Every year, there are approximately 114 million cases of tissue damage caused by surgeries around the world. Surgical patients inevitably suffer from pain during the stitches and wound healing process, and even infection and inflammation caused by improper wound treatment.

Every year, there are about 114 million cases of tissue damage caused by surgeries around the world. Surgery patients inevitably suffer from pain during the stitches and wound healing process, and even improper wound treatment can cause infection and inflammation. The advent and iteration of biomedical adhesives are expected to help surgical patients relieve postoperative pain. It can be likened to "human glue" - it can not only bond skin wounds conveniently and quickly, but also repair soft/hard tissue wounds such as internal organs, cardiovascular, bones and teeth, and promote regeneration. can predict that "human glue" biomedical adhesives will replace surgical sutures, rivets, and instruments used for wound closure, and the market prospects are quite broad. However, strong adhesion to biological tissue in a wet state has always been a problem faced by the scientific community. In order to solve this "stuck neck" problem, researchers followed nature and simulated the adhesion strategies of various animals and plants in nature, and developed a series of bionic medical adhesive . Below, we will introduce the sources of these bionic medical adhesives and their applications in the biomedical field, and look forward to the future development direction of medical adhesives.

Biomimetic medical adhesives and their applications

01 Fibrin glue

As a protein in human blood, fibrin plays an important role in the blood coagulation process, and its application in surgery can be traced back to 1909.

Due to its hemostatic function, fibrin glue is often used as a hemostatic agent and sealant. It is used in various surgical operations to locally stop bleeding, prevent penetration, prevent tissue adhesion and promote healing, and can be used in bone tissue. project, and as a drug carrier for local immunotherapy after tumor resection.

However, fibrin glue has low adhesion strength to biological tissues, and its use may also bring risks and safety threats. The bovine thrombin contained in it can cause allergic reactions in some patients, as well as the risk of infectious diseases. In addition, the low-temperature storage and cold chain transportation of proteins also make the use cost of fibrin glue higher.

(a) Mechanism of action of fibrin glue (b) Cross-linking mechanism of adhesive catalyzed by transglutaminase

02 Adhesive catalyzed by transglutaminase

In the human body, transglutaminase can catalyze inter-protein/intra-acyl transfer reactions, resulting in covalent cross-linking between proteins (or polypeptide ), and is generally used to form cross-linked proteins necessary to create biological barriers and stabilize structures.

The discovery of a calcium-independent microbial transglutaminase has stimulated research on various related applications, especially in the food industry where it is used to cross-link proteins and improve the texture of protein-rich foods, such as Surimi , ham, imitation crab meat and fish balls, etc. This food additive, known as "meat glue", was banned in the EU in 2010. But this does not affect its application in the field of adhesives. The gelation time of the adhesive catalyzed by

aminoamide transferase can be controlled within a few minutes, and the resulting adhesive has strong adhesion to biological tissues and good pH and thermal stability. However, the biological safety of microbial transglutaminase needs to be further verified.

03 Tissue adhesive based on giant salamander skin secretions

According to the "Compendium of Materia Medica" records, during the and Northern and Southern Dynasties period about 1,600 years ago, ancient Chinese used the skin secretions of giant salamanders to treat burns. The tissue adhesive obtained from giant salamander skin secretions after purification, freeze-drying and grinding, in addition to having stronger tissue adhesion ability than fibrin glue, can also promote the healing of skin wounds and completely degrade within three weeks.

In addition, 56 different types of antimicrobial peptides were detected in the skin mucus secreted by three amphibians such as giant salamander and toad, which can significantly inhibit the growth of bacteria. Therefore, the development of tissue adhesives from giant salamander skin secretions opens up a new research field for adhesive bionics.

04 Live bacterial adhesive

Bacteria can colonize in the underwater environment by relying on their adhesion to underwater surfaces under continuous water flow.The researchers got inspiration from underwater bacteria and combined genetic engineering and material science to integrate the underwater adhesion strategies adopted by three marine organisms: mussels, barnacles and sandcastle worms to obtain adhesion. Bacillus subtilis biofilm.

This is the first time that a multifunctional living glue with strong adhesion and biological activity has been developed. It shows the environmental response and self-regeneration capabilities that only living systems have. It can achieve mechanical or even autonomous repair on demand, including light control. Spatially targeted repair and blood-sensing autonomous repair.

Although living glue has not yet been used in the medical field, it is bound to become a research hotspot in the field of medical adhesives.

Environmental response and autonomous repair of engineered live bacterial biofilm adhesives

05 Polyphenol-type adhesives

In insect structural proteins such as dragonfly wing resin protein, silk protein, locustcuticle, tyrosine residues The groups can spontaneously cross-link through photooxidation reaction, giving the protein a certain structural stability and elasticity.

A tyrosine-rich adhesive extracted from insect structural proteins can completely gel within one minute, significantly improving the physical properties and adhesion properties of the adhesive hydrogel . The adhesive uses visible light to activate cross-linking to achieve controllable, safe and rapid wound closure and healing, and has strong application potential.

06 Mussel biomimetic adhesive

The byssus glands of mussels can secrete a large amount of byssal proteins rich in L-3,4-dihydroxyphenylalanine and lysine , allowing mussels to "adhere" The "disk" adheres firmly to various surfaces underwater and has strong tensile strength. This discovery is of great significance for the preparation of bioadhesives with high strength and high toughness.

Inspired by the adhesion mechanism of mussels, scientific researchers have developed a series of mussel-inspired biomimetic polymer adhesives containing dopa or its derivatives dopamine and so on.

(a) Macroscopic photo of mussel; (b) Schematic structural diagram of byssus adhesion disc

Development of citric acid-based adhesive inspired by mussels

07 Natural plant polyphenol adhesive

Natural plant polyphenols are a class of Polymers with polyphenol structures widely found in tea and fruits, most of which contain pyrogallol groups, have strong biological activity and have antioxidant, anti-tumor, antibacterial and hemostatic functions. Therefore, plant polyphenols are widely used in the fields of bionics , materials science and biomedicine, and are widely used in the production and research of adhesives, cosmetics, drugs and food.

Chemical structures of various polyphenols in natural plants and beverages

08 Sandcastle worm bionic adhesive

Each secretory cell of the secretory gland of sandcastle worms is equipped with hundreds or thousands of adhesive particles, which can produce "homogeneous" or “heterogeneous” secretory granules that can be delivered on demand. In addition to a moderate amount of DOPA, the bioadhesive glue secreted by sandcastle worms also contains six different types of adhesion proteins ( cationic and anionic proteins), sulfated polysaccharides and magnesium ions.

Secondary curing occurs a few hours after the initial curing, which enhances the cohesion of the glue. The color of the glue gradually changes from gray-white to brown. The adhesive finally solidifies to form a porous structure filled with interstitial fluid.

(a) Image of a sandcastle worm; (b) Protective shell built with glass beads; (c) Chemical composition of Pc2 and Pc3A

09 Gecko Biomimetic adhesive

Gecko can firmly adhere to various substrate surfaces and even Vertical wall, thanks mainly to the fine structure of its toes. Inspired by the adhesion mechanism of gecko toes, adhesion surfaces that simulate the surface topology of gecko setae have become one of the current research hotspots of bionic materials, and may be used to close wounds instead of surgical sutures or rivets.

The hierarchical structure of the gecko

10 Octopus, Sucker fish Biomimetic adhesive

The octopus's arms are covered with cone-shaped suction cups that serve as muscle hydraulic adjustments, allowing it to adhere to various surfaces that are smooth, rough or irregular. Inspired by the octopus sucker adhesion strategy, researchers have developed a variety of surface-patterned reversible tissue adhesive materials. Some materials show excellent adhesion capabilities on dry and wet surfaces and can be used for hemostasis, wound care, etc.

(a) Octopus sucker structure; (b) Acetabular structure; (c) Adhesion process

11 Ivy bionic adhesive

The reason why ivy can "grab" steep walls and exert strong adhesion force on them is that It can rip bricks from walls and damage building facades because it secretes globular glycoprotein nanoparticles.

The adhesion strategy adopted by Ivy inspires us to change the water dispersion state of the polymer to change its fluidity, which can make the adhesive better infiltrate and penetrate into the bonded surface, providing information for the development of medical adhesives. new ideas.

(a) Ivy branches attached to the wall; (b) AFM image of ivy nanoparticles; (c) Cross-linking and adhesion process of ivy nanoparticles

12 slug bionic and other bionic adhesives

slug can secrete A slime composed of a tough matrix of electrical charge interactions and cationic proteins running through it allows the slug to adhere strongly to the surface on which it crawls. Inspired by this,

developed a type of high-strength solid adhesive with high adhesion strength and good toughness to biological tissue. The wet adhesion energy to biological tissue is as high as 1000 J/m2. It is a fibrin glue (the most widely used medical adhesive) more than 100 times.

(a) Photo of a slug; (b) Mucus secreted by a velvet bug during defense; (c) Photo of a tree frog's foot pads and SEM image of the hexagonal structure on its foot pads

Polymer-based biomimetic medical adhesive as a "Taiwan Balm" products are widely used as adhesives, hemostatics or sealants in the field of tissue regeneration and repair such as soft tissue wound closure or hard tissue damage repair; or as drug carriers for local administration and post-tumor resection prevention. Recurrence and metastasis, etc.; or used to inhibit scar formation in the field of medical beauty .

Compared to the surgical wound adhesion and daily wound care markets, chronic wound regeneration and repair represented by diabetic foot as well as medical cosmetology and micro plastic surgery are larger potential markets for medical adhesives. These adhesives can provide functionalities such as anti-inflammatory, antibacterial, and anti-scarring properties.

In the future, multifunctional and universal medical adhesives or medical adhesives with specific functions will surely emerge in endlessly, and their application scenarios will become wider. Furthermore, as people's requirements for the quality of tissue wound repair further increase, functional adhesives that can prevent scar formation or remove scars (reduce existing scars) will also be a key direction in the development of medical adhesives, and their successful development will Greatly expand the application of medical adhesives in the field of medical beauty.

Original text: Wu Keke, Zhao Yitao, Wu Min, Li Yue, Hu Zhiqi, Lu Zhihui, Guo Jinshan. Development and application of polymer-based biomimetic medical adhesives. Journal of Functional Polymers 2021