Abstract
The term four-dimensional (4D) printing refers to the fabrication via additive manufacturing (AM) of structures with the capability to shape transform over time under a predefined stimulus (e.g., temperature, pH, electric field, humidity). Since its introduction in 2013, 4D printing has been in rapid expansion in several fields, including smart textiles, autonomous and soft robotics, biomedical devices, electronics, and tissue engineering. Shape-changing, self-repairing, and self-assembly are some of the characteristics usually associated with 4D printing, highlighting that 4D printed structures are no longer static objects but programmable active structures that accomplish their function through a change in their physical and/or chemical properties over time when exposed to a predetermined stimulus. Here, AM acts as an enabling technology by allowing a precise arrangement of an exact amount of one or more stimulus-responsive materials in predefined positions, without any constraints on the geometric complexity.
In the last few years, 4D printing has been exploited to develop increasingly sophisticated pharmaceutical and drug delivery systems, providing several advantages when compared with conventional fabrication approaches, such as (i) obtaining a highly controllable kinetic thanks to the smart properties and patterning of the involved stimulus-responsive material(s), (ii) achieving a time- and/or site-dependent drug release according to the shape-shifting of the structure after the sensing of a defined stimulus (e.g., change in pH or temperature, near-infrared lighting), and (iii) increasing the freedom to design systems able to settle, adapt, or remain and then release the conveyed drug in the target districts or move away from them.
In this chapter, we aim to provide the reader with an overview of 4D printing, as an emerging and breakthrough fabrication technology. Then, relevant examples from the recent literature regarding the use of 4D printing for the development of pharmaceutical and drug delivery systems are presented and deeply discussed.
Irene Chiesa and Amedeo Franco Bonatti are co-first authors.
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References
Agarwal T, Hann SY, Chiesa I et al (2021) 4D printing in biomedical applications: emerging trends and technologies. J Mater Chem B 9:7608–7632. https://doi.org/10.1039/d1tb01335a
Bakarich SE, Gorkin R, In PM, Het SGM (2015) 4D printing with mechanically robust, thermally actuating hydrogels. Macromol Rapid Commun 36:1211–1217. https://doi.org/10.1002/marc.201500079
Banwell EF, Abelardo ES, Adams DJ et al (2009) Rational design and application of responsive α-helical peptide. Nat Mater 8:596–600
Bodaghi M, Noroozi R, Zolfagharian A et al (2019) 4D printing self-morphing structures. Materials 12. https://doi.org/10.3390/ma12081353
Bonatti AF, Chiesa I, Vozzi G, De Maria C (2021) Open-source CAD-CAM simulator of the extrusion-based bioprinting process. Bioprinting 24:e00172. https://doi.org/10.1016/j.bprint.2021.e00172
Bonatti AF, Fortunato GM, De Maria C, Vozzi G (2022) Bioprinting technologies: an overview. In: Bioprinting, pp 19–49
Borisova OV, Billon L, Richter RP et al (2015) PH- and electro-responsive properties of poly(acrylic acid) and poly(acrylic acid)-block-poly(acrylic acid-grad-styrene) brushes studied by quartz crystal microbalance with dissipation monitoring. Langmuir 31:7684–7694. https://doi.org/10.1021/acs.langmuir.5b01993
Bozuyuk U, Yasa O, Yasa IC et al (2018) Light-triggered drug release from 3D-printed magnetic chitosan microswimmers. ACS Nano 12:9617–9625. https://doi.org/10.1021/acsnano.8b05997
Breger JC, Yoon C, Xiao R et al (2015) Self-folding thermo-magnetically responsive soft microgrippers. ACS Appl Mater Interfaces 7:3398–3405. https://doi.org/10.1021/am508621s
Castro NJ, Meinert C, Levett P, Hutmacher DW (2017) Current developments in multifunctional smart materials for 3D/4D bioprinting. Curr Opin Biomed Eng 2:67–75. https://doi.org/10.1016/j.cobme.2017.04.002
Ceylan H, Yasa IC, Yasa O et al (2019) 3D-printed biodegradable microswimmer for Theranostic cargo delivery and release. ACS Nano 13:3353–3362. https://doi.org/10.1021/acsnano.8b09233
Chang C, Wei H, Quan C et al (2008) Fabrication of thermosensitive PCL-PNIPAAm-PCL triblock copolymeric micelles for drug delivery. J Polym Sci A Polym Chem 46:3048–3057. https://doi.org/10.1002/pola
Chen PJ, Hu SH, Hsiao CS et al (2011) Multifunctional magnetically removable nanogated lids of Fe 3O4-capped mesoporous silica nanoparticles for intracellular controlled release and MR imaging. J Mater Chem 21:2535–2543. https://doi.org/10.1039/c0jm02590a
Chiesa I, Ligorio C, Bonatti AF et al (2020) Modeling the three-dimensional bioprinting process of β-sheet self-assembling peptide hydrogel scaffolds. Front Med Technol 2:1–16. https://doi.org/10.3389/fmedt.2020.571626
Constantin M, Bucatariu SM, Doroftei F, Fundueanu G (2017) Smart composite materials based on chitosan microspheres embedded in thermosensitive hydrogel for controlled delivery of drugs. Carbohydr Polym 157:493–502. https://doi.org/10.1016/j.carbpol.2016.10.022
Dai S, Ravi P, Tam KC (2008) pH-responsive polymers: synthesis, properties and applications. Soft Matter 4:435–449. https://doi.org/10.1039/b714741d
Dai S, Ravi P, Tam KC (2009) Thermo- and photo-responsive polymeric systems. Soft Matter 5:2513–2533. https://doi.org/10.1039/b820044k
Dai W, Guo H, Gao B et al (2019) Double network shape memory hydrogels activated by near-infrared with high mechanical toughness, nontoxicity, and 3D printability. Chem Eng J 356:934–949. https://doi.org/10.1016/j.cej.2018.09.078
Ding H, Dong M, Zheng Q, Wu ZL (2022) Digital light processing 3D printing of hydrogels: a minireview. Mol Syst Design Eng 7:1017–1029. https://doi.org/10.1039/d2me00066k
El-Mahrouk GM, Aboul-Einien MH, Makhlouf AI (2016) Design, optimization, and evaluation of a novel metronidazole-loaded gastro-retentive pH-sensitive hydrogel. AAPS PharmSciTech 17:1285–1297. https://doi.org/10.1208/s12249-015-0467-x
Firth J, Gaisford S, Basit AW (2018) A new dimension: 4D printing opportunities in pharmaceutics. In: 3D printing of pharmaceuticals, pp 153–162
Ge J, Neofytou E, Cahill TJ et al (2012) Drug release from electric-field-responsive nanoparticles. ACS Nano 6:227–233
Gibson I, Rosen DW, Stucker B et al (2021) Additive manufacturing technologies. Springer, Cham
Han D, Morde RS, Mariani S et al (2020) 4D printing of a bioinspired microneedle array with backward-facing barbs for enhanced tissue adhesion. Adv Funct Mater 30:1909197. https://doi.org/10.1002/adfm.201909197
Hu X, Ge Z, Wang X et al (2022) Multifunctional thermo-magnetically actuated hybrid soft millirobot based on 4D printing. Compos Part B 228:109451. https://doi.org/10.1016/j.compositesb.2021.109451
Jamal M, Kadam SS, Xiao R et al (2013) Bio-origami hydrogel scaffolds composed of photocrosslinked PEG Bilayers.pdf. Adv Healthc Mater 2:1142–1150
Jeong HY, Woo BH, Kim N, Jun YC (2020) Multicolor 4D printing of shape-memory polymers for light-induced selective heating and remote actuation. Sci Rep 10:1–11. https://doi.org/10.1038/s41598-020-63020-9
Jochum FD, Theato P (2013) Temperature- and light-responsive smart polymer materials. Chem Soc Rev 42:7468–7483. https://doi.org/10.1039/c2cs35191a
Karavasili C, Fatouros DG (2016) Smart materials: In situ gel-forming systems for nasal delivery. Drug Discov Today 21:157–166. https://doi.org/10.1016/j.drudis.2015.10.016
Khan H, Shukla RN, Bajpai AK (2016) Genipin-modified gelatin nanocarriers as swelling controlled drug delivery system for in vitro release of cytarabine. Mater Sci Eng C 61:457–465. https://doi.org/10.1016/j.msec.2015.12.085
Khoo ZX, Teoh JEM, Liu Y et al (2015) 3D printing of smart materials: a review on recent progresses in 4D printing. Virtual Phys Prototyping 10:103–122. https://doi.org/10.1080/17452759.2015.1097054
Klouda L, Mikos AG (2011) Thermoresponsive hydrogels in biomedical applications—a review. Eur J Pharm Biopharm 68:34–45. https://doi.org/10.1016/j.ejpb.2007.02.025.Thermoresponsive
Kuang X, Roach DJ, Wu J et al (2019) Advances in 4D printing: materials and applications. Adv Funct Mater 29:1805290. https://doi.org/10.1002/adfm.201805290
Larush L, Kaner I, Fluksman A et al (2017) 3D printing of responsive hydrogels for drug-delivery systems. J 3D Print Med 1:219–229. https://doi.org/10.2217/3dp-2017-0009
Lee H, Cima MJ (2011) An intravesical device for the sustained delivery of lidocaine to the bladder. J Control Release 149:133–139. https://doi.org/10.1016/j.jconrel.2010.10.016
Li L, Shan H, Yue CY et al (2002) Thermally induced association and dissociation of methylcellulose in aqueous solutions. Langmuir 18:7291–7298. https://doi.org/10.1021/la020029b
Li C, Liu Y, Lo CW, Jiang H (2011) Reversible white-light actuation of carbon nanotube incorporated liquid crystalline elastomer nanocomposites. Soft Matter 7:7511–7516. https://doi.org/10.1039/c1sm05776f
Li Y, Qian Y, Liu T et al (2012) Light-triggered concomitant enhancement of magnetic resonance imaging contrast performance and drug release rate of functionalized amphiphilic diblock copolymer micelles. Biomacromolecules 13:3877–3886. https://doi.org/10.1021/bm301425j
Ligorio C, Hoyland JA, Saiani A (2022) Self-assembling peptide hydrogels as functional tools to tackle intervertebral disc degeneration. Gels 8. https://doi.org/10.3390/gels8040211
Lima MD, Li N, De Andrade MJ et al (2012) Electrically, chemically, and photonically powered torsional and tensile actuation of hybrid carbon nanotube yarn muscles. Science 338:928–932. https://doi.org/10.1126/science.1226762
Longenecker R, Mu T, Hanna M et al (2011) Thermally responsive 2-hydroxyethyl methacrylate polymers: soluble-insoluble and soluble-insoluble-soluble transitions. Macromolecules 44:8962–8971. https://doi.org/10.1021/ma201528r
Lui YS, Sow WT, Tan LP et al (2019) 4D printing and stimuli-responsive materials in biomedical aspects. Acta Biomater 92:19–36. https://doi.org/10.1016/j.actbio.2019.05.005
Lutz JF (2011) Thermo-switchable materials prepared using the OEGMA-platform. Adv Mater 23:2237–2243. https://doi.org/10.1002/adma.201100597
Malda J, Visser J, Melchels FP et al (2013) 25th anniversary article: engineering hydrogels for biofabrication. Adv Mater 25:5011–5028. https://doi.org/10.1002/adma.201302042
Melocchi A, Uboldi M, Inverardi N et al (2019a) Expandable drug delivery system for gastric retention based on shape memory polymers: development via 4D printing and extrusion. Int J Pharm 571:118700. https://doi.org/10.1016/j.ijpharm.2019.118700
Melocchi A, Inverardi N, Uboldi M et al (2019b) 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 559:299–311. https://doi.org/10.1016/j.ijpharm.2019.01.045
Melocchi A, Uboldi M, Cerea M et al (2021) Shape memory materials and 4D printing in pharmaceutics. Adv Drug Deliv Rev 173:216–237. https://doi.org/10.1016/j.addr.2021.03.013
Miao S, Castro N, Nowicki M et al (2017) 4D printing of polymeric materials for tissue and organ regeneration. Mater Today 20:577–591. https://doi.org/10.1016/j.mattod.2017.06.005
Mirvakili SM, Langer R (2021) Wireless on-demand drug delivery. Nature Electronics 4:464–477. https://doi.org/10.1038/s41928-021-00614-9
Moroni L, Boland T, Burdick JA et al (2018) Biofabrication: a guide to technology and terminology. Trends Biotechnol 36:384–402. https://doi.org/10.1016/j.tibtech.2017.10.015
Morouço P, Azimi B, Milazzo M et al (2020) Four-dimensional (bio-)printing: a review on stimuli-responsive mechanisms and their biomedical suitability. Appl Sci (Switzerland) 10:1–30. https://doi.org/10.3390/app10249143
Mu X, Sowan N, Tumbic JA et al (2015) Photo-induced bending in a light-activated polymer laminated composite. Soft Matter 11:2673–2682. https://doi.org/10.1039/c4sm02592j
Nishiguchi A, Zhang H, Schweizerhof S et al (2020) 4D printing of a light-driven soft actuator with programmed printing density. ACS Appl Mater Interfaces 12:12176–12185. https://doi.org/10.1021/acsami.0c02781
Okwuosa TC, Pereira BC, Arafat B et al (2017) Fabricating a shell-core delayed release tablet using dual FDM 3D printing for patient-centred therapy. Pharm Res 34:427–437. https://doi.org/10.1007/s11095-016-2073-3
Osouli-Bostanabad K, Masalehdan T, Kapsa RM et al (2022) Traction of 3D and 4D printing in the healthcare industry: from drug delivery and analysis to regenerative medicine. ACS Biomater Sci Eng 8:2764–2797
Palza H, Zapata PA, Angulo-Pineda C (2019) Electroactive smart polymers for biomedical applications. Materials 12. https://doi.org/10.3390/ma12020277
Peralta Ramos ML, González JA, Fabian L et al (2017) Sustainable and smart keratin hydrogel with pH-sensitive swelling and enhanced mechanical properties. Mater Sci Eng C 78:619–626. https://doi.org/10.1016/j.msec.2017.04.120
Plamper FA, Ruppel M, Schmalz A et al (2007) Tuning the thermoresponsive properties of weak polyelectrolytes: aqueous solutions of star-shaped and linear. Macromolecules 40:8361–8366
Price PM, Mahmoud WE, Al-Ghamdi AA, Bronstein LM (2018) Magnetic drug delivery: where the field is going. Front Chem 6:1–7. https://doi.org/10.3389/fchem.2018.00619
Quesada-Pérez M, Maroto-Centeno JA, Forcada J, Hidalgo-Alvarez R (2011) Gel swelling theories: the classical formalism and recent approaches. Soft Matter 7:10536–10547. https://doi.org/10.1039/c1sm06031g
Rivera-Tarazona LK, Shukla T, Singh KA et al (2022) 4D printing of engineered living materials. Adv Funct Mater 32:2106843
Rizwan M, Yahya R, Hassan A et al (2017) pH sensitive hydrogels in drug delivery: brief history, properties, swelling, and release mechanism, material selection and applications. Polymers 9. https://doi.org/10.3390/polym9040137
Roy A, Hossain MS, Bhowmick A et al (2020) Prospects of 4d printing in pharmaceuticals. Pharmacologyonline 3:292–302
Saunders RE, Derby B (2014) Inkjet printing biomaterials for tissue engineering: bioprinting. Int Mater Rev 59:430–448. https://doi.org/10.1179/1743280414Y.0000000040
Schmaljohann D (2006) Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev 58:1655–1670. https://doi.org/10.1016/j.addr.2006.09.020
Shafranek RT, Millik SC, Smith PT et al (2019) Stimuli-responsive materials in additive manufacturing. Prog Polym Sci 93:36–67. https://doi.org/10.1016/j.progpolymsci.2019.03.002
Sponchioni M, Capasso Palmiero U, Moscatelli D (2019) Thermo-responsive polymers: applications of smart materials in drug delivery and tissue engineering. Mater Sci Eng C 102:589–605. https://doi.org/10.1016/j.msec.2019.04.069
Tibbits S (2014) 4D printing: multi-material shape change. Archit Des 84:116–121
Tofail SAM, Koumoulos EP, Bandyopadhyay A et al (2018) Additive manufacturing: scientific and technological challenges, market uptake and opportunities. Mater Today 21:22–37. https://doi.org/10.1016/j.mattod.2017.07.001
Tran TS, Balu R, Mettu S et al (2022) 4D printing of hydrogels : innovation in material design and emerging smart Systems for Drug Delivery. Pharmaceuticals 15:1282
Uboldi M, Melocchi A, Moutaharrik S et al (2021) Dataset on a small-scale film-coating process developed for self-expanding 4d printed drug delivery devices. Coatings 11. https://doi.org/10.3390/coatings11101252
Wang Y, Kohane DS (2017) External triggering and triggered targeting strategies for drug delivery. Nature Rev Mater 2. https://doi.org/10.1038/natrevmats.2017.20
Wang Y, Miao Y, Zhang J et al (2018) Three-dimensional printing of shape memory hydrogels with internal structure for drug delivery. Mater Sci Eng C 84:44–51. https://doi.org/10.1016/j.msec.2017.11.025
Wang W, Narain R, Zeng H (2020) Hydrogels. Elsevier Inc.
Willemen NGA, Morsink MAJ, Veerman D et al (2022) From oral formulations to drug-eluting implants: using 3D and 4D printing to develop drug delivery systems and personalized medicine. Bio-Design Manufacturing 5:85–106. https://doi.org/10.1007/s42242-021-00157-0
Wu C, Wang X (1998) Globule-to-coil transition of a single homopolymer chain in solution. Phys Rev Lett 80:4092–4094. https://doi.org/10.1103/PhysRevLett.80.4092
Zainal MA, Ahmad A, Mohamed Ali MS (2017) Frequency-controlled wireless shape memory polymer microactuator for drug delivery application. Biomed Microdevices 19:1–10. https://doi.org/10.1007/s10544-017-0148-5
Zhang WL, Choi HJ (2014) Stimuli-responsive polymers and colloids under electric and magnetic fields. Polymers 6:2803–2818. https://doi.org/10.3390/polym6112803
Zhao Y-D, Lai J-H, Wang M (2021) 4D printing of self-folding hydrogel tubes for potential tissue engineering applications. Nano LIFE 11:2141001
Zhou Y, Zhou D, Cao P et al (2021) 4D printing of shape memory vascular stent based on βCD-g-polycaprolactone. Macromol Rapid Commun 42:1–9. https://doi.org/10.1002/marc.202100176
Zu S, Zhang Z, Liu Q et al (2022a) 4D printing of core–shell hydrogel capsules for smart controlled drug release. Bio-Design Manufact 5:294–304. https://doi.org/10.1007/s42242-021-00175-y
Zu S, Wang Z, Zhang S et al (2022b) A bioinspired 4D printed hydrogel capsule for smart controlled drug release. Mater Today Chem 24:100789. https://doi.org/10.1016/j.mtchem.2022.100789
Acknowledgements
This research received funding from the Italian Ministry of Education, University and Research (MUR) under the PRIN Project “Development and promotion of levulinic acid and carboxylate platforms by the formulation of novel and advanced PHA-based biomaterials and their exploitation for 3D-printed green-electronics applications” grant 2017FWC3WC. All authors acknowledge the support of the CrossLab Additive Manufacturing Department of Information Engineering of the University of Pisa.
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Chiesa, I., Bonatti, A.F., De Acutis, A., Fortunato, G.M., Vozzi, G., De Maria, C. (2023). 4D Printing in Pharmaceuticals. In: Banerjee, S. (eds) Additive Manufacturing in Pharmaceuticals. Springer, Singapore. https://doi.org/10.1007/978-981-99-2404-2_8
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