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

Chuanchuan Zheng, Shokouh Attarilar, Kai Li, Chong Wang, Jia Liu, Liqiang Wang, Junlin Yang, Yujin Tang

Article ID: 317
Vol 7, Issue 1, 2021, Article identifier:317

VIEWS - 172 (Abstract) 22 (PDF)


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 anti-tuberculosis 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.


Three-dimensional printing; β-tricalcium phosphate; HA15; Endoplasmic reticulum stress; Bone defect

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DOI: http://dx.doi.org/10.18063/ijb.v7i1.317


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