Polymeric Porous Surface Materials: Construction and Drug Delivery Applications

Yanchen Chen; Honglin Qian; Yirong Guo; Jing Wang; Jian Ji

doi:10.7536/PC230919

Progress in Chemistry >

2024 , Vol. 36 >Issue 5: 679 - 695

DOI: https://doi.org/10.7536/PC230919

Review

Polymeric Porous Surface Materials: Construction and Drug Delivery Applications

Yanchen Chen ,
Honglin Qian ,
Yirong Guo ,
Jing Wang ^,^* ,
Jian Ji ^,^*

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MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China

* e-mail: wangjing2015@zju.edu.cn (Jing Wang);

jijian@zju.edu.cn (Jian Ji)

Received date: 2023-10-07

Revised date: 2024-01-03

Online published: 2024-02-12

Supported by

National Natural Science Foundation of China(U20A20262)

National Natural Science Foundation of China(51933009)

National Natural Science Foundation of China(52203190)

Fundamental Research Funds for the Central Universities(226-2023-00108)

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Abstract

combination products present significant opportunities for advancing traditional medical devices by versatile integration of therapeutic drugs and devices.as clinical needs evolve,there remains growing interest in developing new surface and interface engineering technologies for modulating drug delivery behavior.Recently,polymeric porous surface interface technology has emerged As a robust strategy for the flexible amalgamation of functional molecules with medical devices via capillary adsorption.in comparison to the conventional coating method,This technology shows distinctive features like flexible loading,facile dosage control,and tunable release,therefore providing a novel insight for personalized medicine.This review begins by outlining the methods for preparing porous surfaces of polymer materials,including the breath figure,template method,surface non-solvent-induced phase separation,stimulus-induced phase separation method,and electrospinning method.Then,the mechanism for the capillary-based loading process and hindered release behavior of functional species,which play a central role in the development of spongy surface-based Combination devices,is discussed.This review also provides an overview of the latest research on the porous surface interfaces of polymer materials in applications like targeted anti-cancer,cardiovascular implants,and bone repair,summarizes the present challenges in research on the porous surfaces of polymer materials,and highlights insights into potential future directions。

Contents

1 Introduction

2 Construction strategy of porous surface on polymer materials

2.1 Breath figure

2.2 Template method

2.3 Surface non solvent induced phase separation

2.4 Stimulus-induced phase separation

2.5 Electrospinning method

3 Functional molecule delivery based on porous polymer surface

3.1 The driving force of loading and release of functional molecules

3.2 Study on the release behavior of functional molecules

4 Application of polymer porous surface in drug delivery

4.1 Targeted anti-cancer

4.2 Cardiovascular diseases

4.3 Orthopedics diseases

5 Conclusion

Key words： combination products; porous materials; surface engineering; drug delivery

Cite this article

Yanchen Chen , Honglin Qian , Yirong Guo , Jing Wang , Jian Ji . Polymeric Porous Surface Materials: Construction and Drug Delivery Applications[J]. Progress in Chemistry, 2024 , 36(5) : 679 -695 . DOI: 10.7536/PC230919

1 Introduction

According to the Definition of the 2018 Biomaterial definition Consensus Conference,Biomaterial refers to materials designed into a specific form,which can directly affect the treatment or diagnosis process through interaction with living systems^[1]。 In recent years,the field of biomaterials has developed rapidly,and polymer materials have gradually become the most widely used biomaterials because of their good preparability and strong adaptability of mechanical properties^[2]。

clinical application studies have shown that traditional polymer-based biomaterials inevitably interact with the human immune system in use,and even cause strong immune responses and serious complications,threatening the lives and health of patients.For example,Abbott's bioabsorbable stent Absorb BVS,which has been delisted,uses L-polylactic acid as the stent material and racemic polylactic acid as the drug-loaded coating material.Although these biomaterials can theoretically self-degrade and then be completely absorbed by the organism,a meta-analysis of Clinical studies has shown that the incidence of target lesion failure and stent thrombosis in patients undergoing surgical treatment within one year is not lower than that in patients using drug-eluting stents^[3]。

To mitigate the negative effects of polymer-based biomaterials on the human body,researchers have explored a variety of surface modification methods,including surface drug delivery,surface chemical reaction,and surface nanotopography modification^[4]^[5,6]^[7,8]。 In these approaches,drug molecules are able to effectively modulate the immune response and improve therapeutic efficacy.Therefore,people often combine drugs or biological products with devices and call them drug-device combination products^[9]。 Among them,the combination of drugs and devices through polymer coating technology is the classic paradigm of the current drug-device combination device,which is widely used in cardiovascular stents,bone implants,drug balloons,drug delivery catheters and other implantable and interventional medical devices。

However,with the rapid development of biotechnology and the rise of the concept of personalized medicine,the personalized and precise delivery of bioactive drugs poses a new challenge to the design of traditional drug coatings.Compared with the traditional dense drug coating,porous materials have unique capillary action,which can quickly and controllably load functional molecules^[10]; the interpenetrating pore structure restricts the diffusion of loaded molecules,which can realize the slow release of functional molecules^[11]。 In addition,the porous structure is only constructed on the surface of the polymer biomaterial,which has little effect on the physical and mechanical properties of the material itself^[12,13]。

In conclusion,the field of biomaterials and combinatorial products is a rapidly growing research direction,and the development of effective strategies to modulate the foreign body response of biomaterials and improve therapeutic efficacy is the key to materials R&D^[14]。 Capillarity through the porous structure of the polymer surface provides a new paradigm for the combination of drugs and devices,which is expected to achieve precise and personalized delivery of bioactive molecules。

in this paper,the recent progress in the field of polymer porous surface and interface is reviewed,including the porous strategy of polymer surface and interface,the study of loading and releasing molecules,and the application in drug delivery。

2 Construction Strategy of Porous Surface and Interface of Polymer Materials

Porous polymers are widely used in various fields such as separation,catalysis and sensing due to their high specific surface area and high porosity^[15]^[16]^[17]。 In recent years,there has been a wealth of research on the construction mechanism and methods of porous polymers^[18]。 At present,the common strategies of porous structure construction include template method,phase separation method,stretching method and foaming method.Wu et al.Summarized the synthesis methods of porous polymers published since 2005,and evaluated the direct template method,block copolymer self-assembly method,direct synthesis method and other methods in detail^[19]。 the review has greatly advanced the field of porous materials by providing an exhaustive analysis of the advantages and limitations of each method。

However,the preparation strategies of these porous structures are usually limited to bulk porous materials.In view of the requirement of biomaterials to maintain the physical and chemical properties of the bulk,the construction strategy of porous structure on the surface and interface of polymer materials has been paid more and more attention。

2.1 Respirogram

as early As 1994,Fran François et al.First prepared honeycomb polymer porous membranes by breath graph method^[20]。 This method is a typical porosification strategy for polymer surface and interface.In a humid atmosphere,when water encounters the surface of a cold polymer solution,it undergoes a process of nucleation,growth,and self-assembly,forming an array of ordered and closely packed water droplets^[21]。 Eventually,the water droplets and the solvent in the polymer solution evaporate,leaving honeycomb-like pores^[22]。 Based on this principle,the porous structure prepared is generally honeycomb holes arranged in order.in addition,since the water vapor is only in contact with the surface of the polymer solution,the thickness of the porous structure is generally very thin and there is no multilayer structure。

in the actual operation of the breath-figure method,the dynamic process is mainly used,In which the moist airflow is blown through the polymer solution,and the shape,pore size and other parameters of the porous structure can be controlled by controlling the flow rate and humidity of the airflow,the concentration of the polymer solution,the solvent system and other parameters^[22]。 Kim et al.Used the star block copolymer prepared by Kim et al.To study the effects of polymer concentration,solvent type and other parameters on the porous structure prepared by the breath diagram method^[23]。 They found that the use of water-immiscible solvents,such as chloroform and carbon disulfide,was required to form a honeycomb-like porous structure.When the polymer concentration is in the range of 10~40 G/L,the average pore size of the membrane decreases with the increase of the polymer concentration。

spin-coating and dip-coating are commonly used methods for constructing coatings in the breath diagram method.Among them,the method of forming a porous coating by contacting the surface of the polymer solution with water vapor during the rapid solidification of the polymer solution on the spin-coated substrate is called spin-coating breathing pattern method^[24]。 in contrast,the dip-coating breathing pattern method is particularly suitable For substrates with complex shapes:a porous coating can be formed by soaking the substrate in a polymer solution and then placing it in a humid environment.for example,Huang et al.Immersed the substrate in a polymer/toluene/methanol mixture to obtain a coating,and then placed the coating in a humid condition to obtain a honeycomb-like porous structure^[25]。

Ji et al.Slowly removed the polystyrene sheet from the mixed solution of methanol and chloroform and placed it in a humid environment.the separation process of the polymer substrate and the solvent provided a time gradient of evaporation,so that a gradient hole with a diameter difference of more than 400%could be prepared on the sample by the respirogram method^[26]。

in recent years,there has been a new development In the construction of porous coatings based on the breathing diagram method.Ultrasonic atomization technology can atomize the solution into very small droplets,similar to the process of water nucleation growth,thus promoting the formation of porous structures^[27]。 Murchio et al.Used the cavitation effect of ultrasonic nebulizer to produce tiny droplets containing nanoparticles^[28]。 They then sprayed droplets onto the interface of a UV-crosslinkable alkoxy silicone resin to prepare a porous coating embedded with nanoparticles(Figure 1)。

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图1 超声喷涂辅助的呼吸图法。氮气流量计连接装有纳米粒子/水溶液的气体起泡器，起泡器内的超声波雾化器通过空化效应产生包含纳米粒子的水气，水气被输送到含有基材和紫外光的反应室中，从而在基材表面形成蜂窝状孔洞；后续该基材可以通过氨气环境的热解过程进一步转化为氮氧化硅^[28]

Fig. 1 Ultrasonic spray assisted breathing figure method. The nitrogen flowmeter is connected to a gas bubbler containing nanoparticles/aqueous solution. The ultrasonic atomizer inside the bubbler generates water vapor containing nanoparticles through the cavitation effect, which is then transported to a reaction chamber containing a substrate and UV light to form honeycomb holes. Subsequently, it can be further transformed into silicon nitride by pyrolysis process in ammonia environment^[28]

to sum up,the advantage of using the breath diagram method to prepare the porous surface interface is that it is easy to operate and suitable for substrates with complex shapes;Its disadvantage is that it has strict experimental requirements and is greatly affected by environmental humidity.Moreover,the porous structure prepared by the method is relatively neat,and the tortuous degree of the pore channel is insufficient,so that the method may be difficult to achieve the effect of slow release when being used for drug release。

2.2 Template method

the template method is widely used because it can control the morphology and particle size of the pore structure by regulating the shape and size of the template material^[29]。 the template method uses a substrate and a template to build a hybrid structure,and then the template is removed to obtain the desired pore structure.the commonly used template methods are porogen template method,ice template method,salt template method,polymer emulsion template method and so on.the porous structure prepared by the template method is closely related to the template used.For a hard template(such as a salt template),the shape of the porous structure is often the shape of the hard template.However,due to the large particles of the hard template,it is difficult to disperse evenly in the substrate,so the hard template method is rarely used;For soft templates(such as porogen templates),the shape of the porous structure depends on the phase separation of the polymer and porogen in solution。

porogen template method is often used in the preparation of porous polymer surface and interface.the polymer and porogen are mixed and coated on the substrate,and then the porogen is removed to obtain the porous structure.Among them,polyvinylpyrrolidone(PVP)has good hydrophilicity due to the existence of polar lactam groups in the pyrrolidone part,and can be dissolved in water and various organic solvents(such as butanol,chloroform and dichloromethane),so it is a commonly used porogen^[30]。 the porosity of the porous material can be controlled by adjusting the content of PVP,because the water solubility of PVP is particularly good,and the PVP in the mixed coating of the polymer and PVP can be easily removed by water,so the addition amount of PVP is the porosity of the porous material.Ji et al.Used PVP as a porogen to blend and dissolve the amphiphilic PCL-PEG-PCL(PCEC)triblock copolymer,PVP and photoinitiator in dichloromethane,prepared the coating by ultrasonic spraying,and then carried out ultraviolet crosslinking of the triblock copolymer,and then immersed the coating in water to dissolve PVP and freeze-dried to obtain the porous coating^[31]。

Similarly,Jiang et al.Mixed styrene-butyl acrylate copolymer latex and PVP to prepare an emulsion,which was then dried to form a film,which was then soaked in methanol/water solution to dissolve PVP,thereby forming a porous film(Fig.2)^[32]。 the average pore size of the porous membrane decreased from micrometer scale(10μm)to submicrometer scale(0.4μm)with the increase of the molecular weight or the amount of PVP.It can be seen that using PVP as a template to construct polymer porous surface is a general and simple method for porous construction。

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图2 多孔薄膜横截面的TEM图像。（a）未使用PVP的薄膜；（b~e）添加乳胶质量比5%、10%、15%和20%的PVPK30所制备的多孔薄膜^[32]

Fig. 2 TEM images of the cross section of the porous film. (a) The film without PVP; (b~e) porous films prepared by adding PVPK30 with latex mass ratio of 5%, 10%, 15% and 20%, respectively^[32]

to sum up,the advantages of PVP template method are that it is easy to be removed by water,and the porosity of porous materials can be easily controlled.However,the disadvantage of this method is that it is somewhat difficult to adjust the pore size of the porous structure.In addition,some unique surface interface template methods have also been used to construct porous surface interfaces.Kim et al.Designed an extremely fast surface interface ice template method(Fig.3)^[33]。 They placed polystyrene(PS)and polycarbonate sheets on top of the liquid nitrogen tank.Then the solvent was dropped on the sheet,and the solvent quickly dissolved the polymer chains on the surface of the sheet.At the ultra-low temperature of liquid nitrogen,the solvent rapidly freezes into an ice template.Finally,the ice template was removed by freeze-drying to produce the desired porous surface.This technique can control the freezing rate of the solvent by controlling the temperature of the cold surface,which is a reproducible and cost-effective strategy for porous surface and interface manufacturing,but its effect on porous structure is weak。

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图3 极快冰模板法：（a）溶剂在表面极快溶解和定向熔融结晶的示意图；（b, c）为多孔PS表面横截面和表面的SEM图像^[33]

Fig. 3 Extremely fast ice templating process. (a) Schematic diagram of extremely fast solvent dissolution and directional melt crystallization on the surface; (b) and (c) are the SEM images of porous PS surface cross section and surface^[33]

2.3 Surface non-solvent induced phase separation

Non-solvent-induced phase separation(NIPS)is a common porous preparation strategy,which is suitable for polymers such as polyvinylidene fluoride(PVDF),polyamide(PA)and cellulose acetate(CA)^[34]^[35]^[36]。 the non-solvent induced phase separation system is composed of polymer,solvent and non-solvent.After the nonsolvent of the polymer is introduced into the homogeneous polymer solution,the solvent and the nonsolvent undergo interdiffusion.When the exchange reaches a certain degree,the solution becomes a thermodynamically unstable system,and liquid-liquid phase separation occurs,thus forming a hole^[37]。

the mechanism of porous structure preparation by non-solvent-induced phase separation is the liquid-liquid phase separation of polymer solution(Fig.4),and the addition of non-solvent makes the system move from the polymer and solvent end to the non-solvent end.When the system enters the phase separation region composed of binodal line and spinodal line from the upper and lower parts of the homogeneous region respectively,liquid-liquid phase separation occurs,and there are two cases of polymer-poor phase nucleation and polymer-rich phase nucleation,forming spongy and granular porous structures^[18]。 When the system crosses the spinodal line,the polymer-poor phase and the polymer-rich phase nucleate simultaneously and the two phases interlace to form a bicontinuous structure.Latex structures and macroporous structures also occur,which are generally undesirable.Macroscopically,the pore size,surface porosity and pore morphology of porous materials can be controlled by changing the parameters such as polymer concentration and molecular weight,standing temperature,solvent composition and surfactant^[38,39]。

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图4 非溶剂诱导相分离法三元相图：（a）贫聚合物相成核（双节线分相）；（b）双连续结构（旋节线分相）；（c）富聚合物相成核（双节线分相）^[18]

Fig. 4 Ternary phase diagram for nonsolvent-induced phase separation. (a) Nucleation of polymer-poor phase (binodal phase separation); (b) bicontinuous structure (spinodal phase separation); (c) nucleation of polymer-rich phase (binodal phase separation)^[18]

At present,there are two main strategies to apply the non-solvent-induced phase separation method to the surface of polymer materials.One method is to coat the surface of the substrate with a polymer solution and then introduce a non-solvent to create pores.For example,Zhu et al.Prepared porous poly(L-lactic acid)(PLLA)coating on pure magnesium substrate by combining dip-coating and non-solvent-induced phase separation^[40]。 In addition,Ji et al.Proposed a surface swelling non-solvent-induced phase separation method,which can directly generate porous coatings on the surface interface of polymer substrates such as polymethyl methacrylate(PMMA)and polystyrene(PS)(Fig.5)^[11]。 They immersed the polymer substrate in solvent and non-solvent in turn,adjusted the pore size and thickness of the porous structure by adjusting the soaking time,temperature and other parameters,and used ofloxacin and fluorescently labeled bovine serum albumin as model drugs and biomacromolecules to test the loading and release behavior of the porous surface.the experimental results show that this method is promising for the construction of porous structures on medical devices。

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图5 （a）表面溶胀非溶剂诱导相分离法制备多孔表界面示意图。聚合物基材被依次浸入溶剂和非溶剂中，通过相分离形成孔洞；（b）不同浓度的DMF与水混合物作为溶剂制备的PMMA多孔断面的SEM图像^[11]

Fig. 5 (a) Schematic diagram of porous surface/interface prepared by surface swelling non-solvent-induced phase separation;(b) SEM image of porous surface of PMMA prepared with different concentrations of DMF and water mixture as solvent^[11]

the non-solvent-induced phase separation method is to generate a porous structure on the surface of the polymer substrate in situ,so it is suitable for the polymer substrate with complex shape.the advantage of this method is that the bonding force between the porous surface interface and the substrate is strong,and the porous surface interface prepared by this method is expected to be used in complex mechanical environments.However,the consumption of solvent and non-solvent in the preparation process of this method is large,so how to combine with automated devices to achieve continuous preparation and resource recycling is an important challenge for future practical application。

2.4 Stimulus-induced phase separation

Stimulation induced phase separation(SIPP)is a mild method for the construction of porous structures in polymers,and its technological characteristics are extremely suitable for the construction of porous structures in polymer surfaces.First,weak polyelectrolytes with opposite charges are repeatedly deposited on the surface and interface of the substrate,and the layers are self-assembled together through supramolecular interactions,thus forming a coating.Subsequently,under environmental stimuli such as pH,ionic strength,and polarity,the weak polyelectrolyte ion pair is destroyed,resulting in the change of polymer chain conformation,which leads to the change of polyelectrolyte chain mobility,and finally leads to the formation of surface and interface porous structures,whose pore morphology is often monolayer macropores^[41]^[42]。

Ji et al.Used electrostatic layer-by-layer self-assembly(LbL)technique to alternately deposit positively charged polyethyleneimine(PEI)and negatively charged polyacrylic acid(PAA)on the substrate surface to construct polyelectrolyte multilayer films^[43]。 When the multilayer membrane is immersed in an acidic solution with pH=2.9,the polyelectrolyte molecular chains in the membrane migrate and reorganize to a large extent,resulting in a large number of porous structures in the membrane(Fig.6).the longer the acid treatment time,the larger the pore size and the thickness of the porous structure。

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图6 刺激诱导相分离法制备多孔涂层示意图。将无孔(PEI/PAA)自组装膜浸入酸性溶液(pH=2.9)中以诱导孔形成，然后冷冻干燥以除去水。（b~e）分别为在酸性溶液中浸泡0、30、60和90 min的薄膜的SEM横截面图像^[43]

Fig. 6 Schematic diagram of preparation of porous coatings by stimulus-induced phase separation. Poreless (PEI/PAA) self-assembled membranes were immersed in an acidic solution (pH=2.9) to induce pore-formation, then freeze-dried to remove water. (b~e) SEM cross-section images of films soaked in acidic solution for 0, 30, 60 and 90 min, respectively^[43]

Similarly,Cho et al.Prepared weak polyelectrolyte polyethyleneimine(LPEI)and polyacrylic acid(PAA)into coatings by layer-by-layer self-assembly method^[44]。 An electric field is then applied to electrolyze the water.the protons produced by electrolysis drastically change the local pH,thereby changing the chain mobility of the polyelectrolyte in the coating,and finally forming a porous coating with controlled pore size and porosity。

With the development of research in this field,periodic porous structures and layered porous structures have been constructed by stimulation-induced phase separation.Ji et al.Used the periodicity of standing wave optics to generate periodic crosslinked and uncrosslinked layers in a dynamic polyelectrolyte film^[45]。 the polyelectrolyte coating was then immersed in a dilute hydrochloric acid solution to stimulate and induce the phase separation of the non-crosslinked layer to form a periodic layered porous structure.This study greatly broadens the application scenarios of polymer surface and interface porous structures。

The instability of weak polyelectrolytes is used to construct porous structures,which requires mild conditions.Therefore,it is possible to construct a porous structure first and then load molecules,or to load molecules first and then accept environmental stimulation to produce a porous structure and release molecules.Anandhakumar et al.Assembled polyallylamine hydrochloride(PAH)and polymethacrylic acid(PMA)layer by layer into a weak electrolyte coating,which was loaded with bovine serum albumin(BSA)and ciprofloxacin hydrochloride(CH)^[42]。 The coating was subsequently transformed from a nonporous smooth structure to a porous structure under pH and ionic strength stimulation(Fig.7),and this method can be used for stimulus-responsive delivery of drugs。

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图7 通过刺激诱导相分离来传递药物分子的PEM薄膜制备方法示意图：（a）玻璃基板；（a~b） LbL沉积（PAH/PMA）；（b~c） BSA装载；（c~d）附加（PAH/PMA)；（d~e） CH加载；（e~f），刺激响应释放^[42]

Fig. 7 Schematic diagram of the preparation of PEM films for the delivery of the drug and protein by stimulus-induced phase separation. (a) A glass substrate; (a~b) LbL deposition (PAH/PMA); (b~c) BSA loading; (c~d) LbL deposition again (PAH/PMA); (d~e) CH loading; (e~f) stimulus-response release^[42]

the advantage of stimulus-induced phase separation is that the construction process is mild and there are many ways of stimulation.However,due to the chain mobility of polyelectrolyte coatings,which are sensitive to environmental conditions,porous structure stability can be a challenge in applications。

2.5 Electrospinning

in recent years,electrospinning technology has been widely used In many fields because of its unique portability and controllability^[46]。 The core of this technology is to use electrostatic force to prepare continuous fibers with nano-to submicron-scale pore structures^[47]。 Its working principle is briefly summarized:when the viscoelastic fluid is extruded through the spinneret,it initially forms a spherical droplet due to the surface tension,and then under the action of the applied electric field,the droplet exceeds the surface tension due to the repulsive force of the same charge to form a Taylor cone,and finally forms a continuous fiber.By adjusting the voltage,flow rate,environmental humidity and the distance between the spinneret and the collector,the fiber diameter and porosity can be accurately controlled^[48⇓~50]。

In practical applications,Niu et al.Used a specific type of electrospinning machine to prepare PA6/CS fiber scaffolds,which showed excellent biocompatibility and promotion of MC3T3-E1 cell proliferation^[51]。 This is attributed to its ability to mimic the layered structure of the extracellular matrix(ECM)^[52]。 in addition,electrospinning technology also supports the addition of drugs In the spinning process,so that the drugs are directly embedded into the fiber.for example,Aditya et al.Successfully prepared a coating with sustained drug release and excellent mechanical properties by mixing docetaxel into a chloroform solution of poly(lactic-co-glycolic acid)(PLGA)For electrospinning^[53]。

on the other hand,in order to further improve the surface roughness and total surface area of electrospun fibers,researchers have developed methods to construct Porous structures on the surface of fibers.porous structures based on the principle of polymer phase separation can be achieved by selecting specific volatile solvents or applying a two-solvent system of a good solvent and a non-solvent^[54,55]。 This structure endows the fiber with larger surface area and higher roughness,thus improving its biomedical performance.the nanoscale fiber surface porous structure and the micron-scale interfiber porous structure can be matched with substances with different space sizes according to actual needs.Song et al.Prepared polylactic acid(PLLA)fibers by electrospinning(Fig.8A),and produced a porous structure with ultra-high surface area by acetone treatment(Fig.8B),which effectively increased the coating amount and roughness of silk fibroin(SF)(Fig.8C),and promoted the adhesion and growth of smooth muscle cells^[56]。

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图8 多孔电纺丝纤维制备示意图：（a）电纺PLLA纤维膜、（b）后处理后的多孔PLLA纤维以及（c） PLLA纤维上的丝素蛋白涂层的示意图^[56]

Fig. 8 Schematic diagram of preparation of porous electrospun fibers. Schematic illustration of (a) electrospun PLLA fiber membrane, (b) porous PLLA fiber after post-treatment, and (c) silk fibroin coating on PLLA fiber^[56]

electrospinning is especially suitable for the preparation of tissue engineering scaffolds because the nanofibers prepared by Electrospinning have a structure similar to extracellular matrix.the advantage of this method is that the diameter and pore structure of the fiber can be accurately controlled by adjusting the process parameters,while the disadvantage is that the connectivity of the pore structure is large,which leads to less obstruction of functional molecules in it,and is not conducive to the slow release of functional molecules。

3 Functional molecule delivery based on polymer porous surface interface.

In recent years,a variety of drug delivery systems,such as polymer porous surface drug delivery,liposome drug delivery and nanoparticle drug delivery,have been developed to achieve the controlled release of functional molecules such as drugs,proteins and nucleic acids^[57]^[58]^[59]。 Among them,polymer porous surface interface has broad application prospects in the field of drug delivery because of its large surface area and adjustable pore size。

A deeper understanding of the basic mechanisms of functional molecule loading and release in the polymer porous surface/interface can contribute to the development of more efficient and precise functional molecule delivery systems。

3.1 Driving force for loading and release of functional molecules

the loading and release of functional molecules on the porous surface of polymer is a mass transfer process.mass transfer is a basic transfer process in the field of chemical engineering,and its mechanism can be divided into convective mass transfer and molecular mass transfer^[60]。 convective mass transfer is the mass transfer produced in the process of macroscopic motion of fluid.the process of loading molecules on the porous surface of polymer is the Convective mass transfer process,and the motion of fluid is driven by capillary action.molecular mass transfer,also known as molecular diffusion,is a process in which molecules of a substance are transferred from a high concentration to a low concentration in a static medium.the release of molecules from the polymer porous surface is the process of molecular mass transfer。

3.1.1 Capillarity driven molecular loading

the polymer porous surface interface mainly absorbs the molecular solution into the porous structure through capillary action to load the molecules.Dry porous materials spontaneously absorb liquid when in contact with it^[61]。 This is because the surface tension and adhesion between the pores and the medium drive the medium into the pores^[62]。 the dynamics of liquid uptake by capillary action in porous media is important for The study of molecular loading。

as early As the 18th century,Jurin proposed the equation for describing the rise height H of a fluid of densityρand surface tension coefficientσin a capillary of radius R in the form:^[63]

（1）$h=\frac{2\sigma \cos \theta }{\rho gR}$

Capillary flow in porous media is more complex,so the idealization of porous media is the basis for researchers To carry out accurate physical and mathematical treatment.Refer to the conceptual model approach adopted by Jung et al.to understand liquid dynamics^[64]。

the simplest model is that of a single straight capillary assuming a radius a and a length L,$a\ll L$ ,then the solution capacity Q to be aspirated according to the Hagen-Poiseuille equation is:

（2）$q=\frac{\mathrm{ }\!\!\pi\!\!\text{ }{{a}^{\mathrm{4}}}\Delta P}{8\mu L}$

Whereμis the viscosity of the solution and DP is the pressure difference between the inside and outside of the liquid level。

For the flow of an incompressible fluid in a capillary tube,the Hagen-Poiseuille equation can also be expressed in mean velocity form:

（3）$u=\frac{{{a}^{\mathrm{2}}}\Delta P}{8\mu L}$

on the other hand,in a tube with a very small radius a,the fluid will form a curved interface(Fig.9 a).This surface can be approximated by a sphere of radius R.R is a function of the contact angleθ,as shown in equation(4),which in turn depends On the properties of the fluid and the properties of the container material in contact with it。

（4）$R=\frac{a}{\cos \theta }$

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图9 多孔介质负载功能分子示意图：（a）流体曲面示意图；（b）多孔介质理想化概念模型示意图

Fig. 9 Schematic diagram of porous media loaded with functional molecules. (a) Bending interface of fluids; (b) the idealized conceptual model of porous media

According to the Laplace-Young equation,for a porous medium with atmosphere on both sides,the pressure differenceΔP between the loaded liquid and the atmosphere is:

（5）$\Delta P=\frac{\mathrm{2}\sigma }{R}=\frac{\mathrm{2}\sigma \cos \theta }{a}$

After substituting equations(4)and(5)into equation(3)and performing integral operation,the classical equation of propagation distance with time can be obtained as:^[65]

（6）$L={{\left( \frac{\sigma at}{2\mu \cos \theta } \right)}^{\frac{1}{2}}}$

According to this equation,the distance traveled by a liquid in a porous medium is proportional to the 0.5 power of time,and the velocity of the liquid under capillary action decreases with time.A large number of straight capillaries arranged in parallel is an ideal porous medium model(Fig.9b)。

However,the polymer porous surface interface is often on the surface of the solid substrate,which is characterized by unilateral closure,so the situation is more complex,and the filling process of the liquid may lead to the compression or departure of the internal air.If the gas migrates due to an increase in pressure,the pressure difference remains almost constant$\Delta P$ .If the internal gas is compressed without migration,the gas pressure difference shall be corrected as:

（7）$\Delta P=\frac{2\sigma }{R}-\left( {{P}_{r}}-{{P}_{a}} \right)$

P_ris the pressure in the capillary,and P_ais the atmospheric pressure.The P_rcan be solved according to the Clapeyron equation PV=nRT 。

the flow channel of porous media is usually non-circular and tortuous,so Cai et al.Sorted out The modification of Hagen-Poiseuille equation:^[66]

（8）$q=\frac{\mathrm{ }\!\!\pi\!\!\text{ (}ar{{\mathrm{)}}^{\mathrm{4}}}\Delta P}{8\mu {{L}_{a}}}$

（9）$\Delta P=\frac{\mathrm{2}\sigma \cos \theta }{ar}$

In the above equation,R is the equivalent capillary radius,L_ais the actual length of the tortuous capillary,and the geometric correction factorαis a constant≥1,whereα=1 for a capillary with a circular cross-section andα=1.094 for a square.In view of the fact that the thickness of the polymer porous surface interface is often very thin,the static pressure of the liquid is often not considered,so the liquid flow rate of the whole porous material is the integral form of the above Hagen-Poiseuille correction equation 。

According to the conceptual model,the capacity of capillary to absorb aqueous solution is related to capillary radius,capillary length,solution surface tension,capillary tortuosity,etc.the decrease of pore size can enhance the capillarity,increase the loading rate and reduce the loading capacity;the smaller the thickness of the porous medium is,the easier the solution enters the porous medium,and the more fully the porous medium is loaded,but at the same time,the reduction of the thickness also means the reduction of the loading;the improvement of hydrophilicity can increase the capillary action and increase the loading rate.Therefore,the effects of pore size and thickness on capillarity and loading should be balanced as much as possible in the study of porous surface and interface,while enhancing the hydrophilicity of porous media。

3.1.2 Diffusion-driven molecular release

the process of molecular release mainly depends on the diffusion of molecules.diffusion means that the difference in concentration of molecules between regions drives the molecules to move.molecular diffusion in porous media is often divided into bulk diffusion and confined diffusion according to the relationship between pore size and molecular size^[67]。

When the kinetic diameter of the diffusing molecule is much smaller than the pore size,the diffusion of the molecule is the bulk diffusion,which is not limited by the pore structure and is equivalent to the diffusion of free molecules.the bulk diffusion coefficient of a solute can therefore be expressed by the Stocks-Einstein equation,which,in particular,is mainly for a rigid spherical solute in dilute solution:

（10）${{D}_{b}}=\frac{KT}{3\mathrm{ }\!\!\pi\!\!\text{ }\mu d}$

Where,D_bis the bulk diffusion coefficient,m²/s;K is the Boltzmann constant,1.38×10^-23J/K;T is the temperature in Kelvin,K;μis the solvent viscosity,Pa·s;D is the diameter of the solute molecule or its equivalent sphere,m.This equation shows that temperature and solute molecular diameter affect the diffusion coefficient of solute,so these two factors also affect the process of molecular release 。

When the kinetic diameter of the diffusing molecule is similar to or even larger than the pore size,the free diffusion of the diffusing molecule will be restricted,and the diffusion of the molecule is restricted,and the ratio of the pore size to the molecular diameter has a great influence on the diffusion coefficient of the molecule^[68]。

the diffusion-limited factor$F(\lambda )$ is used to represent the degree of influence of the confined space on the diffusion,and has the form:

（11）$F(\lambda )=\frac{{{D}_{e}}\tau }{{{D}_{b}}\varepsilon }$

Where$\lambda $ is the ratio of the kinetic diameter of the diffusing molecules to the pore diameter of the porous material;$D_{e}$ is the effective diffusivity,$D_{b}$ is the bulk diffusivity,$\tau$ is the channel tortuosity factor,and$\varepsilon$ is the porosity.There is extensive research on the expression of the diffusion-limited factor,and as early as 1954,Renkin derived an expression for the diffusion-limited factor of a spherical molecule through a cylindrical pore in the form:^[69]

（11）$F(\lambda )={{(1-\lambda )}^{2}}(1-2.104\lambda +2.09{{\lambda }^{3}}-0.95{{\lambda }^{5}})$

the Renkin equation is considered accurate at<0.5,and in the case of$\lambda $ <0.3,the confinement factor can be simplified as follows:

（12）$F(\lambda )=(1-\lambda )$

Where m denotes the hindered amplitude of the diffusion。

According to the above derivation,the larger the molecular size is,the smaller the confinement factor is,which leads to the smaller the diffusion coefficient in the confined space.At the same time,the tortuosity and porosity of the pore channel also affect the diffusion coefficient。

3.2 Study on release behavior of functional molecules

Whether it is drug delivery or functional surface modification,researchers hope that the functionality will have a long time span rather than disappear in a short time.Therefore,how to use the polymer porous surface interface to achieve the release of functional molecules and how to control the release of functional molecules are the main problems in this field。

Generally speaking,functional molecules are loaded in the polymer porous surface by physical adsorption,and the release behavior of functional molecules can be controlled by adjusting the physical and chemical properties of the polymer porous surface.in addition,in order to further achieve the sustained release of functional molecules,the researchers used embedded embedding to slow down the diffusion of functional molecules。

3.2.1 Physical adsorption loading functional molecular

the porous structure has strong adsorbability.At the atomic level,the uneven solid surface and the uneven force on the atoms on the solid surface lead to a higher surface free energy,while the adsorption of molecules on the surface can reduce the free energy;At the micro-nano level,the surface tension of the liquid-solid interface in the pore is directed toward the inside of the liquid,which makes it difficult for the liquid to flow out of the pore spontaneously and can only remain in the pore.Therefore,the polymer porous surface interface can load drug molecules by physical adsorption,and the forces involved are usually van der Waals interaction,hydrogen bonding,electrostatic interaction and so on.physical adsorption is a dynamic equilibrium process of adsorption and desorption,which involves relatively weak forces and generally does not have selectivity.When there is a concentration difference in the external solution or the temperature rises slightly,the adsorbed molecules will desorb.Therefore,the release time of functional molecules loaded by physical adsorption is short^[70⇓~72]。

Anirudhan et al.Prepared the surface interface of polyelectrolyte composite coated on the surface of aminated mesoporous silica nanoparticles(AMSN)by layer-by-layer self-assembly method^[71]。 the composite surface interface enables controlled delivery of 5-fluorouracil(5-FU)based on pH response.It was found that the drug release profile followed the Korsemeyer-Peppas model,and the surface interface could release about 70%of the drug within 24 H at pH 7.4(simulated intestinal fluid)。

Of course,there is also a strong electrostatic interaction in the physical adsorption category,which can achieve a longer drug release.Liang et al.Employed electrostatic interactions to incorporate positively charged poly(hexamethylene biguanide)hydrochloride(PHMB)into negatively charged silk fibroin(SF)sponges^[73]。 PHMB loaded in porous sponges showed continuous slow release for up to 20 days and can be used as a novel wound dressing for open skin wounds(Fig.10)。

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图10 静电相互作用加强物理吸附：（a）多孔PHMB/SF海绵横截面的SEM图像；（b）不同质量比的PHMB/SF复合物的Zeta电位，SF的负电荷被PHMB中和，表明二者通过静电相互作用结合；（c） PHMB/SF海绵释放曲线图^[73]

Fig. 10 Physical adsorption enhanced by electrostatic interaction. (a) SEM image of the cross section of porous PHMB/SF sponge; (b) the Zeta potential of the PHMB/SF complex at different mass ratios, where the negative charge of SF is neutralized by PHMB, indicating that the binding is through electrostatic interaction; (c) the release curve of PHMB/SF sponge^[73]

3.2.2 Controlling the release of functional molecules by regulating the porous structure

As mentioned in Section 3.1,the physical and chemical properties of porous materials include pore size,pore tortuosity,pore chemical composition,etc.,which have a great influence on the loading and release behavior of functional molecules in porous materials.Among them,the release behavior of functional molecules is more important than the loading behavior,because the release behavior directly affects the final effect of drug delivery.Therefore,the study of the structure-activity relationship between the physicochemical properties of porous materials and the release behavior of functional molecules can better understand the process of drug delivery by porous materials and achieve more sophisticated and controlled drug delivery。

Among these physical and chemical properties,pore size has a very important effect on the release of functional molecules.in the microscopic aspect,Schwartz et al.developed a single particle tracking technique for three-dimensional materials,designed an experiment on the diffusion of particles with different particle sizes in the same pore size,and visualized the movement of the particles.the results showed that the diffusion movement of the particles was very slow,and the diffusion trajectories of particles with different particle sizes(40,100,and 200 nm)in a pore size of 3.1μm were very different(Fig.11)^[67]。 Through this experiment,it can be inferred to a certain extent that under the same particle size,different pore sizes also have a great impact on particle diffusion。

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图11 不同粒径的微粒在同样孔径的多孔介质中扩散的可视化实验：（a）多孔介质的孔径为3.1 μm；（b）粒径40 nm的微粒在多孔介质中的扩散轨迹；（c）粒径100 nm的微粒在多孔介质中的扩散轨迹；（d）粒径200 nm的微粒在多孔介质中的扩散轨迹^[67]

Fig. 11 Visual experiment of diffusion of different particle sizes in porous media with the same aperture. (a) The pore size of the porous medium is 3.1 μm; (b) diffusion trajectory of particles with a particle size of 40 nm in porous media; (c) diffusion trajectory of 100 nm particles in porous media; (d) diffusion trajectory of 200 nm particles in porous media^[67]

At the macro level,the researchers also found that the pore size had a great influence on the release behavior of the drug.Lim et al.Synthesized graphene aerogels with controllable pore structure by combining hydrothermal reaction and controlled drying process^[74]。 they observed that the pore structure of graphene aerogel shrank with the increase of hot air drying time,and then prepared porous graphene aerogel with different pore sizes.Moreover,They used hydrophobic drug ibuprofen and hydrophilic drug diclofenac as model drugs,and found that the larger the pore size of graphene aerogel,the faster the drug release。

Ji et al.Prepared poly(methyl methacrylate)(PMMA)porous surface interfaces with different pore sizes by surface non-solvent phase separation method,and their pore sizes were 0.761 and 0.311μm,respectively^[11]。 They used ofloxacin(OFXC)and bovine serum albumin(BSA)as model drugs and biomacromolecules to test the drug release behavior of porous materials with different pore sizes,and the results showed that the release behavior of drugs loaded on porous materials with 0.761μm pore size was faster。

After the porous material is loaded with functional molecules,the functional molecules are deposited in the pore channels,and drug release requires the functional molecules to first diffuse from the pore channels into the release medium.Therefore,from the perspective of host-guest interaction,the chemical composition of the pore will also affect the release of functional molecules.Lehto et al.Evaluated the loading and release behavior of ibuprofen on mesoporous silicon particles with different surface treatments,and found that the release rate of ibuprofen loaded on TCPSi particles with the best hydrophilicity was the fastest^[75]。 Vallet-Reg Regíet al.Modified the surface of mesoporous silica with hydroxyl groups to amino groups,and found that the release rate of Ibuprofen loaded on mesoporous silica decreased,which may be due to the interaction between amino groups and carboxyl groups of ibuprofen,which inhibited the release of ibuprofen^[124]。

in addition,the physicochemical properties of some polymer porous surfaces are not well studied For drug release,but these parameters can be inferred based on the physicochemical nature of drug release.for example,pore tortuosity(topology)is a difficult parameter to quantify and describe,but it Also has an impact on the release behavior of functional molecules.Schwartz et al.also found that two different media with very similar nominal pore size and porosity values but different pore structures,such as glass fibers and nitrocellulose,have very different diffusion behaviors of particles In them^[67]。

3.2.3 The embedded embedding effect realizes the further sustained release of the drug

in order to prolong the release time,researchers have tried to set up greater resistance for functional molecules,using embedded embedding to bury functional molecules deeper to prevent the movement and diffusion of molecules.Compared with the physical adsorption method,the embedded embedding method prevents the functional molecule from directly contacting with the environmental medium,so the drug release requires the functional molecule itself to diffuse out of the substrate or the environmental medium to diffuse into the substrate,which slows down the release of the functional molecule.Especially for water-soluble molecules that are rapidly released In direct contact with the aqueous environment,embedded entrapment is undoubtedly an excellent sustained-release method.the release time of water-soluble molecules can reach 1 to 20 days or even longer through embedded embedding.Specifically,the embedded embedding method is mainly divided into gel embedding method and dynamic self-healing method。

gel embedding method refers to a loading method in which functional molecules are mixed into the precursor polymer of porous Gel,and then gelation is carried out by ionic crosslinking^[76]^[77⇓~79]。 Naseri-Nosar et al.Mixed recombinant human erythropoietin and chitosan solution for ionic gelation,coated on polyvinyl alcohol/chitosan/aloe electrospun fibers,and then crosslinked^[76]。 The spongy film thus prepared was capable of releasing erythropoietin for up to 7 days.in vivo studies have shown that aloe gel and erythropoietin have synergistic wound healing effects on full-thickness excised wounds In Wistar rats。

in addition,In order to further control the release rate of functional molecules,some studies constructed an additional thin film layer on the gel surface^[80]。 Lv et al.Used electrospray to prepare microgels containing the drug molecule vancomycin hydrochloride,and it is worth noting that they coated the surface of the microgels with a layer of porous polyvinyl butyral fiber felt(PVB)again^[81]。 This strategy of"building another layer"significantly extended the drug release time from 5 min to 20 days,which significantly enhanced the sustained antibacterial effect of vancomycin hydrochloride(Fig.12).the release rate of drug molecules can be effectively controlled by adjusting the pore size of PVB fiber mats through ethanol vapor treatment.This study not only demonstrates its innovation in drug delivery,but also reflects the versatility and flexibility of the method in operation。

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图12 聚合物薄膜和多孔纤维毡复合结构用于控制药物分子的释放：（a）钛金属直骨板表面喷涂载有盐酸万古霉素的聚乙烯醇-硼砂微凝胶（VH@PVA-B）；（b）在微凝胶表面再喷一层多孔聚乙烯醇缩丁醛纤维毡（PVB），一定程度阻止药物分子释放；（c, d）并且可以通过乙醇蒸气处理，调节纤维毡的多孔结构^[81]

Fig. 12 Polymer film and porous fiber felts composite structure to control the release of drug molecules. (a) The surface of Ti metal straight bone plate was sprayed with vancomycin hydrochloride-loaded polyvinyl alcohol-borax microgel (VH@PVA-B); (b) spray another layer of porous polyvinyl butyral fiber felts on the surface of the microgel to block the release of drug molecules; (c, d) the porous structure of the fiber felts can be adjusted by ethanol steam treatment^[81]

Dynamic self-healing method means that after the adsorption of functional molecules on the polymer porous surface,the pore opening and closing are dynamically adjusted under the external stimulation of light,heat,pH and so on,so as to realize the embedding of loaded drug molecules and achieve the purpose of sustained release^[82⇓~84]。

Ji et al.Prepared a polyelectrolyte porous coating by stimulus-induced phase separation method,and then placed it under saturated humidity,in which the polymer chain will move under the influence of water molecules,thus realizing the closure of pores^[57]。 In addition,if the porous layer is loaded with an aqueous solution of a drug,the two processes of drug loading and pore closure are performed simultaneously,which greatly simplifies the operation^[43]。

In addition,Ji et al.Used a synthetic amphiphilic polycaprolactone-polyethylene glycol-polycaprolactone(PCL-PEG-PCL,PCEC)triblock copolymer to prepare a dynamic porous coating with ultrafast self-healing properties(Figure 13 A)^[31]。 Its capillary-based loading mode makes the loading amount linear with the concentration of the loading solution,thus achieving rapid and controllable post-functionalization of the coating(Fig.13b).However,when the temperature is higher than the T_mof the polymer,the coating can rapidly self-heal within 5 s to achieve the embedding of functional molecules and significantly delay the release of loaded molecules(Fig.13C )。

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图13 动态自愈合多孔涂层示意图与表征：（a）负载功能分子后，通过温和的热触发方式进行孔洞的封闭，将功能分子包埋在孔洞中；（b）分子负载量与分子溶液浓度成正比；（c）自修复后分子释放速率显著减小^[31]

Fig. 13 Schematic and characterization of the dynamic self-healing porous coating. (a) After loading the molecules, the pores are closed by mild thermal triggering, then the molecules are embedded in the pores; (b) the molecular loading is proportional to the molecular solution concentration; (c) the molecular release rate is significantly reduced after self-healing^[31]

4 Application of Polymeric Porous Surface and Interface in Drug Delivery

drug delivery is an important scenario for loading and sustained release of functional molecules on the porous surface of polymers.Drug delivery systems(DDS)enable the introduction of therapeutic substances into the body and improve efficacy and safety by controlling factors such as the rate,timing,and location of Drug release in the body^[85]。 Most drugs require frequent dosing,which can challenge patient compliance and result In high and low drug concentrations in the patient.in contrast,the long-acting release mechanism can achieve sustained release of drugs for weeks or months,which requires less patient compliance^[86]。

Polymeric porous surface interface can load drugs into the porous structure by virtue of porous adsorption,so as to realize the long-term release of drug molecules.in addition,the loading process of the polymer porous surface interface has no special requirements for the types of drugs,which is suitable for most drug molecules,and one porous coating can also load multiple drugs at the same time.Therefore,it has a wide range of applications In cardiovascular,orthopedic and other fields^[42,77,87]。

4.1 Study of Polymer Porous Surface and Interface in Targeted Anticancer Field

chemotherapy is one of the main means in the treatment of cancer,and its mechanism is that chemotherapeutic drugs play their role by disrupting the cell cycle through one or more processes,and local targeted drug delivery is an important research in Chemotherapy^[88]。 Locally targeted drug delivery can achieve the purpose of high drug concentration,prolonged drug action and reduced systemic toxicity at the target site of tumor^[89]。 Locally targeted delivery of anticancer drugs can be achieved by a variety of methods,including direct injection,in-situ solidification of injected fluids into gel carriers,implantation of solid materials,etc.Among them,the polymer porous surface interface material implanted in the solid state can be in close contact with the tumor,and the released drug molecules can directly act on the targeted site to realize the in situ treatment of the tumor tissue^[90]^[91]^[92]^[93]。

Liu et al.Prepared polylactic acid(PLA)electrospun mats loaded with anticancer drug diisopropylamine dichloroacetate(DADA),and they directly covered the solid tumors of colorectal cancer model mice^[94]。 After 15 days of treatment,the tumor inhibition rate was 95%,and no signs of recurrence were observed,reflecting good efficacy.It is worth noting that DADA-loaded electrospun mats exhibit tolerable physiological toxicity to organisms even when applied at locally high concentrations in vivo。

Ji et al.Used the stimulation-induced phase separation technique to successfully construct a porous polyelectrolyte coating on the surface of microneedles,aiming to develop a therapeutic method for multidrug-resistant melanoma^[95]。 in This study,a microneedle for multi-drug combination therapy was innovatively designed by skillfully utilizing the characteristics of polymer porous surface and interface that can load multiple drugs(Fig.14).the microneedles were first loaded with hydrophobic drug vorinostat(SAHA)in ethanol solution,and then further loaded with hydrophilic drug carboplatin(CBP)in aqueous solution.combination therapy for multidrug-resistant melanoma was achieved by directly inserting microneedles into the skin.this approach not only demonstrates the high efficiency of polymer porous surface interface in targeted delivery of anticancer drugs,but also provides a new combination therapeutic strategy for the treatment of cancer resistant to traditional treatment methods。

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图14 多孔海绵涂层微针负载多种药物来治疗黑色素瘤。ML-MNP（无涂层微针）、PF-MNP（多孔海绵涂层微针）和PF-MNP吸附乙醇和水后的整体（a）和部分（b）形貌的SEM图像；（c）治疗21天后从不同组的5组小鼠中分离出的肿瘤重量；（d）治疗21天后五组孤立肿瘤的图像^[95]

Fig. 14 Porous sponge-coated microneedles are loaded with multiple drugs to treat melanoma. SEM images of the overall (a) and partial (b) morphology of ML-MNP (uncoated microneedles), PF-MNP (porous sponge-coated microneedles) and PF-MNP after adsorbing ethanol and water; (c) weight of tumors isolated from five groups of mice in different groups after 21 days of treatment; (d) images of isolated tumors in five groups after 21 days of treatment^[95]

Stimulus-responsive delivery of anticancer drugs is also a hot topic in the field of topical drug delivery.Inspired by the acid environment of tumor,Cui et al.Prepared a novel composite electrospun poly(L-lactide)(PLLA)fiber scaffold mixed with mesoporous silica particles(MSN),and they encapsulated sodium bicarbonate as an acid-sensitive"switch"into MSN to achieve pH-responsive release of anticancer drug doxorubicin(DOX)^[96]。 in animal experiments,they used The MDA-MB-231 cells cell line to construct tumors in mice,then removed part of the tumors and inserted the drug-loaded scaffolds into the residual tumors.the results showed that these composite fibers could induce significant apoptosis and necrosis within 10 weeks,and could effectively kill cancer cells in situ for a long time after tumor removal。

4.2 Study on Polymer Porous Surface and Interface in Cardiovascular Field

Cardiovascular disease(CVD)is the leading cause of human mortality worldwide^[97]。 Intravascular drug-eluting stent implantation is an effective clinical treatment for atherosclerotic disease^[98]。 Antiproliferative drugs loaded in the stent are mainly lipid-soluble small molecules such as paclitaxel and sirolimus.in recent years,genetic drugs such as miRNA have also attracted attention because they can target and induce smooth muscle cell differentiation and phenotypic switching,while the non-selective inhibition of proliferation by traditional drugs such as sirolimus can delay endothelial regeneration,which will lead to late thrombosis.However,in the face of water-soluble macromolecular drugs,the existing lipid-soluble polymer coatings are difficult to be loaded by similar dissolution,and may impair the biological activity of these macromolecules.Therefore,the polymer porous surface interface with adsorbability has attracted much attention。

Polymeric porous surface interfaces enable the delivery of novel cardiovascular drugs.Ji et al.Protectively delivered 4-octyl itaconate(OI),a macrophage immunomodulator with anti-inflammatory effects,through a porous surface constructed by a surface solvent-nonsolvent phase separation method^[99]。 the investigators found that delivery of OI specifically inhibited smooth muscle cell SMC proliferation and phenotypic switching,which contributed to the competitive growth of endothelial cells.the researchers further demonstrated that OI significantly inhibited the TGF-β/Smad pathway of SMC,which promoted the switch of SMC contractile phenotype and the reduction of extracellular matrix.Furthermore,in vivo evaluation demonstrated that successful delivery of OI achieved inflammatory modulation and SMCs inhibition,therefore inhibiting in-stent restenosis。

Polymeric porous surface interfaces enable combinatorial delivery of cardiovascular drugs to mitigate the adverse effects of cardiovascular antiproliferative drugs.Ji et al.Developed a layered porous coating with rapamycin-containing dense PLGA as the bottom layer and a microporous sponge-like structure prepared by heparinized PLGA/PVP mixed solution as the upper layer,which was loaded with vascular endothelial growth factor(VEGF)^[100]。 Spatial binding of VEGF to rapamycin not only promotes competitive growth of ECs relative to SMCs but also mitigates the severe effects of rapamycin on endothelial function.Similarly,Ji et al loaded the upper microporous structure with the NO donor SNAP,and the released NO could alleviate endothelial dysfunction caused by rapamycin to reduce endothelial damage and inhibit SMC proliferation(Fig.15)^[101]。

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图15 NO加载和释放到雷帕霉素涂层中并调节细胞行为示意图。仅有雷帕霉素的涂层会同时抑制内皮细胞和平滑肌细胞的生长，NO的引入使受损的ECs得到恢复，而SMCs的生长进一步减少^[101]

Fig. 15 Schematic diagram of loading and releasing NO into rapamycin coating and regulating cell behavior. Only the coating of rapamycin inhibited the growth of both endothelial cells and smooth muscle cells, while the introduction of NO restored the damaged ECs and further reduced the growth of SMCs^[101]

Polymeric porous surface interfaces can enable cardiovascular gene drug delivery.Ji et al.Realized the protective transmission of biomacromolecule miR-22 by using the previously developed PCEC porous coating with ultrafast self-repair function,and explored its regulation on intimal hyperplasia at the stent implantation site^[87]。 Because the loading behavior of the porous structure has the advantage of being fast and controllable,the researchers loaded the active molecule miR-22 after the sterilization of the scaffold material and before implantation(Fig.16A),which avoided the damage to the activity of miR-22 caused by the sterilization process.Animal experiments showed that slowly released miR-22 significantly inhibited intimal hyperplasia by regulating smooth muscle cell phenotype without affecting endothelial repair(Fig.16c),thereby inhibiting in-stent restenosis(ISR)。

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图16 动态自愈合多孔涂层递送基因药物miR-22：（a）多孔涂层负载miR-22后进行自愈合来闭合孔洞；（b）血管内植入支架示意图；（c）递送的miR-22使得平滑肌细胞（SMC）收缩表型改善、细胞外基质（ECM）分泌减少和内膜增生减少^[87]

Fig. 16 Dynamic self-healing porous coating for miR-22 gene drug delivery. (a) The porous coating was loaded with miR-22 and self-healed to close the holes; (b) diagram of stent placement in blood vessels; (c) MiR-22 improved SMC systolic phenotype, decreased ECM secretion, and decreased endometrial hyperplasia^[87]

4.3 Study on Polymeric Porous Surface and Interface in Orthopedic Field

in recent years,more and more attention has been paid to porous implants In the field of orthopaedics,which can not only induce the ingrowth of bone tissue to further fix the implant itself,but also facilitate cell proliferation,and can achieve local drug delivery through porous structure to solve the problems of immune response and bacterial infection after implantation.Singh et al.Summarized the types of drugs administered locally through titanium implants and the methods of manufacturing drug-eluting titanium implants^[102]。 Among them,polymer porous surface interface is a way to construct the porous structure of implants,which has been widely studied as an orthopedic drug carrier^{[81,103⇓⇓~106]}。

the delivery of growth factors in the orthopedic field by polymeric porous materials can promote bone repair.for example,the pharmaco-mechanical combination of recombinant human bone morphogenetic protein 2(rhBMP-2)on an absorbable collagen sponge(ACS)carrier has been shown to induce bone formation.as early as 2002,the US Food and Drug Administration approved the Medtronic rhBMP-2/ACS implant as an autograft replacement For certain interbody spinal fusion procedures^[107]。

However,its high concentration of（1.5 mg·mL^-1）also produces various potentially life-threatening complications,such as ectopic bone formation,neurological problems,etc^[108]。 in order to solve the problem of high dose of traditional growth factor,Cheng et al.Proposed an ultra-low dose growth factor delivery technology based On polymer porous surface interface,which prepared plasma-polymerized poly(ethyl acrylate)(PEA)coating.on this surface,fibronectin(FN)spontaneously organizes into a physiologically similar nanoscale porous network and stimulates growth factor signaling,resulting in synergistic activation of integrins and BMP-2 receptors in mesenchymal stem cells to achieve high bioactivity at low doses(fig.17)^[109]。

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图17 超低剂量生长因子递送技术：（a）定制的等离子体聚合室示意图；（b）FN结构，显示其三种结构域类型(Ⅰ, Ⅱ, Ⅲ)和功能；（c）不同浓度的FN吸附在SC-PEA和pPEA上1 h的表面密度；FN在（d）SC-PEA和（e）pPEA上吸附10 min后的AFM相图。在SC-PEA上观察到薄的纤维网络，而在pPEA上观察到厚的，密集的网络；（f）BMP-2在fn包被表面的相对吸附量^[109]

Fig. 17 Ultralow dose growth factor delivery technology. (a) Schematic diagram of a customized plasma polymerization chamber; (b) FN structure, showing its three domain types (Ⅰ, Ⅱ, Ⅲ) and functions; (c) surface densities of FN adsorbed at different concentrations on SC-PEA and pPEA for 1 h; AFM phase diagram of FN adsorbed on (d) SC-PEA and (e) pPEA for 10 min. Thin fiber networks were observed on SC-PEA, while thick, dense networks were observed on pPEA. (f) The relative adsorption capacity of BMP-2 on FN coated surface^[109]

on the other hand,bacterial infection is an important factor affecting the recovery effect of orthopedic patients after implantation.implant placement often requires invasive surgery,and the implant itself and the surgical process may be contaminated by bacteria,and bacterial adhesion will form biofilm On the surface of the implant,causing serious infection in the human body^[110,111]。 for decades,researchers have developed various antimicrobial strategies,among which antibiotics are the main treatment For internal infections in clinic^[112]。 the addition of the polymer porous surface interface platform can realize the long-term release of antibiotics。

For orthopedic biomaterials with high physical properties,the advantage of polymer porous surface is that it only has surface modification,which has little effect on the mechanical properties and stability of the implant itself.In addition,the antibiotic release trend of the polymeric porous surface interface platform is well suited to the needs of implants,with an initial burst of antibiotics at a greater rate to prevent infection immediately after surgery,followed by a slower release to combat possible subsequent infection^[105]。 Kumar et al.Constructed a polymeric porous surface interface on the acetabular cup liner in a total hip implant to deliver antimicrobial agents^[113]。 Specifically,they constructed porous structures on ultra-high molecular weight polyethylene using electrostatic spraying(ES)and chemical etching(CL),respectively(Fig.18),which achieved In vitro antibacterial by loading chitosan and antibiotic gentamicin.in particular,after drug release,the porous surface prepared by the ES method still maintained the porous morphology,while the porous surface prepared by the CL method became smooth due to the collapse of the thin wall,which maintained the same mechanical and tribological properties as the unmodified surface,which was beneficial to further reduce the impact of surface modification。

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图18 表面多孔的髋臼杯衬垫：（a）髋臼杯衬垫抗菌示意图；（b）静电喷涂法制备的多孔结构表面SEM图像；（c）化学蚀刻法制备的多孔结构表面SEM图像^[113]

Fig. 18 Acetabulum cup liner with porous surface. (a) Antibacterial diagram of acetabular cup liner; (b) SEM images of porous surface prepared by electrostatic spraying; (c) SEM images of porous surface prepared by chemical etching^[113]

in addition to developing new antibiotics for antibiotic resistance in bacteria,researchers often use combination antibiotic therapy,which is in line with the advantages of porous surface interface that can be loaded with multiple drugs^[114]。 For example,Jahanmard et al.Fabricated a porous structure on the surface of a titanium-based orthopedic implant with poly(ε-caprolactone)(PCL)and PLGA by electrospinning,while achieving long-acting release of vancomycin and rifampicin^[115]。 The combination of two antibiotics showed stronger bactericidal activity than single antibiotic,which has potential application value。

5 Conclusion and prospect

To sum up,great progress has been made in the study of polymer porous surface and interface in the past decade.polymer porous surface is derived from polymer porous materials,which not only inherits the characteristics of high specific surface area and strong adsorption,but also can play a role without affecting the physical and chemical properties of the substrate itself because it is built on the surface of the substrate^[116⇓~118]。 In general,The preparation methods of polymer porous materials can be improved and optimized for the preparation of polymer porous surface and interface.the commonly used preparation methods of polymer porous surface and interface include breathing diagram method,template method,surface non-solvent induced phase separation method,stimulation induced phase separation method and electrospinning method。

in terms of functionalization,polymer porous surface interface has received extensive attention in the biomedical field,especially in the field of targeted drug delivery,due to its high loading capacity,controllable loading and adjustable release^[119]。 the polymer porous surface interface can load the drug molecules through physical adsorption and embedded embedding,and prolong the drug release time to achieve the purpose of sustained release.and researchers have manipulated drug delivery behavior by manipulating the physicochemical properties of the porous structure.Therefore,implantable medical devices usually construct polymer porous surface interface on the surface to achieve drug delivery in local space,such as targeted anticancer drugs,anti-proliferative drugs,antibiotics and so on,which has great research potential。

At the same time,there are still many challenges to be solved In polymer porous surface and interface,mainly how to further develop the model study of drug delivery into clinical research.First of all,in the preparation of polymer porous surface interface,due to the complex physiological and mechanical environment in vivo,the polymer porous surface interface and its substrate materials need to have reliable stability and fatigue resistance.for example,the polymer porous surface interface in orthopedics needs strong and stable substrate bonding force.Secondly,the controllable drug release behavior is the basis for the development of polymer porous surface and interface energy to clinical research,which requires researchers to achieve more sophisticated control of the pore structure,and to regulate the release behavior of drug molecules.in addition,how to design specific release behavior for specific drug molecules through hydrophilic-hydrophobic,electrostatic interaction and other interactions also needs further study。

Looking forward to the future,the combination of polymer porous surface and interface with other advanced technologies,such as nanotechnology,smart responsive materials,and bio-based new materials,is also an important direction for future development^[120]^[121,122]^[123]。 These combinations can not only improve the performance of polymer porous surface interface,achieve more precise control of drug release behavior,improve the stimulus responsiveness and targeting of drug delivery systems,but also open up new possibilities for specific medical applications(such as precision medicine,biosensors,etc.)。

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Abstract

Cite this article

1 Introduction

2 Construction Strategy of Porous Surface and Interface of Polymer Materials

2.1 Respirogram

2.2 Template method

图2 多孔薄膜横截面的TEM图像。（a）未使用PVP的薄膜；（b~e） 添加乳胶质量比5%、10%、15%和20%的PVPK30所制备的多孔薄膜[32]

图3 极快冰模板法：（a）溶剂在表面极快溶解和定向熔融结晶的示意图；（b, c）为多孔PS表面横截面和表面的SEM图像[33]

2.3 Surface non-solvent induced phase separation

图4 非溶剂诱导相分离法三元相图：（a）贫聚合物相成核（双节线分相）；（b）双连续结构（旋节线分相）；（c）富聚合物相成核（双节线分相）[18]

图5 （a）表面溶胀非溶剂诱导相分离法制备多孔表界面示意图。聚合物基材被依次浸入溶剂和非溶剂中，通过相分离形成孔洞；（b）不同浓度的DMF与水混合物作为溶剂制备的PMMA多孔断面的SEM图像[11]

2.4 Stimulus-induced phase separation

图6 刺激诱导相分离法制备多孔涂层示意图。将无孔(PEI/PAA)自组装膜浸入酸性溶液(pH=2.9)中以诱导孔形成，然后冷冻干燥以除去水。（b~e）分别为在酸性溶液中浸泡0、30、60和90 min的薄膜的SEM横截面图像[43]

图7 通过刺激诱导相分离来传递药物分子的PEM薄膜制备方法示意图：（a）玻璃基板；（a~b） LbL沉积（PAH/PMA）；（b~c） BSA装载；（c~d） 附加（PAH/PMA)；（d~e） CH加载；（e~f），刺激响应释放[42]

2.5 Electrospinning

图8 多孔电纺丝纤维制备示意图：（a） 电纺PLLA纤维膜、（b） 后处理后的多孔PLLA纤维以及（c） PLLA纤维上的丝素蛋白涂层的示意图[56]

3 Functional molecule delivery based on polymer porous surface interface.

3.1 Driving force for loading and release of functional molecules

3.1.1 Capillarity driven molecular loading

图9 多孔介质负载功能分子示意图：（a）流体曲面示意图；（b）多孔介质理想化概念模型示意图

3.1.2 Diffusion-driven molecular release

3.2 Study on release behavior of functional molecules

3.2.1 Physical adsorption loading functional molecular

图10 静电相互作用加强物理吸附：（a）多孔PHMB/SF海绵横截面的SEM图像；（b） 不同质量比的PHMB/SF复合物的Zeta电位，SF的负电荷被PHMB中和，表明二者通过静电相互作用结合；（c） PHMB/SF海绵释放曲线图[73]

3.2.2 Controlling the release of functional molecules by regulating the porous structure

3.2.3 The embedded embedding effect realizes the further sustained release of the drug

图13 动态自愈合多孔涂层示意图与表征：（a）负载功能分子后，通过温和的热触发方式进行孔洞的封闭，将功能分子包埋在孔洞中；（b）分子负载量与分子溶液浓度成正比；（c）自修复后分子释放速率显著减小[31]

4 Application of Polymeric Porous Surface and Interface in Drug Delivery

4.1 Study of Polymer Porous Surface and Interface in Targeted Anticancer Field

4.2 Study on Polymer Porous Surface and Interface in Cardiovascular Field

图15 NO加载和释放到雷帕霉素涂层中并调节细胞行为示意图。仅有雷帕霉素的涂层会同时抑制内皮细胞和平滑肌细胞的生长，NO的引入使受损的ECs得到恢复，而SMCs的生长进一步减少[101]

4.3 Study on Polymeric Porous Surface and Interface in Orthopedic Field

图18 表面多孔的髋臼杯衬垫：（a）髋臼杯衬垫抗菌示意图；（b）静电喷涂法制备的多孔结构表面SEM图像；（c）化学蚀刻法制备的多孔结构表面SEM图像[113]

5 Conclusion and prospect

References

图2 多孔薄膜横截面的TEM图像。（a）未使用PVP的薄膜；（b~e）添加乳胶质量比5%、10%、15%和20%的PVPK30所制备的多孔薄膜^[32]

图3 极快冰模板法：（a）溶剂在表面极快溶解和定向熔融结晶的示意图；（b, c）为多孔PS表面横截面和表面的SEM图像^[33]

图4 非溶剂诱导相分离法三元相图：（a）贫聚合物相成核（双节线分相）；（b）双连续结构（旋节线分相）；（c）富聚合物相成核（双节线分相）^[18]

图5 （a）表面溶胀非溶剂诱导相分离法制备多孔表界面示意图。聚合物基材被依次浸入溶剂和非溶剂中，通过相分离形成孔洞；（b）不同浓度的DMF与水混合物作为溶剂制备的PMMA多孔断面的SEM图像^[11]

图6 刺激诱导相分离法制备多孔涂层示意图。将无孔(PEI/PAA)自组装膜浸入酸性溶液(pH=2.9)中以诱导孔形成，然后冷冻干燥以除去水。（b~e）分别为在酸性溶液中浸泡0、30、60和90 min的薄膜的SEM横截面图像^[43]

图7 通过刺激诱导相分离来传递药物分子的PEM薄膜制备方法示意图：（a）玻璃基板；（a~b） LbL沉积（PAH/PMA）；（b~c） BSA装载；（c~d）附加（PAH/PMA)；（d~e） CH加载；（e~f），刺激响应释放^[42]

图8 多孔电纺丝纤维制备示意图：（a）电纺PLLA纤维膜、（b）后处理后的多孔PLLA纤维以及（c） PLLA纤维上的丝素蛋白涂层的示意图^[56]

图10 静电相互作用加强物理吸附：（a）多孔PHMB/SF海绵横截面的SEM图像；（b）不同质量比的PHMB/SF复合物的Zeta电位，SF的负电荷被PHMB中和，表明二者通过静电相互作用结合；（c） PHMB/SF海绵释放曲线图^[73]

图13 动态自愈合多孔涂层示意图与表征：（a）负载功能分子后，通过温和的热触发方式进行孔洞的封闭，将功能分子包埋在孔洞中；（b）分子负载量与分子溶液浓度成正比；（c）自修复后分子释放速率显著减小^[31]

图15 NO加载和释放到雷帕霉素涂层中并调节细胞行为示意图。仅有雷帕霉素的涂层会同时抑制内皮细胞和平滑肌细胞的生长，NO的引入使受损的ECs得到恢复，而SMCs的生长进一步减少^[101]

图18 表面多孔的髋臼杯衬垫：（a）髋臼杯衬垫抗菌示意图；（b）静电喷涂法制备的多孔结构表面SEM图像；（c）化学蚀刻法制备的多孔结构表面SEM图像^[113]