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

Achieving strong, stable adhesion on wet and complex biological substrates is difficult due to poor interfacial bonding and mechanical mismatch, especially for tasks like bone fixation where MPa-level strength is required. Many recent wet adhesives (e.g., hydrogels) provide high adhesion energy but limited adhesive strength because polymers have low permeability into tissues and low bulk modulus, and their networks deteriorate upon swelling in wet environments. Small-molecule adhesives like cyanoacrylates (CAs) can diffuse and polymerize in situ to give strong bonds but cure instantly via water-initiated anionic polymerization, forming stiff and brittle layers with weak bonding to wet, soft tissues; CAs are also poorly degradable and can be toxic. Existing degradable adhesives from biomolecules often have limited cohesion due to structural heterogeneity and inferior mechanics. Therefore, creating robust adhesives with tunable degradability remains challenging due to the trade-off between stability and strength. The study addresses this by proposing in situ rROP of hydrophobic cyclic ketene acetal (CKA) and hydrophilic acrylate comonomers to form backbone-degradable robust tissue adhesives (BDRAs) under physiological conditions.

Prior work has improved wet adhesion through supramolecular and electrostatic interactions, covalent bonding, and topological adhesion, often achieving high adhesion energies but not the high adhesive strengths needed for hard tissues. Hydrogels are limited by low polymer permeability into tissues, mechanical mismatch, and swelling-induced deterioration. Cyanoacrylates achieve strong adhesion via rapid in situ polymerization but yield brittle, non-degradable, and potentially toxic bonds, limiting medical use and raising environmental concerns. Degradable adhesives based on biomolecules (e.g., fibrin, gelatine, alginate) provide limited cohesion strength due to poor structural homogeneity and weak mechanics. Radical ring-opening polymerization (rROP) combines attributes of radical vinyl polymerization with degradable backbones from ring-opening of cyclic monomers and has been used to pre-synthesize degradable polymers for biomedical uses (e.g., micelles, nanoparticles, sealing materials). This work leverages in situ rROP for adhesives to integrate robust adhesion with tunable degradability.

Design and synthesis: Amphiphilic BDRA precursors are formulated by mixing a hydrophobic cyclic ketene acetal monomer (2-methylidene-1,3-dioxepane, MDO) with hydrophilic acrylate comonomers (e.g., HEA, HEMA) and a crosslinker (ethylene dimethacrylate, EDMA). Polymerization is initiated in situ via a redox pair (benzoyl peroxide, BPO / N,N-dimethyl-p-toluidine, DMPT) to perform radical ring-opening copolymerization under physiological conditions without deoxygenation or drying. Functional comonomers (e.g., acrylic acid N-hydroxysuccinimide ester, AAc-NHS) are incorporated to introduce reactive NHS ester groups for covalent tissue bonding. Compositions are varied across eighteen acrylate comonomers and different MDO:acrylate feed ratios to tune modulus, degradability, and setting time. Characterization: Chemical structures are verified by 1H NMR and FT-IR; molecular weights by GPC. Wettability is assessed by contact angle measurements of BDRA precursors on various substrates. Penetration into tissues is visualized using fluorescein isothiocyanate (FITC)-labeled precursors and confocal microscopy to quantify depth over time, with and without initiator, and to compare amphiphilic vs hydrophilic/hydrophobic formulations. Mechanical and thermal properties: Dynamic mechanical analysis (DMA) determines storage/loss moduli and glass transition temperatures (Tg); uniaxial tensile testing (ASTM D638) measures elastic modulus, tensile strength, elongation, and toughness. Swelling ratios are measured in PBS at 37 °C. Adhesion testing: Adhesion to hard tissues (bovine bone) is quantified via shear, tensile, and 3-point flexural tests (ASTM D790-10), with bond areas and loading geometries specified; adhesion to soft tissues (porcine skin and organs) is measured via standard lap shear (ASTM F2255), tensile (ASTM F2258), peel/interfacial toughness (ASTM F2256), and wound closure strength (ASTM F2458). Adhesion to engineering polymers (PP, PE, PTFE) and metals is benchmarked against commercial adhesives. Setting time and exotherm: Setting times are measured by vial inversion at 37 °C across different comonomers and feed ratios; thermal imaging (HT-19) records peak temperature during in situ curing on pig skin, compared to CA and acrylate homopolymer controls. Degradation and biocompatibility: In vitro hydrolytic degradation is performed in PBS (37 °C) and accelerated degradation in 1 M NaOH (37 °C); residual mass is tracked over time. In vivo biodegradation is assessed via subcutaneous implantation in rats, with retrieval and weighing at timepoints. Cytocompatibility is evaluated with L929 fibroblasts and MC3T3-E1 osteoblast precursor cells using extract and direct-contact CCK-8 assays and live/dead staining. Potential toxicity from residual monomers/initiators is assessed per ISO 10993-5. Histology (H&E) and immunofluorescence (CD3 lymphocytes, CD68 macrophages) evaluate inflammatory responses; major organ histology assesses systemic toxicity and potential VOC effects. Animal models and imaging: Ex vivo and in vivo demonstrations include rat dorsal skin wound closure (linear and cruciate), hemostasis in rat liver perforation, carotid artery, and caudal vein injury models, and bone applications: ex vivo cattle femur fixation, in vivo rat tibial semitransverse fracture repair, and rat skull full-thickness bone defect with fragment refixation. Micro-CT quantifies bone regeneration (BV/BT) at 2, 4, and 8 weeks; histology (H&E, Masson) assesses new bone formation.

• Strong wet adhesion across diverse substrates: On wet bone, BDRAs achieved >16 MPa flexural strength; on porcine skin, shear adhesion reached ~150 kPa, both exceeding commercial cyanoacrylate (CA) superglue (~4 MPa bone; ~56–60 kPa skin), PEG-based Coseal (~0.2 MPa bone; ~20 kPa skin), and fibrin (Fibingluraas; ~0.1 MPa bone; ~10 kPa skin).
• Engineering plastics: Shear strengths on low-surface-energy polymers were 421 kPa (PP), 265 kPa (PE), and 114 kPa (PTFE), outperforming CA PR100 (~5, 63, 2 kPa) and polyurethane 6310 NS (~25, 53, 48 kPa).
• Demonstrations: A fractured bovine bone bonded with BDRA lifted a 60 kg weight; a 10 × 15 mm2 pigskin bond lifted 2.7 kg of water.
• Thermal effect during curing: Peak temperatures on pigskin were <45 °C for MDO-HEMA BDRAs (below Vetbond ~54 °C and bone necrosis threshold 56 °C) and 39–59 °C for MDO-HEA BDRAs, much lower than acrylate homopolymer systems (~100 °C).
• Mechanism evidence: Amphiphilic precursors showed superior wettability on 12 surfaces and deeper tissue penetration. Penetration depth into porcine skin reached ~200 µm in 60 min (without initiator), >6× CA. Amphiphilic P(MDO-co-HEA/HEMA) gave higher tissue adhesion and thicker bonding interfaces than hydrophilic (PHEA/PHEMA) or hydrophobic (P(MDO-co-BA)) references. Adhesion on bovine bone increased with time, reaching ~2 MPa within 10 min, consistent with formation of a deep covalent interpenetrating and topologically entangled network.
• Low swelling and stable interfaces: Amphiphilic BDRAs had ~3.8% swelling in PBS at 37 °C (~10× lower than PHEMA). BDRA-bonded stainless sheets remained stable for 48 h under water; PHEMA interfaces failed within 8 h due to swelling. Incorporation of AAc-NHS provided covalent tissue bonding without loss of strength over 48 h.
• Tunable degradability: In vitro (PBS, 37 °C) mass loss for optimized MDO1-HEMA1 BDRAs was 43% at 16 weeks; in vivo (rat subcutaneous) mass loss was 36% at 8 weeks. These exceeded CA (8% in vitro; 9% in vivo), PCL (1%; 2%), and PHEMA (18%; 3%). Accelerated degradation (1 M NaOH, 37 °C) showed highest mass loss (24% at 24 h) at an initial MDO feed of 0.5, indicating degradability depends on both ester content and hydrophilicity.
• Biocompatibility: Cell viabilities >87% (L929, MC3T3) for BDRAs vs Vetbond <60%. Residual concentrations of MDO, HEMA, NHS, BPO, and DMPT met ISO 10993-5 cytotoxicity thresholds; highest residual HEA concentrations were cytotoxic in vitro. In vivo, BDRA elicited milder and resolving inflammation vs octyl CA, with fewer CD3+ lymphocytes and CD68+ macrophages at 7 days and near resolution by 14 days; no major organ toxicity was observed.
• Mechanical compliance: MDO-HEA BDRAs had Tg 12–33 °C (rubbery at 37 °C) with elastic moduli 102–103 kPa, matching soft tissue; MDO-HEMA BDRAs had Tg 50–100 °C (glassy at 37 °C) with moduli 106–107 kPa, matching hard tissue.
• Adhesion performance tuned to tissue type: On pigskin, optimized MDO-HEA BDRAs achieved shear 130 kPa, tensile 153 kPa, wound closure 131 kPa, and interfacial toughness 183 J/m2, vs CA at 56, 17, 27 kPa and 20 J/m2, respectively. On wet bovine bone, optimized MDO-HEMA BDRAs showed flexural 16.97 MPa, tensile 6.46 MPa, and shear 3.05 MPa vs Vetbond 1.56, 0.93, and 1.68 MPa.
• Adjustable setting time: In situ rROP completed in seconds to minutes depending on comonomer: 5 s (HEA), 9 s (AA), 12 s (HPA), 32 s (MA), 45 s (EA), 55 s (PEGMA), 60 s (BA), 2 min (2-EHA), 7 min (IEM), 12 min (BzMA), 13 min (MPTMS), and longer; times were further tunable by MDO:acrylate feed ratios.
• Biomedical applications: BDRA enabled fast, tight skin wound closure versus sutures/staples; effective hemostasis in liver, carotid artery, and caudal vein models with lower blood loss (liver <52 mg vs CA ~90 mg and Surgicel ~112 mg; caudal artery ~4× lower than fibrin). For bone, BDRA fixed tibial fractures and skull fragments in vivo within minutes; micro-CT showed superior bone regeneration (BV/BT 31.4%, 50.6%, 59.6% at 2, 4, 8 weeks) with BDRA degradation concurrent with tissue ingrowth, whereas CA persisted and impeded healing (CA BV/BT 33.1% at 8 weeks, lower than blank ~39.7%). BDRA also facilitated integration of meshes, sensors, stents, and bone nails to tissues.

The study demonstrates that combining hydrophobic CKA (MDO) and hydrophilic acrylate comonomers via redox-initiated in situ rROP yields amphiphilic adhesives that effectively wet and penetrate wet tissues and low-surface-energy substrates, forming deep covalent interpenetrating networks with topological entanglement. This mechanism overcomes the rapid, brittle curing and poor wet bonding of cyanoacrylates and the swelling, mechanical mismatch, and low permeability of hydrogels, thereby achieving MPa-level adhesion on wet bone and high-kPa adhesion on soft tissues. The rROP intermittently introduces cleavable ester linkages into the polymer backbone, enabling tunable degradability that aligns with tissue healing timelines. Incorporation of NHS esters provides additional covalent bonding with tissue amines, enhancing interfacial stability. Mechanical compliance is tuned via comonomer selection and composition to match soft or hard tissues, reducing stress concentrations and inflammation at the interface. Setting times spanning seconds to hours allow adaptation from rapid hemostasis to fracture fixation. The adhesives exhibit favorable cytocompatibility and in vivo biocompatibility with resolving inflammation and no major organ toxicity. Collectively, the findings address the central challenge of achieving robust yet degradable wet adhesion and indicate broad applicability in wound closure, hemostasis, bone repair, and device/tissue integration.

This work introduces a versatile strategy for backbone-degradable robust tissue adhesives (BDRAs) based on in situ radical ring-opening copolymerization of hydrophobic CKA and hydrophilic acrylate monomers. The adhesives combine excellent wettability and penetration with covalent interpenetrating network formation to deliver high-strength wet adhesion to diverse tissues and materials, tunable degradation profiles through backbone ester incorporation, wide ranges of mechanical moduli for tissue compliance, and adjustable setting times. BDRAs outperform multiple commercial adhesives (including cyanoacrylates, PEG-based, and fibrin sealants) across adhesion strength, stability, and biocompatibility metrics and promote bone regeneration while degrading in vivo. The authors highlight broad potential for biomedical engineering and medical applications; explicit future research directions are not detailed.

• The highest tested concentrations of residual HEA monomer exhibited cytotoxicity in vitro, indicating precursor composition and residuals require control and evaluation.
• Thermal rise during curing of some formulations (e.g., MDO-HEA up to ~59 °C) warrants consideration for sensitive tissues despite being lower than acrylate homopolymer controls.
• In vivo evaluations were conducted in rodent models; long-term performance and clinical translation in larger animals/humans were not assessed within this study.