TITLE: A MICRONEEDLE PROBE
Field of the Invention
The present invention generally relates to a microneedle probe for sensing or measuring analyte in a skin of a living organism. More particularly, the present invention relates to a microneedle probe for sensing or measuring analyte in the skin, comprising a plurality of conductive microneedles which have individual electrical connections.
Background of the Invention
Over the past decade, microneedle technology has been increasingly applied in various medical fields such as drug delivery, in-vitro diagnostics, and in-situ diagnostics. Microneedles come with some benefits that other competing technologies lack: (1) their minimally invasiveness provides painless sensation which is a primary patient compliance consideration; (2) their abundance provides readily available microneedles for signal processing or signal augmentation (signal processing is having several electrodes namely counter electrode, reference electrode and working electrode to derive a desired signal and signal augmentation is adding several microneedles to one sensor to amplify the detection or measurement); and (3) their tiny size allow them to access obscure sensing area as well as to be incorporated into a wearable device.
There are a lot of applications where microneedles are used as an electrode or as a sensing device. The most common microneedle sensor that is wearable can be seen in the continuous glucose monitoring (CGM) devices. In a typical embodiment, a single microneedle carrying some sensors is implanted into a body for several weeks. The microneedle is normally in electrical connection with an integrated chip which processes the detected signals and converts them into readable form. The microneedle is complex, and the device is bulky in general. In other applications, such as in US patent US8588884B2, a sheet of metallic microneedles is used as a single electrode to enhance the conductivity of the current applied to the skin. These microneedles penetrate the skin to reduce the impedance of the skin, they act as one electrode. There is another US patent US11143534B2 reporting an in-plane microneedle which carries several sensors along its body to measure the sap flow of a plant. In US patent application US20230111253 Al, a microneedle sensor is incorporated into a wristwatch device. The microneedles are hollow so that they can penetrate the skin and carry micropillars in their lumens to the skin for analyte detection. These micropillar sensors are made separately from the microneedles and are individually addressable (having individual electrical connection) through a masking and sputtering process to isolate each micropillar from one another. Yet another US patent application US20230113717A1 employs hydrogel microneedle array as a sensor and incorporates conducting material such as metal nanoparticles or graphene in the hydrogel to make the microneedle conductive.
We can draw several conclusions about the prior arts mentioned herein. The first conclusion is when there is only a single microneedle, it is normally ‘big’ in size and carries several sensors on its body for sensing. The second conclusion is when the microneedles are metallic or conductive, they can only act as a single electrode. The third conclusion is when the microneedles (in some case the micropillars which performs the sensory functions) are non-conductive, they can be made conductive and individually addressable by use of conductive materials such as metal nanoparticles or graphene, and masking and sputtering post-treatments to isolate each micropillar from one another respectively. Summing up our conclusions, there are no microneedles which provide individual electrical connection, which is a vital requirement for sensory and detection applications. The present invention seeks to provide technical solutions so that a microneedle probe with individual electrical connection can be made.
The Closest Prior Arts
We mentioned in the previous paragraph that prior art US20230111253A1 disclosed an array of hollow microneedles carrying a micropillar sensor array which is disposed in the lumens of the hollow microneedles, and the micropillars were made separately and were individually addressable (i.e. having individual electrical connection). It was further disclosed that the micropillar array was fabricated with high precision stereolithography printing or micro-CNC techniques. To make each micropillar conductive and individually addressable, conductive layers such as platinum are sputtered on both sides of the micropillars’ surface via masking and other post-treatment to isolate each micropillar from one another. Lastly, the micropillar array is connected to a PCB (printed circuit board).
Practically, prior art US20230111253A1 is extremely hard to make. In making the hollow microneedle arrays (in paragraph [0082]), it was disclosed that micro-CNC machine was used to machine the shape of the microneedles and to drill holes of 50pm at the centre of the microneedles which has an outer diameter of 200pm. The height of the hollow microneedle is 200pm. With a hole diameter of 50pm, the wall thickness in the microneedles is 75pm. The wall thickness is too thin to sustain the drilling and the microneedles may collapse during the hole drilling process. If we drill the holes first and then machine the bodies of the hollow microneedles, the microneedles may be bent or damaged by the drill bit. Other challenges include aligning an array of micropillars to go through the 50pm holes in the hollow microneedles, multiple handling of the micropillars for achieving individual addressability and others.
The Technical Solutions of the Invention
One of the attractiveness of using a microneedle array as a probe is to have a number of sensors within a probe. This only happens when the microneedles are electrically isolated from each other, i.e., the microneedles are “individually addressable” or having “unique electrical connection”. Most or all microneedles are made for a single material, regardless of whether the material is conductive or non-conductive. These microneedles are made from a bulk material, by either additive or reductive methods. Additive methods are processes involving adding material to form the microneedles, such as injection moulding, mould casting, and deposition of material on a substrate using masks. Reductive methods are processes involving reducing or taking away material from a work piece. It may involve physical contact when removing the material, examples are using a cutter to cut, grind, drill or otherwise shape the material into microneedles. It may also involve non-physical contact removal, examples are dry ion etching, laser machining, etc. The microneedles made using these methods normally are formed with a single unit therefore are not individually addressable. Normally these microneedles are used as a single sensor if they are made from a conductive material. If the microneedles are made from a non-conductive material, they may be made individually addressable by adding a conductive layer on each microneedle and connecting each microneedle with a conductive line that is connectable to some external devices for sensory purposes. This patterning process can be costly and tedious when the dimensions are small, and the conductive layer has bad adhesion to the microneedles and their substrate.
The prior arts reported forming the microneedles on substrate, then adding the electrical connection lines by sputtering or coating process. In contrast, the present invention prepares the microneedles and the substrate separately, and the electrical connection lines are pre-formed on the substrate’s surface before the microneedles are fastened on the substrate.
Firstly, the conductive microneedles 120 (see Fig. 1) are made of thin metal wire that is cut into small lengths, each length having one of its ends sharpened (or tapered, conical, etc.). The cutting and sharpening of thin metal wire can be easily done using a 5-axis CNC lathe machine. Alternatively, the cut wire lengths may be ground into conical or other tapered shape that is capable of penetrating the skin.
Secondly, the non-conductive substrate 140 is made of a sheet of non-conductive material (normally plastics e.g., polycarbonate) which has one or both of its surfaces formed with electrical connection lines 160, which are made of a thin conductive layer (e.g., copper, aluminium and iron). Each electrical connection line 160 connects one unique conductive microneedle 160 to one contact point elsewhere on the substrate. Through holes 180 can be drilled on the substrate where the conductive microneedles 120 are located so that microneedles can be implanted on the substrate.
Thirdly, the separately prepared conductive microneedles 120 are placed in the through holes 180 on the non-conductive substrate 140 and are fastened securely to the substrate by using conductive adhesive. After the fastening process, the individual conductive microneedles 120 should be in electrical connection with one electrical connection line 160 that is formed on the substrate 140. A placement jig 300 (see Fig. 6) may be used to hold the conductive microneedles 120 perpendicular to the substrate 140 with a specific height from the substrate during the fastening process. The conductive adhesive may be applied on either top or bottom side of the substrate, but preferably on the back side of the substrate which is away from the microneedles.
Summary of the Invention
The prior arts formed the microneedles on a substrate as a single article, then added the electrical connection lines on the microneedles and substrate by sputtering or coating process. In contrast, the present invention prepares the microneedles and the substrate separately, and the electrical connection lines are pre-formed on the substrate’s surface before the microneedles are fastened on the substrate.
The first preferred embodiment of the present invention, as shown in Fig. 1, involves a microneedle probe 100 which comprises (a) at least one conductive microneedle 120 having a substantially cylindrical body 122 and a tapered tip 124 (see Fig. 2); and (b) a separately prepared non- conductive substrate 140, comprising electrical connection lines 160 formed on at least one of its top or bottom surfaces, with each electrical connection line 160 connecting to a unique conductive microneedle 120. The conductive microneedles 120 are prepared by cutting metal wire into small lengths and sharpening one of its ends. The formation of electrical connection lines 160 involves coating of a thin layer of conductive material (e.g., copper, iron, or aluminum, etc.) and then removing the negative (i.e., unwanted area) pattern through masking the unwanted area and etching it away. Fig. 3 shows the formation process of electrical connection lines 160 on a non- conductive substrate. Firstly, a thin layer of conductive layer 150 is sputtered on the surface of the non-conductive substrate 140. Secondly, the unwanted area is exposed by masking the wanted area using a masking coating 152. Thirdly, the non-conductive substrate 140 is subjected to an etching process, where the exposed area of the conductive layer 150 is removed. Lastly, the masking coating 152 is removed, and the electrical connection lines 160 are formed.
The second preferred embodiment of the present invention (see Fig. 4) involves a microneedle probe 100 which comprises (a) at least one conductive microneedle 120 having a substantially cylindrical body 122, a tapered tip 124 and a mounting base 126 (see Fig. 5); and (b) a separately prepared non-conductive substrate 140, comprising electrical connection lines 160 formed on at least one of its surfaces, with each electrical connection lines 160 connecting to a unique conductive microneedle 120.
Brief Description of the Figures
Fig. 1 shows the first preferred embodiment of the present invention.
Fig. 2 shows a conductive microneedle in the first preferred embodiment of the present invention.
Fig. 3 shows the formation of the electrical connection lines on the non-conductive substrate.
Fig. 4 second preferred embodiment of the present invention.
Fig. 5 shows a conductive microneedle in the second preferred embodiment of the present invention. Fig. 6 shows the placement jig and the fastening process of the present invention.
Detailed Description of the Invention
It is the objective of the present invention to provide a low-cost microneedle probe for sensory applications. In this section we will explain the spirit of the inventive concept of the present invention through two preferred embodiments of the present invention.
The First Embodiment
The first preferred embodiment of the present invention, as shown in Figs. 1 and 2, comprises a microneedle probe 100, comprising (1) at least one conductive microneedle 120 having a substantially cylindrical body 122 and a tapered tip 124; and (2) a separately prepared non- conductive substrate 140 comprising electrical connection lines 160 formed on at least one of its surfaces, with each electrical connection line 160 connecting to a unique conductive microneedle 120. There are through holes 180 drilled on the non-conductive substrate 140 for receiving the conductive microneedles 120. As shown in Fig. 1, the electrical connection lines 160 are formed on the bottom surface. An insulative layer (not shown) is coated on electrical connection line 160 for protection and short-circuit prevention. Alternatively, the electrical connection lines 160 can be formed on the top surface or both surfaces of the non-conductive substrate 140. An insulative layer is coated on the electrical connection lines 160 the bottom surface, or on the opposite surface of the conductive microneedles 120 so that the conductive microneedles 120 are not obstructed and the electrical connection lines 160 are not damaged or short-circuited during the use. The conductive microneedles 120 are fastened to the non-conductive substrate 140 and at the same time electrically connected to the electrical connection lines 160 by applying conductive adhesive 200 at the bottom surface of the through holes 180 on the non-conductive substrate 140. The conductive adhesive 200 may be eutectic solder.
The conductive microneedles 120, as shown in Fig. 2, which have a substantially cylindrical body 122 and a tapered tip 124, are prepared by cutting metal wire into small lengths and sharpening one of its ends. In practice, stainless steel wire of 0.1mm - 0.5mm wire has been widely used, although other metal wires are suitable for this application. A typical wire diameter is 0.3mm. The height of the conductive microneedles 120 ranges from 0.1mm to a few mm long. The conductive microneedles 120 have substantially cylindrical body 122 with a conical tip 124 at the sharpened end. The minimum distance between two conductive microneedles 120 is roughly 1mm, although smaller distance may be achievable by using precision equipment. Stainless steel wire is chosen for its hardness, toughness, and ability to resist rusting, on top of its availability and low cost. The machined conductive microneedles 120 may be further coated with inert conductive layers using gold, platinum and alloys. One common practice is gold electroplating. The purpose of providing an inert conductive layer is to reduce the allergic reaction by direct contact of stainless steel to tissues.
The non-conductive substate 140 is made of plastic material, namely polycarbonate PC. The thickness ranges from 0.5mm to 2mm. The non-conductive substrate 140 has one or both of its surfaces formed with electrical connection lines 160, which are made of a thin conductive layer (e.g., copper, aluminum and iron). Each electrical connection 160 line is designed to connect to only one unique conductive microneedle 120 and one contact point (not shown in the figure) elsewhere on the substrate. These contact points can be organized and arranged to connect to any external device (not shown in the figure) or external electrical component. The thin conductive layer can be made of copper with 0.01 to 0.1mm thickness.
Through holes 180 can be drilled on the non-conductive substrate 140 where the conductive microneedles 120 are located so that they can be implanted and fastened on the non-conductive substrate 140. The through holes 180 have a diameter the same or slightly bigger than that of the conductive microneedles 120. For example, the diameter of the conductive microneedles 120 is 0.3mm, and the diameter of the through holes 180 is 0.32mm to 0.35mm. the through-holes 180 in practice bolster the conductive microneedle’s upright position.
The Second Embodiment
The second preferred embodiment of the present invention, which is shown in Figs. 4 and 5, involves a microneedle probe 100, comprising (1) at least one conductive microneedle 120 having a substantially cylindrical body 122, a tapered tip 124 and a mounting base 126; and (2) a separately prepared non-conductive substrate 140 comprising electrical connection lines 160 formed on at least one of its surfaces, with each electrical connection line 160 connecting to a unique conductive microneedle 120. Fig. 5 shows the conductive microneedles 120 in the second preferred embodiment. The mounting base 126 of the conductive microneedles 120 sits directly on the electrical connection line 160 and is fastened to it with conductive adhesive 200. The fabrication process of the first preferred embodiment
In this section, the fabrication process flow will be discussed. The stainless-steel wire comes in rolls and is cut into small lengths, such as 3mm to 30mm in length. A 5-axis lathe CNC machine can be used to automatically sharpen and cut the conductive microneedles 120. The machine is programmed to sharpen one end of the wire before cutting the microneedle off the wire, and this process can be repeated automatically. The conductive microneedles 120 are made longer than its required length so that they can be gripped and placed into the non-conductive substrate via the through-holes 180. The conductive microneedles 120 can be tumbled for further sharpening the tips before fabrication. Conductive microneedles 120 can also be electroplated with gold or platinum according to their applications.
Separately, the non-conductive substrate 140 can be made with plastic sheets. A polycarbonate sheet of thickness 0.5mm to 2.0mm are typically used in making the non-conductive substates 140. The non-conductive substrates 140 will be incorporated with electrical connection lines 160 on one or both of its surfaces. Through-holes 180 will be drilled where the conductive microneedles 120 will be placed. In an industrial setting, the polycarbonate sheet may be 2.0mm thick with an area of Imxlm. Repeated patterns of the non-conductive substrate 140 can be formed on the polycarbonate sheet. The Through-holes 180 can be drilled by a bit-drilling machine or a laser machine, with the diameter equal to or slightly bigger than the diameter of the conductive microneedles 120.
The formation of electrical connection lines 160 involves sputtering of a thin layer of conductive material 150 (e.g., copper, iron, or aluminum, etc.) on the non-conductive substrate 140 with a mask 152 exposing the unwanted area of the conductive layer 150. Alternatively, the electrical connection lines 160 can be formed by first coating a thin layer of conductive material 150 (e.g., copper, iron, or aluminum, etc.) on the non-conductive substrate 140 and then removing the negative (i.e., unwanted area) pattern of the conductive material 150 by using a mask to expose the unwanted area and etching it away. This is normally done via a chemical etching process using acids.
For the first preferred embodiment, a placement jig 300 is involved (Fig. 6). Once the non- conductive substrate 140 is incorporated with the required electrical connection lines 160 and through-holes 180, it is placed on a placement jig 300 as shown in Fig. 6. Conductive microneedles 120 are placed with the tips facing upwards. The through-holes 180 and the blind holes 320 on the placement jig 300 holds the conductive microneedles 120 in a substantially upright manner. Next, a fixation sheet 340 is placed on the non-conductive substrate 140 by pushing the fixation sheet 340 from the top direction to completely bury the conductive microneedles 120. The pushing ensures that all the conductive microneedles 120 are pushed to the bottom of the blind holes 320 so that their height is uniform and that all conductive microneedles 120 are temporarily fixated for the following fastening process.
In the following step, the prepared non-conductive substrate 140 is removed from the placement jig 300 to expose the bottom part of the conductive microneedles 120. Conductive adhesive 200 is used to fasten the conductive microneedles 120 securely to the trough-holes 180 on non-conductive substrate 140. The conductive adhesive 200 also ensures that there is an electrical connection between the individual conductive microneedles 120 and the electrical connection lines 160. The conductive adhesive 200 can be a eutectic solder. Alternatively, the prepared non-conductive substrate 140 can be subjected to wave soldering process for fastening the conductive microneedles
120 with a eutectic solder.
The fabrication process of the second preferred embodiment
The fabrication process of the second preferred embodiment is substantially similar with that of the first preferred embodiment. The fabrication process of making the non-conductive substrate is the same, except no through holes are required. Conductive adhesive 200 is dispensed on specific locations where the conductive microneedles 120 are mounted, forming conductive adhesive bumps 200. Next, the conductive microneedles 120 are placed on the conductive adhesive bumps 200, and heat is supplied to the conductive adhesive bumps 200 so that they melt momentarily and solidify, forming a strong adhesion between the non-conductive substrate 140 and the mounting base 126 of the conductive microneedles 120.