Microneedles in advanced microfluidic systems: a systematic review throughout lab and organ-on-a-chip applications

Citation: Maia, R.; Carvalho, V.; Lima, R.; Minas, G.; Rodrigues, R.O. Microneedles in Advanced Microfluidic Systems: A Systematic Review throughout Lab and Organ-on-a-Chip Applications. Pharmaceutics 2023,15, 792. https://doi.org/10.3390/ pharmaceutics15030792 Academic Editor: Kevin Ita Received: 22 January 2023 Revised: 20 February 2023 Accepted: 24 February 2023 Published: 28 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Systematic Review Microneedles in Advanced Microfluidic Systems: A Systematic Review throughout Lab and Organ-on-a-Chip Applications Renata Maia 1,2, Violeta Carvalho 1,2,3,4, Rui Lima 4,5,6 , Graça Minas 1,2 and Raquel O. Rodrigues 1,2,7,8,* 1Center for MicroElectromechanical Systems (CMEMS-UMinho), University of Minho, Campus de Azurém, 4800-058 Guimarães, Portugal 2LABBELS—Associate Laboratory, 4806-909 Braga/Guimarães, Portugal 3ALGORITMI Center, University of Minho, Campus de Azurém, 4800-058 Guimarães, Portugal 4MEtRICs, Mechanical Engineering Department, University of Minho, Campus de Azurém, 4800-058 Guimarães, Portugal 5CEFT—Transport Phenomena Research Center, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal 6ALiCE—Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal 7Advanced (Magnetic) Theranostic Nanostructures Lab, Nanomedicine Unit, INL–International Iberian Nanotechnology Laboratory, Av. Mestre JoséVeiga, 4715-330 Braga, Portugal 8Division of Engineering in Medicine, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Cambridge, MA 02139, USA *Correspondence: raquel.r[email protected] Abstract: Microneedles (MNs) have been widely used in biomedical applications for drug delivery and biomarker detection purposes. Furthermore, MNs can also be used as a stand-alone tool to be combined with microfluidic devices. For that purpose, labor organ-on-a-chip are being developed. This systematic review aims to summarize the most recent progress in these emerging systems, to identify their advantages and limitations, and discuss promising potential applications of MNs in microfluidics. Therefore, three databases were used to search papers of interest, and their selection was made following the guidelines for systematic reviews proposed by PRISMA. In the selected studies, the MNs type, fabrication strategy, materials, and function/application were evaluated. The literature reviewed showed that although the use of MNs for lab-on-a-chip has been more explored than for organ-on-a-chip, some recent studies have explored this applicability with great potential for the monitoring of organ models. Overall, it is shown that the presence of MNs in advanced microfluidic devices can simplify drug delivery and microinjection, as well as fluid extraction for biomarker detection by using integrated biosensors, which is a promising tool to precisely monitor, in real-time, different kinds of biomarkers in laband organ-on-a-chip platforms. Keywords: microfluidic; microneedles; organ-on-a-chip; lab-on-a-chip; drug screening; biomarkers detection 1. Introduction Microfluidic technology is present in lab-on-a-chip and organ-on-a-chip platforms. In order to enable high-throughput screening and automation, lab-on-a-chip (LoC) devices— also known as multitasking devices—combine many (bio)chemical laboratory operations in a single integrated chip that ranges in size from a few millimeters to a few square centimeters [ 1 ]. The most alluring benefits of these platforms are their capacity to autonomously and efficiently execute a number of lab processes on a single chip with minimal external inputs [ 2 ], as well as with low reagent consumption and high-throughput analysis [ 3 ]. To offer an in-situ and quick result for an immediate diagnosis and treatment, point-of-care testing (POCT) is required. For modern POCT diagnostic systems, sample-to-answer format, high sensitivity, and a short analysis time are the most crucial qualities. Since LoC Pharmaceutics 2023,15, 792. https://doi.org/10.3390/pharmaceutics15030792 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2023,15, 792 2 of 19 can miniaturize and combine the majority of the functional modules used in central labs into a tiny chip, LoC technologies have been regarded as one of the potential options that can satisfy the needs of POCT [ 4 ]. For example, Samper et al., 2019, describe a 3D printed chip to create a microfluidic biosensing portable system, where the data is transmitted via Bluetooth [ 5 ]. Another example is the study of Zhang et al., 2020, which demonstrated the integration of a smartphone detection into a microfluidic device (acoustofluidic platform) for hemoglobin measurement. To detect the fluorescent signal, the researchers created a quantum dot-based fluorescence test for hemoglobin and paired it with an integrated UV irradiation source and a commercial smartphone [6]. Organ-on-a-chip (OoC) platforms replicate tissue and miniaturized organs, while preserving tissue/organ-level function and homeostasis [ 7 ]. They are found on microfluidic devices with perfused chambers that range from micrometers to millimeters in size, and are fed by continuous media flow [ 8 ]. As a result of the continuous flow of cellular media, shear flow conditions and nutrient/gas exchanges, OoC can be mimicked as in vivo , extending the cell culture’s lifetime compared to static in vitro cultures [ 9 ]. Therefore, OoC can reproduce important features of the complexity of organs and biosystems [ 10 ]. Several studies in the literature use OoC to examine specific target organs, including the liver [ 11 ], heart [ 12 ], brain [ 13 ], and kidneys [ 14 ], among others. The aim of many of the OoC is to facilitate drug toxicity detection in healthy and diseased organ models. Because OoC can include patient primary human cells or stem-cell-derived cells, the OoC system has the potential to be designed as a model platform capable of predicting optimized and personalized drug treatments [ 15 ]. However, important hurdles must be overcome to create a valid and robust preclinical organ model. For that, appropriate organ scaling, tissue vascularization, recapitulation of the immunological response, repeatability, organ monitoring, oxygenation, pH, shear rate, cell viability, and cell density, are some of the parameters that need to be considered when designing an OoC [ 16 ]. Among all these features, monitoring the OoC platforms is a huge step to guarantee reproducibility and appropriate chemical, physical, and cell analysis. Therefore, OoC and LoC can be combined, especially regarding the integration of micro (bio)sensors of LoC into OoC, bringing advanced microfluidic devices into a new era. Microneedles (MNs), which are based on the concept of miniaturized needles, are increasingly used in biomedical technology. These have the ability to assess biological information with minimal invasion, and are frequently used as a strategy to deliver drugs [ 17 ], biomolecules such as proteins [ 18 ], RNA, or DNA [ 19 ] into cells with temporal and spatial precision [ 20 , 21 ]. The dimensions of MNs may vary depending on the application. The most common dimensions found in the literature have height ranges between 150 to 1500 µ m, with a base width of 50 to 250 µ m and a tip diameter of 1 to 25 µ m [ 22 ]. In terms of shape, needle tips come in a variety of shapes, including triangular, cylindrical, and pentagonal [ 23 ]. The design and size of MNs have been identified as the primary characteristics to be modified for optimal performance of an MNs system. To maximize efficiency, the length of the MN can be customized to achieve the desired depth of penetration. The shape, the number of needles in an array, the height, the aspect ratio (the ratio of the base to the height of the needle), the material, and the thickness of the backing block (if needed), are all criteria that define MN design. In addition, the volume that can be collected and loaded by the array is determined by these criteria. The volume, in turn, contributes to determining the type of MN that best suits the desired application [ 24 ]. Based on applications, MNs can be categorized into various types. MNs systems have mostly been developed for biomolecular/drug delivery and microinjection [ 25 – 32 ]. The design of the MNs device is crucial for the efficient performance of the system, and different materials can be used in MNs fabrication [ 33 ]. The two fundamental designs that are employed to construct MNs are in-plane and out-of-plane (Figure 1A). In contrast to out-of-plane MN arrays, which rise vertically from the base, in-plane MN arrays are parallel to the top fabrication surface [ 34 ]. Typically, due to the numerous microstructures and variety of strategies for the delivery of drugs, MNs are divided into two main categories: traditional needles (solid, coated, or hollow), and emerged needles (dissolving, Pharmaceutics 2023,15, 792 3 of 19 hydrogel-forming) [ 35 ]. In terms of materials, MNs can be divided into degradable and non-degradable materials, such as metal, silicon, ceramic and carbon for non-degradable and natural polymers for degradable ones [ 36 , 37 ]. Figure 1B represents the two main categories with the approaches of the six most used MNs. A more comprehensive review of these MNs structural strategies can be found elsewhere [38]. Pharmaceutics 2022, 14, x FOR PEER REVIEW 3 of 19 In contrast to out-of-plane MN arrays, which rise vertically from the base, in-plane MN arrays are parallel to the top fabrication surface [34]. Typically, due to the numerous microstructures and variety of strategies for the delivery of drugs, MNs are divided into two main categories: traditional needles (solid, coated, or hollow), and emerged needles (dissolving, hydrogel-forming) [35]. In terms of materials, MNs can be divided into degradable and non-degradable materials, such as metal, silicon, ceramic and carbon for non-degradable and natural polymers for degradable ones [36,37]. Figure 1B represents the two main categories with the approaches of the six most used MNs. A more comprehensive review of these MNs structural strategies can be found elsewhere [38]. Figure 1. Schematic representation of MNs. (A) (i) out-of-plane and (ii) in-plane construction. (B) Traditional and emerging MNs structuring approaches according to drug delivery application. Concerning the fabrication methods, several have been described in the literature, but the most commonly used are micro-molding, microfabrication technologies (e.g., lithography, laser, etching), additive manufacturing (i.e., 3D printing), and layer-by-layer assembly [39]. Briefly, microfabrication can also be divided into three main processes: deposition, patterning, and etching. Deposition includes film formation by physical vapor deposition or chemical vapor deposition. The patterning technique shapes the desired geometry on a film, substrate, or wafer. Lithography is a common technique used for patterning, which consists in transferring the mask into a coated photosensitive film using light to develop the exposed photoresist. Although lithography allows the production of smaller feature sizes, it is considered a more complex process that requires high-tech infrastructures and equipment [40]. Etching is a technique that involves removing the unprotected sections of the substrate with a strong caustic chemical to create a microneedle design of interest. A wet or dry etching technique can be used, but the use of chemicals are required, which can contaminate the samples [41]. Laser ablation and laser cutting are also reported to be used to fabricate metal and polymeric MNs. Laser ablation removes material from a solid surface by irradiating it with a laser beam [42]. Laser cutting uses an infra-red laser to cut metallic sheets in the shape of MNs [43]. Both techniques are simple, quick and precise, with no contaminations, but require higher power consumption. Micromolding is used to fabricate various polymeric MNs using cutting tools to sculpt the mold. Afterwards, the polymeric material that comprises the MN is poured into the micro-mold in a liquid or semi-liquid state and then solidified to achieve the desired shape. It is a simple, low-cost, versatile process with high-resolution [44,45]. More recently, 3D printing has also emerged as a process to produce MNs with the potential to simplify the fabrication of multilayer and materials in a few steps [46]. Figure 1. Schematic representation of MNs. ( A ) ( i ) out-of-plane and ( ii ) in-plane construction. ( B ) Traditional and emerging MNs structuring approaches according to drug delivery application. Concerning the fabrication methods, several have been described in the literature, but the most commonly used are micro-molding, microfabrication technologies (e.g., lithography, laser, etching), additive manufacturing (i.e., 3D printing), and layer-by-layer assembly [ 39 ]. Briefly, microfabrication can also be divided into three main processes: deposition, patterning, and etching. Deposition includes film formation by physical vapor deposition or chemical vapor deposition. The patterning technique shapes the desired geometry on a film, substrate, or wafer. Lithography is a common technique used for patterning, which consists in transferring the mask into a coated photosensitive film using light to develop the exposed photoresist. Although lithography allows the production of smaller feature sizes, it is considered a more complex process that requires high-tech infrastructures and equipment [ 40 ]. Etching is a technique that involves removing the unprotected sections of the substrate with a strong caustic chemical to create a microneedle design of interest. A wet or dry etching technique can be used, but the use of chemicals are required, which can contaminate the samples [ 41 ]. Laser ablation and laser cutting are also reported to be used to fabricate metal and polymeric MNs. Laser ablation removes material from a solid surface by irradiating it with a laser beam [ 42 ]. Laser cutting uses an infra-red laser to cut metallic sheets in the shape of MNs [ 43 ]. Both techniques are simple, quick and precise, with no contaminations, but require higher power consumption. Micro-molding is used to fabricate various polymeric MNs using cutting tools to sculpt the mold. Afterwards, the polymeric material that comprises the MN is poured into the micro-mold in a liquid or semi-liquid state and then solidified to achieve the desired shape. It is a simple, low-cost, versatile process with high-resolution [ 44 , 45 ]. More recently, 3D printing has also emerged as a process to produce MNs with the potential to simplify the fabrication of multilayer and materials in a few steps [46]. Overall, the microfabrication techniques to produce MNs and microfluidic devices are identical. Hence, it is expected that microfluidic devices and MNs can be easily combined using those fabrication techniques and in this way to create, in a synergetic way, an advanced microfluidic device for drug screening and/or organ models monitoring [ 47 , 48 ]. Based on this expectation, the present systematic review aims to provide a broad vision on the state-of-the-art of MNs combined with lab and/or organ-on-a-chip, especially focusing on the MNs type, fabrication strategy, materials, and function/applications. Pharmaceutics 2023,15, 792 4 of 19 2. Materials and Methods This work was conducted taking into account the research guidelines for systematic reviews proposed by PRISMA [49,50]. 2.1. Data Sources and Search Strategy The search was performed using three different databases: ScienceDirect, PubMed and Scopus, until the 1st of December 2022. The search string used was (“organoids” OR “organ-on-a-chip” OR “organ on a chip”) AND (“microneedle (s)”) AND (”lab-on-a-chip” OR “microfluidics” OR lab on a chip”) AND (“microneedle (s)”). 2.2. Validity Assessment Review articles, conference papers, short communications, and non-English written articles were removed from the search results, either manually or using the filters from the database. After the elimination of duplicates, the articles were selected based on the relevance of their title in the context of this review. Further screening was performed to evaluate which paper presented the defined inclusion or exclusion criteria presented below. To avoid biases, the two first authors screened and selected the research papers separately and then compared the classifications. Disagreements or doubts regarding the classification were solved by a third author. 2.3. Inclusion and Exclusion Criteira The studies included in this review followed the criteria: •Published since 2000; •Use of microfluidic platforms or organs-on-a-chip in combination with MNs; •Use of microfluidic platforms or lab-on-a-chip in combination with MNs; •MNs for media/ISF collection; •MNs for cell injection; •MNs for biomarkers detection. • MNs for biofluid extraction, microneedle sensors, and analyte-capturing MNs, or combinations thereof. The study did not present the excluded criteria. 3. Results 3.1. Data Collection Results As previously mentioned, the authors followed the PRISMA-recommended guidance to conduct systematic reviews. Based on the title, 91 potentially relevant articles were identified from the three databases selected. In total, 80 studies were included after removing duplicates. After the evaluation of abstracts, 24 articles were dismissed due to a lack of data and different study strategies; thus, 56 full papers were analyzed. In the end, a total of 35 full-text articles were selected. Figure 2shows the PRISMA flow chart for the selection process of studies incorporated in this systematic review. Additionally, a metadata analysis was carried out using the Scopus database with the searched keywords “MNs + microfluidic” and “MNs + organ-on-a-chip” and “MNs + lab-on-a-chip” between 2000 (the year of the first work reported in the literature) and 2022, which shows a total sum in this period of 82 papers (67 articles and 15 reviews) (Figure 3). Among the included studies, 30% corresponded to studies that have addressed the integration of MNs into microfluidic devices. The number of publications tended to increase over the past 20 years, where the majority of the publications were original research articles. This reflects researchers’ increased interest in combining MNs with lab/organ-on-a-chip. Among the most published areas were Engineering, Material Sciences, and Physics and Astronomy, representing a total of 63.4%. Based on the selected articles from the defined criteria, 36 works were included in this systematic revision, which had as main topic MNs applied in advanced microfluidic Pharmaceutics 2023,15, 792 5 of 19 devices (i.e., lab/organ-on-a-chip), and subdivided into two main applications: (1) devices for extraction and biomarker detection, and (2) devices for drug delivery and microinjection, as follows in the sub-chapter. Pharmaceutics 2022, 14, x FOR PEER REVIEW 5 of 19 Figure 2. PRISMA flow diagram displaying the procedure of study selection. Additionally, a metadata analysis was carried out using the Scopus database with the searched keywords “MNs + microfluidic” and “MNs + organ-on-a-chip” and “MNs + lab-on-a-chip” between 2000 (the year of the first work reported in the literature) and 2022, which shows a total sum in this period of 82 papers (67 articles and 15 reviews) (Figure 3). Figure 3. Metadata analysis of the keywords “MNs + microfluidic” and “MNs + organ-on-a-chip” and “MNs + Lab-on-a-chip” between 2000 and 2022. (A) Number of publications per combined years. (B) Documents by subject area. Among the included studies, 30% corresponded to studies that have addressed the integration of MNs into microfluidic devices. The number of publications tended to increase over the past 20 years, where the majority of the publications were original research articles. This reflects researchers’ increased interest in combining MNs with lab/organ-ona-chip. Among the most published areas were Engineering, Material Sciences, and Physics and Astronomy, representing a total of 63.4%. Figure 2. PRISMA flow diagram displaying the procedure of study selection. Pharmaceutics 2022, 14, x FOR PEER REVIEW 5 of 19 Figure 2. PRISMA flow diagram displaying the procedure of study selection. Additionally, a metadata analysis was carried out using the Scopus database with the searched keywords “MNs + microfluidic” and “MNs + organ-on-a-chip” and “MNs + lab-on-a-chip” between 2000 (the year of the first work reported in the literature) and 2022, which shows a total sum in this period of 82 papers (67 articles and 15 reviews) (Figure 3). Figure 3. Metadata analysis of the keywords “MNs + microfluidic” and “MNs + organ-on-a-chip” and “MNs + Lab-on-a-chip” between 2000 and 2022. (A) Number of publications per combined years. (B) Documents by subject area. Among the included studies, 30% corresponded to studies that have addressed the integration of MNs into microfluidic devices. The number of publications tended to increase over the past 20 years, where the majority of the publications were original research articles. This reflects researchers’ increased interest in combining MNs with lab/organ-ona-chip. Among the most published areas were Engineering, Material Sciences, and Physics and Astronomy, representing a total of 63.4%. Figure 3. Metadata analysis of the keywords “MNs + microfluidic” and “MNs + organ-on-a-chip” and “MNs + Lab-on-a-chip” between 2000 and 2022. ( A ) Number of publications per combined years. (B) Documents by subject area. 3.2. MNs Applied in Advanced Microfluidic Devices An increased research effort has been focused on the use of MNs for direct or indirect sensing. This new trend has germinated naturally from former efforts of the use of MNs for OoC and LoC devices. As is possible to observe in Table 1, the majority of the applications of MNs in the microfluidic field are LoC approaches (approximately 89% of papers analyzed). Generally, an MN array is connected to a reservoir to serve as an interstitial fluid (ISF) absorption device or connected with a reservoir to serve as drug storage to release drugs. Hollow MNs are regarded as the best choice for extract/release systems, since they provide the exact amount of drug needed at the desired location in a faster and controlled way. Therefore, hollow MNs are the most common type of MN employed in microfluidic devices, mostly made of silicon, but metals and glass are also used (Table 1). Such devices act as a conduit to access dermal biofluids for on-chip analysis in microfluidic chambers [ 51 ]. However, besides hollow MNs, the application of porous and solid MNs in microfluidic devices are also established (Table 1). To identify the presence of a particular target analyte, microneedle-based biofluid extraction products are mainly combined with downstream analytical techniques [ 52 ]. For example, Wang et al., 2021 explored an MN patch for fast in vivo sampling and on-needle Pharmaceutics 2023,15, 792 6 of 19 quantification of target protein biomarkers [ 53 ]. Microneedle-based in vivo sensors have been used in diagnostic systems functioning as electrodes, particularly for glucose testing [ 54 ]. To overcome the gap between extracting ISF and further analysis, some authors proposed solutions that incorporate the biosensor on the patch of porous MNs [ 55 ]. For example, Kusama et al., 2021, proposed a porous MNs patch combined with anodes and cathodes for efficient drug delivery (penetration) and analysis (extraction) [56]. Ultimately, MNs systems can provide results and detect different biomarkers in realtime, which can be used to monitor in vivo tissues, or in vitro organoids and cell cultures. The main advantage of MNs is that they can be repeatedly used to collect cellular contents without causing cell lysis. They may also promote a decrease in lateral diffusion [57]. Overall, studies show that MNs are mainly used in microfluidic applications for biomarker detection [ 58 – 68 ], cargo delivery [ 69 – 73 ], and cell microinjection [ 74 , 75 ]. Table 1 shows the types of MNs, materials, applications and hydrodynamic forces used in microfluidic devices. The works reviewed show that MNs are designed in two configurations, in-plane and out-of-plane (as shown in Figure 1A). An in-plane MN configuration enables the manipulation of the length and shape of MNs and the time required to produce it. It simplifies the integration into an embedded microfluidic network resulting in a device with fewer layers and steps process. Parameters, such as mechanical rigidity, can be easily tailored by varying the subtract thickness or width of MNs [ 76 – 78 ]. As a result, these MNs are often longer than out-of-plane MNs [ 79 ]. Out-of-plane MNs can also enhance the efficiency of drug delivery/fluid extraction by increasing the MN array density. However, achieving a higher length is more difficult because of the risk of clogging and collapsing [58,80,81]. Another interesting aspect in the design and application of MNs in microfluidic devices is the type of hydrodynamic force mechanism employed, which can be passive, such as capillary force, or active, such as by using micropumps. For instance, the detection of analytes in fluids may be facilitated by the use of capillary action in a microneedle-assisted biosensing [ 82 ]. In this case, capillary forces can propel the fluid to/from the reservoir and then to a biosensor platform. However, in some cases a micropump can be requested to supply specified volumes at higher flow rates, which in turn adds more complexity to the system [ 83 ]. Nevertheless, in many designs, capillary forces are enough and allow the liquid to flow through the MNs on its own, simplifying the manufacture and use of the device [84]. When natural hydrodynamic forces, such as capillary, are not enough, other components such as pumps, valves, and bubble traps must be combined in order to achieve the system. This, as already mentioned, can be challenging from a fabrication and integration standpoint [59]. In some revised works, planar micropumps were used because of their advantage in being simple to integrate and having the ability to change the flow operation (extraction/injection) by just flipping the valve direction. For LoC devices with in-plane MNs, this approach is further explored [60,70], although leaks between the inlet and outlet can occur. Regarding fabrication strategies and materials, typically porous MNs are fabricated using a PDMS mold followed by a leaching method to remove the porogenic casted materials [ 61 , 62 ], or by using a microfabrication process to directly obtain the MNs’ structure, followed by leaching [ 64 ]. The majority of solid MNs are built of metallic components or silicon, or a combination of both [ 65 , 73 , 85 ]. In the studied papers, the solid MNs were produced through micromachining processes, including the use of SU-8 photoresist. On the other hand, coated MNs are in general solid MNs that suffer a process of coating. For example, Trzebinski et al., 2012, developed a microfluidic device with enzyme-coated MNs by immersing the MNs in a solution with the desired enzyme [ 67 ]. Kang et al., 2021 used a silicon-coated MN with Cr/Au by deposition [ 71 ]. In contrast, different types of lithography are commonly used in the case of hollow MNs [ 63 , 86 , 87 ]. Deep reactive ion etching (DRIE) and sacrificial layer sharpening are two other techniques that have been extensively researched in MNs and used in the investigated microfluidic devices [70,74–78,81] . New fabrication processes, such as 3D printing, are starting to be developed as well. A comprehensive review concerning this fabrication methodology for the design of MN for biomedical application can be found elsewhere [88]. Pharmaceutics 2023,15, 792 7 of 19 Table 1. Reviewed MNs-based systems concerning MN type, MN–chip connection, fabrication strategy, material, employed hydrodynamic force, function, application and microfluidic system. MNType In/Out-ofPlane MN–Chip Connection Fabrication Strategy Material Chip/MN Forces Function Application Microfluidic System Reference Porous MNs Out-of-plane MN integrated in the inlets of the microdevice Microfabrication + Leach method Polylactic acid (PLA)/PDMS Pump Biomarker detection ISF collection and glucose detection Lab-on-a-chip [61,62] Porous MNs Out-of-plane Integrated as MN patch Mold + Leach method PDMS/Ethoxylated trimethylolpropane triacrylate (ETPTA) Capillary Action Biomarker detection Extraction and detection of skin interstitial fluid biomarkers Lab-on-a-chip [64] Solid MNs Out-of-plane MN integrated in the inlets of the microdevice Microfabrication (SU-8) PDMS/SU-8 Pressure Drug delivery Delivery functions for inflammation treatment Lab-on-a-chip [73] Solid MNs In-of-plane MN integrated perpendicular to the microfluidic channel Microfabrication Oxide layer + metallic layer/Silicon -Biomarker Detection Microneedle biosensor for direct label-free real-time protein detection Lab-on-a-chip [65] Solid MNs Out-of-plane MN integrated perpendicular to the microfluidic channel -PDMS/Tungsten + parylene Syringe pump Cell Detection Detection of cells in suspension Lab-on-a-chip [85] Coated MNs Out-of-plane MN integrated above microfluidic channel Microfabrication PDMS/Silicon + Cr/AU Capillary Forces Delivery Chemical delivery capability Lab-on-a-chip [71] Coated MNs Out-of-plane MN integrated above chamber Microfabrication (two-photon lithography) PDMS/Gold + enzyme layer Syringe pump Biomarker detection/Biosensor 3D microspike array-based glucose and lactate biosensor Lab-on-a-chip [67] Coated MNs Out-of-plane MN integrated above microfluidic channel SU-8 PDMS/SU-8 resin Syringe pump Biomarker detection/Biosensor Drug delivery and body fluid sampling applications Lab-on-a-chip [68] Hollow MNs Out-of-plane MN integrated above microfluidic channel Microfabrication - Micropump Biomarker detection Nonenzymatic microfluidic glucose sensor Lab-on-a-chip [60] Pharmaceutics 2023,15, 792 8 of 19 Table 1. Cont. MNType In/Out-ofPlane MN–Chip Connection Fabrication Strategy Material Chip/MN Forces Function Application Microfluidic System Reference Hollow MNs Out-of-plane MN integrated in organoid chamber Microfabrication (Photolithography) PMMA/Silicon Pneumatic interface Biomarker detection Microfluidic sampling system for tissue analytics Organ-on-a-chip [87] Hollow MNs Out-of-plane MN integrated above microfluidic channel Microfabrication Pyrex/Silicon Capillary action and evaporation Biomarkerdetection Microneedlebased glucose monitor Lab-on-a-chip [58] Hollow MNs Out-of-plane MN integrated above microfluidic channel Microfabrication/ DRIE Aluminum + Silicon/Silicon Capillary forces Extraction ISF extraction Lab-on-a-chip [81] Hollow MNs Out-of-plane MN integrated above microfluidic channel Microfabrication (two-photon lithography) PDMS/Eshell 300 Pump Analysis Sensor for on-chip potentiometric determination of K+ Lab-on-a-chip [63] Hollow MNs Out-of-plane MN integrated perpendicular to the microfluidic channel Soft lithography PDMS + SU-8/Glass Valve actuation Micro-injection Single cells microinjection system Organ-on-a-chip [74] Hollow MNs Out-of-plane MN integrated above microfluidic channel Direct laser writing PMMA/Photosensitive material Syringe Extraction/ delivery A system for fluid injection and extraction Lab-on-a-chip [86] Hollow and sharp MNs Out-of-plane MN integrated above microfluidic channel Laser Ablation Glass/SU-8 Syringe pump Perfusion 3D micro perfusion system Organ-on-a-chip [89] Hollow MNs Out-of-plane Integrated as MN patch Soft lithography PDMS/metal Pressure Extraction Extraction and transport of blood Lab-on-a-chip [90] Hollow MNs Out-of-plane Integrated as MN patch Soft lithography PDMS + paper sensor Pressure Biomarker detection POCT biosensors for quantification of glucose and cholesterol in blood Lab-on-a-chip [66] Hollow MNs Out-of-plane MN integrated perpendicular to the microfluidic channel 3D printing + DRIE PDMS/Glass Vacuum pump Microinjection Microfluidic device for localized microinjection Lab-on-a-chip [75] Pharmaceutics 2023,15, 792 9 of 19 Table 1. Cont. MNType In/Out-ofPlane MN–Chip Connection Fabrication Strategy Material Chip/MN Forces Function Application Microfluidic System Reference MN with open capillary In-plane Connected with microfluidic device DRIE + photolithography Silicon Pressure Insertion into skin Extraction/delivery Lab-on-a-chip [76,77] MN with open capillary In-plane Connected with microfluidic device DRIE + photolithography Titanium Pressure Insertion into skin Extraction/delivery Lab-on-a-chip [78] MN with open capillary In-plane Connected with microfluidic device MEMS + glass cover on silicon technology Silicon Syring pump Drug Infusion System for brain drug infusion Lab-on-achip/organ-on-achip [72] MN with open capillary In-plane Connected with microfluidic device MEMS + DRIE Silicon Planar Micropump Drug Delivery Continuous on-chip micropumping for microneedle enhanced drug delivery Lab-on-a-chip [70] Pharmaceutics 2023,15, 792 16 of 19 for Research with the support of FCT, AY2022/2023. R.O.R. thanks FCT for her contract funding provided through 2020.03975.CEECIND. The authors also acknowledge the partial financial support within the R&D Unit Project Scope: UIDB/04436/2020, UIDB/04077/2020, UIDB/00532/2020, LA/P/0045/2020. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. References 1. Patabadige, D.E.W.; Jia, S.; Sibbitts, J.; Sadeghi, J.; Sellens, K.; Culbertson, C.T. Micro Total Analysis Systems: Fundamental Advances and Applications. Anal. Chem. 2016,88, 320–338. [CrossRef] 2. Lafleur, J.P.; Jönsson, A.; Senkbeil, S.; Kutter, J.P. Recent advances in lab-on-a-chip for biosensing applications. Biosens. Bioelectron. 2016,76, 213–233. [CrossRef] [PubMed] 3. Mohammed, M.I.; Haswell, S.; Gibson, I. Lab-on-a-chip or Chip-in-a-lab: Challenges of Commercialization Lost in Translation. 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