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A Stable Hydrogel Scaffold with Anti-Inflammatory Effects Treats Intervertebral Disc Degeneration

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Abstract

Intervertebral disc (IVD) degeneration (IDD) has become a global health issue; however, effective treatment remains undeveloped. Although the potential curative effect of resveratrol (Res) on IDD has been reported, the explosive release and rapid disappearance of Res in lesions seriously limit its use. In this study, Res was loaded into solid lipid nanoparticles (SLNs) by emulsification and cryogenic coagulation, and Res–SLNs/gelatin methacryloyl (GelMA) composite hydrogel scaffolds were designed by GelMA hydrogel encapsulation to improve the stability of therapeutic disc degeneration. In vitro studies demonstrated that Res–SLNs can inhibit nucleus pulposus (NP; major IVD cell) apoptosis by upregulating the expression of anabolic proteins. In vivo studies showed that the Res–SLNs/GelMA hydrogel scaffold improved the pinning-induced IDD model in rats and restored the stability of the IVD extracellular matrix (ECM). Our experiments consistently show that implantation of this scaffold can improve the inflammatory microenvironment, reduce the degeneration of NP cells, and reinforce the disc function repair effect. Therefore, the Res–SLNs/GelMA hydrogel scaffold has great application prospects for treating IDD.

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References

  1. Xu, P., Guan, J., Chen, Y., **ao, H., Yang, T., Sun, H., Wu, N., Zhang, C., & Mao, Y. (2021). Stiffness of photocrosslinkable gelatin hydrogel influences nucleus pulposus cell propertiesin vitro. Journal of Cellular and Molecular Medicine, 25(2), 880–891. https://doi.org/10.1111/jcmm.16141

    Article  Google Scholar 

  2. Carlesso, L. C., Raja Rampersaud, Y., & Davis, A. M. (2018). Clinical classes of injured workers with chronic low back pain: A latent class analysis with relationship to working status. European Spine Journal, 27(1), 117–124. https://doi.org/10.1007/s00586-017-4966-1

    Article  Google Scholar 

  3. Vaudreuil, N., Henrikson, K., Pohl, P., Lee, A., Lin, H., Olsen, A., Dong, Q., Dombrowski, M., Kang, J., Vo, N., et al. (2019). Photopolymerizable biogel scaffold seeded with mesenchymal stem cells: Safety and efficacy evaluation of novel treatment for intervertebral disc degeneration. Journal of Orthopaedic Research, 37(6), 1451–1459. https://doi.org/10.1002/jor.24208

    Article  Google Scholar 

  4. Colombier, P., Clouet, J., Hamel, O., Lescaudron, L., & Guicheux, J. (2014). The lumbar intervertebral disc: From embryonic development to degeneration. Joint Bone Spine, 81(2), 125–129. https://doi.org/10.1016/j.jbspin.2013.07.012

    Article  Google Scholar 

  5. Humzah, M. D., & Soames, R. W. (1988). Human intervertebral disc: structure and function. The Anatomical Record, 220(4), 337–356. https://doi.org/10.1002/ar.1092200402

    Article  Google Scholar 

  6. Boos, N., Weissbach, S., Rohrbach, H., Weiler, C., Spratt, K. F., & Nerlich, A. G. (2002). Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science. Spine (Phila Pa 1976), 27(23), 2631–2644. https://doi.org/10.1097/00007632-200212010-00002

    Article  Google Scholar 

  7. Li, X., Lin, F., Wu, Y., Liu, N., Wang, J., Chen, R., & Lu, Z. (2019). Resveratrol attenuates inflammation environment-induced nucleus pulposus cell senescence in vitro. Bioscience Reports, 39(5). https://doi.org/10.1042/BSR20190126

  8. Risbud, M. V., & Shapiro, I. M. (2014). Role of cytokines in intervertebral disc degeneration: Pain and disc content. Nature Reviews Rheumatology, 10(1), 44–56. https://doi.org/10.1038/nrrheum.2013.160

    Article  Google Scholar 

  9. Le Maitre, C. L., Hoyland, J. A., & Freemont, A. J. (2007). Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1beta and TNFalpha expression profile. Arthritis Research & Therapy, 9(4), R77. https://doi.org/10.1186/ar2275

    Article  Google Scholar 

  10. Chen, Z. H., **, S. H., Wang, M. Y., **, X. L., Lv, C., Deng, Y. F., & Wang, J. L. (2015). Enhanced NLRP3, caspase-1, and IL- 1beta levels in degenerate human intervertebral disc and their association with the grades of disc degeneration. The Anatomical Record, 298(4), 720–726. https://doi.org/10.1002/ar.23059

    Article  Google Scholar 

  11. Wang, Y., Che, M., **n, J., Zheng, Z., Li, J., & Zhang, S. (2020). The role of IL-1beta and TNF-alpha in intervertebral disc degeneration. Biomedicine & Pharmacotherapy, 131, 110660. https://doi.org/10.1016/j.biopha.2020.110660

    Article  Google Scholar 

  12. Genevay, S., Finckh, A., Mezin, F., Tessitore, E., & Guerne, P. A. (2009). Influence of cytokine inhibitors on concentration and activity of MMP-1 and MMP-3 in disc herniation. Arthritis Research & Therapy, 11(6), R169. https://doi.org/10.1186/ar2858

    Article  Google Scholar 

  13. Bhat, K. P. L., Kosmeder, J. W., 2nd, & Pezzuto, J. M. (2001). Biological effects of resveratrol. Antioxid Redox Signal, 3(6), 1041–1064. https://doi.org/10.1089/152308601317203567

    Article  Google Scholar 

  14. Wang, W., Li, P., Xu, J., Wu, X., Guo, Z., Fan, L., Song, R., Wang, J., Wei, L., & Teng, H. (2018). Resveratrol attenuates high glucose-induced nucleus pulposus cell apoptosis and senescence through activating the ROS-mediated PI3K/Akt pathway. Bioscience Reports, 38(2). https://doi.org/10.1042/BSR20171454

  15. Gao, J., Zhang, Q., & Song, L. (2018). Resveratrol enhances matrix biosynthesis of nucleus pulposus cells through activating autophagy via the PI3K/Akt pathway under oxidative damage. Bioscience Reports, 38(4). https://doi.org/10.1042/BSR20180544

  16. Li, K., Li, Y., Mi, J., Mao, L., Han, X., & Zhao, J. (2018). Resveratrol protects against sodium nitroprusside induced nucleus pulposus cell apoptosis by scavenging ROS. International Journal of Molecular Medicine, 41(5), 2485–2492. https://doi.org/10.3892/ijmm.2018.3461

    Article  Google Scholar 

  17. Han, X., Leng, X., Zhao, M., Wu, M., Chen, A., Hong, G., & Sun, P. (2017). Resveratrol increases nucleus pulposus matrix synthesis through activating the PI3K/Akt signaling pathway under mechanical compression in a disc organ culture. Bioscience Reports, 37(6). https://doi.org/10.1042/BSR20171319

  18. Li, X., Phillips, F. M., An, H. S., Ellman, M., Thonar, E. J., Wu, W., Park, D., & Im, H. J. (2008). The action of resveratrol, a phytoestrogen found in grapes, on the intervertebral disc. Spine (Phila Pa 1976), 33(24), 2586–2595. https://doi.org/10.1097/BRS.0b013e3181883883

    Article  Google Scholar 

  19. Shen, J., Zhuo, N., Xu, S., Song, Z., Hu, Z., Hao, J., & Guo, X. (2018). Resveratrol delivery by ultrasound-mediated nanobubbles targeting nucleus pulposus cells. Nanomedicine (Lond), 13(12), 1433–1446. https://doi.org/10.2217/nnm-2018-0019

    Article  Google Scholar 

  20. Rajpoot, K. (2019). Solid lipid nanoparticles: A promising nanomaterial in drug delivery. Current Pharmaceutical Design, 25(37), 3943–3959. https://doi.org/10.2174/1381612825666190903155321

    Article  Google Scholar 

  21. Souto, E. B., Doktorovova, S., Campos, J. R., Martins-Lopes, P., & Silva, A. M. (2019). Surface-tailored anti-HER2/neu-solid lipid nanoparticles for site-specific targeting MCF-7 and BT-474 breast cancer cells. European Journal of Pharmaceutical Sciences, 128, 27–35. https://doi.org/10.1016/j.ejps.2018.11.022

    Article  Google Scholar 

  22. Zhou, P., Yan, B., Wei, B., Fu, L., Wang, Y., Wang, W., Zhang, L., & Mao, Y. (2023). Quercetin-solid lipid nanoparticle-embedded hyaluronic acid functionalized hydrogel for immunomodulation to promote bone reconstruction. Regenerative Biomaterials, 10, rbad025. https://doi.org/10.1093/rb/rbad025

    Article  Google Scholar 

  23. Vijayakumar, A., Baskaran, R., Jang, Y. S., Oh, S. H., & Yoo, B. K. (2017). Quercetin-loaded solid lipid nanoparticle dispersion with improved physicochemical properties and cellular uptake. AAPS PharmSciTech, 18(3), 875–883. https://doi.org/10.1208/s12249-016-0573-4

    Article  Google Scholar 

  24. Xu, Y., Gu, Y., Cai, F., **, K., **n, T., Tang, J., Wu, L., Wang, Z., Wang, F., Deng, L., et al. (2020). Metabolism balance regulation via antagonist-functionalized injectable microsphere for nucleus pulposus regeneration. Advanced Functional Materials, 30(52), 2006333. https://doi.org/10.1002/adfm.202006333

    Article  Google Scholar 

  25. Celikkin, N., Mastrogiacomo, S., Jaroszewicz, J., Walboomers, X. F., & Swieszkowski, W. (2018). Gelatin methacrylate scaffold for bone tissue engineering: The influence of polymer concentration. Journal of Biomedical Materials Research Part A, 106(1), 201–209. https://doi.org/10.1002/jbm.a.36226

    Article  Google Scholar 

  26. Wei, B., Wang, W., Liu, X., Xu, C., Wang, Y., Wang, Z., Xu, J., Guan, J., Zhou, P., & Mao, Y. (2021). Gelatin methacrylate hydrogel scaffold carrying resveratrol-loaded solid lipid nanoparticles for enhancement of osteogenic differentiation of BMSCs and effective bone regeneration. Regenerative Biomaterials, 8(5), rbab044. https://doi.org/10.1093/rb/rbab044

    Article  Google Scholar 

  27. Zheng, Z., Chen, A., He, H., Chen, Y., Chen, J., Albashari, A. A., Li, J., Yin, J., He, Z., Wang, Q., et al. (2019). pH and enzyme dual-responsive release of hydrogen sulfide for disc degeneration therapy. Journal of Materials Chemistry B, 7(4), 611–618. https://doi.org/10.1039/c8tb02566e

    Article  Google Scholar 

  28. Gruber, H. E., Hoelscher, G. L., Ingram, J. A., Norton, H. J., & Hanley, E. N., Jr. (2013). Increased IL-17 expression in degenerated human discs and increased production in cultured annulus cells exposed to IL-1ss and TNF-alpha. Biotechnic & Histochemistry, 88(6), 302–310. https://doi.org/10.3109/10520295.2013.783235

    Article  Google Scholar 

  29. Song, Y., Wang, Z., Liu, L., Zhang, S., Zhang, H., & Qian, Y. (2020). 1,4-Dihydropyridine (DHP) suppresses against oxidative stress in nucleus pulposus via activating sirtuin-1. Biomedicine & Pharmacotherapy, 121, 109592. https://doi.org/10.1016/j.biopha.2019.109592

    Article  Google Scholar 

  30. Tao, H., Wu, Y., Li, H., Wang, C., Zhang, Y., Li, C., Wen, T., Wang, X., He, Q., Wang, D., et al. (2015). BMP7-based functionalized self-assembling peptides for nucleus pulposus tissue engineering. ACS Applied Materials & Interfaces, 7(31), 17076–17087. https://doi.org/10.1021/acsami.5b03605

    Article  Google Scholar 

  31. Mao, Y., Chen, Y., Li, W., Wang, Y., Qiu, J., Fu, Y., Guan, J., & Zhou, P. (2022). Physiology-inspired multilayer nanofibrous membranes modulating endogenous stem cell recruitment and osteo-differentiation for staged bone regeneration. Advanced Healthcare Materials, 11(21), e2201457. https://doi.org/10.1002/adhm.202201457

    Article  Google Scholar 

  32. Cabraja, M., Endres, M., Abbushi, A., Zenclussen, M., Blechschmidt, C., Lemke, A. J., Kroppenstedt, S., Kaps, C., & Woiciechowsky, C. (2013). Effect of degeneration on gene expression of chondrogenic and inflammatory marker genes of intervertebral disc cells: A preliminary study. Journal of Neurosurgical Sciences, 57(4), 307–316.

    Google Scholar 

  33. Setton, L. A., & Chen, J. (2006). Mechanobiology of the intervertebral disc and relevance to disc degeneration. Journal of Bone and Joint Surgery, 88(Suppl 2), 52–57. https://doi.org/10.2106/JBJS.F.00001

    Article  Google Scholar 

  34. **ao, S., Zhao, T., Wang, J., Wang, C., Du, J., Ying, L., Lin, J., Zhang, C., Hu, W., Wang, L., et al. (2019). Gelatin methacrylate (GelMA)-based hydrogels for cell transplantation: An effective strategy for tissue engineering. Stem Cell Reviews and Reports, 15(5), 664–679. https://doi.org/10.1007/s12015-019-09893-4

    Article  Google Scholar 

  35. Liu, C., Zhou, Y., Sun, M., Li, Q., Dong, L., Ma, L., Cheng, K., Weng, W., Yu, M., & Wang, H. (2017). Light-induced cell alignment and harvest for anisotropic cell sheet technology. ACS Applied Materials & Interfaces, 9(42), 36513–36524. https://doi.org/10.1021/acsami.7b07202

    Article  Google Scholar 

  36. Zhang, X., Li, J., Ye, P., Gao, G., Hubbell, K., & Cui, X. (2017). Coculture of mesenchymal stem cells and endothelial cells enhances host tissue integration and epidermis maturation through AKT activation in gelatin methacryloyl hydrogel-based skin model. Acta Biomaterialia, 59, 317–326. https://doi.org/10.1016/j.actbio.2017.07.001

    Article  Google Scholar 

  37. Liu, Y., Du, J., Peng, P., Cheng, R., Lin, J., Xu, C., Yang, H., Cui, W., Mao, H., Li, Y., et al. (2021). Regulation of the inflammatory cycle by a controllable release hydrogel for eliminating postoperative inflammation after discectomy. Bioactive Materials, 6(1), 146–157. https://doi.org/10.1016/j.bioactmat.2020.07.008

    Article  Google Scholar 

  38. Molinos, M., Almeida, C. R., Caldeira, J., Cunha, C., Goncalves, R. M., & Barbosa, M. A. (2015). Inflammation in intervertebral disc degeneration and regeneration. Journal of the Royal Society Interface, 12(104), 20141191. https://doi.org/10.1098/rsif.2014.1191

    Article  Google Scholar 

  39. Gluais, M., Clouet, J., Fusellier, M., Decante, C., Moraru, C., Dutilleul, M., Veziers, J., Lesoeur, J., Dumas, D., Abadie, J., et al. (2019). In vitro and in vivo evaluation of an electrospun-aligned microfibrous implant for Annulus fibrosus repair. Biomaterials, 205, 81–93. https://doi.org/10.1016/j.biomaterials.2019.03.010

    Article  Google Scholar 

  40. Dinarello, C. A. (2011). Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood, 117(14), 3720–3732. https://doi.org/10.1182/blood-2010-07-273417

    Article  Google Scholar 

  41. Li, P., Gan, Y., Xu, Y., Song, L., Wang, L., Ouyang, B., Zhang, C., & Zhou, Q. (2017). The inflammatory cytokine TNF-alpha promotes the premature senescence of rat nucleus pulposus cells via the PI3K/Akt signaling pathway. Scientific Reports, 7, 42938. https://doi.org/10.1038/srep42938

    Article  Google Scholar 

  42. Li, X. C., Wang, M. S., Liu, W., Zhong, C. F., Deng, G. B., Luo, S. J., & Huang, C. M. (2018). Co-culturing nucleus pulposus mesenchymal stem cells with notochordal cell-rich nucleus pulposus explants attenuates tumor necrosis factor-alpha-induced senescence. Stem Cell Research & Therapy, 9(1), 171. https://doi.org/10.1186/s13287-018-0919-9

    Article  Google Scholar 

  43. Han, F., Yu, Q., Chu, G., Li, J., Zhu, Z., Tu, Z., Liu, C., Zhang, W., Zhao, R., Mao, H., et al. (2022). Multifunctional nanofibrous scaffolds with angle-ply microstructure and co-delivery capacity promote partial repair and total replacement of intervertebral disc. Advanced Healthcare Materials, 11(19). https://doi.org/10.1002/adhm.202200895

  44. Walter, B. A., Korecki, C. L., Purmessur, D., Roughley, P. J., Michalek, A. J., & Iatridis, J. C. (2011). Complex loading affects intervertebral disc mechanics and biology. Osteoarthritis Cartilage, 19(8), 1011–1018. https://doi.org/10.1016/j.joca.2011.04.005

    Article  Google Scholar 

  45. Kwon, Y. J. (2013). Resveratrol has anabolic effects on disc degeneration in a rabbit model. Journal of Korean Medical Science, 28(6), 939–945. https://doi.org/10.3346/jkms.2013.28.6.939

    Article  Google Scholar 

  46. Li, Z., Zhang, Y., Zhao, Y., Gao, X., Zhu, Z., Mao, Y., & Qian, T. (2022). Graded-three-dimensional cell-encapsulating hydrogel as a potential biologic scaffold for disc tissue engineering. Tissue Engineering and Regenerative Medicine, 19(5), 1001–1012. https://doi.org/10.1007/s13770-022-00480-2

    Article  Google Scholar 

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Funding

This study was supported by grants from the 512 Talents Development Project of Bengbu Medical College (by51202302), the Opening Project of Anhui Province Key Laboratory of Tissue Trans-plantation in Bengbu Medical College (AHTT2022A001), the Domestic Visiting and Training Program for Outstanding Young Backbone Teachers in High Schools (gxgnfx2022036), and the Scientific Research Foundation of Bengbu Medical College (2021bypd006).

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Author notes

  1. Ying Wang and Yidi Xu contributed equally to this work.

Authors and Affiliations

  1. School of Life Sciences, Bengbu Medical College, 2600 Donghai Road, Bengbu, 233030, China

    Ying Wang, Yidi Xu, Shihui Zhang & Yingji Mao

  2. Department of Plastic Surgery and Department of Orthopaedics, First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, 233004, China

    Ying Wang, Yidi Xu & Shihui Zhang

  3. Anhui Province Key Laboratory of Tissue Transplantation, Bengbu Medical College, 2600 Donghai Road, Bengbu, 233030, China

    Yingji Mao

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Contributions

Ying Wang and Yidi Xu have equally contributed to the article. Conceptualization: Yingji Mao. Writing—original draft preparation: Ying Wang and Yidi Xu. Writing—review and editing: Yingji Mao. Data curation and methodology: Ying Wang, Yidi Xu, Shihui Zhang, and Yingji Mao. Funding acquisition: Yingji Mao. All authors read and approved the final manuscript.

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Correspondence to Yingji Mao.

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All rat feeding and experimental surgical operations were approved by the Animal Ethics Committee of the Bengbu Medical College following the NIH guidelines.

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Article Highlights

Intervertebral disc degeneration (IDD) has become a global health problem; however, effective treatment modalities are currently scarce. We designed a GelMA hydrogel as a carrier-encapsulated hydrogel scaffold for Res–SLNs and evaluated the role of this hydrogel (Res–SLNs/GelMA) in modulating the IL-1β-induced inflammatory microenvironment in vitro and restoring IVD function in vivo. Focusing on the treatment of IDD in the in vivo inflammatory environment brings a new therapeutic idea for IDD repair and a new application prospect for Res.

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Wang, Y., Xu, Y., Zhang, S. et al. A Stable Hydrogel Scaffold with Anti-Inflammatory Effects Treats Intervertebral Disc Degeneration. BioNanoSci. 13, 1150–1162 (2023). https://doi.org/10.1007/s12668-023-01150-w

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