pelletier, A.J. Barr, F.M. Cicuttini, P.G. Conaghan, C. Cooper, M.B. Goldring, S.R. Goldring, G. Jones, A.J. Teichtahl, J.P. Pelletier, Nat. Rev. Dis. Primers 2 (2016) 16072.
[2] X. Wu, H. Cao, G. Xiao, Osteoarthritis Cartilage 29 (2021) S4.
[3] G.C. Gracitelli, V.Y. Moraes, C.E. Franciozi, M.V. Luzo, J.C. Belloti, Cochrane Database Syst. Rev. 9 (2016) CD010675.
[4] A. Nixon, H. Sparks, L. Begum, S. McDonough, M. Scimeca, N. Moran, G. Matthews, J. Bone Joint Surg.-Am. 99(2017) 1987-1998.
[5] V. Molnar, E. Pavelić, K. Vrdoljak, M. Čemerin, E. Klarić, V. Matišić, R. Bjel-ica, P. Brlek, I. Kovačić, C. Tremolada, D. Primorac, Genes (Basel) 13(2022) 949.
[6] N. Song, M. Scholtemeijer, K. Shah, Trends Pharmacol. Sci. 41(2020) 653-664.
[7] L. Reppel, J. Schiavi, N. Charif, L. Leger, H. Yu, A. Pinzano, C. Henrionnet, J. Stoltz, D. Bensoussan, C. Huselstein, Stem Cell Res. Ther. 6(2015) 260.
[8] S. Mohamed-Ahmed, I. Fristad, S. Lie, S. Suliman, K. Mustafa, H. Vindenes, S. Idris, Stem Cell Res. Ther. 9(2018) 168.
[9] M. Wang, C.G. Wang, M. Chen, Y.W. Xi, W. Cheng, C. Mao, T.Z. Xu, X.X. Zhang, C. Lin, W.Y. Gao, Y. Guo, B. Lei, ACS Nano 13 (2019) 10279-10293.
[10] Z.G. Zhang, B. Buller, M. Chopp, Nat. Rev. Nephrol. 15(2019) 193-203.
[11] N. Bakhtyar, M. Jeschke, E. Herer, M. Sheikholeslam, S. Amini-Nik, Stem Cell Res. Ther. 9(2018) 193.
[12] M.J. Kuang, Y. Huang, X.G. Zhao, R. Zhang, J.X. Ma, D.C. Wang, X.L. Ma, Int. J. Biol. Sci. 15(2019) 1861-1871.
[13] G. Thomi, D. Surbek, V. Haesler, M. Joerger-Messerli, A. Schoeberlein, Stem Cell Res. Ther. 10(2019) 105.
[14] K. Shen, A. Duan, J.Q. Cheng, T. Yuan, J.C. Zhou, H.H. Song, Z.F. Chen, B. Wan, J.X. Liu, X. Zhang, Y. Zhang, R. Xie, F. Liu, W.M. Fan, Q. Zuo, Acta Biomater. 143(2022) 173-188.
[15] H.X. Hu, L.L. Dong, Z.H. Bu, Y.F. Shen, J. Luo, H. Zhang, S.C. Zhao, F. Lv, Z.T. Liu, J. Extracell. Vesicles 9 (2020) 1778883.
[16] P.F. Guan, C. Liu, D.H. Xie, S.C. Mao, Y.L. Ji, Y.C. Lin, Z. Chen, Q.Y. Wang, L. Fan, Y.J. Sun, Bioact. Mater. 10(2022) 145-158.
[17] S.P. Zhang, K.Y.M. Teo, S.J. Chuah, R.C. Lai, S.K. Lim, W.S. Toh, Biomaterials 200 (2019) 35-47.
[18] S. Yang, B. Zhu, P. Yin, L.S. Zhao, Y.Z. Wang, Z.G. Fu, R.J. Dang, J. Xu, J.J. Zhang, N. Wen, ACS Biomater. Sci. Eng. 6(2020) 1590-1602.
[19] O. Jeznach, D. Kołbuk, P. Sajkiewicz, J. Biomed. Mater. Res. Part A 106 (2018) 2762-2776.
[20] H.R. Jia, X. Lin, D. Wang, J.W. Wang, Q.L. Shang, X. He, K. Wu, B.Y. Zhao, P.D. Peng, H. Wang, D. Wang, P. Li, L. Yang, Z.J. Luo, L. Yang, J. Orthop. Transl. 33(2022) 162-173.
[21] G. Prestwich, J. Control. Release 155 (2011) 193-199.
[22] I. Bayer, Molecules 25 (2020) 2649.
[23] S. Reakasame, A. Boccaccini, Biomacromolecules 19 (2018) 3-21.
[24] W. Wei, Y.Z. Ma, X.D. Yao, W.Y. Zhou, X.Z. Wang, C.L. Li, J.X. Lin, Q.L. He, S. Lep-tihn, H.W. Ouyang, Bioact. Mater. 6(2021) 998-1011.
[25] T.L. Wu, C.Y. Cui, Y.T. Huang, Y. Liu, C.C. Fan, X.X. Han, Y. Yang, Z.Y. Xu, B. Liu, G.W. Fan, W.G. Liu, ACS Appl. Mater. Interfaces 12 (2020) 2039-2048.
[26] W. Liang, J.R. Chen, L.Y. Li, M. Li, X.J. Wei, B.Y. Tan, Y.Y. Shang, G.W. Fan, W. Wang, W.G. Liu, ACS Appl. Mater. Interfaces 11 (2019) 14619-14629.
[27] T. Su, Y.Z. Xiao, Y. Xiao, Q. Guo, C.J. Li, Y. Huang, Q.F. Deng, J.X. Wen, F.L. Zhou, X.H. Luo, ACS Nano 13 (2019) 2450-2462.
[28] J.Y. Park, H.C. Bae, S.H. Pyo, M.C. Lee, H.S. Han, Tissue Eng. Regen. Med. 18(2021) 831-840.
[29] L.H. Chang, S.C. Wu, C.H. Chen, G.J. Wang, J.K. Chang, M.L.Ho, Toxicology(2016) 116-128.
[30] C. Shen, G.Q. Cai, J.P. Peng, X.D. Chen, Osteoarthritis Cartilage 23 (2015) 2279-2287.
[31] L. Chen, J.J.Y.Zheng, G.Y. Li, J. Yuan, J.R. Ebert, H.Y. Li, J. Papadimitriou, Q.W. Wang, D. Wood, C.W. Jones, M.H. Zheng, J. Orthop. Transl. 24(2020) 66-75.
[32] L.P. Tong, H. Yu, X.Y. Huang, J. Shen, G.Z. Xiao, L. Chen, H.Y. Wang, L.P. Xing, D. Chen, Bone Res. 10(2022) 60.
[33] P.L. Wu, Y.Y. Liang, G.M. Sun, Biomater. Transl. 2(2021) 61-71.
[34] S.P. Yu, D.J. Hunter, Expert Opin. Pharmacother. 17(2016) 2057-2071.
[35] H. Hwang, H. Kim, Int. J. Mol. Sci. 16(2015) 26035-26054.
[36] P. Singh, K.B. Marcu, M.B. Goldring, M. Otero, Ann. N.Y. Acad. Sci. 1442(2019) 17-34.
[37] C.R. Liao, S.N. Wang, S.Y. Zhu, Y.Q. Wang, Z.Z. Li, Z.Y. Liu, W.S. Jiang, J.T. Chen, Q. Wu, Redox Biol. 28(2020) 101306.
[38] Y.W. Jia, W. He, H.X. Zhang, L. He, Y.B. Wang, T. Zhang, J.X. Peng, P. Sun, Y. Qian, Drug Des, Dev. Ther. 14(2020) 1227-1240.
[39] A. Steensberg, C. Fischer, C. Keller, K. Møller, B. Pedersen, Am. J. Phys-iol.-Endocrinol. Metab. 285(2003) E433-E437.
[40] L. Vonk, S. van Dooremalen, N. Liv, J. Klumperman, P. Coffer, D. Saris, M. Lorenowicz, Theranostics 8 (2018) 906-920.
[41] J.L. Fei, B. Liang, C.Z. Jiang, H.F. Ni, L.M. Wang, Biomed. Pharmacother. 109(2019) 1586-1592.
[42] J. Mengshol, M. Vincenti, C. Coon, A. Barchowsky, C. Brinckerhoff, Arthritis Rheum. 43(20 0 0) 801-811.
[43] Q. Wei, S.H. Wang, F. Han, H. Wang, W.D. Zhang, Q.F. Yu, C.J. Liu, L.G. Ding, J.Y. Wang, L.L. Yu, C.H. Zhu, B. Li, Biomater. Transl. 2(2021) 323-342.
[44] Q.C. Hu, M. Ecker, Int. J. Mol. Sci. 22(2021) 1742.
[45] Z. Jin, J.A. Ren, S.L. Qi, Cell Tissue Res. 381(2020) 99-114.
[46] M. Tofiño-Vian, M. Guillén, M. Pérez Del Caz, A.Silvestre, M. Alcaraz, Cell. Physiol. Biochem. 47(2018) 11-25.
[47] L. He, T.W. He, J.H. Xing, Q. Zhou, L. Fan, C. Liu, Y.Y. Chen, D.P. Wu, Z.M. Tian, B. Liu, L.M. Rong, Stem Cell Res. Ther. 11(2020) 276.
[48] C. Hoemann, J. Sun, A. Légaré, M. McKee, M. Buschmann, Osteoarthritis Carti-lage 13 (2005) 318-329.
[49] I.C. Liao, F.T. Moutos, B.T. Estes, X.H. Zhao, F. Guilak, Adv. Funct. Mater. 23(2013) 5833-5839.
[50] K.L. Spiller, S.A. Maher, A.M. Lowman, Tissue Eng. Part B-Rev. 17(2011) 281-299.
[51] J. Liu, J. Li, F. Yu, Y. Zhao, X.M. Mo, J.F. Pan, Int. J. Biol. Macromol. 147(2020) 653-666.
[52] S. Kamekura, K. Hoshi, T. Shimoaka, U. Chung, H. Chikuda, T. Yamada, M. Uchida, N. Ogata, A. Seichi, K. Nakamura, H. Kawaguchi, Osteoarthritis Car-tilage 13 (2005) 632-641.