Rational engineering and applications of functional bioadhesives in biomedical engineering

Background

Sutures, staples and clips must be placed and removed manually, require trained personnel and can damage adjacent tissue. Bioadhesives are easier to apply and reduce tissue damage, but most are designed only to provide adhesion and mechanical support. The review argues that this monofunctionality is a practical limitation: a bioadhesive can lose its function in harsh tissue environments, become colonized by microbes, act as a barrier to tissue integration and delay healing.

How the review is organized

The review first covers adhesion mechanisms (van der Waals interaction, mechanical interlocking, covalent bonding through amine-reactive isocyanate, aldehyde and N-hydroxysuccinimide (NHS) ester groups, diffusion and electrostatic bonding) and the design requirements of cohesion, biocompatibility and biodegradability. It then compares natural polymer, synthetic polymer and nature-inspired (gecko, mussel, insect and octopus) bioadhesives, organizes functional bioadhesives into five classes summarized in Table 1, and discusses their applications in tissue regeneration and biosignal sensing.

Scope of the review

The review compiles representative studies for each adhesion mechanism, material class and function, describing their design and the reported performance, from in vitro tests to mouse, rat, rabbit and pig models and human skin recordings. Table 1 lists functional bioadhesives by functionality, mechanism and materials. The final section discusses mechanical strength, biocompatibility, healing monitoring and clinical collaboration as barriers to commercialization.

Main points of the review

Among base materials, natural polymers are biocompatible and biodegradable but generally weak, whereas synthetic polymers provide higher adhesive and cohesive strength but can cause acute inflammation and tissue necrosis. Gelatin-based adhesives tolerate more than 600% tensile strain, a sclerotization-inspired phenol-amine superglue reached about 6 MPa, and an octopus-inspired patch kept stable adhesion over 10,000 attachment cycles under dry, moist, underwater and oil conditions. Gecko-type adhesion is impaired by a thin water layer, and mussel-type adhesives are irreversible, so detachment may damage tissue.

For antimicrobial function, the review separates killing strategies (antibiotics, silver nanoparticles, cationic groups and organic acids) from adhesion prevention with Janus designs; it notes that antibiotic loading is limited and can promote resistance, and that silver raises toxicity and allergy concerns. A multilayer patch with an NHS ester adhesive layer, a blood-repellent silicone oil layer and a zwitterionic antifouling layer inhibited bacterial infection in vivo. For cell infiltration, synthetic adhesives typically have pores smaller than mammalian cells (approximately 10 μm), and reversible host–guest crosslinks, pores of around 15 μm made with silica particles, or gelatin microgels of about 50 μm promoted cell entry in vivo.

For electrical conductivity, ionic hydrogels release ions over time and conduct less well than metals, while carbon nanomaterials can be distributed inhomogeneously and some, such as carbon nanotubes, are cytotoxic. A PEDOT:PSS hydrogel with ionic additives showed no cracks up to about 150% strain and kept its conductivity above 500% strain. For self-healing, capsule-based systems can release precursors into tissue, whereas reversible bonds avoid this; electrostatic polyamine–phosphate adhesives recovered within 10 min after breaking at 200% strain, a Zn2+–catechol hydrogel restored its crosslinking density in 200 s, and a catechol-chitosan/cellulose nanocrystal adhesive reached 20–40 kPa on pig skin. Stimuli-responsive adhesives switched adhesion between 20 and 40 °C or decreased adhesion about 18- and 7-fold on a shift from neutral to basic pH, and a glucose-responsive insulin-releasing adhesive kept blood glucose in the normal range in diabetic mice.

In tissue regeneration, a catechol-modified hyaluronic acid patch adhered about three times more strongly than conventional bioadhesives on mouse skin, an extracellular-matrix-mimicking hydrogel stopped high-pressure bleeding from pig arteries and heart within 20 s, and a catechol–thiourea adhesive crosslinked within 5 s and improved ulcer healing in pig stomach. In biosignal sensing, a PEDOT:PSS/polyurethane/sorbitol adhesive recorded human ECG for over 30 days without significant loss, a PEDOT-modified carbon fabric adhesive reached a contact area of almost 100% on brain tissue, and a strain-absorbing gel maintained contact with a rat heart for 3 h with an improved ECG signal-to-noise ratio.

Open questions

The authors list several barriers to commercialization: most functional bioadhesives reach approximately 0.1 MPa compared with 1 GPa for a surgical suture; DOPA generates hydrogen peroxide during crosslinking; biocompatibility is usually assessed in normal rather than injured tissue, which differs in pH and inflammatory cytokines; current bioadhesives cannot monitor the healing process; and closer collaboration between researchers and clinicians is needed.

How it connects to other research

Yuk and colleagues' dry double-sided tape bonds wet tissues within five seconds by removing interfacial water and forming covalent bonds through NHS ester groups. This review discusses adhesives built on the same poly(acrylic acid)-NHS ester chemistry, a multilayer antifouling patch and a conductive PVA/PAA-NHS/reduced graphene oxide adhesive, as platforms to which antimicrobial and electrical functions are added.