Introduction

Surfaces and interfaces of materials in direct contact with biological systems have consistently constituted central topics in the field of biomaterials and have been the subject of sustained investigation for several decades. In recent years, remarkable progress in synthetic methodologies and analytical techniques has enabled the rational design of polymer-modified solid surfaces [1, 2] and particle surfaces [3, 4] with nanoscale structural control, thereby drawing considerable attention. In contrast, despite the widespread utilization of polymer gels in biomedical applications that involve direct contact with living tissues, such as drug delivery carriers, tissue engineering scaffolds, cell culture substrates, wound dressings, and hemostatic agents [5,6,7], systematic investigations of the structural characteristics of gel surfaces are relatively scarce.

This review focuses on “self-organized structures at gel surfaces,” which represent parameters of potential significance in determining the performance of gels as biomaterials. During the formative period of gel research in the 1980s and 1990s, investigations into self-organized surface structures were actively pursued, and intriguing structures and mechanisms were reported. In those early studies, most investigations were largely exploratory, and the occurrence of these phenomena often depended unpredictably on subtle differences in chemical structure, while challenges remained in achieving systematic structural control. As a consequence, their biomedical applications have remained limited for an extended period. More recently, research efforts have increasingly sought to address these challenges through deliberate structural regulation. As a result, the focus of research has gradually shifted from describing self-organized structures that appear spontaneously under nonequilibrium conditions to establishing strategies that enable their intentional design and stabilization, including those formed under equilibrium conditions. The present review summarizes the historical background of research on self-organized gel surface structures, provides an overview of recent advances in this area, and highlights future perspectives.

Working definition of gel surfaces

In this article, the surface of a gel is operationally defined as the region in the vicinity of the interface between the bulk gel phase and a different phase (Fig. 1). In practice, however, providing a strict definition of a gel surface is extremely difficult. Gels possess continuous structures in which components of different phases, such as water and air, can mutually permeate and intermix. For general solid surfaces, the interfacial region is typically limited to the nm scale, as demonstrated in polymer brush coatings where surface properties are defined within a few tens of nanometers [8]. In contrast, for hydrogels, it may be necessary to define or manipulate a region extending to μm or even sub-mm scales as a functional “surface”. Consequently, unlike solid materials, it is not possible to establish a clear interfacial boundary along the z-axis, and the surface must inevitably be regarded as an ill-defined region with a certain thickness. In the following, this ambiguity is accepted as a working definition, and the discussion continues on this basis.

Fig. 1
Fig. 1
Full size image

Schematic illustration of a gel surface

Gel surfaces are characterized by their openness, which allows free exchange of molecules, and by their high mobility, which imparts flexibility and deformability. Owing to these properties, characteristic surface structures such as skin layers, patterns, and phase-separated structures can form. These self-organized structures frequently appear under nonequilibrium conditions. For instance, they are observed when gels are immersed in solvents of different compositions, subjected to temperature changes, or dried in air. Such phenomena arise from volume changes during the transition of a gel from one equilibrium state to another. These transitions can be macroscopically described by the swelling equilibrium condition (Eq. 1) [9].

$$\Delta {\Pi }_{{swelling}}={\Pi }_{{mixing}}+{\Pi }_{{elastic}}+{\Pi }_{{ion}}=0$$
(1)

From Eq. 1, it follows that the volume change of gels is determined by the balance among the mixing pressure (\({\Pi }_{{mixing}}\)), the elastic pressure (\({\Pi }_{{elastic}}\)), and the ionic pressure (\({\Pi }_{{ion}}\)). In this framework, \({\Pi }_{{mixing}}\) represents the osmotic pressure arising from polymer–solvent mixing, \({\Pi }_{{elastic}}\) denotes the elastic pressure associated with deformation of the gel network, and \({\Pi }_{{ion}}\) corresponds to the osmotic contribution from mobile ions inside and outside the network, typically originating from Donnan equilibrium effects. \({\Pi }_{{mixing}}\) is primarily affected by the polymer concentration and polymer–solvent interactions, \({\Pi }_{{elastic}}\) is governed by the crosslinking density of the polymer network, and \({\Pi }_{{ion}}\) depends on the type and density of fixed charges as well as the ionic strength of the surrounding medium.

Among these contributions, osmotic pressure is particularly important because it directly reflects the thermodynamic balance between the polymer and solvent components. Osmotic pressure not only affects the macroscopic volume change behavior but also plays a critical role in structural organization within gels. Recent studies have demonstrated that osmotic pressure also serves as a key parameter for understanding and quantifying gel structure formation. For example, gel–gel phase separation has been observed in dilute percolated polyethylene glycol (PEG) networks under low osmotic pressure conditions [10]. In another study, the degree of aggregation within hydrogel networks was quantitatively evaluated on the basis of osmotic pressure, and the results demonstrated that osmotic pressure can be directly related to the internal structural organization of gels [11]. Although these findings primarily concern the bulk region, they suggest that osmotic effects are also expected to contribute as one of the driving factors in the emergence of diverse self-organized structures at gel surfaces.

Representative examples of self-organized structures observed at gel surfaces are shown in Fig. 2. In the subsequent sections, these self-organized structures are described in detail, followed by an introduction to strategies for their enforced induction through molecular design and systematic control.

Fig. 2
Fig. 2
Full size image

Self-organized structures formed at gel surfaces across different spatial scales. Reproduced from Ref. [26] under Creative Commons CC BY-NC-ND 4.0 License. Reproduced from Ref. [28] with permission from the Royal Society of Chemistry. Reprinted with permission from Matsukawa K et al.: Thermoresponsive surface-grafted gels: controlling the bulk volume change properties by surface-localized polymer grafting with various densities. Langmuir 2017, 33:13828-13833 (Ref. [27]). Copyright 2025 American Chemical Society

Skin layers

When a gel undergoes rapid shrinkage, a transient layer with suppressed molecular permeability is often formed at the surface; this is commonly referred to as a “skin layer” (Fig. 3). For example, when a hydrogel is immersed in a poor solvent, the surface of the gel first comes into contact with the external environment, causing the polymer chains at the surface to rapidly aggregate. This local contraction leads to the formation of a skin layer [12]. Similarly, the formation of skin layers has been observed when poly(N-isopropylacrylamide) (PNIPAAm) gels are subjected to rapid heating [13]. In this case, however, the phenomenon is not solely attributable to the earlier response of the surface but is also thought to involve temperature gradients and differences in the response kinetics of polymer chains between the surface and the interior of the gel. In any case, the formation of a skin layer demonstrates that the surface responds to changes in the external environment ahead of the bulk interior, thereby highlighting the unique properties of gel surfaces.

Fig. 3
Fig. 3
Full size image

Schematic illustration of a skin layer

The application of skin layers in the biomedical field has a long history. In particular, PNIPAAm gels and their derivatives, which are capable of forming skin layers in aqueous environments, have been studied since the 1990s as drug delivery systems that enable on/off regulation of drug release from within the gel [13, 14]. On the other hand, skin layers are generally transient in nature and often disappear after a certain period of time [14]. In addition, their molecular permeability varies greatly depending on the formation conditions and structural characteristics. Accordingly, the persistent stabilization of skin layers and the systematic control of their molecular permeability remain important challenges. In recent years, studies have attempted to address these challenges by incorporating graphene oxide into PNIPAAm gels to actively control skin layer formation, thereby utilizing the resulting anisotropic swelling and deswelling behavior as an actuator mechanism [15].

Patterns

As described in the previous section, the formation of skin layers in gels is generally a transient phenomenon. This is primarily because solvent concentration or temperature changes occur abruptly on the surface. However, when such external environmental changes occur gradually, skin layers can persist for extended periods. Under these conditions, surface hardening suppresses further volumetric changes in the gel, making subsequent shrinkage difficult. As a result, when skin layer formation continues over long timescales, the coexistence of swollen and shrunken regions leads to pattern formation. In this case, the swollen regions release solvent to the exterior, thereby driving further macroscopic shrinkage of the gel. In cylindrical gels in particular, it has been demonstrated that characteristic patterns emerge depending on the conditions for skin layer formation, the chemical composition of the gel, and the aspect ratio [16].

Conversely, characteristic structural formation is also observed during swelling. When spherical gels are immersed in water, wrinkle patterns emerge on the gel surface, which is initially flat immediately after preparation. These wrinkles grow fractally with time, accompanied by an increase in wavelength, and eventually disappear once the equilibrium swollen state is reached, at which point the surface once again becomes flat [17]. This behavior indicates that swelling, that is, the hydration of polymer chains, proceeds from the surface and that the difference in stiffness between the hydrated surface and the unhydrated interior is responsible for wrinkle formation. During this process, compression stress is generated because the surface layer swells earlier, thereby inducing wrinkle formation. As hydration progresses further into the bulk over time, the mismatch is gradually relaxed, the pattern size increases, and eventually, the mismatch is completely resolved, and the pattern disappears.

Both shrinkage-induced patterns and wrinkle patterns were originally discovered by Toyoichi Tanaka and coworkers. Subsequently, research on gel pattern formation has shifted from the observation of spontaneously emerging patterns to intentional design and functional utilization. For example, by designing gels with a stiffness gradient along the z-axis, states analogous to those observed during nonequilibrium swelling can be constructed, thereby enabling the maintenance of wrinkle patterns even under equilibrium conditions [18]. On the other hand, wrinkle morphologies and sizes are highly diverse, and only a limited number of studies have realized systematic structural control. In recent years, however, a wide range of application-oriented studies have been reported, including the design of adhesive gels aimed at increasing interfacial surface area and anchoring effects [19, 20], as well as the use of cell culture gels for controlling cellular alignment [21, 22].

Phase separation

Phase-separated structures in gels are not confined to the surface but have also been widely observed throughout the bulk in many studies. Nevertheless, because these structures are closely related to skin layer formation and pattern formation, they are discussed here. Phase separation in gels has been investigated using techniques such as electron microscopy, confocal laser scanning microscopy, and scattering methods. With respect to structures formed at the surface, however, atomic force microscopy (AFM) is the most powerful technique. Reports on AFM observations of phase-separated structures at gel surfaces have increased since around 2010. A representative example is the observation of nanoscale phase-separated structures in silicone hydrogels developed for contact lens applications [23]. In the field of contact lens development, it is essential that the phase-separated structures be smaller than the wavelength of visible light. This requirement enables the simultaneous achievement of oxygen permeability and optical transparency. To meet this demand, hydrogels containing both hydrophilic and hydrophobic regions have been actively developed. Other examples include studies that employed AFM-based mechanical property mapping to examine nanoscale heterogeneity characterized by the coexistence of soft and stiff regions at gel surfaces [24], as well as studies that combined AFM with sum frequency generation (SFG) spectroscopy to investigate the orientation of dangling chains, i.e., uncrosslinked polymer chains present at gel surfaces [25]. These efforts represent an ongoing trend toward elucidating finer surface structures.

Whereas skin layers and patterns are typically observed at the μm–mm scale, phase separation spans a broader range, from the nm to the mm scale. (In general, phase-separated structures form on the nm–μm scale, but domain coarsening can progress under certain conditions to reach the mm scale.) The formation of skin layers and patterns is frequently induced by, or accompanied by, phase separation. With further advances in techniques for observing phase separation at the nm scale, experimental studies addressing hierarchical self-organized structures that extend across multiple spatial scales are expected to increase.

Structural control by surface grafting

The present author and coworkers have established a “surface-grafting” method, a technique for locally designing molecular structures at gel surfaces, and have applied it to the enforced induction and systematic control of self-organized structures at surfaces, such as skin layers, patterns, and phase-separated structures [26,27,28]. In contrast to self-organized structures that spontaneously appear during swelling or deswelling processes as intrinsic phenomena of gels, structural control by surface grafting represents an active and quantitatively designable strategy for gel engineering. In this method, activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP), a living radical polymerization technique that occurs even in the presence of oxygen, is employed to carry out surface-initiated polymerization on gels. As a result, grafted polymer chains can be covalently introduced into the surface region of the gel (with a depth of approximately 10 to several hundred μm) (Fig. 4) [26]. Because the grafting parameters such as chain length, grafting density, and penetration depth can be tuned, this approach enables systematic and parameter-based control over surface structures, providing an excellent engineering concept that transforms spontaneous self-organization into rational design. To date, by examining the chemical composition of both the base hydrogel and the grafted polymer chains, a variety of self-organized structures have been successfully constructed, as summarized in Table 1.

Fig. 4
Fig. 4
Full size image

A Schematic representation of a surface-grafted gel. The light blue network represents the base gel, and the pink lines represent the grafted chains. B Confocal microscopy image of a gel cross-section with surface-grafted polymer chains containing fluorescent moieties

Table 1 Design of self-organized structures using the surface grafting method
Full size table

In the case of a temperature-responsive/temperature-responsive combination, in which a copolymer of NIPAAm and N-(3-aminopropyl)methacrylamide (NAPMAm), i.e., P(NIPAAm-co-NAPMAm), was used as the base gel and PNIPAAm as the grafted chains, both components exhibited thermoresponsive behavior: the gel network swelled at approximately 41 °C and shrank at higher temperatures, while the grafted chains swelled below approximately 34 °C and also shrank at higher temperatures. A surface-grafted gel (SG gel) stored in water at 25 °C was transferred to hot water at 50 °C, with the time of transfer defined as 0 min, and the degree of swelling was monitored over time. Owing to the formation of a skin layer that suppressed water permeability, almost no volume change occurred for a certain period, after which cracks appeared at the surface, followed by rapid shrinkage (Fig. 5A) [26]. In contrast, when only the base gel (NG gel) was used with this composition, skin layer formation did not occur owing to its high hydrophilicity, and the degree of swelling decreased exponentially over time (Fig. 5A) [26]. This difference in behavior is readily apparent. Furthermore, the SG gel and NG gel stored in water at 25 °C were subjected to a stepwise temperature increase at 1 °C intervals, and the degree of swelling was measured as a function of temperature. Only the SG gel exhibited a temperature range in which swollen and shrunken regions coexisted, accompanied by the appearance of shrinkage patterns (Fig. 5B) [26]. These results demonstrate that surface grafting successfully induced the forced formation of both skin layers and shrinkage patterns. Moreover, by systematically controlling the grafting density, the presence or absence of wrinkle patterns as well as their size could be controlled (Fig. 6A–D) [27].

Fig. 5
Fig. 5
Full size image

A Time-dependent change in the degree of swelling of a temperature-responsive surface-grafted gel (SG gel) and a base gel (NG gel) upon a sudden temperature shift from 25 °C to 50 °C. B Temperature-dependent change in the degree of swelling of a temperature-responsive SG gel and NG gel during a stepwise temperature increase from 25 °C to 50 °C at 1 °C intervals. Reproduced from Ref. [26] under Creative Commons CC BY-NC-ND 4.0 License

Fig. 6
Fig. 6
Full size image

Surface observations of SG gels A–C and an NG gel D by 3D laser microscopy. The grafting density decreases from A to C. By controlling the grafting density, both the presence/absence of wrinkle patterns and their size can be regulated. Reprinted with permission from Matsukawa K et al.: Thermoresponsive surface-grafted gels: controlling the bulk volume change properties by surface-localized polymer grafting with various densities. Langmuir 2017, 33:13828-13833 (Ref. [27]). Copyright 2025 American Chemical Society

In the case of a hydrophilic/hydrophobic combination, in which a copolymer of N,N-dimethylacrylamide (DMAAm) and NAPMAm, i.e., P(DMAAm-co-NAPMAm), was employed as the base gel and poly(1H,1H,5H-octafluoropentyl acrylate) (POFPA) as the grafted chains, nanoscale phase-separated structures consisting of coexisting hydrophilic and hydrophobic regions were successfully constructed (Fig. 7A and B) [28]. Because the grafting depth decays exponentially from the surface toward the interior, a gradient is formed; grafts have been confirmed to penetrate to a depth of approximately 200 μm (Fig. 7C) [28]. Accordingly, the phase-separated structures are also assumed to be confined to a similar region. The construction of phase-separated structures exclusively at the surface represents a novel approach to the spatial structural control of gels. Notably, in this study, phase-separated structures could not be identified by mapping the surface topography or Young’s modulus but were first visualized by adhesion force mapping using a hydrophobized cantilever. Such “hidden self-organized structures,” which have become observable only through recent advances in analytical techniques, are likely to exist in large numbers even within conventional gel materials.

Fig. 7
Fig. 7
Full size image

A Phase-separated structures of a fluorinated surface-grafted gel in water, observed by high-speed AFM. Light-colored regions correspond to hydrophobic domains, whereas dark-colored regions correspond to hydrophilic domains. B Schematic representation of the nanoscale phase-separated structures constructed at the surface. C Depth profiles of ester bonds in a fluorinated surface-grafted gel (FG gel) and a base gel (NG′ gel) along the z-axis, as measured by confocal Raman spectroscopy. Reproduced from Ref. [28] with permission from the Royal Society of Chemistry

In addition to the examples described above, studies employing the surface grafting method have also achieved control over the adhesivity of gel surfaces [29] and the decoupled regulation of gel properties [30]. In the case of adhesivity control, P(DMAAm-co-NAPMAm) was used as the base gel and PNIPAAm as the grafted chains, and surface grafting was designed to take advantage of the temperature responsiveness of the grafted chains. As a result, temperature-dependent changes in adhesion strength to a Bakelite plate were confirmed, with adhesive forces of 21.0 N m⁻² at 25 °C and 65.8 N m⁻² at 50 °C (Fig. 8) [29]. Future work will aim to expand this temperature-dependent difference in adhesion strength to over 1000 N m⁻² through optimization of the grafting parameters and molecular design, with the ultimate goal of achieving adhesion and detachment on skin surfaces. In the case of decoupled property control, P(DMAAm-co-NAPMAm) was employed as the base gel and POFPA as the grafted chains, and systematic variation in the grafting density demonstrated that swelling behavior in water could be systematically regulated while maintaining a constant bulk modulus [30]. In general, when gels are designed to control a particular property by altering the entire network structure, unintended changes in other properties often occur concomitantly. In contrast, the surface grafting method, which alters only the surface structure, has been shown to suppress such concomitant changes in properties. Although the relationship between the control of these properties and self-organized structures at gel surfaces is still under investigation, it will be an important subject for further detailed study.

Fig. 8
Fig. 8
Full size image

Temperature-dependent adhesion strength of a temperature-responsive surface-grafted gel (SG″ gel) and a base gel (NG″ gel), measured using a custom-built adhesion testing apparatus. Reproduced from Ref. [29] under Creative Commons CC BY-NC-ND 4.0 License

Conclusions and perspective

An overview of the mechanisms underlying the emergence of self-organized structures at gel surfaces, together with their enforced induction and systematic control, reveals the addition of a new perspective on the structure–property relationships of gel materials, namely, the “relationship between surface and bulk.” It has become evident that surface structures not only influence interfacial phenomena such as adhesion, adsorption, and friction but also significantly affect bulk-related properties such as swelling and molecular permeability. Furthermore, even in gels, which possess openness and high mobility that render their surfaces difficult to define sharply, the surface and bulk play distinct roles, each contributing in concert to the creation of functions.

This perspective of the “relationship between surface and bulk” is particularly important when gels are applied in biomedical uses that involve direct contact with living tissues, including drug delivery carriers, tissue engineering scaffolds, cell culture substrates, wound dressings, antiadhesion barriers, and hemostatic agents. In the field of drug delivery carriers, skin layers have been exploited since the 1990s as a basis for material design that explicitly considers the “surface–bulk relationship.” However, this perspective is equally critical for other applications. For instance, tissue engineering scaffolds and cell culture substrates are designed to mimic the extracellular matrix (ECM), which is itself structurally a gel. It is reasonable to assume that ECMs in vivo also exhibit self-organized structures at their surfaces. At present, research in this field has focused primarily on the effects of bulk gel properties on cells and tissues [31, 32]. However, understanding how the ECM surface and bulk each possess distinct structures and functions may enable the design of more precise ECM-mimicking materials. In the case of wound dressings, antiadhesion barriers, and hemostatic agents, optimization of surface and bulk structures is likely to be essential for ensuring sufficient interfacial adhesion with tissues, enhancing anchoring effects, and, when detachment is needed, minimizing tissue damage upon removal.

When top-down patterning using microfabrication technologies is compared with bottom-up self-organization, the former is superior in terms of design and reproducibility, whereas the latter offers advantages in dynamic structural formation driven by environmental stimuli, facile application over large areas, and cost-effectiveness. Combining top-down and bottom-up approaches may therefore provide opportunities to construct more advanced functional structures. To realize such structural designs, a deeper understanding of self-organized structures at the nm scale, as well as comprehensive insights into structure–property relationships across spatiotemporal scales, will become increasingly important in the future.