RYAN F. DONNELLY, PHD, holds the Chair in Pharmaceutical Technology in the School of Pharmacy at Queen's University Belfast and is a registered Pharmacist.THAKUR RAGHU RAJ SINGH, PHD, is Senior Lecturer in Pharmaceutics in the School of Pharmacy at Queen's University Belfast.ENEKO LARRAÑETA, PHD, is Lecturer in Pharmaceutical Sciences in the School of Pharmacy at Queen's University Belfast.MAELÍOSA T.C. MCCRUDDEN, PHD, is a Senior Research Fellow in the School of Pharmacy at Queen's University Belfast.

• List of Contributors xiAbout the Editors xiiiPreface xv1 Genesis of Transdermal Drug Delivery 1Ahlam Zaid-Alkilani1.1 Skin Anatomy 21.1.1 The Epidermis 21.1.2 The Stratum Corneum 41.1.3 The Dermis 51.1.4 Skin Appendages 51.2 Routes to Percutaneous Drug Absorption 61.3 Facilitated Transdermal Drug Delivery 91.3.1 Electrical-based Devices 101.3.1.1 Iontophoresis 101.3.1.2 Electroporation 121.3.1.3 Ultrasound 121.3.1.4 Cryopneumatic and Photopneumatic Technologies 131.3.1.5 Velocity-based Devices 131.3.1.6 Thermal Approaches (Lasers and Radiofrequency Heating) 141.3.1.7 Microneedles 14References 152 Microneedle Manufacturing and Testing 21Eneko Larrañeta and Thakur Raghu Raj Singh2.1 Introduction 212.2 Material Types, Properties and Biocompatibility 232.2.1 Silicon 232.2.1.1 Biocompatibility of Silicon 242.2.2 Metals 242.2.2.1 Biocompatibility of Metals 262.2.3 Ceramics 272.2.3.1 Biocompatibility of Ceramics 272.2.4 Silica Glass 282.2.4.1 Biocompatibility of Silica Glass 292.2.5 Carbohydrates 292.2.5.1 Biocompatibility of Carbohydrates 302.2.6 Polymers 302.2.6.1 Biocompatibility of Polymers 332.3 Microneedles Manufacturing and Design 352.3.1 Basics of Microfabrication 352.3.1.1 Lithography and Etching 362.3.1.2 Thin-film Deposition on Substrates 372.3.1.3 Etching 382.3.2 Microfabrication MNs 392.3.2.1 Fabrication of Silicon MNs 392.3.2.2 Fabrication of Metal and Glass MNs 422.3.2.3 Fabrication of Polymeric MNs 442.3.3 Microneedle Design 502.4 Microneedle Mechanical Characterisation 532.4.1 Axial Force Microneedle Mechanical Tests 542.4.2 Transverse Force and Shear Strength Microneedle Mechanical Tests 552.4.3 Baseplate Strength and Flexibility Tests 552.4.4 Microneedle Insertion Measurements 552.4.4.1 Staining of Microneedle-treated Skin 552.4.4.2 Transepidermal Water Loss Measurements 562.4.4.3 Electrical Impedance Measurements 562.4.4.4 Histological Tissue Staining and Sectioning 562.4.4.5 Confocal Microscopy 572.4.4.6 Optical Coherence Tomography 572.4.5 Significance of Microneedle Test Results 57References 583 Microneedle-mediated Drug Delivery 71Helen L. Quinn and Ryan F. Donnelly3.1 Introduction 713.2 Microneedle Drug Delivery Strategies 733.2.1 Solid Microneedles 743.2.2 Coated Microneedles 773.2.3 Hollow Microneedles 783.2.4 Dissolving Microneedles 803.2.5 Hydrogel-forming Microneedles 833.3 Conclusion 85References 854 Microneedle-mediated Vaccine Delivery 93Maelíosa T.C. McCrudden, Aaron J. Courtenay and Ryan F. Donnelly4.1 Introduction 934.2 Vaccine Delivery 934.2.1 Vaccination 934.2.2 Alternative Vaccine Delivery Options 964.3 Intradermal Vaccination 984.3.1 Skin Structure 984.3.2 Skin Immune Response 1004.3.3 Conventional Strategies for Intradermal Vaccine Delivery 1004.4 MN Delivery of Vaccine Therapeutics 1014.4.1 Dissolving/Biodegrading Polymeric MNs 1014.4.1.1 Viral Vaccines 1024.4.1.2 Bacterial Vaccines 1054.4.1.3 Model and Novel Vaccines 1064.4.2 Hollow MNs 1074.4.3 Solid MN 1104.4.3.1 “Poke and Patch” Methodologies 1104.4.3.2 Coated MNs 1114.5 Future Perspectives 118References 1205 Microneedles for Gene Therapy: Overcoming Extracellular and Intracellular Barriers 129Grace Cole, Nicholas J. Dunne and Helen O. McCarthy5.1 Gene Therapy 1295.2 DNA Vaccination 1305.2.1 Advantages of DNA Vaccination 1305.2.2 Mechanism of Action of DNA Vaccines 1305.3 Treatment of Local Skin Diseases 1355.4 Limitations of Gene Therapy 1365.5 Microneedles as a Physical Delivery Strategy for Gene Therapy 1385.5.1 Solid Microneedles 1395.5.2 Coated Microneedles 1435.5.3 Hollow Microneedles 1475.5.4 Dissolvable Microneedles 1485.5.5 Microneedles in Combination with Other Delivery Technologies 1505.5.5.1 In Combination with Physical Delivery Technologies 1505.5.5.2 In Combination with Vector-based Delivery Technologies 1535.6 Conclusions 162References 1636 Delivery of Nanomedicines Using Microneedles 177Eneko Larrañeta and Lalit Vora6.1 Introduction 1776.2 Skin Structure and Barrier Properties Which Impact on Nanoparticle and Microparticle Penetration 1786.3 Conventional Nanocarriers for Topical and Transdermal Delivery 1796.3.1 Lipidic Vesicles 1796.3.2 Lipid Nanoparticles 1816.3.3 Polymeric Nanoparticles and Microparticles 1816.3.4 Microemulsions 1816.3.5 Metallic and Mineral Nanoparticles 1826.4 Microneedle-mediated Transdermal Delivery of Nanoparticles and Microparticles 1836.4.1 Microneedle-assisted Nanoparticle/Microparticle Permeation 1836.4.2 Drug Delivery 1866.4.3 Vaccine Delivery 1916.4.4 Other Uses 1966.5 Conclusions 198References 1997 Minimally-invasive Patient Monitoring and Diagnosis Using Microneedles 207Aaron J. Courtenay,Marco T.A. Abbate,Maelíosa T.C. McCrudden and Ryan F. Donnelly7.1 Introduction 2077.1.1 What is Patient Monitoring? 2077.1.2 Why is Patient Monitoring Useful? 2077.1.3 Limitations and Challenges of Therapeutic Monitoring 2087.2 Sampling Techniques 2097.2.1 Minimally and Non-invasive Sample Extraction 2097.2.2 Microneedles and Fluid Sampling Technology 2117.3 Microneedle Fluid Extraction Device Technical Considerations 2117.3.1 Mechanical Parameters 2117.3.2 Fluidics 2127.4 Microneedle Innovations 2127.4.1 Glucose Monitoring 2137.5 Microneedle Innovations in Analyte Monitoring 2187.5.1 Therapeutic Drug and Biomarker Detection 2187.6 Microneedle Electrode Technology 2197.6.1 Electro-biochemical Monitoring 2197.7 Sampling and Analytical Systems Integration 2217.7.1 Limitations and Challenges Associated with Systems Integration 2217.8 Interstitial Fluid and Blood Sampling 2237.8.1 Devices and Patents 2237.9 Developments Moving Forwards 2267.9.1 Industrialisation and Commercialisation: Hurdles to Overcome 2267.10 Conclusion 228References 2298 Delivery of Photosensitisers and Precursors Using Microneedles 235Mary-Carmel Kearney, Sarah Brown, Iman Hamdan and Ryan F. Donnelly8.1 Introduction 2358.1.1 Photodynamic Therapy 2358.1.2 Photosensitisers 2368.2 Topical Application of Photodynamic Therapy 2378.3 Methods to Enhance Topical Photodynamic Therapy 2388.3.1 Microneedle-mediated Photodynamic Therapy 2398.3.2 PhotodynamicTherapy and Skin Pre-treatment Using Microneedles 2398.3.3 Delivery of Photosensitisers Using Microneedles Containing the Active Agent 2468.4 Microneedles and Photothermal Therapy 2508.5 Conclusion 252References 2539 Microneedles in Improving Skin Appearance and Enhanced Delivery of Cosmeceuticals 259Emma McAlister, Maelíosa T.C. McCrudden and Ryan F. Donnelly9.1 Introduction 2599.2 The Skin 2599.3 Microneedling Technologies: An Evolutionary Step Towards MN Usage 2609.4 Benefits of Microneedling 2619.5 Commercially Available MN Devices 2629.5.1 Dermaroller® 2629.5.2 Beauty Mouse® 2649.5.3 DermastampTM 2659.5.4 Dermapen® 2669.5.5 Light Emitting MN Devices 2689.6 Patient Factors Relating to MN Devices 2689.6.1 Acceptability of MN Devices by Patients and Healthcare Providers 2699.6.2 Potential Irritation and Erythema 2699.6.3 Patient Safety 2699.6.4 Sterilisation Considerations 2709.7 Delivery of Cosmeceutical Compounds 2719.7.1 A Role for Hyaluronic Acid in MN Delivery Systems 2719.7.2 MN-mediated Peptide Delivery 2729.7.3 The Delivery of Other Cosmeceutical Agents 2739.8 Recent Developments 2759.8.1 Human Stem Cells 2759.8.2 Fractional Radiofrequency 2759.9 Conclusion 276References 27710 Microneedles for Ocular Drug Delivery and Targeting: Challenges and Opportunities 283Ismaiel A. Tekko and Thakur Raghu Raj Singh10.1 Introduction 28310.2 Anatomy of the Eye and Barriers to Drug Delivery 28410.2.1 The Anterior Segment and its Barrier Function 28410.2.2 The Posterior Segment and its Barriers Function 28610.3 Ocular Diseases and Treatments 28810.4 Current Ocular Drug Delivery Systems and Administration Routes 28810.4.1 Topical Route 28810.4.2 Oral/Systemic Administration Route 28810.4.3 Ocular Injections 29010.4.3.1 Anterior Segment Injections 29010.4.3.2 Posterior Segment Injections 29110.5 Microneedles in Ocular Drug Delivery 29310.5.1 Hollow MNs 29310.5.2 Solid MNs with “Coat and Poke” Strategy 29310.5.3 Dissolving MNs 29510.5.4 Hollow MN Strategy 29610.5.5 Other Strategies 29910.6 MN Application Devices 29910.7 MN Safety Concerns 30010.8 Conclusion 301References 30211 Clinical Translation and Industrial Development of Microneedle-based Products 307Ryan F. Donnelly11.1 Introduction 30711.2 Materials 30811.3 Other Potential Applications 31011.4 Patient Application 31011.5 Patient/Healthcare Provider Acceptability 31211.6 Patient Safety 31311.7 Manufacturing and Regulatory Considerations 31511.8 Commercialisation of MN Technologies 31611.9 Conclusion 31811.10 Future Perspectives 319References 319Index 323

RYAN F. DONNELLY, PHD, holds the Chair in Pharmaceutical Technology in the School of Pharmacy at Queen's University Belfast and is a registered Pharmacist.THAKUR RAGHU RAJ SINGH, PHD, is Senior Lecturer in Pharmaceutics in the School of Pharmacy at Queen's University Belfast.ENEKO LARRAÑETA, PHD, is Lecturer in Pharmaceutical Sciences in the School of Pharmacy at Queen's University Belfast.MAELÍOSA T.C. MCCRUDDEN, PHD, is a Senior Research Fellow in the School of Pharmacy at Queen's University Belfast.

• List of Contributors xiAbout the Editors xiiiPreface xv1 Genesis of Transdermal Drug Delivery 1Ahlam Zaid-Alkilani1.1 Skin Anatomy 21.1.1 The Epidermis 21.1.2 The Stratum Corneum 41.1.3 The Dermis 51.1.4 Skin Appendages 51.2 Routes to Percutaneous Drug Absorption 61.3 Facilitated Transdermal Drug Delivery 91.3.1 Electrical-based Devices 101.3.1.1 Iontophoresis 101.3.1.2 Electroporation 121.3.1.3 Ultrasound 121.3.1.4 Cryopneumatic and Photopneumatic Technologies 131.3.1.5 Velocity-based Devices 131.3.1.6 Thermal Approaches (Lasers and Radiofrequency Heating) 141.3.1.7 Microneedles 14References 152 Microneedle Manufacturing and Testing 21Eneko Larrañeta and Thakur Raghu Raj Singh2.1 Introduction 212.2 Material Types, Properties and Biocompatibility 232.2.1 Silicon 232.2.1.1 Biocompatibility of Silicon 242.2.2 Metals 242.2.2.1 Biocompatibility of Metals 262.2.3 Ceramics 272.2.3.1 Biocompatibility of Ceramics 272.2.4 Silica Glass 282.2.4.1 Biocompatibility of Silica Glass 292.2.5 Carbohydrates 292.2.5.1 Biocompatibility of Carbohydrates 302.2.6 Polymers 302.2.6.1 Biocompatibility of Polymers 332.3 Microneedles Manufacturing and Design 352.3.1 Basics of Microfabrication 352.3.1.1 Lithography and Etching 362.3.1.2 Thin-film Deposition on Substrates 372.3.1.3 Etching 382.3.2 Microfabrication MNs 392.3.2.1 Fabrication of Silicon MNs 392.3.2.2 Fabrication of Metal and Glass MNs 422.3.2.3 Fabrication of Polymeric MNs 442.3.3 Microneedle Design 502.4 Microneedle Mechanical Characterisation 532.4.1 Axial Force Microneedle Mechanical Tests 542.4.2 Transverse Force and Shear Strength Microneedle Mechanical Tests 552.4.3 Baseplate Strength and Flexibility Tests 552.4.4 Microneedle Insertion Measurements 552.4.4.1 Staining of Microneedle-treated Skin 552.4.4.2 Transepidermal Water Loss Measurements 562.4.4.3 Electrical Impedance Measurements 562.4.4.4 Histological Tissue Staining and Sectioning 562.4.4.5 Confocal Microscopy 572.4.4.6 Optical Coherence Tomography 572.4.5 Significance of Microneedle Test Results 57References 583 Microneedle-mediated Drug Delivery 71Helen L. Quinn and Ryan F. Donnelly3.1 Introduction 713.2 Microneedle Drug Delivery Strategies 733.2.1 Solid Microneedles 743.2.2 Coated Microneedles 773.2.3 Hollow Microneedles 783.2.4 Dissolving Microneedles 803.2.5 Hydrogel-forming Microneedles 833.3 Conclusion 85References 854 Microneedle-mediated Vaccine Delivery 93Maelíosa T.C. McCrudden, Aaron J. Courtenay and Ryan F. Donnelly4.1 Introduction 934.2 Vaccine Delivery 934.2.1 Vaccination 934.2.2 Alternative Vaccine Delivery Options 964.3 Intradermal Vaccination 984.3.1 Skin Structure 984.3.2 Skin Immune Response 1004.3.3 Conventional Strategies for Intradermal Vaccine Delivery 1004.4 MN Delivery of Vaccine Therapeutics 1014.4.1 Dissolving/Biodegrading Polymeric MNs 1014.4.1.1 Viral Vaccines 1024.4.1.2 Bacterial Vaccines 1054.4.1.3 Model and Novel Vaccines 1064.4.2 Hollow MNs 1074.4.3 Solid MN 1104.4.3.1 “Poke and Patch” Methodologies 1104.4.3.2 Coated MNs 1114.5 Future Perspectives 118References 1205 Microneedles for Gene Therapy: Overcoming Extracellular and Intracellular Barriers 129Grace Cole, Nicholas J. Dunne and Helen O. McCarthy5.1 Gene Therapy 1295.2 DNA Vaccination 1305.2.1 Advantages of DNA Vaccination 1305.2.2 Mechanism of Action of DNA Vaccines 1305.3 Treatment of Local Skin Diseases 1355.4 Limitations of Gene Therapy 1365.5 Microneedles as a Physical Delivery Strategy for Gene Therapy 1385.5.1 Solid Microneedles 1395.5.2 Coated Microneedles 1435.5.3 Hollow Microneedles 1475.5.4 Dissolvable Microneedles 1485.5.5 Microneedles in Combination with Other Delivery Technologies 1505.5.5.1 In Combination with Physical Delivery Technologies 1505.5.5.2 In Combination with Vector-based Delivery Technologies 1535.6 Conclusions 162References 1636 Delivery of Nanomedicines Using Microneedles 177Eneko Larrañeta and Lalit Vora6.1 Introduction 1776.2 Skin Structure and Barrier Properties Which Impact on Nanoparticle and Microparticle Penetration 1786.3 Conventional Nanocarriers for Topical and Transdermal Delivery 1796.3.1 Lipidic Vesicles 1796.3.2 Lipid Nanoparticles 1816.3.3 Polymeric Nanoparticles and Microparticles 1816.3.4 Microemulsions 1816.3.5 Metallic and Mineral Nanoparticles 1826.4 Microneedle-mediated Transdermal Delivery of Nanoparticles and Microparticles 1836.4.1 Microneedle-assisted Nanoparticle/Microparticle Permeation 1836.4.2 Drug Delivery 1866.4.3 Vaccine Delivery 1916.4.4 Other Uses 1966.5 Conclusions 198References 1997 Minimally-invasive Patient Monitoring and Diagnosis Using Microneedles 207Aaron J. Courtenay,Marco T.A. Abbate,Maelíosa T.C. McCrudden and Ryan F. Donnelly7.1 Introduction 2077.1.1 What is Patient Monitoring? 2077.1.2 Why is Patient Monitoring Useful? 2077.1.3 Limitations and Challenges of Therapeutic Monitoring 2087.2 Sampling Techniques 2097.2.1 Minimally and Non-invasive Sample Extraction 2097.2.2 Microneedles and Fluid Sampling Technology 2117.3 Microneedle Fluid Extraction Device Technical Considerations 2117.3.1 Mechanical Parameters 2117.3.2 Fluidics 2127.4 Microneedle Innovations 2127.4.1 Glucose Monitoring 2137.5 Microneedle Innovations in Analyte Monitoring 2187.5.1 Therapeutic Drug and Biomarker Detection 2187.6 Microneedle Electrode Technology 2197.6.1 Electro-biochemical Monitoring 2197.7 Sampling and Analytical Systems Integration 2217.7.1 Limitations and Challenges Associated with Systems Integration 2217.8 Interstitial Fluid and Blood Sampling 2237.8.1 Devices and Patents 2237.9 Developments Moving Forwards 2267.9.1 Industrialisation and Commercialisation: Hurdles to Overcome 2267.10 Conclusion 228References 2298 Delivery of Photosensitisers and Precursors Using Microneedles 235Mary-Carmel Kearney, Sarah Brown, Iman Hamdan and Ryan F. Donnelly8.1 Introduction 2358.1.1 Photodynamic Therapy 2358.1.2 Photosensitisers 2368.2 Topical Application of Photodynamic Therapy 2378.3 Methods to Enhance Topical Photodynamic Therapy 2388.3.1 Microneedle-mediated Photodynamic Therapy 2398.3.2 PhotodynamicTherapy and Skin Pre-treatment Using Microneedles 2398.3.3 Delivery of Photosensitisers Using Microneedles Containing the Active Agent 2468.4 Microneedles and Photothermal Therapy 2508.5 Conclusion 252References 2539 Microneedles in Improving Skin Appearance and Enhanced Delivery of Cosmeceuticals 259Emma McAlister, Maelíosa T.C. McCrudden and Ryan F. Donnelly9.1 Introduction 2599.2 The Skin 2599.3 Microneedling Technologies: An Evolutionary Step Towards MN Usage 2609.4 Benefits of Microneedling 2619.5 Commercially Available MN Devices 2629.5.1 Dermaroller® 2629.5.2 Beauty Mouse® 2649.5.3 DermastampTM 2659.5.4 Dermapen® 2669.5.5 Light Emitting MN Devices 2689.6 Patient Factors Relating to MN Devices 2689.6.1 Acceptability of MN Devices by Patients and Healthcare Providers 2699.6.2 Potential Irritation and Erythema 2699.6.3 Patient Safety 2699.6.4 Sterilisation Considerations 2709.7 Delivery of Cosmeceutical Compounds 2719.7.1 A Role for Hyaluronic Acid in MN Delivery Systems 2719.7.2 MN-mediated Peptide Delivery 2729.7.3 The Delivery of Other Cosmeceutical Agents 2739.8 Recent Developments 2759.8.1 Human Stem Cells 2759.8.2 Fractional Radiofrequency 2759.9 Conclusion 276References 27710 Microneedles for Ocular Drug Delivery and Targeting: Challenges and Opportunities 283Ismaiel A. Tekko and Thakur Raghu Raj Singh10.1 Introduction 28310.2 Anatomy of the Eye and Barriers to Drug Delivery 28410.2.1 The Anterior Segment and its Barrier Function 28410.2.2 The Posterior Segment and its Barriers Function 28610.3 Ocular Diseases and Treatments 28810.4 Current Ocular Drug Delivery Systems and Administration Routes 28810.4.1 Topical Route 28810.4.2 Oral/Systemic Administration Route 28810.4.3 Ocular Injections 29010.4.3.1 Anterior Segment Injections 29010.4.3.2 Posterior Segment Injections 29110.5 Microneedles in Ocular Drug Delivery 29310.5.1 Hollow MNs 29310.5.2 Solid MNs with “Coat and Poke” Strategy 29310.5.3 Dissolving MNs 29510.5.4 Hollow MN Strategy 29610.5.5 Other Strategies 29910.6 MN Application Devices 29910.7 MN Safety Concerns 30010.8 Conclusion 301References 30211 Clinical Translation and Industrial Development of Microneedle-based Products 307Ryan F. Donnelly11.1 Introduction 30711.2 Materials 30811.3 Other Potential Applications 31011.4 Patient Application 31011.5 Patient/Healthcare Provider Acceptability 31211.6 Patient Safety 31311.7 Manufacturing and Regulatory Considerations 31511.8 Commercialisation of MN Technologies 31611.9 Conclusion 31811.10 Future Perspectives 319References 319Index 323

RYAN F. DONNELLY, PHD, holds the Chair in Pharmaceutical Technology in the School of Pharmacy at Queen's University Belfast and is a registered Pharmacist.THAKUR RAGHU RAJ SINGH, PHD, is Senior Lecturer in Pharmaceutics in the School of Pharmacy at Queen's University Belfast.ENEKO LARRAÑETA, PHD, is Lecturer in Pharmaceutical Sciences in the School of Pharmacy at Queen's University Belfast.MAELÍOSA T.C. MCCRUDDEN, PHD, is a Senior Research Fellow in the School of Pharmacy at Queen's University Belfast.

• List of Contributors xiAbout the Editors xiiiPreface xv1 Genesis of Transdermal Drug Delivery 1Ahlam Zaid-Alkilani1.1 Skin Anatomy 21.1.1 The Epidermis 21.1.2 The Stratum Corneum 41.1.3 The Dermis 51.1.4 Skin Appendages 51.2 Routes to Percutaneous Drug Absorption 61.3 Facilitated Transdermal Drug Delivery 91.3.1 Electrical-based Devices 101.3.1.1 Iontophoresis 101.3.1.2 Electroporation 121.3.1.3 Ultrasound 121.3.1.4 Cryopneumatic and Photopneumatic Technologies 131.3.1.5 Velocity-based Devices 131.3.1.6 Thermal Approaches (Lasers and Radiofrequency Heating) 141.3.1.7 Microneedles 14References 152 Microneedle Manufacturing and Testing 21Eneko Larrañeta and Thakur Raghu Raj Singh2.1 Introduction 212.2 Material Types, Properties and Biocompatibility 232.2.1 Silicon 232.2.1.1 Biocompatibility of Silicon 242.2.2 Metals 242.2.2.1 Biocompatibility of Metals 262.2.3 Ceramics 272.2.3.1 Biocompatibility of Ceramics 272.2.4 Silica Glass 282.2.4.1 Biocompatibility of Silica Glass 292.2.5 Carbohydrates 292.2.5.1 Biocompatibility of Carbohydrates 302.2.6 Polymers 302.2.6.1 Biocompatibility of Polymers 332.3 Microneedles Manufacturing and Design 352.3.1 Basics of Microfabrication 352.3.1.1 Lithography and Etching 362.3.1.2 Thin-film Deposition on Substrates 372.3.1.3 Etching 382.3.2 Microfabrication MNs 392.3.2.1 Fabrication of Silicon MNs 392.3.2.2 Fabrication of Metal and Glass MNs 422.3.2.3 Fabrication of Polymeric MNs 442.3.3 Microneedle Design 502.4 Microneedle Mechanical Characterisation 532.4.1 Axial Force Microneedle Mechanical Tests 542.4.2 Transverse Force and Shear Strength Microneedle Mechanical Tests 552.4.3 Baseplate Strength and Flexibility Tests 552.4.4 Microneedle Insertion Measurements 552.4.4.1 Staining of Microneedle-treated Skin 552.4.4.2 Transepidermal Water Loss Measurements 562.4.4.3 Electrical Impedance Measurements 562.4.4.4 Histological Tissue Staining and Sectioning 562.4.4.5 Confocal Microscopy 572.4.4.6 Optical Coherence Tomography 572.4.5 Significance of Microneedle Test Results 57References 583 Microneedle-mediated Drug Delivery 71Helen L. Quinn and Ryan F. Donnelly3.1 Introduction 713.2 Microneedle Drug Delivery Strategies 733.2.1 Solid Microneedles 743.2.2 Coated Microneedles 773.2.3 Hollow Microneedles 783.2.4 Dissolving Microneedles 803.2.5 Hydrogel-forming Microneedles 833.3 Conclusion 85References 854 Microneedle-mediated Vaccine Delivery 93Maelíosa T.C. McCrudden, Aaron J. Courtenay and Ryan F. Donnelly4.1 Introduction 934.2 Vaccine Delivery 934.2.1 Vaccination 934.2.2 Alternative Vaccine Delivery Options 964.3 Intradermal Vaccination 984.3.1 Skin Structure 984.3.2 Skin Immune Response 1004.3.3 Conventional Strategies for Intradermal Vaccine Delivery 1004.4 MN Delivery of Vaccine Therapeutics 1014.4.1 Dissolving/Biodegrading Polymeric MNs 1014.4.1.1 Viral Vaccines 1024.4.1.2 Bacterial Vaccines 1054.4.1.3 Model and Novel Vaccines 1064.4.2 Hollow MNs 1074.4.3 Solid MN 1104.4.3.1 “Poke and Patch” Methodologies 1104.4.3.2 Coated MNs 1114.5 Future Perspectives 118References 1205 Microneedles for Gene Therapy: Overcoming Extracellular and Intracellular Barriers 129Grace Cole, Nicholas J. Dunne and Helen O. McCarthy5.1 Gene Therapy 1295.2 DNA Vaccination 1305.2.1 Advantages of DNA Vaccination 1305.2.2 Mechanism of Action of DNA Vaccines 1305.3 Treatment of Local Skin Diseases 1355.4 Limitations of Gene Therapy 1365.5 Microneedles as a Physical Delivery Strategy for Gene Therapy 1385.5.1 Solid Microneedles 1395.5.2 Coated Microneedles 1435.5.3 Hollow Microneedles 1475.5.4 Dissolvable Microneedles 1485.5.5 Microneedles in Combination with Other Delivery Technologies 1505.5.5.1 In Combination with Physical Delivery Technologies 1505.5.5.2 In Combination with Vector-based Delivery Technologies 1535.6 Conclusions 162References 1636 Delivery of Nanomedicines Using Microneedles 177Eneko Larrañeta and Lalit Vora6.1 Introduction 1776.2 Skin Structure and Barrier Properties Which Impact on Nanoparticle and Microparticle Penetration 1786.3 Conventional Nanocarriers for Topical and Transdermal Delivery 1796.3.1 Lipidic Vesicles 1796.3.2 Lipid Nanoparticles 1816.3.3 Polymeric Nanoparticles and Microparticles 1816.3.4 Microemulsions 1816.3.5 Metallic and Mineral Nanoparticles 1826.4 Microneedle-mediated Transdermal Delivery of Nanoparticles and Microparticles 1836.4.1 Microneedle-assisted Nanoparticle/Microparticle Permeation 1836.4.2 Drug Delivery 1866.4.3 Vaccine Delivery 1916.4.4 Other Uses 1966.5 Conclusions 198References 1997 Minimally-invasive Patient Monitoring and Diagnosis Using Microneedles 207Aaron J. Courtenay,Marco T.A. Abbate,Maelíosa T.C. McCrudden and Ryan F. Donnelly7.1 Introduction 2077.1.1 What is Patient Monitoring? 2077.1.2 Why is Patient Monitoring Useful? 2077.1.3 Limitations and Challenges of Therapeutic Monitoring 2087.2 Sampling Techniques 2097.2.1 Minimally and Non-invasive Sample Extraction 2097.2.2 Microneedles and Fluid Sampling Technology 2117.3 Microneedle Fluid Extraction Device Technical Considerations 2117.3.1 Mechanical Parameters 2117.3.2 Fluidics 2127.4 Microneedle Innovations 2127.4.1 Glucose Monitoring 2137.5 Microneedle Innovations in Analyte Monitoring 2187.5.1 Therapeutic Drug and Biomarker Detection 2187.6 Microneedle Electrode Technology 2197.6.1 Electro-biochemical Monitoring 2197.7 Sampling and Analytical Systems Integration 2217.7.1 Limitations and Challenges Associated with Systems Integration 2217.8 Interstitial Fluid and Blood Sampling 2237.8.1 Devices and Patents 2237.9 Developments Moving Forwards 2267.9.1 Industrialisation and Commercialisation: Hurdles to Overcome 2267.10 Conclusion 228References 2298 Delivery of Photosensitisers and Precursors Using Microneedles 235Mary-Carmel Kearney, Sarah Brown, Iman Hamdan and Ryan F. Donnelly8.1 Introduction 2358.1.1 Photodynamic Therapy 2358.1.2 Photosensitisers 2368.2 Topical Application of Photodynamic Therapy 2378.3 Methods to Enhance Topical Photodynamic Therapy 2388.3.1 Microneedle-mediated Photodynamic Therapy 2398.3.2 PhotodynamicTherapy and Skin Pre-treatment Using Microneedles 2398.3.3 Delivery of Photosensitisers Using Microneedles Containing the Active Agent 2468.4 Microneedles and Photothermal Therapy 2508.5 Conclusion 252References 2539 Microneedles in Improving Skin Appearance and Enhanced Delivery of Cosmeceuticals 259Emma McAlister, Maelíosa T.C. McCrudden and Ryan F. Donnelly9.1 Introduction 2599.2 The Skin 2599.3 Microneedling Technologies: An Evolutionary Step Towards MN Usage 2609.4 Benefits of Microneedling 2619.5 Commercially Available MN Devices 2629.5.1 Dermaroller® 2629.5.2 Beauty Mouse® 2649.5.3 DermastampTM 2659.5.4 Dermapen® 2669.5.5 Light Emitting MN Devices 2689.6 Patient Factors Relating to MN Devices 2689.6.1 Acceptability of MN Devices by Patients and Healthcare Providers 2699.6.2 Potential Irritation and Erythema 2699.6.3 Patient Safety 2699.6.4 Sterilisation Considerations 2709.7 Delivery of Cosmeceutical Compounds 2719.7.1 A Role for Hyaluronic Acid in MN Delivery Systems 2719.7.2 MN-mediated Peptide Delivery 2729.7.3 The Delivery of Other Cosmeceutical Agents 2739.8 Recent Developments 2759.8.1 Human Stem Cells 2759.8.2 Fractional Radiofrequency 2759.9 Conclusion 276References 27710 Microneedles for Ocular Drug Delivery and Targeting: Challenges and Opportunities 283Ismaiel A. Tekko and Thakur Raghu Raj Singh10.1 Introduction 28310.2 Anatomy of the Eye and Barriers to Drug Delivery 28410.2.1 The Anterior Segment and its Barrier Function 28410.2.2 The Posterior Segment and its Barriers Function 28610.3 Ocular Diseases and Treatments 28810.4 Current Ocular Drug Delivery Systems and Administration Routes 28810.4.1 Topical Route 28810.4.2 Oral/Systemic Administration Route 28810.4.3 Ocular Injections 29010.4.3.1 Anterior Segment Injections 29010.4.3.2 Posterior Segment Injections 29110.5 Microneedles in Ocular Drug Delivery 29310.5.1 Hollow MNs 29310.5.2 Solid MNs with “Coat and Poke” Strategy 29310.5.3 Dissolving MNs 29510.5.4 Hollow MN Strategy 29610.5.5 Other Strategies 29910.6 MN Application Devices 29910.7 MN Safety Concerns 30010.8 Conclusion 301References 30211 Clinical Translation and Industrial Development of Microneedle-based Products 307Ryan F. Donnelly11.1 Introduction 30711.2 Materials 30811.3 Other Potential Applications 31011.4 Patient Application 31011.5 Patient/Healthcare Provider Acceptability 31211.6 Patient Safety 31311.7 Manufacturing and Regulatory Considerations 31511.8 Commercialisation of MN Technologies 31611.9 Conclusion 31811.10 Future Perspectives 319References 319Index 323