Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

3D Printing Technology: A New Milestone in the Development of Pharmaceuticals

Author(s): Anish Chandekar, Dinesh K. Mishra*, Sanjay Sharma, Gaurav K. Saraogi, Umesh Gupta and Gaurav Gupta

Volume 25 , Issue 9 , 2019

Page: [937 - 945] Pages: 9

DOI: 10.2174/1381612825666190507115504

Price: $65


The global market of pharmaceuticals has witnessed a new revolution recently in the form of threedimensional printing (3D) technology. 3D printing has its existence since the 1980s that uses a 3D printer to manufacture the different dosage forms through computer-aided drug design technology. The need for 3D printing is due to numerous advantages like personalized medicine, tailored doses, rapid disintegration in case of SLS technique, incorporation of high doses and taste masking capacity. The different techniques used in 3D printing are Powder based (PB), Semi-solid extrusion (EXT), Fused deposition modeling (FDM), Stereolithographic (SLA) and Selective laser sintering (SLS) 3D printing. However, from the latest reports of association of pharmaceutical 3D printing technology, it is evidenced that this technology is still in its infancy and its potential is yet to be fully explored. The present review includes sections for introduction and scope of 3D printing, personalized medicines and their approaches, historical aspects, research milestones, and various 3D printing techniques.

Keywords: Personalized medicine, Powder based printing, Inkjet printing, Semisolid extrusion, 3D printing, Fused deposition modeling (FDM).

Gross BC, Erkal JL, Lockwood SY, Chen C, Spence DM. Evaluation of 3D printing and its potential impact on biotechnology and the chemical sciences. Anal Chem 2014; 86(7): 3240-53.
Raijada D, Genina N, Fors D, et al. A step toward development of printable dosage forms for poorly soluble drugs. J Pharm Sci 2013; 102(10): 3694-704. []. [PMID: 23904182].
Merchant HA, Liu F, Orlu Gul M, Basit AW. Age-mediated changes in the gastrointestinal tract. Int J Pharm 2016; 512(2): 382-95. []. [PMID: 27085646].
Jamei M, Turner D, Yang J, et al. Population-based mechanistic prediction of oral drug absorption. AAPS J 2009; 11(2): 225-37. []. [PMID: 19381840].
Cohen JS. Ways to minimize adverse drug reactions. Individualized doses and common sense are key. Postgrad Med 1999; 106(3): 163-168, 171-172. []. [PMID: 10494273].
Ervasti T, Simonaho SP, Ketolainen J, et al. Continuous manufacturing of extended release tablets via powder mixing and direct compression. Int J Pharm 2015; 495(1): 290-301. []. [PMID: 26320548].
Habib WA, Alanizi AS, Abdelhamid MM, Alanizi FK. Accuracy of tablet splitting: Comparison study between hand splitting and tablet cutter. Saudi Pharm J 2014; 22(5): 454-9. []. [PMID: 25473334].
Helmy SA. Tablet splitting: is it worthwhile? Analysis of drug content and weight uniformity for half tablets of 16 commonly used medications in the outpatient setting. J Manag Care Spec Pharm 2015; 21(1): 76-86. []. [PMID: 25562775].
Hill SW, Varker AS, Karlage K, Myrdal PB. Analysis of drug content and weight uniformity for half-tablets of 6 commonly split medications. J Manag Care Pharm 2009; 15(3): 253-61. []. [PMID: 19326956].
Tahaineh LM, Gharaibeh SF. Tablet splitting and weight uniformity of half-tablets of 4 medications in pharmacy practice. J Pharm Pract 2012; 25(4): 471-6. []. [PMID: 22544621].
Pouplin T, Phuong PN, Toi PV, Nguyen Pouplin J, Farrar J. Isoniazid, pyrazinamide and rifampicin content variation in split fixed-dose combination tablets. PLoS One 2014; 9(7): e102047. []. [PMID: 25004128].
van Riet-Nales DA, Doeve ME, Nicia AE, et al. The accuracy, precision and sustainability of different techniques for tablet subdivision: breaking by hand and the use of tablet splitters or a kitchen knife. Int J Pharm 2014; 466(1-2): 44-51. []. [PMID: 24561329].
Palo M, Holländer J, Suominen J, Yliruusi J, Sandler N. 3D printed drug delivery devices: perspectives and technical challenges. Expert Rev Med Devices 2017; 14(9): 685-96. []. [PMID: 28774216].
Erramouspe J, Jarvi EJ. Effect on dissolution from halving methylphenidate extended-release tablets. Ann Pharmacother 1997; 31(10): 1123-6. []. [PMID: 9337434].
Shah VP, Yamamoto LA, Schuirman D, Elkins J, Skelly JP. Analysis of in vitro dissolution of whole vs. half controlled-release theophylline tablets. Pharm Res 1987; 4(5): 416-9. []. [PMID: 3508552].
Trenfield SJ, Awad A, Goyanes A, Gaisford S, Basit AW. 3D Printing Pharmaceuticals: Drug Development to Frontline Care. Trends Pharmacol Sci 2018; 39(5): 440-51. []. [PMID: 29534837].
Kaae S, Lind JLM, Genina N, Sporrong SK. Unintended consequences for patients of future personalized pharmacoprinting. Int J Clin Pharm 2018; 40(2): 321-4. []. [PMID: 29380235].
Zema L, Melocchi A, Maroni A, Gazzaniga A. Three-Dimensional Printing of Medicinal Products and the Challenge of Personalized Therapy. J Pharm Sci 2017; 106(7): 1697-705. []. [PMID: 28347731].
Pietrzak K, Isreb A, Alhnan MA. A flexible-dose dispenser for immediate and extended release 3D printed tablets. Eur J Pharm Biopharm 2015; 96: 380-7. []. [PMID: 26277660].
Goyanes A, Fina F, Martorana A, Sedough D, Gaisford S, Basit AW. Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing. Int J Pharm 2017; 527(1-2): 21-30. []. [PMID: 28502898].
Goyanes A, Robles Martinez P, Buanz A, Basit AW, Gaisford S. Effect of geometry on drug release from 3D printed tablets. Int J Pharm 2015; 494(2): 657-63. []. [PMID: 25934428].
Martinez PR, Goyanes A, Basit AW, Gaisford S. Influence of Geometry on the Drug Release Profiles of Stereolithographic (SLA) 3D-Printed Tablets. AAPS PharmSciTech 2018; 19(8): 3355-61. []. [PMID: 29948979].
Goyanes A, Scarpa M, Kamlow M, Gaisford S, Basit AW, Orlu M. Patient acceptability of 3D printed medicines. Int J Pharm 2017; 530(1-2): 71-8. []. [PMID: 28750894].
Sadia M, Arafat B, Ahmed W, Forbes RT, Alhnan MA. Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets. J Control Release 2018; 269: 355-63. []. [PMID: 29146240].
Arafat B, Wojsz M, Isreb A, et al. Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets. Eur J Pharm Sci 2018; 118: 191-9. []. [PMID: 29559404].
Okwuosa TC, Pereira BC, Arafat B, Cieszynska M, Isreb A, Alhnan MA. Fabricating a Shell-Core Delayed Release Tablet Using Dual FDM 3D Printing for Patient-Centred Therapy. Pharm Res 2017; 34(2): 427-37. []. [PMID: 27943014].
Maroni A, Melocchi A, Parietti F, Foppoli A, Zema L, Gazzaniga A. 3D printed multi-compartment capsular devices for two-pulse oral drug delivery. J Control Release 2017; 268: 10-8. []. [PMID: 29030223].
Goyanes A, Chang H, Sedough D, et al. Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing. Int J Pharm 2015; 496(2): 414-20. []. [PMID: 26481468].
Downing J. Cycle Pharmaceuticals to use 3D printing to develop ‘orphan drugs. Cambridge Independent 2018.
World 3D printing Healthcare Market- Opportunities and Forecasts, 2014-2020 Allied market research reportwwwalliedmarketresearchcom
Norman J, Madurawe RD, Moore CM, Khan MA, Khairuzzaman A. A new chapter in pharmaceutical manufacturing: 3D-printed drug products. Adv Drug Deliv Rev 2017; 108: 39-50. []. [PMID: 27001902].
Alhnan MA, Okwuosa TC, Sadia M, Wan KW, Ahmed W, Arafat B. Emergence of 3D Printed Dosage Forms: Opportunities and Challenges. Pharm Res 2016; 33(8): 1817-32. []. [PMID: 27194002].
Awad A, Trenfield SJ, Goyanes A, Gaisford S, Basit AW. Reshaping drug development using 3D printing. Drug Discov Today 2018; 23(8): 1547-55. []. [PMID: 29803932].
Kodama H. A scheme for three-dimensional display by automatic fabrication of three-dimensional model. J IEICE 1981; 64: 1981-4.
Mendoza HR. Alain Le Méhauté, the Man Who Submitted Patent for SLA 3D Printing before Chuck Hull.
Moussion A. Interview d‘Alain Le Méhauté, l‘un des pères del‘impression 3D". Primante 3D 2014.
Hull CW. Inventor Uvp Inc., Assignee. Apparatus for production of three-dimensional objects by stereolithography. United States Patent US 4 575 330A 1986.
Hull CW. Inventor; 3D Systems, Inc., assignee. Method for production of three-dimensional objects by stereolithography. United States patent US 5762856A 1990.
Hull CW, Spence ST, Albert DJ, et al. Inventors. Method and apparatus for production of high resolution three-dimensional objects by stereolithography. United States patent US 5184307, 1993.
Gbureck U, Vorndran E, Müller FA, Barralet JE. Low temperature direct 3D printed bioceramics and biocomposites as drug release matrices. J Control Release 2007; 122(2): 173-80. []. [PMID: 17655962].
Infanger S, Haemmerli A, Iliev S, Baier A, Stoyanov E, Quodbach J. Powder bed 3D-printing of highly loaded drug delivery devices with hydroxypropyl cellulose as solid binder. Int J Pharm 2019; 555: 198-206. []. [PMID: 30458260].
Katstra WE, Palazzolo RD, Rowe CW, Giritlioglu B, Teung P, Cima MJ. Oral dosage forms fabricated by three dimensional printing. J Control Release 2000; 66(1): 1-9. []. [PMID: 10708873].
Vuddanda PR, Alomari M, Dodoo CC, et al. Personalisation of warfarin therapy using thermal ink-jet printing. Eur J Pharm Sci 2018; 117: 80-7. []. [PMID: 29414676].
Khaled SA, Burley JC, Alexander MR, Roberts CJ. Desktop 3D printing of controlled release pharmaceutical bilayer tablets. Int J Pharm 2014; 461(1-2): 105-11. []. [PMID: 24280018].
Varan C, Şen M, Sandler N, Aktaş Y, Bilensoy E. Mechanical characterization and ex vivo evaluation of anticancer and antiviral drug printed bioadhesive film for the treatment of cervical cancer. Eur J Pharm Sci 2019; 130: 114-23. []. [PMID: 30690187].
Lee BK, Yun YH, Choi JS, Choi YC, Kim JD, Cho YW. Fabrication of drug-loaded polymer microparticles with arbitrary geometries using a piezoelectric inkjet printing system. Int J Pharm 2012; 427(2): 305-10. []. [PMID: 22366486].
Iftimi L-D, Edinger M, Bar-Shalom D, Rantanen J, Genina N. Edible solid foams as porous substrates for inkjet-printable pharmaceuticals. Eur J Pharm Biopharm 2019; 136: 38-47. []. [PMID: 30630061].
Wu G, Wu W, Zheng Q, Li J, Zhou J, Hu Z. Experimental study of PLLA/INH slow release implant fabricated by three dimensional printing technique and drug release characteristics in vitro. Biomed Eng Online 2014; 13(1): 97. []. [PMID: 25038793].
Wu W, Zheng Q, Guo X, Sun J, Liu Y. A programmed release multi-drug implant fabricated by three-dimensional printing technology for bone tuberculosis therapy. Biomed Mater 2009; 4(6): 065005. []. [PMID: 19901446].
Muwaffak Z, Goyanes A, Clark V, Basit AW, Hilton ST, Gaisford S. Patient-specific 3D scanned and 3D printed antimicrobial polycaprolactone wound dressings. Int J Pharm 2017; 527(1-2): 161-70. []. [PMID: 28461267].
Genina N, Holländer J, Jukarainen H, Mäkilä E, Salonen J, Sandler N. Ethylene vinyl acetate (EVA) as a new drug carrier for 3D printed medical drug delivery devices. Eur J Pharm Sci 2016; 90: 53-63. []. [PMID: 26545484].
Melocchi A, Inverardi N, Uboldi M, et al. Retentive device for intravesical drug delivery based on water-induced shape memory response of poly(vinyl alcohol): design concept and 4D printing feasibility. Int J Pharm 2019; 559: 299-311. []. [PMID: 30707934].
Fu J, Yu X, Jin Y. 3D printing of vaginal rings with personalized shapes for controlled release of progesterone. Int J Pharm 2018; 539(1-2): 75-82. []. [PMID: 29366944].
Liang K, Carmone S, Brambilla D, Leroux JC. 3D printing of a wearable personalized oral delivery device: A first-in-human study. Sci Adv 2018; 4(5): eaat2544. [] [PMID: 29750201]
Scoutaris N, Alexander MR, Gellert PR, Roberts CJ. Inkjet printing as a novel medicine formulation technique. J Control Release 2011; 156(2): 179-85. []. [PMID: 21827800].
Meléndez PA, Kane KM, Ashvar CS, Albrecht M, Smith PA. Thermal inkjet application in the preparation of oral dosage forms: dispensing of prednisolone solutions and polymorphic characterization by solid-state spectroscopic techniques. J Pharm Sci 2008; 97(7): 2619-36. []. [PMID: 17876767].
Buanz AB, Saunders MH, Basit AW, Gaisford S. Preparation of personalized-dose salbutamol sulphate oral films with thermal ink-jet printing. Pharm Res 2011; 28(10): 2386-92. []. [PMID: 21544688].
Boehm RD, Daniels J, Stafslien S, Nasir A, Lefebvre J, Narayan RJ. Polyglycolic acid microneedles modified with inkjet-deposited antifungal coatings. Biointerphases 2015; 10(1): 011004. []. [PMID: 25732934].
Lorber B, Hsiao WK, Hutchings IM, Martin KR. Adult rat retinal ganglion cells and glia can be printed by piezoelectric inkjet printing. Biofabrication 2014; 6(1): 015001. []. [PMID: 24345926].
Uddin MJ, Scoutaris N, Klepetsanis P, Chowdhry B, Prausnitz MR, Douroumis D. Inkjet printing of transdermal microneedles for the delivery of anticancer agents. Int J Pharm 2015; 494(2): 593-602. []. [PMID: 25617676].
Goyanes A, Buanz AB, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm Biopharm 2015; 89: 157-62. []. [PMID: 25497178].
Goyanes A, Buanz AB, Basit AW, Gaisford S. Fused-filament 3D printing (3DP) for fabrication of tablets. Int J Pharm 2014; 476(1-2): 88-92. []. [PMID: 25275937].
Wang J, Goyanes A, Gaisford S, Basit AW. Stereolithographic (SLA) 3D printing of oral modified-release dosage forms. Int J Pharm 2016; 503(1-2): 207-12. []. [PMID: 26976500].
Skowyra J, Pietrzak K, Alhnan MA. Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. Eur J Pharm Sci 2015; 68: 11-7. []. [PMID: 25460545].
Goyanes A, Chang H, Sedough D, et al. Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing. Int J Pharm 2015; 496(2): 414-20. []. [PMID: 26481468].
Goyanes A, Wang J, Buanz A, et al. 3D printing of medicines: engineering novel oral devices with unique design and drug release characteristics. Mol Pharm 2015; 12(11): 4077-84. []. [PMID: 26473653].
Aprecia Zipdose® Technology 12/3/2015 Available from: https://apreciacom/zipdose-platform/zipdose-technologyphp
Rowe CW, Katstra WE, Palazzolo RD, Giritlioglu B, Teung P, Cima MJ. Multimechanism oral dosage forms fabricated by three dimensional printing. J Control Release 2000; 66(1): 11-7. []. [PMID: 10708874].
Huang W, Zheng Q, Sun W, Xu H, Yang X. Levofloxacin implants with predefined microstructure fabricated by three-dimensional printing technique. Int J Pharm 2007; 339(1-2): 33-8. []. [PMID: 17412538].
Yu DG, Shen XX, Branford-White C, Zhu LM, White K, Yang XL. Novel oral fast-disintegrating drug delivery devices with predefined inner structure fabricated by Three-Dimensional Printing. J Pharm Pharmacol 2009; 61(3): 323-9. []. [PMID: 19222904].
Pham DT, Gault RS. A comparison of rapid prototyping technologies. Int J Mach Tools Manuf 1998; 38(10): 1257-87. [].
Waldbaur A, Rapp H, Laenge K, Rapp BE. Let there be chip-towards rapid prototyping of microfluidic devices: one-step manufacturing processes. Anal Methods 2011; 3(12): 2681-716. [].
Luzuriaga MA, Berry DR, Reagan JC, Smaldone RA, Gassensmith JJ. Biodegradable 3D printed polymer microneedles for transdermal drug delivery. Lab Chip 2018; 18(8): 1223-30. []. [PMID: 29536070].
Beck RCR, Chaves PS, Goyanes A, et al. 3D printed tablets loaded with polymeric nanocapsules: An innovative approach to produce customized drug delivery systems. Int J Pharm 2017; 528(1-2): 268-79. []. [PMID: 28583328].
Sood AK, Ohdar RK, Mahapatra SS. Improving dimensional accuracy of fused deposition modelling processed part using grey Taguchi method. Mater Des 2009; 30(10): 4243-52. [].
Wendel B, Rietzel D, Kühnlein F, Feulner R, Hülder G, Schmachtenberg E. Additive processing of polymers 2008; 293(10): 799-809. []
Catanzaro BC. Compilation Techniques for Embedded Data Parallel Languages. Berkeley: University of California 2011.
Dombroski CE, Balsdon ME, Froats A. The use of a low cost 3D scanning and printing tool in the manufacture of custom-made foot orthoses: a preliminary study. BMC Res Notes 2014; 7: 443. []. [PMID: 25015013].
Yu DG, Branford-White C, Ma ZH, Zhu LM, Li XY, Yang XL. Novel drug delivery devices for providing linear release profiles fabricated by 3DP. Int J Pharm 2009; 370(1-2): 160-6. []. [PMID: 19118612].
Tagami T, Fukushige K, Ogawa E, Hayashi N, Ozeki T. 3D Printing Factors Important for the Fabrication of Polyvinylalcohol Filament-Based Tablets. Biol Pharm Bull 2017; 40(3): 357-64. []. [PMID: 28250279].
Awad A, Trenfield SJ, Gaisford S, Basit AW. 3D printed medicines: A new branch of digital healthcare. Int J Pharm 2018; 548(1): 586-96. []. [PMID: 30033380].
Nokhodchi D, Maniruzzaman AM. 3D and 4D printing technologies: innovative process engineering and smart additive manufacturing. 3D and 4D Printing in Biomedical Applications: Process Engineering and Additive Manufacturing 2019; 25-52.
Firth J, Basit AW, Gaisford S. The Role of Semi-Solid Extrusion Printing in Clinical Practice In 3D Printing of Pharmaceuticals. Cham: Springer International Publishing 2018.
Vithani K, Goyanes A, Jannin V, Basit AW, Gaisford S, Boyd BJ. An Overview of 3D Printing Technologies for Soft Materials and Potential Opportunities for Lipid-based Drug Delivery Systems. Pharm Res 2018; 36(1): 4. []. [PMID: 30406349].
Vakili H, Kolakovic R, Genina N, et al. Hyperspectral imaging in quality control of inkjet printed personalised dosage forms. Int J Pharm 2015; 483(1-2): 244-9. []. [PMID: 25527212].
Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of tablets containing multiple drugs with defined release profiles. Int J Pharm 2015; 494(2): 643-50. []. [PMID: 26235921].
Vitale A, Cabral JT. Frontal Conversion and Uniformity in 3D Printing by Photopolymerisation. Materials (Basel) 2016; 9(9): 760. []. [PMID: 28773881].
Konta AA, García-Piña M, Serrano DR. Personalised 3D printed medicines: which techniques and polymers are more successful? Bioengineering (Basel) 2017; 4(4): 79. []. [PMID: 28952558].
Martinez PR, Goyanes A, Basit AW, Gaisford S. Fabrication of drug-loaded hydrogels with stereolithographic 3D printing. Int J Pharm 2017; 532(1): 313-7. []. [PMID: 28888978].
Pere CPP, Economidou SN, Lall G, et al. 3D printed microneedles for insulin skin delivery. Int J Pharm 2018; 544(2): 425-32. []. [PMID: 29555437].
Goole J, Amighi K. 3D printing in pharmaceutics: A new tool for designing customized drug delivery systems. Int J Pharm 2016; 499(1-2): 376-94. []. [PMID: 26757150].
Schmidt M, Pohle D, Rechtenwald T. Selective laser sintering of PEEK. CIRP Ann 2007; 56(1): 205-8. [].
Lim SH, Ng JY, Kang L. Three-dimensional printing of a microneedle array on personalized curved surfaces for dual-pronged treatment of trigger finger. Biofabrication 2017; 9(1): 015010. []. [PMID: 28071597].
Bloomquist CJ, Mecham MB, Paradzinsky MD, et al. Controlling release from 3D printed medical devices using CLIP and drug-loaded liquid resins. J Control Release 2018; 278: 9-23. []. [PMID: 29596874].
Salmoria GV, Cardenuto MR, Roesler CRM, Zepon KM, Kanis LA. PCL/ibuprofen implants fabricated by selective laser sintering for orbital repair. Procedia CIRP 2016; 49: 188-92. [].
Awad A, Fina F, Trenfield SJ, et al. 3D Printed Pellets (Miniprintlets): A Novel, Multi-Drug, Controlled Release Platform Technology. Pharmaceutics 2019. 11.4: 148. [].
Wening K, Breitkreutz J. Oral drug delivery in personalized medicine: unmet needs and novel approaches. Int J Pharm 2011; 404(1-2): 1-9. []. [PMID: 21070842].
Fina F, Goyanes A, Gaisford S, Basit AW. Selective laser sintering (SLS) 3D printing of medicines. Int J Pharm 2017; 529(1-2): 285-93. [].
Jamróz W, Szafraniec J, Kurek M, Jachowicz R. 3D Printing in Pharmaceutical and Medical Applications - Recent Achievements and Challenges. Pharm Res 2018; 35(9): 176. []. [PMID: 29998405].
University College London- School of Pharmacy, 3D printed animal- shaped tablets for children, 2015 Available from: https://wwwuclacuk/pharmacy/ pharmacy-news/animal-shapedtablets
Srai JS, Badman C, Krumme M, Futran M, Johnston C. Future Supply Chains Enabled by Continuous Processing-Opportunities Challenges May 20–21 2014 Continuous Manufacturing Symposium. J Pharm Sci 2015; 104: 840-9. [].
Siyawamwaya M, du Toit LC, Kumar P, Choonara YE, Kondiah PPPD, Pillay V. 3D printed, controlled release, tritherapeutic tablet matrix for advanced anti-HIV-1 drug delivery. Eur J Pharm Biopharm 2018; 138: 99-110. [PMID: 29655904].
Goyanes A, Wang J, Buanz A, et al. 3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics. Mol Pharm 2015; 12(11): 4077-84. [].
Li Q, Wen H, Jia D, et al. Preparation and investigation of controlled-release glipizide novel oral device with three-dimensional printing. Int J Pharm 2017; 525(1): 5-11. []. [PMID: 28377316].
Genina N, Boetker JP, Colombo S, Harmankaya N, Rantanen J, Bohr A. Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing. J Control Release 2017; 268: 40-8. []. [PMID: 28993169].

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy