Biophysical Techniques of Transcutaneous Drug Sampling and Drug Delivery

Monitoring the time course of drug in the skin is critical for determining the frequency and dose of drug administration from safety and efficacy perspectives. Intermittent blood sampling is used as a surrogate for approximating concentration of drugs in the tissues, which leads to blood loss and discomfort to patients. A novel noninvasive technique called “Electroporation and transcutaneous sampling” (ETS) was developed for estimating the drug concentration in the skin extracellular fluid. The application of ETS technique in studying dermatokinetics of cephalexin, ciprofloxacin, and 8-methoxypsoralen was investigated. The results demonstrated the ability of ETS technique in dermatokinetic studies of drugs with different physicochemical properties. ETS technique was also found to be a promising method for noninvasive estimation of blood glucose levels. Two novel techniques were developed for enhancing the transdermal delivery of drugs. “ChilDrive”, a technique of combining regional cutaneous hypothermia with iontophoresis was used for enhancing the bioavailability of transdermally administered drug in the deeper musculoskeletal tissue like synovial fluid. The bioavailability of drugs in the synovial fluid of knee joint was enhanced by ?6-12-fold and ?2-4-fold by ChilDrive when compared to passive and iontophoretic transdermal drug delivery. Magnetophoresis, a technique of enhancing transdermal drug delivery by application of magnetic field was developed. The mechanistic studies demonstrated that transdermal magnetophoresis of drugs was due to contribution of multiple factors such as magnetorepulsion, magnetohydrokinesis and magnetically enhanced partition coefficient. Magnetophoretic patch system was designed and pharmacokinetic studies were performed. Magnetophoresis resulted in higher dermal bioavailability of drugs compared to passive transdermal drug delivery. It was also found from the in vitro studies that combination of chemical enhancers would further enhance the efficiency of magnetophoretically mediated drug delivery enhancement

Advances in transdermal insulin delivery

Insulin therapy is necessary to regulate blood glucose levels for people with type 1 diabetes and commonly used in advanced type 2 diabetes. Although subcutaneous insulin administration via hypodermic injection or pump-mediated infusion is the standard route of insulin delivery, it may be associated with pain, needle phobia, and decreased adherence, as well as the risk of infection. Therefore, transdermal insulin delivery has been widely investigated as an attractive alternative to subcutaneous approaches for diabetes management in recent years. Transdermal systems designed to prevent insulin degradation and offer controlled, sustained release of insulin may be desirable for patients and lead to increased adherence and glycemic outcomes. A challenge for transdermal insulin delivery is the inefficient passive insulin absorption through the skin due to the large molecular weight of the protein drug. In this review, we focus on the different transdermal insulin delivery techniques and their respective advantages and limitations, including chemical enhancers-promoted, electrically enhanced, mechanical force-triggered, and microneedle-assisted methods

Wearable Devices for Single-Cell Sensing and Transfection

Wearable healthcare devices are mainly used for biosensing and transdermal delivery. Recent advances in wearable biosensors allow for long-term and real-time monitoring of physiological conditions at a cellular resolution. Transdermal drug delivery systems have been further scaled down, enabling wide selections of cargo, from natural molecules (e.g., insulin and glucose) to bioengineered molecules (e.g., nanoparticles). Some emerging nanopatches show promise for precise single-cell gene transfection in vivo and have advantages over conventional tools in terms of delivery efficiency, safety, and controllability of delivered dose. In this review, we discuss recent technical advances in wearable micro/nano devices with unique capabilities or potential for single-cell biosensing and transfection in the skin or other organs, and suggest future directions for these fields. Highlights • Current wearable sensors have allowed for long-term, real-time detection of specific biomarkers directly from patients. • Miniaturized wearable biosensors with sensing elements interacting with skin or organs can capture target molecules from single cells, which results in significantly increased sensitivity, responding time, and precision. • Emerging wearable devices based on novel nanomaterials or nanofabrication show potential for single-cell detection in cancer cell screening, cardiomyocyte detection, and optogenetics. • Transdermal delivery devices have been scaled down to the micro- and/or nanoscale, and their applications have extended to wide selections of natural molecules and bioengineered molecules. • Emerging nanodevices show unique capabilities in precise single-cell gene transfection in vivo, with improved delivery efficiency, safety, and dose controllability

상처 치료 및 경피 약물전달을 향상시키기 위한 하이드로겔 기반 피부 패치

학위논문 (박사) -- 서울대학교 대학원 : 공과대학 화학생물공학부, 2020. 8. Nathaniel Suk-Yeon Hwang.Hydrogel, three-dimensional polymeric networks, can hold lots of water and continuously provide the concentration gradient of drugs, it has been widely used as a skin patch for wound repair and transdermal drug delivery as a drug reservoir. However, when using hydrogels only, they implement passive roles without external stimulation. For this reason, a functional substrate can be utilized not only to facilitate the handling of the hydrogel with fabricating the hydrogel patch but also to provide some stimulation to the hydrogel for enhancing drug delivery efficacy. In this thesis, the approaches for promoting wound repair and transdermal drug delivery using hydrogel-based skin patches were studied. In chapter one and chapter two, the general introduction and scientific backgrounds about the strategies were addressed. In chapter three, a hydrogel-functionalized Janus membrane was developed for delivering a protein drug, recombinant human vascular endothelial growth factor (rhVEGF), into the skin wounds. A hydrophobic fluoropolymer was uniformly coated onto macroporous polyester membrane through initiated chemical vapor deposition (iCVD) process, followed by being cleaved, resulting in the carboxylic acid residue. This carboxylic acid residue was then further functionalized with gelatin methacrylate (GelMA)-based photo-cross-linkable hydrogel for moisture retention and growth factor release. When applied to full-thickness dorsal skin defect model, functionalized hydrogel allowed moisture retention, and hydrophobic surface prevented exudate leaks via water repellence. In chapter four, an iontophoretic hydrogel patch for transdermal drug delivery was developed. This system consists of a portable and disposable reverse electrodialysis (RED) battery that generates electric power for iontophoresis through the ionic exchange. In addition, in order to provide a drug reservoir to the RED-driven iontophoretic system, electroconductive hydrogel composed of polypyrrole-incorporated poly(vinyl alcohol) (PYP) hydrogels were used. PYP hydrogel facilitated electron transfer from the RED battery. For the effective drug delivery, electrically mobile drug nanocarriers (DNs) were prepared. Both the RED-driven iontophoresis and PYP hydrogel accelerated the mobility of electrically mobile DNs. Remarkably, applying the RED-driven iontophoresis of rosiglitazone loaded DNs resulted in an effective anti-obese condition displaying decreased bodyweight, reduced glucose level, and increased conversion of white adipose tissues to brown adipose tissues in vivo. In chapter five, the critical analysis of current technologies and future perspectives on the transdermal drug delivery systems were discussed. This thesis described the application of hydrogel-based skin patch systems. The innovative hydrogel-functionalized Janus membrane and the PYP/RED system with electrically mobile DNs may offer a new perspective on the wound repair and transdermal drug delivery using a hydrogel-based skin patch.하이드로겔은 다량의 수분을 흡수하고 저장할 수 있는 친수성 고분자의 3차원 구조체로서 세포와 상호작용할 수 있고 지속적으로 약물의 농도구배를 제공할 수 있다. 이로 인해 하이드로겔은 피부재생 혹은 경피 약물전달을 위한 피부 패치 제작에 광범위하게 사용되고 있다. 그러나, 하이드로겔 자체만으로는 수동적인 역할에 그치는 문제점이 있다. 기능적인 기판과 하이드로겔의 하이브리드 형태의 패치는 하이드로겔의 적용을 용이하게할 뿐 아니라 약물전달 효율을 향상시키기 위한 외부자극을 제공하기 위한 중간매질로서 사용되어져 왔다. 본 논문은 피부 상처 치료 및 경피 약물전달을 촉진하기 위한 하이드로겔 기반의 능동형 피부 패치 연구에 대한 것이다. 제 1장과 제 2장에서는 일반적인 서론 및 과학적 배경에 대해 서술하였다. 제 3장에서는 상처부위에의 혈관성장인자 전달을 위한 하이드로겔로 기능화된 양면성 기판을 개발하였다. 일반적인 드레싱 재료를 손쉽게 기능화하기 위한 화학기상증착법을 사용하여 소수성 불소고분자인 PHFDMA를 증착 및 중합하고 에스터 기의 가수분해를 통해 카복실기를 드러나게 함으로써 양면성 드레싱을 제작할 수 있었다. 카복실기는 자외선 광중합이 가능한 젤라틴 메타크릴레이트 (GelMA)와 EDC/NHS 반응을 거쳐 화학적으로 반응하고 하이드로겔로 제작해 고정했다. GelMA 하이드로겔은 성장인자를 방출할 수 있고 수분을 함유하여 상처재생을 위해 사용되었다. 이렇게 제작된 GelMA 하이드로겔이 고정화된 양면성 폴리에스터 드레싱을 쥐 피부 전층 창상 모델이 적용하였을 때, 하이드로겔에 의해 상처의 습윤한 환경은 유지되었고 양면성 드레싱에 의해 삼출액이 새어나가는 것을 방지할 수 있었다. 제 4장에서는 경피약물전달을 위한 하이드로겔 기반 이온영동패치를 개발하였다. 이 시스템은 휴대가능하고 일회성인 역삼투전위(RED) 배터리를 전원장치로 하여 약물 저장 및 전극으로 사용하기 위해 전기전도성 고분자인 폴리피롤(Ppy)이 폴리비닐알코올(PVA)에 도입된 하이드로겔 (PYP)을 사용하였다. 또한, 효과적인 약물전달을 위해, 전기유동성을 갖는 약물 나노입자(drug nanocarriers, DNs)를 제작하였다. RED에 의한 이온영동과 PYP 하이드로겔은 DNs의 피부전달을 촉진시켰다. 특히, 나노입자의 표면전하를 조정함을 통해 이온영동법에 의한 전기적 반발력을 극대화하였다. PYP/RED 패치는 DNs을 효과적으로 피부 내로 흡수시켰으며 마우스 모델에서 국소적인 적용을 통해 전신적인 비만 치료효과를 나타내었다. 제 5장에서는 기술에 대한 비평적 분석과 추구할 방향을 논의했다. 종합적으로 본 논문은 양면성 드레싱 기반의 하이드로겔 패치를 통한 피부상처 치료에 대한 새로운 접근법을 제시하였고 전기전도성 재료를 이용한 이온영동패치를 통해 향후 다양한 치료물질의 비침습적인 경피 약물전달을 위한 유용한 플랫폼 기술을 제시하였다.CHAPTER ONE: Introduction １ 1.1 Objective and overview of the thesis 1 1.2 Organization of the thesis 2 CHAPTER TWO: The Scientific Background and Research Progress ４ 2.1 Hydrogel-based skin patch 4 2.1.1 Hydrogels 4 2.1.2 Current limitations of hydrogel 5 2.1.3 Substrate-mediated functionalization of the hydrogels for wound repair and transdermal drug delivery 7 2.2 Transdermal drug delivery 12 2.3 Barrier functions of the skin 18 2.3.1 Structure of the stratum corneum (SC): The physical barrier of the skin 18 2.3.2 Immune responses: the immunological barrier of the skin, and its pros and cons 22 2.4 Chemical adjuvants (CAs) for the transdermal drug delivery 25 2.4.1 Chemical penetration enhancers (CPEs) 25 2.4.2 Hyaluronic acid (HA)-based adjuvants 27 2.4.3 Skin penetrating peptides 28 2.4.4 Nanovesicles 31 2.4.5 Microemulsion 40 2.4.6 Nanoparticles 42 2.5 Noninvasive physical penetration enhancers (PPEs) for the transdermal drug delivery 45 2.5.1 Iontophoresis 47 2.5.2 Electroporation 51 2.5.3 Sonophoresis 54 CHAPTER THREE: Hydrogel-Based Janus Patch for Wound Repair 57 3.1 Introduction 57 3.2 Materials and methods 63 3.2.1 Janus membrane preparation 63 3.2.2 Physical properties of Janus membrane 64 3.2.3 Antibacterial analysis 64 3.2.4 In vitro cell culture 65 3.2.5 Synthesis of methacrylate-incorporated gelatin (GelMA) hydrogel 66 3.2.6 Characterization of the hydrogel 67 3.2.7 Janus membrane functionalization with GelMA hydrogel 68 3.2.8 In vitro biocompatibility 69 3.2.9 In vitro cell proliferation 70 3.2.10 Release kinetic analysis 71 3.2.11 HUVECs adhesion on GelMA hydrogel and biofunctionality of rhVEGF 71 3.2.12 In vivo wound healing analysis 72 3.2.13 Histological analysis and vessel formation in vivo 73 3.2.14 Statistical analysis 73 3.3 Results and discussion 74 3.3.1 Preparation of Janus membrane and characterization 74 3.3.2 Antibacterial ability and biocompatibility of Janus membrane 79 3.3.3 Hydrogel characterization for optimal growth factor release 85 3.3.4 In vitro biocompatibility and biofunctionality of rhVEGF-incorporated GelMA hydrogel 88 3.3.5 GelMA hydrogel immobilization onto Janus membrane 91 3.3.6 In vivo wound healing application 95 3.4 Summary 102 CHAPTER FOUR: Hydrogel-Based Iontophoretic Patch for Transdermal Drug Delivery 103 4.1 Introduction 103 4.2 Materials and methods 108 4.2.1 Materials 108 4.2.2 Preparation and characterization of drug nanocarriers (DNs) 108 4.2.3 Preparation of carbon-printed cotton fabric 110 4.2.4 Fabrication of electrically conductive hydrogels 110 4.2.5 The mechanical property of the hydrogels 111 4.2.6 Raman spectroscopy 111 4.2.7 Thermal properties of the hydrogels 112 4.2.8 Electrical properties of the hydrogels 112 4.2.9 Electrochemical impedance spectroscopy (EIS) 113 4.2.10 Scanning electron microscopy (SEM) 113 4.2.11 Swelling behavior of the hydrogels 114 4.2.12 Preparation of the RED system 114 4.2.13 Hydrogel adhesive properties 115 4.2.14 Preparation and voltage profile measurement of the RED-coupled hydrogel patches 116 4.2.15 Preparation of DNs-loaded hydrogels 116 4.2.16 Release behavior of the DNs 116 4.2.17 Transdermal delivery of electrically mobile DNs 117 4.2.18 Cryo-section of the tissue and quantification of fluorescence 118 4.2.19 Transdermal delivery of Fluc-DNs 119 4.2.20 Preparation of diet-induced obese mice 120 4.2.21 Topical delivery of Rosi-DNs with RED-driven iontophoresis 121 4.2.22 Histological analysis 121 4.2.23 Dermal toxicity test 122 4.2.24 Statistical Analysis 123 4.3 Results and discussion 124 4.3.1 Fabrication and characterization of electrically conductive PVA-Ppy hydrogels. 124 4.3.2 Modulation of electrical properties of PVA-Ppy hydrogels 132 4.3.3 Construction of PYP hydrogel and coupling with the RED battery system 136 4.3.4 Preparation of electrically mobile drug nanocarrier (DNs) and DNs-loaded hydrogels 141 4.3.5 Validation of the transdermal delivery efficacy of the system 144 4.3.6 Transdermal delivery of therapeutic Flu-DNs 149 4.3.7 Therapeutic efficacy of Rosi-DNs with PYP/RED system 152 4.4 Summary 159 CHAPTER FIVE: Concluding Remarks 160 5.1 Critical analysis of the current transdermal drug delivery system 160 5.2 Future perspectives on the clinical implications of the hydrogel-based skin patch 162 References 164 Bibliography 183 국 문 초 록 186Docto

Perspectives on Transdermal Electroporation

Transdermal drug delivery offers several advantages, including avoidance of erratic absorption, absence of gastric irritation, painlessness, noninvasiveness, as well as improvement in patient compliance. With this mode of drug administration, there is no pre-systemic metabolism and it is possible to increase drug bioavailability and half-life. However, only a few molecules can be delivered across the skin in therapeutic quantities. This is because of the hindrance provided by the stratum corneum. Several techniques have been developed and used over the last few decades for transdermal drug delivery enhancement. These include sonophoresis, iontophoresis, microneedles, and electroporation. Electroporation, which refers to the temporary perturbation of the skin following the application of high voltage electric pulses, has been used to increase transcutaneous flux values by several research groups. In this review, transdermal electroporation is discussed and the use of the technique for percutaneous transport of low and high molecular weight compounds described. This review also examines our current knowledge regarding the mechanisms of electroporation and safety concerns arising from the use of this transdermal drug delivery technique. Safety considerations are especially important because electroporation utilizes high voltage pulses which may have deleterious effects in some cases

Use of fibroin/hyaluronic acid matrices as a drug reservoir in iontophoretic transdermal delivery

Thesis (Master)--Izmir Institute of Technology, Chemical Engineering, Izmir, 2004Includes bibliographical references (leaves: 62-67)Text in English; Abastract: Turkish and Englishx, 67 leavesTransdermal drug delivery is gaining importance due to the extensive research in genetics and resulting increase of protein and peptide based drugs in the market. In order to develop materials to be used in iontophoretic transdermal drug delivery systems, various forms of silk fibroin (SF) and blending agents as hyaluronic acid (HA) have been tested for their feasibility as a potential drug reservoir. For this purpose different forms of silk such as raw silk, degummed silk fibroin, insolubilized freezedried fibroin, membranes of fibroin in pure and blended with HA were investigated for their adsorption capacities of timolol maleate, which is used as the model drug. It was found that silk fibroin and derivatives have considerable adsorption capacities for timolol maleate with 0.35 mmol per gram, comparable with commercial membranes. The insolubilization of the membranes was required for drug loading and delivery in aqueous media. Membrane insolubility was achieved by post treatment, manipulation of drying conditions, and blending with different agents. Configurational changes of fibroin protein and interactions between silk fibroin and hyaluronic acid were investigated by Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction analyses. Insoluble fibroin glutaraldehyde membranes were produced. The obtained insoluble membranes were investigated for drug delivery performance in a custom-made diffusion cell under passive diffusion and iontophoretic conditions. It was demonstrated that the silk fibroin glutaraldehyde films could be successfully used for controlled drug delivery. It was found that current densities of 1.5 and 3 mA/cm2 were suitable to accomplish controlled delivery of the drug in a pulsatile manner. The results of this study are expected to be useful in controlled transdermal delivery of positively charged drug molecules

Soft and flexible bioelectronic micro-systems for electronically controlled drug delivery

The concept of targeted and controlled drug delivery, which directs treatment to precise anatomical sites, offers benefits such as fewer side effects, reduced toxicity, optimized dosages, and quicker responses. However, challenges remain to engineer dependable systems and materials that can modulate host tissue interactions and overcome biological barriers. To stay aligned with advancements in healthcare and precision medicine, novel approaches and materials are imperative to improve effectiveness, biocompatibility, and tissue compliance. Electronically controlled drug delivery (ECDD) has recently emerged as a promising approach to calibrated drug delivery with spatial and temporal precision. This article covers recent breakthroughs in soft, flexible, and adaptable bioelectronic micro-systems designed for ECDD. It overviews the most widely reported operational modes, materials engineering strategies, electronic interfaces, and characterization techniques associated with ECDD systems. Further, it delves into the pivotal applications of ECDD in wearable, ingestible, and implantable medical devices. Finally, the discourse extends to future prospects and challenges for ECDD