皮肤类器官的构建、功能及其应用研究进展

皮肤类器官作为一种新型的类器官模型,不仅能高度模拟皮肤组织的生理结构和功能,更好地在不同体外环境下还原较真实的皮肤生态,还可以应用于皮肤发育研究、皮肤疾病病理研究及药物筛选等领域。在干细胞研究中,皮肤类器官模型可以在特殊的生境下对具有特定功能的皮肤细胞及其附属物进行重建和改造,以弥补现有体外皮肤模型在结构、功能等方面的不足。基于此,皮肤类器官将会在皮肤再生、组织修复、药物筛选及医学美容等方面扮演越来越重要的角色。本文详述了皮肤类器官构建中所参与的细胞来源及近年来的应用,并对未来皮肤类器官的发展与优化做出了展望。     

织物电极的皮肤-电极接触阻抗测量方法分析

随着可穿戴式健康监测技术的发展,新型心电传感器-织物电极成为人们关注的热点,本文对织物电极的皮肤-电极接触阻抗测量方法进行了综述。首先介绍了织物电极的概念,分析了织物电极的皮肤-电极电化学界面、皮肤-电极电化学界面的等效电路和简化电路模型,得出了皮肤-电极接触阻抗的计算公式;其次,将皮肤-电极接触阻抗的测量方法归纳为直接测量法、参比测量法和模拟皮肤测量法三类,讨论了它们的测量原理和优缺点。本文认为需将模拟皮肤测量法和真实皮肤测量法有机结合,才能有效评价织物电极的阻抗特性,为织物电极的性能评价和心电信号采集电路的设计提供重要依据。最后,本文对织物电极待解决的问题进行了分析讨论。     

皮肤的光学模型

基于人体皮肤的组织结构,光在皮肤组织中的传输特性以及皮肤各层的组织光学参数,建立了正常皮肤的光学模型,介绍了该模型中的组织光学参数的确定方法。本文建立的皮肤组织光学模型及其方法,可应用于皮肤光学基础与临床的其它研究中。     

组织工程皮肤生物反应器的研究与设计

目的设计一套生物反应器,能针对不同支架材料———细胞复合物进行构建组织工程皮肤。方法根据皮肤的自身生长特点和不同支架材料-细胞复合物的特性,模拟皮肤的生长环境和力学环境,通过生物反应器解决组织工程皮肤构建中支架的装夹和气液界面问题。结果生物反应器由控制系统和生物反应器主体两部分构成,能提供对多种皮肤细胞复合物的动态培养。结论皮肤生物反应器能够满足不同组织工程皮肤产品的需要。能够形成气液界面和模拟生物力学的刺激。     

微针技术用于非经皮途径的药物递送研究进展

近年来,微针作为一种新兴的经皮给药技术,具有微创、无痛、使用方便和高效的特点,逐渐成为一种极具研究价值和应用潜力的给药策略。微针技术在过去20年中得到迅速发展并呈现出多样化的趋势,已可根据不同需求来定制微针的形状、组成、机械性能和其他特殊功能等。由于微针能以微创方式穿越各种生物屏障,因此许多研究人员探索了微针在除皮肤外各类组织和器官中的药物递送应用。本文综述了微针技术及其近年来在眼睛、血管、心脏等组织和器官的药物递送中的应用研究,以期推动微针技术的应用发展。     

基于物理方法的皮肤创伤动物模型构建及评价指标研究进展

皮肤创伤已成为全球性公共问题,尤其是慢性伤口的难愈合严重影响了患者的健康生活。目前,物理方法构建皮肤创伤动物模型是研究皮肤创面的主要方法,而不同的皮肤创伤动物模型其生物学特点不同。因此,本文通过检索Pubmed、中国知网近5年与皮肤创伤动物模型构建的相关资料,以小鼠、大鼠、其他动物的皮肤创伤模型进行分类,总结并分析了基于物理方法的皮肤创伤动物模型的构建方法及评价指标,并评价不同动物模型的优缺点,旨在对皮肤创伤动物模型的合理构建及药物的研究开发提供思路。     

基于壳聚糖的搭载光源可溶性微针的制备与评价

光动力疗法与给药微针(microneedle, MN)相结合为治疗肿瘤提供了一种安全有效的途径。本文设计了一种基于壳聚糖搭载高能光子的可控缓释型载药微针贴片(LED-losartan-HEMA/ CS-MN, LLH-CSMN),重点研究了其制备工艺,并且以氯沙坦为模型药物对微针阵列的形貌尺寸进行了表征,探究了LLH-CSMN的力学性能、皮肤穿刺性能、缓释性能以及高能光子在长时间工作下的光热性能。结果表明,基于壳聚糖搭载高能光子的微针贴片能够有效地在皮肤表面打开通道进行药物递送,并进行光动力治疗。同时,体外透皮扩散试验表明,以氯沙坦为模型药物制备的微针在1 h内释放了约30%的药物,在1 d内总共释放了约60%的药物,随后进行缓慢释放,在6 d后最终释放了93%的药物,LLH-CSMN具有可控缓释特性以及良好的长效光辅助治疗效果,为肿瘤治疗提供了一个新的安全有效途径。     

组织工程皮肤研究现状

组织工程皮肤是通过培养功能细胞,将其与细胞外基质及支架材料互相作用,制成的具有生物活性的人工皮肤替代物。组织工程皮肤的发展为修复皮肤创面,重建皮肤功能,治疗皮肤病提供了新的方法。本文从皮肤种子细胞培养、真皮支架材料和体外构建活性复合皮三个方面对组织工程皮肤的研究进展进行了综述。目前组织工程皮肤在一定程度上克服了原有的皮肤供区不足、免疫排斥、传播疾病等各种问题。新的种子细胞和支架材料逐渐成熟,并逐渐应用于临床治疗;在种子细胞和真皮替代物基础上发展起来的复合皮肤可以更快速的促进缺损皮肤的愈合,但与在体皮肤比较尚有差距。组织工程皮肤是理想的皮肤替代物,具有良好的发展前景,未来的研究应该着眼于模仿机体皮肤的生理结构和功能,使愈合后的皮肤与在体皮肤融为一体。     

组织工程皮肤研究现状

组织工程皮肤是通过培养功能细胞,将其与细胞外基质及支架材料互相作用,制成的具有生物活性的人工皮肤替代物。组织工程皮肤的发展为修复皮肤创面,重建皮肤功能,治疗皮肤病提供了新的方法。本文从皮肤种子细胞培养、真皮支架材料和体外构建活性复合皮三个方面对组织工程皮肤的研究进展进行了综述。目前组织工程皮肤在一定程度上克服了原有的皮肤供区不足、免疫排斥、传播疾病等各种问题。新的种子细胞和支架材料逐渐成熟,并逐渐应用于临床治疗;在种子细胞和真皮替代物基础上发展起来的复合皮肤可以更快速的促进缺损皮肤的愈合,但与在体皮肤比较尚有差距。组织工程皮肤是理想的皮肤替代物,具有良好的发展前景,未来的研究应该着眼于模仿机体皮肤的生理结构和功能,使愈合后的皮肤与在体皮肤融为一体。     

体外皮肤刺激模型的生物标志研究进展

皮肤刺激试验是人类健康相关产品危险性评价的常见项目,传统皮肤刺激试验采用实验动物进行,成本高周期长,给动物造成一定程度的痛苦。近年来,多种替代动物试验的体外模型被开发和应用。体外试验主要通过定量检测细胞活性和代谢变化的生物标志物预测体内的效应,应用最广泛的生物标志物是细胞活性、炎性因子、胞质酶等,在生物技术的推动下,新的特异性标志物被开发和验证。     

Numerical simulation of microneedles' insertion into skin

Microneedles have recently received much attention as a novel way for transdermal drug delivery. In this paper, a numerical simulation of the insertion process of the microneedle into human skin is reported using the finite element method. A multilayer skin model consisting of the stratum corneum, dermis and underlying hypodermis has been developed. The effective stress failure criterion has been coupled with the element deletion technique to predict the complete insertion process. The numerical results show a good agreement with the reported experimental data for the deformation and failure of the skin and the insertion force. The influences of the mechanical properties of the skin and the microneedle geometry (e.g. tip area, wall angle and wall thickness) on the insertion force are discussed. The numerical results are helpful for the optimum design of the microneedles for the transdermal drug delivery system.     

Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force

As a hybrid between a hypodermic needle and transdermal patch, we have used microfabrication technology to make arrays of micron-scale needles that transport drugs and other compounds across the skin without causing pain. However, not all microneedle geometries are able to insert into skin at reasonable forces and without breaking. In this study, we experimentally measured and theoretically modeled two critical mechanical events associated with microneedles: the force required to insert microneedles into living skin and the force needles can withstand before fracturing. Over the range of microneedle geometries investigated, insertion force was found to vary linearly with the interfacial area of the needle tip. Measured insertion forces ranged from approximately 0.1-3N, which is sufficiently low to permit insertion by hand. The force required to fracture microneedles was found to increase with increasing wall thickness, wall angle, and possibly tip radius, in agreement with finite element simulations and a thin shell analytical model. For almost all geometries considered, the margin of safety, or the ratio of fracture force to insertion force, was much greater than one and was found to increase with increasing wall thickness and decreasing tip radius. Together, these results provide the ability to predict insertion and fracture forces, which facilitates rational design of microneedles with robust mechanical properties.     

生物相容透皮给药微针治疗浅表肿瘤

复杂的肿瘤微环境导致抗肿瘤药物在肿瘤组织内递送效率低下，严重阻碍了药物对浅表肿瘤的治疗效果。生物相容透皮给药微针凭借较高的机械强度，刺穿皮肤角质层，将微针内的药物递送至浅表肿瘤组织内，提高生物利用度，改善静脉注射、口服给药的肝肾毒性等问题。本文介绍了生物相容透皮给药微针的设计及其在癌症化疗、光动力治疗、光热治疗、免疫治疗、基因治疗等领域的研究进展，对浅表肿瘤的微创、局部递药和精准、高效治疗具有重要指导意义。     

Numerical simulation of microneedles' insertion into skin

Microneedles have recently received much attention as a novel way for transdermal drug delivery. In this paper, a numerical simulation of the insertion process of the microneedle into human skin is reported using the finite element method. A multilayer skin model consisting of the stratum corneum, dermis and underlying hypodermis has been developed. The effective stress failure criterion has been coupled with the element deletion technique to predict the complete insertion process. The numerical results show a good agreement with the reported experimental data for the deformation and failure of the skin and the insertion force. The influences of the mechanical properties of the skin and the microneedle geometry (e.g. tip area, wall angle and wall thickness) on the insertion force are discussed. The numerical results are helpful for the optimum design of the microneedles for the transdermal drug delivery system.     

The Troy Microneedle: A Rapidly Separating,Dissolving Microneedle Formed by Cyclic Contact and Drying on the Pillar (CCDP)

In dissolving microneedle (DMN)-mediated therapy, complete and rapid delivery of DMNs is critical for the desired efficacy. Traditional patch-based DMN delivery, however, may fail due to incomplete delivery from insufficient skin insertion or rapid separation of microneedles due to their strong bond to the backing film. Here, we introduce the Troy microneedle, which was created by cyclic contact and drying on the pillar (CCDP), and which enabled simultaneous complete and rapid delivery of DMN. This CCDP process could be flexibly repeated to achieve a specific desired drug dose in a DMN. We evaluated DMN separation using agarose gel, and the Troy microneedle achieved more complete and rapid separation than other, more deeply dipped DMN, primarily because of the Troy’s minimal junction between the DMN and pillar. When Troy microneedles were applied to pig cadaver skin, it took only 15 s for over 90% of encapsulated rhodamine B to be delivered, compared to 2 h with application of a traditional DMN patch. In vivo skin penetration studies demonstrated rapid DMN-separation of Troy microneedles still in solid form before dissolution. The Troy microneedle overcomes critical issues associated with the low penetration efficiency of flat patch-based DMN and provides an innovative route for DMN-mediated therapy, combining patient convenience with the desire drug efficacy.     

聚四氟乙烯微针模具的性能考察

目的:考察用聚四氟乙烯(PTFE)制作相转化水凝胶微针模具的性能。方法:聚四氟乙烯模具经过粉末的过筛、压制、烧结、制孔而得。实验制备了不同聚四氟乙烯粉料粒度、不聚四氟乙烯粉料用料量、不同生料板压制压力的聚四氟乙烯微针模具,向模具中浇注以PVA为基质的聚合物溶液,通过冷冻解冻制得相转化水凝胶微针,考察模具的孔径、载料量以及微针的揭膜难易程度和完形率。结果:80目以上细度的模具透光性能均一;随着聚四氟乙烯用料量的增加和生料板压制压力的增大,模具的孔径和载药量减小,揭膜更容易、完形率更高。结论:聚四氟乙烯模具的性能与其密度密切相关,密度越大的模具,蠕变的随意性越大,因而孔洞均一性下降,但是揭膜性能变好,完形率提高。这两个相反的趋势提示我们,四氟乙烯模具的优劣是相转化水凝胶微针中的第一个控制性因素,聚四氟乙烯是制作微针模具的可接受材料,有进一步研究的价值。     

Fabrication,Physicochemical Characterization,and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.     

Predicting the optimal geometry of microneedles and their array for dermal vaccination using a computational model

Microneedle arrays have been developed to deliver a range of biomolecules including vaccines into the skin. These microneedles have been designed with a wide range of geometries and arrangements within an array. However, little is known about the effect of the geometry on the potency of the induced immune response. The aim of this study was to develop a computational model to predict the optimal design of the microneedles and their arrangement within an array. The three-dimensional finite element model described the diffusion and kinetics in the skin following antigen delivery with a microneedle array. The results revealed an optimum distance between microneedles based on the number of activated antigen presenting cells, which was assumed to be related to the induced immune response. This optimum depends on the delivered dose. In addition, the microneedle length affects the number of cells that will be involved in either the epidermis or dermis. By contrast, the radius at the base of the microneedle and release rate only minimally influenced the number of cells that were activated. The model revealed the importance of various geometric parameters to enhance the induced immune response. The model can be developed further to determine the optimal design of an array by adjusting its various parameters to a specific situation.