Extensible and swellable hydrogel-forming microneedles for deep point-of-care sampling and drug deployment

Microneedles are considered to be an effective,convenient,non-invasive,biosafety and compliant medical technology for vaccinations,biomarker testing,medical aesthetics and other related fields.Nonetheless,further clinical and commercial translation of regular microneedles is hampered by challenges in manufacturability,cost variability,insufficient comfort,contamination and so on.Recent innovations in functional biomaterials and chemical engineering technologies have been applied to develop extensible and swellable hydrogel-forming microneedles,achieving precise and controlled drug delivery and localized sampling from the target tissues.In this review,we systematically summarize the latest development of the extensible and swellable hydrogel-forming microneedles,including deep point-of-care testing,drug deployment,wound healing and mucoadhesion improvement.In addition,further analysis of the challenges and prospects for clinical application of current strategies is well presented.It is believed that the combined efforts of engineering,material,pharmaceutical and clinical research will contribute to the future success of this clinical and commercial translation.

Advances in Polysaccharide-Based Microneedle Systems for the Treatment of Ocular Diseases

The eye,a complex organ isolated from the systemic circulation,presents significant drug delivery challenges owing to its protective mechanisms,such as the blood-retinal barrier and corneal impermeability.Conventional drug administration methods often fail to sustain therapeutic levels and may compromise patient safety and compliance.Polysaccharidebased microneedles(PSMNs)have emerged as a transformative solution for ophthalmic drug delivery.However,a comprehensive review of PSMNs in ophthalmology has not been published to date.In this review,we critically examine the synergy between polysaccharide chemistry and microneedle technology for enhancing ocular drug delivery.We provide a thorough analysis of PSMNs,summarizing the design principles,fabrication processes,and challenges addressed during fabrication,including improving patient comfort and compliance.We also describe recent advances and the performance of various PSMNs in both research and clinical scenarios.Finally,we review the current regulatory frameworks and market barriers that are relevant to the clinical and commercial advancement of PSMNs and provide a final perspective on this research area.

Flexible capacitive pressure sensor based on interdigital electrodes with porous microneedle arrays for physiological signal monitoring

Flexible pressure sensors have many potential applications in the monitoring of physiological signals because of their good biocompatibil-ity and wearability.However,their relatively low sensitivity,linearity,and stability have hindered their large-scale commercial application.Herein,aflexible capacitive pressure sensor based on an interdigital electrode structure with two porous microneedle arrays(MNAs)is pro-posed.The porous substrate that constitutes the MNA is a mixed product of polydimethylsiloxane and NaHCO3.Due to its porous and interdigital structure,the maximum sensitivity(0.07 kPa-1)of a porous MNA-based pressure sensor was found to be seven times higher than that of an imporous MNA pressure sensor,and it was much greater than that of aflat pressure sensor without a porous MNA structure.Finite-element analysis showed that the interdigital MNA structure can greatly increase the strain and improve the sensitivity of the sen-sor.In addition,the porous MNA-based pressure sensor was found to have good stability over 1500 loading cycles as a result of its bilayer parylene-enhanced conductive electrode structure.Most importantly,it was found that the sensor could accurately monitor the motion of afinger,wrist joint,arm,face,abdomen,eye,and Adam’s apple.Furthermore,preliminary semantic recognition was achieved by monitoring the movement of the Adam’s apple.Finally,multiple pressure sensors were integrated into a 33 array to detect a spatial pressure distribu-×tion.Compared to the sensors reported in previous works,the interdigital electrode structure presented in this work improves sensitivity and stability by modifying the electrode layer rather than the dielectric layer.

Microneedle-based interstitial fluid extraction for drug analysis:Advances,challenges,and prospects

Similar to blood,interstitial fluid(ISF)contains exogenous drugs and biomarkers and may therefore substitute blood in drug analysis.However,current ISF extraction techniques require bulky instruments and are both time-consuming and complicated,which has inspired the development of viable alternatives such as those relying on skin or tissue puncturing with microneedles.Currently,microneedles are widely employed for transdermal drug delivery and have been successfully used for ISF extraction by different mechanisms to facilitate subsequent analysis.The integration of microneedles with sensors enables in situ ISF analysis and specific compound monitoring,while the integration of monitoring and delivery functions in wearable devices allows real-time dose modification.Herein,we review the progress in drug analysis based on microneedle-assisted ISF extraction and discuss the related future opportunities and challenges.

Multidrug dissolvable microneedle patch for the treatment of recurrent oral ulcer

Recurrent oral ulcer is a painful oral mucosal disorder that affects 20%of the world’s population.The lack of a radical cure due to its unknown underlying cause calls for innovative symptomatic treatments.This work reports a hyaluronic acid-based dissolvablemicroneedle patch(ROUMNpatch,short for recurrent oral ulcer microneedle)loaded with dexamethasone acetate,vitamin C and tetracaine hydrochloride for the treatment of recurrent oral ulcers.The ROUMN patch shows enhancement in both the anti-inflammatory effect elicited by dexamethasone and the pro-proliferation effect of vitamin C.In vitro experiments show that ROUMN has a higher efficiency in suppressing lipopolysaccharide(LPS)-induced interleukin-6(IL-6)expression than dexamethasone alone.Cell proliferation and migrationwere also significantly promoted byROUMNcompared to vitamin C alone.The healing-promoting effect of ROUMN was also verified in vivo using an acetic acid-cauterized oral ulcer model in rats.ROUMN as a treatment accelerated the healing process of oral ulcers,shortening the total healing time to 5 days compared with the 7 days required by treatment using watermelon frost,a commonly used over-the-counter(OTC)drug for oral ulcers.The rapid dissolution of the hyaluronic acid-based microneedles and the superior healing-promoting effect of the drug combination could lead to a broad application prospect of the ROUMN patch in the treatment of recurrent oral ulcers.

Microneedles for Enhanced Topical Treatment of Skin Disorders:Applications,Challenges,and Prospects

Microneedles(MNs)can be used for the topical treatment of skin disorders as they directly deliver therapeutics to the site of skin lesions,resulting in increased therapeutic efficacy while having minimum side effects.MNs are used to deliver different kinds of therapeutics(e.g.,small molecules,macromolecules,nanomedicines,living cells,bacteria,and exosomes)for treating various skin disorders,including superficial tumors,wounds,skin infections,inflammatory skin diseases,and abnormal skin appearance.The therapeutic efficacy of MNs can be improved by integrating the advantages of multiple therapeutics to perform combination therapy.Through careful designing,MNs can be further modified with biomimetic structures for the responsive drug release from internal and external stimuli and to enhance the transdermal delivery efficiency for robust therapeutic outcomes.Some studies have proposed the use of drug-free MNs as a promising mechanotherapeutic strategy to promote wound healing,scar removal,and hair regeneration via a mechanical communication pathway.Although MNs have several advantages,the practical application of MNs suffers from problems related to industrial manufacture and clinical evaluation,making it difficult for clinical translation.In this study,we summarized the various applications,emerging challenges,and developmental prospects of MNs in skin disorders to provide information on ways to advance clinical translation.

Dissolvable polymeric microneedles loaded with aspirin for antiplatelet aggregation

To reduce mucosal damage in the gastrointestinal tract caused by aspirin,we developed a dissolvable polymeric microneedle(MN)patch loaded with aspirin.Biodegradable polymers provide mechanical strength to the MNs.The MN tips punctured the cuticle of the skin and dissolved when in contact with the subcutaneous tissue.The aspirin in the MN patch is delivered continuously through an array of micropores created by the punctures,providing a stable plasma concentration of aspirin.The factors affecting the stability of aspirin during MNs fabrication were comprehensively analyzed,and the hydrolysis rate of aspirin in the MNs was less than 2%.Compared to oral administration,MN administration not only had a smoother plasma concentration curve but also resulted in a lower effective dose of antiplatelet aggregation.Aspirin-loaded MNs were mildly irritating to the skin,causing only slight erythema on the skin and recovery within 24 h.In summary,aspirin-loaded MNs provide a new method to reduce gastrointestinal adverse effects in patients requiring aspirin regularly.

Revolutionizing diabetic wound healing:The power of microneedles

Diabetic wounds significantly affect patient quality of life.Microneedles are a promising treatment to accelerate wound healing owing to their high drug-loading capacity and efficient drug delivery;however,few studies to date have comprehensively reviewed microneedles for diabetic wound healing.This up-to-date review summarizes the research progress in microneedles for diabetic wound healing,including manufacturing materials and techniques,structures,designs,release mechanisms,delivery substances,and their specific effects.This study showed that most microneedles designed for diabetic wounds are made of synthetic polymers and/or natural materials using polydimethylsiloxane micromolding.The geometric structure and design directly influence penetration ability and drug delivery capacity.Microneedles can deliver antibiotics,hypoglycemic agents,traditional Chinese medicines,metal ions,growth factors,exosomes,stem cells,and microorganisms,thus promoting diabetic wound healing through diverse mechanisms,such as antibacterial,anti-inflammatory,antioxidant,hypoglycemic,and angiogenic activities,at different stages of the healing process.In conclusion,microneedles are promising drug delivery systems for the treatment of diabetic wounds.

Development, Application and Prospect of Dissolving Microneedles

In recent years, as a new transdermal drug delivery method, microneedle transdermal drug delivery technology accelerates the absorption of drugs through micron pores, which has been widely used in the field of medicine and cosmetics. Dissolving microneedles have the characteristics of good biocompatibility and fast dissolution speed, which attract more and more researchers’ attention and research. In this paper, the concept, properties and preparation methods of dissolving microneedles as well as the research status of dissolving microneedles in the field of medicine and cosmetics in recent years were summarized and prospected, so as to enable researchers to have a clearer and comprehensive understanding of dissolving microneedles and prospect the application and development prospects of dissolving microneedles in the industry.

Hydrogel Microneedle Arrays for Transdermal Drug Delivery

Stratum corneum is the main obstacle for drugs to pass through the skin. Microneedles are composed of arrays of micro-projections formed with different materials, generally ranging from 25-2000 μm in height. Microneedles straightly pierce the skin with its short needle arrays to overcome this barrier. Microneedles can be divided into several categories, for instance, solid microneedles, coated microneedles, and hollow microneedles and so on. However, all these types have their weak points related to corresponding mechanisms.In recent years, pioneering scientists have been working on these issues and some possible solutions have been investigated. This article will focus on the microneedle arrays consisting of hydrogels. Hydrogels are commonly used in drug delivery field. Hydrogel microneedles can be further divided into dissolving and degradable microneedles and phase transition microneedles. The former leaves drug with matrix in the skin. The latter has the feature that drugs in the matrix are delivered while the remaining ingredients can be easily removed from the skin after usage. For drugs which are required to be used every day, the phase transition microneedles are more acceptable. This article is written in order to summarize the advantages of these designs and summarize issues to be solved which may hinder the development of this technology.

Engineering Microneedle Patches for Improved Penetration:Analysis,Skin Models and Factors Affecting Needle Insertion

Transdermal microneedle(MN)patches are a promising tool used to transport a wide variety of active compounds into the skin.To serve as a substitute for common hypodermic needles,MNs must pierce the human stratum corneum(~10 to 20μm),without rupturing or bending during penetration.This ensures that the cargo is released at the predetermined place and time.Therefore,the ability of MN patches to sufficiently pierce the skin is a crucial requirement.In the current review,the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared.This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice.Factors that affect insertion(e.g.,geometry,material composition and cross-linking of MNs),along with recent advancements in developed strategies(e.g.,insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography)to improve the skin penetration are highlighted to provide a backdrop for future research.

Fabrication of gelatin methacryloyl hydrogel microneedles for transdermal delivery of metformin in diabetic rats

Injection therapy for diabetes has poor patient compliance,and the pain occurring at the site of subcutaneous injections causes significant inconvenience to diabetic patients.In this work,to demonstrate the benefits of an alternative drug delivery technique that overcomes these issues,methacrylated gelatin hydrogel-forming microneedles integrated with metformin were developed to adjust blood glucose levels in diabetic rats.Gelatin methacryloyl microneedles(GelMA-MNs)with different degrees of substitution were successfully prepared by a micro-molding method.The resultant GelMA-MNs exhibited excellent mechanical properties and moisture resistance.Metformin,an anti-diabetic drug,was further encapsulated into the GelMA-MNs,and its release rate could be controlled by the three-dimensional cross-linked network of microneedles,thereby exhibiting sustained drug release behaviors in vitro and implying a better therapeutic effect compared with that of subcutaneous injection in diabetic rats.The drug release period could be significantly prolonged by improving the cross-link density of GelMA-MNs.The results of hypoglycemic effect evaluation show that the application of GelMA-MNs for transdermal delivery in diabetic rats has promising benefits for diabetes treatment.

Depressed Acne Scars—Effective, Minimal Downtime Treatment with a Novel Smooth Motion Non-Insulated Microneedle Radiofrequency Technology

Background: The microneedle fractional RF handpiece used in our study (Intensif Handpiece, EndyMed Medical, Caesarea, Israel) is a novel handpiece that uses a tip with 25 non-insulated, gold plated microneedle electrodes. The needles are inserted into the skin by a specially designed electronically controlled, smooth motion motor minimizing patient discomfort. RF emission delivered over the whole dermal portion of the needle allows effective coagulation resulting in minimal or no bleeding, together with bulk volumetric heating. Study Design/Materials and Methods: The study included 20 patients, treated for depressed acne scars using the IntensifTM?Microneedles handpiece (EndyMed PRO Platform System, EndyMed Medical, Caesarea, Israel). The degree of clinical improvement was assessed by the global aesthetic improvement scale (GAIS) and subjects satisfaction by post treatment questionnaires. Results: The number of treatments per patient varied between 1 and 6 (average 3.3 treatments per patient). Eleven patients (55%) reported none to minimal pain, six (30%) moderate discomfort and only three (15%) reported significant pain. Objective evaluation of the improvement by a board certified dermatologist showed improvement in 95% of patients. 25% showed excellent improvement, 50% experienced good improvement, and the 20% showed minimal improvement. One patient showed no improvement. Conclusions: The presented results show that the tested electronically controlled motorized insertion, non-insulated microneedle treatment technology provides a minimal discomfort, minimal downtime, effective and safe treatment for depressed acne scars.

Design and fabrication of r-hirudin loaded dissolving microneedle patch for minimally invasive and long-term treatment of thromboembolic disease

Cardiovascular disease is the leading cause of global mortality,with anticoagulant therapy being the main prevention and treatment strategy.Recombinant hirudin(r-hirudin)is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous(SC)and intravenous(IV)administration,but there is a risk of haemorrhage via SC and IV.Thus,microneedle(MN)provides painless and sanitary alternatives to syringes and oral administration.However,the current technological process for the micro mould is complicated and expensive.The micro mould obtained via three-dimensional(3D)printing is expected to save time and cost,as well as provide a diverse range of MNs.Therefore,we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch.The results show that r-hirudin-loaded and hyaluronic acid(HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models.These results indicate that based on 3D printing technology,MNs combined with r-hirudin are expected to achieve diverse customizableMNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.

High‑Performance Flexible Microneedle Array as a Low‑Impedance Surface Biopotential Dry Electrode for Wearable Electrophysiological Recording and Polysomnography

Microneedle array(MNA)electrodes are an effective solution to achieve high-quality surface biopotential recording without the coordination of conductive gel and are thus very suitable for long-term wearable applications.Existing schemes are limited by flexibility,biosafety,and manufacturing costs,which create large barriers for wider applications.Here,we present a novel flexible MNA electrode that can simultaneously achieve flexibility of the substrate to fit a curved body surface,robustness of microneedles to penetrate the skin without fracture,and a simplified process to allow mass production.The compatibility with wearable wireless systems and the short preparation time of the electrodes significantly improves the comfort and convenience of electrophysiological recording.The normalized electrode–skin contact impedance reaches 0.98 kΩcm^(2)at 1 kHz and 1.50 kΩcm^(2)at 10 Hz,a record low value compared to previous reports and approximately 1/250 of the standard electrodes.The morphology,biosafety,and electrical/mechanical properties are fully characterized,and wearable recordings with a high signal-to-noise ratio and low motion artifacts are realized.The first reported clinical study of microneedle electrodes for surface electrophysiological monitoring was conducted in tens of healthy and sleep-disordered subjects with 44 nights of recording(over 8 h per night),providing substantial evidence that the electrodes can be leveraged to substitute for clinical standard electrodes.

Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery

Parenteral sustained release drug formulations, acting as preferable platforms for longterm exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.

Fabrication of High-Density Out-of-Plane Microneedle Arrays with Various Heights and Diverse Cross-Sectional Shapes

Out-of-plane microneedle structures are widely used in various applications such as transcutaneous drug delivery and neural signal recording for brain machine interface.This work presents a novel but simple method to fabricate high-density silicon(Si)microneedle arrays with various heights and diverse cross-sectional shapes depending on photomask pattern designs.The proposed fabrication method is composed of a single photolithography and two subsequent deep reactive ion etching(DRIE)steps.First,a photoresist layer was patterned on a Si substrate to define areas to be etched,which will eventually determine the final location and shape of each individual microneedle.Then,the 1st DRIE step created deep trenches with a highly anisotropic etching of the Si substrate.Subsequently,the photoresist was removed for more isotropic etching;the 2nd DRIE isolated and sharpened microneedles from the predefined trench structures.Depending on diverse photomask designs,the 2nd DRIE formed arrays of microneedles that have various height distributions,as well as diverse cross-sectional shapes across the substrate.With these simple steps,high-aspect ratio microneedles were created in the high density of up to 625 microneedles mm^(-2)on a Si wafer.Insertion tests showed a small force as low as~172μN/microneedle is required for microneedle arrays to penetrate the dura mater of a mouse brain.To demonstrate a feasibility of drug delivery application,we also implemented silk microneedle arrays using molding processes.The fabrication method of the present study is expected to be broadly applicable to create microneedle structures for drug delivery,neuroprosthetic devices,and so on.

Enhanced delivery efficiency and sustained release of biopharmaceuticals by complexation-based gel encapsulated coated microneedles:rhIFNα-1b example

Coated microneedles(MNs) are widely used for delivering biopharmaceuticals. In this study, a novel gel encapsulated coated MNs(GEC-MNs) was developed. The water-soluble drug coating was encapsulated with sodium alginate(SA) in situ complexation gel. The manufacturing process of GEC-MNs was optimized for mass production. Compared to the water-soluble coated MNs(72.02% ± 11.49%), the drug delivery efficiency of the optimized GEC-MNs(88.42% ± 6.72%) was steadily increased, and this improvement was investigated through in vitro drug release. The sustained-release of BSA was observed in vitro permeation through the skin. The rhIFN α-1 b GEC-MNs was confirmed to achieve biosafety and 6-month storage stability. Pharmacokinetics of rhIFN α-1 b in GEC-MNs showed a linearly dosedependent relationship. The AUC of rhIFN α-1 b in GEC-MNs(4.51 ng/ml ·h) was bioequivalent to the intradermal(ID) injection(5.36 ng/ml ·h) and significantly higher than water-soluble coated MNs(3.12 ng/ml ·h). The rhIFN α-1 b elimination half-life of GEC-MNs, soluble coated MNs, and ID injection was 18.16, 1.44, and 2.53 h, respectively. The complexation-based GECMNs have proved to be more efficient, stable, and achieve the sustained-release of watersoluble drug in coating MNs, constituting a high value to biopharmaceutical.

Transdermal delivery of fluorescein isothiocyanate-dextrans using the combination of microneedles and low-frequency sonophoresis

This study aimed to evaluate the patient-friendly methods that are used in the delivery of hydrophilic macromolecules into deep skin layers,in particular,the combination of microneedles patch(MNs patch)and low-frequency sonophoresis(SN).The hydrophilic macromolecule drug fluorescein isothiocyanate(FITC)-dextrans(FD-4:MW 4.4 kDa)was used as the model drug in our experimental design.In this study,excised porcine skin was used to investigate and optimize the key parameters that determine effective MNs-and SNfacilitated FD-4 delivery.In vitro skin permeation experiments revealed that the combination of MNs patch with SN had a superior enhancing effect of skin permeation for FD-4 compared to MNs alone,SN alone or untreated skin,respectively.The optimal parameters for the combination of MNs and SN included the following:10 N insertion force of MNs,4 W/cm^(2)SN intensity,6 mm radiation diameter of the SN probe,2 min application time,and the continuous mode duty cycle of SN.In addition,vertical sections of skin,clearly observed under a confocal microscope,confirmed that the combination of MNs and SN enhanced permeation of FD-4 into the deep skin layers.These studies suggest that the combination of MNs and SN techniques could have great potential in the delivery of hydrophilic macromolecules into deep skin.

Mathematical modeling of drug release from biodegradable polymeric microneedles

Transdermal drug delivery systems have overcome many limitations of other drug administration routes,such as injection pain and first-pass metabolism following oral route,although transdermal drug delivery systems are limited to drugs with low molecular weight.Hence,new emerging technology allowing high molecular weight drug delivery across the skin—known as‘microneedles’—has been developed,which creates microchannels that facilitate drug delivery.In this report,drug-loaded degradable conic microneedles are modeled to characterize the degradation rate and drug release profile.Since a lot of data are available for polylactic acid-co-glycolic acid(PLGA)degradation in the literature,PLGA of various molecular weights-as a biodegradable polymer in the polyester family-is used for modeling and verification of the drug delivery in themicroneedles.The main reaction occurring during polyester degradation is hydrolysis of steric bonds,leading to molecular weight reduction.The acid produced in the degradation has a catalytic effect on the reaction.Changes in water,acid and steric bond concentrations over time and for different radii of microneedles are investigated.To solve the partial and ordinary differential equations simultaneously,finite difference and Runge–Kutta methods are employed,respectively,with the aid of MATLAB.Correlation of the polymer degradation rate with its molecular weight and molecular weight changes versus time are illustrated.Also,drug diffusivity is related to matrix molecular weight.The molecular weight reduction and accumulative drug release within the system are predicted.In order to validate and assess the proposed model,data series of the hydrolytic degradation of aspirin(180.16 Da)-and albumin(66,000 Da)-loaded PLGA(1:1 molar ratio)are used for comparison.The proposed model is in good agreement with experimental data from the literature.Considering diffusion as themain phenomena and autocatalytic effects in the reaction,the drug release profile is predicted.Based on our results for a microneedle containing drug,we are able to estimate drug release rates before fabrication.