A novel microdevice for the treatment of hydrocephalus: design and fabrication of an array of microvalves and microneedles

We present an implantable, microfabricated device for the treatment of hydrocephalus. Hydrocephalus is a medical condition, in which an abnormal accumulation of cerebrospinal fluid (CSF, a water-like fluid that circulates around and protects the brain and spinal cord.) occurs in the brain. The novel microdevice presented here mimics the function of natural one-way valves, arachnoid villi, found in the human brain. Hence, we name it microfabricated arachnoid villi (MAV). The MAV consists of an array of one-way microvalves and hollow microneedles. The one-way microvalves control flow based on pressure differential. A Parylene microvalve array with a dome petal geometry was designed and fabricated. Initial flow tests demonstrated the desired low cracking pressure of the valve and a sufficient mechanical stability. The hollow microneedle array was designed to pierce the dura mater membrane (A tough fibrous membrane covering the brain and the spinal cord and lining the inner surface of the skull.) and provide a conduit for CSF. An SU-8 microneedle array was designed and successfully microfabricated. The innovative MAV may open a new era in the treatment of hydrocephalus.     

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.     

High aspect ratio tapered hollow metallic microneedle arrays with microfluidic interconnector

We present a novel microfabrication method for a tapered hollow metallic microneedle array and its complete microfluidic packaging for drug delivery and body fluid sampling applications. Backside exposure of SU-8 through a UV transparent substrate was investigated as a means of fabricating a dense array of tall (up to 400 μm) uniformly tapered SU-8 pillar structures with angles in the range of 3.1–5° on top of the SU-8 mesa. Conformal electroplating of metals on top of the array of the tapered SU-8 pillars, lapping of the tip of the metallic microneedles with planarizing polymer, and removal of the SU-8 sacrificial layers resulted in an array of tapered hollow metallic microneedles with a fluidic reservoir on the backside. A microfluidic interconnector assembly was designed and fabricated using SU-8 and conventionally machined PMMA in a way that it has a male interconnector, which directly fits into the fluidic reservoir of the microneedle array at one end and the other male interconnector, which provides fluidic interconnection to external devices at the other end. The fluid flow rate was measured and it showed 0.69 μL/s. per microneedle when the pressure of 6.89 KPa (1 psi) was applied.     

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.     

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.     

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.     

Geometrical strengthening and tip-sharpening of a microneedle array fabricated by X-ray lithography

A novel fabrication method for LIGA (from the German “Lithographie”, “Galvanik”, and “Abformung”) microneedles with through holes is presented. Such microneedles are in demand by most bio-medical MEMS applications and in some fluidic MEMS applications. We propose a technique that combines conventional deep X-ray lithography, plane-pattern to cross-section transfer (PCT) process, and alignment X-ray lithography. The technique provides precise hole alignment with ± 3 μm tolerance. Finite-element simulations on various hole locations were performed to determine the optimum position. We previously fabricated a microneedle with a 100-μm base and a 300-μm height by a right-triangular mask. The resultant microneedle had a very sharp tip but was excessively steep, and thus resulted in a very low strength. Improved strength and tip sharpness was consequently achieved by changing the mask-pattern from a triangular pattern to a polygonal mask and changing the dimensions of the microneedle to have a 300-μm base with various heights between 350 and 800 μm. Using the proposed technique, we could produce a total of 100 hollow microneedles on a 5 × 5 mm² chip. Moreover, we successfully fabricated sharpened microneedles that were stronger than that we have fabricated so far. The molding process or electroplating and the cost list of the LIGA microneedle will also be included.     

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.     

Hollow metallic microneedles fabricated by combining bulk silicon micromachining and UV–LIGA technology

As one of the promising research aspects in BioMEMS, microneedle technology has been widely applied in drug delivery. Compared with the solid microneedles, hollow microneedles can provide continuous delivering drugs. However, the fabrication processes and costs of the hollow microneedles are often complex and high accordingly. We propose a low-cost method to fabricate the hollow metallic microneedles, which contains procedures of using a wet method to etch silicon wafer to get the tapered cavities firstly, filling the tapered cavities with the SU-8 photoresist, developing the SU-8 to pattern the shapes of microneedles, and electroplating one metal in the patterns to form hollow metallic microneedles. According to the method, microneedles with different shape tips that include the triangular pyramids or the rectangular pyramids have been fabricated. In addition, these microneedles have been analysed using a finite element method and tested on artificial skins, which demonstrate the strength of microneedles is sufficient for piercing skins.     

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.     

Polymeric microneedle fabrication using a microinjection molding technique

Polymeric microneedles fabricated by microinjection molding techniques have been demonstrated using Topas^®COC as the molding plastic material. Open-channel microneedles with cross-sectional area of 100 μm × 100 μm were designed and fabricated on top of a shank of 4.7 mm in length, 0.6 mm in width, and 0.5 mm in depth. The tip of the microneedle has a round shape with a radius of 125 μm as limited by the drill used in fabricating the mold insert. The injection molding parameters including clamping force, shot size, injection velocity, packing pressure, and temperature were characterized in order to achieve best reproducibility. Experimentally, a fabricated microneedle was successfully injected into a chicken leg and a beef liver freshly bought from a local supermarket and about 0.04 μL of liquid was drawn from these tissues immediately. This new technology allows mass production of microneedles at a low cost for potential biomedical applications.     

Silicon micromachined hollow microneedles for transdermal liquid transport

This paper presents a novel process for the fabrication of out-of-plane hollow microneedles in silicon. The fabrication method consists of a sequence of deep-reactive ion etching (DRIE), anisotropic wet etching and conformal thin film deposition, and allows needle shapes with different, lithography-defined tip curvature. In this study, the length of the needles varied between 150 and 350 micrometers. The widest dimension of the needle at its base was 250 /spl mu/m. Preliminary application tests of the needle arrays show that they are robust and permit skin penetration without breakage. Transdermal water loss measurements before and after microneedle skin penetration are reported. Drug delivery is increased approximately by a factor of 750 in microneedle patch applications with respect to diffusion alone. The feasibility of using the microneedle array as a blood sampler on a capillary electrophoresis chip is demonstrated.     

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.     

Overview of microneedle system: a third generation transdermal drug delivery approach

Transdermal drug delivery has given cardinal contribution to medical practices. First-generation transdermal delivery of small, lipophilic, low-dose drugs and second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in various clinical products provides added functionality. Third-generation delivery systems using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound targeting skin’s barrier layer of stratum corneum. Microneedles acquire pronounced intrigue in recent days. Currently, microneedles are advancing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. The review explains about the concept of transdermal drug microneedle system comprising of microreservoir, micropumps, flow sensors, types of microneedles. Various researches carried out on these components of microneedle system is elaborately discussed in this review.     

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.     

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.     

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.

     

Optical Analysis of Implants from the Dura Mater

Presents the results of the spectral analysis using the method of Raman scattering spectroscopy (RS) of dura mater (DM) samples, manufactured by technology “Lioplast” practised in the clinic in the area of atrophic processes at multiple gum recessions. The method of Fourier deconvolution and selection of the spectral profile by the method of least squares is used to increase the resolution and informativity of the spectrum. With the help of mathematical methods of separation of overlapping spectral contours, the main bands corresponding to the main components of the implants were found: amides, proteins, glycosaminoglycans, DNA/RNA. On the basis of the two-dimensional spectral analysis, the coefficients reflecting the composition of the dura mater with different methods of its treatment were introduced. It has been established that Raman spectroscopy can be used to evaluate implants from the dura mater.     

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.