Progress in Preparation of Silk Fibroin Microspheres for Biomedical Applications

Author(s): Shihe Long, Yun Xiao*, Xingdong Zhang

Journal Name: Pharmaceutical Nanotechnology

Volume 8 , Issue 5 , 2020

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Graphical Abstract:


As a natural biomaterial, silk fibroin (SF) holds great potential in biomedical applications with its broad availability, good biocompatibility, high mechanical strength, ease of fabrication, and controlled degradation. With emerging fabrication methods, nanoand microspheres made from SF have brought about unique opportunities in drug delivery, cell culture, and tissue engineering. For these applications, the size and distribution of silk fibroin particles (SFPs) are critical and require precise control during fabrication. Herein, we review common and emerging SFPs fabrication methods and their biomedical applications, and also the challenges and opportunities for SFPs in the near future.

Lay Summary: The application of silk in textile has an extraordinarily long history and new biomedical applications emerged owing to the good biocompatibility and versatile fabrication options of its major protein component, silk fibroin. With the development of nanotechnology and microfabrication, silk fibroin has been fabricated into nano- or microspheres with precisely controlled shape and distribution. In this review, we summarize common and emerging silk fibroin particle fabrication methods and their biomedical applications, and also discuss their challenges and opportunities in the nearest future.

Keywords: Biomedical applications, fabrication method, microspheres, silk fibroin, nanospheres, size control.

Kawaguchi H. Functional polymer microspheres. Prog Polym Sci 2000; 25(8): 1171-210.
Luo X, Zhang L. Creation of regenerated cellulose microspheres with diameter ranging from micron to millimeter for chromatography applications. J Chromatogr A 2010; 1217(38): 5922-9.
[ ] [PMID: 20723904]
Gomes S, Leonor IB, Mano JF, Rui LR, Kaplan DL. Silk-based biomaterials Weinheim: Wiley‐VCH Verlag GmbH and Co KGaA 2012.
Huang XW, Liang H, Li Z, et al. Monodisperse phase transfer and surface bioengineering of metal nanoparticles via a silk fibroin protein corona. Nanoscale 2017; 9(8): 2695-700.
[ ] [PMID: 28186214]
Pritchard EM, Kaplan DL. Silk fibroin biomaterials for controlled release drug delivery. Expert Opin Drug Deliv 2011; 8(6): 797-811.
[ ] [PMID: 21453189]
Rockwood DN, Preda RC, Yücel T, Wang X, Lovett ML, Kaplan DL. Materials fabrication from Bombyx mori silk fibroin. Nat Protoc 2011; 6(10): 1612-31.
[ ] [PMID: 21959241]
Wray LS, Hu X, Gallego J, et al. Effect of processing on silk-based biomaterials: reproducibility and biocompatibility. J Biomed Mater Res B Appl Biomater 2011; 99(1): 89-101.
[ ] [PMID: 21695778]
Chiasson R, Hasan M, Al Nazer Q, Farokhzad OC, Kamaly N. The use of silk in nanomedicine applicationsnanomedicine. New York, NY: Springer 2016; pp. 245-78.
Dharadhar S, Majumdar A. Biomaterials and its medical applications Application of biomedical engineering in neuroscience. Singapore: Springer 2019; pp. 355-80.
Altman GH, Diaz F, Jakuba C, et al. Silk-based biomaterials. Biomaterials 2003; 24(3): 401-16.
[ ] [PMID: 12423595]
Floren M, Migliaresi C, Motta A. Processing techniques and applications of silk hydrogels in bioengineering. J Funct Biomater 2016; 7(3): 26.
[ ] [PMID: 27649251]
Crivelli B, Bari E, Perteghella S, et al. Silk fibroin nanoparticles for celecoxib and curcumin delivery: ROS-scavenging and anti-inflammatory activities in an in vitro model of osteoarthritis. Eur J Pharm Biopharm 2019; 137: 37-45.
[ ] [PMID: 30772432]
Pham DT, Saelim N, Tiyaboonchai W. Alpha mangostin loaded crosslinked silk fibroin-based nanoparticles for cancer chemotherapy. Colloids Surf B Biointerfaces 2019; 181: 705-13.
[ ] [PMID: 31228853]
Lozano-Pérez AAR-NA, Rodriguez-Nogales A, Ortiz-Cullera V, et al. Silk fibroin nanoparticles constitute a vector for controlled release of resveratrol in an experimental model of inflammatory bowel disease in rats. Int J Nanomedicine 2014; 9(1): 4507-20.
[PMID: 25285004]
Totten JD, Wongpinyochit T, Carrola J, Duarte IF, Seib FP. PEGylation-dependent metabolic rewiring of macrophages with silk fibroin nanoparticles. ACS Appl Mater Interfaces 2019; 11(16): 14515-25.
[ ] [PMID: 30977355]
Srihanam P, Srisuwan Y, Imsombut T, Baimark Y. Silk fibroin microspheres prepared by the water-in-oil emulsion solvent diffusion method for protein delivery. Korean J Chem Eng 2011; 28(1): 293-7.
Srisa-Ard M, Baimark Y. Controlling conformational transition of silk fibroin microspheres by water vapor for controlled release drug delivery. Particul Sci Technol 2013; 31(4): 379-84.
Bian X, Wu P, Sha H, et al. Anti-EGFR-iRGD recombinant protein conjugated silk fibroin nanoparticles for enhanced tumor targeting and antitumor efficiency. OncoTargets Ther 2016; 9: 3153-62.
[PMID: 27313461]
Li H, Tian J, Wu A, Wang J, Ge C, Sun Z. Self-assembled silk fibroin nanoparticles loaded with binary drugs in the treatment of breast carcinoma. Int J Nanomedicine 2016; 11: 4373-80.
[PMID: 27621628]
Cao Z, Chen X, Yao J, Huang L, Shao Z. The preparation of regenerated silk fibroin microspheres. Soft Matter 2007; 3(7): 910-5.
[PMID: 32900086]
Lammel AS, Hu X, Park S-H, Kaplan DL, Scheibel TR. Controlling silk fibroin particle features for drug delivery. Biomaterials 2010; 31(16): 4583-91.
[PMID: 20219241]
Tian Y, Jiang X, Chen X, Shao Z, Yang W. Doxorubicin-loaded magnetic silk fibroin nanoparticles for targeted therapy of multidrug-resistant cancer. Adv Mater 2014; 26(43): 7393-8.
[ ] [PMID: 25238148]
Sun N, Lei R, Xu J, et al. Fabricated porous silk fibroin particles for pH-responsive drug delivery and targeting of tumor cells. J Mater Sci 2019; 54: 3319-30.
Huang Y, Lu Q, Li M, Zhang B, Zhu H. Silk fibroin microsphere drug carriers perpared under electric fields. Chin Sci Bull 2011; 56(13): 1013-8.
Qu J. Preparation of Silk Fibroin Microspheres and its cytocompatibility. J Biomater Nanobiotechnol 2013; 04: 84-90.
Zhang X, Fan Z, Lu Q, Huang Y, Kaplan DL, Zhu H. Hierarchical biomineralization of calcium carbonate regulated by silk microspheres. Acta Biomater 2013; 9(6): 6974-80.
[ ] [PMID: 23518477]
Gholami A, Tavanai H, Moradi AR. Production of fibroin nanopowder through electrospraying. J Nanopart Res 2011; 13(5): 2089-98.
Qu J, Liu Y, Yu Y, Li J, Luo J, Li M. Silk fibroin nanoparticles prepared by electrospray as controlled release carriers of cisplatin. Mater Sci Eng C 2014; 44: 166-74.
[ ] [PMID: 25280693]
Cao Y, Liu F, Chen Y, et al. Drug release from core-shell PVA/silk fibroin nanoparticles fabricated by one-step electrospraying. Sci Rep 2017; 7(1): 11913.
[ ] [PMID: 28931908]
Yeo J, Lee K, Lee Y, Kim SY. Simple preparation and characteristics of silk fibroin microsphere. Eur Polym J 2003; 39(6): 1195-9.
Hino T, Tanimoto M, Shimabayashi S. Change in secondary structure of silk fibroin during preparation of its microspheres by spray-drying and exposure to humid atmosphere. J Colloid Interface Sci 2003; 266(1): 68-73.
[ ] [PMID: 12957583]
Faragò S, Lucconi G, Perteghella S, et al. A dry powder formulation from silk fibroin microspheres as a topical auto-gelling device. Pharm Dev Technol 2016; 21(4): 453-62.
[PMID: 25757645]
Wongpinyochit T, Totten JD, Johnston BF, Seib FP. Microfluidic-assisted silk nanoparticle tuning. Nanoscale Advances 2019; 1(2): 873-83.
Breslauer DN, Muller SJ, Lee LP. Generation of monodisperse silk microspheres prepared with microfluidics. Biomacromolecules 2010; 11(3): 643-7.
[ ] [PMID: 20131893]
Mitropoulos AN, Perotto G, Kim S, Marelli B, Kaplan DL, Omenetto FG. Synthesis of silk fibroin micro- and submicron spheres using a co-flow capillary device. Adv Mater 2014; 26(7): 1105-10.
[ ] [PMID: 24339048]
Wang X, Yucel T, Lu Q, Hu X, Kaplan DL. Silk nanospheres and microspheres from silk/pva blend films for drug delivery. Biomaterials 2010; 31(6): 1025-35.
[ ] [PMID: 19945157]
Elia R, Guo J, Budijono S, et al. Encapsulation of volatile compounds in silk microparticles. J Coat Technol Res 2015; 12(4): 793-9.
[ ] [PMID: 26568787]
Gianak O, Pavlidou E, Sarafidis C, Karageorgiou V, Deliyanni E. Silk fibroin nanoparticles for drug delivery: effect of bovine serum albumin and magnetic nanoparticles addition on drug encapsulation and release. Separations 2018; 5(2): 25.
Montalbán MG, Coburn JM, Lozano-Pérez AA, Cenis JL, Víllora G, Kaplan DL. Production of curcumin-loaded silk fibroin nanoparticles for cancer therapy. Nanomaterials (Basel) 2018; 8(2): 126.
[ ] [PMID: 29495296]
Wen X, Peng X, Fu H, et al. Preparation and in vitro evaluation of silk fibroin microspheres produced by a novel ultra-fine particle processing system. Int J Pharm 2011; 416(1): 195-201.
[ ] [PMID: 21741461]
Li R, Wu Z, Wangb Y, Ding L, Wang Y. Role of pH-induced structural change in protein aggregation in foam fractionation of bovine serum albumin. Biotechnol Rep (Amst) 2016; 9: 46-52.
[ ] [PMID: 28352591]
Lohcharoenkal W, Wang L, Chen YC, Rojanasakul Y. Protein nanoparticles as drug delivery carriers for cancer therapy. BioMed Res Int 2014; 2014180549
[ ] [PMID: 24772414]
Langer K, Balthasar S, Vogel V, Dinauer N, von Briesen H, Schubert D. Optimization of the preparation process for human serum albumin (HSA) nanoparticles. Int J Pharm 2003; 257(1-2): 169-80.
[ ] [PMID: 12711172]
Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 2011; 153(3): 198-205.
[ ] [PMID: 21663778]
Wongpinyochit T, Johnston BF, Seib FP. Manufacture and drug delivery applications of silk nanoparticles. Journal Visualized Exp JoVE 2016; 116e54669
Ding B, Wahid MA, Wang Z, et al. Triptolide and celastrol loaded silk fibroin nanoparticles show synergistic effect against human pancreatic cancer cells. Nanoscale 2017; 9(32): 11739-53.
[ ] [PMID: 28782773]
Xie RJ, Wu HY, Zhu MN, Huang YY. Preparation and characterization of silk fibroin microspheres. Adv Mat Res 2011; 175-176: 110-5.
Yang D. The preparation of silk fibroin microsphere. J Pharm Res 2013; 32(10): 590-2.
Wang Z, Wang D, Zhou H, Li J. Effect of ultrasonic assistance on morphology of silk fibroin microspheres prepared by emulsion cross-linking process. J Textile Res 2019; 40(2): 125-30.
Imsombut T, Srisuwan Y, Srihanam P, Baimark Y. Genipin-cross-linked silk fibroin microspheres prepared by the simple water-in-oil emulsion solvent diffusion method. Powder Technol 2010; 203(3): 603-8.
Feng J, Wu Y, Chen W, et al. Sustained release of bioactive IGF-1 from a silk fibroin microsphere-based injectable alginate hydrogel for the treatment of myocardial infarction. J Mater Chem B Mater Biol Med 2020; 8(2): 308-15.
[ ] [PMID: 31808500]
Ratanavaraporn J, Soontornvipart K, Shuangshoti S, Shuangshoti S, Damrongsakkul S. Localized delivery of curcumin from injectable gelatin/Thai silk fibroin microspheres for anti-inflammatory treatment of osteoarthritis in a rat model. Inflammopharmacology 2017; 25(2): 211-21.
[ ] [PMID: 28251487]
Zeng S, Ye M, Qiu J, et al. Preparation and characterization of genipin-cross-linked silk fibroin/chitosan sustained-release microspheres. Drug Des Devel Ther 2015; 9: 2501-14.
[ ] [PMID: 25999693]
Whitesides GM, Grzybowski B. Self-assembly at all scales. Science 2002; 295(5564): 2418-21.
[ ] [PMID: 11923529]
Cheng C, Teasdale I, Brüggemann O. Stimuli-responsive capsules prepared from regenerated silk fibroin microspheres. Macromol Biosci 2014; 14(6): 807-16.
[ ] [PMID: 24532252]
Garay RP, Labaune JP. Immunogenicity of Polyethylene Glycol (PEG). Open Conf Proc J 2011; 2(1): 228-31.
Jing W, Roberts JW, Green DE, Almond A, DeAngelis PL. Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia. Glycobiology 2017; 27(11): 1052-61.
[ ] [PMID: 28973394]
Wu J, Zheng Z, Li G, Kaplan DL, Wang X. Control of silk microsphere formation using polyethylene glycol (PEG). Acta Biomater 2016; 39: 156-68.
[ ] [PMID: 27181879]
Wu J, Xie X, Zheng Z, Li G, Wang X, Wang Y. Effect of pH on polyethylene glycol (PEG)-induced silk microsphere formation for drug delivery. Mater Sci Eng C 2017; 80: 549-57.
[ ] [PMID: 28866200]
Lu Q, Wang X, Hu X, Cebe P, Omenetto F, Kaplan DL. Stabilization and release of enzymes from silk films. Macromol Biosci 2010; 10(4): 359-68.
[ ] [PMID: 20217856]
Kim C, Yang Y, Bahn S, Cha HJ. A bioinspired dual-crosslinked tough silk protein hydrogel as a protective biocatalytic matrix for carbon sequestration. NPG Asia Mater 2017; 9e391
Patel SKS, Choi SH, Kang YC, Lee J-K. Eco-friendly composite of Fe3O4-reduced graphene oxide particles for efficient enzyme immobilization. ACS Appl Mater Interfaces 2017; 9(3): 2213-22.
[ ] [PMID: 28004579]
Olga G, George ZK, Victoria FS, Eleni AD. A review for the synthesis of silk fibroin nanoparticles with different techniques and their ability to be used for drug delivery. Curr Anal Chem 2019; 15(4): 339-48.
Xiao M, Lv S. Self-assembled regenerated silk fibroin microsphere-embedded fe3o4 magnetic nanoparticles for immobilization of zymolyase. ACS Omega 2019; 4(25): 21612-9.
[ ] [PMID: 31867558]
Zhang H, Ma X, Cao C, Wang M, Zhu Y. Multifunctional iron oxide/silk-fibroin (Fe3O4-SF) composite microspheres for the delivery of cancer therapeutics. RSC Advances 2014; 4(78): 41572-7.
Zeng DM, Pan JJ, Wang Q, Liu X-F, Wang H, Zhang KQ. Controlling silk fibroin microspheres via molecular weight distribution. Mater Sci Eng C 2015; 50: 226-33.
[ ] [PMID: 25746265]
Ding X, Wei X, Huang Y, et al. Delivery of demineralized bone matrix powder using a salt-leached silk fibroin carrier for bone regeneration. J Mater Chem B Mater Biol Med 2015; 3(16): 3177-88.
[ ] [PMID: 32262311]
Wang L, Xia ZR, Lv LL, Tang Q, Li MZ. Preparation of silk fibroin microspheres. Adv Mat Res 2011; 236-238: 1902-5.
Lu Q, Huang Y, Li M, et al. Silk fibroin electrogelation mechanisms. Acta Biomater 2011; 7(6): 2394-400.
[ ] [PMID: 21345387]
Wang Q, Yan S, Han G, et al. Facile fabrication of silk fibroin microspheres via electrostatic assembly. Mater Res Express 2018; 5(7)075401
Huang YLLUQ, Li M, Zhang B, Zhu H. Silk fibroin microsphere drug carriers perpared under electric fields. Chin Sci Bull 2011; 56(13): 1013-8.
Balgis R, Ernawati L, Ogi T, Okuyama K, Gradoń L. Controlled surface topography of nanostructured particles prepared by spray drying process. AIChE J 2017; 63(5): 1503-11.
Muljani S, Setyawan H, Sumada K. The morphology of Si-K-HAs composite prepared by spray drying. Mater Sci Forum 2019; 966: 19-24.
Gharsallaoui A, Roudaut G, Chambin O, Voilley A, Saurel R. Applications of spray-drying in microencapsulation of food ingredients: an overview. Food Res Int 2007; 40(9): 1107-21.
Palmieri GF, Bonacucina G, Di Martino P, Martelli S. Spray-drying as a method for microparticulate controlled release systems preparation: advantages and limits. I. Water-soluble drugs. Drug Dev Ind Pharm 2001; 27(3): 195-204.
[ ] [PMID: 11291199]
Sapra M, Mayya YS, Venkataraman C. Engineering of layered, lipid-encapsulated drug nanoparticles through spray-drying. Colloids Surf B Biointerfaces 2017; 154: 178-85.
[ ] [PMID: 28340484]
Bayraktar O, Köse M, Baspinar Y. Development of olive leaf extract loaded fibroin microparticles by spray drying. Drug Discovery 2019; 13: 39-45.
Sosnik A, Seremeta KP. Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers. Adv Colloid Interface Sci 2015; 223: 40-54.
[ ] [PMID: 26043877]
Whitesides GM. The origins and the future of microfluidics. Nature 2006; 442(7101): 368-73.
[ ] [PMID: 16871203]
Jo YK, Lee D. Biopolymer Microparticles Prepared by microfluidics for biomedical applications. Small 2020; 16(9)e1903736
[ ] [PMID: 31559690]
Chen L, Lei M, Zhang D. Preparation of silk fibroin microspheres by microfluidic techniques. Mod Silk Sci Technol 2018; 33(2): 1-4.
Mbanjwa MB, Land KJ, Windvoel T, et al. Production of self-immobilised enzyme microspheres using microfluidics. Process Biochem 2018; 69: 75-81.
Daly AC, Riley L, Segura T, Burdick JA. Hydrogel microparticles for biomedical applications. Nat Rev Mater 2020; 5(1): 20-43.
[ ]

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Article Details

Year: 2020
Published on: 09 October, 2020
Page: [358 - 371]
Pages: 14
DOI: 10.2174/2211738508666201009123235
Price: $65

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