Tunable backbone-degradable robust tissue adhesives via in situ radical ring-opening polymerization

The development of adhesives with robust adhesion and tunable degradability is crucial for various clinical and ecological applications. Current challenges in adhesive design include achieving strong interfacial bonding to wet surfaces, particularly biological tissues, while maintaining desirable mechanical properties and biocompatibility. Existing wet adhesives often exhibit high adhesion energy but insufficient adhesive strength (in kPa to MPa range needed for applications such as bone adhesion). Hydrogels, for example, suffer from limited permeability, low bulk modulus leading to mechanical mismatch with high-modulus substrates, and mechanical deterioration in wet environments. Small molecule adhesives, such as cyanoacrylate (CA) superglue, offer high adhesion strength due to good monomer diffusion during in situ polymerization; however, CA's rapid and brittle curing leads to weak bonding with wet and soft tissues, it is non-degradable, and it is toxic. Degradable adhesives made from biomolecules or biobased polymers often lack sufficient cohesion strength and mechanical properties. This research aims to overcome these limitations by developing a new family of adhesives that combine high strength, tunable degradability, and biocompatibility.

Existing literature highlights the challenges in creating robust and degradable adhesives. While advances have been made using supermolecule and electrostatic interactions, covalent bonding, and topological adhesion to improve wet adhesion, particularly to biological tissues, the resulting adhesives often lack sufficient strength for many applications, such as bone fixation. The use of hydrogels, while offering some biocompatibility and degradability, is limited by their low permeability and susceptibility to swelling and mechanical degradation in aqueous environments. Small molecule adhesives, such as cyanoacrylates, while possessing high adhesion strength, suffer from issues related to toxicity, non-degradability, and brittle adhesion to soft tissues. Biomolecule-based adhesives, such as those using fibrin or alginate, often lack the required mechanical properties for many applications. This underscores the need for a novel approach that combines the advantages of small molecule adhesives and the benefits of biocompatibility and degradability.

The researchers developed a novel in situ radical ring-opening polymerization (rROP) strategy to create backbone-degradable robust adhesives (BDRAs). The method involves copolymerizing a hydrophobic cyclic ketene acetal (CKA) monomer (2-methylidene-1,3-dioxepane, MDO) with various hydrophilic acrylate comonomers (e.g., hydroxyethyl methacrylate (HEMA), hydroxyethyl acrylate (HEA)) at room temperature without the need for water and oxygen removal. The redox-initiated rROP, using benzoyl peroxide (BPO) and N,N-dimethyl-p-toluidine (DMPT), allows for the in situ formation of a degradable polymer network. The amphipathic nature of the BDRA precursors ensures good wettability and penetration into diverse substrates. The adhesion strength was evaluated using standard flexural and shear tests on various substrates (wet bone, porcine skin, polymers, and metals). The adhesion mechanism was investigated by examining the wettability and penetration depth of the precursors using confocal laser scanning microscopy. Degradation profiles were determined in vitro using phosphate-buffered saline (PBS) and in vivo through subcutaneous implantation in rats. Biocompatibility was assessed using in vitro cytotoxicity assays (CCK-8 and live/dead assays) and in vivo histological analysis. Mechanical properties (glass transition temperature, elastic modulus) were characterized using dynamic mechanical analysis (DMA). The setting time of the BDRAs was determined by the vial inversion method. Various ex vivo and in vivo animal experiments were conducted to explore the potential applications of BDRAs in wound management, hemostasis, and bone fracture fixation. Specific details regarding concentrations, ratios of monomers, and experimental protocols are provided in the paper's supplementary information.

The synthesized BDRAs demonstrated significantly higher adhesion strength compared to commercial adhesives on various substrates. On wet bone, the adhesion strength exceeded 16 MPa (compared to -4 MPa for cyanoacrylate), and on porcine skin it reached 150 kPa (compared to 56 kPa for cyanoacrylate). The BDRAs exhibited strong adhesion to various materials, including low-surface-energy polymers. The enhanced adhesion is attributed to the amphiphilic nature of the precursors, allowing for deep penetration into the substrates and the formation of a robust covalent interpenetrating network. The in situ rROP process avoids the premature stiffening observed with cyanoacrylate, leading to superior bonding with wet tissues. The BDRAs exhibited tunable degradability, with degradation rates ranging from 18% to 43% in vitro and up to 36% in vivo. The mechanical modulus could be tuned from 100 kPa to 10 GPa by adjusting the monomer composition, allowing for compatibility with both soft and hard tissues. The setting time could be adjusted from seconds to hours. In vivo studies demonstrated good biocompatibility, with minimal inflammation and efficient tissue regeneration. The BDRAs showed promise in various applications, including wound closure, hemostasis (demonstrating superior performance compared to cyanoacrylate and fibrin adhesives), and bone fracture fixation (where they facilitated significant bone regeneration).

The results demonstrate the successful development of a new family of tunable, backbone-degradable robust adhesives. The superior adhesion strength, tunable degradability, and biocompatibility of BDRAs address the limitations of existing adhesives. The in situ rROP strategy provides a versatile platform for tailoring the adhesive's properties to specific applications. The superior performance of BDRAs in wound closure, hemostasis, and bone fracture fixation suggests significant potential for translational applications. The ability to tune the mechanical properties and setting time makes them suitable for various clinical scenarios. The observed biocompatibility and biodegradability address critical concerns related to long-term safety and tissue regeneration.

This study successfully developed a new family of tunable, backbone-degradable robust adhesives (BDRAs) using an in situ radical ring-opening polymerization strategy. These adhesives demonstrate significantly superior adhesion strength, tunable degradability, and biocompatibility compared to existing adhesives. Their versatility in terms of mechanical properties and setting time suggests broad applicability in various biomedical applications, including wound healing, hemostasis, and fracture repair. Future studies should focus on further optimization of the BDRA formulations and conducting larger-scale clinical trials to assess their long-term efficacy and safety.

While the study demonstrates excellent performance in preclinical models, further research is needed to fully assess the long-term in vivo effects and potential for adverse reactions in humans. The current study focused on a limited set of tissues and materials, so future studies should expand the range of applications. The in vivo degradation rate might vary with changes in the physiological environment, so more robust analysis is needed.