PDMS의 중합 억제와 Polyvinyl Chloride 패턴을 이용한 약물 전달 기기 공정 방법 제안

학위논문 (박사)-- 서울대학교 대학원 : 공과대학 전기·정보공학부, 2019. 2. 서종모.Effective drug therapy requires an adequate dosage control that can control the plasma concentration to be in between Maximum Tolerated Concentration (MTC) and Minimum Effective Concentration (MEC). The conventional drug administration methods fail to achieve effective drug therapy. Therefore, localized drug delivery devices have been devised to overcome the shortcomings of systemic drug administration, oral gavage and intravenous injection. Localized drug delivery devices realize spatial control simply by installing it on desired sites. Challenges of drug delivery devices are precise control of dosage, exact time of release, and low power consumption. All of these can be achieved by controlling the actuation components of the device: microvalves and pumps. The proposed device utilizes a balloon-like inflatable and deflatable drug reservoir, which eliminates the use of a pump. Moreover, a normally closed magnetically actuated microvalve that requires power consumption only when it opens was constructed. Consequently, the device was designed to release drug substances driven by the tension and stress formed by the inflated drug chamber only upon the actuation of the microvalve. Conventional PDMS patterning methods introduced in Micro Electromechanical Systems (MEMS) include photolithography and etching. Previous methods, however, require several steps and long processing time. A novel PDMS patterning method that only employs vapor deposition, oxygen plasma treatment, and stencil screen-printing was devised for simpler and faster procedure. Vapor deposition of trichlorosilane is a commonly used method to coat a barrier between PDMS layers from bonding. In the contrary, oxygen plasma treatment is a method used to bond layers of polymerized PDMS. Coordinating the two methods, along with a polyvinyl chloride (PVC) stencil patterned using a cutting plotter or a diode pumped solid-state laser, selective bonding was implemented. Selective bonding of PDMS accounted for the formation of the drug reservoir and the pump. Moreover, inhibition of PDMS polymerization was exploited over PVC substrates to acquire results similar to PDMS etching. This new etching alternative was used to construct microchannels with widths ranging from approximately 200 to 1000 micrometers. These microchannels with varying cross-sectional area served as a secondary drug release rate regulator. A magnetically actuated microvalve consist of two components. The opening mechanism of this normally closed valve was driven by an external magnet that produces magnetic field and a circular magnetic membrane with a neodymium magnet bonded on the surface with PDMS that deflects towards the external magnetic source. All the component of the microvalve were fabricated using only PVC stencils and PDMS-metal powder composites. Nickel powder-PDMS composite was used for the deflection membrane. The completed device was evaluated on biocompatibility for implantation and durability for reusability. PDMS may be biocompatible, PDMS-metal powder may show different results. In the device, even though PDMS-metal powder composites were encapsulated with pure PDMS, long-term use may increase cytotoxicity. Moreover, surface modification using trichlorosilane and oxygen plasma may also have an adverse effect on biocompatibility. Therefore, the device was tested for biocompatibility using elution and cell growth evaluation. Furthermore, the device was intended to be refillable and reusable. Thus, the durability of the microvalve and the inflatable chamber was evaluated by actuating the valve multiple times and whether or not the mechanical characteristic changed over the experiment.의료 분야의 발전에 따라 수많은 약들이 개발되어 왔지만 아직까지 투여 방법은 경구 투여 방법과 정맥에 바로 주입하는 주사기를 통한 방법으로만 지속되고 있다. 경구 투여와 정맥 주사는 투여 방법이 쉽다는 이유 때문에 아직도 주로 쓰이지만 특정 부위 또는 목표 세포에만 약물을 전달하는 것은 어렵다. 효율적인 약물 전달은 최소독성혈중농도 (MTC) 와 최소유효혈중농도 (MEC) 사이를 유지하도록 약물을 적정량 그리고 적정 기간을 두고 전달해야 한다. 현재에도 흔히 쓰이는 약물 전달 방식은 이러한 효율적인 약물 요법의 조건들을 만족하지 못한다. 그러므로 경구 투약이나 주사에 의한 투여 방법의 단점들을 보완할 수 있는 약물 전달 기기들이 활발히 연구되고 있다. 국소 부위에 설치하는 약물 전달 기기들은 약물 전달이 필요한 부위에 설치되는 방법으로 공간적인 제어를 실현한다. 이러한 전달 기기들이 만족해야 하는 조건들은 적정량의 약물, 정확한 시간에 그리고 저전력으로 구동이 가능해야 한다는 것이다. 이 모든 조건들은 대부분의 약물 전달 기기들이 가지고 있는 밸브와 펌프를 통해 달성할 수 있다. 본 논문에서 제안하는 약물 전달 기기는 풍선과 같이 부풀고 수축이 가능한 약물 저장소 구조를 제작하는 방법을 제안하여 전력이 필요한 펌프가 없이도 약물 전달이 가능하게 하였다. 이 펌프는 자기장 혹은 전자기장의 유무에 따라 구동되는 밸브를 만들어 약물 전달은 이 밸브를 열고 닫는 것만으로 가능하게 하였다. 이 밸브는 평상시에 닫혀 있는 형태로 열릴 때만 전력을 사용하여 전력 사용량을 최소화 하였다. 이 약물 전달 기기의 제작은 Polydimethylsiloxane (PDMS) 와 PDMS 와 금속 기반의 마이크로 입자의 합성물로만 이루어지도록 하였다. PDMS 패터닝은 일반적으로 Micro Electromechanical Systems (MEMS) 의 포토리소그래피 (photolithography) 와 식각 (etching) 방식을 통해 이루어진다. 하지만 이런 방식은 여러층과 복잡한 구조를 만들려면 여러 단계 그리고 긴 시간 동안의 공정 시간이 필요하다. 본 논문에서는 사진석판술이나 식각과 같은 결과를 낳을 수 있는 새로운 PDMS 공정 방법을 산소 플라즈마 표면처리 (oxygen plasma treatment), 자기조립분자막 (self-assembled monolayer) 그리고 폴리염화 비닐 시트지 패터닝을 사용해 약물 전달 기기 제작법을 제안한다. 자기조립분자막은 PDMS 와 PDMS 간의 접착이 이루어지지 않게 하기 위한 막을 분자 단위의 두께로 제작하는 방법이다. 반대로 산소 플라즈마 표면처리는 PDMS 간의 접착이 더 효과적으로 이루어지게 하는 방식이다. 자기조립분자막과 산소 플라즈마 표면처리를 조합하여 폴리염화비닐 패턴을 통해 선택적 표면 접착을 실행하였다. 폴리염화비닐 패턴은 칼로 잘라내는 자동 플로터 (blade plotter) 와 레이저로 잘라내는 다이오드 펌핑 고체 레이저 (diode pumped solid state laser) 두 기기로 제작하였다. 선택적 표면 접착 방법은 약물 저장소를 만드는데 사용하였다. 더 나아가, 폴리염화비닐과 PDMS 의 중합 억제 관련성을 조사하여 PDMS 식각을 실현하였다. PDMS 식각은 약물 저장소와 밸브를 연결하는 마이크로 채널을 만드는데 사용하였다. 이 약물 전달 기기의 약물 전달량은 기기의 약물 저장소의 크기, 막 두께, 저장소를 빠져나가는 마이크로 채널의 단면적 크기 등 복합적인 요소에 따라 달라진다. 약물 전달 시기를 제어하는 것은 자기장 또는 전자기장을 통해 구동되는 마이크로 밸브이다. 이 밸브는 저전력 구동이 가능하도록 평상시에는 닫혀 있도록 설계되었다. 약물의 전달 시기를 조절하는 밸브는 외부 자기장으로 구동 될 수 있도록 제작되었다. 이 밸브는 얇은 니켈 마이크로 입자와 PDMS로 섞은 얇은 막에 네오디뮴 자석이 접합되어 있어 평소에는 닫혀있는 상태를 유지하다 자기장으로 구동되어 당겨지는 힘에 의해 열리는 구조를 가지고 있다. 자기 구동은 막이 당겨지는 방향으로 자석을 위치시켜 밸브가 열리게 할 수 있다. 마지막으로, 제작된 약물 전달 기기는 생체 적합성을 분석하기 위해 용출물 실험과 세포 독성 실험을 진행하였다. PDMS는 높은 생체적합성을 가지는 물질로 판명된 물질이다. 하지만 PDMS만 쓰지 않고 금속 마이크로 입자를 섞은 PDMS와 네오디뮴 자석도 사용하였기에, 또 이 기기는 피부에 접합하여 사용하거나 약물이 전달되어야 하는 체내에 설치하는 방식으로 사용 되기 때문에 생체 적합성 실험을 진행하였다. 더 나아가, 이 기기의 중요한 구성 요소인 밸브와 펌프의 내구성도 조사되었다. 반복적인 실험으로 약물 전달량의 변화가 없는지 또는 밸브에서 누출이 이루어지지 않는지도 실험하였다.Table of Contents Abstract i Table of Contents iv List of Figures vii List of Tables x Chapter 1. Introduction 1 1.1 Drug Delivery Device in Microfluidics 2 1.2 Localized Drug Delivery Device 3 1.3 Microvalves and Pumps in Microfluidic Devices 5 1.4 Polydimethylsiloxane (PDMS) Etching 8 1.5 PDMS Surface Modification: Hydrophilic Alteration 10 1.6 Circular Cross-sectional Microchannels 12 1.7 Flexible Conductive PDMS 15 1.8 PDMS Adhesion 17 1.9 Previously Developed Drug Delivery Devices 19 1.9.1 Electro-actively Controlled Thin Film 19 1.9.2 Drug Release through Microchannel Configuration 20 1.9.3 Frequency Controlled Hydrogel Microvalve 21 1.9.4 Magentically Controlled MEMS Device 22 1.9.5 Electrochemical Intraocular Drug Delivery Device 23 1.9.6 Electrostatic Valve with Thermal Actuation 25 1.9.7 Transdermal Delivery through Microneedles 27 1.9.8 Osmotic Drug Delivery Devices 28 1.10 Summary 35 Chapter 2. Materials and Procedure 39 2.1 System Overview 39 2.2 Materials 41 2.2.1 Polydimethylsiloxane (PDMS) 41 2.2.2 Polyvinyl Chloride (PVC) Adhesive Sheets 42 2.2.3 Magnetic Microparticles and Neodymium Magnet 45 2.2.4 Silver Microparticles 46 2.3 Procedures 48 2.3.1 Spin Coating 48 2.3.2 Oxygen Plasma Treatment 49 2.3.3 Silanization (Self-Assembled Monolayer) 51 2.3.4 Plasma Bonding 53 2.4 Fabrication 54 2.4.1 PDMS Etching via PVC Stencils 54 2.4.2 Inflatable Chamber Fabrication 59 2.4.3 Full Fabrication of the Drug Delivery Device 63 2.4.3.1 Primary and Secondary Drug Chamber 64 2.4.3.2 Microvalve 67 2.4.3.3 Magnetic Actuation 71 Chapter 3. Results 74 3.1 PVC Stencil Preparation 74 3.2 Surface Modification and Selective Bonding 76 3.3 PDMS Polymerization Inhibition 83 3.4 PDMS Etching 86 3.5 Three Dimensional Microchannel Fabrication 91 3.6 Circular Cross-sectional Microchannel 94 3.7 Inflatable Chamber Fabrication 97 3.8 Conductive PDMS Fabrication 99 3.9 Drug Delivery Device 104 3.9.1 Dimensions and Profile of the Device 105 3.9.2 Fluid Release Amount of the Device 105 3.8.2.1 Case 1 105 3.9.2.2 Case 2 106 3.9.2.3 Case 3 107 3.10 In Vitro Cytotoxicity of the Device 110 Chapter 4. Discussion 116 4.1 Electromagnetic Actuation 116 4.2 Drug Substance Delivery 118 4.3 Comparison with Similar Drug Delivery Devices 119 4.4 Integration of the Device with PDMS Electrodes 121 Bibliography 123 Abstract in Korean 143Docto

Bio-Micro-Systems for Diagnostic Applications, Disease Prevention and Creating Tools for Biological Research

This thesis, divided into two parts, describes the development of 5 novel Bio-Micro-System devices. The term Bio-Micro-System has been used here to describe BioMEMS and 3D printed devices, with the dimensions of key components ranging from micrometers to a millimeter. Part A is focused on ‘Medical’ Micro-System devices that can potentially solve common medical problems. Part B is focused on ‘Biological’ Micro-System devices/tools for facilitating/enabling biological research. Specifically, Part A describes two implantable, electronics-free intraocular pressure (IOP) microsensors for the medical management of glaucoma: 1) Near Infrared Fluorescence-based Optomechanical (NiFO) technology - Consists of an implantable, pressure sensor that ‘optically encodes’ pressure in the near infrared (NIR) regime. A non-implantable, portable and compact optical head is used to excite the sensor and collect the emitted NIR light. The thesis discusses optimized device architecture and microfabrication approaches for best performance commercialization. 2) Displacement based Contrast Imaging (DCI) technology - A proof of concept, fluid pressure sensing scheme is shown to operate over a pressure range of 0–100 mbar (∼2 mbar resolution between 0–20 mbar,∼10 mbar resolution between 20–100 mbar), with a maximum error of <7% throughout its dynamic range. The thesis introduces the DCI technology and discusses its application as an IOP sensor. Moreover, Part A also describes a Touch-activated Sanitizer Dispensing (TSD) system for combating community acquired infections. The TSD can be mounted on any surface that is exposed to high human traffic and consists of an array of human-powered, miniaturized valves that deliver a small amount of disinfectant when touch actuated. The device disinfects the person’s hand that is touching it while being self-sterilized at the same time. The thesis describes the design and implementation of a proof of concept TSD that can disinfect an area equivalent to the size of a thumb. A significant (~ 10 fold) reduction in microbiological load is demonstrated on the fingertip and device surface within the first 24 hours. The size and footprint of the TSD can be scaled up as needed to improve hand hygiene compliance. In Part B, we developed a microfluidic chip for immobilizing Drosophila melanogaster larva by creating a cold micro-environment around the larva. After characterizing on chip temperature distribution and larval body movement, results indicate that the method is appropriate for repetitive and reversible, short-term (several minutes) immobilization. The method offers the added advantage of using the same chip to accommodate and immobilize larvae across all developmental stages (1st instar-late 3rd instar). Besides the demonstrated applications of the chip in high resolution observation of sub cellular events such as mitochondrial trafficking in neurons and neuro-synaptic growth, we envision the use of this method in a wide variety of biological imaging studies employing the Drosophila larval system, including cellular development and other studies. Finally, Part B also describes a 3D printed millifluidic device for CO2 immobilization of Caenorhabditis elegans populations. We developed a novel 3D printed device for immobilizing populations of Caenorhabditis elegans by creating a localized CO2 environment while the animals are maintained on the surface of agar. The results indicate that the method is easy to implement, is appropriate for short-term (20 minutes) immobilization and allows recovery within a few minutes. We envision its use in a wide variety of biological studies in Caenorhabditis elegan, including cellular development and neuronal regeneration studies.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144050/1/amritarc_1.pd

Valve Regulated Implantable Intrathecal Drug Deliver for Chronic Pain Management.

Chronic pain afflicts an estimated 100 million people in the United States with annual costs exceeding $100 billion. Treatment modalities for severe chronic pain include implantation of an intrathecal drug delivery device (IDDD). Conventionally, these devices are of two types: passive, permitting the delivery of a single analgesic mixture at a fixed rate; or active, permitting variable delivery by virtue of a peristaltic pump. This thesis presents an implantable system for medication delivery from multiple reservoirs with micromachined components. These components permit the use of an architecture that can provide superior volume efficiency and permit complex multi-drug delivery protocols. The system comprises three main components: regulatory valves, pressurized reservoirs, and control electronics. Important design considerations for each of these components are emphasized. Piezoelectric microvalves were designed and tested for use with aqueous flows. Two types of spring pressurized reservoirs were also designed and tested for feasibility in an IDDD. Reservoirs were pressurized using springs fabricated from silicon and generated up to 80kPa of pressure. Alternative reservoirs were pressurized using compressive metal springs and generated up to 18kPa of pressure. A first-generation system was developed that demonstrated controlled diffusion into agar gel. Water flow was regulated from 0.2-5mL/day, and bolus delivery was demonstrated. A second-generation system utilizing a two-valve manifold with embedded sensors was used to independently regulate isopropyl alcohol flow at set rates between 0.05-1mL/hr. Both systems demonstrated liquid delivery at intrathecal flow rates using continuous and duty-cycle flow regulation. Outlet pressure sensors were used to detect acute catheter occlusions and disconnects. A smart refill port was developed to allow for power transfer rates necessary to recharge batteries during a reservoir refill session. Recharging at current rates up to 500mA was demonstrated. The proposed valve-regulated architecture and two preliminary prototypes allowed evaluation of potential solutions to challenges for application of the architecture in an IDDD. Recommendations for future systems and plans for bench-top and in vitro testing are detailed. The proposed work may lead to a system that provides the functionality of commercially available implantable drug delivery devices with high volume efficiency, and the ability to independently regulate multiple medications.Ph.D.Electrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/75815/1/evansall_1.pd

Rapid Prototyping of Microfluidic Devices:Realization of Magnetic Micropumps, Fuel Cells and Protein Preconcentrators

With the growing importance of miniaturized energy applications and the development of micro Total Analysis Systems (μTAS), we have realized microfluidic devices, namely, magnetic micropumps, microfluidic fuel cells and membrane-based protein preconcentrators, all having high application potential in future. The choice of rapid prototyping microfabrication technologies and the selection of affordable materials are important aspects, when thinking of commercialization. Thus, we have employed powder blasting, polymer molding and assembly technologies during devices fabrication throughout the thesis. The first type of microfluidic device that we present is a poly(methyl methacrylate) (PMMA) ball-valve micropump with two different designs of the electromagnetic actuator, as optimized by the finite element method. The integration of a permanent magnet in a flexible polydimethylsiloxane (PDMS) membrane, which is clamped into PMMA structure, is proposed for providing a large stroke of the pumping membrane, making the micropump bubble-tolerant and self-priming Focusing on low power consumption for μTAS integration, another type of magnetic micropump with active valves is realized. It consists of a microfluidic chamber structure in glass that is assembled with a PDMS sheet, which comprises two valving membranes and a central actuation membrane, having each an integrated permanent magnet that is peristaltically actuated by a rotating arc-shaped permanent magnets assembly. A lumped circuit model is developed to predict and describe the frequency-dependent flow rate behavior for this type of pump. Powder blasting and PDMS molding rapid prototyping technologies are employed for realization of these two types of micropumps. Fuel cells with fluid delivery and removal options, having chemical reaction sites and electrode structures that can be realized in a microfluidic format, have high potential for applications. Therefore, microfluidic direct methanol fuel cells with embedded ion- permselective medium are studied and such type of fuel cell is realized by integrating a narrow Nafion strip in a molded elastomeric structure. A mechanical clamping assembly technology enables leakage-free operation and stable performance. The characterization reveals its output power density, using H2O2-based oxidant, is among the high-performance direct methanol fuel cells in microscale. Re-using the technology of the fuel cell chip, with its particular ion-permselective Nafion membrane and assembly method, we also have developed a protein preconcentrator with high purification performance. Our device can preconcentrate negatively charged biomolecules located at the anodic compartment side of the Nafion strip within only a few minutes with a high preconcentration factor. Moreover, a complex microfluidic finite element model is proposed to study and understand the physics of the preconcentration effect. Finally, we conclude the thesis with an outlook on future developments based on our work of the project and on the assembly technologies for microfluidic device integration

Electrostatic Elastomer Devices for Reconfigurable High-Density Microfluidics.

Components and systems for the scalable, very large-scale integration (VLSI) of thousands of microfluidic devices into Micro Total Analysis Systems (μTAS) are the fo-cus of much ongoing research. Most solutions to date have focused on either a) the scal-ing and modification of conventional pneumatically-driven elastomer microfluidics or b) the development of electrically or magnetically addressable fluidic components and sys-tems. Although these technologies have each solved the integration problem partially, they still leave something to be desired such as lack of on-chip power or degradation in chip performance due to cross contamination. This thesis presents the design, fabrication, and characterization of an electrostati-cally actuated user-reconfigurable elastomer microfluidic system intended for VLSI mi-crofluidics. Capacitor plates form top (deformable) and bottom of the micro chan-nel/chamber, facilitating gap-closing actuation. Device fabrication followed standard mi-cromaching process. We also present experimental results of flow and pressure data for valves, pumps and demonstrate various multi-component configurations of the system. The presented technology is compatible with standard polydimethylsiloxane (PDMS) mi-crofluidics, has actuation voltages low enough to be driven by commercial CMOS IC’s and can be used to displace aqueous, gaseous and lipid phases. By adding thin film metal flexures into the PDMS polymer, individual elastomer channels were made to self-close without the use of pneumatics via the application of 10 – 20 V, 5 MHz signals synthesized digitally by a microcontroller and a radio-frequency amplifier IC. These valves were integrated into discrete micro valve and three-valve peristaltic micro pumps. A single valve was able to hold 6 psi pressure, and the peristaltic pump had a flow rate 4.4 valve-volume/min (1 - 2 nL/min), depending on the actuation frequency and device configuration. Further, these valves were arranged into hexagonal or quadricular arrays with 75% fill factor. During use, valves were selected to be permanently closed, permanently open or addressable; this allowed for the on-the-fly determination of channels, valves and pumps. We demonstrated various multi-component configurations of the system: distributed valving, fluid switching, flow splitting and mix-ing. The primary contribution of this technology is to provide a scalable reconfigurable liquid manipulation platform for the very large scale integration of μTAS.Ph.D.Mechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61769/1/mpchang_1.pd

Significant NASA inventions available for licensing in foreign countries

Abstracts of various NASA-owned inventions which are available for foreign licensing in the identified countries are listed in accordance with the NASA Patent Licensing Regulations. Instructions for requested applicatons are explained

NASA Tech Briefs, October 1990

Topics: New Product Ideas; NASA TU Services; Electronic Components and Circuits; Electronic Systems; Physical' Sciences; Materials; Computer Programs; Mechanics; Machinery; Fabrication Technology; Mathematics and Information Sciences; Life Sciences

BIOMIMETIC STRATEGIES TO CONTROL THERAPEUTIC RELEASE FROM NOVEL DNA NANOPARTICLES

The inherent chemical, mechanical, and structural properties of nucleic acids make them ideal candidates for the formulation of tunable, personalized drug nanocarriers. However, none so far have exploited these properties for the controlled release of therapeutic drugs. In this dissertation, a biomimetic approach to controlling drug release is exhibited by specifically manipulating the architecture of novel, DNA nanoparticles to take advantage of drug binding mechanisms of action. Rationally designed DNA strands were immobilized on gold surfaces via a terminal thiol modification. Immobilized monomers can be manipulated to form distinct monolayer architectures including flat, folded, coiled, or stretched structures. Increasing the rate of folding is shown to restrict the diffusion of a surface-bound drug while upright architectures released drug at a 2 - 10 fold rate, depending on sequence length - using this strategy an over four-week release of dexamethasone was achieved. Furthermore, the release of an intercalating drug is controlled by exploiting sequence-specific affinities of the drug toward DNA. Here, using a high-affinity sequence and increasing the strand length a near zero-order release of daunomycin was achieved for up to 12 days. With this work, it is shown for the first time that the mechanisms of drug binding to nucleic acids can be utilized to produce highly controlled drug release from gold-core nucleic acid nanoparticles. These results will have a profound impact on the future design of novel, therapeutic nanocarriers