A zwitterion-based hydrogel with high-strength, high transparency, anti-adhesion and degradability
一种基于离子双性体的水凝胶，具有高强度、高透明度、抗粘附和可降解性

Received: 1 April 2022
收到：2022 年 4 月 1 日

Accepted: 22 August 2022
接受日期：2022 年 8 月 22 日

Published online: 在线发布：

10 September 2022 2022 年 9 月 10 日

(c) The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
（c）作者，独家许可给施普林格科学+商业媒体有限责任公司，施普林格自然集团 2022 年的一部分

Hydrogels with high strength have been widely studied to expand application. For example, Chen et al. [1] reported a double network (DN) hydrogel with tensile strength of 1.03 MPa , obtained by chemical crosslinking and ionic coordination. Liang et al. [2] proposed a facile approach to prepare a DN hydrogel whose nominal stress reached 0.27 MPa , in the hydrogel system, covalently crosslinked polyacrylamide (PAM) network, cation-chelated ( or ) alginate and non-covalent interactions in polydopamine (PDA) together contribute to the high strength. However, the preparations of above-mentioned hydrogel involve small molecule chemical crosslinking agents, their residues may affect the biocompatibility and the hydrogels are nondegradable.
具有高强度的水凝胶已被广泛研究以扩展应用。例如，Chen 等人[1]报道了一种拉伸强度为 1.03 MPa 的双网络(DN)水凝胶，通过化学交联和离子配位获得。Liang 等人[2]提出了一种简便的方法来制备 DN 水凝胶，其名义应力达到 0.27 MPa，在水凝胶系统中，共价交联的聚丙烯酰胺(PAM)网络，阳离子螯合（ 或 ）的海藻酸盐以及多巴胺(PDA)中的非共价相互作用共同促成了高强度。然而，上述水凝胶的制备涉及小分子化学交联剂，它们的残留物可能影响生物相容性，而且这些水凝胶是不可降解的。

When used in biomedical applications, traditional hydrogels lack natural antibacterial properties and require additional antibacterial agent, which may cause adverse immune responses or the emergence of drug-resistant bacteria [3]. Besides, the hydrogel materials generally have high water content, which results in the scattering of light at the water-polymer interface and the decrease of transmittance [4]. Another challenge of the hydrogel that cannot be ignored is environmental instability since its main component is water, which will evaporate over time or freeze below sub-zero temperature, restricting its practical applications in extreme environment [5].
在生物医学应用中使用时，传统水凝胶缺乏天然抗菌性能，需要额外的抗菌剂，这可能引起不良的免疫反应或产生耐药细菌[3]。此外，水凝胶材料通常具有高含水量，导致水-聚合物界面的光散射和透射率降低[4]。另一个不能忽视的水凝胶挑战是环境不稳定性，因为其主要成分是水，随着时间的推移会蒸发或在零下温度下结冰，限制其在极端环境中的实际应用[5]。

The zwitterionic monomer has both positive and negative charges, which can firmly bind water molecules through electrostatic interaction to increase the saturated water content and reduce the scattering center effect, giving the hydrogel high transmittance [4]. And the dense hydration layer makes adhesion of proteins difficult. Furthermore, due to the lack of adhesion proteins on the surface, zwitterionic materials also have excellent resistance to bacteria and cells [6]. Glycerol is commonly used as non-toxic hygroscopic and antifreezing agent due to the strong hydrogen bonds with water, which can improve the tolerance of environment [7]. Meanwhile, the mechanical property can be significantly improved by simply replacing the water in the hydrogel with glycerol [5, 8].
带电离子单体具有正负电荷，可以通过静电相互作用牢固地结合水分子，增加饱和水含量并减少散射中心效应，使水凝胶具有高透明度[4]。而密集的水合层使蛋白质的粘附变得困难。此外，由于表面缺乏粘附蛋白质，带电离子材料还具有出色的抗菌和抗细胞性能[6]。甘油常用作无毒的吸湿防冻剂，因为它与水有强氢键结合，可以提高环境的耐受性[7]。同时，通过简单地用甘油替换水，可以显著改善水凝胶的机械性能[5, 8]。

In this work, we prepared a zwitterion-based hydrogel by a simple one-pot method. The P(SBMAco-HEMA) molecular chain was first formed by copolymerization between SBMA and HEMA, and GelMA crosslinked the P(SBMA-co-HEMA) molecular chain. Then, the P(SBMA-co-HEMA) hydrogel was soaked into glycerol to achieve solvent replacement. As expected, the hydrogel exhibits remarkable mechanical properties with tensile strength up to 1.21 MPa and good elasticity and fatigue resistance, while providing high transmittance and antibacterial properties as well. And glycerol effectively improves the water retention properties and freezing resistance of the hydrogel. Both HEMA and SBMA are proven to be non-toxic and biocompatible [9], in vitro and in vivo assays reveal that the hydrogel has good biocompatibility and stability, maintaining the shape intact without degradation. Thus, we believe that the P(SBMA-co-HEMA)/glycerol hydrogel hold promising prospect in biomedical application such as wound dressings.
在这项工作中，我们通过简单的一锅法制备了一种带电离基的水凝胶。首先通过 SBMA 和 HEMA 之间的共聚反应形成 P(SBMAco-HEMA)分子链，然后 GelMA 交联 P(SBMA-co-HEMA)分子链。接着，将 P(SBMA-co-HEMA)水凝胶浸泡在甘油中以实现溶剂置换。正如预期的那样，水凝胶表现出卓越的机械性能，抗拉强度高达 1.21 MPa，具有良好的弹性和抗疲劳性，同时具有高透明度和抗菌性能。甘油有效地提高了水凝胶的保水性和抗冻性。HEMA 和 SBMA 都被证明是无毒且生物相容的[9]，体外和体内实验表明水凝胶具有良好的生物相容性和稳定性，保持形状完整且不会降解。因此，我们相信 P(SBMA-co-HEMA)/甘油水凝胶在医学应用中具有很好的前景，如伤口敷料。

Methacryloylated gelatin (GelMA) was synthesized according to our previous work [10]. [2-(Methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl) ( , SBMA), glycerol (99%), 2-Hydroxyethyl methacrylate (99%, HEMA), (2-Hydroxy-4'-(2-hydroxyethoxy)-2methylpropiophenone (I2959) and phosphate-buffered saline (20X concentrate, PBS) were purchased from Aladdin (Shanghai) Chemistry Co. Ltd.
甲基丙烯酰化明胶（GelMA）是根据我们先前的工作[10]合成的。[2-（甲基丙烯酰氧基）乙基]二甲基-（3-磺丙基）（ ，SBMA）、甘油（99%）、2-羟基乙基甲基丙烯酸酯（99%，HEMA）、（2-羟基-4'-(2-羟基乙氧基)-2-甲基丙烯苯酮（I2959）和磷酸盐缓冲液（20 倍浓缩，PBS）均从阿拉丁（上海）化学有限公司购买。

We prepared the hydrogel by a simple one-pot method. First, the hydrogel pre-liquid was configured according to different formulas containing 5-25% GelMA, 2.5-20% HEMA, 0.5-4 M SBMA and I2959. The bubbles in the solution were removed by ultrasound, and then, the reaction was initiated by 365 nm UV. After the reaction, P(SBMA-co-HEMA) hydrogel was obtained. Then the P(SBMA-co-HEMA) hydrogel was soaked into glycerol for different time ( 15 min-4 h) to obtain P(SBMA-co-HEMA)/glycerol hydrogel.
我们通过简单的一锅法制备了水凝胶。首先，根据不同配方配置了含有 5-25% GelMA、2.5-20% HEMA、0.5-4 M SBMA 和 I2959 的水凝胶预液。通过超声波去除溶液中的气泡，然后通过 365 nm 紫外光引发反应。反应后得到了 P(SBMA-co-HEMA)水凝胶。然后将 P(SBMA-co-HEMA)水凝胶浸泡在甘油中不同时间（15 分钟至 4 小时）以获得 P(SBMA-co-HEMA)/甘油水凝胶。

We used the mold to prepare the dumbbell-shaped sample and tested the tensile properties of the hydrogel by an electromechanical universal test machine (CMT4104), the tensile speed was
我们使用模具制备哑铃形样品，并通过电动机械万能试验机（CMT4104）测试了水凝胶的拉伸性能，拉伸速度为

ted by the universal test machine (Instron 5966, USA), the sample was made into a cylindrical shape through the mold, and the compression rate was .
通过通用试验机（Instron 5966，美国）测试，样品通过模具制成圆柱形，压缩率为 。

The circular hydrogel sample with the diameter of 2.5 cm and the thickness of 1 mm was prepared. The transmittance of the samples was tested by ultraviolet-visible near-infrared spectrophotometer (Agilent Cary5000).
直径为 2.5 厘米，厚度为 1 毫米的圆形水凝胶样品已经准备好。样品的透射率是通过紫外可见近红外分光光度计（Agilent Cary5000）进行测试的。

In order to compare the antifreezing property of the hydrogel, we put P(SBMA-co-HEMA) hydrogel and
为了比较水凝胶的防冻性能，我们放置了 P(SBMA-co-HEMA)水凝胶

P(SBMA-co-HEMA)/glycerol hydrogel in the refrigerator at , and took photos at regular intervals.
P(SBMA-co-HEMA)/甘油水凝胶放在 冰箱里，并定期拍照。

The mass of the original hydrogel was weighed as . The hydrogel was soaked into 0.01 M PBS buffer at room temperature (RT, ). Then the hydrogel was removed from the PBS buffer at regular intervals, the water on the surface was absorbed with filter paper, and the hydrogel was weighed as . The swelling rate (SR) of the hydrogel was calculated from the following equation.
原水凝胶的质量为 。水凝胶在室温（RT， ）下浸泡在 0.01 M PBS 缓冲液中。然后定期将水凝胶从 PBS 缓冲液中取出，用滤纸吸干表面的水，然后将水凝胶称重为 。水凝胶的膨胀率（SR）由以下方程计算。

The original quality of the hydrogel was weighed as . The hydrogel samples were placed at RT and water bath, respectively. The quality of the sample was measured at different intervals . The quality change rate was calculated by the following equation to evaluate the water retention of the hydrogel.
水凝胶的原始质量为 。水凝胶样品分别放置在室温和 水浴中。在不同时间间隔 测量样品的质量。通过以下方程计算质量变化率 ，以评估水凝胶的保水性能。

Antibacterial adhesion test was performed according to our previous literature [10-12]. Specifically, hydrogel samples were placed in Escherichia coli (E.coli) solution of 0.1 optical density. After co-culture in constant temperature oscillator at and 120 rpm for 24 h , the adhesion of bacterium on the surface of the hydrogel was observed by fluorescence microscope following dying.
根据我们先前的文献[10-12]进行了抗菌粘附测试。具体来说，将水凝胶样品放入光密度为 0.1 的大肠杆菌（E.coli）溶液中。在 和 120 rpm 的恒温振荡器中共培养 24 小时后，通过荧光显微镜观察水凝胶表面的细菌粘附情况。

The samples were cut into square shapes ) and placed into trypsin saturated solutions. Then the degradation was observed after one day and fourteen days.
样本被切成正方形 )并放入胰蛋白酶饱和溶液中。然后在一天和十四天后观察降解情况。

Cytotoxicity test was performed according to our previous literature [10]. Different concentrations of hydrogel leachate were co-cultured with mouse fibroblasts cells (L929) of 50000 cell/mL density. After 1 day, 4 days and 7 days, cell viability was detected by MTT assay. The cell viability of the blank control group (co-cultured with cell culture medium) was equivalent to .
细胞毒性测试是根据我们先前的文献[10]进行的。不同浓度的水凝胶浸出液与 50000 个细胞/毫升密度的小鼠成纤维细胞(L929)共培养。培养 1 天、4 天和 7 天后，通过 MTT 测定检测细胞存活率。空白对照组的细胞存活率（与细胞培养基共培养）等同于 。

We embedded the hydrogel subcutaneously in mice to evaluate the biocompatibility. 20-30 g C57 male mice were divided into two groups of six mice in each. First, C57 male mice were anesthetized with sodium pentobarbital, and their back hair was removed. A subcutaneous incision was made on the back of the mouse with a scalpel, and then a diskshaped sample with diameter of 5 mm was embedded under the skin. The mice were kept in individual cages with an ample supply of food and water. The mice were euthanized in the first and fourth weeks. The skin tissues around the sample were taken for hematoxylin-eosin (H&E) staining, and the inflammatory response was observed under the microscope. The experiment was approved by the Institutional Animal Care and Use Committee.
我们将水凝胶植入小鼠皮下以评估生物相容性。将 20-30 克 C57 雄性小鼠分为两组，每组六只小鼠。首先，用戊巴比妥钠麻醉 C57 雄性小鼠，剃掉它们的背毛。用手术刀在小鼠背部做一个皮下切口，然后将直径为 5 毫米的圆盘状样本植入皮下。小鼠被单独放在笼子里，有充足的食物和水。第一周和第四周对小鼠实施安乐死。取样本周围的皮肤组织进行苏木精-伊红（H&E）染色，用显微镜观察炎症反应。该实验已获得机构动物护理和使用委员会的批准。

Scheme 1A shows the preparation process of the hydrogel. The prepared pre-solution was initiated by 365 nm UV to form the P(SBMA-co-HEMA) hydrogel. In this step, the random copolymerized P(SBMAco-HEMA) molecular chain was formed, and the molecular chain was crosslinked by GelMA. Subsequently, the (SBMA-co-HEMA) hydrogel was soaked into glycerol for solvent replacement to obtain the P(SBMA-co-HEMA)/glycerol hydrogel.
方案 1A 显示了水凝胶的制备过程。经 365 纳米紫外光引发的预制前溶液形成了 P(SBMA-co-HEMA)水凝胶。在这一步骤中，形成了随机共聚的 P(SBMA-co-HEMA)分子链，并且分子链被 GelMA 交联。随后，(SBMA-co-HEMA)水凝胶被浸泡在甘油中进行溶剂置换，得到 P(SBMA-co-HEMA)/甘油水凝胶。

Formulation of the hydrogel directly affects its performance, we first studied the influence of soaking time and different component content on the tensile
水凝胶的配方直接影响其性能，我们首先研究了浸泡时间和不同成分含量对拉伸性能的影响

Scheme 1 a Preparation of the P(SBMA-co-HEMA)/glycerol hydrogel by "one-pot" method; Chemical reaction equation of the hydrogel preparation.
方案 1：通过“一锅法”制备 P(SBMA-co-HEMA)/甘油水凝胶； 水凝胶制备的化学反应方程。

properties of the hydrogel. As shown in Fig. 1A, the volume of the hydrogel decreases significantly as the time of soaking glycerol increases since the water molecules in hydrogels are replaced by glycerol, resulting in phase separation and shrinkage of some molecular chains.
水凝胶的性质。如图 1A 所示，随着浸泡甘油的时间增加，水凝胶的体积显著减小，因为水凝胶中的水分子被甘油取代，导致相分离和一些分子链的收缩。

Figure 1B compares the tensile properties of hydrogels after soaking in glycerol for different time. During the process of increasing the soaking time (a)
图 1B 比较了不同时间浸泡在甘油中的水凝胶的拉伸性能。在增加浸泡时间的过程中（a）

Figure 1 a Volume changes of P(SBMA-co-HEMA) hydrogels after soaking in glycerol for different time; Tensile properties of P(SBMA-co-HEMA)/glycerol hydrogel after soaking in glycerol for different time; Tensile properties of SBMA-co-HEMA)/
图 1：P(SBMA-co-HEMA)水凝胶在甘油中浸泡不同时间后的体积变化；P(SBMA-co-HEMA)/甘油水凝胶在不同时间浸泡后的拉伸性能；P(SBMA-co-HEMA)/甘油水凝胶在不同时间浸泡后的拉伸性能

glycerol hydrogel with different GelMA contents; d Tensile properties of P(SBMA-co-HEMA)/glycerol hydrogel with different SBMA contents; e Tensile properties of P(SBMA-coHEMA)/glycerol hydrogel with different HEMA contents.
不同 GelMA 含量的甘油水凝胶；不同 SBMA 含量的 P(SBMA-co-HEMA)/甘油水凝胶的拉伸性能；不同 HEMA 含量的 P(SBMA-co-HEMA)/甘油水凝胶的拉伸性能。
from 15 min to 4 h , the elastic modulus of the hydrogel undergoes a rise. This is due to the strong hydrogen bonds between glycerol and molecular chains, which could break down when subjected to external forces, giving hydrogel energy dissipation mechanism to increase the strength. However, excessive soaking time leads to high hydrogen bond density, the hydrogel becomes more brittle and the fracture strain decreases significantly. Therefore, we take 3 h as the best immersion time, and the tensile strength and breaking strain are 0.88 MPa and , respectively.
从 15 分钟到 4 小时，水凝胶的弹性模量会上升。这是由于甘油和分子链之间的强氢键，当受到外部力量时可能会破裂，从而使水凝胶的能量耗散机制增强。然而，过度浸泡时间会导致氢键密度增高，水凝胶变得更加脆弱，断裂应变显著降低。因此，我们将 3 小时作为最佳浸泡时间，拉伸强度和断裂应变分别为 0.88 MPa 和 。

In this system, GelMA acts as a crosslinking agent. With the increase of GelMA content, the crosslinking point in the network increases as well as the force between molecular chains. Therefore, the elastic modulus and tensile strength of the hydrogel continue to increase. As shown in Fig. 1C, when the GelMA content is and , the tensile strength of the hydrogel is 0.22 MPa , and 1.21 MPa , respectively. However, when the crosslinking point is too dense, the molecular chains are not easy to move and the rigidity is too large, resulting in a decrease of the fracture strain. The fracture strain of the hydrogel containing GelMA is only , while the fracture strain of the hydrogel containing GelMA is the largest ).
在这个系统中，GelMA 充当交联剂。随着 GelMA 含量的增加，网络中的交联点增加，分子链之间的力也增加。因此，水凝胶的弹性模量和抗拉强度继续增加。如图 1C 所示，当 GelMA 含量为 和 时，水凝胶的抗拉强度分别为 0.22 MPa 和 1.21 MPa。然而，当交联点过于密集时，分子链不容易移动，刚度过大，导致断裂应变减小。含有 GelMA 的水凝胶的断裂应变仅为 ，而含有 GelMA 的水凝胶的断裂应变最大为 。

The positive and negative charges exist simultaneously on the SBMA monomer, and the electrostatic force between the PSBMA molecular chains increases the strength of the hydrogel. From Fig. 1D we can see that the elastic modulus of the hydrogel increases with the increasing SBMA content. The tensile strength of the hydrogel increases from 0.14 MPa at 0.5 M SBMA content to 1.0 MPa at 3 M SBMA. However, excessive electrostatic interactions restrict the movement of molecular chains, the flexibility of the hydrogel suffers a decline. After peaking at at 2 M , the fracture strain drops considerably down to at 4 M . Finally, we studied the effect of different HEMA content on the tensile properties of hydrogels. As shown in Fig. 1E, when the HEMA content is , the elastic modulus of the hydrogel is as high as 4.20 MPa. As the HEMA content increases, the elastic modulus decreases to 1.22 MPa at content and then increases. One possible explanation for this phenomenon is that the strong electrostatic force between the PSBMA chains in the system gives the hydrogel a higher modulus. And after the addition of HEMA copolymerization, a part of the electrostatic force will be destroyed, resulting in the decrease in the modulus of hydrogel. However, the toughness is enhanced, and it can be seen that the fracture strain of the hydrogel has been improved. When the HEMA content increases further, the hydrogen bond density and solid content in the system increase, resulting in the increase of the modulus, and the fracture strain decreases.
SBMA 单体上同时存在正负电荷，PSBMA 分子链之间的静电力增强了水凝胶的强度。从图 1D 中我们可以看到，随着 SBMA 含量的增加，水凝胶的弹性模量也在增加。水凝胶的抗拉强度从 0.5M SBMA 含量下的 0.14 MPa 增加到 3M SBMA 下的 1.0 MPa。然而，过多的静电相互作用限制了分子链的运动，水凝胶的柔韧性下降。在 2M 时达到顶峰后，断裂应变在 4M 时急剧下降至 。最后，我们研究了不同 HEMA 含量对水凝胶拉伸性能的影响。如图 1E 所示，当 HEMA 含量为 时，水凝胶的弹性模量高达 4.20 MPa。随着 HEMA 含量的增加，弹性模量降至 含量下的 1.22 MPa，然后再增加。这种现象的一个可能解释是系统中 PSBMA 链之间的强静电力使水凝胶具有更高的模量。 在添加 HEMA 共聚物之后，部分静电力将被破坏，导致水凝胶模量降低。然而，韧性得到增强，可以看到水凝胶的断裂应变得到改善。当 HEMA 含量进一步增加时，系统中的氢键密度和固含量增加，导致模量增加，而断裂应变减少。

Considering the strength and fracture strain, we determined that the best formulation of the hydrogel was 15% GelMA, 2 M SBMA, 10% HEMA and soaked in glycerol for 3 h .
考虑到强度和断裂应变，我们确定了水凝胶的最佳配方为 15% GelMA，2 M SBMA，10% HEMA，并在甘油中浸泡 3 小时。

We also studied the compressive properties of the material. It is clear to see that in Fig. 2A, the P(SBMAco-HEMA) hydrogel fractures at strain, and the compressive stress is only 0.1 MPa . After soaking in glycerol, the compressive stress of the P(SBMA-coHEMA)/glycerol hydrogel is significantly improved, reaching 1.25 MPa with the compressive strain of . Then we performed 50 continuous compression cycles on the P(SBMA-co-HEMA)/glycerol hydrogel. As shown in Fig. 2B, after compression recovery, the P(SBMA-co-HEMA)/glycerol hydrogel can return to its original shape without breaking. From Fig. 2C, we can see that the 50 continuous compression cycles of the hydrogel almost overlap, indicating that it has good fatigue resistance and stability. Because there are a large number of ionic bonds and hydrogen bonds in the hydrogel network, these reversible physical bonds can be restored immediately after damage, giving the hydrogel excellent fatigue resistance. In Fig. 2D, we can clearly observe that during the 50 continuous cycles, the compression stress of the hydrogel gradually increases and then remains stable. We suspect the reason is that during the test, the molecular chains of the hydrogel occurred directional rearrangement along the compression direction [6].
我们还研究了材料的抗压性能。从图 2A 可以清楚地看到，P(SBMAco-HEMA)水凝胶在 应变时断裂，抗压应力仅为 0.1 MPa。在甘油中浸泡后，P(SBMA-co-HEMA)/甘油水凝胶的抗压应力显著提高，达到 1.25 MPa，应变为 。然后我们对 P(SBMA-co-HEMA)/甘油水凝胶进行了 50 次连续压缩循环。如图 2B 所示，在压缩恢复后，P(SBMA-co-HEMA)/甘油水凝胶可以恢复到原始形状而不会破裂。从图 2C 可以看出，水凝胶的 50 次连续压缩循环几乎重叠，表明它具有良好的疲劳抗性和稳定性。由于水凝胶网络中存在大量离子键和氢键，这些可逆的物理键可以在损坏后立即恢复，使水凝胶具有出色的疲劳抗性。在图 2D 中，我们可以清楚地观察到在 50 次连续循环中，水凝胶的压缩应力逐渐增加，然后保持稳定。 我们怀疑的原因是，在测试过程中，水凝胶的分子链沿着压缩方向发生了定向重排列。

In order to facilitate real-time monitoring, visualization of the wound dressing is desirable, which can reduce the number of replacement and avoid secondary injury [13]. We studied the transmittance of hydrogel materials. It is obvious that the hydrogels prepared by all formulations have high transmittance in the visible wavelength range (400-780 nm) (Fig. 3). Hydrogel materials usually
为了方便实时监测，希望能够对伤口敷料进行可视化处理，这样可以减少更换次数，避免二次伤害[13]。我们研究了水凝胶材料的透射率。显然，所有配方制备的水凝胶在可见光波长范围（400-780 nm）内具有高透射率（图 3）。水凝胶材料通常

Figure 2 a Compression curves of P(SBMA-coHEMA) and P(SBMA-coHEMA)/glycerol hydrogels; b Photographs of original, compressed and recovered P(SBMA-co-HEMA)/glycerol hydrogel; c A continuous 50 compression cycles curve of P(SBMA-co-HEMA)/glycerol hydrogel under compressive strain; The change of the compressive stress of P(SBMA-co-HEMA)/ glycerol hydrogel during 50 compression cycles.
图 2 P(SBMA-coHEMA)和 P(SBMA-coHEMA)/甘油水凝胶的压缩曲线；b 原始、压缩和恢复的 P(SBMA-co-HEMA)/甘油水凝胶的照片；c P(SBMA-co-HEMA)/甘油水凝胶在 压缩应变下连续 50 次压缩循环曲线； P(SBMA-co-HEMA)/甘油水凝胶在 50 次压缩循环中的压缩应力变化。

have high water content, which results in the scattering of light at the water-polymer interface and the decrease of transmittance. In this hydrogel system, the PSBMA component can strongly adsorb water molecules through electrostatic interaction. At the same time, the PHEMA component adsorbs water molecules through hydrogen bonds, which increases the saturated water content and reduces the scattering center effect, giving the hydrogel high transmittance [4]. In addition, through hydrogen bonding, the compatibility between the polymer and water is increased, so a transparent hydrogel can be formed [14]. Surprisingly, after soaking into glycerol for 3 h , the transmittance of the material hardly decreased because of the strong hydrogen bonding force between glycerol and water molecules. The above results confirm that the prepared hydrogel material is highly transparent and promises to enable visualization of wounds.
具有高含水量，导致水-聚合物界面的光散射和透射率降低。在这种水凝胶系统中，PSBMA 组分可以通过静电相互作用强烈吸附水分子。同时，PHEMA 组分通过氢键吸附水分子，增加了饱和水含量并减少了散射中心效应，使水凝胶具有高透射率。此外，通过氢键作用，聚合物与水之间的相容性增强，因此可以形成透明的水凝胶。令人惊讶的是，浸泡在甘油中 3 小时后，材料的透射率几乎没有下降，这是由于甘油与水分子之间的强氢键作用力。上述结果证实了制备的水凝胶材料具有高透明度，并有望实现伤口的可视化。

Long-term immersion in exudate will affect wound healing [15], an ideal wound dressing should be able to absorb the large amount of exudate from the wound [16]. Here, we studied the swelling property of the hydrogel. The hydrogel was soaked in PBS buffer, and the swelling rate was calculated to evaluate the ability of the hydrogel to absorb wound exudate. It can be seen from Fig. 4A that both the two kinds of hydrogels have high swelling capacity. Only after 0.5 h of soaking, the mass of P(SBMA-coHEMA) hydrogel increases by , while the swelling rate of glycerol hydrogel is as high as . After being soaked for 24 h , the swelling rate of and SBMA-coHEMA)/glycerol hydrogel reaches and , respectively. The strong hydrogen bonding between glycerol and water molecules gives P(SBMA-coHEMA)/glycerol hydrogel more excellent swelling property. In addition, after placing a weight of 40 g on the swollen P(SBMA-co-HEMA)/glycerol hydrogel for 1 min , it can be observed that the napkin under the hydrogel remains dry. The result indicates that the hydrogel has good water holding capacity, the absorbed water will not leak out.
长期浸泡在渗出物中会影响伤口愈合[15]，理想的敷料应该能够吸收伤口大量的渗出物[16]。在这里，我们研究了水凝胶的膨胀性能。水凝胶浸泡在 PBS 缓冲液中，通过计算膨胀率来评估水凝胶吸收伤口渗出物的能力。从图 4A 可以看出，两种水凝胶都具有很高的膨胀能力。仅在浸泡 0.5 小时后，P(SBMA-coHEMA)水凝胶的质量增加了 ，而 甘油水凝胶的膨胀率高达 。浸泡 24 小时后，P(SBMA-coHEMA)/甘油水凝胶的膨胀率分别达到 和 。甘油与水分子之间的强氢键使 P(SBMA-coHEMA)/甘油水凝胶具有更优异的膨胀性能。此外，在膨胀的 P(SBMA-co-HEMA)/甘油水凝胶上放置 40 克的重物 1 分钟后，可以观察到水凝胶下的餐巾纸仍然保持干燥。结果表明水凝胶具有良好的持水能力，吸收的水不会泄漏出来。

Next, we tested the tolerance of hydrogels in the environment. We put P(SBMA-co-HEMA) and P(SBMA-co-HEMA)/glycerol hydrogels at RT and water bath to evaluate the water retention properties of the hydrogels by measuring the quality changes at different times. As shown in Fig. 4B, the ) hydrogel is dehydrated at RT and , the quality change rates after 24 h are and , respectively. In contrast, the quality of P(SBMA-co-HEMA)/glycerol hydrogel
接下来，我们测试了水凝胶在环境中的耐受性。我们将 P(SBMA-co-HEMA)和 P(SBMA-co-HEMA)/甘油水凝胶放置在室温和 水浴中，通过测量不同时间点的质量变化来评估水凝胶的保水性能。如图 4B 所示， )水凝胶在室温下脱水， 后，24 小时后的质量变化率分别为 和 。相比之下，P(SBMA-co-HEMA)/甘油水凝胶的质量

Figure 3 The transmittance of hydrogels with different GelMA contents before (a) and after (b) soaking in glycerol; the transmittance of hydrogels with different SBMA contents before (c) and after (d) soaking in glycerol; the transmittance of hydrogels with different HEMA content before (e) and after (f) soaking in glycerol.
图 3 不同 GelMA 含量的水凝胶在浸泡甘油前（a）和后（b）的透光率；不同 SBMA 含量的水凝胶在浸泡甘油前（c）和后（d）的透光率；不同 HEMA 含量的水凝胶在浸泡甘油前（e）和后（f）的透光率。

Figure 4 a The swelling property of the HEMA) and P(SBMA-coHEMA)/glycerol hydrogel; b The water retention property of the P(SBMA-co-HEMA) and P(SBMA-co-HEMA)/ glycerol hydrogel after being placed at RT and for 24 h
图 4 a HEMA)和 P(SBMA-coHEMA)/甘油水凝胶的膨胀性能; b 在室温和 放置 24 小时后，P(SBMA-co-HEMA)和 P(SBMA-co-HEMA)/甘油水凝胶的保水性能

increases after 24 h , and the quality change rates are and at RT and , respectively. The strong hydrogen bond between glycerol and water molecules enable hydrogel to absorb moisture in the environment therefore increasing quality. On the other hand, glycerol can slow down the evaporation of water [17] and prevent dehydration of the hydrogel. When applied to wounds, the P(SBMA-coHEMA)/glycerol hydrogel is expected to absorb exudate and maintain soft without additional antidehydration layer.
24 小时后增加，室温和 时的质量变化率分别为 和 。甘油与水分子之间的强氢键使水凝胶能够吸收环境中的湿气，从而提高质量。另一方面，甘油可以减缓水分蒸发[17]，防止水凝胶脱水。当应用于伤口时，预计 P(SBMA-coHEMA)/甘油水凝胶将吸收渗出物并保持柔软，无需额外的抗脱水层。

From Fig. 5A, we can observe that the P(SBMA-coHEMA) hydrogel has been frozen after being placed in the refrigerator at for only 1 h . Due to the
从图 5A 可以看出，P(SBMA-coHEMA)水凝胶在 冰箱中放置 1 小时后已经被冻结。由于
growth of ice crystals, the P(SBMA-co-HEMA) hydrogel loses its elasticity as well as the transparency and becomes fragile. On the contrary, even being stored at low temperature for 48 h , the P(SBMA-co-HEMA)/glycerol hydrogel still has good elasticity and maintains a high degree of transparency. According to the literature [18], the strong hydrogen bond between glycerol and water molecules is more stable than that between glycerol molecules, and between water molecules. Therefore, in a sub-zero environment, these stable hydrogen bonds can inhibit the growth of ice crystals and endow the hydrogel with good freezing resistance.
冰晶的生长，P(SBMA-co-HEMA) 凝胶失去了其弹性以及透明度，并变得脆弱。相反，即使在低温下存放 48 小时，P(SBMA-co-HEMA)/甘油凝胶仍然具有良好的弹性并保持高度透明度。根据文献[18]，甘油与水分子之间的强氢键比甘油分子之间以及水分子之间的氢键更稳定。因此，在零下环境中，这些稳定的氢键可以抑制冰晶的生长，并赋予凝胶良好的抗冻性。

It is known that trypsin can decompose a variety of proteins including gelatin [19]. We suppose that in this hydrogel system, GelMA, which acts as the crosslinking point, can be hydrolyzed by trypsin. However, as shown in Fig. 5B, during the 2-week degradation experiment, the hydrogel only swelled and remained in its intact shape without disintegration. Glycerol is known to be a commonly used enzyme storage agent and will not affect the activity of trypsin [20], so we guess that the strong hydration of zwitterionic components resists the contact between trypsin and crosslinking point, thereby inhibits hydrolysis.
已知胰蛋白酶可以分解多种蛋白质，包括明胶[19]。我们假设在这种水凝胶系统中，作为交联点的 GelMA 可以被胰蛋白酶水解。然而，如图 5B 所示，在为期 2 周的降解实验中，水凝胶只是膨胀并保持其完整形状而没有分解。甘油被认为是一种常用的酶储存剂，不会影响胰蛋白酶的活性[20]，因此我们猜测带电离子成分的强烈水合作用阻止了胰蛋白酶与交联点的接触，从而抑制了水解。

To prove our hypothesis, we prepared pure GelMA hydrogel (G) and GelMA-crosslinked PHEMA hydrogel (H), soaked in PBS and trypsin solution, respectively, to observe the degradation (Fig. 5C). After one day, all groups of hydrogels soaked in PBS buffer did not degrade. The GelMA hydrogel and PHEMA hydrogel that immersed in trypsin solution were completely degraded, while P(SBMA-coHEMA) hydrogel (S) only swelled, resulting in significant increase in volume. The results confirm that the GelMA crosslinking point can be decomposed by trypsin. After introducing the PSBMA component, the hydrogel has excellent hydrophilicity, which is the main reason for improving the antifouling performance [21, 22]. The hydrogel resists the adhesion of the trypsin on the surface [23, 24], making it difficult to further spread to the interior and delay the degradation. In summary, the P(SBMA-co-HEMA)/ glycerol hydrogel has good stability.
为了证明我们的假设，我们准备了纯 GelMA 水凝胶（G）和 GelMA 交联的 PHEMA 水凝胶（H），分别浸泡在 PBS 和胰蛋白酶溶液中，以观察降解情况（图 5C）。一天后，所有浸泡在 PBS 缓冲液中的水凝胶组都没有降解。浸泡在胰蛋白酶溶液中的 GelMA 水凝胶和 PHEMA 水凝胶完全降解，而 P(SBMA-co-HEMA)水凝胶（S）只是膨胀，导致体积显著增加。结果证实了 GelMA 交联点可以被胰蛋白酶分解。引入 PSBMA 组分后，水凝胶具有优异的亲水性，这是改善防污性能的主要原因[21, 22]。水凝胶抵抗胰蛋白酶在表面的附着[23, 24]，使其难以进一步扩散到内部并延迟降解。总之，P(SBMA-co-HEMA)/甘油水凝胶具有良好的稳定性。

Bacteria are easy to adhere to the open wound surface of the human body and then cause diseases in different ways, posing a threat to health [25, 26]. Here, we evaluated the ability of the material to resist bacterial adhesion. As shown in Fig. 6, after 24 h of co-culture, we can clearly observe a large number of intact E. coli on the surface of the commercially available dressing, which was mainly composed of agar, polyethylene glycol and polyvinylpyrrolidone. On the contrary, almost no E. coli existed on the surface of the two prepared hydrogels. Because the
细菌很容易附着在人体开放伤口表面，然后以不同方式引起疾病，对健康构成威胁[25, 26]。在这里，我们评估了材料抵抗细菌附着的能力。如图 6 所示，在共培养 24 小时后，我们可以清楚地观察到大量完整的大肠杆菌附着在商用敷料表面上，该敷料主要由琼脂、聚乙二醇和聚乙烯吡咯烷酮组成。相反，两种制备的水凝胶表面几乎没有大肠杆菌存在。因为
Figure 5 a After being placed in a refrigerator at for different time, the photographs of frozen P(SBMA-co-HEMA) hydrogel and unfrozen P(SBMA-co-HEMA)/glycerol hydrogel; Degradation of the P(SBMA-co-HEMA)/glycerol hydrogel after being placed into trypsin saturated solution for different times;
图 5a 在 冰箱中放置不同时间后，冻结的 P(SBMA-co-HEMA)水凝胶和未冻结的 P(SBMA-co-HEMA)/甘油水凝胶的照片； 将 P(SBMA-co-HEMA)/甘油水凝胶放入三种不同时间的胰蛋白酶饱和溶液中后的降解情况；

c Degradation of three kinds of hydrogel after being placed into PBS and trypsin saturated solution for 1 d . (a)
三种水凝胶放入 PBS 和胰蛋白酶饱和溶液中 1 天后的降解。(a)

(b)

1 d

14 d

zwitterionic component forms a continuous and robust hydration layer on the surface of the hydrogel, which can resist the attachment of bacteria by repelling the proteins decorated on the cell membrane [27].
带电离子组分在水凝胶表面形成连续且坚固的水合层，可以通过排斥细胞膜上装饰的蛋白质来抵抗细菌的附着。

Biocompatibility is an indispensable property as wound dressing material. It is well known that SBMA and HEMA have excellent biocompatibility in the field of biomedicine [28-30]. We first tested the biocompatibility of the whole material using the MTT method. As shown in Fig. 7A, after co-culture with different concentration P(SBMA-co-HEMA) hydrogel extract of and for one day, the viability of L929 cells were and , respectively. Even after seven days of co-culture, the cell viability of each concentration group was still higher than . This result confirms that the extract of SBMA-co-HEMA) hydrogel is not toxic to the cell and has good in vitro biocompatibility. The cytotoxicity test results of the P(SBMA-co-HEMA)/glycerol hydrogel showed the same trend. After co-culture with different concentrations of extracts for different days, the cell viability was higher than , which proved that the glycerol has almost no effect on the biocompatibility of the material.
生物相容性是一种不可或缺的性质，作为伤口敷料材料。众所周知，在生物医学领域，SBMA 和 HEMA 在生物相容性方面表现出色[28-30]。我们首先使用 MTT 方法测试了整个材料的生物相容性。如图 7A 所示，在与不同浓度 P(SBMA-co-HEMA)水凝胶提取物的共培养一天后，L929 细胞的存活率分别为 和 。即使在共培养七天后，每个浓度组的细胞存活率仍高于 。这一结果证实了 P(SBMA-co-HEMA)水凝胶提取物对细胞无毒，并具有良好的体外生物相容性。P(SBMA-co-HEMA)/甘油水凝胶的细胞毒性测试结果显示了相同的趋势。与不同浓度的提取物共培养不同天数后，细胞存活率高于 ，证明甘油对材料的生物相容性几乎没有影响。

It is mentioned in the literature [31] that most commercial hydrogel dressing products have adopted some strategies to improve the mechanical properties, but generally the biocompatibility will decline. Therefore, we embedded hydrogel samples into the back of the mice to further confirm the in vivo biocompatibility (Fig. 7B). After implantation for 1 week and 4 weeks, we can clearly observe that the hydrogel samples still exist under the skin of mice without damage or loss, which is consistent with the results of the above degradation test. After 1 week, it can be seen from the E staining images that there was no obvious foreign body granuloma or inflammatory reaction in the embedding sites of the two groups of mice, only a small amount of inflammatory cell infiltrated. Surprisingly, after 4 weeks, no inflammatory cells were observed in the tissues surrounding of the implanted hydrogel. This is because HEMA is hydrophilic and the zwitterionic component PSBMA can strongly bind water molecules through electrostatic interactions. A dense hydration layer can be formed on the surface of the hydrogel to resist the adsorption of non-specific proteins [32-34], which is the main reason for foreign body reactions [35, 36]. The above results prove that the hydrogel has excellent biocompatibility and is expected to be used in the field of biomaterials.
文献[31]中提到，大多数商业水凝胶敷料产品采用了一些策略来改善机械性能，但通常生物相容性会下降。因此，我们将水凝胶样品嵌入小鼠背部以进一步确认体内生物相容性（图 7B）。植入 1 周和 4 周后，我们可以清楚地观察到水凝胶样品仍然存在于小鼠皮下而没有损坏或丢失，这与上述降解测试结果一致。1 周后，从 E 染色图像中可以看到，在两组小鼠的嵌入部位没有明显的异物肉芽肿或炎症反应，只有少量炎症细胞浸润。令人惊讶的是，4 周后，在植入水凝胶周围的组织中没有观察到炎症细胞。这是因为 HEMA 是亲水性的，而带电离子成分 PSBMA 可以通过静电相互作用强烈结合水分子。 在水凝胶表面可以形成一层致密的水合层，以抵抗非特异性蛋白质的吸附[32-34]，这是异物反应的主要原因[35, 36]。以上结果证明了水凝胶具有优异的生物相容性，有望在生物材料领域得到应用。

Here, we prepared P(SBMA-co-HEMA)/glycerol hydrogel by a simple one-pot method. The strong hydrogen bond between glycerol and molecular chain makes the hydrogel have good mechanical properties, and the tensile strength is as high as 1.21 MPa. The compression cycle test proves that the hydrogel has good elasticity and fatigue resistance. The strong adsorption capacity of the PSBMA component for water molecules endows the hydrogel with good transparency, in the visible wavelength range, the transmittance of the hydrogel is always higher than . The hydrogel also exhibits excellent antifreezing property and is expected to be used in extremely cold environment. In addition, the
在这里，我们通过简单的一锅法制备了 P(SBMA-co-HEMA)/甘油水凝胶。甘油与分子链之间的强氢键使水凝胶具有良好的机械性能，拉伸强度高达 1.21 MPa。压缩循环测试证明水凝胶具有良好的弹性和抗疲劳性。PSBMA 组分对水分子的强吸附能力赋予水凝胶良好的透明性，在可见光波长范围内，水凝胶的透射率始终高于 。水凝胶还表现出优异的防冻性能，预计可用于极寒环境中。此外，

Figure 6 Adhesion of Escherichia coli (E. coli) on the P(SBMA-co-HEMA) hydrogel (a), P(SBMA-co-HEMA)/glycerol hydrogel (b) and commercially available wound dressing (c).
图 6 大肠杆菌（E. coli）在 P(SBMA-co-HEMA)水凝胶（a）、P(SBMA-co-HEMA)/甘油水凝胶（b）和商业可用伤口敷料（c）上的粘附。

Figure 7 a The cell viability of the -co-HEMA) and glycerol hydrogel; Implantation site of the hydrogel on the back of mice and representative staining of skin tissue sections.
图 7 a -co-HEMA) 和 甘油 水凝胶的细胞存活率; 小鼠背部水凝胶植入部位和皮肤组织切片的代表性 染色。

hydrogel also has excellent swelling capacity and water retention property, which can provide a comfortable environment for wounds. The hydrogel can significantly resist the adhesion of bacteria. In vitro and in vivo assays revealed that it has good biocompatibility and stability, for always maintaining its shape intact without being degraded. The hydrogel is expected to be used in the biomedical application such as wound dressings.
水凝胶还具有出色的膨胀能力和保水性能，可以为伤口提供舒适的环境。水凝胶可以显著抵抗细菌的附着。体外和体内实验表明，它具有良好的生物相容性和稳定性，始终保持其形状完整而不被降解。水凝胶有望用于生物医学应用，如敷料。

This work was supported in part by the Key R&D Projects of Zhejiang Province (2021C03035).
本工作部分得到浙江省重点研发项目（2021C03035）的支持。

Conflict of interest The authors have no financial interests of any products mentioned in this article.
利益冲突 作者在本文提到的任何产品上都没有任何财务利益。

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