Hydrogel Microneedle Research Articles

An Ultraswelling Microneedle Device for Facile and Efficient Drug Loading and Transdermal Delivery.

The advancement and extensive demand for transdermal therapies can benefit from a safe, and efficient and user-friendly transdermal technology with broad applicability in delivering various hydrophilic drugs. Here the design and proof of concept applications of an ultraswelling microneedle device that enables the facile and efficient loading and transdermal delivery of hydrophilic drugs with different molecular weights is reported. The device consists of a super-hydrophilic hydrogel microneedle array and a resin base substrate. Using a special micromolding technique that involves hydrated crosslinking and cryogenic-demolding, the microneedle part displays a rapid swelling ratio of ≈3800%, enabling the loading of drugs up to 500kDa in molecular weight. The drug loading process using the device just involves incubating the microneedle part in a drug solution for 1min, followed by 15min of drying. The microneedles can easily penetrate the skin under press and detach from the base substrate under shear, thereby releasing the payload. Administration of desired therapeutic agents using the device outperformed conventional administration methods in mitigating psoriasis and eliciting immunity. This biocompatible device, capable of withstanding ethylene oxide sterilization, can enhance the efficacy and accessibility of transdermal therapies in research institutes, hospitals, and even home settings.

A swellable hydrogel microneedle based on cerium-metal organic frame composite nanozyme for detection of biomarkers

Skin interstitial fluid (ISF) has been an alternative source in the field of biomarkers analysis. This work developed swellable hydrogel microneedles (MNs) composed of polyvinyl alcohol and sodium alginate by chemical crosslinking (PVA/SA). Here, PVA/SA was firstly used to fabricate hydrogel MNs, achieving a swellable ratio of 150 % and a rapid extraction of 6.4 mg ISF in 15 min. To replace expensive and non-reusable test kits, hydrogel MNs based on composite nanozyme with high oxidase-like activity were successfully developed to recover and detect biomarkers. The nanozyme was composed of MnO2-modified mixed valence cerium-metal organic frame (MCM). MCM was characterized by multiple techniques to further confirm its composition and structure. MCM combined with the reduction reaction of glutathione (GSH) with oxidized substrate to achieve a colorimetric GSH detection, which had a detection limit (LOD, 0.36 μM) of GSH. The hydrogel MNs based on MCM (MCM-MNs) were firstly applied to the rapid detection of GSH in ISF. All in all, this method combines the advantages of nanozyme and hydrogel MNs to achieve a timely and minimally invasive analysis, which provides a new dimension for the in vivo detection of GSH by skin ISF and holds great implications in biomedical and bioanalysis fields.

Dissolving and Swelling Hydrogel-Based Microneedles: An Overview of Their Materials, Fabrication, Characterization Methods, and Challenges.

Polymeric hydrogels are a complex class of materials with one common feature-the ability to form three-dimensional networks capable of imbibing large amounts of water or biological fluids without being dissolved, acting as self-sustained containers for various purposes, including pharmaceutical and biomedical applications. Transdermal pharmaceutical microneedles are a pain-free drug delivery system that continues on the path to widespread adoption-regulatory guidelines are on the horizon, and investments in the field continue to grow annually. Recently, hydrogels have generated interest in the field of transdermal microneedles due to their tunable properties, allowing them to be exploited as delivery systems and extraction tools. As hydrogel microneedles are a new emerging technology, their fabrication faces various challenges that must be resolved for them to redeem themselves as a viable pharmaceutical option. This article discusses hydrogel microneedles from a material perspective, regardless of their mechanism of action. It cites the recent advances in their formulation, presents relevant fabrication and characterization methods, and discusses manufacturing and regulatory challenges facing these emerging technologies before their approval.

Layered GelMA/PEGDA Hydrogel Microneedle Patch as an Intradermal Delivery System for Hypertrophic Scar Treatment.

Hypertrophic scar (HS) is an unfavorable skin disorder that typically develops after trauma, burn injury, or surgical procedures and causes numerous physical and psychological issues in patients. Currently, intralesional multi-injection of corticosteroid, particularly compound betamethasone (CB), is one of the most prevalent treatments for HS. However, injection administration could result in severe pain and dose-related side effects. Additionally, the vacuum therapeutic efficacy of this treatment relies on the level of expertise of the healthcare professional. To overcome the limitations of conventional injections, a new method that is convenient, painless, and self-administrable is urgently required. In this study, we developed a methacrylate gelatin (GelMA)/polyethylene glycol diacrylate (PEGDA) double-network hydrogel microneedle patch loaded with CB (CB-HMNP) as an intradermal delivery system for HS treatment. The double-network structure conferred the CB-HMNP with sufficient mechanical properties to successfully penetrate scar tissue while also helping to regulate the drug's sustained release rate. Subsequently, we confirmed that the CB-HMNP had a pronounced inhibitory effect on human HS fibroblasts (hHSFs), whereas drug-free HMNPs had no effect on hHSFs, indicating its high biocompatibility. In order to assess the therapeutic efficacy of CB-HMNPs, HS models of New Zealand rabbit ears were developed. The administration of CB-HMNP three times significantly decreased the scar elevation index (SEI), collagen I/III, and transforming growth factor-β1 (TGF-β1) protein. Therefore, the CB-HMNP may offer an administration pathway for the treatment of HS that is less painful, more convenient, less invasive, and sustain-released.

Hydrogel microneedle patch for treatment of liver fibrosis

RationaleChronic liver fibrosis is a common and irreversible disease in clinical practice, and Pirfenidone (PFD) has been shown to effectively inhibit the progression of liver fibrosis in multiple studies. However, some critically ill patients cannot take oral medications, and high dose and frequency of administration can cause higher physical burden to the critically ill. Therefore, we are committed to finding a material that can provide an efficient mode of drug delivery to address chronic disease. MethodsWe have developed a hydrogel microneedle patch (MNP) based on GelMA material to provide sustained release of PFD for reducing dosing frequency, alleviating the physical burden, and enhancing therapeutic efficacy. In vitro experiments were conducted to verify the effectiveness of the microneedle patch, and a chronic liver fibrosis model was established in C57 mouse for further validation. ResultsGel-PFD MNP demonstrated good biocompatibility in vitro and in vivo studies. Cy7 fluorescence showed complete degradation of the MNP after 1 week in vivo. In vitro, Gel-PFD MNP inhibited fibroblast migration and proliferation. In mice treated with Gel-PFD, markers of fibrosis, inflammation and apoptosis in tissue or serum RNA and protein expression were relatively low, and liver enzymes and behavioral levels were also relatively normal. ConclusionsGel-PFD has good biocompatibility and sustained-release abilities, which can significantly reduce the frequency of administration and has better anti-fibrosis ability than oral PFD. It has extremely positive implications for improving chronic liver injury in patients who are unable to eat or severely ill.

A Universal Hydrogel Microneedle for on-Site Detection of Small Molecules, Proteins, and Ribonucleic Acids

Point-of-care testing (POCT) of clinical biomarkers is critical to health monitoring and timely treatment, yet biosensing assays capable of detecting biomarkers without the need for costly external equipment and reagents are limited. Blood-based assays are, specifically, challenging as blood collection is invasive, and several processing steps are required. A promising alternative to blood is interstitial fluid (ISF), which originates from blood and fills the extracellular space; thus, it has common biomarkers with plasma/serum while also containing biomarkers unique to the local cells. A wide range of metabolites, including amino acids, lipids, nucleotides, and protein biomarkers, can be detected in ISF, emphasizing the potential of ISF for health monitoring. Microneedle (MN)-based biosensors have recently emerged as a promising approach for investigating the ISF. They enable minimally invasive penetration through the skin for ISF access. Specifically, Hydrogel-based MNs have two main advantages; i) their fabrication is cost-effective and simple, ii) they are highly biocompatible. Therefore, they overcome the challenges with conventional solid MNs. However, Hydrogel Microneedles (HMN) capable of both extracting ISF and sensing an analyte on-microneedle (without any need for post-sampling processing) have been limited. Here, we report a versatile assay that employs HMNs to both extract (ISF) and perform on-MN sensing of a specific analyte/biomarker in a minimally invasive manner. Our assay incorporates graphene oxide-nucleic acid (GO.NA) optical sensors for sensing. The GO.NA optical sensor consists of GO nanosheets conjugated to fluorophore-modified nucleic acid (NA), in which GO acts as a quencher. Single-stranded NAs have high affinity for binding to GO, therefore, in the absence of the biomarker of interest the NAs are tightly bound to GO; in turn, their fluorophore tag is quenched. However, in the presence of a specific biomarker, the NAs bind to their target, inducing a conformational change that distances the fluorophore tag from GO, leading to fluorescence recovery and generation of an optical signal. GO also acts as a substrate for NA immobilization; therefore, it protects the NA from degradation and prevents any potential NA release from HMN-GO.NA. To enable microscope-free patch visualization and optical measurements for POCT, we developed a miniaturized smartphone-based system that captures fluorescence images of the HMN-GO.NA patches (Scheme 1A and 1B), which are then analyzed using freely available software (ImageJ). Our system could successfully measure six clinically important biomarkers (glucose, uric acid, insulin, and serotonin as well as microribonucleic acid 210 and 21) in-vitro (using phantom gel) and ex-vivo (using porcine skin). Further, we have been able to accurately detect glucose and uric acid in live diabetic animal models, proving the efficacy of our system. Figure 1

(Invited) Next-Generation Enabling Technologies for Disease Diagnosis and Therapeutic Monitoring

To enable personalized and precision medicine, it is crucial to monitor patient health status and bring information on disease-related agents and therapeutic drug molecules into the clinic. This requires new technologies to interrogate different body fluids that are rich sources of biomarkers, such as whole blood and interstitial fluid (ISF). Such technologies enable rapid, sensitive and - ultimately - real-time and continuous analysis of the clinically important biomarkers. Micro and nanofabrication and nanomaterials as well as materials chemistry and polymer and molecular engineering are crucial tools in this endeavor.At IDEATION Lab, we apply innovative engineering solutions to advance patient health monitoring using two main technologies: Microneedles and Microfluidics. Our new transdermal biosensing technologies powered by engineered hydrogel microneedles (HMNs), aptamer probes, and in-situ metallic nanoparticle synthesis enable minimally invasive, on-needle, and real-time measurement of clinically important biomarkers in ISF. Our HMN assays expect to pave the way for the next-generation of polymeric-based wearable biosensors. We developed a real-time biosensor driven by microfluidic techniques that continuously updates specific biomolecules’ fluctuating concentration levels with picomolar sensitivity directly in whole blood. For the first time, our microfluidic assay enables measuring the dynamic changes in blood insulin which is an important knowledge gap in diabetes management. Another microfluidic technology integrated with electrochemical biosensor has been recently developed in our lab that enables cervical cancer screening at point-of-care setting.These new advances enrich the level of information that can be collected from different body fluids and provide new means and potentials for highly accurate patient health status monitoring, thus transforming the field of personalized and precision medicine. Figure 1

A Novel Methacryloyl Chitosan Hydrogel Microneedles Patch with Sustainable Drug Release Property for Effective Treatment of Psoriasis.

Psoriasis is a chronic and recurrent skin disease that often requires long-term treatment, and topical transdermal drug delivery can reduce systemic side effects. However, it is still a challenge in efficient transdermal drug delivery for psoriasis treatment due to low penetration efficiency of most drugs and the abnormal skin conditions of psoriasis patients. Here, a safe and effective methacryloyl chitosan hydrogel microneedles (CSMA hMNs) patch is developed and served as a sustained drug release platform for the treatment of psoriasis. By systematically optimizing the CSMA preparation, CSMA hMNs with excellent morphological characteristics and strong mechanical properties (0.7 Nneedle-1 ) are prepared with a concentration of only 3% (w/v) CSMA. As a proof-of-concept, methotrexate (MTX) and nicotinamide (NIC) are loaded into CSMA hMNs patch, which can produce a sustained drug release of 80% within 24h in vitro. In vivo experiments demonstrated that the CSMA hMNs patch can effectively inhibit the skin thickening and spleen enlargement of psoriatic mice and has a good biosafety profile at sufficient therapeutic doses. This study provides a new idea for the preparation of hMN systems using modified CS or other biocompatible materials and offers an effective therapeutic option for psoriasis treatment. This article is protected by copyright. All rights reserved.

Gold Nanocluster-Based Fluorescent Microneedle Platform toward Visual Detection of ATP.

Adenosine triphosphate (ATP) participates in the regulation of most biological processes, and the ATP level is closely associated with many diseases. However, it still remains challenging to achieve on-site monitoring of ATP in an equipment-free and efficient way. Microneedles, a minimally invasive technology that can extract biomarkers from liquid biopsies, have recently emerged as useful tools for early diagnosis of a broad range of diseases. In this work, we developed hydrogel microneedles that are loaded with ATP-specific dual-emitting gold nanoclusters (RhE-AuNCs) for fast sampling and on-needle detection of ATP. These RhE-AuNCs were photo-crosslinked to the hydrogel matrix to form a fluorescent microneedle patch. Based on the ATP-induced Förster resonance energy transfer in RhE-AuNCs, a highly selective, sensitive, and reliable ATP sensor was developed. Moreover, simultaneous capture and visual detection of ATP was achieved by the AuNC-loaded microneedle sensing platform, which exhibits promising sensing performance. This work provides a new approach to design a point-of-care ATP sensing platform, which also holds great potential for the further development of microneedle-based analytical devices.

Antimicrobial hydrogel microneedle loading verteporfin promotes skin regeneration by blocking mechanotransduction signaling

Excessive scar formation has severe physiological and psychological effects on patients, and tissue restoration to functioning without scar generation after wounding continues to be a significant challenge. Yes-associated protein (YAP) is a downstream effector of the Hippo pathway that interacts with the transcriptional-enhanced associate domain to regulate stem cell proliferation, tissue growth, and organ size. Blocking mechanotransduction signaling can reduce tissue fibrosis and scar formation. This study developed a biocompatible detachable hydrogel microneedle (MN) system for scarless wound healing. The photosensitizing drug bismuth nanosheets (Bi) and YAP signaling pathway inhibitor verteporfin (Vp) were integrated into the pyramidal MN array. The MN system has sufficient mechanical strength to penetrate the skin, after the separable connection degrades, the tips can be left inside the tissue for continuous active release, and the substrate can be removed safely. The study shows that inhibition of YAP signaling encouraged scar-free wound healing without fibrosis and with the regeneration of secondary skin elements (hair follicles, sebaceous glands). Therefore, MN can serve as an excellent drug delivery system and will have numerous practical benefits in scar-free wound regeneration.

Antimicrobial releasing hydrogel forming microneedles

Hydrogel-forming microneedle arrays as a technique for transdermal drug delivery show promise as an alternative to traditional drug delivery methods. In this work, hydrogel-forming microneedles have been created with effective, controlled delivery of amoxicillin and vancomycin within comparable therapeutic ranges to that of oral delivered antibiotics. Fabrication using reusable 3D printed master templates enabled quick and low-cost hydrogel microneedle manufacturing through micro-molding. By 3D printing at a tilt angle of 45° the resolution of the microneedle tip was improved by double (from ca. 64 μm down to 23 μm). Amoxicillin and vancomycin were encapsulated within the hydrogel's polymeric network through a unique room temperature swell/deswell drug loading method within minutes, eliminating the need for an external drug reservoir. The hydrogel-forming microneedle mechanical strength was maintained, and successful penetration of porcine skin grafts observed with negligible damage to the needles or surrounding skin morphology. Hydrogel swell rate was tailored by altering the crosslinking density, resulting in controlled antimicrobial release for an applicable delivered dosage. The potent antimicrobial properties of the antibiotic-loaded hydrogel-forming microneedles against both Escherichia coli and Staphylococcus aureus, highlights the beneficial use of hydrogel-forming microneedles towards the minimally invasive transdermal drug delivery of antibiotics.

Silk Fibroin-Based Hydrogel Microneedles Deliver α-MSH to Promote Melanosome Delivery for Vitiligo Treatment.

Microneedles have shown great advantages in subcutaneous drug delivery and skin disease treatment. Vitiligo is a difficult-to-cure skin disease characterized by the depigmentation of the epidermis. Melanosomes produced in melanocytes are transported through dendrites to adjacent keratinocytes, where they accumulate, resulting in skin pigmentation. However, melanocytes in vitiligo patients are functionally disrupted. Silk fibroin (SF) methacrylate hydrogel microneedle can deliver α-MSH to the epidermis directly, where α-MSH helps the protection of melanocytes, extension of melanocytic dendrites, and transfer of melanosomes. In addition, the expression of melanogenesis-related melanocyte-inducing transcription factor and tyrosinase-related protein 1 (TRP1) was up-regulated, and the number of hair follicle stem cells increased with good proliferative activity. This slow release α-MSH SF-based hydrogel microneedles provides a new idea for the treatment of vitiligo.

A Hydrogel Microneedle Assay Combined with Nucleic Acid Probes for On-site Detection of Small Molecules andProteins.

Point-of-care testing (POCT) of clinical biomarkers is critical to health monitoring and timely treatment, yet biosensing assays capable of detecting biomarkers without the need for costly external equipment and reagents are limited. Blood-based assays are, specifically, challenging as blood collection is invasive while pre-processing is required. Here, we report a versatile assay that employs hydrogel microneedles (HMNs) to extract interstitial fluid (ISF), in a minimally invasive manner integrated with graphene oxide-nucleic acid (GO.NA)-based fluorescence biosensor to sense the biomarkers of interest in situ. The HMN-GO.NA assay is supplemented with a portable detector, enabling a complete POCT procedure. Our system could successfully measure four clinically important biomarkers (glucose, uric acid (UA), insulin, and serotonin) ex-vivo, in addition, to accurately detecting glucose and UA in-vivo.

A Hydrogel Microneedle Assay Combined with Nucleic Acid Probes for On‐Site Detection of Small Molecules and Proteins

AbstractPoint‐of‐care testing (POCT) of clinical biomarkers is critical to health monitoring and timely treatment, yet biosensing assays capable of detecting biomarkers without the need for costly external equipment and reagents are limited. Blood‐based assays are, specifically, challenging as blood collection is invasive and follow‐upprocessing is required. Here, we report a versatile assay that employs hydrogel microneedles (HMNs) to extract interstitial fluid (ISF), in a minimally invasive manner integrated with graphene oxide‐nucleic acid (GO.NA)‐based fluorescence biosensor to sense the biomarkers of interest in situ. The HMN‐GO.NA assay is supplemented with a portable detector, enabling a complete POCT procedure. Our system could successfully measure four clinically important biomarkers (glucose, uric acid (UA), insulin, and serotonin) ex vivo, in addition, to accurately detecting glucose and UA in vivo.

Biodegradable Microneedles Array with Dual-Release Behavior and Parameter Optimization by Finite Element Analysis

Microneedles (MNs) are particularly attractive for transdermal administration because of the improved safety, patient compliance and convenience. Dissolving MNs could provide rapid transdermal delivery, but with relatively low mechanical strength and almost no sustainability. On the other hand, hydrogel MNs are complicated to fabricate and have risk concerns. Herein, we developed a biodegradable MNs array composed of biocompatible silk fibroin and poly(vinyl alcohol) to overcome these limitations. Finite element analysis was employed for parameter optimization. The MNs array fabricated by the optimal parameters and material displayed sufficient mechanical strength to disrupt stratum corneum and formed microchannels for transdermal delivery. Dual-release profile was observed in the MNs array, with rapid release in the beginning, and prolonged release afterward. This release behavior fits Weibull release model and is favorable for topical application. The initial immediate release can quickly deliver active compounds to reach the therapeutic effective concentration and facilitate skin penetration, and the sustained release may supply the skin with active compounds over a prolonged period. This biodegradable MNs array is easy to fabricate, mechanically robust, could eliminate safety concerns, and provide the sustainability and advantage for large-scale production.

Advances in dermatological application of GelMA hydrogel microneedles.

Compared with systemic administration methods like injection and oral administration, traditional transdermal drug delivery has the advantages of rapid onset of activity and low side effects. However, hydrophilic drugs and bioactive substances are often unsuitable for traditional transdermal drug delivery. The application of microneedles made from gelatin methylacryloyl (GelMA) has greatly expanded thepossibilities for skin transdermal drug delivery. We have reviewed the latest literatures about the dermatological application of GelMA hydrogel microneedles in recent years using Google Scholar, PubMed and Springer. GelMA hydrogel microneedles exhibit huge potency in the diagnosis and treatment of skin diseases, and this technology also brings broad application prospects for subcutaneous micro-invasive transdermal targeted drug delivery, which mainly used in skin tissue fluid collection, local substance delivery and wound healing. With in-depth research on GelMA hydrogel, this technology will bring more breakthroughs and developments in the clinical diagnosis and treatment of skin diseases.

3D Printed Hydrogel Microneedle Arrays for Interstitial Fluid Biomarker Extraction and Colorimetric Detection

To treat and manage chronic diseases, it is necessary to continuously monitor relevant biomarkers and modify treatment as the disease state changes. Compared to other bodily fluids, interstitial skin fluid (ISF) is a good choice for identifying biomarkers because it has a molecular composition most similar to blood plasma. Herein, a microneedle array (MNA) is presented to extract ISF painlessly and bloodlessly. The MNA is made of crosslinked poly(ethylene glycol) diacrylate (PEGDA), and an optimal balance of mechanical properties and absorption capability is suggested. Besides, the effect of needles' cross-section shape on skin penetration is studied. The MNA is integrated with a multiplexed sensor that provides a color change in a biomarker concentration-dependent manner based on the relevant reactions for colorimetric detection of pH and glucose biomarkers. The developed device enables diagnosis by visual inspection or quantitative red, green, and blue (RGB) analysis. The outcomes of this study show that MNA can successfully identify biomarkers in interstitial skin fluid in a matter of minutes. The home-based long-term monitoring and management of metabolic diseases will benefit from such practical and self-administrable biomarker detection.

Hydrogel Microneedles Extracting Exosomes for Early Detection of Colorectal Cancer.

There are several methods for early diagnosis of tumors, such as detecting circulating tumor DNAs, detecting circulating tumor cells, or imaging with tumor-targeting contrast agents. However, these assays are time-consuming and may cause patient discomfort during the biopsy collecting process. Here, we develop a facile method for early diagnosis of tumors by extracting exosomes from interstitial fluid (ISF) using hydrogel microneedles (MNs). The hydrogel MNs expand in the skin to absorb the ISF, and the tumor exosomes contained in the ISF bind with the glypican-1 antibodies inside the hydrogel of MNs. After removing the hydrogel on the MNs, exosomes are separately purified from the ISF to analyze tumor-related biomarkers. Finally, colorectal cancer can be diagnosed by ELISA for the colorectal cancer-induced model mice. This noninvasive hydrogel MN system to obtain the exosome samples would play an important role in early cancer diagnosis.

Biodegradable double-network GelMA-ACNM hydrogel microneedles for transdermal drug delivery.

As a minimally invasive drug delivery platform, microneedles (MNs) overcome many drawbacks of the conventional transdermal drug delivery systems, therefore are favorable in biomedical applications. Microneedles with a combined burst and sustained release profile and maintained therapeutic molecular bioactivity could further broaden its applications as therapeutics. Here, we developed a double-network microneedles (DN MNs) based on gelatin methacrylate and acellular neural matrix (GelMA-ACNM). ACNM could function as an early drug release matrix, whereas the addition of GelMA facilitates sustained drug release. In particular, the double-network microneedles comprising GelMA-ACNM hydrogel has distinctive biological features in maintaining drug activity to meet the needs of application in treating different diseases. In this study, we prepared the double-network microneedles and evaluated its morphology, mechanical properties, drug release properties and biocompatibility, which shows great potential for delivery of therapeutic molecules that needs different release profiles in transdermal treatment.

Tofacitinib combined with melanocyte protector α-MSH to treat vitiligo through dextran based hydrogel microneedles

Vitiligo can cause serious damage to the appearance of patients and affect physical and mental health, but there is currently no simple and effective treatment. According to the theory of autoimmune disorder, the separable hydrogel microneedles delivering alpha-melanocyte-stimulating hormone (α-MSH) and tofacitinib were designed to treat vitiligo. This hydrogel microneedles were formed by dextran methacrylate (DexMA) and cyclodextrin-adamantane based host-guest supramolecules (HGSM) through CC double bond polymerization and host-guest assembly. The microneedle tips formed by the double cross-linked hydrogel can pierce the stratum corneum and deliver melanocyte protector α-MSH and JAK inhibitor tofacitinib directly to the epidermis and dermis. Under the treatment of α-MSH/tofacitinib microneedles, massive deposition of melanin in epidermis and hair follicles significantly accelerated skin and hair pigmentation.