3D-printed HA15-loaded β-Tricalcium Phosphate/ Poly (Lactic-co-glycolic acid) Bone Tissue Scaffold Promotes Bone Regeneration in Rabbit Radial Defects

Chuanchuan Zheng^1†, Shokouh Attarilar^2†, Kai Li^3†, Chong Wang⁴, Jia Liu^1*, Liqiang Wang⁵, Junlin Yang², Yujin Tang^1*

Show Less

¹ Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China

² Department of Pediatric Orthopaedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

³ Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510000, China

⁴ School of Mechanical Engineering, Dongguan University of Technology, Dongguan, Guangdong, 523808, China

⁵ State Key Laboratory of Metal Matrix Composites, School of Material Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China

IJB 2021, 7(1), 317 https://doi.org/10.18063/ijb.v7i1.317

© Invalid date by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

Download PDF

Cite

XML

Abstract

In this study, a β-tricalcium phosphate (β-TCP)/poly (lactic-co-glycolic acid) (PLGA) bone tissue scaffold was loaded with osteogenesis-promoting drug HA15 and constructed by three-dimensional (3D) printing technology. This drug delivery system with favorable biomechanical properties, bone conduction function, and local release of osteogenic drugs could provide the basis for the treatment of bone defects. The biomechanical properties of the scaffold were investigated by compressive testing, showing comparable biomechanical properties with cancellous bone tissue. Furthermore, the microstructure, pore morphology, and condition were studied. Moreover, the drug release concentration, the effect of antituberculosis drugs in vitro and in rabbit radial defects, and the ability of the scaffold to repair the defects were studied. The results show that the scaffold loaded with HA15 can promote cell differentiation into osteoblasts in vitro, targeting HSPA5. The micro-computed tomography scans showed that after 12 weeks of scaffold implantation, the defect of the rabbit radius was repaired and the peripheral blood vessels were regenerated. Thus, HA15 can target HSPA5 to inhibit endoplasmic reticulum stress which finally leads to promotion of osteogenesis, bone regeneration, and angiogenesis in the rabbit bone defect model. Overall, the 3D-printed β-TCP/PLGA-loaded HA15 bone tissue scaffold can be used as a substitute material for the treatment of bone defects because of its unique biomechanical properties and bone conductivity.

Keywords

Three-dimensional printing

β-tricalcium phosphate

HA15

Endoplasmic reticulum stress

Bone defect

References

1. Trejo-Iriarte CG, Serrano-Bello J, Gutiérrez-Escalona R, et al., 2019, Evaluation of Bone Regeneration in a Critical Size Cortical Bone Defect in Rat Mandible Using MicroCT and Histological Analysis. Arch Oral Biol, 101:165–71. https://doi.org/10.1016/j.archoralbio.2019.01.010

2. Tarafder S, Davies NM, Bandyopadhyay A, et al., 2013, 3D Printed Tricalcium Phosphate Bone Tissue Engineering Scaffolds: Effect of SrO and MgO Doping on In Vivo Osteogenesis in a Rat Distal Femoral Defect Model. Biomater Sci, 1:1250. https://doi.org/10.1039/c3bm60132c

3. Giannoudis PV, Dinopoulos H, Tsiridis E, 2005, Bone Substitutes: An Update. Injury, 36:S20–7. https://doi.org/10.1016/j.injury.2005.07.029

4. Pape HC, Evans A, Kobbe P, 2010, Autologous Bone Graft: Properties and Techniques. J Orthop Trauma, 24:S36–40. https://doi.org/10.1097/BOT.0b013e3181cec4a1

5. Ebraheim NA, Elgafy H, Xu R, 2001, Bone-Graft Harvesting From Iliac and Fibular Donor Sites: Techniques and Complications. J Am Acad Orthop Surg, 9:210–8. https://doi.org/10.5435/00124635-200105000-00007

6. Arrington ED, Smith WJ, Chambers HG, et al., 1996, Complications of Iliac Crest Bone Graft Harvesting. Clin Orthop Relat Res, 329:300–9. https://doi.org/10.1097/00003086-199608000-00037

7. Burg KJ, Porter S, Kellam JF, 2000, Biomaterial Developments for Bone Tissue Engineering. Biomaterials, 21:2347–59. https://doi.org/10.1016/S0142-9612(00)00102-2

8. Khojasteh A, Fahimipour F, Eslaminejad MB, et al., 2016, Development of PLGA-coated β-TCP Scaffolds Containing VEGF for Bone Tissue Engineering. Mater Sci Eng C, 69:780–8. https://doi.org/10.1016/j.msec.2016.07.011

9. Yang S, Leong KF, Du Z, et al., 2001, The Design of Scaffolds for Use in Tissue Engineering. Part I. Traditional Factors. Tissue Eng, 7:679–89. https://doi.org/10.1089/107632701753337645

10. Ng WL, Chua CK, Shen YF, 2019, Print me an Organ! Why we are not there YET. Prog Polym Sci, 97:101145. https://doi.org/10.1016/j.progpolymsci.2019.101145

11. Zhou H, Lawrence JG, Bhaduri SB, 2012, Fabrication Aspects of PLA-CaP/PLGA-CaP Composites for Orthopedic Applications: A Review. Acta Biomater, 8:1999–2016. https://doi.org/10.1016/j.actbio.2012.01.031

12. Hollister SJ, 2009, Scaffold Design and Manufacturing: From Concept to Clinic. Adv Mater, 21:3330–42. https://doi.org/10.1002/adma.200802977

13. Badekila AK, Kini S, Jaiswal AK, 2020, Fabrication Techniques of Biomimetic Scaffolds in Three-dimensional Cell Culture: A Review. J Cell Physiol, 2020:29935. https://doi.org/10.1002/jcp.29935

14. Logeart-Avramoglou D, Anagnostou F, Bizios R, et al., 2005, Engineering Bone: Challenges and for Bone Tissue Engineering and Regenerative Medicine: A Review. J Cell Mol Med, 9:72–84. https://doi.org/10.1111/j.1582-4934.2005.tb00338.x

15. Pina S, Oliveira JM, Reis RL, 2015, Natural-Based Nanocomposites. Adv Mater, 27:1143–69. https://doi.org/10.1002/adma.201403354

16. Asti A, Gioglio L, 2014, Natural and Synthetic Biodegradable Polymers: Different Scaffolds for Cell Expansion and Tissue Formation. Int J Artif Organs, 37:187–205. https://doi.org/10.5301/ijao.5000307

17. Shrivats AR, McDermott MC, Hollinger JO, 2014, Bone Tissue Engineering: State of the Union. Drug Discov Today, 19:781–86. https://doi.org/10.1016/j.drudis.2014.04.010

18. Winkler T, Sass FA, Duda GN, et al., 2018, A Review of Biomaterials in Bone Defect Healing, Remaining Shortcomings and Future Opportunities for Bone Tissue Engineering. Bone Joint Res, 7:232–43. https://doi.org/10.1302/2046-3758.73.BJR-2017-0270.R1

19. Nandi SK, Fielding G, Banerjee D, et al., 2018, 3D-Printed β-TCP Bone Tissue Engineering Scaffolds: Effects of Chemistry on In Vivo Biological Properties in a Rabbit Tibia Model. J Mater Res, 33:1939–47. https://doi.org/10.1557/jmr.2018.233

20. Liu Q, Cen L, Yin S, et al., 2008, A Comparative Study of Proliferation and Osteogenic Differentiation of Adipose derived Stem Cells on Akermanite and β-TCP Ceramics. Biomaterials, 29:4792–99. https://doi.org/10.1016/j.biomaterials.2008.08.039

21. Gentile P, Chiono V, Carmagnola I, et al., 2014, An Overview of Poly(lactic-co-glycolic) Acid (PLGA)-Based Biomaterials for Bone Tissue Engineering. Int J Mol Sci, 15:3640–59. https://doi.org/10.3390/ijms15033640

22. Yadav RK, Chae SW, Kim HR, et al., 2014, Endoplasmic Reticulum Stress and Cancer. J Cancer Prev, 19 (2014) 75–88. https://doi.org/10.15430/JCP.2014.19.2.75.

23. Urra H, Dufey E, Avril T, et al., 2016, Endoplasmic Reticulum Stress and the Hallmarks of Cancer. Trends Cancer, 2:252–62. https://doi.org/10.1016/j.trecan.2016.03.007

24. Díaz-Villanueva J, Díaz-Molina R, García-González V, 2015, Protein Folding and Mechanisms of Proteostasis. Int J Mol Sci, 16:17193–230. https://doi.org/10.3390/ijms160817193

25. Sano R, Reed JC, 2013, ER Stress-induced Cell Death Mechanisms. Biochim Biophys Acta Mol Cell Res, 1833:3460–70. https://doi.org/10.1016/j.bbamcr.2013.06.028

26. Attarilar S, Yang J, Ebrahimi M, et al., 2020, The Toxicity Phenomenon and the Related Occurrence in Metal and Metal Oxide Nanoparticles: A Brief Review From the Biomedical Perspective. Front Bioeng Biotechnol, 8:822. https://doi.org/10.3389/fbioe.2020.00822

27. Cerezo M, Lehraiki A, Millet A, et al., 2016, Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance. Cancer Cell, 29:805–19. https://doi.org/10.1016/j.ccell.2016.04.013

28. Xiao G, Jiang D, Ge C, et al., 2005, Cooperative Interactions between Activating Transcription Factor 4 and Runx2/Cbfa1 Stimulate Osteoblast-specific Osteocalcin Gene Expression. J Biol Chem, 280:30689–96. https://doi.org/10.1074/jbc.M500750200

29. Wang W, Chen J, Hui Y, et al., 2018, Down-Regulation of miR-193a-3p Promotes Osteoblast Differentiation through up-regulation of LGR4/ATF4 Signaling. Biochem Biophys Res Commun, 503:2186–93. https://doi.org/10.1016/j.bbrc.2018.08.011

30. Zhang K, Kaufman RJ, 2004, Signaling the Unfolded Protein Response from the Endoplasmic Reticulum. J Biol Chem, 279:25935–8. https://doi.org/10.1074/jbc.R400008200

31. Ni M, Lee AS, 2007, ER Chaperones in Mammalian Development and Human Diseases. FEBS Lett, 581:3641–51. https://doi.org/10.1016/j.febslet.2007.04.045

32. Macario L, Alberto J, 2007, Molecular Chaperones: Multiple Functions, Pathologies, and Potential Applications. Front Biosci, 12:2588. https://doi.org/10.2741/2257

33. Hasnain SZ, Lourie R, Das I, et al., 2012, The Interplay between Endoplasmic Reticulum Stress and Inflammation. Immunol Cell Biol, 90:260–70. https://doi.org/10.1038/icb.2011.112

34. Chen Y, Mi Y, Zhang X, et al., 2019, Dihydroartemisinin-Induced Unfolded Protein Response Feedback Attenuates Ferroptosis via PERK/ATF4/HSPA5 Pathway in Glioma Cells. J Exp Clin Cancer Res, 38:402. https://doi.org/10.1186/s13046-019-1413-7

35. Uckun FM, Qazi S, Ozer Z, et al., 2011, Inducing Apoptosis in Chemotherapy-Resistant B-Lineage Acute Lymphoblastic Leukaemia Cells by Targeting HSPA5, a Master Regulator of the Anti-apoptotic Unfolded Protein Response Signalling Network. Br J Haematol, 153:741–52. https://doi.org/10.1111/j.1365-2141.2011.08671.x

36. Touri M, Kabirian F, Saadati M, et al., 2019, Additive Manufacturing of Biomaterials the Evolution of Rapid Prototyping. Adv Eng Mater, 21:1800511. https://doi.org/10.1002/adem.201800511

37. Nakashima K, Zhou X, Kunkel G, et al., 2002, The Novel Zinc Finger-Containing Transcription Factor Osterix is Required for Osteoblast Differentiation and Bone Formation. Cell, 108:17–29. https://doi.org/10.1016/S0092-8674(01)00622-5

38. Pirraco RP, Reis RL, Marques AP, 2013, Effect of Monocytes/Macrophages on the Early Osteogenic Differentiation of hBMSCs. J Tissue Eng Regen Med, 7:392–400. https://doi.org/10.1002/term.535

39. Catelas I, Sese N, Wu BM, et al., 2006, Human Mesenchymal Stem Cell Proliferation and Osteogenic Differentiation in Fibrin Gels In Vitro. Tissue Eng, 12:2385–96. https://doi.org/10.1089/ten.2006.12.2385

40. Scheiber AL, Guess AJ, Kaito T, et al., 2019, Endoplasmic Reticulum Stress is Induced in Growth Plate Hypertrophic Chondrocytes in G610C Mouse Model of Osteogenesis Imperfecta. Biochem Biophys Res Commun, 509:235–40. https://doi.org/10.1016/j.bbrc.2018.12.111

41. Tataria M, Quarto N, Longaker MT, et al., 2006, Absence of the p53 Tumor Suppressor Gene Promotes Osteogenesis in Mesenchymal Stem Cells. J Pediatr Surg, 41:624–632. https://doi.org/10.1016/j.jpedsurg.2005.12.001

42. Gerhardt LC, Boccaccini AR, 2010, Bioactive Glass and Glass-Ceramic Scaffolds for Bone Tissue Engineering. Materials (Basel), 3:3867–910. https://doi.org/10.3390/ma3073867

43. Nazarian A, von Stechow D, Zurakowski D, et al., 2008, Bone Volume Fraction Explains the Variation in Strength and Stiffness of Cancellous Bone Affected by Metastatic Cancer and Osteoporosis. Calcif Tissue Int, 83:368–79. https://doi.org/10.1007/s00223-008-9174-x

44. Lee JY, Son SJ, Son JS, et al., 2016, Bone-Healing Capacity of PCL/PLGA/Duck Beak Scaffold in Critical Bone Defects in a Rabbit Model. Biomed Res Int, 2016:1–10. https://doi.org/10.1155/2016/2136215

45. Collin-Osdoby P, 1994, Role of Vascular Endothelial Cells in Bone Biology. J Cell Biochem, 55:304–9. https://doi.org/10.1002/jcb.240550306

46. Chen SH, Lei M, Xie XH, et al., 2013, PLGA/TCP Composite Scaffold Incorporating Bioactive Phytomolecule Icaritin for Enhancement of Bone Defect Repair in Rabbits. Acta Biomater, 9:6711–22. https://doi.org/10.1016/j.actbio.20

Previous article in this issue

Next article in this issue

International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing