Toward next-generation smart medical care wearables: where microfluidics meet microneedles

Abstract

The integration of microneedles (MNs) with microfluidic platforms has emerged as a transformative approach for developing next-generation smart wearable devices aimed at precise drug delivery and real-time physiological monitoring. This review introduces a multifunctional wearable device that combines the minimally invasive penetration of MNs with the dynamic fluid manipulation capabilities of microfluidics to enhance wound care and chronic disease management. We systematically examine recent advancements in materials, structural design, and manufacturing techniques that enable this integration, highlighting the role of porous, hollow, and bioinspired microneedles in synergistic drug administration and biosensing. By leveraging microfluidic control, these devices enable autonomous therapeutic modulation and high-resolution biomarker detection with potential for closed-loop feedback systems. This convergence of MNs and microfluidics paves the way for intelligent, personalized healthcare solutions with broad applicability beyond wound healing, including telemedicine, chronic condition management, and on-demand therapy.

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1. Introduction

In recent years, fully integrated smart wearable platform combining microneedles (MNs) with microfluidic systems has recently emerged as a promising solution for next-generation biomedical applications, particularly in wound management and chronic disease monitoring.^1–5 These hybrid devices leverage the minimally invasive nature of MNs and the precise fluid manipulation capabilities of microfluidics to achieve dual functionality—real-time biosensing and controlled drug delivery—within a single compact system. This integration marks a significant advancement in personalized medicine by enabling continuous health monitoring and responsive therapeutic intervention without the need for traditional invasive procedures.^6–13

Over the past decade, extensive research has been devoted to developing microneedle-based transdermal systems and flexible microfluidic devices. Microneedles have evolved from simple solid structures for passive delivery to complex porous, hollow, and bioinspired architectures capable of active sensing and programmable release.^14–16 Similarly, microfluidic systems have transformed from rigid lab-on-chip platforms into soft, stretchable, and skin-conformal devices compatible with long-term wear. However, integrating these technologies into a unified platform remains challenging, due to trade-offs between mechanical robustness, biocompatibility, fabrication scalability, and multifunctionality.^17,18

Previous reviews have primarily examined microneedles or microfluidic wearables as isolated technologies, focusing on specific aspects such as sweat analysis, glucose monitoring, or polymeric microneedle design.^19–23 Yet, there is a critical need for a comprehensive review that addresses the multidimensional convergence of these systems—including structural integration, material innovation, smart actuation, and biosensor interface—especially as the demand for intelligent wound care and decentralized diagnostics continues to rise.^24–28

In this review, we present an in-depth analysis of recent developments in microfluidic smart wearables based on microneedles. We begin by introducing various MN architectures—such as hollow, porous, arrayed, composite, and bioinspired structures—and their roles in enabling multifunctional capabilities. Next, we examine material strategies for MN fabrication, including metals, natural polymers, and synthetic polymers, and how these materials affect mechanical performance, fluid compatibility, and biological interactions. We then explore advanced manufacturing techniques, such as 3D printing, photolithography, and laser micromachining, that facilitate the integration of MNs with microfluidic channels.^29–37 Finally, we highlight the biomedical applications of MN-based wearables in wound healing, biosensing, closed-loop drug delivery, and AI-assisted diagnostics (Table 1), while also discussing ongoing challenges and future research directions.^23,38–43

Table 1 Summary of the characteristics of the MN Patches

Material		Structure	Fabrication method	Microfluidic	Application	Advantages	Disadvantages or limitations	Ref.
Metals	Stainless steel and titanium	Solid microneedles, hollow microneedles and porous microneedles	Laser cutting, electrochemical etching and microcasting	Precision drug release and fluid guidance	Biosensing, drug delivery, disease diagnosis	Metal microneedles offer superior mechanical strength, durability and precise control of drug delivery and biosensing	Facing challenges related to biocompatibility, manufacturing complexity and potential skin irritation	47 and 48
Single substance	Silicon	Sharp conical or arrayed structures	Photolithography, deep reactive ion etching, molding, laser etching and nanoimprinting	Precision drug release and fluid guidance	Drug delivery, vaccination and sensor technology	High mechanical strength and precision	More brittle, difficult to degrade and more expensive to manufacture	49
Natural polymers	Alginate	Tapered microneedles, hollow microneedles, microneedle arrays	Electrostatic spinning, rolling microneedles	Passive diffusion, capillary action, dissolution-controlled release, and pressure-driven hollow microneedles	Transdermal drug delivery, biosensing and smart wound care	Highly biocompatible, degradable and suitable for hydrogel microfluidics	Low mechanical strength, easy to dissolve and deform	50
	Silk proteins, recombinant arachnid protein				Precision drug delivery, biofluid harvesting and flexible biosensors, suitable for smart wearable devices	High mechanical strength, controlled degradation, suitable for flexible microfluidics	Complex preparation process, limited dissolution rate.	51–56
	Deacetyl chitosan				Antimicrobial therapy, tissue engineering and electrochemical biosensing for chronic wound management and infection control	Antimicrobial, biocompatible, can incorporate electrochemical sensing	Dissolution rate is unstable and susceptible to pH	57
	Prolamins		Microfluidic spinning		Healing of a wound	Excellent biocompatibility, biodegradability and adjustable mechanical properties	Mechanical strength may be limited and degradation is slow	58
	Hyaluronic acid	Solid, hollow, multilayer composite, dissolution or light-cured stent structures	Mold casting, microfluidic photocuring, 3D printing	Material tunability and microfluidic design	Degradable microneedle arrays	Good biocompatibility, high degradability and modulation of drug release	Low mechanical strength, complex preparation process and stability affected by environmental factors	38 and 59–61
Artificial polymers	Polylactic acid (PLA)	Solid, hollow, multilayer composite, dissolution or light-cured stent structures	Mold casting, microfluidic photocuring, 3D printing	Material tunability and microfluidic design	Hollow microneedles loaded with microfluidic channels, osmotic control systems and microfluidic sensors	Biodegradable and mechanically strong for long-acting drug release	May affect drug release efficiency	62 and 63
	Polyethylene glycol diacrylate (PEGDPA)					High hydrophilicity and rapid light-curing, suitable for loading hydrophilic drugs	Low mechanical strength	64
	Dissolvable polyvinylpyrrolidone (PVP)	Solid microneedles, core–shell microneedles, porous microneedles	Solvent casting-centrifugation, micromolding, photopolymerization, electrospinning-template	Laminar flow focusing, droplet microfluidics,	Efficient delivery of vaccines, insulin, anticancer drugs and cosmetic active ingredients, achieving painless transdermal drug delivery	High solubility, flexible drug loading, good biocompatibility	Low mechanical strength	65–69

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By providing a comprehensive overview of the interdisciplinary advances in this field, we aim to guide researchers toward the design and development of next-generation intelligent wearable systems capable of revolutionizing real-time healthcare monitoring and treatment (Fig. 1).^44–46

Fig. 1 Next-generation wearables: integration of microneedles and microfluidics. Reproduced with permission.⁸⁹ Copyright 2021, Elsevier.¹¹⁴ Copyright 2021, IEEE.¹²⁵ Copyright 2022, Elsevier.¹¹⁸ Copyright 2023, ACS.⁸⁹ Copyright 2021, Elsevier. Created with BioRender.com.

2. Next generation microneedle types

As microneedle technologies continue to mature, next-generation designs are being developed to overcome the limitations of conventional microneedles and expand their functional capabilities. These advanced microneedle types incorporate novel structures, responsive materials, and multifunctional features to enable dynamic drug delivery, real-time biosensing, and enhanced patient compliance. By leveraging innovations in materials science, microfabrication, and bioengineering, these new designs aim to address unmet clinical needs and unlock broader applications in personalized medicine, minimally invasive diagnostics, and smart therapeutics.

2.1. Hollow microneedles

Hollow microneedles are arrays of microneedles with micrometer-sized pore structures that are able to penetrate the stratum corneum of the skin and directly access subcutaneous tissues for drug delivery or biofluid harvesting.⁷⁰ Their structures are usually made of biocompatible materials and processed by micro-molding technology or photolithography. The advantage of hollow microneedles is their microporous design, which allows liquid drugs or biofluids (e.g., interstitial fluids) to flow by capillary action or negative pressure actuation, thus avoiding the pain and invasiveness of conventional injections. For example, Ye⁷¹ developed a tip-hollow microneedle array to form micro-pit structures during micromolding by adjusting the vacuum level (−80 kPa), enabling efficient drug loading and delivery.

In microfluidic applications, hollow microneedles are often integrated with microfluidic chips to form a closed-loop sampling and detection system. The microfluidic channel delivers the collected biofluid to the sensing region through negative pressure or capillary force, which is combined with optical or electrochemical detection techniques to achieve instantaneous analysis. Xiao designed a microfluidic plasma microneedle sensor that utilizes an array of hollow microneedles to collect interstitial fluids, and then delivers the samples through the microfluidic channel to the surface enhanced Raman scattering (SERS) sensing chip, which achieves a uric acid highly sensitive detection of uric acid (detection limit 0.51 μM) (Fig. 2a and b).⁷² This integrated design not only simplifies the sample handling steps, but also improves the portability and accuracy of the assay.

Fig. 2 (a) Scanning electron microscope (SEM) image of the hollow microneedle array. (b) Optical images of the hollow microneedle array. Reproduced with permission.⁷² Copyright 2024, Elsevier. (c) SEM images of the porous MN patch; (d) SEM images revealed the porous channels distributed on the porous MN patch. Reproduced with permission.⁷⁴ Copyright 2022, Wiley. (e) Monolithic fabrication of microneedles in various height distributions on a single wafer. A photomask design for a convex microneedle array and (f) SEM images of the fabricated convex microneedle array. Reproduced with permission.⁷⁶ Copyright 2022, Springer Nature. (g) Fluorescence images of DL-AMNB fabricated by a double-casting method under backside vacuum. (h) FITC and rhodamine B were loaded into SF and MAP-BFP prehydrogel solutions, respectively. Reproduced with permission.⁸⁴ Copyright 2021, Elsevier. (i) Biomimetic inspiration: (i) the cat tongue is a backward-facing, barb-shaped prick. (ii) Magnified view of the prick's intricate structure. (iii) Schematic illustrating the angular arrangement of the prick on the cat's tongue. (j) Fabrication program and structure of the TPMNs. Reproduced with permission.⁸⁷ Copyright 2025, Wiley. (k) Schematic of a microneedle patch with an eagle claw clamping structure with liquid metal encapsulation. The schematic shows that the microneedle patch can tighten the injured area and prevent cracking. Reproduced with permission.⁸⁹ Copyright 2021, Elsevier.

Microfluidic applications of hollow microneedles show great potential in personalized medicine and real-time monitoring. For example, in diabetes management, insulin can be precisely delivered via hollow microneedles; and in metabolite monitoring, microfluidic systems enable continuous analysis of multiple biomarkers (e.g., uric acid, glucose). In the future, with the advancement of material science and micro–nano-processing technology, hollow microneedles and their microfluidic systems will further develop towards multifunctionalization, intelligence and wireless transmission, providing more efficient solutions for disease diagnosis and treatment.

2.2. Porous structure

Porous microneedles are micrometer-sized needle arrays with an internal pore structure, which are prepared by methods such as template replication and UV polymerization, usually based on materials such as polyethylene glycol diacrylate (PEGDA).⁶⁴ The porous structure endows the microneedles with extremely high specific surface area and continuous pore channels, which facilitate efficient loading and release of active molecules.⁷³ For example, porous MOF microneedles utilize pores for deep delivery of NO by encapsulating NO@HKUST-1@GO particles (NHGs) and achieve controllable release through near-infrared (NIR) photothermal responses (Fig. 2c and d).⁷⁴ The mechanical strength of the porous microneedles can be optimized by adjusting the PEGDA concentration to ensure that they can penetrate the skin while maintaining structural integrity, thus demonstrating excellent transdermal delivery in scenarios such as diabetic wound healing.

The pore structure of porous microneedles can be used as microfluidic channels for targeted fluid delivery and response modulation. For example, by combining microfluidics with porous microneedles, micrometer-sized reaction chambers can be formed inside the tip for real-time monitoring or delivery of biomolecules. The porous MOF microneedles in the literature have been confirmed by nitrogen adsorption experiments for their mesoporous properties (average pore size of 107.6 Å), which not only facilitates the adsorption and release of NO, but can also be extended as microreactors in microfluidic systems for controlled exchange of gases or liquids. In addition, the hydrophobicity modulation of porous microneedles (contact angle <45°) further enhances their compatibility with biofluids, providing an ideal platform for microfluidic integration.

Another key application of porous microneedles in microfluidic systems is to synergize photothermal response with drug release.⁷⁵ Graphene oxide (GO)-coated NHGs generate localized warming (42 °C) under NIR irradiation, triggering on-demand release of NO, a “switching” effect that can be precisely regulated by the microfluidic system. The porous structure not only enlarges the drug loading capacity, but also optimizes the molecular diffusion kinetics through the microfluidic channel, such as the significant time-dependence of NO release rate under intermittent NIR irradiation. This design provides new ideas for the development of smart microfluidic delivery systems, such as dynamic dose modulation or time-sequential therapy, with great potential especially in chronic wound management or personalized medicine.

2.3. Microneedle arrays

Microneedle arrays are high-density, micron-scale needle-like structures, usually made of silicon or other biocompatible materials, with a wide range of controllable heights and cross-sectional shapes. Roh and colleagues (Fig. 2e and f)⁷⁶ achieved microneedle arrays with densities as high as 625 needles per square millimeter by a single photolithography and a two-step deep reactive ion etching (DRIE) process with microneedle heights flexibly tunable by photomask design. This structure exhibits extremely low insertion force when penetrating tissues and is suitable for applications such as neural signal recording and drug delivery.⁷⁷ The sharp tips and diverse cross-sectional shapes of the microneedles further optimize their penetration performance and reduce tissue damage.

In microfluidic applications, microneedle arrays can be used as efficient fluid delivery interfaces for precise localized drug delivery or biofluid sampling. By integrating microneedles with microfluidic channels, controlled transdermal drug delivery systems can be constructed to deliver drugs directly to the epidermis or dermis, avoiding the pain problem of traditional injections.^78,79 For example, sericin protein microneedle arrays prepared by a molding process demonstrate the potential of biodegradable materials for microfluidic drug delivery. In addition, the high-density nature of microneedles allows them to target multiple tissue regions simultaneously, enhancing delivery efficiency.

The combination of microneedle arrays and microfluidics also expands their applications in biosensing and neural engineering.⁸⁰ High-density microneedle electrodes can be used to record or stimulate neural signals, while microfluidic channels are responsible for delivering electrolytes or drugs in real time, forming a closed-loop system. Convex or irregularly height-distributed arrays of microneedles, capable of adapting to complex three-dimensional tissues (e.g., cerebral cortex), provide new design ideas for neural interface devices. This integrated system not only improves the spatial resolution, but also reduces the external interference through the precise control of microfluidics, offering the possibility of personalized medicine and real-time monitoring.⁸¹

2.4. Multilayer composites

The composite structure of microneedles is usually constructed from multiple functional materials by layering or blending to synergistically optimize mechanical properties, drug-carrying capacity and biocompatibility.⁸² Typical composite designs include a rigid support layer to ensure puncture capability and a functional drug-carrying layer for drug loading and controlled release. By modulating the mechanical properties, degradation rate and interfacial bonding of each layer, composite microneedles are able to adapt to different tissue environments and achieve long-term therapeutic functionality while maintaining structural integrity.⁸³ This modular design provides a highly customizable platform for diverse applications of microneedles (Fig. 2g and h).⁸⁴

Composite microneedles can be used as miniature fluidic interfaces for precise drug delivery or biological sampling. For example, hydrophobic–hydrophilic composite microneedles can guide the directional flow of intertissue fluids through capillary action, while hollow microneedles combined with microfluidic channels can build active delivery systems.⁸⁵ The solubility or degradability of the composite structures can also be used to modulate fluid resistance for on-demand release. In addition, the integration of conductive materials into microneedles allows for the development of electroosmotic flow or electroporation-assisted microfluidic systems, which significantly enhance the delivery efficiency of macromolecular drugs. These properties make composite microneedles a key component in connecting macroscopic drug delivery devices with microscopic physiological environments.⁸⁶

In the future, the integration of composite microneedles and microfluidics will develop in the direction of intelligence.⁸³ By embedding microsensors and responsive materials in microneedles, closed-loop systems can be constructed to monitor physiological signals and trigger drug release in real time, and 3D printing technology can also enable the precise fabrication of complex heterogeneous structures, such as gradient pores or bionic microchannel networks. These intelligent composite microneedles are not only suitable for transdermal drug delivery, but also show great potential in cutting-edge fields such as organ microarrays and tissue engineering, providing a brand-new technical means for precision medicine.

2.5. Bioinspired structures

Bionic designs in microneedle structures significantly enhance their mechanical properties and functional versatility by mimicking features of natural organisms, such as cat's tongue barbs (Fig. 2i and j), bee stings, or eagle's claw structures (Fig. 2k).^87–89 For example, the cat's tongue barb bionic microneedle enhances the grip on the skin and reduces wound tension through the angle-adjustable design, while the bee stinger bionic barb structure improves the drug delivery efficiency by increasing the contact area of the microneedle with the tissue. These bionic structures not only optimize the mechanical stability of the microneedles, but also achieve precise regulation of the microenvironment by mimicking the dynamic properties of living organisms.⁹⁰

In microfluidic applications, bionic microneedles modulate fluid transport through unique structural designs such as tilt angles or bifurcation channels. For example, the tilt angle of the catgut bionic microneedle guides the capillary force distribution to achieve controlled fluid flow without pumping drive, which is suitable for wound exudate management or drug slow release. In addition, the bifurcated channel design can mimic vascular branching to optimize fluid pathways and enhance the efficiency of targeted delivery of biomolecules, thereby improving the integration and functionality of microfluidic systems.

The versatility of these biomimetic microneedles is demonstrated by their adaptability to multiple application scenarios. When combined with friction nanogenerators (TENGs), the microneedles can generate electric fields through biomechanical signal conversion to promote cell migration and tissue repair; while in drug delivery, the barbed or claw-like structures can extend the retention time of the microneedles in tissues and enhance drug utilization. This multi-functional bionic design provides a highly scalable technology platform for smart wearable devices, real-time monitoring systems and precision medicine.⁹¹

3. Microneedle materials for microfluidics

Microneedles (MNs) have emerged as a promising platform for interfacing with biological tissues in both therapeutic delivery and diagnostic applications. In recent years, the integration of microneedles with microfluidic systems has attracted considerable attention due to its potential for minimally invasive, real-time monitoring and precise control of fluid transport. The performance and functionality of such hybrid systems critically depend on the choice of microneedle materials, which must balance mechanical strength, biocompatibility, and fluidic compatibility. This section reviews the materials currently employed in the fabrication of microneedles for microfluidic integration, highlighting their advantages, limitations, and suitability for specific biomedical applications.⁹²

3.1 Metals

3.1.1. Stainless steel and titanium. Metallic microneedles are miniaturized needle-like structures usually made of metallic materials (e.g., stainless steel, titanium, etc.) with excellent mechanical strength and biocompatibility (Fig. 3a and b).^47,48 Their main functions include penetration of the skin barrier for painless or minimally invasive drug delivery, biosignal monitoring or body fluid sampling. Through their high aspect ratio geometry, metal microneedles are able to effectively minimize irritation of nerve endings, thereby reducing pain. In addition, metal microneedles can be used as electrodes for electrochemical sensing or impedance monitoring, e.g., in blood glucose monitoring or antioxidant detection by modifying conductive materials to enhance their electrochemical properties and achieve high sensitivity and selectivity. The versatility and reusability of metal microneedles make them an important tool in the biomedical field.⁸¹

Fig. 3 (a) and (b) Green bodies of a titanium microneedle array fabricated by a microforming method. The microforming process consists of uniformly filling the PDMS mold and a drying step during which the solvent evaporates and a green body is formed. Reproduced with permission.⁴⁸ Copyright 2017, PLOS ONE. (c) Freshly produced soluble microneedles based on seaweed sugar and (d) dissolved in isolated human skin for 15 minutes, leaving microneedles behind. Reproduced with permission.⁵⁰ Copyright 2022, John Wiley and Sons Inc. (e) Soluble hyaluronic acid microneedles and drug-loaded microspheres of hyaluronic acid microneedles. Reproduced with permission.⁶¹ Copyright 2021, Elsevier. (f) Schematic diagrams of silk MN wrap, perivascular conformal installation of the silk MN wrap around the damaged blood vessel, and localized & controlled delivery of an anti-proliferative drug into the vascular tissue and sufficient molecular exchange between the blood vessel and its surrounding environment through a porous silk MN wrap. Reproduced with permission.⁵⁶ Copyright 2021, Elsevier.

Microfluidic monitoring technology combined with metal microneedles enables precise manipulation and real-time analysis of biofluids. Through microchannels inside the microneedles or surface-modified porous structures, microfluidic systems can control the flow of minute quantities of fluids for slow drug release or continuous sampling. For example, titanium porous microneedles (TPMA) are formed with 30% porosity through a sintering process and can be used as drug carriers for storing dry drugs or delivering liquid drugs through microchannels. Microfluidic monitoring can also be coupled with electrochemical assays, such as measuring changes in skin impedance via microneedle electrodes to assess drug penetration efficiency or detecting the concentration of specific molecules (e.g., 3-caffeoylquinic acid) using cyclic voltammetry. This integrated technology shows great potential for small-volume, high-throughput biosensing and immediate detection (POCT).

The applications of metal microneedles and microfluidic monitoring cover a wide range of medical diagnostics, drug delivery and health monitoring. In the field of drug delivery, porous metal microneedles can realize transdermal delivery of large molecules through “puncture-release” or “puncture-flow” modes, which significantly improves bioavailability. In biosensing, microneedle electrodes are used to detect metabolites or antioxidants in body fluids, which can be combined with wireless transmission technology to realize long-term dynamic monitoring. In addition, microneedle arrays are used in tissue engineering and aesthetic medicine, e.g., to promote collagen production or deliver cosmetically active ingredients. With the advancement of material science and micro–nano-processing technology, metal microneedles will further develop in the direction of intelligence and multifunctionality, providing innovative solutions for personalized medicine and precise health management.⁹³

3.2 Natural polymers

3.2.1. Alginate. Alginate microneedles are soluble microneedle arrays (dMNAs) based on a blend of alginate and pullulan, with the core advantage of combining the biostability of alginate with the mechanical strength of branched-chain starch.⁸⁵ Alginose, a natural disaccharide, effectively protects biologically active ingredients (e.g., inactivated viruses in influenza vaccines) from heat and dehydration stresses during drying and storage, while branched-chain starch imparts the microneedles with sufficient stiffness and penetrating power to allow for smooth puncture into the skin and rapid dissolution (within approximately 15 minutes) (Fig. 3c and d).⁵⁰ The microneedles maintain mechanical stability and antigenic activity under storage conditions from 4 °C to 37 °C and do not require cold-chain transportation, making them particularly suitable for vaccine delivery in resource-limited areas. In addition, its minimally invasive nature reduces vaccination pain and improves patient compliance.

In the application of microfluidic technology, the preparation of alginate microneedles can be achieved through a precision-controlled microfluidic system to achieve efficient and uniform drug loading.⁹⁴ For example, using centrifugal microfluidics, a mixed alginate-branched starch solution is co-injected with antigen into a polydimethylsiloxane (PDMS) mold and the solution is driven by centrifugal force to fill the microneedle cavities, which are subsequently dried and molded. Microfluidics not only optimizes the geometry of the microneedle, but also ensures uniform distribution of the antigen in the microneedle and improves the delivery efficiency.⁹⁵ In addition, combined with the real-time monitoring function of microfluidics, the process parameters can be further optimized to reduce the loss of antigenic activity during the production process, providing new ideas for the development of personalized vaccine and drug delivery systems.

3.2.2. Deacetyl chitosan. Deacetylated chitosan microneedle is a biodegradable microneedle system based on natural cationic polysaccharides with excellent biocompatibility, antimicrobial and pro-wound healing properties.⁵⁷ Their preparation is usually carried out by a micromolding method, in which chitosan is combined with other functional materials to form nanoparticles or loaded directly onto the microneedle tip. For example, the chitosan/fucoidan nanoparticles (MOXNPs) mentioned in the study were prepared by electrostatic interactions, with a particle size of about 258 nm and a positive surface charge (+45.1 mV), which enables a slow release of the drug and at the same time the mechanical strength of the microneedle (2.73 N per needle) is sufficient to penetrate the skin, rapidly dissolve (within 55 min) and release the drug.

The application of deacetylated chitosan microneedles is mainly in the construction of precise drug delivery and controlled release systems. Microfluidic chips can be used to regulate the synthesis parameters of chitosan nanoparticles (e.g., flow rate, pH) and realize the scale-up production of monodisperse nanoparticles. For example, precise control of the mixing ratio of chitosan and fucoidan (e.g., 3 : 1) through microfluidic channels can optimize the particle size and drug-carrying efficiency of the nanoparticles (EE% up to 90.1%). In addition, microfluidic technology can be integrated into the microneedle preparation process, enabling high-throughput fabrication of microneedle arrays and precise localization of drug-loading regions (e.g., rapid release of thrombin at the tip of the needle, slow release of antibiotics in the body of the needle) by microfluidic spray printing or light-curing technology.

The synergistic application of chitosan microneedles in combination with microfluidics demonstrates the potential for multistage responsive therapy in infected wound treatment. For example, microfluidic-designed temperature-sensitive hydrogel microneedles can release drugs on-demand in the wound microenvironment (e.g., pH 6.5 or enzyme-triggered), while the inherent antimicrobial properties of chitosan (MIC of 256 μg mL⁻¹ against Staphylococcus aureus) synergistically eliminates biofilms in conjunction with the microneedle's physical penetration properties (725 μm depth). In the future, this technology can be expanded to personalized medicine, such as real-time monitoring of wound markers (e.g., IL-6) by microfluidics to dynamically adjust the drug release profile of the microneedle for intelligent wound management.

3.2.3. Hyaluronic acid. Hyaluronic acid (HA) microneedles are micrometer-sized needle arrays based on natural polysaccharides widely used in drug delivery and cosmetic applications (Fig. 3e).⁶¹ Hyaluronic acid is an ideal material for the preparation of soluble microneedles due to its excellent biocompatibility, degradability and high water solubility. Microneedles form microchannels by penetrating the stratum corneum of the skin to realize painless drug delivery, which is especially suitable for the delivery of large molecules and hydrophilic drugs. The advantages of microneedles include avoiding first-pass effects, improving bioavailability, and reducing the pain and risk of infection associated with traditional injections. In drug delivery, hyaluronic acid microneedles can rapidly dissolve and release drugs into the epidermis or dermis through the “puncture-release” mechanism, which is suitable for a variety of conditions, such as chemotherapy, immunization, and diabetes treatment.^38,59,60

The use of hyaluronic acid microneedles in microfluidic technology further extends its capabilities. The microfluidic system is able to precisely control the drug loading and release kinetics, combined with the programmable degradation characteristics of hyaluronic acid microneedles, to achieve on-demand drug delivery. For example, microneedles prepared by microfluidic chips can integrate multiple drug carriers to realize synergistic therapy. In addition, microfluidics can be used to optimize the morphology and mechanical properties of microneedles, ensuring that they penetrate the skin while maintaining sufficient mechanical strength. This combination offers new ideas for personalized medicine and precision drug delivery.

Hyaluronic acid microneedles are particularly useful in aesthetic applications such as skin anti-wrinkle, scar repair and moisturization. Its microfluidic application can be used to design microneedles with different dissolution rates and drug release profiles by modulating the molecular weight and cross-linking degree of hyaluronic acid to meet different cosmetic needs. For example, high molecular weight hyaluronic acid microneedles can prolong skin hydration, while low molecular weight microneedles promote rapid penetration of active ingredients. In the future, smart responsive design combined with microfluidics is expected to further promote its innovative applications in chronic disease management and aesthetic medicine.^35,74

3.2.4. Silk proteins. Silk fibroin microneedles (SF MNs) are micron-sized drug delivery systems prepared from natural silk fibroin (SF).⁹⁷ Silk fibroin, derived from silk, has excellent biocompatibility, degradability and mechanical properties, and its β-folded structure can be modulated by alcohol treatment or water vapor annealing to optimize the stiffness and solubility of the microneedles.⁹⁸ SF microneedles, which are usually prepared by micro-molding, photolithography, or 3D printing, are capable of being loaded with hydrophobic drugs or biomolecules, and can achieve long-lasting release through controlled degradation (Fig. 3f).⁵⁶ In addition, the low immunogenicity and pro-tissue repair properties of filaggrin proteins make them particularly suitable for topical delivery of drugs in chronic wounds, oncology treatments, and vascular diseases.

Filipoprotein microneedles are often combined with microfluidic chips for precise drug loading and release kinetics studies. For example, microfluidics can build a gradient drug-loading structure inside SF microneedles through a laminar or multiphase flow control system to achieve spatiotemporally controlled drug release. In addition, microfluidic chips can simulate the vascular microenvironment (e.g., shear force, pH gradient) for evaluating the penetration and delivery efficiency of SF microneedles under dynamic physiological conditions.⁹⁹ This integrated system can also be combined with a sensing module to monitor the drug loading, release rate and biocompatibility of the microneedles in real time, providing data support for personalized therapy.^100,101

In the future, the synergistic application of filipin microneedles and microfluidics will be expanded to the field of intelligent delivery systems and organ chips.⁸⁰ For example, responsive SF microneedles can be prepared by microfluidics for targeting tumor or inflammatory tissues; in organ-on-chip systems, SF microneedle arrays can simulate perivascular drug delivery to study the inhibitory effect of drugs on vascular smooth muscle cells. In addition, combined with bio-3D printing, microfluidic-assisted SF microneedles can be customized with complex structures for combined delivery of drugs and cells, advancing the development of regenerative medicine and neural interface technologies.

3.3 Artificial polymers

3.3.1. PCL. Polycaprolactone (PCL) is a biodegradable polyester material with excellent biocompatibility and mechanical properties suitable for microneedle preparation.³⁸ PCL microneedles are able to effectively penetrate skin or biofilm barriers for precise drug delivery due to its high mechanical strength and controlled degradation rate. In addition, the hydrophobicity of PCL enables it to encapsulate hydrophobic drugs and achieve responsive drug release through hydrolysis or enzymatic degradation of ester bonds, thus reducing the risk of antibiotic abuse and bacterial resistance.

In microfluidic technology, PCL microneedles can be prepared in a high throughput and homogeneous manner by microfluidic chips. The microfluidic channel can precisely control the flow and solidification process of PCL solution to generate microneedle arrays with uniform size. This technology not only improves the preparation efficiency of microneedles, but also optimizes the morphology and drug loading rate of microneedles by adjusting microfluidic parameters, which provides the possibility of personalized medicine.

PCL microneedles combined with microfluidics are not only suitable for chronic wound treatment, but can also be extended to vaccine delivery, cosmetic skin care and biosensing. For example, in vaccine delivery, PCL microneedles can be loaded with antigens via microfluidics for painless and efficient immunization; in biosensing, PCL microneedles can be integrated with microfluidic detection units for real-time monitoring of physiological indicators. This multifunctional combination shows the broad prospect of PCL microneedles in biomedical engineering.

3.3.2. PEGDA. The PEGDA (polyethylene glycol diacrylate) microneedle is a degradable microneedle system based on photocured hydrogel with excellent biocompatibility and tunable mechanical properties. PEGDA is polymerized by UV-initiated polymerization to form a cross-linking network structure, and its hardness, solubility, and degradation rate can be precisely adjusted by adjusting the concentration of the monomers, the ratio of cross-linking agents, and the light conditions. This microneedle can gently penetrate the skin stratum corneum and gradually dissolve and release the drug in the body fluid environment, which is suitable for the delivery of biological macromolecules such as proteins and vaccines. In addition, the high water content of PEGDA reduces irritation to the surrounding tissues, making it suitable for long-term implantation or repeated drug delivery applications.^64,102

PEGDA microneedles are often used as core components of microfluidic channels or valves, utilizing their light-curing properties to achieve in situ molding of microstructures and functional integration. For example, by controlling the flow of PEGDA prepolymerization fluid and UV exposure through microfluidic chips, arrays of microneedles with complex internal channels can be prepared to achieve synergistic release of multiple drugs or gradient concentration delivery. The light transmission of PEGDA also facilitates the combination with optical sensors for real-time monitoring of drug release kinetics or changes in the tissue microenvironment (e.g., pH, glucose concentration), which can be used to provide support for closed-loop intelligent drug delivery systems. The PEGDA microneedle can be used to support closed-loop intelligent drug delivery systems.

In the future, the combination of PEGDA microneedles with microfluidics will drive the development of responsive drug delivery and organ-on-a-chip systems. By introducing temperature-sensitive or enzyme-responsive monomers (e.g., N-isopropylacrylamide), smart microneedles with environmentally triggered release can be designed. In addition, the high-throughput nature of microfluidics can be used to mass-produce homogenized PEGDA microneedles, reducing costs and facilitating clinical translation. Such systems show great potential for vaccine delivery, chronic disease management and immediate diagnostics such as transdermal biomarker assays.

3.3.3. PVP. Dissolvable polyvinylpyrrolidone (PVP) is chosen for its biocompatibility, flexibility, and ability to dissolve in aqueous environments,^66,67 making it an ideal candidate for controlled drug delivery systems. The MNs are further coated with a thermoresponsive layer of thermosensitive dextran (TD) to regulate the release of the antimicrobial peptide W379 and the photosensitizer IR780 iodide dye.⁶⁸ This coating acts as a barrier to prevent premature dissolution of the MNs and ensures that the payload is only released upon near-infrared (NIR) light irradiation, providing a triggered release mechanism.⁶⁹

The advantages of using PVP for microneedle fabrication include its nontoxic nature, which is crucial for applications involving direct contact with biological tissues. The solubility of PVP allows for controlled dissolution of the MNs post application, facilitating the gradual release of the encapsulated therapeutic agents.⁶⁵ The material's mechanical properties enable the creation of microneedles with the necessary strength to penetrate the skin but also sufficient flexibility to avoid breakage during application. Additionally, the thermoresponsive TD coating enhances the precision of drug release, ensuring that it occurs only upon specific external stimuli, which is beneficial for targeted therapy and minimizing systemic side effects.

PVP microneedles are often integrated into microchip systems as microreactors or carriers: their porous structure allows precise control of drug/vaccine loading via microfluidics, and the dissolution rate matches the microchannel flow rate to achieve controlled release; microneedle arrays can be used in conjunction with microfluidic pumps and valves to construct a closed-loop percutaneous detection system (e.g., glucose monitoring), and optimize release kinetics by using the pH-responsive properties of PVP. This material serves as both a structural support and functionalization platform in the microfluidic–microneedle coupling system, providing a technological path for the integration of transdermal diagnosis and treatment.

3.3.4. PLA. PLA (polylactic acid) microneedles are micron-sized needle-like structures made of biodegradable materials that are widely used in transdermal drug delivery systems. Advantages include good biocompatibility, degradability, and mechanical strength, and the ability to penetrate the stratum corneum of the skin for painless drug delivery. By combining 3D printing with chemical etching, the size and shape of microneedles can be precisely tuned, e.g., by reducing the tip size to 173 microns, thus optimizing their skin penetration properties. In addition, PLA microneedles can be combined with drug reservoirs to achieve high drug loading capacity and long-lasting slow release, which is suitable for the delivery of hormonal drugs.^62,63

PLA microneedles can be used as an integral part of microfluidic channels for precise control of the flow and distribution of minute amounts of fluid. For example, by integrating microneedle arrays with microfluidic chips, on-demand release of drugs or real-time monitoring of biomarkers can be achieved. The degradable nature of PLA gives it an advantage in single-use or short-term implantable devices, avoiding the need for secondary surgical removal. Microfluidics can also optimize the drug loading efficiency of microneedles, for example, by injecting drug solutions into microneedle reservoirs via the injection volume filling method, avoiding the destruction of heat-sensitive drugs by high-temperature processing.

In the future, the combination of PLA microneedles and microfluidics is expected to drive the development of personalized medicine and intelligent drug delivery systems. For example, by integrating sensors and feedback mechanisms, the microfluidic system can dynamically adjust the drug release rate according to the patient's physiological parameters. In addition, the modification of PLA materials can further regulate drug release kinetics, providing innovative solutions for long-term therapeutic needs such as diabetes and contraception. This technology integration not only improves drug delivery efficiency, but also reduces production costs, which has broad clinical application prospects.

4. Advanced manufacturing technology

The advancement of microneedle systems relies heavily on the evolution of manufacturing technologies that enable precise control over geometry, scalability, and functional integration. Traditional fabrication methods, while effective for basic designs, often face limitations in throughput, customization, and material compatibility. In response, emerging advanced manufacturing techniques—such as 3D printing, lithography-based processes, and laser micromachining—offer enhanced flexibility and resolution, allowing for the production of complex, multi-material, and application-specific microneedle architectures. This section explores the state-of-the-art manufacturing approaches that are driving the next generation of microneedle innovations.

4.1. 3D printing

3D printing technology has become an important method for microneedle manufacturing due to its high precision, customizability and rapid prototyping (Fig. 4a).³⁹ Through additive manufacturing technologies such as fused deposition modeling (FDM), stereolithography (SLA), or digital light processing (DLP), the geometric parameters of microneedles can be precisely controlled to meet the needs of different applications (Fig. 4b).¹⁰³ Multi-material 3D printing technology also allows combining a rigid tip and a flexible substrate in the same structure, enhancing the mechanical strength and wearing comfort of microneedles. In addition, 3D printing allows the fabrication of hollow microneedles that form drug delivery channels by dissolving the support material, offering the possibility of precise delivery.

Fig. 4 (a) Schematic of 3D-printed MNA showing (i) the fabrication process and (ii) a representative computer model view of the designed hollow MNAs. Reproduced with permission.³⁹ Copyright 2022, Wiley. (b) Schematic diagram showing the fabrication of the hybrid MN patch. Reproduced with permission.¹⁰³ Copyright 2021, AAAS. (c) Polydopamine-melatonin-loaded mesoporous silica nanoparticle-embedded MN patches. Reproduced with permission.⁹⁶ Copyright 2023, Wiley. (d) Scheme of the MN fabrication process. Reproduced with permission.⁸⁹ Copyright 2021, Elsevier. (e) Fabrication processes of the microneedle arrays and microneedle sensors, glucose sensors, and differential sensors. Reproduced with permission.²⁴ Copyright 2024, Elsevier. (f) Schematic diagram of the SF-based MN dressing fabrication process using proportionally stretched Ecoflex molds engraved by a laser. Reproduced with permission.¹¹⁰ Copyright 2022, John Wiley & Sons.

Microfluidics enables microneedles to achieve controlled, on-demand drug delivery by precisely manipulating microliters or even nanoliters of fluid. Microfluidic channels are typically made of flexible materials such as PDMS (polydimethylsiloxane), which are biocompatible and breathable for long-term wear. By integrating micro pumps, valves and sensors, microfluidic systems can regulate the release rate, timing and dosage of drugs to meet the needs of different scenarios, such as chronic wound treatment and vaccination. In addition, microfluidic technology can realize multi-drug synergistic delivery, avoid drug–drug interactions, and improve therapeutic effects.

The combination of 3D printing and microfluidics provides a highly integrated manufacturing solution for microneedle systems.^104–106 3D printing can directly build an integrated structure of microneedles and microfluidic channels, reducing the assembly steps in traditional manufacturing and improving the sealing and reliability of the system. For example, 3D printed microneedle arrays can be seamlessly connected to microfluidic chips to form a closed-loop controlled smart delivery system. This co-design not only simplifies the manufacturing process, but also enhances the mechanical stability and drug delivery accuracy of the microneedles, making them suitable for personalized medicine and remote controllable therapy.

Although 3D printing and microfluidics show great potential in microneedle manufacturing, they still face some challenges. First, the biocompatibility and long-term safety of 3D printed materials need to be further validated, especially for long-term implantation or repeated-use scenarios. Second, the mechanical properties of microneedles need to be optimized to ensure reliable skin penetration and patient comfort. In addition, miniaturization, power consumption, and cost issues of microfluidic systems still need to be addressed to facilitate mass production and clinical applications. Future directions include developing novel biocompatible materials, optimizing 3D printing resolution, enhancing the intelligent control capability of microfluidic systems, and exploring more efficient manufacturing processes to promote the widespread use of microneedle technology in precision medicine.

4.2. Negative mold

Negative mold technology is a method of replicating microstructures by means of negative molds (Fig. 4c),⁹⁶ usually using photolithography, etching, or machining to form specific shapes of microholes or grooves in the substrate (Fig. 4d).⁸⁹ The core of the process lies in precisely controlling the morphology of the microneedles through the geometry of the mold to ensure uniformity and consistency of the microneedle array. The advantages of negative molds are that they are highly reproducible, suitable for mass production, and capable of realizing complex three-dimensional structural designs, such as bionic tilted microneedles or hollow microneedles, laying the foundation for subsequent functionalized encapsulation.

Microfluidics enables high-precision material filling and patterning in negative molds by manipulating micron-scale fluids. For example, a prepolymer solution is injected into the microvia of a negative mold, vacuum debubbled to ensure complete filling, and then combined with UV curing to form a solid microneedle. The laminar flow characteristics of microfluidics can be used for multi-material layered encapsulation (e.g., liquid metal conductive tracks), while the microchannel design enables targeted loading of drugs or active ingredients. In addition, microfluidics coupled with negative molding can prepare heterogeneous structured microneedles, such as core–shell or gradient composition microneedles, expanding their applications in delivery systems and sensing.

The combination of negative molds and microfluidics provides a modular platform for microneedle fabrication for a wide range of materials.¹⁰⁷ By adjusting the mold design and fluidic parameters, the mechanical and functional properties of microneedles can be tailored. This combination of technologies is not only applicable to the field of wound repair, but can also be extended to transdermal drug delivery, biosensing and tissue engineering, demonstrating interdisciplinary versatility and industrialization potential.

4.3. Electrodeposition

Electrodeposition is a technique for depositing metals or alloys on an electrically conductive substrate by means of an electrochemical reaction (Fig. 4e).^24,108,109 The core principle is to utilize metal ions in the electrolyte to migrate to the cathode (working electrode) under the action of an electric field and to form a solid metal deposition layer through a reduction reaction. Key parameters of the method include current density, electrolyte composition, temperature and additives, which directly affect the uniformity, crystallization quality and mechanical properties of the deposited layer. The electrodeposition method is particularly suitable for the fabrication of high-precision metal microneedles with complex three-dimensional structures, as it is able to achieve nanoscale resolution of morphology control through the modulation of electric field distribution and ion transport. In addition, the electrodeposition process is compatible with a wide range of metals (e.g., copper, nickel, gold, etc.), and functional alloys or composites can be introduced by adapting the electrolyte formulation to meet biocompatibility or mechanical property requirements.

The significant advantages of electrodeposition in microneedle fabrication are its high design freedom and dimensional accuracy. By combining templates prepared by photolithography, electrodeposition enables precise replication of complex geometries. In addition, electrodeposited metal microneedles have excellent mechanical strength and electrical conductivity, making them suitable for puncturing tissues or integrating sensing functions. However, the method also faces challenges: for example, uneven ion concentration gradients and electric field distributions are likely to occur in molds with large depth-to-width ratios, leading to inconsistent thickness of the deposited layer or void defects; the adsorption kinetics of additives may interfere with the deposition rate, and numerical simulations are needed to optimize the process parameters to address these issues.

Metal microneedles fabricated by electrodeposition can be used as efficient fluidic interfaces or sensor carriers. Microneedle arrays can be used for minimally invasive sampling or drug delivery, and their internal channels can be seamlessly integrated with an external microfluidic chip through electrodeposition for precise flow control. In addition, the conductive properties of metallic microneedles support electrochemical detection or enhance biomolecule capture through surface functionalization modifications.

4.4. Lithography technology

Laser engraving technology is a high-precision method of microneedle fabrication, in which a laser beam selectively ablates or cuts the material to form microneedle structures with specific shapes and sizes (Fig. 4f).¹¹⁰ The core advantage of this technology lies in its extremely high resolution and controllability, which enables micrometer or even nanometer-level processing precision. Laser engraving is typically performed with UV or femtosecond lasers.¹¹¹ By adjusting the laser power, pulse frequency and scanning path, the taper, height and surface morphology of the microneedles can be precisely controlled. In addition, laser engraving is applicable to a wide range of materials, including metals, polymers, and biodegradable materials, providing flexibility in the diverse design of microneedles. During processing, the non-contact nature of the laser avoids mechanical stress damage to the material, making it particularly suitable for fabricating microneedle structures with high aspect ratios.

In microfluidic applications, laser engraving technology is able to directly integrate microneedles and microfluidic channels for integrated functional design. For example, microfluidic systems for drug delivery or biosampling can be constructed by laser engraving microneedle arrays and connected microchannels on a polymer substrate. The high precision of laser engraving ensures a seamless connection between the microneedles and microchannels, reducing the risk of fluid leakage. In addition, the laser can process nanoscale pores or textures on the surface of the microneedles to enhance their hydrophilicity or drug-loading capacity, thereby optimizing the efficiency of fluid control in microfluidic systems.¹¹²

Another important application of laser engraving technology is the fabrication of wearable or implantable microfluidic devices. By combining laser cutting and lamination processes, multilayer microneedle–microfluidic composite structures can be rapidly prepared for patch-type devices for continuous monitoring or therapy. The flexibility of the laser allows the integration of microneedles with different functionalities on the same device and multitasking collaboration through microfluidic networks. This technology is particularly suited to personalized medical needs, as laser parameters can be adjusted in real time to the specific application without the need to change molds or tools, significantly reducing development costs and time.

5. MNs in smart wearable devices

The integration of microneedles (MNs) into smart wearable devices is a transformative step towards continuous, user-friendly health monitoring and intervention. By embedding microneedle arrays into flexible skin-adhesion platforms, wearable systems can painlessly enable real-time biochemical sensing. These systems are designed for long-term use, mobility and data connectivity. This section will focus on the functional convergence of MNs with wearable electronics and biosensors, exploring their design, fabrication and application in digital health.

5.1. Bioelectrochemical interfaces

An important application of microneedle technology is as a bioelectrochemical interface for closed-loop neuromodulation and electrophysiological monitoring, especially in the treatment of neurological disorders such as epilepsy and Parkinson's disease. There is a smart wearable patch system that combines a series of conductive microneedles and flexible circuits that can penetrate directly through the stratum corneum to the dermis and form stable, low-impedance electrical contacts with subcutaneous nerves or muscle tissues for high-precision electrical stimulation and nerve signal acquisition (Fig. 5a–c).^113–116 The system uses polypyrrole (PAni) or gold nanoparticle-modified microneedles as electrodes, and the substrate material is selected from biodegradable gelatin methacryloyl (GelMA) or poly(lactic acid)-hydroxyglycolic acid copolymer (PLGA), to ensure sufficient mechanical strength to penetrate the skin while avoiding the foreign body reaction of long-term implantation.¹¹⁷

Fig. 5 (a) Schematic of the main functions of a self-sensing intelligent drug-loaded MN patch system. Reproduced with permission.¹¹³ Copyright 2025, Wiley. (b) Overview of the NFC-based smart bandage for wireless strain and temperature real-time monitoring. Powering and bidirectional communication is achieved by means of custom-developed smartphone application. Reproduced with permission.¹¹⁴ Copyright 2021, IEEE. (c) Wearable patch with soft microfluidics and flexible electrodes for sweat cortisol monitoring. Reproduced with permission.¹¹⁵ Copyright 2023, Elsevier. (d) The components of the microneedle include a detection microneedle and a delivery microneedle. (e) Transmission of blood glucose data to a mobile application via Bluetooth. Reproduced with permission.¹¹⁸ Copyright 2023, ACS. (f) Left: Concept of the WMNC sensor worn on the arm. Right: Digital photograph of the WMNC sensor worn on the arm, secured by a compression band. (g) Schematic of the sensing mechanism of sodium ions and uric acid in the hose of the WMNC sensor. Reproduced with permission.¹²⁴ Copyright 2025, Wiley. (h) Schematic diagram of the microneedle sensor patch and how it works. Where uricase is inside the bottom microneedle layer and PPy NPs-TMB is on the top display layer. Reproduced with permission.¹²⁵ Copyright 2022, Elsevier.

When integrated with electromyography (EMG) or electroencephalography (EEG) sensors, the system monitors abnormal neuroelectric activity in real time and applies customized electrical impulses to targeted nerves or muscles via microneedle electrodes to create closed-loop feedback therapy.¹¹⁶ Compared to conventional surface electrodes, the penetrating design of microneedles significantly reduces the skin–electrode interface impedance and avoids signal attenuation by sweat and epidermal stratum corneum, while improving the spatial resolution of the stimulation. In addition, the multi-point distributed layout of the microneedle arrays enables precise modulation of nerve bundles or muscle groups at specific depths, which is suitable for rehabilitation training of complex motor functions.

This technology breaks through the limitations of traditional wearable devices that only allow for epidermal monitoring, and provides a minimally invasive and dynamic means of intervention for neuromodulation therapies while avoiding the risk of trauma associated with implantable electrodes, which has significant clinical translational potential.

5.2. Biofuel cells

A cutting-edge application of microneedles in the field of smart wearables is the transdermal biofuel cell (BFC), which is used to realize self-powered medical monitoring systems (Fig. 5d and e).¹¹⁸ Traditional wearable devices rely on external batteries for power supply, which are bulky and need to be replaced frequently. In contrast, microneedle-based BFCs can directly penetrate the stratum corneum and utilize glucose and oxygen in the interstitial fluid as fuel to continuously generate electricity through electrochemical reactions.¹¹⁹ Glucose oxidase (GOD) is modified at the anode to catalyze glucose oxidation, and platinum nanoparticles are modified at the cathode to catalyze the oxygen reduction reaction, forming a complete redox pathway. The high aspect ratio structure of the microneedles ensures full contact between the electrodes and the biofluid, while biodegradable materials such as PLA avoid the rejection of long-term implantation. This design can provide in situ energy for low-power medical devices such as continuous glucose monitoring (CGM), or even drive drug micropumps through energy storage modules for a fully self-contained, closed-loop therapeutic system.

There is also a bionic multilayered hydrogel microneedle structure that incorporates a friction nanogenerator (TENG) for battery-free, wireless electrical stimulation therapy. The electrical conductivity of the microneedles is provided by doped silver nanowires (AgNWs),¹²⁰ which are able to deliver physiologically synchronized pulsed currents generated by the TENG to the deep wound tissues to promote cell migration, proliferation, and vascular regeneration. This design not only solves the limitation of traditional electrical stimulation devices that rely on external power sources, but also ensures long-term stable contact with the skin through the mechanical interlocking structure of the microneedles.¹²¹ The energy harvesting function of microneedles in smart wearable systems further expands their application scenarios. The GP-eMN system continuously generates AC electrical signals by triggering the TENG's vertical contact-detachment or horizontal sliding friction modes through the patient's daily activities.

The core advantage of this technology lies in the integration of energy harvesting and physiological monitoring functions in a miniaturized patch,¹²⁰ indirectly reflecting the blood glucose concentration (current is positively correlated with the glucose concentration) through the current output signal of the microneedle BFC, thus synchronizing energy supply and sensing. Experiments show that such systems can generate a power density of 0.1–0.5 mW cm⁻² in a simulated body fluid environment, which is sufficient to support the Bluetooth transmission module. Combined with flexible circuits and energy management algorithms in the future, microneedle BFCs are expected to be the cornerstone of next-generation passive wearable medical devices.¹²²

5.3. Sampling medium

The core of the color-responsive visualization-based monitoring system lies in the use of the microneedle's penetration ability to obtain interstitial tissue fluid (ISF) and achieve intuitive monitoring of physiological indices through color changes. For example, Wang¹²³ developed a pH-responsive and glucose-responsive hydrogel microneedle system, which consists of a gelatin methacrylamide (GelMA) and nano-CMC-pHEA hydrogel, and is capable of reacting with glucose in the ISF after penetration of the skin, leading to changes in the microneedle's height and swelling rate, and thus enabling glucose levels to be monitored through color or morphology changes of visual monitoring. Similarly, Xie further combined microneedles with convolutional neural network (CNN)-enhanced colorimetric analysis to design a wearable microneedle colorimetric sensor (WMNC) for detecting sodium and uric acid levels in ISF (Fig. 5f and g).¹²⁴ This microneedle array efficiently extracts ISF by vacuum tube drive and visualizes the detection of target analytes using pre-modified colorimetric test paper, while eliminating ambient light interference by CNN algorithms to enhance detection accuracy. These studies demonstrate the unique advantages of microneedles in smart wearable devices, i.e., acquiring biomarkers in a minimally invasive manner and combining them with optical or machine learning techniques to achieve real-time monitoring (Fig. 5h).¹²⁵ A stretchable wireless wearable bioelectronic system for multiplexed monitoring and combination treatment of infected chronic wounds for intuitive physiological monitoring, provides a new technological path for personalized health management.

6. Microfluidics for sensing and drug delivery

Microfluidics allows precise manipulation of tiny fluid volumes for highly controlled drug delivery and sensitive biochemical sensing. In biomedical applications, microfluidic systems are often miniaturized to interact with the biological environment in a localized and efficient manner. When integrated with drug delivery or diagnostic components, microfluidics can regulate drug delivery kinetics, multiplex biomarker analysis, and automate sample processing in a compact format. This section explores the principles, materials, and configurations of microfluidic systems customized for therapeutic and diagnostic purposes.

6.1. Microfluidics monitoring

Microneedles are used as miniature sampling platforms for real-time biomarker monitoring.¹¹³ While traditional microneedles are mostly used for drug delivery or sensing, this application uses microneedle arrays to penetrate the stratum corneum of the skin and directly contact the interstitial fluid (ISF) to extract the biomarkers therein and combine with wearable devices for continuous monitoring (Fig. 6a).¹²⁶ Xiao⁷² developed a microfluidic-based plasmonic microneedle biosensor capable of ultrasensitive uric acid monitoring, demonstrating the potential of microfluidics in enhancing detection sensitivity and specificity. By leveraging microfluidic principles such as capillary action, electroosmotic flow, and passive pumping, these systems allow for the efficient collection and analysis of minute fluid samples without requiring bulky external equipment.

Fig. 6 (a) Schematic of a soft wearable patch on an infected chronic nonhealing wound on a diabetic foot. Reproduced with permission.¹²⁶ Copyright 2023, Wiley. (b) Schematic diagram of the structure of a closed-loop system in tissue fluid, with microneedles for glucose detection and insulin delivery. Reproduced with permission.¹¹⁸ Copyright 2023, ACS. (c) Optical images of the SAB mounted onto a human forearm with enlarged details. (d) Optical image of the microelectronics powered by four integrated SABs, which can monitor physiological signals such as activity status, body temperature, pulse rate, and oxygen saturation. Reproduced with permission.¹³¹ Copyright 2022, Elsevier. (e) Illustration of the PETAL sensor adhered onto a burn wound for colorimetric analysis of wound healing status with the detailed layer-by-layer structure of the PETAL sensor. Reproduced with permission.¹³² Copyright 2023, AAAS.

The integration of microfluidics into microneedles offers precise fluid manipulation, enabling high-resolution, low-volume biochemical analysis. Microfluidic-based microneedles utilize various fluid transport mechanisms, including negative pressure suction, osmotic flow, and surface tension-driven movement, to extract ISF without the need for traditional venipuncture. As highlighted by Poudineh,¹²⁷ these systems have been successfully applied in continuous health monitoring, allowing for real-time measurement of biomarkers such as glucose, cortisol, and electrolytes. The primary advantages of microfluidic microneedle systems include minimal sample volume requirements, rapid response times, and enhanced biocompatibility, making them ideal for wearable and point-of-care diagnostic applications.

Microfluidic microneedle platforms are often coupled with biosensors to enable on-site biochemical analysis. This integration allows for the direct detection of analytes through electrochemical, plasmonic, or fluorescence-based methods. Wang¹²⁸ proposed a swellable microneedle-based system for melanoma diagnosis, in which interstitial fluid is extracted via osmotic-driven swelling and subsequently analyzed using microfluidic biosensing techniques. These advanced sensing modalities provide high specificity and sensitivity, enabling early disease detection and continuous health monitoring. Furthermore, microfluidic-based microneedle biosensors can be engineered with multi-analyte detection capabilities, facilitating comprehensive health assessments through a single, minimally invasive device.

One of the most promising applications of microfluidic microneedles is in continuous health monitoring for chronic disease management. These systems are particularly relevant for diabetes care, where real-time glucose monitoring is crucial for optimizing insulin therapy. By integrating wireless communication technologies, microfluidic microneedle biosensors can transmit real-time biochemical data to mobile devices, allowing for remote health management. Poudineh¹²⁷ discusses the feasibility of microneedle assays for continuous biomarker detection, emphasizing their potential for long-term physiological monitoring with minimal patient discomfort. Such advancements pave the way for personalized medicine, where treatment regimens are dynamically adjusted based on real-time physiological data.

Despite their numerous advantages, microfluidic microneedle systems face several technical and translational challenges. These include optimizing fluid extraction efficiency, ensuring sensor stability over prolonged use, and addressing potential biofouling issues that may affect analytical accuracy. Additionally, the scalability of manufacturing and regulatory approval processes remain key hurdles for widespread clinical adoption. Future research should focus on enhancing the integration of microfluidics with advanced biosensing technologies, improving device biocompatibility, and developing robust data analytics frameworks for real-time health insights. With continued advancements, microfluidic microneedle systems are poised to revolutionize non-invasive diagnostics and personalized healthcare.

6.2. Closed-loop treatment

In the specialized context of closed-loop therapeutic systems, microneedles function as both minimally invasive access points and intelligent transdermal interfaces that support autonomous drug delivery and continuous biomarker monitoring (Fig. 6b).¹¹⁸ The work by Luo¹²⁹ exemplifies this dual-function capability, showcasing a wearable, sensing-controlled microneedle platform designed for closed-loop diabetes management. In this system, microneedles are central to both the sensing and actuation subsystems: they extract interstitial fluid from the dermal layer to supply real-time glucose concentrations to integrated electrochemical sensors and concurrently serve as drug delivery conduits. When hyperglycemic levels are detected, the system automatically triggers an ultrasound-assisted transdermal release of insulin through the same microneedle patch. This intelligent feedback-driven mechanism leverages the microneedles’ unique ability to interface directly with the skin's vasculature and interstitial space, making them indispensable to the system's closed-loop functionality.

From a biomedical engineering perspective, the integration of microneedles into closed-loop systems overcomes several challenges inherent to traditional subcutaneous sensors and insulin pumps.¹³⁰ Notably, conventional glucose sensors suffer from latency issues due to their placement in subcutaneous tissue, and insulin pumps deliver bolus doses that may not align with real-time physiological demands. Microneedle systems, by contrast, operate at the dermal level with rapid equilibration between interstitial fluid and capillary blood, enabling timely detection of glucose fluctuations. Moreover, the microneedles porous or dissolvable structure can be engineered to control drug release kinetics precisely, while the accompanying ultrasound enhances permeability via cavitation and sonophoresis, ensuring efficient and controlled delivery. These features result in a significantly improved pharmacokinetic–pharmacodynamic coupling, reducing risks of hypo- or hyperglycemia in diabetic patients and embodying the principles of precision medicine.

Furthermore, the microneedle-based closed-loop approach offers considerable advantages in terms of miniaturization, biocompatibility, and integration with flexible electronics and microfluidics. This allows for seamless, long-term skin adherence without irritation or tissue damage, critical for continuous monitoring applications. From a systems design standpoint, microneedles enable high spatial resolution in sampling and delivery, which can be further optimized using AI-driven algorithms to tailor therapeutic outputs. The potential to integrate multiplexed sensors for other analytes within the same platform expands the scope of microneedle-enabled closed-loop systems beyond diabetes, heralding a new era of autonomous, self-regulating therapeutics in wearable healthcare (Fig. 6c).¹³¹

6.3. AI-based treatment of chronic wounds

The combination of microneedles with microfluidics and artificial intelligence (AI) technologies provides a precise and intelligent solution for chronic wound treatment (Fig. 6d).¹³² The potential of this technology is demonstrated by the AI-assisted microfluidic wearable colorimetric sensor-based system (AI-WMCS) developed by Wang.¹³³ The system uses a flexible microfluidic patch to collect wound exudate and deliver detection reagents to the wound microenvironment via a microneedle array, enabling real-time monitoring of inflammatory factors and metabolic markers. The design of the microfluidic channel optimizes fluid transfer efficiency, while the microneedle ensures precise release of reagents and efficient sampling of the wound localization. AI algorithms analyze the colorimetric signals and automatically correct for errors due to changes in pH and temperature, which significantly improves the accuracy of the assay. This integrated system provides closed-loop feedback for dynamic monitoring of chronic wounds and helps personalize treatment plans.^134,135

Another key application of the microneedle–microfluidic system in chronic wound management is the combination of AI for intelligent regulation of drug delivery. For example, Xu¹³⁶ designed an eye-applied microfluidic sensor that collects tear fluid through a microneedle, and after detecting inflammatory markers, an AI model analyzes the data and triggers the microneedle to release anti-inflammatory drugs (e.g., TSA). This integrated “detect-feedback-treat” design could be extended to chronic wound treatment: the microneedle array is loaded with multiple drugs, the microfluidic network analyzes biomarkers in real time in the wound exudate, and the AI algorithm dynamically adjusts the dose and timing of the drug release based on the inflammatory state. Studies have shown that such systems can significantly reduce the risk of wound infection and accelerate healing, especially for complex chronic wounds such as diabetic foot ulcers.

The convergence of microneedle–microfluidics–AI will further advance the precision and automation of chronic wound treatment. By predicting wound healing trends through deep learning, the system can autonomously optimize drug combinations for microneedling. In addition, the introduction of flexible electronics can enhance the real-time monitoring capability of microfluidics. This multidisciplinary cross-platform not only solves the limitations of passive drug delivery with traditional wound dressings, but also enables telemedicine through cloud-based data sharing, providing a revolutionary tool for chronic wound management.

7. Conclusions and perspective

In this review, we provide a comprehensive overview of recent advancements in the integration of microneedle (MN) systems with microfluidic technologies for the development of next-generation smart wearable devices. By exploring a diverse range of MN architectures—including hollow, porous, multilayered composites, and bioinspired designs—and their material foundations spanning metals, natural polymers, and synthetic polymers, we highlighted the structural and functional innovations that have expanded the capabilities of transdermal devices. The fusion of microfluidics further enhances these platforms by enabling controlled drug release, real-time biochemical sensing, and feedback-driven therapeutic interventions. Collectively, this convergence of MNs and microfluidics lays the foundation for intelligent, minimally invasive solutions in wound care, disease monitoring, and personalized medicine.

Despite rapid advancements, several critical technical and translational challenges must still be overcome before MN-integrated microfluidic wearables can achieve widespread clinical adoption. One of the foremost challenges lies in the efficient extraction of interstitial fluid (ISF), which is essential for real-time biosensing. ISF resides in the dermal interstitium and is present in small volumes (∼20% of total body fluid), making its extraction through microneedles particularly difficult. The low driving pressure, risk of tissue clogging, and variability in skin hydration significantly limit fluid flow into microchannels. To address this, researchers are exploring strategies such as negative pressure-assisted extraction, capillary-action-driven porous microneedles, and hydrogel-tip MNs that swell upon contact to draw ISF more efficiently. Future designs may also benefit from integrating osmotic agents, surface modifications to enhance hydrophilicity, or bioinspired fluid conduits to improve sampling efficiency.

Beyond ISF collection, other persistent challenges include maintaining mechanical strength without compromising biocompatibility, especially under repeated use or long-term skin contact. While metals provide sufficient rigidity, their stiffness can lead to discomfort and potential tissue damage. Conversely, polymers—though more biocompatible—often suffer from low penetration forces or instability in biological environments. Hybrid composite microneedles combining a rigid core and soft outer shell, or stimuli-responsive materials that harden during insertion and soften afterward, represent promising directions.

Manufacturing complexity also remains a bottleneck. Advanced fabrication techniques such as 3D printing, photolithography, or laser micromachining offer high-resolution patterning but are often expensive, time-consuming, or difficult to scale. Modular negative-mold systems, roll-to-roll microfabrication, and inkjet-assisted layer-by-layer printing have shown potential for scalable production with reduced cost and better material versatility. Finally, seamless integration of electronics, power units, and wireless modules into the patch structure still poses design and durability issues. Strategies such as flexible printed circuits, self-powered biosensors (e.g., biofuel cells), and biodegradable energy harvesters could help realize a fully autonomous, skin-conformal therapeutic platform.

Looking ahead, the future of MN-integrated microfluidic wearables is expected to be shaped by interdisciplinary innovations that incorporate artificial intelligence, soft robotics, and flexible electronics. AI-assisted closed-loop systems will enable real-time decision-making based on multi-analyte data streams, while advanced materials may allow for self-healing, biodegradable, or stimuli-responsive devices tailored to dynamic physiological environments. Importantly, the commercial landscape for MN-based technologies is rapidly expanding. Startups and companies such as Raphas (South Korea), Micron Biomedical (USA), and Zense-Life (Singapore) are actively developing MN platforms for drug delivery and wearable biosensing, with some already entering clinical trials or early market stages. These industry efforts reflect a growing demand for minimally invasive, easy-to-use healthcare solutions, especially in resource-limited or remote settings. With continued collaboration across academia, industry, and clinical stakeholders, MN-based smart wearables are poised to redefine the future of digital healthcare and decentralized diagnostics.

Author contributions

Writing – original draft preparation: Dr X. Li, S. S. Wan, T. S. Pronay; writing – review and editing: Prof. B. B. Gao, X. J. Yang and C. T. Lim. All the authors have read and agreed to the published version of the manuscript.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Acknowledgements

The authors gratefully acknowledge financial support from the National Key Research and Development Program of China (2024YFA0919100), the National Natural Science Foundation of China (32371435), the Qinglan Project of Jiangsu Province (2025 Excellent Young Scholar, Bingbing Gao), the Jiangsu government scholarship for overseas studies (Bingbing Gao) and Nanjing Tech University Teaching Reform Project (20250281) (Bingbing Gao).

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