Microneedle Arrays Research Articles

Intradermal Delivery of Cell Vaccine via Ice Microneedles for Cancer Treatment.

The living tumor cell vaccine (TCV) holds a promise for cancer immunotherapy. Microneedle arrays provide a tool to improve the immune response of vaccines by the intradermal administration in a painless manner. However, it remains challenges for microneedle arrays to deliver the living TCV intradermally. Here, an ice microneedle array delivered living TCVsis shown with sustained granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion for cancer treatment. The ice microneedle array is composed of ice microneedles and a matching polymer holder, which are customized fabricated by a static optical projection lithography (SOPL) technique. The living TCV consisted ofirradiated melanoma cells transfected with nanoparticle-mediated GM-CSF plasmids. After the living TCV is readily loaded into the ice microneedle via a cryopreservation process, it couldbe efficiently delivered into the dermis by the microneedle device. Compared to the subcutaneous injection, intradermal administration led to the recruitment of more dendritic cells at the vaccination site and the increased infiltration of CD8+ T cells in the tumor. The ice microneedle array deliveres intradermal TCVssignificantly inhibited melanoma growth and effectively prevented melanoma recurrence without obvious side effects. This work demonstrates a promising TCVs for melanoma treatment, which will inspire the future of cancer immunotherapy.

Investigation of swelling mechanisms in self-adherent microneedles

Abstract Swellable microneedles (MNs) expand to mechanically interlock with wet biological tissue, offering improved adhesion and enhanced drug delivery over non-swellable counterparts. This study numerically evaluates how the material and geometric parameters of swellable MN arrays influence shape change. Using finite element simulation, MNs were subjected to unconstrained swelling, approximated via a thermal-strain analogy. Optimal MN design must support mechanical interlocking to prevent dislodgement. We observed that wet in vivo environments induce unwanted swelling-mediated curvature, hindering contact and interlocking. We quantified this bending and calibrated gel material swellability using experimental data. To counteract curling, we introduced a design approach to shift the direction of the unwanted curling and improve MN array conformability.

Wearable platform based on 3D-printed solid microneedle potentiometric pH sensor for plant monitoring

The continuous chemical monitoring of analytes in plants can provide a better understanding of plant dynamics and the identification of health conditions. pH can be an indicator of plant abiotic stress due to changes in environmental conditions or biotic stress as a result of damage done to the plant by other living organisms. With the intensification of climate change, abiotic and biotic stresses are exacerbated. Hence, the engineering of miniaturized tools to monitor chemical signaling such as pH can be highly valuable as smart sensors for precision agriculture. Herein, 3D-printed microneedle-based electrochemical sensors are presented for in-plant monitoring of pH in leaf sap. First, affordable 3D-printed microneedle arrays (MNAs) of 900 µm in height, 300 µm in width, and 30 µm in tip diameter were manufactured. Subsequently, a metallic layer was sputtered on top of the MNAs to create microneedle electrodes. A novel plug-in two-electrode setup based on two MNAs was used to develop the MNA pH sensor employing polyaniline as a pH-sensitive layer. The MNA pH sensor was analytically characterized exhibiting near-Nernstian response (i.e., −59.9 ± 1.5 mV pH-1) even after several insertions in a leaf proving its mechanical robustness. Ex vivo analysis with plant sap from different species was successfully validated with a standard glass pH electrode. Finally, MNA sensors were used to continuously monitor pH in two plant species under regular conditions for four days. Interestingly, MNA sensors were also able to distinguish shifting pH events in plants under abiotic stress conditions (i.e., drought and watering). This new design brings a leap forward in smart sensors for applications in precision agriculture.

Fabrication of Self-powered Silicon Microneedles for Transdermal Drug Delivery

Abstract Transdermal drug delivery has been widely studied in recent years. Compared with other methods of drug delivery, this method has many advantages, such as convenient, improving patient compliance and avoiding first-pass effect. However, the low efficiency of this method needs to be overcome. In this paper, a micro-invasive transdermal drug delivery mechanism with synergic coupling of microneedle force field and triboelectric field is proposed, which can enhance the efficiency of transdermal drug delivery and is easy to operate and use. First, a silicon solid microneedle array was fabricated by micromachining technology, and its size parameters could be flexibly adjusted. Second, a metal layer with microstructure was fabricated on the back of the microneedle by sputtering technology as the positive friction layer of the triboelectric structure. Last, the microneedle and the triboelectric structure were combined into a single composite structure by using FPC wires. The experimental results showed that the transdermal amount increased with the increase of external excitation force, frequency and the number of microneedle arrays. Under the same conditions, the skin penetration of the two mechanisms combined was 3-8 times higher than that of the single use.

Treatment Considerations to Overcome the Barriers Associated with Skin Cancer Targeting

: Skin cancer is a prevalent and diverse group of malignancies affecting the skin, with three primary types: basal cell carcinoma, squamous cell carcinoma, and melanoma. Each subtype varies in terms of its histological origin, behavior, and potential for metastasis. Despite advances in treatment, skin cancer poses challenges due to biological barriers that hinder drug delivery, multidrug resistance mechanisms that limit treatment effectiveness, and the complex interplay of genetic alterations driving tumorigenesis. Current treatment strategies encompass a spectrum of approaches, including chemotherapies, immunotherapies, gene therapies, and innovative techniques such as photothermal therapy, iontophoretic therapy, electroporation therapy, microneedle array therapy, and nanotechnology- based treatments. The latter involves liposomes, niosomes, carbon nanotubes, dendrimers, hydrogels, and gold nanoparticles, all tailored to enhance drug delivery and therapeutic efficacy. Additionally, herbal drug-based therapy harnesses the potential of natural compounds to target various aspects of skin cancer progression. This review provides an overview of skin cancer types, challenges in treatment, and an extensive exploration of current therapeutic strategies, highlighting the everevolving landscape of innovative approaches that promise to transform how skin cancer is managed.

3D‐Printed Latticed Microneedle Array Patches for Tunable and Versatile Intradermal Delivery (Adv. Mater. 44/2024)

3D‐Printed Latticed Microneedle Array Patches for Tunable and Versatile Intradermal Delivery (Adv. Mater. 44/2024)

Fabrication of a Polyglycolic Acid Porous Microneedle Array Patch Using the Nonsolvent Induced Phase Separation Method for Body Fluid Extraction

ABSTRACTTraditional blood sampling is essential for early diagnosis and subsequent analysis, but the methods using hypodermic needles are painful and burdensome. Recently, a minimally invasive approach utilizing porous microneedles has been developed and various porous microneedle array patches (MAPs) composed of biodegradable polymers have been investigated. To address issues about low mechanical strength and liquid absorption with porous MAPs, we used polyglycolic acid (PGA) as it is a biodegradable and hydrophilic polymer with high mechanical properties. In this study, we established a nonsolvent‐induced phase separation (NIPS) method for the fabrication of PGA porous MAPs, as the porous MAPs can be fabricated by simply immersing the molds injected with PGA‐hexafluoro‐2‐propanol (HFIP) solution in nonsolvents. We achieved the maximum liquid absorption rate of 16 ± 8.2 × 10−2 µL/min per one microneedle using the PGA porous MAPs fabricated by using ethanol as nonsolvent and PGA concentration of 10% (w/w). Our study provides a comprehensive understanding of porous MAPs fabricated using PGA material as well as its characteristics regarding the structural and mechanical properties of PGA MAPs, with potential as a diagnostic device to substitute conventional hypodermic needles for interstitial fluid (ISF) sampling and diagnosis.

Photonic-Metamaterial-Based, Near-Field-Enhanced Biosensing Approach for Early Detection of Lung and Ovarian Cancer

Early detection of lung and ovarian cancers relies heavily on identifying tumor biomarkers, but current methods require large blood samples and complex genetic testing. This study presents a novel photonic-metamaterial-based biosensing approach that leverages near-field radiative enhancement to detect cancer biomarkers (CA 125, CEA, and CYFRA 21-1) with high sensitivity. By utilizing structured photonic metamaterials, we optimize specific wavelengths to identify these biomarkers in interstitial fluid, which can be easily collected via minimally invasive microneedle arrays. Integrating near-field interactions with wavelength-selective metamaterials amplifies the thermal response at the nanoscale, allowing for the detection of deficient concentrations of biomarkers. This photonic metamaterial technique provides a faster, more accessible, and affordable alternative to conventional blood-based methods, significantly improving early detection and monitoring of cancer. Ultimately, this approach offers a transformative tool for clinical and research applications in cancer diagnostics.

Low-cost fabrication of digital light processing 3D printed conical microneedles for biomedical applications

The 3D printing of microneedles has become an emerging area of research focus due to its ability to rapidly create microneedle arrays with parametrically variable geometry and composition. Through direct fabrication or via replica molding, 3D printed microneedles can facilitate iterative array assessment and act as a screening tool to quickly establish optimal parameters for tissue insertion and capacity for biomarker monitoring or drug release. However, the widespread adoption of 3D printing by microneedle array researcher group faces multiple barriers: (1) Investment in 3D printing systems that are traditionally associated with high-resolution pose a significant financial cost, (2) Current high-resolution printing methods are often slow and not conducive to rapid manufacturing, (3) Material selection can be limited in some ‘proprietary’ 3D printing systems (e.g. CLIP, SLA, or 2PP), (4) Given the multidisciplinary nature of the microneedle-field, researchers may not have the expertise to optimize printing parameters for a given material or printer. This work explores how ultra-low-cost digital light processing (DLP) printers can rapidly produce functional microneedle arrays for a variety of purposes, whether direct print, master mold production, or creation of coated microneedles, at a fraction of the cost of currently used systems. Further, this work highlights that high quality microneedle arrays can be created using DLP printing methods with reliability exceeding 98 %, tip radii on the order of 30 µm, and with appropriate parameter input optimization, high quality microneedle arrays can be fabricated that express desirable characteristics for multiple forms of solid microneedle array production.

Advances in Spiky Antibacterial Materials: From Bioinspired Design to Application

Bacterial infections, particularly those caused by drug‐resistant bacteria, pose a significant threat to human life and health safety. Despite the preparation and application of numerous antibacterial and disinfection materials, addressing their low efficiency and the emergence of drug resistance remains an urgent concern. Inspired by natural spike antibacterial structures such as those found on cicada wings, extensive research has been conducted on biomimetic antibacterial materials with spiky structures. This review provides an overview of the natural spike antibacterial structure and mechanism, introduces surface coatings and micro/nanoparticle materials featuring spike structures inspired by nature, explores microneedle arrays based on spike antibacterial properties, and showcases applications of these innovative antibacterial materials. Finally, potential avenues for optimization and future development directions for antibacterial materials with spike structures are discussed.

Long-term Immunity of a Microneedle Array Patch of SARS-CoV-2 S1 Protein Subunit Vaccine Irradiated by Gamma Rays in Mice.

COVID-19 vaccines effectively prevent symptomatic infection and severe disease, including hospitalization and death. However, unequal vaccine distribution during the pandemic, especially in low- and middle-income countries, has led to the emergence of vaccine-resistant strains. This underscores the need for alternative, safe, and thermostable vaccine platforms, such as dissolved microneedle array patches (MAP) delivering a subunit vaccine, which eliminate the need for cold chain and trained healthcare personnel. This study demonstrates that the SARS-CoV-2 S1 monomer with RS09, a TLR-4 agonist peptide, serves as an optimal protein subunit immunogen. This combination stimulates a stronger S1-specific immune response, resulting in binding to the membrane-bound spike on the cell surface and ACE2-binding inhibition, compared to the monomer S1 alone or trimer S1, regardless of RS09. MAP delivery of the rS1RS09 subunit vaccine elicited higher and longer-lasting immunity compared to conventional intramuscular injection. S1-specific IgG levels remained significantly elevated for up to 70 weeks post-administration. Additionally, different doses of 5, 15, and 45 μ g of MAP vaccines induced robust and sustained Th2-prevalent immune responses, suggesting a dose-sparing effect and inducing significantly high neutralizing antibodies against the Wuhan, Delta, and Omicron variants at 15 and 45 μ g dose. Moreover, gamma irradiation as a terminal sterilization method did not significantly affect immunogenicity, with irradiated vaccines maintaining comparable efficacy to non-irradiated ones. The stability of MAP vaccines was evaluated after long-term storage at room temperature and refrigeration for 19 months, showing minimal protein degradation. Further, after an additional one-month of storage at elevated temperature (42°C), rS1RS09 in both non-irradiated and irradiated MAP degraded less than 3%, while the liquid subunit vaccine degraded over 23%. Overall, these results indicate that gamma irradiation sterilized MAP-rS1RS09 vaccines maintain stability during extended storage without refrigeration, supporting their potential for mass production and widespread use in global vaccination efforts.

Development and evaluation of biocompatible coated microneedle array for controlled insulin delivery: Fabrication, characterization, in vitro, and in vivo investigations

Traditional insulin administration for people with diabetes often involves painful injections, leading to discomfort and challenges with patient compliance. A promising alternative to these conventional methods is transdermal insulin delivery using microneedle arrays, which offer a more comfortable way to deliver insulin through the skin. This study introduces an innovative approach using 3D-printed microneedle arrays coated with insulin via a dip-coating process. These microneedles present a compelling alternative to traditional injections, particularly due to their ability to gently pierce the stratum corneum, the outermost layer of skin, while minimizing discomfort. The microneedle arrays were fabricated using biocompatible resin polymers through 3D printing, creating solid conical needles with a length of 1200 µm, a base diameter of 200 µm, a tip diameter of 80 µm, and a needle spacing of 1.2 mm. The insulin coating was achieved by dip-coating the microneedles in a solution of insulin and polyvinyl alcohol (PVA), with careful optimization of the solution concentration, immersion time, and withdrawal speed to ensure a uniform and controlled coating thickness. Mechanical stability and skin penetration capabilities of the microneedles were assessed using skin models such as parafilm and porcine skin. The tests confirmed that the coated microneedles are robust enough to consistently penetrate the skin. In vivo studies with diabetic rats were conducted to evaluate skin irritation, penetration, and drug delivery efficiency. The insulin-coated microneedle arrays successfully penetrated the skin and delivered the drug with approximately 90 % efficiency. The study also showed that the microneedles provided consistent drug delivery, and the skin recovered without any signs of injury. Additionally, the hypoglycemic effect of the insulin-coated microneedles was comparable to that of traditional subcutaneous insulin injections. These findings underscore the potential of microneedle arrays as a painless and effective method for insulin delivery, maintaining stable glucose levels over an extended period. The demonstrated safety and efficacy of the coated microneedles open the door for clinical trials and potential use in diabetic patients, offering a promising advancement in diabetes management.

Assembly of a tumor microtissue by stacking normal and cancer spheroids on Kenzan using a bio-3D printer to monitor dynamic cancer cell invasion in the microtissue

In the present study, a tumor microtissue was assembled by precisely stacking normal and cancer cell spheroids on Kenzan (microneedle array) using a spheroid stacking type bio-3D printer. This is the first study to non-invasively observe the dynamic behavior of GFP-tagged cancer cell invasion in the microtissue assembled by a spheroid stacking type bio-3D printer. First, the cancer cell spheroid was prepared using 10 % cancer cells (MCF-7 expressing GFP) and 90 % normal cells (70 % HNDF and 20 % HUVEC). The normal cell spheroid was prepared using 100 % normal cells (80 % HNDF and 20 % HUVEC). The tumor microtissue was then assembled on Kenzan by placing 1 cancer cell spheroid in the center position of the microtissue and 8 normal cell spheroids around it. 9 spheroids stacked on Kenzan were fused into 1 tumor microtissue after 24 hours of culture. The green fluorescence derived from cancer cells spread from the central position to the entire area of the tumor microtissue. The spread dynamics of cancer cell-derived GFP fluorescence can be used as a simple measure to evaluate cancer cell migration/invasion and response to anticancer drugs.

An Integrated Microcurrent Delivery System Facilitates Human Parathyroid Hormone Delivery for Enhancing Osteoanabolic Effect.

Human parathyroid hormone (1-34) (PTH) exhibits osteoanabolic and osteocatabolic effects, with shorter plasma exposure times favoring bone formation. Subcutaneous injection (SCI) is the conventional delivery route for PTH but faces low delivery efficiency due to limited passive diffusion and the obstruction of the vascular endothelial barrier, leading to prolonged drug exposure times and reduced osteoanabolic effects. In this work, a microcurrent delivery system (MDS) based on multimicrochannel microneedle arrays (MMAs) is proposed, achieving high efficiency and safety for PTH transdermal delivery. The internal microchannels of the MMAs are fabricated using high-precision 3D printing technology, providing a concentrated and safe electric field that not only accelerates the movement of PTH but also reversibly increases vascular endothelial permeability by regulating the actin cytoskeleton and interendothelial junctions through Ca2+-dependent cAMP signaling, ultimately promoting PTH absorption and shortening exposure times. The MDS enhances the osteoanabolic effect of PTH in an osteoporosis model by inhibiting osteoclast differentiation on the bone surface compared to SCI. Moreover, histopathological analysis of the skin and organs demonstrated the good safety of PTH delivered by MDS in vivo. In addition to PTH, the MDS shows broad prospects for the high-efficiency transdermal delivery of macromolecular drugs.

Minimally invasive detection of buprenorphine using a carbon-coated 3D-printed microneedle array.

Amachine learning-assisted 3D-printed conducting microneedle-based electrochemical sensing platformwas developed for wireless, efficient, economical, and selective determination of buprenorphine. The developed microneedle array-based sensing platform used 3D printing and air spray coating technologies for rapid and scalable manufacturing of a conducting microneedle surface. Upon optimization and understanding of the electrode stability, redox behavior, and electrochemical characteristics of as-prepared conducting microneedle array, the developed electrochemical platform was investigated for monitoring different levels of buprenorphine in the artificial intestinal fluid and found to be highly sensitive and selective towards buprenorphine for a wide detection range from 2 to 140μM, with a low limit of detection of 0.129μM. Furthermore, to make the sensing platform user accessible, the experimentally recorded sensing data was used to train a machine learning model and develop a web application for the numerical demonstration of buprenorphine levels at the point of site. Finally, the proof-of-concept study demonstrated that by advancing our prevailing 3D printing and additive manufacturing techniques, a low-cost, user-accessible, and compelling wearable electrochemical sensor could be manufactured for minimally invasive determination of buprenorphine in interstitial fluid.

Visualizing the transdermal delivery of berberine loaded within chitosan microneedles using mass spectrometry imaging.

Berberine (BR), an alkaloid isolated from theChinese traditional medicine Coptidis rhizoma, exhibits therapeutic effects on several diseases including bacterial infections, diabetes, and hyperlipidemia, but the oral availability is poor. In this work, we prepared the chitosan microneedle array-loaded BR (BR-CS MNAs) to transdermally deliver BR, and the spatial distribution of BR in heterogeneous skin tissues was analyzed and imaged by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). Some endogenous phospholipids with specific spatial distribution were used to differentiate the epidermis and dermis regions of the skin. The results showed that BR was effectively delivered and could permeate to both epidermis and dermis regions of the skin. This demonstrated the feasibility of MALDI-MSI to evaluate the transdermal delivery efficiency of microneedle arrays and suggested BR could be transdermally delivered by CS MNAs.

3D Polymeric Lattice Microstructure-Based Microneedle Array for Transdermal Electrochemical Biosensing.

Microneedles (MNs) or microneedle arrays (MNAs) are critical components of minimally invasive devices comprised of a single or a series of micro-scale projections. MNs can bypass the outermost layer of the skin and painlessly access microcirculation of the epidermis and dermis layers, attracting great interest in the development of personalized healthcare monitoring and diagnostic devices. However, MN technology has not yet reached its full potential since current micro- and nanofabrication methods do not address the need of fabricating MNs with complex surfaces to facilitate the development of clinically adequate devices. This work presents a new approach that combines 3D printing technology based on two-photon polymerization with soft lithography for cost-effective and time-saving fabrication of complex MNAs. Specifically, this method relies on printing complex 3D objects efficiently replicated into polymeric substrates via soft lithography, resulting in a free-standing polymeric lattice (PL) membrane that can be transferred onto gold-coated MNs and used for electrochemical biosensing. This platform shows excellent electrochemical performance in detecting metabolite (glucose) and protein (insulin) biomarkers with a dynamic linear range sufficient for detecting biomarkers in healthy individuals and patients. The approach holds great potential for fabricating next-generationMNs, including their transfer into clinically adequate devices.

A smart lab on a wearable microneedle patch with convolutional neural network‐enhanced colorimetry for early warning of syndrome of inappropriate antidiuretic hormone secretion

AbstractFrequent nocturia‐induced nighttime visits aggravate falls in seniors, requiring synthetic antidiuretic drugs that risk the dangerous syndrome of inappropriate antidiuretic hormone secretion (SIADH), thus the detection of sodium ion and uric acid alterations during treatment is obligatory for drug‐safe management. Herein, we design a convolutional neural network (CNN)‐enhanced smart wearable microneedle array‐based colorimetric (WMNC) sensor to independently detect in vivo interstitial fluid (ISF) sodium ions and uric acid alterations. The WMNC sensor is composed of a vacuum tube‐driven microneedle array patch and a built‐in colorimetric sensing paper, enabling an efficient ISF extraction and rapid colorimetric assay. Furthermore, leveraging self‐designed CNNs, the WMNC sensor efficiently eliminates the influence of ambient light on colorimetric outcomes, facilitating a rapid and accurate colorimetric result classification. This study provides an ISF‐based rapid, intuitionistic, user‐friendly, wearable point‐of‐care technique for the elderly suffering from nocturia in monitoring their health status for early warnings of SIADH.

Augmenting dermal collagen synthesis through hyaluronic acid-based microneedle-mediated delivery of poly(l-lactic acid) microspheres

Poly(L-lactic acid) (PLLA) can stimulate collagen synthesis through a foreign body response. However, inappropriate injection techniques and localized PLLA clustering can lead to complications and adverse events. This study developed a composite microneedle (MN) device comprising an array of PLLA microsphere (PLLA MP)-loaded hyaluronic acid needle tips with a supporting patch (PLLA MP-MN). This device was designed to deliver PLLA MPs precisely and uniformly to the dermis and to provide dual stimulation through MN puncture and MP implantation, thereby enabling the rapid and long-lasting regeneration of dermal collagen. When applied to rat skin, the MN array evenly distributed the PLLA MPs throughout the penetrated regions, which prevented local PLLA overdosing and elicited a milder inflammatory response compared with that induced by intradermal PLLA MP injections. An in vivo efficacy study revealed that MN-mediated delivery of PLLA MPs not only promptly initiated collagen production through microwound-triggered wound-healing cascades in the early treatment stage but also enabled the long-term stimulation of collagen deposition through MP-induced foreign body reactions, thereby significantly enhancing neocollagenesis. This innovative PLLA MP-MN system can augment the benefits and minimize the adverse effects associated with traditional PLLA fillers, providing a safe and reliable anti-aging therapeutic option.

Panoramic review on polymeric microneedle arrays for clinical applications.

Transdermal drug delivery (TDD) has significantly advanced medical practice in recent years due to its ability to prevent the degradation of substances in the gastrointestinal tract and avoid hepatic metabolism. Among different available approaches, microneedle arrays (MNAs) technology represents a fascinating delivery tool for enhancing TDD by penetrating the stratum corneum painless and minimally invasive for delivering antibacterial, antifungal, and antiviral medications. Polymeric MNAs are extensively utilized among many available materials due to their biodegradability, biocompatibility, and low toxicity. Therefore, this review provides a comprehensive discussion of polymeric MNAs, starting with understanding stratum corneum and developing MNA technology. Furthermore, the engineering concepts, fundamental considerations, challenges, and future perspectives of polymeric MNAs in clinical applications are properly outlined, offering a comprehensive and unique overview of polymeric MNAs and their potential for a broad spectrum of clinical applications.