The state-of-the-art of atmospheric pressure plasma for transdermal drug delivery

Plasma-enhanced transdermal drug delivery(TDD) presents advantages over traditional methods,including painless application, minimal skin damage, and rapid recovery of permeability. To harness its clinical potential, factors related to plasma’s unique properties, such as reactive species and electric fields, must be carefully considered.This review provides a concise summary of conventional TDD methods and subsequently offers a comprehensive examination of the current state-of-the-art in plasma-enhanced TDD. This includes an analysis of the impact of plasma on HaCaT human keratinocyte cells, ex vivo/in vivo studies, and clinical research on plasma-assisted TDD. Moreover, the review explores the effects of plasma on skin physical characteristics such as microhole formation, transepidermal water loss(TEWL), molecular structure of the stratum corneum(SC), and skin resistance. Additionally, it discusses the involvement of various reactive agents in plasma-enhanced TDD, encompassing electric fields,charged particles, UV/VUV radiation, heat, and reactive species. Lastly, the review briefly addresses the temporal behavior of the skin after plasma treatment, safety considerations, and potential risks associated with plasma-enhanced TDD.

Transdermal Drug Delivery by Electroporation： The Effects of Surfactants on Pathway Lifetime and Drug Transport

Electroporation creates aqueous pathways by short high-voltage pulses resulting in a transient perme- abilization of stratum corneum and an increase in the transdermal delivery rate.However the aqueous pathways will reseal after pulsing,which leads to the rapid drop of transdermal flux.In the present study,the surfactants were added to the donor solution to hinder the shrinkage and resealing of the electropore,and to prolong the lifetime of the aqueous pathways with the consideration that the surfactants could reduce the surface energy of the electropore. These effects of surfactants were demonstrated by the dynamic electrical resistance of the skin and the fluorescent imaging of the local transport regions.Piroxicam(PIX)was transported percutaneously in the presence of surfac- tants in vitro.Owing to the longer lifetime of aqueous pathways,together with the promotion of PIX availability at the barrier exterior and the improvement in the partition of PIX into the aqueous pathways,the presence of surfac- tants led to a remarkable increase in the transdermal delivery rate during electroporation and a significant growth of the accumulative transdermal amount of PIX.

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.

Research progress on the application of microneedle transdermal drug delivery system in dermatology

Transdermal drug delivery systems(TDDs)have the advantages on good local targeting,controlled and sustainable drug delivery.Hoewever,the stratum corneum,as the main skin barrier,severely limits the transdermal penetration of drugs and reduces bioavailability,which also limits their application.Microneedles(MNS)penetrate the stratum corneum and create several reversible microchannels in a minimally invasive manner to significantly improve the penetration of therapeutic agents,and are considered a milestone for effective transdermal drug delivery.As an emerging drug delivery modality,microneedle transdermal drug delivery systems have the advantages of being minimally invasive,safe,efficient,economical and convenient.In addition to the extensive research on microneedles for improving transdermal drug delivery,there is a growing interest in using them to manage and treat dermatological conditions.Being the largest organ in the human body,the skin acts as a barrier between the body and the external environment,while having an immense influence on appearance and self-confidence.Indeed,there is now a considerable body of evidence on how dermatological conditions can lead to psychological problems and a reduced quality of life.The utilisation of microneedle transdermal drug delivery systems for the management and treatment of dermatological conditions is of great therapeutic and commercial value.The principleof microneedle transdermal drug delivery systems and the progress of its clinical application in dermatology are reviewed here.

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.

Recent advances in microneedles-mediated transdermal delivery of protein and peptide drugs

Proteins and peptides have become a significant therapeutic modality for various diseases because of their high potency and specificity.However,the inherent properties of these drugs,such as large molecular weight,poor stability,and conformational flexibility,make them difficult to be formulated and delivered.Injection is the primary route for clinical administration of protein and peptide drugs,which usually leads to poor patient’s compliance.As a portable,minimally invasive device,microneedles(MNs)can overcome the skin barrier and generate reversible microchannels for effective macromolecule permeation.In this review,we highlighted the recent advances in MNs-mediated transdermal delivery of protein and peptide drugs.Emphasis was given to the latest development in representative MNs design and fabrication.We also summarize the current application status of MNs-mediated transdermal protein and peptide delivery,especially in the field of infectious disease,diabetes,cancer,and other disease therapy.Finally,the current status of clinical translation and a perspective on future development are also provided.

Microneedle patch loaded with ferritin-nanocaged doxorubicin for locally targeted drug delivery and efficient skin cancer treatment

Ferritin has emerged as a promising nanocarrier for delivering therapeutic agents to tumours.However,the limited drug loading and the off-target impacts after systemic administration remain challenges for cancer treatment with ferritin-based agents.Herein,we develop a microneedle patch loaded with ferritin-nanocaged doxorubicin(DoxFe@Fn/MN)for skin cancer treatment.Briefly,doxorubicin(Dox)is encapsulated in ferritin(Fn)using an iron core-assisted strategy,which results in a 3.4-fold increase in Dox loading compared to the direct loading method.Then,a polyvinyl alcohol-based microneedle(MN)patch is used for the transdermal delivery of DoxFe@Fn,enabling targeted tumour accumulation of DoxFe@Fn and preventing off-target impacts.The released DoxFe@Fn can bind to CD71 highly expressed on skin cancer cells,facilitating its uptake.As a result,the DoxFe@Fn/MN therapy presents a robust antitumour effect in a melanoma tumour model,showing its potential as a promising therapeutic modality for skin cancer treatment.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic,systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate.Several drugs have been used for the treatment of rheumatoid arthritis,but their use is limited by suboptimal bioavailability,serious adverse effects,and nonnegligible first-pass effects.In contrast,transdermal drug delivery systems(TDDSs)can avoid these drawbacks and improve patient compliance,making them a promising option for the treatment of rheumatoid arthritis(RA).Of course,TDDSs also face unique challenges,as the physiological barrier of the skin makes drug delivery somewhat limited.To overcome this barrier and maximize drug delivery efficiency,TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology,and different generations of TDDSs have been derived,which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery.In this review,we summarize the different generations of transdermal drug delivery systems,the corresponding transdermal strategies,and their applications in the treatment of RA.

Transdermal delivery of Chinese herbal medicine extract using dissolvable microneedles for hypertrophic scar treatment

Hypertrophic scars are unfavorable skin diseases characterized by excessive collagen deposition.Although systemic treatments exist in clinic to manage hypertrophic scars,they pose significant side effects and tend to lose efficacy over prolonged applications.Traditional Chinese medicine(TCM)offers as a promising candidate to treat pathological scars.A large number of TCMs have been studied to show anti-scarring effect,however,the natural barrier of the skin impedes their penetration,lowering its therapeutic efficacy.Herein,we reported the use of dissolvable hyaluronic acid(HA)microneedles(MNs)as a vehicle to aid the transdermal delivery of therapeutic agent,a model TCM called shikonin for the treatment of hypertrophic scars.Here,shikonin was mixed with HA to make MNs with adequate mechanical strength for skin penetration,making its dosage controllable during the fabrication process.The therapeutic effect of the shikonin MNs was studied in vira using HSFs and then further verified with quantitative reverse transcriptase polymerase chain reaction.Our data suggest that the shikonin HA MNs significantly reduce the viability and proliferation of the HSFs and downregulate the fibrotic-related genes(i.e.,TGFβ1,FAP-αand COL1 A1).Furthermore,we observed a localized therapeutic effect of the shikonin HA MNs that is beneficial for site-specific treatment.

Wearable patches for transdermal drug delivery

Transdermal drug delivery systems(TDDs) avoid gastrointestinal degradation and hepatic first-pass metabolism, providing good drug bioavailability and patient compliance. One emerging type of TDDs is the wearable patch worn on the skin surface to deliver medication through the skin. They can generally be grouped into passive and active types, depending on the properties of materials,design principles and integrated devices. This review describes the latest advancement in the development of wearable patches, focusing on the integration of stimulus-responsive materials and electronics.This development is deemed to provide a dosage, temporal, and spatial control of therapeutics delivery.

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.

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment

Insulin is widely used in treating diabetes, but still needs to be administered by needle injection. This study investigated a new needle-free approach for insulin delivery. A portable powder needleless injection（PNI） device with an automatic mechanical unit was designed. Its efficiency in delivering insulin was evaluated in alloxan-induced diabetic rabbits. The skin irritation caused by the device was investigated and the results were analyzed in relation to aerodynamic parameters. Inorganic salt-carried insulin powders had hypoglycemic effects, while raw insulin powders were not effective when delivered by PNI, indicating that salt carriers play an important role in the delivery of insulin via PNI. The relative delivery efficiency of phosphate-carried insulin powder using the PNI device was 72.25%. A safety assessment test showed that three key factors（gas pressure, cylinder volume, and nozzle distance） were related to the amount of skin irritation caused by the PNI device. Optimized injection conditions caused minimal skin lesions and are safe to use in practice. The results suggest that PNI has promising prospects as a novel technology for delivering insulin and other biological drugs.

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.

The progress of fabrication designs of polymeric microneedles and related biomedical applications

Microneedles(MNs)have been broadly used for transdermal delivery of a variety of drugs,ranging from small chemicals to biological macromolecules,due to the properties of increased drug permeability,minimal invasiveness and improved patient compliance.Despite these MNs can be made of different materials,such as metal,silicon,and glass,polymers have attracted the most attention as a microneedle(MN)matrix because of their excellent biocompatibility and biodegradability,which eliminates the requirement of MN removal after drug release.To satisfy different needs of transdermal drug delivery,polymeric MNs have been fabricated with several special designs.In this review,we summarize the advancement of the fabrication designs of polymeric MNs,including integrated MNs,two-segment MNs,core-shell or multi-layered MNs,and arrowhead MNs.The related biomedical applications of MNs with these different specific designs are also discussed.Finally,we provide our perspectives on the future development of polymeric MNs.

水凝胶微针在经皮给药系统中的研究进展

微针是一种微凸起阵列组成的微创装置,穿过皮肤角质层形成暂时性微通道,可实现对药物的经皮递送。对微针在经皮给药应用中的优缺点进行了简单阐述,重点介绍了水凝胶微针。综述了水凝胶微针的形成机制、基质材料及制备方法,并对水凝胶微针在疾病诊断和治疗方面的应用进行了介绍,指出了水凝胶微针在生物安全性、制定载药量标准等方面存在的问题,对未来的研究方向进行了展望。智能化、便携化是未来的微针发展趋势,若可以实现根据患者需求在给药时间、给药部位、给药剂量等方面的精准调控,水凝胶微针将在疾病诊断与治疗方面发挥更大的潜力。

皮肤脂质与仿皮肤脂类脂质体经皮给药的研究进展

目的对皮肤脂质与仿皮肤脂类脂质体(liposomes resembling skin lipids,LRSL)进行综述。方法参阅国内外209篇文献,总结了皮肤脂质组成及其含量、皮肤脂质的功能和皮肤疾病,并对LRSL的发现、形成与稳定性、脂质组成、形态大小、制备方法、在体内的变化、优势及应用进行归纳、总结和分析。结果LRSL能将有效成分递送至皮肤的深层,具有较好的稳定性和安全性,并能起到修复皮肤屏障的作用。因此,LRSL在药物的治疗方面具有非常大的优越性与可行性。结论为LRSL的开发提供了参考。

脂质纳米粒在经皮给药系统中治疗皮肤病的应用

经皮给药作为一种非侵入性给药方式,正逐渐受到广大医药工作者和患者的青睐。然而,皮肤角质层的屏障功能限制了药物的经皮吸收。脂质纳米粒作为一种新型的药物载体能够有效提高皮肤渗透性、减少药物相关副作用。本文就脂质纳米粒的特点、透皮作用机制以及在多种皮肤病中的应用做一综述,阐明脂质纳米粒在经皮给药领域的广阔发展前景,为脂质纳米粒的开发及临床应用提供参考。

点阵激光辅助透皮给药在皮肤美容及损容性皮肤病中的应用

点阵激光通过产生矩阵排列的微光束,在皮肤上形成分布均匀的微热治疗区,最大限度地保留了正常皮肤组织,与传统激光相比创伤小、恢复快。近年来发现点阵激光能够作为辅助透皮给药手段,可控地破坏皮肤屏障,促进局部用药的透皮吸收,拓展了外用制剂的选择范围。本文就点阵激光辅助透皮给药技术在皮肤美容及损容性皮肤病中的应用做一综述。

经皮给药系统皮肤模型的研究进展

经皮给药系统(transdermal drug delivery system,TDDS)的皮肤模型是指构建能够模拟人体皮肤结构和功能,并用于研究和评估药物在经皮给药过程中的吸收、渗透及药效等方面的实验模型。该模型可代替传统人体皮肤实验,减少药物开发过程中对人体皮肤的使用,为经皮制剂的研发提供一种便捷、可控且经济高效的方法。针对经皮给药系统的皮肤模型,本文从药物经皮吸收途径出发,对目前常用的动物皮肤模型、人工皮肤模型、重组人体皮肤模型进行介绍,并对其优缺点及应用进行了分析,为经皮制剂的研发提供参考。