Toward Self‐Powered Wearable Adhesive Skin Patch with Bendable Microneedle Array for Transdermal Drug Delivery

Abstract

A wearable adhesive skin patch for transdermal drug delivery is developed with bendable microneedles, dry adhesive and triboelectric energy harvester (TEH). The bendable microneedle array can overcome the needle breakage issue. The dry adhesive can realize a conformal attachment. The TEH can generate power when attached on flat skin or joint to power active components to be integrated in the future. Wearable flexible electronic medical devices have received major attention recently owing to their considerable practicability for several applications,1-10 including health monitoring and drug delivery for disease treatment.11-13 The traditional drug delivery method using hypodermic needles may be an unpleasant process to many patients. Thus, microneedle-based transdermal drug delivery approaches have been investigated by changing different kinds of materials and configurations.14-41 Currently the safety issue caused by needle breakage after skin penetration step is the main concern for clinically relevant applications. High aspect ratio and sharp tips made of rigid materials are necessary for conventional microneedles to provide a successful and reliable skin penetration.16, 25, 26 Normally, microneedles made of materials of high Young's modulus such as nickel,12, 38 stainless steel,26, 42 and silicon,14, 25 can avoid this needle breakage. However, these materials lack of biocompatibility, which is a key requirement for medical devices. On the other hand, microneedles made of biocompatible polymers or natural fibers suffer from low mechanical strength. The consequent needle breakage can be induced either by very high buckling force attributed to the deformable skin surface during the skin penetration or by the lateral movement between the microneedle patch and the skin surface during the drug administration. Here we propose a novel drug delivery skin patch using an array of bendable microneedles. This bendable microneedle array with a soft base and a rigid sharp tip can tolerate the deformation associated with skin stretching without breakage when the skin patch is applied on the joint such as elbow and knuckle for osteoporosis treatment. In other cases, such as diabetes, for which microneedle patches are normally applied on the arm or abdomen, a lateral movement between the microneedle patch and skin surface may occur due to either the occasional touch or friction. In such case, the bendable microneedle will be dragged out of the skin instead of leaving a broken needle in the skin when lateral movement occurs. The sharp tips assembled onto the soft bases can be either non bio-dissolvable, i.e., made of SU-8,43 or biodissolvable, i.e., made of maltose.44 For the configuration with SU-8 sharp tips, the outlets of the microneedles, connecting with the drug reservoirs, are always exposed to air. Both water-soluble and lipophilic drugs can be immediately delivered just after skin penetration. For the configuration with maltose sharp tips, the outlets can be fully encapsulated by maltose to inhibit the solvent evaporation of lipophilic drug formulation.45 The drug can be delivered when the maltose tips are melted after skin penetration. However, the microneedle with maltose tip is not suitable for application of water-soluble drug formulation.46The evaporation of water in solvent will cause maltose tip melting. Therefore, the water-soluble drug formulation can only be stored in patches with SU-8 sharp tips. Another key feature for wearable medical device is the fixation method. Acrylic medical bandage is widely used for medical patches. However, there are increasing demands on less-irritating, biocompatible medical bondages, as aging skin is more sensitive and vulnerable to a prolonged exposure, e.g., insulin delivery, as in the case of conventional medical patches. Dry adhesive, which is inspired by the hierarchical structure on Gecko foot hair,44, 43 possesses several advantages compared with conventional acrylic medical bandages: First, it shows repeatable and restorable adhesion with surface cleaning after each usage. Second, the physical structure to generate adhesive force is less affected by surface contamination, oxidation and other environmental stimuli. Third, the space between the pillars for ventilation of air should provide better bio-compatibility. Hence, we also adopt the dry adhesive for the fixation of the whole device on the skin. To construct a complete drug delivery system for home healthcare monitoring, it is important to have feedback control function of the delivered drug. It can alert patients and provide the guidance when the dose of the drug to be delivered should be accurately controlled.47-50 Currently, several wearable sensors for health monitoring have been explored, including devices that measure hydration,51 strain,52 glycaemia,53-55 metabolic acid,56 and cardiorespiratory signals.53 For a further integration of diversified sensors mentioned above and construct a standalone wearable drug delivery skin patch with capability of health monitoring, signal process and interfacing with external cloud computing apparatus, a build-in energy source is inevitable to power components such as integrated circuits(ICs), microprocessor, liquid-crystal display(LCD) reading panel. Triboelectric energy harvester (TEH) typically using patterned PDMS is compatible with the fabrication process of flexible skin patch with microneedles. Thus, TEH is the most promising technique to fulfil the above-mentioned requirements. In this paper, we leverage the same microstructure of the dry adhesive for triboelectric patch to harvest energy from the contact with human skin, which has not been reported yet. Considering the locations for patch attached can be on flat skin surface like arm and abdomen or on joints like elbow and knuckle in different applications, we studied and developed two kinds of configurations to adapt these two situations for energy harvesting. We propose a stretchable adhesive flexible microneedle skin patch attached onto flat skin surface or joint parts, i.e., elbow and knuckle, as shown in Scheme 1a. The whole skin patch consists of four functional components: bendable microneedle patch; dry adhesive patch; triboelectric energy harvester patch and drug delivery system with pump and drug reservoirs connected to the bendable microneedle skin patch. The detailed structure is depicted in Scheme 1b. The microneedle and triboelectric patches are connected with three dry adhesive patches to make the whole wearable device able to be fixed onto the curved skin surface. The microfluidic control system with pump and drug reservoirs57 can be assembled at the backside of the microneedle patch to control the drug delivery after the skin penetration. The detailed working principle of the pump system is provided in Figure S3 (Supporting Information). The structure of an individual bendable microneedle is shown in Scheme 1c where it consists of a bendable four-beam-pillar base and a rigid sharp tip. The bendable pillar base is made of PDMS with optimized stiffness to ensure a high success rate of skin penetration, while certain volume deformation is allowed. A rigid sharp tip for skin penetration can be assembled onto the four-beam-pillar base structure by using double-drawing lithography process.58, 59 The gaps between the pillars can be partially filled with the same materials to form microneedles during the drawing lithography step. It provides anchoring between the sharp tip and soft base in order to fix the sharp tip onto the soft base and protect it from breakage when the whole microneedle is bent. Another functional component is the TEH patch for energy harvester. The triboelectric contact surface with PDMS micropatterned structure can enhance the performance. Here, we used the micropillar array with and without mushroom top, which is obtained from the same fabrication process of the dry adhesive patch, as the surface micro structure for TEH patch. Meanwhile, we also tested the sample with pyramid micro structure, which is normally used for THE,60-66 as a comparison. Two methods were developed to generate power from the TEH patch by applying the skin patch on different locations of the human body. When the patch is attached to the elbow of a straight forearm, the spacing between two dry adhesive patches is slightly shorter than the length of the TEH patch. Thus the TEH patch is bent and has no contact with skin surface at this initial state. Then when the joint is bent, the TEH patch is stretched and in contact with the skin. Thereafter, when the joint is straight again, the spacing between two dry adhesive patches is compressed to make the TEH bent and separate from skin. Power can be harvested by repeating this cycle as illustrated in Scheme 1g. For the case in which the patch is applied onto a flat skin surface like arm and abdomen, power can be generated by pressing and releasing the TEH patch to induce contact and separation between TEH patch and skin surface as illustrated in Scheme 1f. However, due to the sticky surface of PDMS, once the triboelectric contact surface is pressed onto skin, it cannot automatically separate from skin when the pressing is released. To solve this problem, a dry adhesive patch is assembled at the backside of the TEH patch as shown in Scheme 1d. When the finger lifts up, the dry adhesive can provide a pulling force to make the TEH detach from the skin surface. Because the adhesive force provided by the dry adhesive is limited, the dry adhesive will detach from finger when lifted up to a certain height. In order to have a maximized output power of TEH patch, the dry adhesive is optimized to provide a maximum lift-up height. In order to solve the needle breakage issue after skin penetration, a unique bendable microneedle design is proposed here. The bendable microneedle consists of two parts: a soft four-beam-pillar base made of PDMS and a stiff SU-8 sharp tip. The material of the sharp tips can be either SU-8 (Figure 1a) or maltose (Figure 1b). These sharp tips were assembled onto the four-beam-pillar structured array, which has four vertical gaps along the sidewalls (Figure 1a2 and Figure 1b2). These four vertical gaps serve two functions: first, because the sharp tips made of SU-8 are not biodissolvable, the drug could be delivered out through these gaps; second, during the drawing lithography process, the sharp tips could form an anchor shape in these gaps to enhance the adhesion between sharp tips and four-beam-pillar base. Due to the flexibility of the PDMS pillars, the needle will bend when the lateral force applied onto the microneedle exceeds the threshold. These anchors of the rigid sharp tips in the gaps could fix the sharp tips onto the PDMS pillar and protect them from detaching the PDMS pillars when the whole microneedle is bent. Figure 1a3 and Figure 1b3 show the demonstrations of the bendable needle when a glass slide pushes the microneedle array from a lateral direction. These needles will bend when the lateral force is applied. They will recover to the initial state as long as the force is removed. After skin penetration, the relative movement between the microneedle patch and skin is inevitable during the manual operation, which is one the major reasons for needle breakage. The soft PDMS pillars at the bottom of the microneedles will bend to absorb the mechanical strain caused by lateral movement and further prevent the breaking when this relative movement occurs. Figure 1a4 shows a demonstration when the relative movement between skin and microneedle occurs after skin penetration. The dash line indicates the contour profile of needle position inside skin; from (a4-i) to (a4-iii), the needle penetrated the skin, the whole sharp tip was into the skin; from (a4-iv) to (a4-v), a lateral movement occurred, the needle had a displacement from its original position. The PDMS pillars beneath the SU-8 tip bended and the SU-8 tip still remained within the skin (a4-vi); the needle was taken out of the skin and recovered to its original shape without breakage. This demonstration confirms that when the relative movement occurs, the needles will bend to match the new position of the skin. If the relative movement is too large, then the needles will be dragged out the skin and recover the initial state. Due to the elasticity of PDMS, the bottom part of the microneedles, which is represented by the PDMS pillars, will bend when the force applied onto the microneedles exceeds the buckling To realize a successful skin penetration, the stiffness of the PDMS pillars are to be as high as Thus, we a of the stiffness of the PDMS by the ratio of and The PDMS with of can have a Here we tested the with a ratio of and for microneedles with SU-8 and maltose sharp tips. microneedles with PDMS base and SU-8 sharp tips were to in order to their mechanical The of force displacement was Figure shows the of one are three parts: contact and bend as in this The sharp of the force after the bend confirms that the needles will not bend when the applied force is the threshold. The of bend of the with different ratio of PDMS are shown in Figure For each needles were shown in Figure for the ratio of the force is for SU-8 sharp tips and for maltose sharp tips. The bend force with the of the The buckling force of needle with maltose sharp tip is than that of the needle with SU-8 sharp tip because of the different of the sharp tips. shown in Figure 1a2 and the SU-8 sharp tip is than the maltose This is because the of SU-8 is than that of the drawing lithography process, the SU-8 sharp tip to have a part while maltose sharp tip to have a and Thus the force to make the needle with SU-8 sharp tip bent is than that of the needle with maltose sharp tip. We also the skin penetration with of different PDMS A microneedle array was applied onto skin and the of penetrated by needles was and the are shown in Figure and in For the with a ratio of there are Figure and Figure penetrated on skin for needles with SU-8 sharp tips and maltose sharp tips For the with ratio of there are Figure and Figure penetrated on skin for needles with SU-8 sharp tips and maltose sharp tips, For the with a ratio of there is no penetrated that can be on skin for needle as shown in Figure and Figure Thus, we could in order to ensure a skin penetration, the ratio of is for the device The success penetration rate of the needle with maltose sharp tip is than that of needle with SU-8 sharp tip when the of buckling force show an the maltose needle can a buckling it also force to the skin. This is because the needle of maltose sharp tip will a surface during skin penetration, in a to bent during skin penetration. Figure shows the of skin penetration by needles with SU-8 sharp tip and maltose sharp tip. The by the maltose sharp (Figure tip is than that of the SU-8 sharp which confirms that the maltose sharp tip more force to skin. Another that may the buckling force of the bendable microneedles is the of the PDMS pillars beneath the rigid sharp tips. When the of the pillars from to and the of gaps between pillars from to the anchor of the rigid sharp tip will a the needle more rigid and the buckling However, for the of SU-8 sharp tips by drawing lithography as shown in Figure (Supporting the to the SU-8 tip assembled by the step drawing cannot be to realize a partially filled for the with pillar than Because of the once the SU-8 always the whole leaving no for the drug to be Therefore, for the needles with SU-8 sharp tips, we only the pillars of pillar The drawing process to maltose sharp tip is not by the pillar the buckling force of needle with maltose needle by changing the pillar is and reported in Figure For each pillar needles were When the pillar from to (Figure the buckling force of the individual needle from to because the whole microneedle more However, the contact between maltose and PDMS pillars also with the of the pillar Thus the maltose sharp tip cannot be fixed within the PDMS pillars and to or detach from the PDMS pillars when the vertical force is applied to make the microneedle bent. For the case of pillar of needles sharp tip breakage. The of the needle breakage with the of pillar For the needles of pillar more than no needle breakage was in the buckling force a to avoid needle breakage and have buckling force as high as pillar of is the for microneedles with maltose sharp tips. The dry adhesive in the skin patch is used to fix the whole device onto skin surface and also provides the pulling force to separate the TEH patch from the skin, which will be mentioned in the The detailed fabrication process can be in Figure (Supporting Information). To ensure the patch can be fixed onto the skin, the adhesive force of the dry adhesive patch with two of pillar of and and different ratio of pillar spacing pillar from to was The adhesion was up to repeating for each sample by The sample was attached onto the glass or skin and the force was applied by the from the backside to the dry adhesive The maximum force was as the adhesive Figure show the adhesive force on glass and skin of each The dry adhesive was with after each cycle to prevent the and recover the adhesive The sample with pillar spacing can adhesive force than the sample with pillar spacing when the pillar is For the on the the adhesive force not have an as shown in Figure However, for the on the skin, there is a of the adhesive force when repeating the This is because the deformable skin will cause more on the mushroom when the dry adhesive was pressed onto skin surface. Thus repeating the will the of mushroom and further the adhesive The adhesive force will recover after cleaning the dry adhesive patch with The of the adhesive force on the glass and skin by changing the pillar spacing for pillars of and is shown in Figure The with the in and The adhesive force when the spacing the adhesive force of the patch with is a than that with due to the pillar aspect ratio when the pillar is on the of the dry adhesive we can that the sample with pillar and pillar spacing can the adhesive Therefore, this is for the dry adhesive to be integrated on the patch of complete To a power source on the flexible skin patch for active components which may be integrated in the a triboelectric patch was The detailed structure and fabrication process is shown in Figure (Supporting Information). A PDMS with was used to enhance the surface and output Here we studied the by using micropillar with and without mushroom and pyramid as the the backside of the PDMS a of was by Then a was attached above the to protect the from and friction. mentioned to adapt the different locations for patch to be we developed two methods to generate For the case when the patch is applied on flat skin as shown in Figure the between two dry adhesive patches is a shorter than the original length of the TEH patch, the TEH patch bent and no contact with skin surface (Figure Then the TEH patch is pressed by finger and contact with the skin as shown in Figure then is from skin by up the finger as shown in Figure Due to the sticky surface of PDMS, once the TEH is attached onto the skin, it cannot separate from skin without a pulling Thus, a dry adhesive patch is assembled at the backside of the TEH patch, the pulling force by the adhesive force between the finger and dry adhesive patch. The detailed process is shown in Figure When the TEH patch was pressed onto the skin surface (Figure there is between to the triboelectric are from the PDMS to the skin during the process, PDMS is more than skin as shown in Figure The of the on the surface of the PDMS on the to from the to the output or signal is the finger is lifted up, the PDMS and skin (Figure the of the surface on PDMS surface will induce a of from to signal will be The TEH is working in a and the which is in (Supporting Information). To the maximum output the TEH should be lifted up as high as The maximum to be lifted up is by the spacing between the two When this spacing the TEH can bend more and have a from the skin surface. However, a shorter spacing between the two dry adhesive patches also the contact between the TEH patch and skin. It will further the of the to be The spacing between the two dry adhesive patches is optimized in Figure (Supporting to a maximum lift-up height. The adhesive force should provide a certain adhesive force to up the TEH to the maximum height. the TEH is lifted up to the maximum the finger will detach from the dry adhesive because of the on the adhesive force in Figure output of dry adhesive patches with different adhesive are tested in Figure (Supporting Information). The dry adhesive with output was to be assembled at the backside of the TEH for output power in Figure In order to the power generated by the a was connected between TEH patch and The finger pressing of was applied to generate the The was then the to the power generated by the the was the power output at a and then The and power of TEH with different surface and are shown in Figure The maximum power output for TEH patch with pillar with and without mushroom and pyramid are and when the are and as shown in Figure This for output power the of the TEH patch. The TEH with pyramid surface a and output also a A detailed for this is shown in (Supporting Information). Another method to generate the power is to the device to the In this case, when bend and straight their the skin will be stretched and the TEH patch contact and detach the skin. Thus, the dry adhesive on the backside of TEH patch is not The of the output and output power is shown in Figure the same as that of and The maximum power output for TEH patch with pillar with and without mushroom and pyramid are and when the are and In order to that the device has for an drug delivery transdermal delivery of insulin was tested in to the function by using the patch with SU-8 sharp tips in The are shown in Figure The in with microneedles during the insulin delivery and was after the with microneedle the delivery volume can be by the pressing The delivered volume was by the to the different volume delivered during the as shown in Figure were four in the For the two only one pressing was applied during the The delivery volume was and For the two the pump were pressed and the delivery volume was as and The of the is shown in Figure For the with delivery the However, for the the at a certain after The confirms that the manual control delivery with pump system can control insulin delivery and further control the In we developed a stretchable wearable flexible medical device for transdermal drug bendable microneedles were proposed to overcome the safety issue associated with the microneedle breakage during the The PDMS ratio and pillar spacing are optimized for a maximum buckling force to enhance the skin penetration success To adapt the for water-soluble and lipophilic drug two kinds of microneedle configurations are with SU-8 sharp tips are more suitable for the of drugs while microneedles with maltose sharp tips are more suitable for the of We leverage the dry adhesive as the fixation method to realize a conformal attachment. The micropillar structure in fabrication of dry adhesive is also investigated as a TEH patch, which is a promising energy source for other active Two methods for power on different for skin patch to be were developed and Thus the TEH patch can generate power no the patch is attached on flat skin or joint The drug delivery function by using the bendable microneedle and pump system is by in in of In the were and by the and at the of with a of were with in to generate a These were with to and water for Then their was by a The with a between and were and the on the abdomen skin were with a the After the were the microneedle patch skin patch with insulin was applied on the abdomen skin surface. The pump was pressed to insulin of different volume from the drug were taken from the after the of the in The monitoring for A was used to the This was by from the for and and A in a to and this provides by the materials are and may be for delivery, are not or from than should be to the The is not for the or of by the than should be to the for the