Microneedle technologies for (trans)dermal drug and vaccine delivery.

Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small molecular weight drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. However, until now there are no microneedle-based (trans)dermal drug delivery systems on the market. In the past decade various types of microneedles have been developed by a number of production processes. Numerous geometries of microneedles have been designed from various materials. These microneedles have been used for different approaches of microneedle-based (trans)dermal drug delivery. Following a brief introduction about dermal and transdermal drug delivery, this review describes different production methods for solid and hollow microneedles as well as conditions that influence skin penetration. Besides, the four microneedle-based (trans)dermal drug delivery approaches are discussed: "poke and flow", "poke and patch", "poke and release", and "coat and poke". A separate section of this review is devoted to the use of microneedles for the delivery of therapeutic proteins and vaccines. Finally, we give our view on research and development that is needed to render microneedle-based (trans)dermal drug delivery technologies clinically useful in the near future.

[1]  Göran Stemme,et al.  Novel Microneedle Patches for Active Insulin Delivery are Efficient in Maintaining Glycaemic Control: An Initial Comparison with Subcutaneous Administration , 2007, Pharmaceutical Research.

[2]  Mark R Prausnitz,et al.  Kinetics of skin resealing after insertion of microneedles in human subjects. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[3]  P. van Damme,et al.  Safety and efficacy of a novel microneedle device for dose sparing intradermal influenza vaccination in healthy adults. , 2009, Vaccine.

[4]  Jim Euchner Design , 2014, Catalysis from A to Z.

[5]  D. Irvine,et al.  Layer-by-layer-assembled multilayer films for transcutaneous drug and vaccine delivery. , 2009, ACS nano.

[6]  Huub Schellekens,et al.  Oxidized and Aggregated Recombinant Human Interferon Beta is Immunogenic in Human Interferon Beta Transgenic Mice , 2011, Pharmaceutical Research.

[7]  Maria Ponec,et al.  The skin barrier in healthy and diseased state. , 2006, Biochimica et biophysica acta.

[8]  N. Mickuvienė,et al.  Intradermal influenza vaccination of healthy adults using a new microinjection system: a 3-year randomised controlled safety and immunogenicity trial , 2009, BMC medicine.

[9]  Mark R. Prausnitz,et al.  Intradermal Vaccination with Influenza Virus-Like Particles by Using Microneedles Induces Protection Superior to That with Intramuscular Immunization , 2010, Journal of Virology.

[10]  Kelly M. Smith,et al.  Optimizing transdermal drug therapy. , 2008, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[11]  Lutz Heinemann,et al.  Microneedle-based intradermal versus subcutaneous administration of regular human insulin or insulin lispro: pharmacokinetics and postprandial glycemic excursions in patients with type 1 diabetes. , 2011, Diabetes technology & therapeutics.

[12]  Mark R Prausnitz,et al.  Pocketed Microneedles for Drug Delivery to the Skin. , 2008, The Journal of physics and chemistry of solids.

[13]  Jalpa G. Patel,et al.  Transdermal Drug Delivery Systems: A Review , 2012 .

[14]  M. Prausnitz,et al.  Stabilization of Influenza Vaccine Enhances Protection by Microneedle Delivery in the Mouse Skin , 2009, PloS one.

[15]  J. Kanitakis,et al.  Anatomy, histology and immunohistochemistry of normal human skin. , 2002, European journal of dermatology : EJD.

[16]  D. Barrow,et al.  Microfabricated silicon microneedles for nonviral cutaneous gene delivery , 2004, The British journal of dermatology.

[17]  Asim Nisar,et al.  Structural and microfluidic analysis of hollow side-open polymeric microneedles for transdermal drug delivery applications , 2010 .

[18]  S. Sivaloganathan,et al.  Drug delivery through the skin: molecular simulations of barrier lipids to design more effective noninvasive dermal and transdermal delivery systems for small molecules, biologics, and cosmetics. , 2011, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[19]  Ciprian Iliescu,et al.  Microfabricated microneedle with porous tip for drug delivery , 2006 .

[20]  Tielin Shi,et al.  Iontophoresis-driven penetration of nanovesicles through microneedle-induced skin microchannels for enhancing transdermal delivery of insulin. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Yong-Kyu Yoon,et al.  Polymer particle-based micromolding to fabricate novel microstructures , 2007, Biomedical microdevices.

[22]  M. Prausnitz,et al.  Stability Kinetics of Influenza Vaccine Coated onto Microneedles During Drying and Storage , 2010, Pharmaceutical Research.

[23]  遠山 正彌,et al.  人体の解剖生理学 = Human anatomy & physiology , 2010 .

[24]  Lutz Heinemann,et al.  Intradermal microneedle delivery of insulin lispro achieves faster insulin absorption and insulin action than subcutaneous injection. , 2011, Diabetes technology & therapeutics.

[25]  Mark R Prausnitz,et al.  Influenza virus-like particles coated onto microneedles can elicit stimulatory effects on Langerhans cells in human skin. , 2010, Vaccine.

[26]  Bai Xu,et al.  Controlled transdermal delivery of model drug compounds by MEMS microneedle array. , 2005, Nanomedicine : nanotechnology, biology, and medicine.

[27]  M.J. de Boer,et al.  Integrated Lithographic Molding for Microneedle-Based Devices , 2007, Journal of Microelectromechanical Systems.

[28]  Mark G. Allen,et al.  Hollow metal microneedles for insulin delivery to diabetic rats , 2005, IEEE Transactions on Biomedical Engineering.

[29]  Keizo Fukushima,et al.  Two-Layered Dissolving Microneedles for Percutaneous Delivery of Peptide/Protein Drugs in Rats , 2010, Pharmaceutical Research.

[30]  M. Rathbone,et al.  Modified release drug delivery in veterinary medicine. , 2002, Drug discovery today.

[31]  Mark R. Prausnitz,et al.  Dissolving Polymer Microneedle Patches for Influenza Vaccination , 2010, Nature Medicine.

[32]  L. Babiuk,et al.  Poly[di(carboxylatophenoxy)phosphazene] is a potent adjuvant for intradermal immunization , 2009, Proceedings of the National Academy of Sciences.

[33]  A. B. Frazier,et al.  Mechanical characterization of surface micromachined microneedle array , 2002, 2nd Annual International IEEE-EMBS Special Topic Conference on Microtechnologies in Medicine and Biology. Proceedings (Cat. No.02EX578).

[34]  Wim Jiskoot,et al.  Small is beautiful: N-trimethyl chitosan-ovalbumin conjugates for microneedle-based transcutaneous immunisation. , 2011, Vaccine.

[35]  W. Jiskoot,et al.  Adjuvant effect of cationic liposomes and CpG depends on administration route. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[36]  Huub Schellekens,et al.  Structure-Immunogenicity Relationships of Therapeutic Proteins , 2004, Pharmaceutical Research.

[37]  K. Sugibayashi,et al.  Enhancement of skin permeation of high molecular compounds by a combination of microneedle pretreatment and iontophoresis. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[38]  Jung-Hwan Park,et al.  Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery , 2004, The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[39]  Dorian Liepmann,et al.  Microfabricated Polysilicon Microneedles for Minimally Invasive Biomedical Devices , 2000 .

[40]  Paul Henman Targeted! , 2004 .

[41]  Eiji Nakamachi,et al.  Development of Blood Extraction System for Health Monitoring System , 2004, SPIE Micro + Nano Materials, Devices, and Applications.

[42]  M. Prausnitz,et al.  Enhanced memory responses to seasonal H1N1 influenza vaccination of the skin with the use of vaccine-coated microneedles. , 2010, The Journal of infectious diseases.

[43]  J. Bouwstra,et al.  Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[44]  Conor O'Mahony,et al.  Determination of parameters for successful spray coating of silicon microneedle arrays. , 2011, International journal of pharmaceutics.

[45]  Ciprian Iliescu,et al.  Silicon microneedle array with biodegradable tips for transdermal drug delivery , 2008 .

[46]  A. Morrissey,et al.  Clinical administration of microneedles: skin puncture, pain and sensation , 2009, Biomedical microdevices.

[47]  M. Prausnitz,et al.  Cutaneous vaccination using microneedles coated with hepatitis C DNA vaccine , 2010, Gene Therapy.

[48]  M. Garland,et al.  Laser-Engineered Dissolving Microneedle Arrays for Transdermal Macromolecular Drug Delivery , 2011, Pharmaceutical Research.

[49]  W H Smart,et al.  The use of silicon microfabrication technology in painless blood glucose monitoring. , 2000, Diabetes technology & therapeutics.

[50]  Mark G. Allen,et al.  Polymer Microneedles for Controlled-Release Drug Delivery , 2006, Pharmaceutical Research.

[51]  Yong-Kyu Yoon,et al.  An electrically active microneedle array for electroporation , 2010, Biomedical microdevices.

[52]  Regina Luttge,et al.  Silicon micromachined hollow microneedles for transdermal liquid transport , 2003 .

[53]  A. Stinchcomb,et al.  Diclofenac Enables Prolonged Delivery of Naltrexone Through Microneedle-Treated Skin , 2011, Pharmaceutical Research.

[54]  T. Tanner,et al.  Delivering drugs by the transdermal route: review and comment , 2008, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[55]  Cheryl H. Dean,et al.  Cutaneous Delivery of a Live, Attenuated Chimeric Flavivirus Vaccines against Japanese Encephalitis (ChimeriVaxTM-JE) in Non-Human Primates , 2005, Human vaccines.

[56]  Guangjiong Qin,et al.  Sustained release of insulin through skin by intradermal microdelivery system , 2010, Biomedical microdevices.

[57]  Elly van Riet,et al.  Efficient induction of immune responses through intradermal vaccination with N-trimethyl chitosan containing antigen formulations. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[58]  I. Frazer,et al.  Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[59]  S. Singh,et al.  An industry perspective on the monitoring of subvisible particles as a quality attribute for protein therapeutics. , 2010, Journal of pharmaceutical sciences.

[60]  A. Banga Microporation applications for enhancing drug delivery. , 2009, Expert opinion on drug delivery.

[61]  Shyh-Chyi Kuo,et al.  A Novel Polymer Microneedle Arrays and PDMS Micromolding Technique , 2004 .

[62]  M Shirkhanzadeh,et al.  Microneedles coated with porous calcium phosphate ceramics: Effective vehicles for transdermal delivery of solid trehalose , 2005, Journal of materials science. Materials in medicine.

[63]  X. Zha,et al.  Study on a piezoelectric micropump for the controlled drug delivery system , 2007 .

[64]  M. Prausnitz,et al.  Transdermal Influenza Immunization with Vaccine-Coated Microneedle Arrays , 2009, PloS one.

[65]  A. Banga,et al.  Molecular charge mediated transport of a 13 kD protein across microporated skin. , 2009, International journal of pharmaceutics.

[66]  David Trebotich,et al.  Microdialysis Microneedles for Continuous Medical Monitoring , 2005, Biomedical microdevices.

[67]  A. Andrianov,et al.  Microneedles with Intrinsic Immunoadjuvant Properties: Microfabrication, Protein Stability, and Modulated Release , 2010, Pharmaceutical Research.

[68]  Manabu Mizutani,et al.  Liquid acrylate-endcapped biodegradable poly(epsilon-caprolactone-co-trimethylene carbonate). II. Computer-aided stereolithographic microarchitectural surface photoconstructs. , 2002, Journal of biomedical materials research.

[69]  Scott A. Kaestner,et al.  Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs , 2010, Pharmaceutical Research.

[70]  T. Prow,et al.  The effect of strain rate on the precision of penetration of short densely-packed microprojection array patches coated with vaccine. , 2010, Biomaterials.

[71]  C. Shearwood,et al.  Transdermal microneedles for drug delivery applications , 2006 .

[72]  Angel Rodriguez,et al.  Fabrication of silicon oxide microneedles from macroporous silicon , 2005 .

[73]  Samir Mitragotri,et al.  Micro-scale devices for transdermal drug delivery. , 2008, International journal of pharmaceutics.

[74]  R. K. Sharma,et al.  TRANSDERMAL DRUG DELIVERY , 2010 .

[75]  Mark R Prausnitz,et al.  Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[76]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[77]  Wijaya Martanto,et al.  Microinfusion Using Hollow Microneedles , 2006, Pharmaceutical Research.

[78]  Mark G. Allen,et al.  Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Ryan F. Donnelly,et al.  Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety , 2010, Drug delivery.

[80]  Elly van Riet,et al.  Advances in transcutaneous vaccine delivery: do all ways lead to Rome? , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[81]  J. Matriano,et al.  Macroflux® Microprojection Array Patch Technology: A New and Efficient Approach for Intracutaneous Immunization , 2004, Pharmaceutical Research.

[82]  H. Schild,et al.  Initiation of adaptive immune responses by transcutaneous immunization. , 2007, Immunology letters.

[83]  H. Schellekens How to predict and prevent the immunogenicity of therapeutic proteins. , 2008, Biotechnology annual review.

[84]  S. Zhai,et al.  Microneedle pretreatment improves efficacy of cutaneous topical anesthesia. , 2010, The American journal of emergency medicine.

[85]  Mark R. Prausnitz,et al.  Layer-by-layer assembly of DNA- and protein-containing films on microneedles for drug delivery to the skin. , 2010, Biomacromolecules.

[86]  Takaya Miyano,et al.  Sugar Micro Needles as Transdermic Drug Delivery System , 2005, Biomedical microdevices.

[87]  Ryan F. Donnelly,et al.  Design, Optimization and Characterisation of Polymeric Microneedle Arrays Prepared by a Novel Laser-Based Micromoulding Technique , 2010, Pharmaceutical Research.

[88]  M. Cormier,et al.  Effect of delivery parameters on immunization to ovalbumin following intracutaneous administration by a coated microneedle array patch system. , 2006, Vaccine.

[89]  J. G. E. Gardeniers,et al.  Lab-on-a-chip systems for biomedical and environmental monitoring , 2003, Int. J. Comput. Eng. Sci..

[90]  M. Prausnitz,et al.  Rapid Local Anesthesia in Humans Using Minimally Invasive Microneedles , 2012, The Clinical journal of pain.

[91]  J. Bouwstra,et al.  Improved piercing of microneedle arrays in dermatomed human skin by an impact insertion method. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[92]  Mark R. Prausnitz,et al.  Coating Formulations for Microneedles , 2007, Pharmaceutical Research.

[93]  Jung-Hwan Park,et al.  Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[94]  Jeffrey D Zahn,et al.  Microneedle Insertion Force Reduction Using Vibratory Actuation , 2004, Biomedical microdevices.

[95]  Hyungil Jung,et al.  Dissolving microneedles for transdermal drug administration prepared by stepwise controlled drawing of maltose. , 2011, Biomaterials.

[96]  J. Eppstein,et al.  Transdermal Delivery of Interferon Alpha-2B using Microporation and Iontophoresis in Hairless Rats , 2007, Pharmaceutical Research.

[97]  Huub Schellekens,et al.  Antibody response to aggregated human interferon alpha2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. , 2006, Journal of pharmaceutical sciences.

[98]  Samuel K Sia,et al.  Lab-on-a-chip devices for global health: past studies and future opportunities. , 2007, Lab on a chip.

[99]  Kinam Park Improving the reach of vaccines to low-resource regions with a needle-free vaccine delivery device and long-term thermostabilization. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[100]  B. Combadière,et al.  Particle-based vaccines for transcutaneous vaccination. , 2008, Comparative immunology, microbiology and infectious diseases.

[101]  M. Prausnitz,et al.  Improved influenza vaccination in the skin using vaccine coated microneedles. , 2009, Vaccine.

[102]  M. Danhof,et al.  Cutaneous side‐effects of transdermal iontophoresis with and without surfactant pretreatment: a single‐blinded, randomized controlled trial , 2005, The British journal of dermatology.

[103]  Greg W. Rouse,et al.  Anatomy , 1836, The British and foreign medical review.

[104]  Dong-il Dan Cho,et al.  In-plane single-crystal-silicon microneedles for minimally invasive microfluid systems , 2004 .

[105]  M. Slijper,et al.  Chapter 6 Structural characterization and immunogenicity in wildtype and immune tolerant mice of degraded recombinant human interferon alpha 2 b , 2005 .

[106]  A. B. Frazier,et al.  Characterization of surface micromachined hollow metallic microneedles , 2003, The Sixteenth Annual International Conference on Micro Electro Mechanical Systems, 2003. MEMS-03 Kyoto. IEEE.

[107]  Göran Stemme,et al.  Painless Drug Delivery Through Microneedle-Based Transdermal Patches Featuring Active Infusion , 2008, IEEE Transactions on Biomedical Engineering.

[108]  Mahmoud Ameri,et al.  Demonstrated Solid-State Stability of Parathyroid Hormone PTH(1–34) Coated on a Novel Transdermal Microprojection Delivery System , 2009, Pharmaceutical Research.

[109]  Mark R Prausnitz,et al.  Microneedles permit transdermal delivery of a skin-impermeant medication to humans , 2008, Proceedings of the National Academy of Sciences.

[110]  Wijaya Martanto,et al.  Transdermal Delivery of Insulin Using Microneedles in Vivo , 2004, Pharmaceutical Research.

[111]  D. Irvine,et al.  Nano‐Layered Microneedles for Transcutaneous Delivery of Polymer Nanoparticles and Plasmid DNA , 2010, Advanced materials.

[112]  Michael L. Reed,et al.  Microsystems for drug and gene delivery , 2004, Proceedings of the IEEE.

[113]  W. Hennink,et al.  Covalently stabilized trimethyl chitosan-hyaluronic acid nanoparticles for nasal and intradermal vaccination. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[114]  Mark R Prausnitz,et al.  Precise microinjection into skin using hollow microneedles. , 2006, The Journal of investigative dermatology.

[115]  Mark R Prausnitz,et al.  Microneedles for transdermal drug delivery. , 2004, Advanced drug delivery reviews.

[116]  Henry,et al.  Microfabricated microneedles: A novel approach to transdermal drug delivery , 1999, Journal of pharmaceutical sciences.

[117]  Dorian Liepmann,et al.  Microneedles and transdermal applications , 2007, Expert opinion on drug delivery.

[118]  M. Allen,et al.  microneedle devices and methods of manufacture. , 1999 .

[119]  Zhengrong Cui,et al.  Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin , 2011, International journal of nanomedicine.

[120]  Hoo-Kyun Choi,et al.  Recent advances in transdermal drug delivery , 2010, Archives of pharmacal research.

[121]  Mark R Prausnitz,et al.  Coated microneedles for transdermal delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[122]  Mahmoud Ameri,et al.  Transdermal delivery of desmopressin using a coated microneedle array patch system. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[123]  Jung Dong Kim,et al.  A high-capacity, hybrid electro-microneedle for in-situ cutaneous gene transfer. , 2011, Biomaterials.

[124]  Patrick Garidel,et al.  Strategies for the Assessment of Protein Aggregates in Pharmaceutical Biotech Product Development , 2010, Pharmaceutical Research.

[125]  S. Singh,et al.  Impact of product-related factors on immunogenicity of biotherapeutics. , 2011, Journal of pharmaceutical sciences.

[126]  Jung-Hwan Park,et al.  Dissolving microneedles for transdermal drug delivery. , 2008, Biomaterials.

[127]  M. Prausnitz,et al.  Immunization by vaccine-coated microneedle arrays protects against lethal influenza virus challenge , 2009, Proceedings of the National Academy of Sciences.

[128]  Yeu-Chun Kim,et al.  Formulation of Microneedles Coated with Influenza Virus-like Particle Vaccine , 2010, AAPS PharmSciTech.

[129]  Vincent J. Sullivan,et al.  Protective immunization against inhalational anthrax: a comparison of minimally invasive delivery platforms. , 2005, The Journal of infectious diseases.

[130]  Mark R Prausnitz,et al.  Selective removal of stratum corneum by microdermabrasion to increase skin permeability. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[131]  M. Prausnitz,et al.  Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. , 2009, Diabetes technology & therapeutics.

[132]  Laser-Based Deposition Technique : Patterning Nanoparticles into Microstructures , 2004 .

[133]  W. Jiskoot,et al.  Immunogenicity of Therapeutic Proteins: The Use of Animal Models , 2011, Pharmaceutical Research.

[134]  ROBERT G. ROSE,et al.  Robert G , 2001 .

[135]  Diane E. Sutter,et al.  Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery , 2002, Nature Medicine.

[136]  M. Prausnitz,et al.  Assessment of trueness of a glucose monitor using interstitial fluid and whole blood as specimen matrix. , 2006, Diabetes technology & therapeutics.

[137]  Mark R Prausnitz,et al.  Rapid pharmacokinetics of intradermal insulin administered using microneedles in type 1 diabetes subjects. , 2011, Diabetes technology & therapeutics.

[138]  H. Kalluri,et al.  Characterization of Microchannels Created by Metal Microneedles: Formation and Closure , 2011, The AAPS Journal.

[139]  S. Chandrasekaran Surface micromachined hollow metallic microneedles , 2003 .

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

[141]  Huub Schellekens,et al.  Immunological mechanism underlying the immune response to recombinant human protein therapeutics. , 2010, Trends in pharmacological sciences.

[142]  Mark R Prausnitz,et al.  Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: Bubble and pedestal microneedle designs. , 2010, Journal of pharmaceutical sciences.

[143]  Huub Schellekens,et al.  Factors influencing the immunogenicity of therapeutic proteins. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[144]  J. Stockman,et al.  Dissolving polymer microneedle patches for influenza vaccination , 2012 .

[145]  A. Rosenberg,et al.  Effects of protein aggregates: An immunologic perspective , 2006, The AAPS Journal.

[146]  G. Leroux-Roels,et al.  Seasonal influenza vaccine delivered by intradermal microinjection: A randomised controlled safety and immunogenicity trial in adults. , 2008, Vaccine.

[147]  Hervé Bourhy,et al.  Safety and efficacy of novel dermal and epidermal microneedle delivery systems for rabies vaccination in healthy adults. , 2010, Vaccine.

[148]  A. Andrianov,et al.  Carboxymethylcellulose–Chitosan-coated microneedles with modulated hydration properties , 2011 .

[149]  J. Bouwstra,et al.  In vivo assessment of safety of microneedle arrays in human skin. , 2008, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[150]  Michael S Roberts,et al.  Dry-coated microprojection array patches for targeted delivery of immunotherapeutics to the skin. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[151]  J. Yoshimitsu,et al.  Self-dissolving microneedles for the percutaneous absorption of EPO in mice , 2006, Journal of drug targeting.

[152]  M. Cormier,et al.  Transdermal Delivery of Antisense Oligonucleotides with Microprojection Patch (macroflux®) Technology , 2001, Pharmaceutical Research.

[153]  M. Allen,et al.  Microfabricated microneedles for gene and drug delivery. , 2000, Annual review of biomedical engineering.

[154]  M. Kendall,et al.  Targeted, needle-free vaccinations in skin using multilayered, densely-packed dissolving microprojection arrays. , 2010, Small.

[155]  Ying Zhang,et al.  Development of Lidocaine-Coated Microneedle Product for Rapid, Safe, and Prolonged Local Analgesic Action , 2011, Pharmaceutical Research.

[156]  Haripriya Kalluri,et al.  Formation and Closure of Microchannels in Skin Following Microporation , 2010, Pharmaceutical Research.

[157]  D. Ejima,et al.  Aggregation Analysis of Therapeutic Proteins , Part 1 General Aspects and Techniques for Assessment , 2006 .

[158]  David Trebotich,et al.  Microfabricated microdialysis microneedles for continuous medical monitoring , 2000, 1st Annual International IEEE-EMBS Special Topic Conference on Microtechnologies in Medicine and Biology. Proceedings (Cat. No.00EX451).

[159]  Huub Schellekens,et al.  Structural Characterization and Immunogenicity in Wild-Type and Immune Tolerant Mice of Degraded Recombinant Human Interferon Alpha2b , 2005, Pharmaceutical Research.

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