Micromachined pyramidal shaped biodegradable microneedle and its skin penetration capability

A biodegradable pyramidal shaped microneedle array made of hyaluronic acid-based material was fabricated by anisotropic wet etching and a molding process. First, pyramidal shaped needles were fabricated on a Si wafer by anisotropic wet etching as an original master and then a mixture of two biodegradable materials, hyaluronic acid and a collagen, were replicated with the same shape as the original Si needle by a molding process. The height and pitch of the needle were 0.21 and 0.62 mm, respectively. The tip radius in the replicated biodegradable needle became 0.005 mm. The penetration capability of the needle arrays was evaluated by applying the load to skin multiple times. Results showed that both the Si and biodegradable needle arrays could successfully penetrate silicone rubber sheets with the applied load of 100 g. The developed biodegradable needle arrays also successfully penetrated mouse skin with the load of 50 g.     

Silicon microneedle array with biodegradable tips for transdermal drug delivery

This paper presents the fabrication process, characterization results and basic functionality of silicon microneedle array with biodegradable tips for transdermal drug delivery. In order to avoid the main problems related to silicon microneedles; the breaking of the top part of the needles inside the skin, a simple solution can be the fabrication of microneedle array with biodegradable tips. A silicon microneedle array was fabricated by deep reactive ion etching (RIE), using the photoresist reflow effect and RIE notching effect. The biodegradable tips were successfully realized using the electrochemical anodization process that selectively generated porous silicon only on the top part of the skin. The porous tips can be degraded within a few weeks if some of them are broken inside the skin during the insertion and release process. The paper presents also the results of in vitro release of calcein with animal skins using a microneedle array with biodegradable tips. Compared to the transdermal drug delivery without microneedle enhancer, the microneedle array had presented significant enhancement of drug release.     

Design and fabrication of MEMS-based microneedle arrays for medical applications

Fabrication results for MEMS-based microneedle arrays are presented in this paper. The microneedle array was fabricated by employing a bi-mask technique to facilitate sharp tips, a cylindrical body and side openings. The presented array has advantages over previously published microneedle arrays in terms of ease of fabrication and bonding; high needle density and robustness; and side openings, which are expected to minimize the potential for clogging from skin debris during insertion. In addition, control over the process via etch-stop markers employed as stop layers, which assure the depth of long blind holes and the structure of the needle top, allows for different needle lengths and needle top structures to be easily implemented. The preliminary fluid flow and insertion experiments were performed to demonstrate the efficiency of the microneedle arrays.     

A PZT insulin pump integrated with a silicon microneedle array for transdermal drug delivery

Many of the compounds in drugs cannot be effectively delivered using current drug delivery techniques (e.g., pills and injections). Transdermal delivery is an attractive alternative, but it is limited by the extremely low permeability of the skin. As the primary barrier to transport is located in the upper tissue, Micro-Electro-Mechanical-System (MEMS) technology provides novel means, such as microneedle array and PZT pump, in order to increase permeability of human skin with efficiency, safety and painless delivery, and to decrease the size of the pump. Microneedle array has many advantages, including minimal trauma at penetration site because of the small size of the needle, free from condition limitations, painless drug delivery, and precise control of penetration depth. These will promote the development of biomedical sciences and technology and make medical devices more humanized. So far, most of the insulin pumps being used are mechanical pumps. We present the first development of this novel technology, which can assemble the PZT pump and the microneedle array together for diabetes mellitus. The microneedle array based on a flexible substrate can be mounted on non-planar surface or even on flexible objects such as a human fingers and arms. The PZT pump can pump the much more precision drug accurately than mechanical pump and the overall size is much smaller than those mechanical pumps. The hollow wall straight microneedle array is fabricated on a flexible silicon substrate by inductively coupled plasma (ICP) and anisotropic wet etching techniques. The fabricated hollow microneedles are 200 μm in length and 30 μm in diameter. The microneedle array, which is built with on-board fluid pumps, has potential applications in the chemical and biomedical fields for localized chemical analysis, programmable drug-delivery systems, and very small, precise fluids sampling. The microneedle array has been installed in an insulin pump for demonstration and a leak free packaging is introduced.The support from Ministry of Science and Technology of the People’s Republic of China with contract number of 2005AA40420.     

Characterization of out-of-plane cone metal microneedles and the function of transdermal delivery

The key issue in the research of microneedles is how to fabricate microneedles with low cost and good quality. This paper presents a process for fabrication of cone out-of-plane Ni microneedles and characterizes their properties. The fabrication process consisted of inclined rotational MASK and wafer exposure, fine pattern transfer of polydimethylsiloxane (PDMS) and electroplating. The efficiency of transdermal delivery of baicalin, as well as related mechanical properties, are evaluated using rat skin pretreated by a 10 × 10 microneedle array. The fracture strength of the microneedle is 355 MPa. The cumulative permeability rate improves approximately 100 % due to the effect of the microneedle. The method presented in this paper offers the potential for mass production and wide choice of needle material.     

Fabrication of microneedle array using LIGA and hot embossing process

We demonstrate a novel fabrication technology of the microneedle array applied to painless drug delivery and minimal invasive blood extraction. The fabrication technology consists of a vertical deep X-ray exposure and a successive inclined deep X-ray exposure with a deep X-ray mask whose pattern has a hollow triangular array. The vertical exposure makes triangular column array with a needle conduit. With the successive inclined exposure, the column array shapes into the microneedle array without deep X-ray mask alignment. Changing the inclined angle and the gap between the mask and PMMA (PolyMethylMetaAcrylic) substrate, different types of microneedle array are fabricated in 750–1000 m shafts length, 15^o–20^o tapered tips angle, and 190–300 m bases area. The masks are designed to 400–600 m triangles length, 70–100 m conduits diameter, 25–60EA/5 mm² arrays density, and various tip shapes such as triangular, rounded, or arrow-like features. In the medical application, the fabricated PMMA microneedle array fulfills the structural requirements such as three-dimensional sharp tapered tip, HAR (High-Aspect-Ratio) shafts, small invasive surface area, and out-of-plane structure. In the skin test, the microneedle array penetrates back of the hand skin with minimum pain and without tip break and blood is drawn after puncturing the skin. Hot embossing process and mold fabrication process are also investigated with silicon and PDMS mold. The processed tetrahedral PMMA structures are fabricated into the microneedle array by the additional deep X-ray exposure. With these processes, the microneedle array can be utilized as the mold base for electroplating process.The author thanks the staff in 9 C LIGA beamline, Pohang Light Source (PLS), Korea for their assistance on the fabrication process.     

Penetration-Enhanced Ultrasharp Microneedles and Prediction on Skin Interaction for Efficient Transdermal Drug Delivery

This paper presents penetration-enhanced hollow microneedles and an analysis on the biomechanical interaction between microneedles and skin tissue. The aim of this paper is to fabricate microneedles that reliably penetrate the skin tissue without using penetration enhancers or special insertion tools that were used in the previous studies. The microneedles are made of silicon and feature ultrasharp tips and side openings. The microneedle chips were experimentally tested in vivo by injection of dye markers. To further investigate the penetration, the insertion progression and the insertion force were monitored by measuring the electrical impedance between microneedles and a counter electrode on the skin. The microneedle design was also tested using a novel simulation approach and compared to other previously published microneedle designs. The purpose of this specific part of the paper was to investigate the interaction mechanisms between a microneedle and the skin tissue. This investigation is used to predict how the skin deforms upon insertion and how microneedles can be used to create a leak-free liquid delivery into the skin. The fabricated microneedles successfully penetrated dry living human skin at all the tested sites. The insertion characteristic of the microneedle was superior to an earlier presented type, and the insertion force of a single microneedle was estimated to be below 10 mN. This low insertion force represents a significant improvement to earlier reported results and potentially allows a microneedle array with hundreds of needles to be inserted into tissue by hand.     

A novel fabrication method of micro-needle mold by using the micro-lens mask through contact printing

This study presents a novel and precision process for fabricating a microneedle mold. The process includes a microlens array mask with contact printing in ultraviolet lithography. This method can precisely control the geometric profile of a microneedle array without the use of an etching process. The micro tapered cone microneedle mold utilizes the microlens array mask with geometrical optics. The light passes through the microlens and a hole in a Cr film of a mask, and then radiates onto the photoresist film. The light transmitted through the microlens has an aligned focal point on the photoresist film. An optical system is set up to characterize the optical performance of the machined microneedle, and then compared with theoretical data. The results show that the length of the microneedle from the experiment is close to the derived results. Moreover, the length of the microneedle is significantly influenced by the height and diameter of the microlens. Therefore, this method could also simplify the process and reduce the time needed for the fabrication of the microneedle. The micro cone microneedle has have great potential in the area of the drug delivery applications.     

Characterization of surface micromachined metallic microneedles

The purpose of the paper is to provide quantitative characterization of metallic microneedles. Mechanical and fluid flow experiments were performed to evaluate the buckling force, the penetration force, and the pressure versus flow rate characteristics of the microneedles. The microneedle design variations characterized included varying the shaft lengths, varying the tip taper angles/geometries, and the inclusion of micromechanical barbs. The penetration force was found to range from 7.8 gF for a microneedle of shaft length 500 /spl mu/m, to 9.4 gF for a length of 1500 /spl mu/m, both with a tip taper angle of 30/spl deg/. Microneedles with a linear tip taper angle of 30/spl deg/ penetrated 95 +% of the time without failure. The microneedles with a 15/spl deg/ and 20/spl deg/ linear tip taper penetrated 10% and 25% of the time, respectively. The buckling force was found to be 98.4 gF for a 500 /spl mu/m long microneedle shaft, 72.3 gF for a needle of shaft length 1000 /spl mu/m, and 51.6 gF for a 1500 /spl mu/m long shaft. The results demonstrate that the penetration force was 7.9% of the buckling force for 500 /spl mu/m long shafts, 11.6% for a 1000 /spl mu/m long shaft, and 18.2% for a 1500 /spl mu/m long microneedle shafts. The microneedle fluid flow characteristics were studied. An inlet pressure of 49.0 Pa was required for a flow rate of 1000 /spl mu/L/h and 243.0 Pa for a flow rate of 4000 /spl mu/L/h using air as the fluid medium. For water, an average pressure of 30.0 kPa was required for a flow rate of 1000 /spl mu/L/h and 106.0 kPa for a flow rate of 4000 /spl mu/L/h.     

Structural and microfluidic analysis of hollow side-open polymeric microneedles for transdermal drug delivery applications

In this paper, we present a new design of hollow, out-of-plane polymeric microneedle with cylindrical side-open holes for transdermal drug delivery (TDD) applications. A detailed literature review of existing designs and analysis work on microneedles is first presented to provide a comprehensive reference for researchers working on design and development of micro-electromechanical system (MEMS)-based microneedles and a source for those outside the field who wish to select the best available microneedle design for a specific drug delivery or biomedical application. Then, the performance of the proposed new design of microneedles is numerically characterized in terms of microneedle strength and flow rate at applied inlet pressures. All the previous designs of hollow microneedles have side-open holes in the lumen section with no integrated reservoir on the same chip. We have proposed a new design with side-open holes in the conical section to ensure drug delivery on skin insertion. Furthermore, the present design has an integrated drug reservoir on the back side of the microneedles. Since MEMS-based, hollow, side-open polymeric microneedles with integrated reservoir is a new research area, there is a notable lack of applicable mathematical models to analytically predict structural and fluid flow under various boundary conditions. That is why, finite element (FE) and computational fluid dynamic (CFD) analysis using ANSYS rather than analytical systems has been used to facilitate design optimization before fabrication. The analysis has involved simulation of structural and CFD analysis on three-dimensional model of microneedle array. The effect of axial and transverse loading on the microneedle during skin insertion is investigated in the stress analysis. The analysis predicts that the resultant stresses due to applied bending and axial loads are in the safe range below the yield strength of the material for the proposed design of the microneedles. In CFD analysis, fluid flow rate and pressure drop in the microneedles at applied inlet pressures are numerically and theoretically investigated. The CFD analysis predicts uniform flow through the microneedle array for each microneedle. Theoretical and numerical results for the flow rate and pressure drop are in close agreement with each other, thereby validating the CFD analysis. For the proposed design of microneedles, feasible fabrication techniques such as micro-hot embossing and ultraviolet excimer laser methods are proposed. The results of the present theoretical study provide valuable benchmark and prediction data to fabricate optimized designs of the polymeric, hollow microneedles, which can be successfully integrated with other microfluidic devices for TDD applications.     

Arrays of hollow out-of-plane microneedles for drug delivery

Drug delivery based on MEMS technology requires an invasive interface such as microneedles, which connects the microsystem with the biological environment. Two-dimensional arrays of rigid hollow microneedles have been fabricated from single-crystal silicon using a combination of deep reactive ion etching and isotropic etching techniques. The fabricated needles are typically 200 /spl mu/m long with a wide base and a channel diameter of 40 /spl mu/m. The fabrication process allows creating either blunt needles or needles with sharp tips. Their shape and size make these needles extremely suitable for minimally invasive painless epidermal drug delivery. MEMS technology allows for batch fabrication and integration with complex microsystems. Fluid has been successfully injected 100 /spl mu/m deep into sample tissue through arrays of microneedles. Needle breakage did not occur during this procedure. Experiments have shown that the modified Bernoulli equation is a good model for liquid flowing through the narrow microneedle lumen.     

基于MEMS技术的异平面空心金属微针

MEMS微针的一个重要应用是透皮给药.文中提出了一种基于MEMS技术的异平面空心金属微针.该微针首先利用硅(100)面刻蚀技术在硅片上刻蚀出深度为330μm的倒四棱锥,然后采用电镀技术电镀出壁厚为50μm的空心金属倒四棱锥.从背面开出微流道并去除残余硅,就得到了倾斜角度为70.6°的异平面金属空心微针.最后采用ANSYS有限元仿真软件建立微针模型,验证了微针具有足够的强度.     

Fabrication method with high-density,high-height microneedle using microindentation method for drug delivery system

We have developed a microneedle formation method that has high needle height and density by forming indentations on a metal plate using a micro-machined silicon microneedle, called the “microindentation method.” When a silicon microneedle is used as an indenter that is stamped onto a metal plate and the formed indentation has the same shape as the Si microneedle formed by plastic deformation of metal plate, it is possible to fabricate a microneedle mold arranged in an array by repeating indentation formation while changing the position using a single silicon microneedle. In this research, we developed an indentation apparatus that repeatedly forms indentations on lead plates to successfully fabricate a high-density microneedle array that has the height of the silicon microneedle as the indenter.

     

Realistic imitation of mosquito's proboscis: Electrochemically etched sharp and jagged needles and their cooperative inserting motion

Aiming at the use in low-invasive medical treatments, this paper proposes a realistic imitation of mosquito's proboscis. A silicon needle is electrochemically etched, making the three-dimensionally sharp tip with finely smooth surface. The jagged shank shape is machined by a deep reactive ion etching (DRIE). The combined needles comprising a central straight needle and two outer jagged needles are fabricated, imitating a labrum and two maxillas of the mosquito, respectively. The cooperative motion of the three needles imitating the mosquito's motion is realized by applying PZT actuators independently to all the needles. The effectiveness of inserting these needles cooperatively was experimentally confirmed. Considering practical medical application, a biodegradable polymer needle with three-dimensionally sharp tip is also developed. The fabrication process based on micromolding is as follows: a nickel negative cavity is made by electroplating on a silicon sharp needle, to which melted polymer is injected, and it is finally released using a lost molding technique. The effectiveness of sharp tip for easy insertion was experimentally proven.     

Surface micromachined metallic microneedles

In this paper, a method for fabricating surface micromachined, hollow, metallic microneedles is described. Single microneedle and multiple microneedle arrays with process enabled features such as complex tip geometries, micro barbs, mechanical penetration stops and multiple fluid output ports were fabricated, packaged and characterized. The microneedles were fabricated using electroplated metals including palladium, palladium-cobalt alloys and nickel as structural materials. The microneedles were 200 mm-2.0 cm in length with a cross-section of 70-200 /spl mu/m in width and 75-120 /spl mu/m in height, with a wall thickness of 30-35 /spl mu/m. The microneedle arrays were typically 9.0 mm in width and 3.0 mm in height with between 3 and 17 needles per array. Using water as the fluid medium, the average inlet pressure was found to be 30.0 KPa for a flow rate of 1000 /spl mu/L/h and 106 KPa for a flow rate 4000 /spl mu/L/h.     

Side-opened out-of-plane microneedles for microfluidic transdermal liquid transfer

We present the first hollow out-of-wafer-plane silicon microneedles having openings in the shaft rather than having an orifice at the tip. These structures are well suited for transdermal microfluidic applications, e.g., drug or vaccine delivery. The developed deep-reactive ion etching (DRIE) process allows fabrication of two dimensional, mechanically highly resistant needle arrays offering low resistance to liquid flows and a large exposure area between the fluid and the tissue. The presented process does not require much wafer handling and only two photolithography steps are required. Using a 3/spl times/3 mm/sup 2/ chip in a typical application, e.g., vaccine delivery, a 100 /spl mu/l volume of aqueous fluid injected in 2 s would cause a pressure drop of less than 2 kPa. The presented needles are approximately 210 /spl mu/m long.     

A novel microneedle array for the treatment of hydrocephalus

We present a microfabricated 10 by 10 array of microneedles for the treatment of a neurological disease called communicating hydrocephalus. Together with the previously reported microvalve array, the current implantable microneedle array completes the microfabricated arachnoid granulations (MAGs) that mimic the function of normal arachnoid granulations. The microneedle array was designed to enable the fixation of the MAGs through dura mater membrane in the brain and thus provide a conduit for the flow of cerebrospinal fluid. Cone-shaped microneedles with hollow channels were fabricated using a series of microfabrication techniques: SU-8 photolithography for tapered geometry, reactive ion etching for sharpening the microneedles, 248 nm deep UV excimer laser machining for creating through-hole inside the microneedles, and metal sputtering for improved rigidity. Puncture tests were conducted using porcine dura mater and the results showed that the fabricated microneedle array is strong enough to pierce the dura mater. The in vitro biocompatibility test result showed that none of the 100 outlets of the microneedles exposed to the bloodstream were clogged significantly by blood cells. We believe that these test results demonstrate the potential use of the microneedle array as a new treatment of hydrocephalus.     

Innovative design of hollow polymeric microneedles for transdermal drug delivery

Hypodermic injections give the best results in terms of drug administration efficiency, but benefit from a negative image among patients due to the fear of pain linked to needles. Transdermal drug delivery (TDD) has thus been greatly developed in the past ten years in order to be able to by-pass the skin protective layers in a minimally invasive way. With the advent of micro electro mechanical systems, opportunities have appeared, particularly in the area of microneedles. In this paper we present a new design of hollow polymeric microneedles aimed at being used for TDD by allowing injection of a liquid in the non-innerve part of the dermis. The design has been studied in order to be able to manufacture these microneedles arrays using techniques that may be applicable to industrial production at low cost. The envisioned microfabrication processes and their stacking are presented which involve injection micromolding and excimer laser ablation. Microneedles are also numerically characterized in terms of mechanics and microfluidics showing that the design also involves interesting features in terms of needles resistance and microfluidic. Due to the innovative double-molding technique, the micro-needles are indeed emptied leaving a cavity. An outlet channel on the side of the needle allows fluid flowing out of the needles. The characteristics of this outlet channel contribute to flow homogenization when several needles are placed in an array pattern. This microneedle design thus combines interesting characteristics in terms of ease of fabrication at large scale, mechanical resistance and fluid dynamics.

     

Innovative design of hollow polymeric microneedles for transdermal drug delivery

Hypodermic injections give the best results in terms of drug administration efficiency, but benefit from a negative image among patients due to the fear of pain linked to needles. Transdermal drug delivery (TDD) has thus been greatly developed in the past ten years in order to be able to by-pass the skin protective layers in a minimally invasive way. With the advent of micro electro mechanical systems, opportunities have appeared, particularly in the area of microneedles. In this paper we present a new design of hollow polymeric microneedles aimed at being used for TDD by allowing injection of a liquid in the non-innerve part of the dermis. The design has been studied in order to be able to manufacture these microneedles arrays using techniques that may be applicable to industrial production at low cost. The envisioned microfabrication processes and their stacking are presented which involve injection micromolding and excimer laser ablation. Microneedles are also numerically characterized in terms of mechanics and microfluidics showing that the design also involves interesting features in terms of needles resistance and microfluidic. Due to the innovative double-molding technique, the micro-needles are indeed emptied leaving a cavity. An outlet channel on the side of the needle allows fluid flowing out of the needles. The characteristics of this outlet channel contribute to flow homogenization when several needles are placed in an array pattern. This microneedle design thus combines interesting characteristics in terms of ease of fabrication at large scale, mechanical resistance and fluid dynamics.     

Integrated Lithographic Molding for Microneedle-Based Devices

This paper presents a new fabrication method consisting of lithographically defining multiple layers of high aspect-ratio photoresist onto preprocessed silicon substrates and release of the polymer by the lost mold or sacrificial layer technique, coined by us as lithographic molding. The process methodology was demonstrated fabricating out-of-plane polymeric hollow microneedles. First, the fabrication of needle tips was demonstrated for polymeric microneedles with an outer diameter of 250 mum, through-hole capillaries of 75-mum diameter and a needle shaft length of 430 mum by lithographic processing of SU-8 onto simple v-grooves. Second, the technique was extended to gain more freedom in tip shape design, needle shaft length and use of filling materials. A novel combination of silicon dry and wet etching is introduced that allows highly accurate and repetitive lithographic molding of a complex shape. Both techniques consent to the lithographic integration of microfluidic back plates forming a patch-type device. These microneedle-integrated patches offer a feasible solution for medical applications that demand an easy to use point-of-care sample collector, for example, in blood diagnostics for lithium therapy. Although microchip capillary electrophoresis glass devices were addressed earlier, here, we show for the first time the complete diagnostic method based on microneedles made from SU-8.