Double-protein-loaded 3D-printed polyetheretherketone cage for promoting interbody fusion via osteogenic differentiation
Intervertebral disc degeneration (IDD) is a common condition characterized by age-related wear and tear of the spine. In advanced stages or severe cases of IDD, surgical treatment involving the implantation of an interbody cage is often the primary treatment approach. Polyetheretherketone (PEEK) has been widely used in orthopedic and spinal implants due to its remarkable mechanical properties, biocompatibility, and corrosion resistance. However, when used in interbody cages, PEEK exhibits poor processability and biological inertness, which are significant disadvantages that need to be addressed. In this work, we first fabricated the PEEK cage via the fused deposition modeling (FDM) method. To improve its fusion effect, bone morphogenetic protein 2 (BMP2) was loaded onto sulfonated PEEK and sealed with gelatin/chitosan (Gel/Chi) multilayer films. Substance P was then grafted on the surface with a Schiff base. When the cage is implanted, substance P is released first, recruiting bone marrow-mesenchymal stem cells (MSCs) to the implant surface. Subsequently, upon degradation of the Gel/Chi multilayer films, BMP2 is slowly released and promotes osteogenic differentiation of MSCs. In vivo results revealed that the double-protein-loaded PEEK cage exhibited remarkable fusion effects. This work provides a novel approach for the design and fabrication of a PEEK intervertebral fusion device with an excellent fusion effect.
- Song C, Hu P, Peng R, Li F, Fang Z, Xu Y. Bioenergetic dysfunction in the pathogenesis of intervertebral disc degeneration. Pharmacol Res. 2024;26:107119. doi: 10.1016/j.phrs.2024.107119
- Novais EJ, Narayanan R, Canseco JA, et al. A new perspective on intervertebral disc calcification-from bench to bedside. Bone Res. 2024;12(1):3. doi: 10.1038/s41413-023-00307-3
- Samanta A, Lufkin T, Kraus P. Intervertebral disc degeneration-current therapeutic options and challenges. Front Public Health. 2023;11:1156749. doi: 10.3389/fpubh.2023.1156749
- Tong W, Lu Z, Qin L, et al. Cell therapy for the degenerating intervertebral disc. Transl Res. 2017,181:49-58. doi: 10.1016/j.trsl.2016.11.008
- Kirnaz S, Capadona C, Wong T, et al. Fundamentals of intervertebral disc degeneration. World Neurosurg. 2022;157:264-273. doi: 10.1016/j.wneu.2021.09.066
- Xin J, Wang Y, Zheng Z, Wang S, Na S, Zhang S. Treatment of intervertebral disc degeneration. Orthop Surg. 2022;14(7):1271-1280. doi: 10.1111/os.13254
- Kos N, Gradisnik L, Velnar T. A brief review of the degenerative intervertebral disc disease. Med Arch. 2019;73(6):421-424. doi: 10.5455/medarh.2019.73.421-424
- Zhu C, He M, Mao L, et al. Titanium-interlayer mediated hydroxyapatite coating on polyetheretherketone: a prospective study in patients with single-level cervical degenerative disc disease. J Transl Med. 2021;19(1):14. doi: 10.1186/s12967-020-02688-z
- Kersten RF, van Gaalen SM, de Gast A, Öner FC. Polyetheretherketone (PEEK) cages in cervical applications: a systematic review. Spine J. 2015;15(6):1446-1460. doi: 10.1016/j.spinee.2013.08.030
- de Ruiter L, Rankin K, Browne M, Briscoe A, Janssen D, Verdonschot N. Decreased stress shielding with a PEEK femoral total knee prosthesis measured in validated computational models. J Biomech. 2021;118:110270. doi: 10.1016/j.jbiomech.2021.110270
- Zheng Z, Liu P, Zhang X, et al. Strategies to improve bioactive and antibacterial properties of polyetheretherketone (PEEK) for use as orthopedic implants. Mater Today Bio. 2022;16:100402. doi: 10.1016/j.mtbio.2022.100402
- Kurtz SM, Devine JN. PEEK biomaterials in trauma, orthopedic, and spinal implants. Biomaterials. 2007;28(32):4845-4869. doi: 10.1016/j.biomaterials.2007.07.013
- Li T, Song Z, Yang X, Du J. Influence of processing parameters on the mechanical properties of peek plates by hot compression molding. Materials (Basel). 2022;16(1):36. doi: 10.3390/ma16010036
- Yu D, Lei X, Zhu H. Modification of polyetheretherketone (PEEK) physical features to improve osteointegration. J Zhejiang Univ Sci B. 2022;23(3):189-203. doi: 10.1631/jzus.B2100622
- Zhang Z, Zhang X, Zheng Z, et al. Latest advances: improving the anti-inflammatory and immunomodulatory properties of PEEK materials. Mater Today Bio. 2023;22:100748. doi: 10.1016/j.mtbio.2023.100748
- Wang G, Han D, Cao Z, Guan H, Xuan T. Outcomes of autograft alone versus PEEK+ autograft interbody fusion in the treatment of adult lumbar isthmic spondylolisthesis. Clin Neurol Neurosurg. 2017;155:1-6. doi: 10.1016/j.clineuro.2017.01.020
- Wang L, Yang C, Sun C, et al. Fused deposition modeling PEEK implants for personalized surgical application: from clinical need to biofabrication. Int J Bioprint. 2022;8(4):615. doi: 10.18063/ijb.v8i4.615
- Wang Y, Müller WD, Rumjahn A, Schwitalla A. Parameters influencing the outcome of additive manufacturing of tiny medical devices based on PEEK. Materials (Basel). 2020;13(2):466. doi: 10.3390/ma13020466
- Rendas P, Figueiredo L, Machado C, Mourão A, Vidal C, Soares B. Mechanical performance and bioactivation of 3D-printed PEEK for high-performance implant manufacture: a review. Prog Biomater. 2023;12(2):89-111. doi: 10.1007/s40204-022-00214-6
- Florian B, Michel K, Steffi G, et al. MSC differentiation on two-photon polymerized, stiffness and BMP2 modified biological copolymers. Biomed Mater. 2019;14(3):035001. doi: 10.1088/1748-605X/ab0362
- Zhou N, Hu N, Liao JY, et al. HIF-1α as a regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral ossification in stem cells. Cell Physiol Biochem. 2015;36(1):44-60. doi: 10.1159/000374052
- Bedair TM, Lee CK, Kim DS, et al. Magnesium hydroxide-incorporated PLGA composite attenuates inflammation and promotes BMP2-induced bone formation in spinal fusion. J Tissue Eng. 2020;11:2041731420967591. doi: 10.1177/2041731420967591
- Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, Dana R. Neuropeptide substance P and the immune response. Cell Mol Life Sci. 2016;73(22):4249-4264. doi: 10.1007/s00018-016-2293-z
- Sun T, Jiang X, Wang Q, et al. Substance P mediated DGLs complexing with DACHPt for targeting therapy of Glioma. ACS Appl Mater Interfaces. 2017;9(40):34603-34617. doi: 10.1021/acsami.7b05997
- Zieglgänsberger W. Substance P and pain chronicity. Cell Tissue Res. 2019;375(1):227-241. doi: 10.1007/s00441-018-2922-y
- Kim S, Piao J, Son Y, Hong HS. Substance P enhances proliferation and paracrine potential of adipose-derived stem cells in vitro. Biochem Biophys Res Commun. 2017;485(1):131-137. doi: 10.1016/j.bbrc.2017.02.036
- Bhatia M. H₂S and substance P in inflammation. Methods Enzymol. 2015;555:195-205. doi: 10.1016/bs.mie.2014.11.024
- Hong HS, Kim S, Jin Y, Son Y. Substance P enhances the therapeutic effect of MSCs by modulating their angiogenic potential. J Cell Mol Med. 2020;24(21):12560-12571. doi: 10.1111/jcmm.15804
- Kim SJ, Kim JE, Choe G, et al. Self-assembled peptide-substance P hydrogels alleviate inflammation and ameliorate the cartilage regeneration in knee osteoarthritis. Biomater Res. 2023;27(1):40. doi: 10.1186/s40824-023-00387-6
- Mu C, Hu Y, Hou Y, et al. Substance P-embedded multilayer on titanium substrates promotes local osseointegration via MSC recruitment. J Mater Chem B. 2020;8(6):1212-1222. doi: 10.1039/c9tb01124b
- Huang L, Luo Z, Hu Y, et al. Enhancement of local bone remodeling in osteoporotic rabbits by biomimic multilayered structures on Ti6Al4V implants. J Biomed Mater Res A. 2016;104(6):1437-1451. doi: 10.1002/jbm.a.35667
- Beierfuß A, Dietrich H, Kremser C, et al. Knockout of Apolipoprotein E in rabbit promotes premature intervertebral disc degeneration: a new in vivo model for therapeutic approaches of spinal disc disorders. PLoS One. 2017;12(11):e0187564. doi: 10.1371/journal.pone.0187564
- Pan M, Li Q, Li S, et al. Percutaneous endoscopic lumbar discectomy: indications and complications. Pain Physician. 2020; 23(1):49-56. doi: 10.36076/ppj.2020/23/49
- Perera K, Ivone R, Natekin E, Wilga CA, Shen J, Menon JU. 3D bioprinted implants for cartilage repair in intervertebral discs and knee menisci. Front Bioeng Biotechnol. 2022;9:754113. doi: 10.3389/fbioe.2021.754113
- Thavaneswaran P, Vandepeer M. Lumbar artificial intervertebral disc replacement: a systematic review. ANZ J Surg. 2014;84(3):121-127. doi: 10.1111/ans.12315
- Han X, Gao W, Zhou Z, et al. Application of biomolecules modification strategies on PEEK and its composites for osteogenesis and antibacterial properties. Colloids Surf B Biointerfaces. 2022;215:112492. doi: 10.1016/j.colsurfb.2022.112492
- Dua R, Rashad Z, Spears J, Dunn G, Maxwell M. Applications of 3D-printed PEEK via fused filament fabrication: a systematic review. Polymers (Basel). 2021;13(22):4046. doi: 10.3390/polym13224046
- Schönhoff LM, Mayinger F, Eichberger M, Reznikova E, Stawarczyk B. 3D printing of dental restorations: mechanical properties of thermoplastic polymer materials. J Mech Behav Biomed Mater. 2021;119:104544. doi: 10.1016/j.jmbbm.2021
- Zhang H, Duan M, Qin S, Zhang Z. Preparation and modification of porous polyetheretherketone (PEEK) cage material based on fused deposition modeling (FDM). Polymers (Basel). 2022;14(24):5403. doi: 10.3390/polym14245403
- Jung J, Jeong J, Hong HS. Substance P improves MSC-mediated RPE regeneration by modulating PDGF-BB. Biochem Biophys Res Commun. 2019;515(4):524-530. doi: 10.1016/j.bbrc.2019.05.186
- Kim JE, Lee JH, Kim SH, Jung Y. Skin regeneration with self-assembled peptide hydrogels conjugated with substance P in a diabetic rat model. Tissue Eng Part A. 2018; 24(1-2):21-33. doi: 10.1089/ten.TEA.2016.0517
- Zhang Y, An S, Hao J, Tian F, Fang X, Wang J. Systemic injection of substance P promotes murine calvarial repair through mobilizing endogenous mesenchymal stem cells. Sci Rep. 2018;8(1):12996. doi: 10.1038/s41598-018-31414-5