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Electrical Stimulation Responsive Hydrogel Drug Controlled Release System and Application

Zetao He , Mengru Wang , Xiao Chang , Jiale Li , Guohe Xu , Qiang Ma

Progress in Chemistry ›› 2026, Vol. 38 ›› Issue (5) : 904 -920.

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Progress in Chemistry ›› 2026, Vol. 38 ›› Issue (5) : 904-920 DOI: 10.7536/PC20250725
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Electrical Stimulation Responsive Hydrogel Drug Controlled Release System and Application
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Abstract

Electrical stimulation responsive hydrogel drug controlled release system has attracted wide attention in the field of drug controlled release due to the advantages of precise and controllable electrical stimulation and good reversibility. Such hydrogels are usually composed of conductive polymers or polymer networks doped with conductive materials， which can undergo morphological or structural changes under the action of an external electric field， thereby achieving on-demand release of drugs. Nowadays， significant progress has been made in material design， preparation methods and release mechanisms of electrical stimulation-responsive hydrogel drug controlled release systems， such as improving the stability and response efficiency in vivo and in vitro by optimizing the conductivity， mechanical properties and biocompatibility of hydrogels. In this paper， the electrical response mechanism （ionic， electron， ion-electron mixed response type） and drug release mechanism （swelling drug release， contraction drug release） of the electrical stimulation responsive hydrogel drug controlled release system are introduced. Then， the research progress of electrical stimulation-responsive hydrogel drug controlled release system was summarized according to different electrical response mechanisms. The application of electrical stimulation-responsive hydrogel drug controlled release system in cancer treatment， diabetes treatment， heart disease treatment and nerve repair was summarized. Finally， based on some shortcomings of the current electric response hydrogel drug controlled release system （in vivo residue， drug release rate is difficult to accurately control， performance degradation after recycling）， the prospect is made.

Contents

1 Introduction

2 Electroresponsive hydrogels electrical response mechanism and the drug release mechanism of the drug controlled release system

2.1 Electroresponsive hydrogels electrical response mechanism

2.2 Electroresponsive hydrogels drug release mechanism of drug controlled release system

3 Electroresponsive hydrogels research progress of drug controlled release system

3.1 Ionic electroresponsive hydrogels drug controlled release systems

3.2 Electron electroresponsive hydrogels drug controlled release systems

3.3 Ion-electron mixed response type electroresponsive hydrogels drug controlled release systems

4 Electroresponsive hydrogels application of drug controlled release system

4.1 Cancer therapy

4.2 Diabetes treatment

4.3 Heart disease treatment

4.4 Repair of nerve

5 Conclusions and prospects

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Keywords

hydrogels / electroresponse / drug controlled release systems / applications

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Zetao He, Mengru Wang, Xiao Chang, Jiale Li, Guohe Xu, Qiang Ma. Electrical Stimulation Responsive Hydrogel Drug Controlled Release System and Application. Progress in Chemistry, 2026, 38(5): 904-920 DOI:10.7536/PC20250725

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1 Introduction

Traditional membrane-based drug delivery methods not only fail to sustain drug release over long periods but also lack selectivity. Consequently, patients often require large doses and repeated administrations for treatment. However, excessively high blood drug concentrations can lead to toxic side effects and harm the body, while insufficient concentrations fail to produce therapeutic effects.[1-2]. To overcome these challenges, extensive research efforts have shifted towards designing and fabricating polymer-based drug delivery systems, such as nanoparticles[3], liposomes[4], polymeric micelles[5], and hydrogels[6]. These systems are capable of controlling the release of drug molecules in terms of time and location, thereby enhancing efficacy and reducing toxicity.
Hydrogels formed through physical or chemical crosslinking possess an interconnected three-dimensional porous network structure. This special structure can restrict the mobility of water, thereby endowing hydrogels with soft solid-like properties.[7-8]. Furthermore, as a soft material, hydrogels feature high water content, good biocompatibility, high physical similarity to tissues, and tunable mechanical properties, providing a carrier for the transport of water, nutrients, drug molecules, and cells.[9-11]. Smart responsive hydrogels prepared through functionalization design can react to external environmental stimuli, leading to matrix deformation or degradation.[12]. This unique attribute enables hydrogels to achieve sustained and controlled drug release, thereby improving drug utilization, reducing the medication burden, and minimizing the occurrence of toxic side effects in patients.[13-15].
Intelligent responsive hydrogels have broad application prospects in the field of controlled drug release. Among them, electrically stimulated responsive hydrogels (ERHs) control drug release through an applied electric field. ERHs contain polymer networks with ionizable groups or incorporate electroactive components such as conductive polymers and carbon nanomaterials. Under the action of an electric field, processes such as ion migration or electron transfer occur within the gel, causing changes in volume and shape. However, factors such as the type, intensity, and duration of the electric field all affect the controlled release of drugs by ERHs to varying degrees. Using electrical stimulation as an external trigger signal offers numerous advantages over other stimulation methods (such as pH, temperature, light, etc.)[16-17]. First, electrical stimulation enables precise and controllable drug release. By adjusting the electric field strength, the duration, or the frequency of the applied voltage, the degree of swelling/shrinking of the hydrogel can be precisely controlled, thereby regulating the drug release rate to achieve on-demand dosing.[18]. Second, as a simple and clean stimulus source, electrical stimulation does not introduce additional chemical substances when acting on hydrogels, avoiding carrier contamination or metabolic burden. Furthermore, electrical stimulation usually possesses good reversibility, enabling the hydrogel to be reused multiple times and improving drug utilization efficiency.[19-21]. Meanwhile, the electric field can be applied locally to avoid systemic side effects, making it suitable for implantable drug delivery systems.[22]. Therefore, electrically stimulated responsive hydrogels (ERHs) possess unique advantages in the field of controlled drug release. Moreover, ERHs have wide applications in the fields of flexible electronics and intelligent actuation (such as flexible sensors and bionic robots) and environmental engineering (such as wastewater treatment and oil-water separation).
This article reviews the electrical response mechanisms of ERHs (ionic, electronic, and ionic-electronic hybrid) and their drug release mechanisms in controlled drug delivery systems (swelling-based release and shrinking-based release). Classified by electrical response mechanism, it systematically summarizes research achievements on ionic (based on synthetic/natural polyelectrolytes), electronic (based on polypyrrole (PPy) and poly(3,4-ethylenedioxythiophene) (PEDOT)), and ionic-electronic hybrid hydrogel drug controlled release systems. Subsequently, it elaborates on the applications of ERH drug controlled release systems in cancer, diabetes, heart disease, and nerve repair. Finally, based on current limitations of electrically responsive hydrogel drug controlled release systems (in vivo residue, difficulty in precisely controlling drug release rates, and performance degradation after cyclic use), future prospects are outlined.

2 Mechanism of electrical response of ERHs and drug release mechanism of drug-controlled release systems

2.1 ERHs Electrical Response Mechanism

ERHs can be classified into ionic, electronic, and ion-electron hybrid response types based on their electrical response mechanisms.

2.1.1 Ionic

Ionic ERHs primarily rely on the directional migration of free ions under an applied electric field to achieve electrical response[23-25]. When an electrical stimulus is applied to the hydrogel, free ions are driven by the electric field force to move rapidly along the direction of the field, causing significant changes in local ion concentration, which leads to osmotic pressure imbalance and results in gel swelling or contraction[26-28].
For polyanionic hydrogels (such as systems containing carboxyl or sulfonic acid groups), the anionic groups on the backbone are immobile, while the cations generated by dissociation exhibit high mobility. Under an applied electric field, these cations tend to migrate toward the cathode, resulting in an uneven ion distribution across the gel: cation concentration increases on the cathode side and decreases significantly on the anode side. This concentration gradient leads to a relatively lower ion concentration in the external solution on the anode side, thereby creating an osmotic pressure difference between the inside and outside of the gel. Consequently, the interior of the gel on the anode side exhibits higher osmotic pressure, ultimately driving water infiltration and inducing local swelling, causing the gel to bend toward the cathode.[29-30], asshown in Figure 1(a).
For polycationic hydrogels (such as systems containing amino groups), the cationic groups on the backbone are immobile, while the anions generated by dissociation exhibit high mobility. Under an applied electric field, these anions tend to migrate toward the anode, resulting in an uneven ion distribution across the gel: the anion concentration increases on the anode side and decreases significantly on the cathode side. This concentration gradient leads to a relatively lower ion concentration in the external solution on the cathode side, thereby creating an osmotic pressure difference between the inside and outside of the gel. Consequently, the interior of the gel on the cathode side exhibits higher osmotic pressure, ultimately driving water infiltration and inducing local swelling, causing the gel to bend toward the anode.[31-32], asshown in Figure 1(b).
In addition, the hydrogel chains containing ionic groups generate repulsion under the action of an electric field, causing the voids in the gel network to enlarge and the gel to swell.[33].

2.1.2 Electronic type

Electronic ERHs primarily rely on conductive polymers with reversible redox activity within the hydrogel to achieve electrical response; these conductive polymers possess multiple conjugated planar structures[34-35]. The presence of a π-conjugated backbone and the delocalization of π-bond electrons in conductive polymers form the basis of their conductivity[36-37]. Conductive polymers interweave with the gel matrix as independent networks, forming interpenetrating or double network structures. Under an applied electric field, electron transfer occurs at the interface between the conductive polymer and the electrode, causing a change in the electron content of the conductive polymer within the gel. This further induces conformational changes in the polymer chains, leading to swelling or contraction of the gel network[38-40]. When the conductive polymer loses electrons and is in an oxidized state, the polymer chains become positively charged. Due to electrostatic repulsion, the network within the gel tends to extend, enhancing the delocalization of π electrons in the conjugated structure and increasing chain rigidity, which further expands the network space. When the conductive polymer gains electrons and is in a reduced state, the electrostatic repulsion between conductive polymer chains disappears. The molecular chains tend to coil due to interactions such as hydrogen bonding, and segment folding causes the gel network to contract[41-42], asshown in Figure 2. Since electron transport speed is far faster than ion migration rates, electronic ERHs feature fast response speeds, stable response processes, and reversibility.

2.1.3 Ion-electron hybrid responsive

The conductive components within ion-electron hybrid responsive ERHs include both free ions (polyelectrolytes) and free electrons (conductive polymers, carbon nanotubes (CNTs), reduced graphene oxide (rGO), and metal wires).
For polyanion-electron hybrid responsive ERHs, the anionic groups on the backbone carry negative charges, causing repulsion between polymer chains and leading to enlarged gel network voids, resulting in significant gel swelling. Upon application of a positive potential, hydrogen ions generated from water dissociation combine with the anionic groups, rendering them electrically neutral and eliminating the original repulsion. Although the conductive components containing free electrons within the gel become positively charged after electron migration and also generate repulsion, this effect is much weaker than the original repulsion between polyionic groups; therefore, macroscopically, the gel exhibits a contracted state.[43], asshown in Figure 3(a).
For polycation-electron mixed responsive ERHs, the ionic groups on the backbone are uncharged under reducing potential. After applying a positive potential, hydrogen ions generated by water dissociation bind to the polymer chains, becoming positively charged and causing mutual repulsion between the chains. Furthermore, the conductive components within the gel are in an oxidized state and carry a positive charge under positive potential, exacerbating charge repulsion inside the gel and further leading to gel swelling.[44], as shown in Figure 3(b).
Among them, the electronic network provides a high-speed charge transport channel, while ion migration amplifies the magnitude of volume changes.[45]. The synergistic effect of the two achieves a performance balance for ion-electron hybrid responsive ERHs, combining the fast response of near-electronic types with the large deformation of near-ionic types.

2.2 Drug release mechanism of ERHs controlled-release systems

The ERHs drug controlled-release system utilizes an external electric field to regulate the hydrogel structure, thereby achieving precise drug release. This system primarily relies on two drug release mechanisms: swelling-based release and contraction-based release.[46].

2.2.1 Swelling drug release

Hydrogels that release drugs through swelling typically contain a large number of hydrophilic groups (such as hydroxyl, carboxyl, amide bonds, ether bonds, etc.). Upon electrical stimulation, electrostatic interactions within the molecules and hydrogen bonding between hydrophilic groups on the polymer chains and external water molecules become dominant. A large amount of water molecules enters the interior of the hydrogel, causing it to swell, and drug molecules are released from the inside of the gel to the outside due to the diffusion gradient, asFigure 4shows. This process can control the drug release rate by regulating the intensity and duration of the electric field, achieving the goal of on-demand drug delivery[47].

2.2.2 Shrinkage drug release

Hydrogels that release drugs through contraction typically contain a large number of hydrophobic groups (such as long-chain alkyl, ester, and nitro groups). Upon electrical stimulation, intramolecular hydrogen bonding and hydrophobic interactions within the hydrogel molecules become dominant, hindering the formation of hydrogen bonds between the hydrophilic groups of the hydrogel and water molecules, or leading to the formation of a hydrophobic layer. This causes the hydrogel to contract, forcing internal water out while simultaneously carrying away some drug molecules, such asFigure 5shows, resulting in a one-time or short-term high-concentration drug release[48].

3 Research Progress on ERHs Drug Controlled Release Systems

3.1 Ionic ERHs drug controlled-release system

Ionic ERHs can exhibit macroscopic responses to electrical stimulation and are typically synthesized using polyelectrolytes containing ionizable groups (such as carboxyl, sulfonic acid, or amine groups).[49]. Depending on their source, polyelectrolytes can be classified into two categories: synthetic polyelectrolytes and natural polyelectrolytes. Ionic ERHs are relatively milder, possess superior biocompatibility, avoid tissue damage, and are suitable for long-term in vivo implantation for drug delivery.

3.1.1 Drug-controlled release system based on synthetic polyelectrolyte ionic ERHs

Synthetic polyelectrolytes refer to polymer electrolytes prepared via chemical synthesis, where the polymer chains carry a large number of ionizable ionic groups. In aqueous solutions, these groups can ionize to form charged polymer chains and free ions, thereby exhibiting electrolyte properties.[50]. Under an applied electric field, free ions within the gel undergo directional migration, ultimately leading to hydrogel swelling or shrinkage caused by osmotic pressure differences. For instance, polyacrylic acid (PAA) can be processed into various sizes and shapes at different concentrations; it exhibits high adhesion to biological tissues and holds broad application prospects in the field of drug delivery.[51].
Mallawarachchi et al.[52]usedN,N-methylenebisacrylamide and potassium persulfate as crosslinker and initiator, respectively, to synthesize PAA gels and poly(methacrylic acid) (PMA) gels via free radical polymerization. Experiments revealed that both PMA and PAA gels exhibit electrical responsiveness. Without electrical stimulation, protein release from PAA gels was only 20%, whereas upon applying electrical stimulation, protein release reached 80%. However, PMA gels released a significant amount of protein even without electrical stimulation; this is because the methylated structure of PMA weakens hydrogen bonding, enhances hydrophobicity, and facilitates protein diffusion out of the gel network. Therefore, PAA is more suitable for applications requiring precise control of drug release via electrical stimulation. PAA gels primarily retain insulin within the gel matrix through hydrogen bonding with insulin. Upon application of electrical stimulation, these hydrogen bonds between insulin and PAA are disrupted. Simultaneously, electrical stimulation induces migration of protons ionized from PAA and electrostatic repulsion among negatively charged polymer chains, leading to gel swelling and facilitating insulin release. Furthermore, electrical stimulation triggers electrophoresis of insulin molecules, further enhancing insulin release, asshown in Figure 6. The insulin loaded in this gel holds great promise for diabetes treatment but remains in the research stage and has not yet been applied clinically. Additionally, gaining deeper insight into the molecular interactions influencing insulin retention and release mechanisms in PAA gels will aid in developing and optimizing hydrogel-based controlled drug delivery systems.

3.1.2 Drug controlled release system based on natural polyelectrolyte ionic ERHs

Natural polyelectrolytes are charged macromolecular substances derived from natural polymers, containing ionizable functional groups on their molecular chains. Under an applied electric field, free ions within the gel also undergo directional migration, ultimately leading to osmotic pressure differences that cause swelling or shrinkage of the hydrogel. Such polyelectrolytes typically exhibit good biocompatibility and biodegradability, and are commonly used in biomedical fields. For instance, alginate (Alg) is a unique material for drug delivery systems, characterized by biocompatibility, biodegradability, and non-toxicity.[53].
Zhang et al.[54]developed an electrically driven nanocomposite hydrogel for the release and migration of glyphosate (Gly) using attapulgite (ATP), glyphosate (Gly), and calcium alginate (CA) as raw materials. ATP-CA served as a nanonetwork carrier to effectively load Gly, forming porous ATP-Gly-CA hydrogel beads. The surface of the ATP rods features abundant micro-nanopores and hydroxyl groups, which facilitate hydrogen bonding with Gly and adsorb Gly within the pores of the ATP-CA nanonetwork and on the ATP surface. Under an electric field, calcium ions detach from the polymer chains within the hydrogel and undergo directional migration, altering the osmotic pressure of the hydrogel and causing it to swell and release the drug. Furthermore, the pores within the hydrogel beads expand due to electrostatic forces between anionic polymer chains, leading to hydrogel volume expansion and accelerating the electric-field-driven release of negatively charged Gly, asshown in Figure 7. Finally, experiments involving zebrafish and mice demonstrated that the hydrogel possesses good biocompatibility, indicating its biosafety. The precise release and delivery of Gly by this hydrogel offer a novel approach to reducing harmful environmental impacts, enabling weed control while minimizing ecological hazards. However, since all experimental conditions were conducted in the laboratory, effectiveness in complex ecosystems such as outdoor farmland cannot be guaranteed. Nevertheless, this study provides a promising method for controlling Gly release, achieving precise Gly delivery, and improving utilization efficiency, showing strong application prospects in facility agriculture. However, due to the requirement for a relatively high driving voltage of 20 V and the influence of response time, costs remain elevated; therefore, it is essential to develop hydrogels capable of responding to lower voltages and achieving faster electrical responses.
Tverdokhlebova et al.[55]prepared a gel that uses low voltage to indirectly affect local pH, triggering gel swelling/shrinking. By applying an oxidative potential in a solution containing Fe2+and soluble Alg, Fe2+is oxidized to Fe3+. Subsequently, crosslinking with alginate forms an Alg hydrogel layer on the electrode surface, where ion concentration and deposition time determine the gel layer thickness. To enable repeated swelling-shrinking cycles of the gel, cation exchange is performed when treating the alginate hydrogel with a solution containing ascorbate and Ca2+, ultimately yielding a Ca2+-crosslinked alginate hydrogel deposited on the electrode surface. This gel requires only a driving voltage of ±0.6~0.8 V to achieve controlled drug release, with a response time of 3 min to complete the switch from gel contraction to expansion. When a positive potential is applied to the gel, ascorbic acid is oxidized, releasing hydrogen ions; simultaneously, the carboxylate groups of alginic acid attract and migrate these hydrogen ions, causing the gel to become hydrophobic and contract, thereby inhibiting protein release. When a negative potential is applied, oxygen is reduced to water, consuming hydrogen ions, while carboxyl groups ionize to release hydrogen ions that migrate to the electrode surface, causing the gel to become hydrophilic and expand, promoting protein release. This reversible process can cyclically stimulate and inhibit protein release by applying alternating positive and negative potentials, asFigure 8shows. Additionally, it was found that release behavior depends on the size and charge of the protein, with smaller and negatively charged proteins exhibiting more effective release activation. Currently, this alginate hydrogel has not yet been applied to any disease treatment, but its ability to regulate the on-demand release of small-molecular-weight negatively charged proteins/enzymes via electrical stimulation holds potential for various biomedical applications. For instance, it shows promising prospects in the field of enzyme-based unconventional computing (information processing).

3.2 Electronic ERHs drug controlled-release system

Electronic ERHs achieve electrically controlled drug release by combining conductive polymers with traditional hydrogels. Conductive polymers typically possess a π-π conjugated backbone structure, enabling the regulation of drug adsorption and release through the doping of ionic drugs and changes in the polymer's redox state.[56]. The response core of electronic ERHs is electron conduction driven by an electric field; therefore, they offer advantages such as fast response speed and high precision in controlled release, enabling on-demand drug administration for acute diseases. The following section introduces several typical PPy and PEDOT-based electrically responsive controlled release systems.

3.2.1 PPy-based electronic ERHs drug controlled release system

PPy is a conductive polymer material formed by the polymerization of pyrrole monomers[57]. Its molecular chain possesses a continuous π-π conjugated structure, enabling delocalized electron migration along the chain, thereby imparting conductivity[58-60]. After chemical or electrochemical doping treatment, the conductivity of polypyrrole can be further improved, allowing it to serve as an effective charge transfer medium in gels[61-64]; furthermore, polypyrrole exhibits excellent mechanical stability and biocompatibility, making its application prospects very broad[65-67].
Krathumkhet et al.[68]fabricated a pectin-bacterial cellulose (BC)/PPy hydrogel composite for an electrically controlled transdermal drug delivery system. This system influences the release of the internal anionic drug ibuprofen (IBU) from the hydrogel based on variations in BC concentration, pH value, and electric field strength. IBU-doped PPy was prepared via chemical oxidative polymerization; π-π stacking and electrostatic interactions between IBU and the PPy network retain the drug within the network. The PPy network was then loaded into the pectin/BC hydrogel. Upon application of a negative potential, PPy is reduced from its oxidized state to a neutral state, weakening the electrostatic attraction to IBU molecules and causing the drug molecules to detach from the PPy backbone. Furthermore, the negatively charged electrode generates a repulsive force against carboxylate groups in the gel, inducing hydrogel swelling and facilitating the release of negatively charged IBU molecules from the gel via the iontophoretic effect, asFigure 9shows. Additionally, it was demonstrated that the incorporation of PPy into the pectin/BC hydrogel matrix increases IBU release under electrical stimulation. A significant feature of this composite is that only the smaller IBU drug molecules can be released from the gel, whereas PPy cannot. Since PPy is not released, the system poses no hazard to human health. Moreover, the optimal BC mass fraction is 30%, at which point the drug release reaches a maximum of 78% after electrical stimulation. The hydrogel composite also exhibits significant antibacterial activity against Gram-positive bacteria. Therefore, this gel is an excellent alternative material for transdermal drug delivery. However, the gel achieves a maximum drug release rate of 78% only at a voltage of 7 V; this relatively high response voltage affects its practical application.
Bansal et al.[69]formed a fully interpenetrating network based on methacrylated hydrogel (GelMA) and PPy, exhibiting a more sensitive release mechanism. The conductive polymer hydrogel (CPH), composed of GelMA and PPy doped with glutamate (Glu), enables controlled release of the excitatory neurotransmitter Glu. The drug release amount from this CPH under continuous electrical stimulation is five times that without electrical stimulation. Notably, compared to traditional PPy/Glu films, the GelMA/PPy/Glu coating can deliver 14 times the amount of Glu under -0.6 V electrical stimulation. When a positive potential is applied to the gel, PPy retains negatively charged Glu via electrostatic attraction, with only a small amount released through diffusion. When a negative potential is applied, PPy transitions from an oxidized state to a neutral state, significantly weakening or even eliminating electrostatic interactions with anionic drugs, causing Glu to detach from the polymer chains to achieve release, asFigure 10shown. Although this study focuses on electrically controlled delivery of Glu, the hydrogel can be used to deliver drugs with different charges and sizes. Therefore, this CPH holds great promise for treating neurological diseases in bioelectronics. However, its drug release performance still needs improvement.
To further optimize the drug release performance of the gel, Orduño Rodríguez et al.[70]synthesized PPy nanoparticles using a biocatalytic method, with PVA as the matrix and glutaraldehyde as the crosslinker, to prepare PVA/PPy composite hydrogels via in situ encapsulation. Using metoprolol as a model drug, they evaluated its controlled release performance. At higher PPy content, the gel achieved 100% release within 6 hours under electrical stimulation at -5 V. The hydrophilicity and porous structure of PVA facilitate drug adsorption and retention; hydrogen bonding interactions exist between PPy and PVA, which alter the three-dimensional structure of PVA. Meanwhile, the swelling capacity and molecular diffusivity of the PVA network may also retain drug molecules through physical entrapment. When a negative potential is applied to the gel, electrons enter, reducing PPy and triggering gel volume contraction, thereby releasing the carried drug. Conversely, switching the potential to positive inhibits release from the gel. The hydrogel exhibits tunable swelling, thermal stability, and electrical responsiveness, making it suitable for electrically regulated cardiovascular disease treatment scenarios, such as on-demand drug delivery for hypertension and angina. However, this study has not yet conducted in vivo experiments, having only performed in vitro indirect tests, necessitating further investigation for practical applications.

3.2.2 PEDOT-based n-type ERHs drug controlled release system

PEDOT is a conductive polymer that combines high electrical conductivity, good chemical and thermal stability, and excellent optical transparency[71-74]. Its conductivity principle stems from the extended π-π conjugated system on the molecular backbone, which significantly enhances electron mobility and achieves high-level conductivity through chemical or electrochemical doping[75-77]. In flexible electronic devices[78], displays[79], solar cells[80], sensors[81], and energy storage devices[82], it has widespread applications.
Cheah et al.[83]developed a CPH composed of biocompatible GelMA and the conductive polymer PEDOT. The GelMA hydrogel provides a porous network for protein loading, promoting drug diffusion upon swelling, while PEDOT is electropolymerized within the GelMA to form a semi-interpenetrating network. When PEDOT is in its oxidized, positively charged state, it can adsorb negatively charged bovine serum albumin (BSA). Upon applying a constant negative potential to the CPH, PEDOT becomes electrically neutral, and the residual p-toluenesulfonate anions (pTS-) within the hydrogel impart an overall negative charge, repelling the negatively charged BSA and promoting protein release, asshown in Figure 11, where the release amount over 4 hours increased by 68% compared to passive release. When a positive potential is applied, electrostatic attraction inhibits release, reducing the release amount by 38%. Notably, this composite hydrogel underwent passive release for the first 14 days; from day 15 to 21, biphasic pulses at 0.1 Hz were applied daily for 1 hour, increasing the release rate threefold compared to the unstimulated group and achieving sustained controlled drug release over 21 days. The GelMA/PEDOT conductive polymer hydrogel achieves electrically responsive controlled protein release by combining electrostatic interactions driven by the electrochemical redox of PEDOT with the high drug-loading reservoir characteristics of the GelMA hydrogel. Electrical stimulation parameters (potential, waveform, frequency) are key to regulating the release rate and total amount; the biphasic pulse strategy enhances potential for in vivo applications while ensuring safety, making this hydrogel highly suitable as a therapeutic delivery carrier in tissue engineering applications.

3.3 Ion-electron hybrid responsive ERHs drug controlled release system

Ion-electron hybrid responsive ERH drug-controlled release systems combine dual ion and electron response mechanisms, composed of different types of conductive components forming a synergistic transport network. Under electrical stimulation, ion migration and electron charge transfer trigger structural changes to regulate drug release, offering advantages of dual-response synergy and precise dynamic control. Ion-electron hybrid responsive ERHs integrate the strengths of both while compensating for the limitations of single-type systems, enabling adaptation to more complex physiological environments and broader types of drug release.
Kleber et al.[84]fabricated a CPH using the hydrogel precursor poly(dimethylacrylamide-co-4-methacryloyloxybenzophenone (5%)-co-4-styrenesulfonate (2.5%)) (PDMAAp) and PEDOT. The conductive PEDOT network within the gel modulates its charge state via electrochemical redox reactions, facilitating electrostatic adsorption/release of drugs. Using anionic fluorescein and dexamethasone as drug models, applying a positive potential to the gel oxidizes PEDOT, attracting negatively charged drugs to bind to the hydrogel through electrostatic interactions. Subsequently, applying a negative potential reduces PEDOT; the composite network formed by the negatively charged hydrogel matrix and the reduced PEDOT becomes dominated by negative charges, causing the release of negatively charged drug molecules due to electrostatic repulsion, asFigure 12shows. The synergy between electrochemically induced charge repulsion and swelling-induced diffusion, with electrostatic interactions dominating, results in a release amount more than six times higher than that of pure diffusion (passive release). In the future, this system can be adjusted or optimized according to different drugs, release profiles, and dosing regimens. In this way, it can be applied in the fields of bioelectronics and neural interfaces, particularly suitable for neurological diseases requiring neural implants accompanied by local inflammation. Additionally, the gel achieves electrical response at a voltage of 0.5 V, triggering release within 60 s of electrical stimulation, and remains responsive after soaking for 28 days. Cytotoxicity test results indicate that the survival rate of skin fibroblasts is greater than 90%, though there is still room for improvement.
Using greener raw materials can further improve the biosafety of the hydrogel. Ha et al.[85]developed an electrically responsive conductive hybrid hydrogel patch (Gel-Alg-AgNW) composed of Alg, GelMA, and silver nanowires (AgNW), which combines mechanical enhancement, conductivity, and electrically controlled drug release capabilities. The gel achieved optimal release conditions at 3 V, releasing 57% of DOX after 2 hours. Cytotoxicity test results showed that the viability of human keratinocytes was greater than 95%, representing a significant improvement. The hydrogel forms an interpenetrating polymer network from Alg (ionic crosslinking) and GelMA (photo-crosslinking); its abundant porous structure provides ample storage space for drug molecules, facilitating efficient drug loading and sustained release. Positively charged doxorubicin (DOX) binds to the negatively charged alginate segments in the gel via electrostatic interactions, while secondary interactions such as hydrogen bonds and van der Waals forces with the gel network further enhance loading stability. Upon applying a positive potential stimulus to the gel, DOX molecules are repelled and released outward; simultaneously, the electric field promotes the migration of sodium ions within the gel, creating an osmotic pressure gradient that further drives drug diffusion into the external solution. Electrical stimulation also triggers redox reactions, causing swelling-shrinking cycles in the hydrogel network, which disrupts hydrogen bond/van der Waals interactions between the drug and the gel, thereby accelerating drug release, asFigure 13shows. The transdermal topical delivery and electrically controlled precise release of this hydrogel make it suitable for treating skin and superficial tissue diseases, enabling the development of wearable skin patches. However, its stimulation voltage of 3 V can still be further optimized and reduced.
Puiggalí-Jou et al.[86]Optimized the gel material by selecting superior conductive materials to prepare an electrochemically active hydrogel based on PEDOT and Alg. This gel can be used for the controlled release of curcumin (CUR), achieving controlled release of hydrophobic drugs. Under electrical stimulation at -1.0 V, it sustained release within 2 hours, with a 25% release in 2 hours significantly higher than the 3% from passive release. Further optimization of the gel's biocompatibility and cytotoxicity tests showed no adverse effects on skin fibroblast proliferation. CUR was dissolved in ethanol, added to the Alg solution, and then mixed with PEDOT to induce gelation, achieving uniform distribution of the drug within the gel network. The conjugated thiophene rings of PEDOT bind to the aromatic rings of CUR via hydrophobic interactions; CUR embeds into the hydrophobic microdomains between PEDOT molecular chains, forming molecular aggregates in a hydrophobic environment. Furthermore, the conjugated π-electron systems of both undergo π-π stacking, enhancing intermolecular interactions and stabilizing CUR loading within the gel. When a positive potential is applied to the gel, an electrochemical oxidation reaction occurs, generating H+, which binds to carboxylate groups, weakening electrostatic repulsion between molecular chains. Chain segment contraction causes the gel to shrink, hindering the release of hydrophobic drugs. When a negative potential is applied to the gel, an electrochemical reduction reaction occurs, producing OH-; carboxyl groups remain deprotonated, but voltage-driven electron transfer induces structural rearrangement of the hydrogel network, increasing molecular chain extension and promoting the release of hydrophobic drugs from the gel, asshown in Figure 14. The CUR loaded in this gel possesses antibacterial and antitumor efficacy, suggesting its potential application in cancer therapy. Moreover, with advantages such as simple synthesis, good biocompatibility, and electrically responsive controlled drug release, this gel holds significant research prospects for drug delivery applications.
Aycan et al.[87]prepared an implantable composite hydrogel for the treatment of nerve-related diseases, which also exhibits extremely high biosafety. First, methacrylic anhydride (MA) was grafted onto hyaluronic acid (HA) molecular chains via esterification to prepare methacrylated hyaluronic acid (HA/MA). rGO was dispersed in the HA/MA solution, and after adding a photoinitiator, UV crosslinking was performed to form an HA/MA-rGO hydrogel. Subsequently, the HA/MA-rGO hydrogel was soaked in an aniline monomer solution, and ammonium persulfate (APS) was added to initiate polymerization, forming an HA/MA-rGO-polyaniline (PANI) composite hydrogel. Under voltage tests ranging from 1 to 3 V, optimal drug release was observed at 3 V. The release of IBU reached up to 86% within 140 minutes, representing a significant improvement compared to the 37% released via passive diffusion. Cytotoxicity test results indicated that the survival rate of human keratinocytes exceeded 99%, a substantial increase compared to previous studies, demonstrating better cell affinity. The hydrophobic anti-inflammatory drug IBU was selected as the model drug; IBU forms hydrogen bonds with the hydroxyl and carboxyl groups of HA, and electrostatic interactions exist between the negatively charged IBU and the oxidized PANI. When a negative potential is applied to the hydrogel, the hydrogen bonds between IBU and the hydrogel are disrupted. Furthermore, PANI is reduced to its neutral state, weakening the electrostatic adsorption force. Simultaneously, the electric field drives IBU migration toward the positive electrode, accelerating the diffusion process of the drug from the interior of the hydrogel to the external solution, asFigure 15shown. In addition, the "on-off" drug release capability of the composite hydrogel was demonstrated. This hydrogel can serve as a coating for neural implant electrodes; the loaded IBU can inhibit inflammatory factors, reduce inflammation around the implant, and protect neural tissue, providing a new approach for the treatment of neural implants.
In addition, our research group[88]prepared a low-pressure/temperature-sensitive dual-responsive deformable double-network hydrogel, which also possesses electrically stimulated "on-off" controllability, demonstrating great flexibility for subsequent applications. This gel incorporatesN-isopropylacrylamide (NIPAM), CNTs, as well as crosslinkers and initiators dissolved in an ethanol/water mixed solvent to form a porous NIPAM/CNTs first network. Subsequently, it was freeze-dried and immersed in a prepolymer solution containing crosslinkers, initiators, and 5-acrylamido-1,10-phenanthroline di(1,10-phenanthroline)iron(II) (Fe(phen)3)) for saturated adsorption, ultimately synthesizing a low-pressure/temperature-sensitive dual-responsive deformable double-network hydrogel with strong mechanical properties. After freeze-drying this gel, it was immersed in a BSA solution; BSA formed hydrogen bonds with polymer chains to load into the gel network and could also bind with CNTs via π-π stacking. Drug release responsive to electrical stimulation occurred at merely 10 V, and under optimal conditions, the BSA release amount reached 66%, a significant increase compared to the 16.8% from passive release. Cytotoxicity test results indicated that its viability for A549 cells was greater than 99%. Upon application of electrical stimulation, the Fe(phen)3redox reaction alters the charge distribution of the gel, generating an osmotic pressure gradient that drives gel contraction; meanwhile, BSA migrates under electrophoretic force in the electric field, further synergistically promoting contraction and release, asFigure 16shows. Furthermore, CNTs enhance mechanical strength, but their content affects contraction efficiency; a mass fraction of 0.5% CNTs achieves a balance between conductivity and network flexibility. The drug release from this gel follows Fick's law of diffusion and is not affected by cavity collapse or skeleton dissolution. Although in vivo experiments were not conducted for the local drug delivery using BSA-loaded gel in this study, it can serve as a dressing for dermatological treatment.
This paper summarizes different ERHs drug controlled-release systems, the results are shown inTable 1.

4 Application of ERHs drug controlled-release systems

4.1 Cancer treatment

The treatment of cancer remains a major challenge in modern medicine. Chemotherapy is the primary treatment method, involving the intravenous injection of conventional drugs that reach and accumulate in tumors to inhibit their growth and promote regression.[89]However, the complex and hypoxic tumor microenvironment, along with poor drug permeability, leads to issues such as drug resistance and systemic toxicity. To overcome these limitations, local drug delivery has garnered attention, particularly using hydrogels as injectable depots for precise, site-specific therapy.[90]Although hydrogels can improve therapeutic efficacy and reduce side effects, their large pore size and high water content often result in rapid drug release, thereby limiting their effectiveness. Thus, designing and preparing drug-controlled release systems capable of sustaining content release over extended periods holds profound significance for cancer treatment.[91].
Gangrade et al.[92]grafted folic acid (FA) onto single-walled carbon nanotubes (SWCNTs), then loaded DOX, and mixed it with a polymer solution of silk fibroin to obtain a nanocomposite silk fibroin hydrogel. Since the gel contains SWCNTs internally, it belongs to electronic-type ERHs. Its rapid response, precise controlled release, and sensitivity to near-infrared (NIR) laser and electric fields well accommodate the complex requirements of chemotherapy for solid tumors. The hydrogel is minimally invasively implanted around the tumor via a syringe, covering most of the tumor tissue, thereby avoiding the systemic toxicity of traditional intravenous chemotherapy. Positively charged DOX molecules are adsorbed onto the SWCNT-FA surface via π-π stacking and electrostatic interactions, and subsequently loaded into the nanoscale silk fibroin hydrogel. When an external electric field is applied, the directional movement of ions in the surrounding PBS causes local relaxation of the three-dimensional network structure, forming pores that facilitate drug release. Simultaneously, the electric field weakens the electrostatic attraction between SWCNT-FA and DOX, causing the drug to dissociate and release from the nanocarrier surface, asFigure 17shown. In vivo experiments demonstrated that in a breast cancer mouse model, treatment groups stimulated by NIR laser, electric field, or both exhibited significant reductions in tumor volume and mass within 21 days (tumor mass < 0.5 g, compared to approximately 3 g in the control group), with no obvious decrease in body weight, indicating an absence of systemic toxicity. Furthermore, the study revealed that DOX released from the hydrogel induces tumor cell apoptosis through mitochondrial and endoplasmic reticulum stress pathways, effectively inhibiting solid tumor growth in vivo while circumventing the major drawbacks of traditional chemotherapy, thus providing a safe and efficient new method for local cancer treatment.
Resina et al.[93]An electrochemical hydrogel capable of loading CAM, prepared by grafting PAA onto SA and in situ encapsulating PEDOT nanoparticles loaded with chloramphenicol (CAM) (PEDOT/CAM NPs). As an ion-electron hybrid responsive ERH, it can achieve precise electrically stimulated triggered release, avoiding antibiotic resistance caused by passive leakage, while also adapting to the pH-sensitive pathological microenvironment to improve drug diffusion efficiency. CAM molecules form strong interactions with polar groups in the hydrogel matrix, thereby being loaded into the interior of the hydrogel. Upon application of electrical stimulation, the interaction between CAM and water molecules is enhanced, weakening the binding force between CAM and the polar groups of the hydrogel. Furthermore, alternating positive and negative potentials cause cyclic swelling and shrinking of the gel; under electrical stimulation, CAM molecules released from the nanoparticles into the hydrogel diffuse outward following these gel changes, asFigure 18shown. The inhibitory effect of electrically stimulated released CAM on cervical cancer cells and normal monkey kidney cells is concentration-dependent. At lower drug concentrations, the cell viability in both cell lines exceeds 80%. At a mass concentration of 33 μg/mL, the cell viability of normal monkey kidney cells is significantly higher than that of cervical cancer cells, confirming that the anticancer properties of CAM remain unchanged after the encapsulation process and electrical stimulated release. Notably, this gel also possesses pH responsiveness; through the synergistic effect of electrical stimulation and pH response, it achieves precise drug release in the acidic tumor microenvironment, reducing the toxicity of systemic administration and the risk of antibiotic resistance.

4.2 Diabetes Treatment

Diabetes is a global chronic disease. In recent years, the number of cases has increased annually, and the premature mortality rate has risen by 5%. Insulin deficiency (due to pancreatic dysfunction or insulin resistance) leads to hyperglycemia, thereby accelerating the risk of complications in organs such as the heart and kidneys.[94]. In terms of treatment, besides lifestyle interventions, insulin injection is a necessary method, but it suffers from poor compliance and high risks of complications, and insulin is limited by bioavailability. Regulating insulin release through nanoparticle and hydrogel systems, and developing self-regulating insulin delivery systems that combine electric stimulation-induced rapid insulin release with receptor degradation-induced slow insulin release, are beneficial for improving diabetes treatment.[95].
Muñoz-Galán et al.[96]designed two insulin delivery systems. The first system consists of a layer of insulin sandwiched between a conductive PEDOT film and a poly-γ-glutamic acid (γ-PGA) hydrogel, where negatively charged insulin is adsorbed at the interface with positively charged PEDOT via electrostatic interactions. Applying a negative potential reduces PEDOT, sharply decreasing the strength of insulin-PEDOT interactions at the PEDOT/insulin interface, which facilitates hormone release, asshown in Figure 19(a). The second system is a γ-PGA hydrogel containing insulin and PEDOT nanoparticles; as the hydrogel degrades, it can slowly and continuously release insulin, asshown in Figure 19(b). Although both gels use the same raw materials, only the first gel releases insulin triggered by electrical stimulation, classifying it as an ion-electron hybrid responsive ERH. The two different gels correspond to two distinct release modes; their combination not only avoids the drawbacks of single-type hydrogels but also precisely addresses the dual requirements of diabetes treatment. The rapid release mode manages postprandial blood glucose peaks (e.g., electrically stimulated rapid drug release within 10 minutes), while the sustained release mode maintains stable fasting blood glucose, forming dual regulation covering short-term fluctuations and long-term baselines, thereby reducing the risk of hypoglycemia and the frequency of patient administration. By combining the two release modes of "electrically stimulated rapid release + degradation-mediated sustained release," this approach effectively solves the problem of insufficient blood glucose fluctuation control in traditional insulin therapy. It offers biocompatibility, controllable release, and potential for personalized regulation, providing an innovative smart delivery carrier for diabetes management.
Liu et al.[97]using polyN-isopropylacrylamide (PNIPAM), ionic liquid [VBIM]Br, and spirulina as raw materials, an oxygen-producing conductive hydrogel (PVNP-SP) was prepared via UV-initiated copolymerization. As an ionic ERH, it achieves current conduction through ion migration of the ionic liquid [VBIM]Br under an applied electric field. Its mild stimulation, functional compatibility, and high biosafety are well-suited to the fragility of diabetic chronic wound tissues. Spirulina releases oxygen via photosynthesis under light, increasing the dissolved oxygen mass concentration from 0 to 14.9 mg/L within 30 min, significantly alleviating hypoxia in diabetic wounds. It inhibits hypoxia-inducible factor HIF-1α nuclear translocation, activates the Nrf2/HO-1 antioxidant pathway, and reduces reactive oxygen species damage. The hydrogel activates voltage-gated ion channels under an external electric field, promoting fibroblast proliferation and migration, and accelerating wound closure. The synergistic effect of spirulina's light-responsive oxygen production and electrical stimulation significantly reduces wound inflammation, promotes collagen deposition and angiogenesis, and facilitates early wound healing, asFigure 20shown. This therapeutic strategy provides an efficient approach for improving chronic wound healing in diabetic patients by alleviating hypoxia and integrating electrical stimulation.

4.3 Heart Disease Treatment

Myocardial infarction (MI) leads to cardiac tissue damage, scar formation, and heart failure[98]. Current treatment modalities such as antithrombotic therapy, percutaneous coronary intervention, and heart transplantation are available; however, they are associated with contraindications, adverse effects, limited availability, or high complication rates. Therefore, new strategies need to be explored to avoid these limitations. Combining polymer hydrogels with bioactive substances can improve myocardial function and inhibit left ventricular remodeling. Their sustained drug release enhances local effects and reduces systemic adverse reactions[99-100].
Chen et al.[101]developed an injectable conductive hydrogel using hyperbranched polymer polyethylene glycol diacrylate/4-vinylphenylboronic acid (PEGDA-PBA) and thiolated hyaluronic acid (HA-SH) as the matrix, loaded with astragaloside IV nanoparticles (AST NPs) and gold nanorods (GNRs). As an electronic ERH, it can not only connect electrical signals interrupted by myocardial infarction but also inhibit cardiomyocyte apoptosis and promote angiogenesis. GNRs impart conductivity to the hydrogel, facilitating electrical signal transmission between cardiomyocytes, upregulating connexin Cx43 expression, improving intercellular coupling, restoring electromechanical synchrony of the myocardium, and reducing the risk of arrhythmia. PBA binds to the sugar ring structures on the surface of AST NPs via boronate ester bonds, thereby achieving high drug loading capacity and controlled adsorption. Upon application of electrical stimulation, conformational changes are induced in the gel network, leading to the cleavage of boronate ester bonds between PBA and AST. Simultaneously, the pores of the gel network enlarge, prompting the diffusion-mediated release of AST NPs, asFigure 21shown. Following in situ injection of the hydrogel, mRNA expression of collagen 1 and collagen 3 was reduced, the area of myocardial fibrosis decreased, the orderliness of collagen deposition in the infarct zone increased, ventricular wall thickness was maintained, and left ventricular dilation was slowed. The injectable conductive hydrogel constructed in this study promotes neovascularization and cardiac function recovery through a dual strategy of conductive support plus drug delivery, featuring both biosafety and controlled release characteristics, providing an effective therapeutic strategy for treating myocardial infarction.

4.4 Nerve Repair

Peripheral nerve injury leads to the loss of motor, sensory, and autonomic functions, severely affecting patients' lives. Currently, nerve conduits are widely used for repairing damaged nerves, but hollow conduits suffer from insufficient nutrient supply, which may lead to regeneration failure. Therefore, one method to improve nerve conduits is to fill the interior of the conduit with biocompatible materials, such as fiber guides, sponges, or gels, to provide a favorable regenerative microenvironment.[102-103]. Additionally, nerve growth factor (NGF) is crucial for cell growth and neural differentiation, but its delivery in vitro faces challenges.[104]. The main issue lies in the difficulty of controlling growth factor release; burst release leads to rapid depletion of NGF, reducing therapeutic efficacy and weakening cellular responses. Therefore, it is necessary to develop delivery systems capable of precise spatiotemporal control to promote neuronal regeneration and repair. Due to their highly cross-linked hydrophilic structure, ability to fill irregular defects, and capacity to bind with bioactive substances, hydrogels can be used both as sustained-release systems and as filling materials within nerve conduits, helping to provide nutrients and support nerve cell migration and proliferation.[105-106].
Zheng et al.[107]prepared a CS/oxidized hydroxyethyl cellulose (OHEC) hydrogel to load asiaticoside liposomes and rGO, aiming to remodel the microenvironment for peripheral nerve regeneration, asFigure 22shows. The incorporation of rGO endows it with electron transfer conductivity, making it a typical electronic ERH. It possesses high electrical conductivity that is stable and unaffected by ion concentration, allowing precise control of electrical stimulation intensity. This hydrogel aims to provide a conductive and scar-inhibiting microenvironment to support the growth and proliferation of nerve cells. The negatively charged asiaticoside liposomes stably bind to the positively charged CS in the gel through electrostatic interactions and hydrogen bonds. Upon application of electrical stimulation, changes in the porosity or crosslinking density of the rGO network structure facilitate the release of the encapsulated liposomes. Furthermore, the CS/OHEC/rGO/asiaticoside liposome hydrogel exhibits a porous structure, good mechanical properties, and electrical conductivity. Asiaticoside released from the hydrogel has been proven to inhibit fibroblast growth and collagen secretion, thereby reducing scar formation. The combination of electrical stimulation and scar inhibition accelerates the differentiation and proliferation of nerve cells, promoting functional recovery of peripheral nerve defects, and offering a highly promising novel material strategy for nerve tissue engineering.
Mendes et al.[108]proposed a novel method to enhance neural tissue regeneration by combining GO with GelMA hydrogels and modulating them via electrical stimulation, achieving the encapsulation and sustained release of NGF. As an electronic-type ERH, the composite gel utilizes its internal GO to maintain stable electrical stimulation, guiding neural cell differentiation and axon network formation, while also regulating NGF release to address the challenges of burst release and inactivation in hydrogels. GO adsorbs NGF through electrostatic interactions, reducing the burst release of NGF from GelMA/GO hydrogels by 1/30 compared to GelMA alone, with a cumulative release rate of only 0.37% over 7 days. When electrical stimulation is applied to the GelMA/GO hydrogel, this electrostatic interaction is further strengthened, promoting the uptake of NGF from the culture medium into the gel, asFigure 23shows. This effectively resolves the issue of neurotrophic factor burst release, significantly improving NGF retention rates and neural differentiation efficiency. The synergy between GO's electrostatic adsorption and electrical stimulation optimizes the spatiotemporal release of NGF, promoting neuronal gene expression and neurite formation. This provides a new carrier with both controllability and bioactivity for neural tissue engineering, holding potential application value in peripheral nerve regeneration and the treatment of neurodegenerative diseases.

5 Conclusion and Outlook

The application of electro-stimuli-responsive hydrogels in controlled drug delivery systems has demonstrated immense potential. Their unique electrical responsiveness enables precise drug release, reduces unnecessary drug consumption, and lowers side effects. In recent years, researchers have made significant progress in the conductivity, response speed, mechanical properties, and biocompatibility of these hydrogels, greatly advancing the development of this field.
Although electrically stimulated responsive hydrogels offer significant advantages in terms of low-voltage reversible controlled release, programmable drug delivery, and rapid response, their application in practical drug-controlled release systems still faces several urgent challenges: (1) Insufficient biocompatibility and biodegradability of electrically stimulated hydrogel materials, where long-term residual presence in the body may trigger inflammation or immune responses; (2) When the gel carrier reaches the target site, the drug release rate is sometimes difficult to precisely match therapeutic needs, easily leading to phenomena such as "burst release" or delayed release; (3) Electrically stimulated responsive systems exhibit significant performance degradation after cyclic use, failing to meet the stability requirements for implantable or wearable long-acting drug delivery devices.
To address these issues, the following response strategies can be adopted. (1) As a typical non-toxic, biocompatible, and biodegradable natural polymer, dextran has been fabricated into hydrogels for biomedical applications. Aniline oligomers possess well-designed solubility and electroactivity, and can be incorporated into different degradable polymer segments to generate degradable conductive polymers. Qu et al.[109]used hexamethylene diisocyanate as a crosslinker to mix dextran and aniline trimer, preparing a biodegradable conductive hydrogel system with electrical responsiveness and biocompatibility. Although not yet fully applied, this provides new ideas for solving the problem of ERH residue in vivo. Carboxymethyl chitosan, as a chitosan derivative, inherits the biodegradability of chitosan and is the core prerequisite for the gel's degradability. Xu et al.[110]prepared a conductive composite hydrogel via in situ chemical polymerization, using carboxymethyl chitosan as the biodegradable base macromolecular network and PEDOT as the conductive polymer layer. In vitro degradation experiments concluded that the degradation rate decreased with increasing PEDOT content, while pure CMCS hydrogels degraded the fastest. Finally, the potential of this material for nerve tissue engineering was proposed. In this regard, we believe that natural polymers or their derivatives such as chitosan, dextran, hyaluronic acid, and cellulose derivatives can be used as matrices to improve biocompatibility and ease of degradation in vivo. Designing stimulus-triggered cleavable crosslinks, such as borate bonds, amine bonds, ester bonds, or amide bonds, which break under the pH of body fluids, enzymatic catalysis, or specific electric fields, allows the gel network structure to decompose on its own, thereby avoiding residue. (2) Miar et al.[111]employed an in situ chemical polymerization technique and added biotin as a co-dopant during the polymerization step to obtain a stable PPy coating around polyvinylidene fluoride electrospun fibers. The system was loaded with the aforementioned growth factors for electrically stimulated drug release experiments. The results showed that drug release remained stable over 14 days. Muñoz-Galán et al.[112]prepared an electrically responsive thiol-yne click hydrogel to address issues of sustained insulin release and leakage control. Density functional theory calculations identified tetra-arm polyethylene glycol amine precursors as the most suitable crosslinker choice, and the optimal PEDOT nanoparticle concentration was also established. Finally, in vitro validation confirmed the gel's control over insulin release, and high-performance liquid chromatography was used to detect the released insulin. These studies can achieve hierarchical and controlled delivery channels by finely adjusting gel pore size, crosslinking density, and hierarchical structure. For example, by constructing micrometer-scale pore structures, the initial diffusion rate of drugs can be suppressed on one hand to avoid burst release; on the other hand, upon stimulation, pores or channels can dynamically enlarge to rapidly release drugs. Alternatively, composite stimulation mechanisms can be introduced, such as coupling electric fields with pH, light, or magnetic field responses, adding extra dimensions of regulation to achieve more precise drug release. (3) Yang et al.[113]prepared an injectable multifunctional ICAA hydrogel. The introduced tannic acid not only regulates reaction kinetics but also forms multiple non-covalent interactions with the PEG matrix and conductive fillers through hydrogen bonding, enhancing mechanical fatigue resistance. Experiments showed that this ICAA hydrogel system maintained its performance without attenuation after 100,000 charge-discharge cycles, and its electrical stimulation response capability remained stable after soaking for 4 weeks. Zhou et al.[114]prepared a dynamic wearable electro-responsive drug-release hydrogel, where an electric field induces the rearrangement of anionic surfactants to achieve sensitive response below the safe voltage threshold for the human body. The crosslinked chains in these ERHs are realized through hydrophobic interactions, thus possessing self-healing functions and extensibility. Experiments also indicated that the gel's self-healing efficiency reached 91%, and its tensile properties after repair were close to the original state. This holds significant research implications for the future in the fields of wearable bioelectronics and smart drug delivery systems. Therefore, dual-network or multi-network systems with reversible crosslinks should be constructed to enhance mechanical toughness and cycling durability. For example, combining covalent crosslinks with physical crosslinks can form a crosslinked network integrating strong networks with hydrogen bonds, electrostatic bonds, and other interactions. Such dual-network gels typically exhibit excellent mechanical strength, self-healing properties, and conductivity. Additionally, to resist fatigue damage under repeated electrical stimulation, high-strength nanofibers, carbon nanotubes, graphene, or other reinforcing phases, as well as reconfigurable conductive pathways, can be introduced into the gel. For instance, doping flexible carbon nanotube networks into conductive polymers can maintain conductivity during stretching or electrochemical changes.
Ultimately, the goal is to obtain a novel electrically stimulus-responsive hydrogel drug controlled-release system that is biodegradable in vivo, allows precise control of drug release rates, and can be reused multiple times, to meet the purposes and requirements of clinical treatment. This represents the development direction of electrically stimulus-responsive hydrogel drug controlled-release systems.

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Funding

Basic Scientific Research Funds for Universities Affiliated to Hebei Province of China(KY2022056)

Basic Scientific Research Funds for Universities Affiliated to Hebei Province of China(KY2024016)

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