PERTANIKA JOURNAL OF SCIENCE AND TECHNOLOGY

Natural pharmaceutical ingredients have been widely used in recent decades due to their safety and biocompatibility. Zein, a plant-derived natural protein, has several advantages over other synthetic polymers in bone tissue engineering (BTE). This study of zein protein focuses more on its application in BTE as potential biopolymer material used in scaffold development. The use of zein in BTE has shown its benefits in the production of scaffolds. Therefore, attention has been given to studies of the effect of zein usage in bone scaffold development, as it offers a great ability based on its porosity, mechanical strength, in vitro degradation study, cell proliferation, and osteogenic differentiation, which is important for healing bone tissue damage. Therefore, this review aims to critically analyze the current research on the method of scaffold fabrication and the effect of zein usage in scaffolds for BTE. In addition, the common methods used in creating the scaffold are addressed.

• Alizadeh, M., Abbasi, F., Khoshfetrat, A. B., & Ghaleh, H. (2013). Microstructure and characteristic properties of gelatin/chitosan scaffold prepared by a combined freeze-drying/leaching method. Materials Science & Engineering: C, 33(7), 3958-3967. https://doi.org/10.1016/j.msec.2013.05.039

• An, J., Teoh, J. E. M., Suntornnond, R., & Chua, C. K. (2015). Design and 3D printing of scaffolds and tissues. Engineering, 1(2), 261-268. https://doi.org/10.15302/J-ENG-2015061

• Anderson, T. J., & Lamsa, B. P. (2011). Zein extraction from corn, corn products, and coproducts and modifications for various applications: A review. Cereal Chemistry, 88(2), 159-173. https://doi.org/10.1094/CCHEM-06-10-0091

• Arango-ospina, M., Lasch, K., Weidinger, J., & Boccaccini, A. R. (2021). Manuka honey and zein coatings impart bioactive glass bone tissue scaffolds antibacterial properties and superior mechanical properties. Front Mater, 7, Article 610889. https://doi.org/10.3389/fmats.2020.610889

• Bajaj, P., Schweller, R. M., Khademhosseini, A., West, J. L., & Bashir, R. (2014). 3D biofabrication strategies for tissue engineering and regenerative medicine. Annual Review of Biomedical Engineering, 16, 247-276. https://doi.org/10.1146/annurev-bioeng-071813-105155

• Berardi, A., Bisharat, L., AlKhatib, H. S., & Cespi, M. (2018). Zein as a pharmaceutical excipient in oral solid dosage forms: State of the art and future perspectives. AAPS PharmSciTech, 19, 2009-2022. https://doi.org/10.1208/s12249-018-1035-y

• Bharadwaz, A., & Jayasuriya, A. C. (2020). Recent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration. Materials Science and Engineering: C, 110, Article 110698. https://doi.org/10.1016/j.msec.2020.110698

• Bitar, K. N., & Zakhem, E. (2014). Design strategies of biodegradable scaffolds for tissue regeneration. Biomedical Engineering and Computational Biology, 6, 13-20. https://doi.org/ 10.4137/BECB.S10961

• Bohner, M., Baroud, G., Bernstein, A., Do, N., Galea, L., Hesse, B., Heuberger, R., Meille, S., Michel, P., von Rechenberg, B., Sague, J., & Seeherman, H. (2017). Characterization and distribution of mechanically competent mineralized tissue in micropores of b -tricalcium phosphate bone substitutes. Materials Today, 20(3), 106-115. https://doi.org/10.1016/j.mattod.2017.02.002

• Bose, S., Vahabzadeh, S., & Bandyopadhyay, A. (2013). Bone tissue engineering using 3D printing. Materials Today, 16(12), 496-504. https://doi.org/10.1016/j.mattod.2013.11.017

• Chen, H., Wang, J., Cheng, Y., Wang, C., Liu, H., Bian, H., Pan, Y., Sun, J., & Han, W. (2019). Application of protein-based films and coatings for food packaging: A review. Polymers, 11(12), Article 2039. https://doi.org/10.3390/polym11122039

• Chen, Q. Z., Thompson, I. D., & Boccaccini, A. R. (2006). 45S5 bioglasss-derived glass-ceramic scaffolds for bone tissue engineering. Biomaterials, 27(11), 2414-2425. https://doi.org/10.1016/j.biomaterials.2005.11.025

• Chocholata, P., Kulda, V., & Babuska, V. (2019). Fabrication of scaffolds for bone-tissue regeneration. Materials, 12(4), Article 568. https://doi.org/10.3390/ma12040568

• Demir, M., Ramos‐Rivera, L., Silva, R., Nazhat, S. N., & Boccaccini, A. R. (2017). Zein-based composites in biomedical applications. Journal of Biomedical Materials Research Part A, 105(6), 1656-1665 https://doi.org/10.1002/jbm.a.36040

• Esen, A. (1987). A proposed nomenclature for the alcohol-soluble proteins (zeins) of maize (Zea mays L.). Journal of Cereal Science, 5(2), 117-128. https://doi.org/10.1016/S0733-5210(87)80015-2

• Fereshteh, Z., Nooeaid, P., Fathi, M., Bagri, A., & Boccaccini, A. R. (2015). The effect of coating type on mechanical properties and controlled drug release of PCL/zein coated 45S5 bioactive glass scaffolds for bone tissue engineering. Materials Science and Engineering: C, 54, 50-60. https://doi.org/10.1016/j.msec.2015.05.011

• Francesca, D., Emanuela, J., Monica, S., & Manuela, T. R. (2020). Natural and synthetic polymers. In S. Chandra & Y. Ohama (Eds.), Polymers in concrete, (pp. 5-25). CRC Press. https://doi.org/10.1201/9781003068211-2

• Francis, L. F., & Roberts, C. C. (2016). Dispersion and solution processes. In Material Processing (pp. 415-512). Academia Press. https://doi.org/10.1016/B978-0-12-385132-1.00006-9

• Ghassemi, T., Shahroodi, A., Ebrahimzadeh, M. H., Mousavian, A., Movaffagh, J., & Moradi, A. (2018). Current concepts in scaffolding for bone tissue engineering. Archives of Bone and Joint Surgery, 6(2), 90-99. https://doi.org/10.22038/abjs.2018.26340.1713

• Gomes, M. E., Azevedo, H. S., Moreira, A. R., & Ell, V. (2008). Starch-poly (lactic acid) fibre-mesh scaffolds for bone tissue engineering applications: Structure, mechanical properties and degradation behaviour. Journal of Tissue Engineering and Regenerative Medicine, 2(5), 243-252.

• Gong, S., Wang, H., Sun, Q., Xue, S. T., & Wang, J. Y. (2006). Mechanical properties and in vitro biocompatibility of porous zein scaffolds. Biomaterials, 27(20), 3793-3799. https://doi.org/10.1016/j.biomaterials.2006.02.019

• Gungor-Ozkerim, P. S., Inci, I., Zhang, Y. S., Khademhosseini, A., & Dokmeci, M. R. (2018). Bioinks for 3D bioprinting: An overview. Biomaterials Science, 6(5), 915-946. https://doi.org/10.1039/c7bm00765e

• Hospodiuk, M., Dey, M., Sosnoski, D., & Ibrahim, T. (2016). The bioink: A comprehensive review on bioprintable materials. Biotechnology Advances, 35(2), 217-239. https://doi.org/10.1016/j.biotechadv.2016.12.006

• Hum, J., Naseri, S., & Boccaccini, A. R. (2018). Bioactive glass combined with zein as composite material for the application in bone tissue engineering. Biomedical Glasses, 4(1), 72-81. https://doi.org/10.1515/bglass-2018-0007

• Hum, J. K., (2016). Bioactive glass combined with natural derived proteins as composite materials for the application in bone tissue engineering (Doctoral dissertation). University of Erlangen-Nuremberg, Germany. https://d-nb.info/1103801953/34

• Ji, C., Annabi, N., Khademhosseini, A., & Dehghani, F. (2011). Fabrication of porous chitosan scaffolds for soft tissue engineering using dense gas CO2. Acta Biomaterialia, 7(4), 1653-1664. https://doi.org/10.1016/j.actbio.2010.11.043

• Jing, L., Wang, X., Liu, H., Lu, Y., Bian, J., Sun, J., & Huang, D. (2018). Zein increases the cytoaffinity and biodegradability of scaffolds 3D-printed with zein and poly(ϵ-caprolactone) composite ink. ACS Applied Materials and Interfaces, 10(22), 18551-18559. https://doi.org/10.1021/acsami.8b04344

• Labib, G. (2018). Overview on zein protein: A promising pharmaceutical excipient in drug delivery systems and tissue engineering. Expert Opinion on Drug Delivery, 15(1), 65-75. https://doi.org/10.1080/17425247.2017.1349752

• Lawton, J. W. (2002). Zein: A history of processing and use. Cereal Chemistry, 79(1), 1-18. https://doi.org/10.1094/CCHEM.2002.79.1.1

• Li, W., Nooeaid, P., Roether, J. A., Schubert, D. W., & Boccaccini, A. R. (2014). Preparation and characterization of vancomycin releasing PHBV coated 45S5 Bioglass® -based glass-ceramic scaffolds for bone tissue engineering. Journal of the European Ceramic Society, 34(2), 505-514. https://doi.org/10.1016/j.jeurceramsoc.2013.08.032

• Maji, K., & Dasgupta, S. (2017). Effect of β-tricalcium phosphate nanoparticles additions on the properties of gelatin-chitosan scaffolds. Bioceramics Development and Applications, 7(2), Article 10000103. https://doi.org/10.4172/2090-5025.1000103

• Mikos, A. G., & Temenoff, J. S. (2000). Formation of highly porous biodegradable scaffolds for tissue engineering. Electronic Journal of Biotechnology, 3(2), 1995-2000.

• Murphy, C. M., & O’Brien, J. F. (2010). Understanding the effect of mean pore size on cell activity in collagen-glycosaminoglycan scaffolds. Cell Adhesion & Migration, 4(3), 377-381. https://doi.org/10.4161/cam.4.3.11747

• Murphy, C. M., Haugh, M. G., & Brien, F. J. O. (2010). The effect of mean pore size on cell attachment, proliferation and migration in collagen-glycosaminoglycan scaffolds for bone tissue engineering. Biomaterials, 31(3), 461-466. https://doi.org/10.1016/j.biomaterials.2009.09.063

• Nam, Y. S., Yoon, J. J., & Park, T. G. (2000). A novel fabrication method of macroporous biodegradable polymer scaffolds using gas foaming salt as a porogen additive. Journal of Biomedical Materials Research, 53(1), 1-7. https://doi.org/10.1002/(SICI)1097-4636(2000)53:1<1::AID-JBM1>3.0.CO;2-R

• Patel, M., & Fisher, J. P. (2008). Biodegradable materials for tissue engineering. McGraw-Hill Global Education Holdings, LLC. https://doi.org/10.1036/1097-8542.YB080510

• Philippart, A., Boccaccini, A. R., Fleck, C., Schubert, D. W., & Roether, J. A. (2015). Toughening and functionalization of bioactive ceramic and glass bone scaffolds by biopolymer coatings and infiltration : A review of the last 5 years. Expert Review of Medical Devices, 12(1), 93-111. https://doi.org/10.1586/17434440.2015.958075

• Polak, S. J., Lan, S. K., Wheeler, M. B., Maki, A. J., Clark, S. G., & Wagoner, A. J. (2011). Analysis of the roles of microporosity and BMP-2 on multiple measures of bone regeneration and healing in calcium phosphate scaffolds. Acta Biomaterialia, 7(4), 1760-1771. https://doi.org/10.1016/j.actbio.2010.12.030

• Prasadh, S., & Wong, R. C. W. (2018). Unraveling the mechanical strength of biomaterials used as a bone scaffold in oral and maxillofacial defects. Oral Science International, 15(2), 48-55. https://doi.org/10.1016/S1348-8643(18)30005-3

• Qu, H., Fu, H., Han, Z., & Sun, Y. (2019). Biomaterials for bone tissue engineering scaffolds: A review. RSC Advances, 9, 26252-26262. https://doi.org/10.1039/c9ra05214c

• Qu, Z. H., Wang, H. J., Tang, T. T., Zhang, X. L., Wang, J. Y., & Dai, K. R. (2008). Evaluation of the zein/inorganics composite on biocompatibility and osteoblastic differentiation. Acta Biomaterialia, 4(5), 1360-1368. https://doi.org/10.1016/j.actbio.2008.03.006

• Reddy, N., & Yang, Y. (2011). Potential of plant proteins for medical applications. Trends in Biotechnology, 29(10), 490-498. https://doi.org/10.1016/j.tibtech.2011.05.003

• Reddy, N., & Yang, Y. (2013). Thermoplastic films from plant proteins. Journal of Applied Polymer Science, 130(2), 729-738. https://doi.org/10.1002/app.39481

• Reinwald, Y., Johal, R. K., Ghaemmaghami, A. M., Rose, F. R. A. J., Howdle, S. M., & Shakesheff, K. M. (2014). Interconnectivity and permeability of supercritical fl uid-foamed scaffolds and the effect of their structural properties on cell distribution. Polymer, 55(1), 435-444. https://doi.org/10.1016/j.polymer.2013.09.041

• Rezwan, K., Chen, Q. Z., Blaker, J. J., & Roberto, A. (2006). Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials, 27(18), 3413-3431. https://doi.org/10.1016/j.biomaterials.2006.01.039

• Rosa, D. S., Lopes, D. R., & Calil, M. R. (2005). Thermal properties and enzymatic degradation of blends of poly (ɛ-caprolactone) with starches. Polymer Testing, 24(6), 756-761. https://doi.org/10.1016/j.polymertesting.2005.03.014

• Roseti, L., Parisi, V., Petretta, M., Cavallo, C., Desando, G., Bartolotti, I., & Grigolo, B. (2017). Scaffolds for bone tissue engineering: State of the art and new perspectives. Materials Science and Engineering: C, 78, 1246-1262. https://doi.org/10.1016/j.msec.2017.05.017

• Ru, J., Wei, Q., Yang, L., Qin, J., Tang, L., Wei, J., Guo, L., & Niu, Y. (2018). Zein regulating apatite mineralization, degradability, in vitro cells responses and in vivo osteogenesis of 3D-printed scaffold of n-MS/ZN/PCL ternary composite. RSC Advances, 8, 18745-18756. https://doi.org/10.1039/c8ra02595a

• Sabudin, S., Marzuke, M. A., & Hussin, Z. (2019). Effect of mechanical properties on porous calcium phosphate scaffold. Materials Today: Proceedings, 16(Part 4), 1680-1685. https://doi.org/10.1016/j.matpr.2019.06.036

• Sah, M. K., & Pramanik, K. (2011). Computational approaches in tissue engineering. International Journal of Computer Applications, 27(4), 0975-8887.

• Salerno, A., Di Maio, E., Iannace, S., & Netti, P. A. (2011). Tuning the microstructure and biodegradation of three-phase scaffolds for bone regeneration made of PCL, Zein, and HA. Journal of Cellular Plastics, 47(3), 245-260. https://doi.org/10.1177/0021955X11404832

• Salerno, A., Oliviero, M., Di Maio, E., Netti, P. A., Rofani, C., Colosimo, A., Guida, V., Dallapiccola, B., Palma, P., Procaccini, E., Berardi, A. C., Velardi, F., Teti, A., & Iannace, S. (2010a). Design of novel three-phase PCL/TZ-HA biomaterials for use in bone regeneration applications. Journal of Materials Science: Materials in Medicine, 21, 2569-2581. https://doi.org/10.1007/s10856-010-4119-0

• Salerno, A., Zeppetelli, S., Di Maio, E., Iannace, S., & Netti A., P. (2010b). Novel 3D porous multi-phase composite scaffolds based on PCL, thermoplastic zein and ha prepared via supercritical CO2 foaming for bone regeneration. Composites Science and Technology, 70(13), 1838-1846. https://doi.org/10.1016/j.compscitech.2010.06.014

• Salerno, A., Oliviero, M., Maio, E. Di, & Iannace, S. (2006). Thermoplastic foams from zein and gelatin. International Polymer Processing, 22(5), 480-488. https://doi.org/10.3139/217.2065

• Shahbazarab, Z., Teimouri, A., Chermahini, A. N., & Azadi, M. (2018). Fabrication and characterization of nanobiocomposite scaffold of zein/chitosan/nanohydroxyapatite prepared by freeze-drying method for bone tissue engineering. International Journal of Biological Macromolecules, 108, 1017-1027. https://doi.org/10.1016/j.ijbiomac.2017.11.017

• Shamaz, M., & Halima, S. B. (2015). Bone Tissue Engineering and Bony Scaffolds. International Journal of Dentistry & Oral Health, 1(1), 15-20. https://doi.org/10.25141/2471-657X-2015-1.0001

• She, H., Xiao, E. X., & Liu, E. R. (2007). Preparation and characterization of polycaprolactone-chitosan composites for tissue engineering applications. Journal of Material Science, 42, 8113-8119. https://doi.org/10.1007/s10853-007-1706-7

• Shukla, R., & Cheryan, M. (2001). Zein: The industrial protein from corn. Industrial Crops and Products, 13(3), 171-192. https://doi.org/10.1016/S0926-6690(00)00064-9

• Subuki, I., Adnan, N., & Sharudin, R. W. (2018). Biodegradable scaffold of natural polymer and hydroxyapatite for bone tissue engineering: A short review. AIP Conference Proceedings, 2031(1), 1-5. https://doi.org/10.1063/1.5066975

• Subuki, I., Akhbar, S., & Nor Wahid, F. K. (2020). Influence of thermoplastic PEG, GLY and Zein in PCL/TZ and HAp bio composite via solid state supercritical CO2 foaming. Scientific Research Journal, 17(2), 177-190. https://doi.org/10.24191/srj.v17i2.9534

• Tariverdian, T., Sefat, F., Gelinsky, M., & Mozafari, M. (2019). Scaffold for bone tissue engineering. In M. Mozafari, F. Sefat & A. Atala (Eds.), Handbook of Tissue Engineering Scaffolds: Volume One (pp. 189-209). Elsevier Ltd. https://doi.org/10.1016/B978-0-08-102563-5.00010-1

• Thavornyutikarn, B., Chantarapanich, N., & Chen, Q. (2014a). Bone tissue engineering scaffolding: Computer-aided scaffolding techniques. Progress in Biomaterials, 3, 61-102. https://doi.org/10.1007/s40204-014-0026-7

• Thavornyutikarn, B., Chantarapanich, N., Sitthiseripratip, K., Thouas, G. A., & Chen, Q. (2014b). Bone tissue engineering scaffolding: computer-aided scaffolding techniques. In Progress in Biomaterials (pp. 61-102). Springer. https://doi.org/10.1007/s40204-014-0026-7

• Tong, W., Suihuai, Y., Dengkai, C., & Yanen, W. (2017). Bionic design, materials and performance of bone tissue scaffolds. Materials, 10(10), Article 1187. https://doi.org/10.3390/ma10101187

• Torabi, K., Farjood, E., & Hamedani, S. (2015). Rapid prototyping technologies and their applications in prosthodontics, a Review of Literature. Journal of Dentistry, 16(1), 1-9.

• Tortorella, S., Maturi, M., Vetri Buratti, V., Vozzolo, G., Locatelli, E., Sambri, L., & Franchini, M. C. (2021). Zein as a versatile biopolymer: Different shapes for different biomedical applications. RSC Advances, 11, 39004-39026. https://doi.org/10.1039/d1ra07424e

• Wahid, F., Khan, T., Hussain, Z., & Ullah, H. (2018). Nanocomposite scaffolds for tissue engineering; properties, preparation and applications. In A. M. A. Inamudin & A. Mohammad (Eds.), Applications of Nanocomposite Materials in Drug Delivery (pp. 701-735). Elsevier. https://doi.org/10.1016/B978-0-12-813741-3.00031-5

• Wang, C., Huang, W., Zhou, Y., He, L., He, Z., Chen, Z., He, X., Tian, S., Liao, J., Lu, B., Wei, Y., & Wang, M. (2020). 3D printing of bone tissue engineering scaffolds. Bioactive Materials, 5(1), 82-91. https://doi.org/10.1016/j.bioactmat.2020.01.004

• Wang, H. J., Gong, S. J., & Wang, J. Y. (2008). Mechanical improvement of zein protein as scaffold for bone tissue engineering. Materials Science and Technology, 24(9), 1045-1052. https://doi.org/10.1179/174328408X341735

• Wu, F., Wei, J., Liu, C., O’Neill, B., & Ngothai, Y. (2012). Fabrication and properties of porous scaffold of zein/PCL biocomposite for bone tissue engineering. Composites Part B: Engineering, 43(5), 2192-2197. https://doi.org/10.1016/j.compositesb.2012.02.040

• Xiaohao, L., & Peter, X. M. (2004). Polymeric scaffolds for bone tissue engineering. Annals of Biomedical Engineering, 32(3), 477-486.

• Yao, Q., Nooeaid, P., Roether, J. A., Dong, Y., Zhang, Q., & Boccaccini, A. R. (2013). Bioglass® -based scaffolds incorporating polycaprolactone and chitosan coatings for controlled vancomycin delivery. Ceramics International, 39(7), 7517-7522. https://doi.org/10.1016/j.ceramint.2013.03.002

• Yoshimoto, H., Shin, Y. M., Terai, H., & Vacanti, J. P. (2003). A biodegradable nanofiber scaffold by electrospinning and its potential for bone tissue engineering. Biomaterials, 24(12), 2077-2082. https://doi.org/10.1016/S0142-9612(02)00635-X

• Zhao, H., Li, L., Ding, S., Liu, C., & Ai, J. (2018). Effect of porous structure and pore size on mechanical strength of 3D-printed comby scaffolds. Materials Letters, 223, 21-24. https://doi.org/10.1016/j.matlet.2018.03.205