图1 聚合物微针发展历程示意图

Fig. 1 Schematic diagram of polymer microneedles development

图2 微针的制备方法:(A,B) 减压浇筑法,(A) 利用浓度差制备微针的流程示意图[20]; 使用DPFM制造微针的流程示意图 (B-i); 微针的电子显微图像 (B-ii)[21]; (C) 热压花法[22],热压花制作示意图 (C-i); 微针的扫描电镜图像 (C-ii); (D) 浸渍包覆法,涂层微针制作工艺的示意图[24]; (E,F) 3D打印法[26],(E) 利用FDM3D打印和化学刻蚀技术制作微针的示意图; 制造微针 (F-i) 和在KOH溶液中腐蚀之后 (F-ii) 的光学图像; 制造的微针 (F-iii) 和在KOH溶液中腐蚀之后 (F-iv) 的扫描电子显微镜图像

Fig. 2 Preparation method of microneedles. (A,B) Decompression pouring method. (A) Schematic diagram of the process for preparation of microneedles using concentration differences[20]; Schematic diagram of the process for manufacturing microneedles using DPFM (B-i); Electron microscopic images of microneedles (B-ii)[21]; (C) Hot embossing[22]. Schematic diagram of hot embossing (C-i); Scanning electron microscopic images of microneedles (C-ii); (D) Impregnation and coating method. Schematic diagram of the coating microneedle fabrication process[24]; (E,F) 3D printing method[26]. (E) The schematic illustration of the fabrication of MNs by FDM 3D printing and chemical etching; Optical images of MNs as FDM-fabricated (F-i) and after etching in KOH solution (Fii); SEM images of MNs as fabricated (F-iii) and after etching in KOH solution (F-iv)

图3 微针系统性能表征方法。(A,B) 微针系统的力学性能[28]。(A) 应力建模示意图 (H: 微针的初始高度; H': 微针缺失尖端的高度; r1: 四边形微针底座的一半边长; r2: 四边形微针尖端的初始半侧长度; δ: 微针的位移; rδ: 压缩位移为δ时,接触面的半边长); (B) 不同类型的微针下位移变化 (*: p < 0.05;**: p < 0.01;***: p < 0.001); (C,D) 微针系统的药物递送性能。(C) 微针给药方式[31]; 不同治疗模式下的抑菌率(D-i); SA、PIL-MN和SA-PIL-MN在小鼠模型中的皮肤痤疮治疗的示意图(D-ii)[32]

Fig. 3 Characterization of polymer microneedle systems. (A,B) Mechanical properties of the microneedle system[28]. (A) Schematic diagram of stress modeling (H: initial height of microneedles; H': height of microneedle missing tip; r1: half the side length of the quadrilateral microneedle base; r2: initial half length of the tip of the quadrilateral micro pin; δ: displacement of microneedle; rδ: when the compression displacement is δ, the half length of the contact surface); (B) Displacement changes under different types of microneedles (* : p < 0.05;** : p < 0.01;*** : p < 0.001); (C,D) Drug delivery performance of the microneedle system. (C) microneedle administration method[31]; Bacteriostatic rate under different treatment modes (D-i); Schematic representation of SA, PIL-MN and SA-PIL-Mn for skin acne treatment in a mouse model (D-ii)[32]

图4 不同类型刺激响应性聚合物微针系统的触发释放机制

Fig. 4 Trigger release mechanisms of different types of stimulation-responsive polymer microneedles

图5 外界环境刺激响应性聚合物微针。(A) 光响应性聚合物微针系统:5-Fu-ICG-MPEG-PCL的制备示意图 (A-i); 各组A431荷瘤小鼠的生长曲线 (平均值±标准偏差 (n=5) “**” 表示P<0.01) (A-ii); 1 W/cm2 808nm激光照射5 min后A431荷瘤小鼠的近红外光热效应 (A-iii)[40]; (B) 电响应性聚合物微针系统:MXene微针生物传感器测量的方式和信号处理后的电位峰值 (B-i); MXene微针生物传感器应用 (B-ii)[45]; (C) 磁响应性聚合物微针系统:带有多层MN贴片的磁性驱动胶囊 (C-i); 使用磁力驱动胶囊将微针贴片递送至靶病变的过程 (C-ii)[50]; (D) 热响应性聚合物微针系统。用于控制透皮给药的明胶-PNIPAm微针意图 (D-i); 不同浓度的H2O2中药物释放速率图 (D-ii); 在37 ℃ RS-GP微针(1)、室温下RS-GP微针 (2)、 37 ℃ 普通明胶微针(3) 下的体外释放速率图 (D-iii)[52]; (E) 机械力响应性聚合物微针系统:装有药物的可穿戴设备与微针阵列贴集成 (E-i); 在不同治疗方式下小鼠血糖水平变化 (E-ii)[57]

Fig. 5 Environmentally responsive polymer microneedles. (A) Photoresponsive polymer microneedle system. Schematic diagram of the preparation of 5-Fu-ICG-MPEG-PCL (A-i); Growth curves of A431 tumor-bearing mice in each group (mean ± standard deviation (n=5) “**” denotes P < 0.01) (A-ii); Near-infrared thermal effect of A431 tumor-bearing mice irradiated with 1 W/cm2 808nm laser for 5 min (A-iii)[40]; (B) Electrically responsive polymer microneedle system. MXene microneedle biosensor measurement method and signal processing potential peak (B-i); MXene microneedle biosensor application (B-ii)[45] ; (C) Magnetically responsive polymer microneedle system. magnetically driven capsules with multi-layer MN patches (C-i); The process of using a magnetically driven capsule to deliver a microneedle patch to a target lesion (C-ii)[50]; (D) Thermal responsive polymer microneedle system. Intent of gelatin-PNIPam microneedles for control of transdermal drug delivery (D-i); Drug release rates in different concentrations of H2O2 (D-ii); In vitro release rates of RS-GP microneedles at 37 ℃ (1), room temperature (2) and common gelatin microneedles at 37 ℃ (3) (D-iii)[52]; (E) Mechanical force responsive polymer microneedle system. Integration of medicine-equipped wearable devices with microneedle array patches (E-i); Changes in blood glucose levels of mice under different treatment methods (E-ii)[57]

图6 体内生理信号刺激响应性聚合物微针。(A) pH响应性聚合物微针系统:ZIF-8包封微针的示意图 (A-i); 不同pH条件下CCM释放曲线 (A-ii)[67]; (B) 葡萄糖响应性聚合物微针系统:GRS胰高血糖素递送系统的机制和体外性能 (B-i); 用贴剂治疗后糖尿病小鼠的血浆胰高血糖素浓度变化 (B-ii)[70]; (C) 活性氧响应性聚合物微针系统:微针响应H2O2递释MTX治疗银屑病机理图 (C-i); 在不同浓度H2O2下微针体外释放EGCG速率图 (C-ii)[74]; (D) 酶响应性聚合物微针系统:微针溶解感染伤口清除治疗生物膜的机理示意图 (D-i); 不同pH值和温度下的左旋释放曲线 (D-ii)[82]

Fig. 6 Stimulus-responsive polymer microneedles for physiological signals in vivo. (A) pH-responsive polymer microneedle system. Schematic diagram of ZIF-8 encapsulated microneedles (A-i); CCM release curves under different pH conditions (A-ii)[67]; (B) Glucose-responsive polymer microneedle system. The mechanism and in vitro performance of GRS glucagon delivery system (B-i); Changes in plasma glucagon concentrations in diabetic mice treated with the patch (B-ii)[70]; (C) Reactive oxygen reactive polymer microneedle system. Mechanism diagram of microneedles in response to H2O2 delivered MTX in the treatment of psoriasis (C-i); EGCG release rate of microneedles in vitro at different concentrations of H2O2 (C-ii)[74]; (D) Enzyme-responsive polymer microneedle system. Schematic diagram of the mechanism of microneedle lysis of biofilms in infected wound removal (D-i); left-handed release curves at different pH values and temperatures (D-ii)[82]

图7 刺激响应性聚合物微针系统在不同方面的应用

Fig. 7 Application of Stimulus-responsive polymer microneedle systems

图8 刺激响应性聚合物微针经皮递释应用。(A) 组织器官治疗应用:1 W/cm2 NIR照射2 min前后, MN施加到大鼠背部皮肤的热图像 (A-i); 不同组 (对照组、BP组、BP + Hb组和BP + Hb + NIR组) 的氧释放情况 (A-ii); 第0、3、5、7和9 d不同组皮肤伤口的代表性照片(A-iii)[88]; (B) 检测及传感装置应用:葡萄糖传感器的制造工艺和检测机理图 (B-i); 在0.75 V下连续添加0.2 mM葡萄糖的PBS中的I (A)-t响应曲线 (B-ii); 0.75 V下连续添加0.5 mM葡萄糖、0.025 mM AA、0.5 mM葡萄糖、1 mM尿素和0.025 mM Gly、0.5 mM葡萄糖、0.025 mM AP (B-iii)[91]; (C) 样品提取应用:常规CTAB提取和MN提取示意图 (C-i); 微针贴片穿刺和切断后番茄叶的图像 (C-ii); 微针提取方法和CTAB提取方法作用下的DNA提取量 (C-iii)[93]; (D) 美白及抗衰应用:在对照组、HA微针、明胶微针作用下的皮肤发组织学图像 (D-i); 使用微针前后4周内皮肤弹性变化率 (P<0.05) (D-ii)[99]; (E) 防脱发应用:聚乳酸-乙醇酸接枝透明质酸 (HA-PLGA) 的合成 (E-i); 累积释放曲线(MXD溶液(●)、PLGA/MXD-NP(■)、HA-PLGA/MXD-NP(▲) ) (E-ii)[100]

Fig. 8 Transdermal delivery of stimulus-responsive polymer microneedles. (A) Tissue and organ therapy. Thermal images of MN applied to the back skin of rats before and after 1 W/cm2 NIR irradiation for 2 min (A-i); Oxygen release in different groups (control group, BP group, BP + Hb group and BP + Hb + NIR group) (A-ii);Representative photographs of different groups of skin wounds on days 0, 3, 5, 7 and 9 (A-iii)[88](B) Detection and sensing device application[91]. Diagram of the manufacturing process and detection mechanism of the glucose sensor (B-i); I(A)-t response curve in stirred PBS continuously supplemented with 0.2 mM glucose at 0.75 V (B-ii); 0.5 mM glucose, 0.025 mM AA, 0.5 mM glucose, 1 mM urea, 0.025 mM Gly, 0.5 mM glucose and 0.025 mM AP were added continuously at 0.75 V (B-iii); (C) Sample extraction application. Schematic diagram of conventional CTAB extraction and MN extraction (C-i); Image of tomato leaves after puncture and cut of microneedle patch (C-ii); The amount of DNA extracted by microneedle extraction method and CTAB extraction method (C-iii)[93]; (D) Whitening and anti-aging applications. Histological images of skin hair treated with control, HA and gelatin microneedles (D-i); Change rate of skin elasticity within 4 weeks before and after microneedle application (P<0.05) (D-ii)[99]; (E) Anti-hair loss application. synthesis of polylactic acid-glycolate grafted hyaluronic acid (HA-PLGA) (E-i)[100]; the cumulative release curve (MXD solution (●), PLGA/MXD-NP (■), the HA-PLGA/MXD-NP (▲)) (E-ii)