“Modular Design of Hydrogel Adhesives for Enhanced Tissue Healing”

Today, we are sharing a research article led by the team of Kuan Zhang, published in Advanced Materials. This study proposes a modular design strategy that successfully develops a new generation of hydrogel bioadhesives by integrating genetically engineered supercharged polypeptides (SUP) with synthetic hydrogel networks. This strategy skillfully balances adhesion strength and cohesive strength, achieving rapid and effective hemostasis and wound healing in various complex physiological environments (such as the liver, beating heart, and acidic stomach). For the first time in such materials, it also enables gentle, triggerable benign detachment, providing a universal new paradigm for the development of biomedical adhesives.

01 Research Background:

In surgical procedures and wound management, bioadhesives are widely studied as alternatives to sutures and staples. However, existing adhesive solutions face significant limitations: slow adhesion speed, weak bonding strength, poor biocompatibility, mechanical mismatch with tissues, and most critically, a lack of controllable, benign detachment capability. Hydrogels, due to their structural and mechanical similarity to biological tissues, are ideal candidates for bioadhesives. However, a universal method to endow hydrogels with excellent adhesive properties is still lacking, often requiring complex chemical modifications tailored to specific hydrogel networks. Strong adhesion characteristics frequently conflict with the criteria for ideal bioadhesives; for instance, enhancing performance may involve introducing non-degradable backbones or toxic molecules. Furthermore, achieving rapid and strong adhesion often comes at the cost of controllable detachment. In clinical practice, adhesives sometimes need to be removed for secondary surgeries, and direct peeling can cause secondary tissue damage. Therefore, there is an urgent need to develop universal hydrogel adhesive strategies that combine robust adhesion with controllable, benign detachment.

Figure 1. Schematic illustration of the modular design strategy for hydrogel adhesives.

02 Innovative Highlights

The core innovation of this study lies in its "modular" design concept, which decouples the functions of the hydrogel network and the protein coacervate phase, then achieves performance breakthroughs through synergistic effects.

• Functional Modularity and Synergistic Enhancement: The research team did not perform complex chemical modifications on the hydrogel network itself but instead used it as a "skeleton" providing mechanical support. Concurrently, they introduced a previously developed super-strong adhesive "SUP glue" – a coacervate formed by electrostatic complexation of cationic polypeptides and the anionic surfactant SDBS – as a functional module into the hydrogel, creating a semi-interpenetrating network. The hydrogel skeleton provides cohesive strength, preventing the material from disintegrating in wet conditions, while the internal coacervate module migrates to the interface during adhesion, providing adhesive strength. Their synergy results in performance far exceeding that of individual components.

• Significantly Reduced Protein Usage and Improved Handling: Although the original SUP glue has strong adhesion, it suffers from high protein content, poor cohesion in wet environments, and difficulty in applying the viscous coacervate to wounds. This design uniformly disperses the protein within the hydrogel network, greatly improving protein utilization. The amount of protein required to achieve equivalent adhesive strength is reduced by more than 50-fold, and the resulting dry film is easier to apply.

• Introduction of a Gentle, Triggerable Benign Detachment Mechanism: Leveraging the properties of the coacervate protein components, localized application of trypsin can rapidly degrade the protein, enabling gentle, non-damaging detachment of the adhesive within minutes. This addresses the clinical challenge of difficult removal associated with strong adhesives.

03 Results and Discussion

3.1 Material Preparation, Characterization, and Validation of Super-Strong Adhesion

The study used commonly available polyethylene glycol (PEG) hydrogel as the model skeleton. During preparation, cationic SUP polypeptides (e.g., K72) were added to the hydrogel precursor. After UV polymerization to form the hydrogel, the anionic surfactant SDBS was introduced via diffusion, forming protein coacervate phases within the gel, ultimately yielding a dry adhesive film.

Observation via cryogenic scanning electron microscopy (cryo-SEM) and confocal microscopy confirmed the uniform distribution of coacervate particles within the hydrogel network. Small-angle X-ray scattering (SAXS) data showed new characteristic peaks, confirming the ordered structure of the coacervate phase. Adhesion performance tests (lap-shear tests) demonstrated that PEG hydrogels containing the K72-SDBS coacervate achieved extremely high adhesive strength (3-5 MPa) on glass surfaces, sufficient to lift a 1 kg weight. Control groups lacking SUP or SDBS showed almost no adhesion. Simultaneously, the peel toughness of this material (~340 J m⁻²) was significantly higher than that of the original SUP glue (~30 J m⁻²), demonstrating the contribution of the hydrogel skeleton to enhanced cohesion.

Figure 2. Preparation and characterization of the hydrogel adhesive. 

3.2 Investigation of Adhesion Mechanism and Demonstration of Generality and Controllable Detachment

To explore the mechanism of strong adhesion, the study used fluorescently labeled protein (GFP-K72) for observation. It was found that during adhesion formation, the coacervate phase within the gel actively migrates and enriches at the adhesion interface, thereby achieving high interfacial adhesion with a relatively low total amount of protein. Atomic force microscopy (AFM) tests also confirmed the presence of the coacervate phase on the adhesive surface, exhibiting high adhesion force.

The generality of this design is impressive. The research team successfully combined different hydrogel skeletons (e.g., polyacrylamide PAAm, polyacrylic acid PAA, HEMA, NVP) with the SUP coacervate. All these combinations exhibited high adhesive strength and toughness, proving the broad applicability of the modular strategy. More importantly, controllable detachment was achieved: by using trypsin treatment to degrade the protein at the interface, the adhesive strength could be reduced by approximately 10-fold, allowing for easy, non-traumatic peeling of the adhesive, whereas direct tearing caused tissue damage and triggered a stronger inflammatory response.

Figure 3. Investigation of the generality and the controllable detachment properties of the hydrogel adhesive system.

3.3 Validation of Excellent Hemostasis and Healing Effects in Multiple Animal Models

The advantage of modular design is the ability to "customize" the hydrogel skeleton to suit specific physiological environments. The research team demonstrated three application scenarios:

Liver Hemostasis: Using a conventional PEG hydrogel (PEG-K72-SDBS). In a rat liver incision model, this adhesive achieved rapid hemostasis within 5 seconds, performing comparably to commercial cyanoacrylate glue but with far superior biocompatibility and detachability. Histological analysis showed it significantly promoted wound healing, reducing inflammation and collagen deposition. 

Cardiac Wound Sealing: To address the wet and dynamic environment of a beating heart, a low-swelling HEMA hydrogel (HEMA-K72-SDBS) was designed. In a penetrating cardiac injury model, this adhesive achieved immediate hemostasis, whereas the control commercial fibrin glue showed continuous bleeding. Histological analysis confirmed a milder inflammatory response and faster wound healing in the adhesive-treated group.

Figure 4. In vivo cardiac wound healing

Gastric Perforation Repair: To withstand the acidic stomach environment, an acid-resistant NVP hydrogel (NVP-K72-SDBS) was synthesized. In a rat gastric perforation model, this adhesive effectively sealed the perforation within 5 seconds and remained firmly adhered even after 7 days. Compared to the suture control, it avoided secondary puncture damage caused by suturing and promoted more complete regeneration of the three-layer structure of the gastric wall.

Figure 5. In vivo gastric perforation repair.

04 Conclusion and Future Perspectives

This study successfully demonstrates a universal and powerful modular design platform for hydrogel bioadhesives. Its core value lies in decoupling and freely combining functions by physically mixing the "adhesive functional module" (protein coacervate) with the "structural support module" (hydrogel network), rather than through chemical coupling. This approach not only simplifies the design process, avoiding tedious chemical modifications, but also enables the material to possess multiple ideal characteristics simultaneously: robust adhesion, excellent cohesion, environmental adaptability, and triggerable benign detachment.

In summary, this work moves beyond the traditional approach of "one material for one problem" towards a more scalable "material platform" concept. Researchers can independently select and optimize the mechanical properties, swelling behavior, and chemical stability of the hydrogel skeleton based on the requirements of the target application scenario (e.g., dynamic wet conditions, acidic environments), while retaining its powerful interfacial adhesion function. This design philosophy provides significant guidance for future biomaterial development. Although clinical translation still faces challenges (such as precise control of enzymatic trigger detachment under endoscopy), this study offers a practical and innovative solution to the long-standing "adhesion-detachment" dilemma in the field of bioadhesives, laying a solid foundation for the development of next-generation intelligent surgical materials.

 Original Article:

Zhang K, Wei Y, Ding H, Zhou Y, Zhou X, Mourran A, Zeng X, Liu S, Song Z, Dittrich B, Chen G, Herrmann A, Zheng L. Modular Design of Hydrogel Adhesives for Enhanced Tissue Healing. Adv Mater. 2025 Nov 10:e16770. 

https://advanced.onlinelibrary.wiley.com/doi/10.1002/adma.202516770