Usage of Nanotechnology in Tissue Adhesives

With millions of people enduring traumatic or surgical wounds each year, establishing innovative approaches for proper wound closure has long been considered imperative research and clinical objective. The massive demand for improving wound-closing procedures and the disadvantages of conventional closure techniques foreshadow the robust investigation in the field and inspire researchers to combine more advanced technologies to develop clinically feasible approaches. Tissue adhesives, liquid monomers that can transform into a polymer to form tissue bonds when exposed to the skin, have long been considered prominent candidates as sealants and non-invasive wound-closure devices [1]. Despite being promising therapeutics, tissue adhesives have potential disadvantages, including cell toxicity, weak tissue-adhesive strength, and the possibility of inflammation [2]. In response to these deficiencies, considerable efforts have been made to explore the usage of nanotechnology in promoting tissue adhesives’ properties. 

Nanostructured biomaterials, such as nanoparticles (NPs), nanofibers, and nanocomposites, possess unique properties mainly endowed by their specific surface area and sizes [3,4]. With the ability to penetrate biological membranes and barriers, they can promote wound healing by mimicking the extracellular matrix’s characteristics at the nanoscale [5], enabling interactions between material and biological surfaces [6], and functioning as a delivery system combined with regenerative medicine [7,8]. Current studies demonstrate nanotechnology applications in wound healing through two strategies: nanomaterials as drugs with intrinsic therapeutic abilities to assist wound healing and nanomaterial-based delivery systems for therapeutic agents [3]. 

Recently, researchers have investigated the potential of NPs as promising candidates for addressing wound treatment and have managed to discover enhanced nanotechnology-based adhesive hydrogels. In a recent review, we explored the literature concerning the progress in using nanotechnology in tissue adhesives [9]. The article focused on two fields in which nanotechnology is employed: the possibility of NPs to enhance tissue adhesives’ mechanical and biochemical properties and the new functions applied to tissue adhesives. 

Several models have been proposed to improve tissue adhesives’ properties, including but not limited to mechanical strength (elasticity, adhesive strength, and durability) and biocompatibility. While the mechanical strength of a hydrogel can be simply improved by controlling the crosslinking density and polymer chemistry, incorporating nanostructures gives rise to more pronouncedly enhanced products [2]. The NPs can either crosslink the polymer network, be attached to polymer chains, or add new properties to the gel by physical entrapment [10]. For example, Chitin Nanocrystals (ChNCs) have been explored to reinforce polymer gels even at low loadings [11]. Xu et al., [12] incorporated ChNCs into a citrate-based tissue adhesive, improving tensile strength and bulk cohesion by extra crosslinks. Pang et al. formulated a novel tissue adhesive by incorporating Chitin Nano-Whiskers (CtNWs) into a Schiff base crosslinking hydrogel, maintaining the rapid formation of the Schiff base reaction but overcoming its poor structural integrity [13]. Although not ideal for cell attachment, ChNCs can also provide bioactivity to the scaffolds through their chemical characteristics, promoting attachment and spreading of cells (human fibroblast, mesenchymal stem, keratinocyte cells, etc.) to facilitate tissue engineering [14]. Other types of NPs that have attracted attention in recent years include carbon?based nanomaterials (carbon nanotubes, graphene, etc.), inorganic nanoparticles (hydroxyapatite, silica, etc.), and metal/metal?oxide nanoparticles [10]. 

NPs are also employed in tissue adhesives to increase durability and stability and to provide reliable adhesion until wounds are completely healed. For example, they contribute to producing long-lasting adhesive hydrogels containing catechol moieties, which under normal conditions would be oxidized to quinone groups and hence lose adhesion [15,16]. Xiao et al., first described a durable adhesive hydrogel based on quercetin-assisted photo-radical chemistry [16]. With similar ideas, Gan et al. developed an Ag-Lignin NP to construct a dynamic redox system to maintain the quantity of catechol groups, thus ensuring long-lasting adhesiveness [15]. The Cui group also used functionalized lignin NP fillers to fabricate reinforced hydrogels with stable adhesiveness, toughness, and antibacterial properties [17]. More recently, Zhao et al. developed a highly elastic conductive hydrogel exploiting the synergistic effect of sulfonated lignin-coated silica NPs (LSNs), polyacrylamide chains, and ferric ions (Fe³⁺), with the dynamic redox reaction constructed between LSNs’ catechol groups and Fe³⁺ [18]. The product has been demonstrated with exceptional mechanical robustness, self-adhesiveness, UV-blocking capability, and stable electrical performance. 

Biocompatibility and potential toxicity have long been the focus of research regarding the safety of tissue adhesives. While the toxicity of NP-based adhesives is primarily determined by the NPs’ physical and chemical characteristics, its control is mainly achieved by reducing required doses to limit NPs’ dissolution or by developing new NP structures. Several NPs, including gold, silver, and silica NPs, possess relatively low toxicity while maintaining the desired properties. For example, gold NPs are highly biocompatible and not immunogenic owing to their inherent antioxidant properties [3,19]. Therefore, they have long been used in various biomedical applications [19]. Nanocrystalline silver/silver NPs are effective at lower concentrations, thus resulting in lower toxicity [3]. Silver NP-embedded dressings can achieve controllable release of silver ions that help overcome potential toxicity without causing cell cytotoxicity [3]. Last but not least, Silica-coated/silica-NPs also demonstrate good biocompatibility, being capable of entering the cell without affecting cell functions [20]. Researchers can draw support from this system to improve imageable tissue adhesive for clinical use, minimizing the cellular toxicity and inflammation caused by the mixture of cyanoacrylate and Lipiodol (CA-Lp), the widely used imageable tissue adhesive [21]. 

Nanostructured biomaterials help enhance conventional tissue adhesives’ characteristics and make new functions feasible to enhance the wound healing process. In particular, mesoporous silica nanoparticles (MSNs) attract researchers’ attention to improve tissue adhesives’ regenerative properties with excellent biocompatibility, tunable physicochemical properties, and site-specific functionalization. These can be achieved by exploiting MSNs’ intrinsic properties or combing them with other components. First, the porous structure and active surface enable MSNs to achieve fast degradation and strong adhesion to tissues [22]. Pan et al., demonstrated an MSN-incorporated tissue adhesive that can recruit acute inflammation and degrade after tissue reformation, reducing the delayed healing process caused by the slow elimination of exogenous adhesives [22]. Taking a step further, Ren et al. in 2018 generated the aligned porous poly (L-lactic acid) (PLLA) electrospun fibrous membranes containing dimethyloxalylglycine (DMOG)-loaded MSNs (D-MSN) to promote chronic diabetic wound healing [23]. The derived membrane can simultaneously release DMOG and Si ions in a controlled manner to synergistically promote adhesion, proliferation, and angiogenetic differentiation at the wound site [23]. Many efforts have also been made to promote regenerative wound healing through ROS-modulating agents, which can alleviate the elevated oxidative stress at injured sites [24]. For example, a study by Wu et al. demonstrates a ROS-scavenging tissue adhesive nanocomposite based on ceria nanocrystals decorated with MSNs (MSNs-Ceria) [24]. Combining MSN’s adhesion property and ceria nanocrystals’ ROS-reducing capacity, the derived product allows a reduced inflammatory response, creating a friendly microenvironment that enables the restoration of tissue integrity and function while maintaining strong adhesiveness. 

Tissue adhesives provide a promising alternative to traditional wound closure methods and have attracted extensive interest in recent years. At the same time, with increasing findings demonstrating their potential, nanotechnology-based tissue adhesives became a promising approach to facilitate the process. For now, studies have provided insights into the molecular mechanisms of wound healing, and more studies are still needed to translate nano-based therapies to the clinic. It is expected that new nanotechnology platforms for introducing extra features, such as antibacterial and hemostatic properties, into tissue adhesives will arise soon, as well as novel designs for next-generation wound-healing methods.

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