A 3D-printed microfluidic-enabled hollow microneedle architecture for transdermal drug delivery

Embedding microfluidic architectures with microneedles enables fluid management capabilities that present new degrees of freedom for transdermal drug delivery. To this end, fabrication schemes that can simultaneously create and integrate complex millimeter/centimeter-long microfluidic structures and micrometer-scale microneedle features are necessary. Accordingly, three-dimensional (3D) printing techniques are suitable candidates because they allow the rapid realization of customizable yet intricate microfluidic and microneedle features. However, previously reported 3D-printing approaches utilized costly instrumentation that lacked the desired versatility to print both features in a single step and the throughput to render components within distinct length-scales. Here, for the first time in literature, we devise a fabrication scheme to create hollow microneedles interfaced with microfluidic structures in a single step. Our method utilizes stereolithography 3D-printing and pushes its boundaries (achieving print resolutions below the full width half maximum laser spot size resolution) to create complex architectures with lower cost and higher print speed and throughput than previously reported methods. To demonstrate a potential application, a microfluidic-enabled microneedle architecture was printed to render hydrodynamic mixing and transdermal drug delivery within a single device. The presented architectures can be adopted in future biomedical devices to facilitate new modes of operations for transdermal drug delivery applications such as combinational therapy for preclinical testing of biologic treatments.

[1]  Ali Khademhosseini,et al.  Drug delivery systems and materials for wound healing applications. , 2018, Advanced drug delivery reviews.

[2]  C. Rigatto,et al.  Lab-on-chip technology for chronic disease diagnosis , 2018, npj Digital Medicine.

[3]  Mark R Prausnitz,et al.  Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. , 2004, Journal of biomechanics.

[4]  Lifeng Kang,et al.  A simple method of microneedle array fabrication for transdermal drug delivery , 2013, Drug development and industrial pharmacy.

[5]  Nitin Afzulpurkar,et al.  Micro Electromechanical Systems (MEMS) Based Microfluidic Devices for Biomedical Applications , 2011, International journal of molecular sciences.

[6]  Koen van der Maaden,et al.  Microneedle technologies for (trans)dermal drug and vaccine delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[7]  P. Uzor,et al.  Perspectives on Transdermal Drug Delivery , 2011 .

[8]  Aydin Sadeqi,et al.  Low-cost and cleanroom-free fabrication of microneedles , 2018, Microsystems & Nanoengineering.

[9]  Fabrication process for tall, sharp, hollow, high aspect ratio polymer microneedles on a platform , 2013 .

[10]  B. Bittner,et al.  Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities , 2018, BioDrugs.

[11]  Evangelia Bouzos,et al.  Three-Dimensional (3D) Printed Microneedles for Microencapsulated Cell Extrusion , 2018, Bioengineering.

[12]  Mark G. Allen,et al.  Hollow microneedles for intradermal injection fabricated by sacrificial micromolding and selective electrodeposition , 2013, Biomedical microdevices.

[13]  Ronen Polsky,et al.  Integrated carbon fiber electrodes within hollow polymer microneedles for transdermal electrochemical sensing. , 2011, Biomicrofluidics.

[14]  G. Kim,et al.  Porous polymer coatings on metal microneedles for enhanced drug delivery , 2018, Royal Society Open Science.

[15]  Gary P. Martin,et al.  Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects , 2006, Drug delivery.

[16]  Dennis Douroumis,et al.  3D printing applications for transdermal drug delivery , 2018, International journal of pharmaceutics.

[17]  A. Scheynius,et al.  Bioceramic microneedle arrays are able to deliver OVA to dendritic cells in human skin. , 2018, Journal of materials chemistry. B.

[18]  Howard Bernstein,et al.  Microneedle-based device for the one-step painless collection of capillary blood samples , 2018, Nature Biomedical Engineering.

[19]  Robert Langer,et al.  Transdermal drug delivery , 2008, Nature Biotechnology.

[20]  Michael S. Roberts,et al.  Microneedle Enhanced Delivery of Cosmeceutically Relevant Peptides in Human Skin , 2014, PloS one.

[21]  Albert Folch,et al.  Mail-order microfluidics: evaluation of stereolithography for the production of microfluidic devices. , 2014, Lab on a chip.

[22]  Clive G. Wilson,et al.  Flux of ionic dyes across microneedle-treated skin: effect of molecular characteristics. , 2012, International journal of pharmaceutics.

[23]  Nithyanand Kota,et al.  Fabrication of circular microfluidic channels by combining mechanical micromilling and soft lithography. , 2011, Lab on a chip.

[24]  Sam Emaminejad,et al.  A rapid and low-cost fabrication and integration scheme to render 3D microfluidic architectures for wearable biofluid sampling, manipulation, and sensing. , 2019, Lab on a chip.

[25]  Ashley R Johnson,et al.  Low cost additive manufacturing of microneedle masters , 2019, 3D Printing in Medicine.

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

[27]  Ryan F. Donnelly,et al.  A proposed model membrane and test method for microneedle insertion studies , 2014, International journal of pharmaceutics.

[28]  Urs O. Häfeli,et al.  Arrays of hollow out-of-plane microneedles made by metal electrodeposition onto solvent cast conductive polymer structures , 2013 .

[29]  Mark R. Prausnitz,et al.  Effect of Microneedle Design on Pain in Human Volunteers , 2008, The Clinical journal of pain.

[30]  W. Jiskoot,et al.  Parameter optimization toward optimal microneedle-based dermal vaccination. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[31]  Chenjie Xu,et al.  Microneedle-Assisted Topical Delivery of Photodynamically Active Mesoporous Formulation for Combination Therapy of Deep-Seated Melanoma. , 2018, ACS nano.

[32]  C. Hibert,et al.  Silicon microneedle electrode array with temperature monitoring for electroporation , 2005 .

[33]  Swaminathan Rajaraman,et al.  3D Printing, Ink Casting and Micromachined Lamination (3D PICLμM): A Makerspace Approach to the Fabrication of Biological Microdevices , 2018, Micromachines.

[34]  Jung-Hwan Park,et al.  Spray-Formed Layered Polymer Microneedles for Controlled Biphasic Drug Delivery , 2019, Polymers.

[35]  Jung-Hwan Park,et al.  Microneedles for drug and vaccine delivery. , 2012, Advanced drug delivery reviews.

[36]  Yong He,et al.  3D Printed Paper-Based Microfluidic Analytical Devices , 2016, Micromachines.

[37]  Robert Langer,et al.  Microfluidic platform for controlled synthesis of polymeric nanoparticles. , 2008, Nano letters.

[38]  Wijaya Martanto,et al.  Fluid dynamics in conically tapered microneedles , 2005 .

[39]  Sam Emaminejad,et al.  A wearable electrofluidic actuation system. , 2019, Lab on a chip.

[40]  Andrew deMello,et al.  Microscale reactors: nanoscale products. , 2004, Lab on a chip.

[41]  S. Pennathur,et al.  A repeatable and scalable fabrication method for sharp, hollow silicon microneedles , 2018 .

[42]  A. Oseroff,et al.  A pulsed electric field enhances cutaneous delivery of methylene blue in excised full-thickness porcine skin. , 1998, The Journal of investigative dermatology.

[43]  S. D. Collins,et al.  Microneedle array for transdermal biological fluid extraction and in situ analysis , 2004 .

[44]  Ryan F Donnelly,et al.  Effects of microneedle length, density, insertion time and multiple applications on human skin barrier function: assessments by transepidermal water loss. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[45]  T. Walther,et al.  Towards a versatile point-of-care system combining femtosecond laser generated microfluidic channels and direct laser written microneedle arrays , 2019, Microsystems & Nanoengineering.

[46]  Klavs F Jensen,et al.  Microfluidic based single cell microinjection. , 2008, Lab on a chip.

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