Application of Micro-Scale 3D Printing in Pharmaceutics

3D printing, as one of the most rapidly-evolving fabrication technologies, has released a cascade of innovation in the last two decades. In the pharmaceutical field, the integration of 3D printing technology has offered unique advantages, especially at the micro-scale. When printed at a micro-scale, materials and devices can provide nuanced solutions to controlled release, minimally invasive delivery, high-precision targeting, biomimetic models for drug discovery and development, and future opportunities for personalized medicine. This review aims to cover the recent advances in this area. First, the 3D printing techniques are introduced with respect to the technical parameters and features that are uniquely related to each stage of pharmaceutical development. Then specific micro-sized pharmaceutical applications of 3D printing are summarized and grouped according to the provided benefits. Both advantages and challenges are discussed for each application. We believe that these technologies provide compelling future solutions for modern medicine, while challenges remain for scale-up and regulatory approval.

[1]  Nathaniel Huebsch,et al.  Three-dimensional filamentous human diseased cardiac tissue model. , 2014, Biomaterials.

[2]  Adnan Nasir,et al.  Polyglycolic acid microneedles modified with inkjet-deposited antifungal coatings. , 2015, Biointerphases.

[3]  A. Leshansky,et al.  Swimming by reciprocal motion at low Reynolds number , 2014, Nature Communications.

[4]  Ryan B Wicker,et al.  Microstereolithography and characterization of poly(propylene fumarate)-based drug-loaded microneedle arrays , 2015, Biofabrication.

[5]  Steve Simon,et al.  Options for additive rapid prototyping methods (3D printing) in MEMS technology , 2014 .

[6]  Christine M. Madla,et al.  Fabricating 3D printed orally disintegrating printlets using selective laser sintering. , 2018, International journal of pharmaceutics.

[7]  M. Ghert,et al.  Lost in translation: animal models and clinical trials in cancer treatment. , 2014, American journal of translational research.

[8]  Dong-Woo Cho,et al.  Efficacy of rhBMP-2 loaded PCL/PLGA/β-TCP guided bone regeneration membrane fabricated by 3D printing technology for reconstruction of calvaria defects in rabbit , 2014, Biomedical materials.

[9]  Hermann Seitz,et al.  A review on 3D micro-additive manufacturing technologies , 2012, The International Journal of Advanced Manufacturing Technology.

[10]  Albert Folch,et al.  The upcoming 3D-printing revolution in microfluidics. , 2016, Lab on a chip.

[11]  J M García-Aznar,et al.  Scaffold microarchitecture determines internal bone directional growth structure: a numerical study. , 2010, Journal of biomechanics.

[12]  Simon Gaisford,et al.  Direct powder extrusion 3D printing: Fabrication of drug products using a novel single-step process. , 2019, International journal of pharmaceutics.

[13]  Wei Zhu,et al.  3D bioprinting of functional tissue models for personalized drug screening and in vitro disease modeling. , 2018, Advanced drug delivery reviews.

[14]  Hugh Smyth,et al.  3D Printing technologies for drug delivery: a review , 2016, Drug development and industrial pharmacy.

[15]  Boris N. Chichkov,et al.  Two Photon Polymerization of Polymer–Ceramic Hybrid Materials for Transdermal Drug Delivery , 2007 .

[16]  Jianhua Sun,et al.  A programmed release multi-drug implant fabricated by three-dimensional printing technology for bone tuberculosis therapy , 2009, Biomedical materials.

[17]  Seng Han Lim,et al.  Three-dimensional printing of a microneedle array on personalized curved surfaces for dual-pronged treatment of trigger finger , 2017, Biofabrication.

[18]  S. Van Vlierberghe,et al.  Bioink properties before, during and after 3D bioprinting , 2016, Biofabrication.

[19]  Katja Schenke-Layland,et al.  ECM and ECM-like materials - Biomaterials for applications in regenerative medicine and cancer therapy. , 2016, Advanced drug delivery reviews.

[20]  Jason A Inzana,et al.  3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection. , 2015, European cells & materials.

[21]  Federico Parietti,et al.  3D printing by fused deposition modeling (FDM) of a swellable/erodible capsular device for oral pulsatile release of drugs , 2015 .

[22]  Oliver G Schmidt,et al.  Sperm-Hybrid Micromotor for Targeted Drug Delivery. , 2017, ACS nano.

[23]  Danilo Demarchi,et al.  Accuracy and feasibility of piezoelectric inkjet coating technology for applications in microneedle-based transdermal delivery , 2017 .

[24]  A. Basit,et al.  Effect of geometry on drug release from 3D printed tablets. , 2015, International journal of pharmaceutics.

[25]  K. Huanbutta,et al.  Design and development of zero-order drug release gastroretentive floating tablets fabricated by 3D printing technology , 2019, Journal of Drug Delivery Science and Technology.

[26]  Aleksandr Ovsianikov,et al.  The effects of geometry on skin penetration and failure of polymer microneedles , 2013, Journal of adhesion science and technology.

[27]  M. Khan,et al.  A new chapter in pharmaceutical manufacturing: 3D‐printed drug products☆, ☆☆ , 2017, Advanced drug delivery reviews.

[28]  Aleksandr Ovsianikov,et al.  Two-photon polymerization of microneedles for transdermal drug delivery , 2010, Expert opinion on drug delivery.

[29]  Abdul W. Basit,et al.  3D printing of drug‐loaded gyroid lattices using selective laser sintering , 2018, International journal of pharmaceutics.

[30]  H. Exner,et al.  Principles of Laser Micro Sintering , 2007 .

[31]  Scott J. Hollister,et al.  Mitigation of tracheobronchomalacia with 3D-printed personalized medical devices in pediatric patients , 2015, Science Translational Medicine.

[32]  Antonios G Mikos,et al.  3D printing PLGA: a quantitative examination of the effects of polymer composition and printing parameters on print resolution , 2017, Biofabrication.

[33]  Jeremiah J Gassensmith,et al.  Biodegradable 3D printed polymer microneedles for transdermal drug delivery. , 2018, Lab on a chip.

[34]  M. Sitti,et al.  Mobile Microrobots for Active Therapeutic Delivery , 2018, Advanced Therapeutics.

[35]  Kartik V. Bulusu,et al.  A synergistic approach to the design, fabrication and evaluation of 3D printed micro and nano featured scaffolds for vascularized bone tissue repair , 2016, Nanotechnology.

[36]  Tais Gratieri,et al.  The Digital Pharmacies Era: How 3D Printing Technology Using Fused Deposition Modeling Can Become a Reality , 2019, Pharmaceutics.

[37]  Ibrahim T. Ozbolat,et al.  The bioink: A comprehensive review on bioprintable materials. , 2017, Biotechnology advances.

[38]  Aleksandr Ovsianikov,et al.  Fabrication of Polymer Microneedles Using a Two-Photon Polymerization and Micromolding Process , 2009, Journal of diabetes science and technology.

[39]  Yiğit Karpat,et al.  Fabrication of polymer micro needles for transdermal drug delivery system using DLP based projection stereo-lithography , 2016 .

[40]  A. Basit,et al.  3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[41]  Shane J. Stafslien,et al.  Inkjet deposition of itraconazole onto poly(glycolic acid) microneedle arrays. , 2016, Biointerphases.

[42]  M. Mehrali,et al.  A review on powder-based additive manufacturing for tissue engineering: selective laser sintering and inkjet 3D printing , 2015, Science and technology of advanced materials.

[43]  Jesper Gantelius,et al.  3D Bioprinting of Tissue/Organ Models. , 2016, Angewandte Chemie.

[44]  Siowling Soh,et al.  Printing Tablets with Fully Customizable Release Profiles for Personalized Medicine , 2015, Advanced materials.

[45]  K. Fukushige,et al.  Defined drug release from 3D‐printed composite tablets consisting of drug‐loaded polyvinylalcohol and a water‐soluble or water‐insoluble polymer filler , 2018, International journal of pharmaceutics.

[46]  Simon Gaisford,et al.  3D printed medicines: A new branch of digital healthcare , 2018, International journal of pharmaceutics.

[47]  Seymour Reichlin,et al.  Handbook of experimental pharmacology , 1984 .

[48]  Conor O'Mahony,et al.  Dissolvable microneedle fabrication using piezoelectric dispensing technology. , 2016, International journal of pharmaceutics.

[49]  Huibi Xu,et al.  Levofloxacin implants with predefined microstructure fabricated by three-dimensional printing technique. , 2007, International journal of pharmaceutics.

[50]  Simon Gaisford,et al.  Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing. , 2017, International journal of pharmaceutics.

[51]  Y. Li,et al.  Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting , 2016, Proceedings of the National Academy of Sciences.

[52]  S. Kawata,et al.  Three-dimensional microfabrication with two-photon-absorbed photopolymerization. , 1997, Optics letters.

[53]  Adnan Nasir,et al.  Deposition of antimicrobial coatings on microstereolithography-fabricated microneedles , 2011 .

[54]  Ali Khademhosseini,et al.  Bioprinted 3D vascularized tissue model for drug toxicity analysis. , 2017, Biomicrofluidics.

[55]  Ian Ashcroft,et al.  3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[56]  C. L. Ventola Medical Applications for 3D Printing: Current and Projected Uses. , 2014, P & T : a peer-reviewed journal for formulary management.

[57]  Jin Sha,et al.  Micropattern width dependent sarcomere development in human ESC-derived cardiomyocytes. , 2014, Biomaterials.

[58]  Liju Yang,et al.  Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. , 2014, Assay and drug development technologies.

[59]  Simon Gaisford,et al.  An Overview of 3D Printing Technologies for Soft Materials and Potential Opportunities for Lipid-based Drug Delivery Systems , 2018, Pharmaceutical Research.

[60]  Aleksandr Ovsianikov,et al.  Two Photon Polymerization‐Micromolding of Polyethylene Glycol‐Gentamicin Sulfate Microneedles , 2010, Advanced engineering materials.

[61]  Ibrahim T. Ozbolat,et al.  Bioprinting for vascular and vascularized tissue biofabrication. , 2017, Acta biomaterialia.

[62]  Aleksandr Ovsianikov,et al.  Multiphoton microscopy of transdermal quantum dot delivery using two photon polymerization-fabricated polymer microneedles. , 2011, Faraday discussions.

[63]  M. Vallet‐Regí,et al.  Fabrication of novel Si-doped hydroxyapatite/gelatine scaffolds by rapid prototyping for drug delivery and bone regeneration. , 2015, Acta biomaterialia.

[64]  Satoshi Kawata,et al.  Finer features for functional microdevices , 2001, Nature.

[65]  Joseph M. DeSimone,et al.  Single-Step Fabrication of Computationally Designed Microneedles by Continuous Liquid Interface Production , 2016, PloS one.

[66]  Aleksandr Ovsianikov,et al.  Fabrication of microneedles using two photon polymerization for transdermal delivery of nanomaterials. , 2010, Journal of nanoscience and nanotechnology.

[67]  Touraj Ehtezazi,et al.  The Application of 3D Printing in the Formulation of Multilayered Fast Dissolving Oral Films. , 2017, Journal of pharmaceutical sciences.

[68]  Joseph Wang,et al.  Micro/nanorobots for biomedicine: Delivery, surgery, sensing, and detoxification , 2017, Science Robotics.

[69]  James J. Yoo,et al.  A 3D bioprinting system to produce human-scale tissue constructs with structural integrity , 2016, Nature Biotechnology.

[70]  Waqar Ahmed,et al.  Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[71]  Basel Arafat,et al.  Fabricating a Shell-Core Delayed Release Tablet Using Dual FDM 3D Printing for Patient-Centred Therapy , 2016, Pharmaceutical Research.

[72]  K A Holbrook,et al.  Regional differences in the thickness (cell layers) of the human stratum corneum: an ultrastructural analysis. , 1974, The Journal of investigative dermatology.

[73]  Metin Sitti,et al.  3D-Printed Biodegradable Microswimmer for Drug Delivery and Targeted Cell Labeling , 2018, bioRxiv.

[74]  Li Zhang,et al.  Artificial bacterial flagella for remote-controlled targeted single-cell drug delivery. , 2014, Small.

[75]  Jurgen Kosel,et al.  Biocompatible 3D printed magnetic micro needles , 2017 .

[76]  Dennis Douroumis,et al.  Inkjet printing of transdermal microneedles for the delivery of anticancer agents. , 2015, International journal of pharmaceutics.

[77]  Ibrahim T. Ozbolat,et al.  3D bioprinting for modelling vasculature. , 2018, Microphysiological systems.

[78]  Bharat Bhushan,et al.  An overview of additive manufacturing (3D printing) for microfabrication , 2017 .

[79]  Niklas Sandler,et al.  Additive manufacturing of personalized orodispersible warfarin films. , 2019, International journal of pharmaceutics.

[80]  Dimitrios Mitsouras,et al.  Measuring and Establishing the Accuracy and Reproducibility of 3D Printed Medical Models. , 2017, Radiographics : a review publication of the Radiological Society of North America, Inc.

[81]  E. O. Olakanmi Selective laser sintering/melting (SLS/SLM) of pure Al, Al-Mg, and Al-Si powders: Effect of processing conditions and powder properties , 2013 .

[82]  Dennis Douroumis,et al.  3D printed microneedles for insulin skin delivery , 2018, International journal of pharmaceutics.

[83]  A. Kashani,et al.  Additive manufacturing (3D printing): A review of materials, methods, applications and challenges , 2018, Composites Part B: Engineering.

[84]  Yaxiong Liu,et al.  The Emerging Frontiers and Applications of High-Resolution 3D Printing , 2017, Micromachines.

[85]  Xinggang Yang,et al.  Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing. , 2018, International journal of pharmaceutics.

[86]  Peter Timmins,et al.  From ‘fixed dose combinations’ to ‘a dynamic dose combiner’: 3D printed bi‐layer antihypertensive tablets , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[87]  Wei Zhu,et al.  3D-Printing of Functional Biomedical Microdevices via Light- and Extrusion-Based Approaches. , 2018, Small methods.

[88]  Amirali Zandinejad,et al.  Process Development of Porcelain Ceramic Material with Binder Jetting Process for Dental Applications , 2016 .

[89]  Doyoung Byun,et al.  3D printing of high-resolution PLA-based structures by hybrid electrohydrodynamic and fused deposition modeling techniques , 2016 .

[90]  Alida Mazzoli,et al.  Selective laser sintering in biomedical engineering , 2012, Medical & Biological Engineering & Computing.

[91]  Wei Sun,et al.  Biofabrication of a three-dimensional liver micro-organ as an in vitro drug metabolism model , 2010, Biofabrication.

[92]  Ji-Seon Lee,et al.  A novel cell-printing method and its application to hepatogenic differentiation of human adipose stem cell-embedded mesh structures , 2015, Scientific Reports.

[93]  Prabir K. Basu,et al.  Improving Pharmaceutical Product Development and Manufacturing: Impact on Cost of Drug Development and Cost of Goods Sold of Pharmaceuticals , 2008, Journal of Pharmaceutical Innovation.

[94]  Christos Salpistis,et al.  Hyaline cartilage next generation implants from adipose‐tissue–derived mesenchymal stem cells: Comparative study on 3D‐printed polycaprolactone scaffold patterns , 2019, Journal of tissue engineering and regenerative medicine.

[95]  Lifeng Kang,et al.  Effect of microneedle geometry and supporting substrate on microneedle array penetration into skin. , 2013, Journal of pharmaceutical sciences.

[96]  Aishwarya Bhargav,et al.  Applications of additive manufacturing in dentistry: A review. , 2018, Journal of biomedical materials research. Part B, Applied biomaterials.

[97]  Xingyou Ye,et al.  Hydroxypropyl methylcellulose-based controlled release dosage by melt extrusion and 3D printing: Structure and drug release correlation. , 2017, Carbohydrate polymers.

[98]  Xiaojian Ye,et al.  3D-printed hierarchical scaffold for localized isoniazid/rifampin drug delivery and osteoarticular tuberculosis therapy. , 2015, Acta biomaterialia.

[99]  Wei Zhu,et al.  Biologically Inspired Smart Release System Based on 3D Bioprinted Perfused Scaffold for Vascularized Tissue Regeneration , 2016, Advanced science.

[100]  Antoine Al-Achi,et al.  St John's wort and depression. , 2002 .

[101]  Waqar Ahmed,et al.  Emergence of 3D Printed Dosage Forms: Opportunities and Challenges , 2016, Pharmaceutical Research.

[102]  Angelo S. Mao,et al.  3D Printed Microtransporters: Compound Micromachines for Spatiotemporally Controlled Delivery of Therapeutic Agents , 2015, Advanced materials.

[103]  Waqar Ahmed,et al.  Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[104]  Rigoberto C. Advincula,et al.  3D Printing of Polymer Nanocomposites via Stereolithography , 2017 .

[105]  Niklas Sandler,et al.  Tailoring controlled-release oral dosage forms by combining inkjet and flexographic printing techniques. , 2012, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[106]  Jiang Peng,et al.  Osteogenic magnesium incorporated into PLGA/TCP porous scaffold by 3D printing for repairing challenging bone defect. , 2019, Biomaterials.

[107]  Krzysztof K. Krawczyk,et al.  Magnetic Helical Micromachines: Fabrication, Controlled Swimming, and Cargo Transport , 2012, Advanced materials.

[108]  Anthony Atala,et al.  3D bioprinting of tissues and organs , 2014, Nature Biotechnology.

[109]  Guang Yang,et al.  Osteogenic effect of controlled released rhBMP-2 in 3D printed porous hydroxyapatite scaffold. , 2016, Colloids and surfaces. B, Biointerfaces.

[110]  P. Hardouin,et al.  Porous HA ceramic for bone replacement: Role of the pores and interconnections – experimental study in the rabbit , 2001, Journal of materials science. Materials in medicine.

[111]  Jean-Pierre Kruth,et al.  Effect of Powder Size and Shape on the SLS Processability and Mechanical Properties of a TPU Elastomer , 2016 .

[112]  R. Narayan,et al.  Modification of microneedles using inkjet printing. , 2011, AIP advances.

[113]  M. Alexander,et al.  3D printing of tablets containing multiple drugs with defined release profiles. , 2015, International journal of pharmaceutics.

[114]  Yvonne Förster,et al.  Design and Fabrication of Complex Scaffolds for Bone Defect Healing: Combined 3D Plotting of a Calcium Phosphate Cement and a Growth Factor-Loaded Hydrogel , 2016, Annals of Biomedical Engineering.

[115]  M. Alexander,et al.  3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[116]  Pamela Robles Martinez,et al.  Fabrication of drug-loaded hydrogels with stereolithographic 3D printing. , 2017, International journal of pharmaceutics.

[117]  Simon Gaisford,et al.  3D Printing Pharmaceuticals: Drug Development to Frontline Care. , 2018, Trends in pharmacological sciences.

[118]  Jake E. Barralet,et al.  Simultaneous Immobilization of Bioactives During 3D Powder Printing of Bioceramic Drug‐Release Matrices , 2010 .

[119]  Lara Rebaioli,et al.  A review on benchmark artifacts for evaluating the geometrical performance of additive manufacturing processes , 2017 .

[120]  A. Gazzaniga,et al.  3D printed multi‐compartment capsular devices for two‐pulse oral drug delivery , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[121]  Pamela Robles Martinez,et al.  Influence of Geometry on the Drug Release Profiles of Stereolithographic (SLA) 3D-Printed Tablets , 2018, AAPS PharmSciTech.

[122]  M. Sitti,et al.  Light-Triggered Drug Release from 3D-Printed Magnetic Chitosan Microswimmers. , 2018, ACS nano.

[123]  Renata Jachowicz,et al.  3D printed orodispersible films with Aripiprazole. , 2017, International journal of pharmaceutics.

[124]  Simon Gaisford,et al.  Reshaping drug development using 3D printing. , 2018, Drug discovery today.

[125]  Gagandeep Kaur,et al.  Engineering of Micro- to Nanostructured 3D-Printed Drug-Releasing Titanium Implants for Enhanced Osseointegration and Localized Delivery of Anticancer Drugs. , 2017, ACS applied materials & interfaces.

[126]  Simon Gaisford,et al.  3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics. , 2015, Molecular pharmaceutics.

[127]  Renata Jachowicz,et al.  3D printing of tablets containing amorphous aripiprazole by filaments co‐extrusion , 2018, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[128]  Dong-Woo Cho,et al.  3D Printing of Organs-On-Chips , 2017, Bioengineering.

[129]  T. Singer,et al.  Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro , 2016, PloS one.

[130]  L Van Hoorebeke,et al.  3D printing of high drug loaded dosage forms using thermoplastic polyurethanes. , 2018, International journal of pharmaceutics.

[131]  Vijay Kumar,et al.  Toward Soft Micro Bio Robots for Cellular and Chemical Delivery , 2018, IEEE Robotics and Automation Letters.

[132]  Joseph M. DeSimone,et al.  Controlling release from 3D printed medical devices using CLIP and drug‐loaded liquid resins , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[133]  Chee Kai Chua,et al.  Fundamentals and applications of 3D printing for novel materials , 2017 .