Abstract: Drug delivery with customized combinations of drugs, controllable drug dosage, and on-demand release kinetics is critical for personalized medicine. In this study, inspired by successive opening of layered structures and compartmentalized structures in plants, we designed a multiple compartmentalized capsular structure for controlled drug delivery. The structure was designed as a series of compartments, defined by the gradient thickness of their external walls and internal divisions. Based on the careful choice and optimization of bioinks composed of gelatin, starch, and alginate, the capsular structures were successfully manufactured by fused deposition modeling three-dimensional (3D) printing. The capsules showed fusion and firm contact between printed layers, forming complete structures without significant defects on the external walls and internal joints. Internal cavities with different volumes were achieved for different drug loading as designed. In vitro swelling demonstrated a successive dissolving and opening of external walls of different capsule compartments, allowing successive drug pulses from the capsules, resulting in the sustained release for about 410 min. The drug release was significantly prolonged compared to a single burst release from a traditional capsular design. The bioinspired design and manufacture of multiple compartmentalized capsules enable customized drug release in a controllable fashion with combinations of different drugs, drug doses, and release kinetics, and have potential for use in personalized medicine.

3D打印仿生多腔室药物控释胶囊

[1]AnG, GuoFX, LiuXM, et al., 2020. Functional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells. Nat Commun, 11:2687.

[2]BohidarHB, JenaSS, 1993. Kinetics of sol‒gel transition in thermoreversible gelation of gelatin. J Chem Phys, 98(11): 8970-8977.

[3]BoseS, KeDX, SahasrabudheH, et al., 2018. Additive manufacturing of biomaterials. Prog Mater Sci, 93:45-111.

[4]CarlierE, MarquetteS, PeerboomC, et al., 2019. Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions. Int J Pharm, 565:367-377.

[5]ChenG, XuYH, KwokPCL, et al., 2020. Pharmaceutical applications of 3D printing. Addit Manuf, 34:101209.

[6]DuconseilleA, AstrucT, QuintanaN, et al., 2015. Gelatin structure and composition linked to hard capsule dissolution: a review. Food Hydrocoll, 43:360-376.

[7]EconomidouSN, UddinMJ, MarquesMJ, et al., 2021. A novel 3D printed hollow microneedle microelectromechanical system for controlled, personalized transdermal drug delivery. Addit Manuf, 38:101815.

[8]ElviraC, ManoJF, RomanJS, et al., 2002. Starch-based biodegradable hydrogels with potential biomedical applications as drug delivery systems. Biomaterials, 23(9):1955-1966.

[9]FinaF, GoyanesA, MadlaCM, et al., 2018. 3D printing of drug-loaded gyroid lattices using selective laser sintering. Int J Pharm, 547(1-2):44-52.

[10]GioumouxouzisCI, KaravasiliC, FatourosDG, 2019. Recent advances in pharmaceutical dosage forms and devices using additive manufacturing technologies. Drug Discov Today, 24(2):636-643.

[11]GuvendirenM, LuHD, BurdickJA, 2012. Shear-thinning hydrogels for biomedical applications. Soft Matter, 8(2):260-272.

[12]HollandI, LoganJ, ShiJZ, et al., 2018. 3D biofabrication for tubular tissue engineering. Bio-Des Manuf, 1(2):89-100.

[13]HolländerJ, GeninaN, JukarainenH, et al., 2016. Three-dimensional printed PCL-based implantable prototypes of medical devices for controlled drug delivery. J Pharm Sci, 105(9):2665-2676.

[14]IsrebA, BajK, WojszM, et al., 2019. 3D printed oral theophylline doses with innovative ‘radiator-like’ design: impact of polyethylene oxide (PEO) molecular weight. Int J Pharm, 564:98-105.

[15]JamesonJL, LongoDL, 2015. Precision medicine-personalized, problematic, and promising. N Engl J Med, 372(23):2229-2234.

[16]KadryH, Al-HilalTA, KeshavarzA, et al., 2018. Multi-purposable filaments of HPMC for 3D printing of medications with tailored drug release and timed-absorption. Int J Pharm, 544(1):285-296.

[17]KyobulaM, AdedejiA, AlexanderMR, et al., 2017. 3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release. J Control Release, 261:207-215.

[18]LawlorKT, VanslambrouckJM, HigginsJW, et al., 2021. Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation. Nat Mater, 20(2):260-271.

[19]LeeKY, MooneyDJ, 2012. Alginate: properties and biomedical applications. Prog Polym Sci, 37(1):106-126.

[20]LiQJ, GuanXY, CuiMS, et al., 2018. Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing. Int J Pharm, 535(1-2):325-332.

[21]LiXR, DengQF, ZhuangTT, et al., 2020. 3D bioprinted breast tumor model for structure—activity relationship study. Bio-Des Manuf, 3(4):361-372.

[22]LiXY, WuMB, XiaoM, et al., 2019. Microencapsulated β-carotene preparation using different drying treatments. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(11):901-909.

[23]LiawCY, GuvendirenM, 2017. Current and emerging applications of 3D printing in medicine. Biofabrication, 9(2):024102.

[24]LigonSC, LiskaR, StampflJ, et al., 2017. Polymers for 3D printing and customized additive manufacturing. Chem Rev, 117(15):10212-10290.

[25]LimSH, ChiaSMY, KangLF, et al., 2016. Three-dimensional printing of carbamazepine sustained-release scaffold. J Pharm Sci, 105(7):2155-2163.

[26]LimSH, KathuriaH, TanJJY, et al., 2018. 3D printed drug delivery and testing systems—a passing fad or the future? Adv Drug Deliv Rev, 132:139-168.

[27]MaharjanS, BonillaD, SindurakarP, et al., 2021. 3D human nonalcoholic hepatic steatosis and fibrosis models. Bio-Des Manuf, 4(2):157-170.

[28]MaroniA, MelocchiA, PariettiF, et al., 2017. 3D printed multi-compartment capsular devices for two-pulse oral drug delivery. J Control Release, 268:10-18.

[29]NoorN, ShapiraA, EdriR, et al., 2019. 3D printing of personalized thick and perfusable cardiac patches and hearts. Adv Sci, 6(11):1900344.

[30]NormanJ, MaduraweRD, MooreCMV, et al., 2017. A new chapter in pharmaceutical manufacturing: 3D-printed drug products. Adv Drug Deliv Rev, 108:39-50.

[31]OzbolatIT, HospodiukM, 2016. Current advances and future perspectives in extrusion-based bioprinting. Biomaterials, 76:321-343.

[32]OzbolatIT, PengWJ, OzbolatV, 2016. Application areas of 3D bioprinting. Drug Discov Today, 21(8):1257-1271.

[33]PaxtonN, SmolanW, BockT, et al., 2017. Proposal to assess printability of bioinks for extrusion-based bioprinting and evaluation of rheological properties governing bioprintability. Biofabrication, 9(4):044107.

[34]PengWM, LiuYF, JiangXF, et al., 2019. Bionic mechanical design and 3D printing of novel porous Ti6Al4V implants for biomedical applications. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(8):647-659.

[35]PereiraBC, IsrebA, ForbesRT, et al., 2019. ‘Temporary plasticiser’: a novel solution to fabricate 3D printed patient-centred cardiovascular ‘polypill’ architectures. Eur J Pharm Biopharm, 135:94-103.

[36]PlaconeJK, EnglerAJ, 2018. Recent advances in extrusion-based 3D printing for biomedical applications. Adv Healthc Mater, 7(8):1701161.

[37]RastogiP, KandasubramanianB, 2019. Review of alginate-based hydrogel bioprinting for application in tissue engineering. Biofabrication, 11(4):042001.

[38]TrivediM, JeeJ, SilvaS, et al., 2018. Additive manufacturing of pharmaceuticals for precision medicine applications: a review of the promises and perils in implementation. Addit Manuf, 23:319-328.

[39]UrciuoloA, PoliI, BrandolinoL, et al., 2020. Intravital three-dimensional bioprinting. Nat Biomed Eng, 4(9):901-915.

[40]Velasco-HoganA, XuJ, MeyersMA, 2018. Additive manufacturing as a method to design and optimize bioinspired structures. Adv Mater, 30(52):1800940.

[41]WuMX, ZhangYJ, HuangH, et al., 2020. Assisted 3D printing of microneedle patches for minimally invasive glucose control in diabetes. Mater Sci Eng C, 117:111299.

[42]YouF, WuX, KellyM, et al., 2020. Bioprinting and in vitro characterization of alginate dialdehyde—gelatin hydrogel bio-ink. Bio-Des Manuf, 3(1):48-59.

[43]ZhangB, XueQ, HuHY, et al., 2019. Integrated 3D bioprinting-based geometry-control strategy for fabricating corneal substitutes. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(12):945-959.

[44]ZhangBQ, SunH, WuLN, et al., 2019. 3D printing of calcium phosphate bioceramic with tailored biodegradation rate for skull bone tissue reconstruction. Bio-Des Manuf, 2(3):161-171.

[45]ZhangHB, JacksonJK, ChiaoM, 2017. Microfabricated drug delivery devices: design, fabrication, and applications. Adv Funct Mater, 27(45):1703606.

[46]ZhangNZ, LiuHS, YuL, et al., 2013. Developing gelatin-starch blends for use as capsule materials. Carbohydr Polym, 92(1):455-461.

[47]ZhuYZ, JoralmonD, ShanWT, et al., 2021. 3D printing biomimetic materials and structures for biomedical applications. Bio-Des Manuf, 4(2):405-428.