Astragalus membranaceus(Fisch.)Bge.administered by dissolving microneedles achieves systemic therapeutic effects at low doses Author links open overlay panel

Objective:To determine the main components of Astragalus membranaceus(Fisch.)Bge(A.membranaceus,Huang Qi),Astragaloside IV(AIV)and Astragalus polysaccharides(AP),to characterize their properties,evaluate their in vivo efficacy,and to analyze drug diffusion using dissolving microneedle(DMN)technology in vivo.Methods: Respectively,AIV-and AP-loaded DMNs comprising chitosan(CTS)and polyvinyl alcohol(PVA)were prepared via dual-mold forming.Their morphology,mechanical properties,in vivo solubility,and skin irritation characteristics were tested.In vivo efficacy was assessed in cyclophosphamide-induced immunosuppressed mice,in vivo diffusion of AIV and AP by DMNs and conventional methods was compared,and the rheological properties of AIV-CTS-PVA and AP-CTS-PVA mixtures were measured.Results: Subcutaneous dissolution and absorption of AIV-CTS-PVA and AP-CTS-PVA microneedles(MNs)at low doses(50%–17%of intraperitoneal AIV injection and 12%–4%of intravenous AP injection)reduced the spleen index and acid phosphatase activity in immunosuppressed mouse models,increased the thymus index,and achieved equivalent or better systemic therapeutic effects.Compared with injections,AIV and AP achieved controllable solid-liquid conversion through delivery with CTS-PVA MNs,resulting in highly localized aggregation within 48 h,reducing the initial explosive effect of the drug,and achieving stable and slow drug release.Conclusion: The present study enhances our understanding of the efficacy and remote effects of drug-loaded DMNs from a traditional Chinese medicine(TCM)perspective,thereby promoting the development of precise and efficient delivery of TCM and further expanding the drug-loading range and application scenarios for DMNs.

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.

pH-activatable oxidative stress amplifying dissolving microneedles for combined chemo-photodynamic therapy of melanoma

Photodynamic therapy(PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation,but the strong hydrophobicity and poor tumor selectivity of photosensitizers,as well as the oxygen-consuming properties of PDT,leading to unsatisfactory therapeutic outcomes.Herein,a tumor acidic microenvironment activatable dissolving microneedle(DHA@HPFe-MN)was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification.The versatile DHA@HPFe-MN was fabricated by crosslinking a self-synthesized protoporphyrin(PpIX)-ADH-hyaluronic acid(HA)conjugate HA-ADH-PpIX with“iron reservoir”PA-Fe 3+complex in the needle tip via acylhydrazone bond formation,and dihydroartemisinin(DHA)was concurrently loaded in the hydrogel network.HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect.DHA@HPFe-MN with sharp needle tip,efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites,where the acidic pH triggered the degradation of microneedles,enabling Fe-activated and DHA-mediated oxidation treatment,as evidenced by abundant reactive oxygen species(ROS)generation.Moreover,under light irradiation,a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation.Importantly,the Fe-catalyzed ROS production of DHA was oxygen-independent,which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells.This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodynamic therapy of melanoma.

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.

Application of Curcumin Microneedles

[Objectives]To prepare curcumin solid dispersion(Cur SD)by the melting method,using povidone(PVP K30),polyethylene glycol 6000(PEG 6000),and poloxamer 188(block polyether F-68,poloxamer 188,F68)as the carrier matrix,the body was directly inverted and pressed to make microneedles,and the dissolution was examined.[Methods]The dissolution in 0.2%sodium lauryl sulfate(SDS)solution within 120 min was studied,and the objects were identified by scanning electron microscopy,differential scanning calorimetry and infrared spectroscopy.[Results]The cumulative dissolution rate of 10%solid dispersion microneedles reached more than 60%in 120 min.The results of object identification also showed that curcumin was dispersed in the carrier matrix in an amorphous state.[Conclusions]Microneedles were well formed and curcumin solid dispersion significantly improved the dissolution of curcumin in 120 min.

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.

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.

Usefulness of Basic Fibroblast Growth Factor (bFGF) Loaded Dissolving Microneedles for Local Therapy of Skin Wounds

Purpose: The usefulness of dissolving microneedles (DMs) for local skin therapy by basic fibroblast growth factor (bFGF) was studied in rats. Methods: We prepared four kinds of bFGF-loaded DMs, approximately 500 μm length and 300 μm diameter at the bottom. Long-term stability and dissolution studies were performed by HPLC method. Pharmacokinetic and pharmacological evaluations were performed after administration of bFGF loaded DMs to rats. Results: The bFGF contents were 2.15 ± 0.07, 1.07 ± 0.04, 0.56 ± 0.07 and 0.12 ± 0.03 μg. The 100.2 ± 3.4%, 100.2 ± 3.3%, 99.3 ± 1.4% and 100.4 ± 3.0% of bFGF were recovered after 1, 3 and 6 months and 1 year incubation at 40°C. The bFGF was released from DMs within 5 min. In a pharmacokinetic study using 2.0 and 1.0 μg bFGF-loaded DMs, no systemic exposure of bFGF was detected. The initial bFGF concentrations in the rat skin tissue after administration of bFGF-loaded DMs to the hair-removed rat abdominal skin were 510.2 ± 20.1 ng/g wet weight for 2 μg bFGF DMs and 264.2 ± 56.5 ng/g wet weight for 1 μg DMs, declining slowly thereafter to 226.3 ± 33.5 and 105.1 ± 27.4 ng/g wet weight at 6 hr after administration. Good dose-dependency was observed. Pharmacological evaluation of bFGF-loaded DMs of 2.0, 1.0, 0.5, and 0.1 μg, in the wound healing rat model, all used DMs, but 0.1 μg DMs, showed good healing effects. Considered collectively, these results suggest the usefulness of bFGF-loaded DMs for local therapy of skin wound disease.

Two-and Three-Layered Dissolving Microneedles for Transcutaneous Delivery of Model Vaccine Antigen in Rats

Purpose: Comparison of transcutaneous immunization of ovalbumin (OA) between two-and three-layered dissolving microneedles (MN) in rats. Methods: We prepared 500 μm long two-layered and three-layered dissolving microneedle (2-MN and 3-MN, respectively) arrays from chondroitin sulfate as the base, and OA as the model antigen. The 2-MN containing OA at the acral portion and 3-MN with OA at the second portion were administered to rat skin transcutaneously. As a positive control, OA solution was injected subcutaneously (sc). The OA delivery and diffusion in the rat skin were studied using confocal microscopy with fluorescein-conjugated OA (FL-OA). Results: The formulated positions of OA were 0-155 ± 5 μm for 2-MN and 175 ± 4 – 225 ± 5 μm for 3-MN. The administered doses of OA were 2.2 ± 0.1 μg, 12.0 ± 0.2 μg and 22.0 ± 0.2 μg for 2-MN, 1.8 ± 0.2 μg, 12.6 ± 0.7 μg, and 20.4 ± 0.3 μg for 3-MN, 10 μg, 100 μg and 1000 μg for sc injection. At 4 weeks after the first administration, 3-MN showed about 2.5-7.0 fold and 5.4 fold higher total Ig (G + A + M) antibody than 2-MN and sc injection of the OA solution. Conclusions: The 3-MN, which delivered OA to the epidermis, is a useful drug delivery system for transcutaneous antigen delivery.

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.

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.

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.

Transdermal Study of Curcumin Solid Dispersion Microneedles in vitro

[Objectives]To investigate the in vitro transdermal effect of curcumin solid dispersion needles prepared with povidone K 30(PVP K30),polyethylene glycol 6000(PEG 6000)and poloxamer 188(block polyether F68,poloxamer 188,F68)as carrier matrix,respectively.[Methods]Vertical Franz diffusion cell and HPLC method were used to detect the cumulative penetration and skin retention of the microneedles within 12 h.[Results]Within 12 h,the cumulative penetration of PVP K30 microneedles was as high as 7.098μg/cm2,and the skin retention reached 35.28μg/cm2;PEG 6000 and poloxamer 188 microneedles all showed good transdermal effect;while normal curcumin solid dispersion(control)had no obvious transdermal effect.[Conclusions]The transdermal penetration of curcumin is improved after prepared into solid dispersion microneedles,and among different matrixes,PVP K30 is the best choice.

Drug Loading on Microneedles

An experimental study was carried out to investigate the amount of drugs loaded on microneedles. The microneedles were made with poly (lactic acid). Aqueous poly (vinyl alcohol) solutions were prepared as drug solutions. Two drug loading approaches, i.e., dropping and dipping, were examined. It was found that capillary number is the only relevant dimensionless group for the two methods. For the dropping approach, dried drugs will spread near the bottom of a microneedle patch provided the surface tension is low. As for the dipping approach, both a single microneedle and an array of nine microneedles were examined. For a single microneedle, high capillary rises before pulling and pulling speed are two key factors to increase the drug loading volume. For an array of microneedles, the effect of capillary rise owing to the interaction between microneedles would increase the drug loading volume several times higher than a single microneedle of the same dimension.

Lidocaine hydrochloride loaded isomaltulose microneedles for efficient local anesthesia of the skin

Lidocaine hydrochloride(LIDH) as an anesthetic is widely used in local anesthesia. Dissolving microneedles(MNs) have great application value in the field of skin anesthesia. However, the limited drug-loading of dissolving MNs is an existing challenge that affects clinical use. In this study, we have screened isomaltulose(ISO) as the proper matrix material for the MNs by using molecular dynamics(MD) simulation. Our findings indicate that ISO has good compatibility with LIDH, and the LIDH-loaded ISO MNs(LI-MNs) have high drug-loading capacity. The drug-loading capacity of LI-MNs could reach 80%, and it could effectively puncture the skin. In addition, the preparation method of customized LI-MNs was established based on three-dimensional(3D) printing technology. It was shown that the administration time of LI-MNs could be controlled within 3 min. Also, the LI-MNs were able to provide the local anesthetic efficacy within2 min and sustained for more than 2 h. Significantly, LI-MNs had more efficient drug efficacy compared to the topical creams and the majority of existing LIDH-loaded dissolving MNs. They even provided a longer duration of action than the injections. Overall, the LI-MNs with high drug-loading have a promising application prospect.

Recent progress of vaccines administration via microneedles for cancer immunotherapy

Therapeutic cancer vaccines have undergone a resurgence in the past decade.Because of the high level of immune cell accumulation and abundant capillary lymphatic system in the dermis,percutaneous vaccination is considered to be an ideal treatment route.For convenient administration,the recent development of microneedles(MNs)provides a safe,painless,and low-cost transdermal delivery strategy,which could bypass the first-pass metabolism of vaccines for enhanced stability and bioavailability.However,the therapeutic effect of MNs-based cancer vaccines is not optimal,which is limited by the complex set of host,tumor,and environmental factors,as well as the limited vaccine loading capacity.Therefore,further improvements are still required to push their clinical translation.In this critical review,we deliberate on how to improve the therapeutic effect of MNs-based vaccines for cancer immunotherapy,summarize the recent advances in MNs-based cancer vaccination,and provide an overview of various design strategies and mechanisms for active or passive targeting delivery,aiming to develop safer,more effective,and more stable MNs-based cancer vaccines.Finally,we briefly describe the potential of vaccine platforms in combination with other therapies,suggest the need to design vaccines according to specific circumstances,and discuss the biosafety of repeated administration for enhancing clinical efficacy.

Pharmacokinetic and pharmacodynamic study of triptolide-loaded liposome hydrogel patch under microneedles on rats with collagen-induced arthritis

Triptolide (TP), a major active component of Triptelygium wilfordii Hook.F. (TWHF), is used to treat rheumatoid arthritis (RA). However, it has a narrow therapeutic window due to its serious toxicities. To increase the therapeutic index, a new triptolide-loaded transdermal delivery system, named triptolide-loaded liposome hydrogel patch (TP-LHP), has been developed. In this paper, we used a micro-needle array to deliver TP-LHP to promote transdermal absorption and evaluated this treatment on the pharmacokinetics and pharmacodynamics of TP-LHP in a rat model of collagen-induced arthritis (CIA). The pharmacokinetic results showed that transdermal delivery of microneedle TP-LHP yielded plasma drug levels which fit a one compartment open model. The relationship equation between plasma concentration and time was C=303.59 x (e(-0.064t)-e(-0.287t)). The results of pharmacodynamic study demonstrated that TP-LHP treatment mitigated the degree of joint swelling and suppressed the expressions of fetal liver kinase-1, fetal liver tyrosine kinase-4 and hypoxia-inducible factor-1a in synovium. Other indicators were also reduced by TP-LHP, including hyperfunction of immune, interleukin-1/3 and interleukin-6 levels in serum. The therapeutic mechanism of TP-LHP might be regulation of the balance between Thl and Th2, as well as inhibition of the expression and biological effects of vascular endothelial growth factor. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

Synergistic immunoreaction of acupuncture-like dissolving microneedles containing thymopentin at acupoints in immune-suppressed rats

Dissolving microneedles carried drug molecules can effectively penetrate the stratum corneum of skin to improve the transdermal drug delivery. The traditional Chinese medicine acupuncture is based on the needle stimulation at a specific location(acupoint) to generate and transmit biochemical and physiological signals which alter the pathophysiological state of patients. However, the pain associated with conventional acupuncture needles and the requirement of highly trained professionals limit the development of acupuncture in non-Asian countries. The purpose of this study is to investigate whether the dissolving microneedles can be utilized as a self-administered painless replacement for acupuncture and locally released drug molecules can achieve expected therapeutic outcomes. Immunosuppressive rats were treated with acupuncture at Zusanli(ST36) acupoint using microneedles containing thymopentin.The immune functions and psychological mood of the immunosuppressed animals were examined. The proliferation of splenocytes was examined by CCK-8 assay. CD4 and CD8 expression patterns in spleen cells were detected by flow cytometry. The current study showed that use of either microneedles containing thymopentin or conventional acupuncture both resulted in immune cell proliferation, which was confirmed by flow cytometry. Furthermore, either conventional acupuncture or microneedles were able to effectively mitigate the anxiety caused by immune-suppression when applied on the ST36.

High-fidelity replication of thermoplastic microneedles with open microfluidic channels

Development of microneedles for unskilled and painless collection of blood or drug delivery addresses the quality of healthcare through early intervention at point-of-care.Microneedles with submicron to millimeter features have been fabricated from materials such as metals,silicon,and polymers by subtractive machining or etching.However,to date,large-scale manufacture of hollow microneedles has been limited by the cost and complexity of microfabrication techniques.This paper reports a novel manufacturing method that may overcome the complexity of hollow microneedle fabrication.Prototype microneedles with open microfluidic channels are fabricated by laser stereolithography.Thermoplastic replicas are manufactured from these templates by soft-embossing with high fidelity at submicron resolution.The manufacturing advantages are(a)direct printing from computeraided design(CAD)drawing without the constraints imposed by subtractive machining or etching processes,(b)high-fidelity replication of prototype geometries with multiple reuses of elastomeric molds,(c)shorter manufacturing time compared to three-dimensional stereolithography,and(d)integration of microneedles with open-channel microfluidics.Future work will address development of open-channel microfluidics for drug delivery,fluid sampling and analysis.