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Smeets, R.;  Henningsen, A.;  Burg, S.;  Vollkommer, T.;  Rutkowski, R.;  Grust, A.L.C.;  Fuest, S.;  Gosau, M.;  Aavani, F. Tissue Adhesives in Reconstructive and Esthetic Surgery. Encyclopedia. Available online: https://encyclopedia.pub/entry/25698 (accessed on 08 July 2024).
Smeets R,  Henningsen A,  Burg S,  Vollkommer T,  Rutkowski R,  Grust ALC, et al. Tissue Adhesives in Reconstructive and Esthetic Surgery. Encyclopedia. Available at: https://encyclopedia.pub/entry/25698. Accessed July 08, 2024.
Smeets, Ralf, Anders Henningsen, Simon Burg, Tobias Vollkommer, Rico Rutkowski, Audrey Laure Céline Grust, Sandra Fuest, Martin Gosau, Farzaneh Aavani. "Tissue Adhesives in Reconstructive and Esthetic Surgery" Encyclopedia, https://encyclopedia.pub/entry/25698 (accessed July 08, 2024).
Smeets, R.,  Henningsen, A.,  Burg, S.,  Vollkommer, T.,  Rutkowski, R.,  Grust, A.L.C.,  Fuest, S.,  Gosau, M., & Aavani, F. (2022, July 30). Tissue Adhesives in Reconstructive and Esthetic Surgery. In Encyclopedia. https://encyclopedia.pub/entry/25698
Smeets, Ralf, et al. "Tissue Adhesives in Reconstructive and Esthetic Surgery." Encyclopedia. Web. 30 July, 2022.
Tissue Adhesives in Reconstructive and Esthetic Surgery
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23147687

Tissue adhesives have been successfully used in various kinds in the surgical field and especially in oral and maxillofacial surgery for some time. They serve as a substitute for suturing of tissues and shorten treatment time. Besides synthetic-based adhesives, a number of biological-based formulations are finding their way into research and clinical application. In natural adhesives, proteins play a crucial role, mediating adhesion and cohesion at the same time. Silk fibroin, as a natural biomaterial, represents an interesting alternative to conventional medical adhesives.

wound healing tissue adhesives silk fibroin silk-based adhesives

1. Introduction

The earliest records of surgical wound care date back to 1100 BC. At that time, ligatures made of leather were used to close abdominal wounds [1]. Over the years, suture materials have evolved, but the basic principle of wound closure remains unchanged: adaptation of wound edges with minimal tissue tension. Ideally, the method should be simple, safe to use, quick, inexpensive, as painless and bactericidal as possible, and should produce an optimal esthetic result [2]. However, a material or procedure that meets all of these requirements optimally does not yet exist.
Currently, there are various methods of wound care that are used in everyday clinical practice. These include sutures, staplers or wound closure tapes, which have a wide variety of advantages and disadvantages. Alternatively, tissue adhesives could be used to attach skin, mucosa, or muscle, allowing the natural healing process to take place [3].
Currently, suturing is considered the most basic and common method of tissue union in all surgical disciplines. Synthetic and biological sutures as well as absorbable and non-absorbable sutures are used in this process. Appropriate tensile strength and low dehiscence are important [2][4]. Additionally, the penetration of healthy tissues creates a possible entry portal for pathogens, thus increasing the risk of infection [5]. Non-absorbable material may be removed in future because they may require other uncomfortable and costly interventions. Recently used methods may be associated with further complications, such as nerve lesion, postoperative adhesions, and necrosis due to injury to blood vessels [2].
So-called stackers represent an alternative. The application is fast and simple. However, healthy tissue has always to be injured and inflammation and significant scarring are more likely. Additionally, the failure rate of the procedure is relatively high. For complex, uneven lesions, stackers are also rather unsuitable. Closure strips or tapes are another option since their quick and easy application and the lack of risk of needlestick injuries leads to their common use in clinical settings. The material is inexpensive, has a low risk of infection, and does not require professional removal. The esthetic results are promising. However, tapes have the lowest tensile strength and have the greatest risk of dehiscence. This also limits their use to linear, tension-free, dry wounds without body hair [2][5].
Another problem that may occur is the formation of a seroma. This is an accumulation of lymphatic fluid in the dead space below the wound edges, which is regularly treated with the aid of drains and / or aspiration [6]. This may mean increased risk of foreign body infection, prolonged healing time, and prolonged hospitalization for the patients. The development of a tissue adhesive that specifically adheres to moist surfaces, minimizing the free space within the tissue could reduce seroma formation, and thus, revolutionize the surgical standard of care [6].
Numerous chemical and mechanical wound closure materials have been developed over the past decades [5]. The most common methods of wound care in reconstructive and aesthetic surgery and the current state of the art of tissue adhesives are presented as follows.

2. Principals of Tissue Adhesives

According to their function, tissue glues can be categorized into hemostats, sealants and adhesives. Correspondingly, a hemostat is a substance that provokes blood clots and ceases to function without blood. A sealant also establishes a barrier layer to prevent fluid or gas escape, and an adhesive bond keeps the two surfaces together effectively through different mechanisms [7][8].
Generally, tissue adhesives are being placed between tissues to hold the edges of the wound together [9]. The function of adhesives, for the purpose of providing adhesion between two surfaces, relies on a combination of adhesive and cohesive strength. Accordingly, for adhesive strength, there must be strong intermolecular forces maintaining the bond between the adhesives and the adherent tissue surface, and for cohesive strength, there must be tight internal forces of the adhesive for holding the network together [10].
Therefore, it is essential to find the right balance between these two parameters for owing a satisfactory adhesiveness [11]. Mechanical interlocking, intermolecular bonding, electrostatic bonding, chain entanglement, and cross-link creation are examples of adhesive and cohesive interactions.
An applicable tissue adhesive should be safe to use for both patient and practitioner. Thus, the agent must have neither toxic nor hemolytic properties and elicit only a minimal immune response (biocompatibility). Additionally, any carcinogenic effect must be prevented [12].
Natural wound healing should be promoted but in no case disturbed and could even be accelerated by integrated drugs or growth factors [5]. The aforementioned requirements can be tested both in vitro using cell cultures and in animal experiments related to postoperative infection rates [2]. In addition, the tissue adhesive must be safe and effective in its action and for the surgical indication in question [5]. Both experimentally and clinically based studies are suitable for this purpose, with the majority choosing to compare new materials to commercially available wound closure methods in terms of wound dehiscence and time to closure for incisions of variable length and complexity [2]. Deformation behavior, tensile strength, and adhesiveness can be studied using physical testing methods [13][14]. In addition, the curing, bonding, and degradation time of the adhesive must be modifiable for different applications. Biodegradation can only take place once the wound has healed sufficiently (ideally starting after about three weeks, with complete degradation after three months [5]). In conclusion, the swelling index (swelling value), i.e., the retention capacity for water, must be minimal to prevent compression of surrounding structures [15]. The compound should also adhere securely to moist surfaces [12], which would enable internal application and avoid the development of a postoperative seroma. Effectiveness in this regard can be determined sonographically [6].
There are also some tissue considerations regarding developing an ideal tissue adhesive. The tissue characteristics can be classified as mechanical properties, surface characteristics, and local environment. Every tissue exhibits specific mechanical properties, such as elasticity, stiffness, and rigidity. The satisfactory performance of tissue adhesives depends intensely on their ability to match the chemical and physical properties of the underlying tissue for the required period of time [16][17]. Tissue microarchitecture, regardless of the type of the adhesive interactions, is a significant factor determining the potential of polymers to penetrate and interlock within the tissue [18][19]. The tissue macro and microenvironment will also adjust the material performance over time. For example, pH variations, oxidative species, or endogenous enzymes can directly affect the material characteristics by reducing both the adhesive and cohesive strengths. One of the more important factors to develop an ideal tissue adhesive is tissue regeneration time. This factor alters the stability of the material while ensuring the maintenance of material adhesive properties. In addition, the dynamic behavior of the fabric emphasizes the need for fatigue resistance of the material. Flexibility of tissue adhesives is another critical requirement for applications where the adhesive material must be bent or twisted (e.g., topical sealants in the neck or knee). Elasticity is also critical for applications such as lung sealants, where the size of the underlying tissue changes significantly over time [20]. Table 1 displays some specific characteristics of adhesives regarding tissue types.
Table 1. Some specific characteristics of adhesives regarding tissue types.
Tissue Types Adhesive Characteristic
Dura
  • Must maintain stability during regeneration
  • Regeneration time is up to 1 month
Eye
  • Must be flexible
  • Elastic modulus ~120 kPa
Lung
  • Must maintain adhesion in a dynamic environment (lung expansion)
  • Must be elastic (elastic modulus ~5–30 kPa)
Vasculature
  • Must maintain its properties in wet as well as the dynamic environment (pulsatile)
  • Elastic modulus ~0.1–1 GPa
Skin
  • Must be flexible
  • Should maintain adhesion in a dynamic environment (tension)
  • Elastic modulus ~300 kPa (epidermis)
Gastrointestinal tract
  • Must be elastic
  • Material stability should be maintained during regeneration time (up to 1 month)
  • Elastic modulus ~60 kPa
The first adhesive substances were synthesized in the form of cyanoacrylates (CA) by a German chemist named Ardis, as early as 1949, and are currently attracting increasing attention [21]. However, these substances are not free of undesirable side effects, such as minor skin irritation or allergic reactions [22]. A relatively new approach is the development of biomimetic adhesives. The focus is here on the transfer of phenomena from nature to technology. The best-known representatives of bioadhesion are tissue adhesives based on mussel proteins. In addition, adhesives based on gecko proteins, indoparasites, and worms have already been investigated [5][12].
Silk proteins show promising possibilities to modify chemical and mechanical properties of biomedical products [23].
Silk can be processed into a wide variety of forms, such as gels, coatings, nanofibers, membranes, or scaffolds, or combined with other substances and drugs, making it an attractive option for numerous application areas [23]. With the help of improved understanding of the interaction between silk and living cells, adhesives with extremely high strength could be produced through structural modifications. In addition, caterpillar silk could be an ideal basis for a tissue adhesive through customization of its absorbability, antibacterial properties, and potentially self-healing properties [6][23].

3. Categories of Tissue Adhesives

3.1. Synthetic Polymers

Polycyanoacrylates have been developed since 1949 and first found their medical application as tissue adhesives ten years later by Cooler et al. [5]. Polycyanoacrylate tissue adhesives demonstrate antimicrobial properties [24], showing an activity against gram-positive microorganisms such as S. aureus and S. pneumoniae, thus destroying their cell walls during polymerization [25][26].
The liquid monomer polymerizes within seconds at room temperature without the addition of a catalyst [5]. Adhesion occurs via covalent bonds between the cyanoacrylates and the functional groups of the tissue proteins. Due to its electron-repelling nitrile group, the acrylic compound is susceptible to nucleophilic attack by weak bases such as water or amines [5]. In an exothermic reaction, this creates a stable cross-link with the skin [4].
Some characteristics of the Polycyanoacrylates compounds can be directly affected by their carbon side chains. For instance, the longer carbon side chains provide more flexibility and stability for these compounds [2][4].
Initially, short-chain derivatives (methyl and ethyl 2-cyanoacrylates) were developed. However, the rapid degradation and accumulation led to inflammatory reactions through the release of histotoxic formaldehyde and cyanoacetate [5].
In Europe and Canada, n-butyl 2-cyanoacrylates in particular found their use [5] (However, this material has an extremely low fracture strength and is particularly brittle [2][5]. In contrast, the development of long-chain CAs (octyl-2 cyanoacrylate, Dermabond®, Ethicon Inc., Somerville, New Jersey) proved far more successful [27]. The substance is degraded after approximately 7–10 days before histotoxic degradation can even occur. Thus, the release of formaldehyde and cyanoacetate no longer plays a role, so that the product was also approved in the USA by the FDA (Food and Drug Administration) in 1998 [5]. In addition, improved flexibility and tensile strength of the material could be achieved [2].
Tissue adhesives made from cyanoacrylates are currently the most widely used. Due to initial concerns caused by the toxicity of short-chain CAs, acceptance has only been steadily increasing in recent years in many surgical disciplines [5].
Another approach considers at synthetic sealants made from polyethylene glycol (PEG). These PEG sealants form hydrogels designed to seal tissues from fluid leakage. Substances already in use show acceptable biocompatibility and are hardly recognized by the immune system due to a kind of stealth effect. The material is water-soluble and binds even to moist surfaces [28]. Sufficient elasticity and ductility are also among their advantages [4]. However, a major safety risk is the particularly high swelling index, whereby PEG-based materials can swell up to 400% of their original size, compressing nerves and vessels in the immediate vicinity and clogging application materials [5]. Furthermore, the application is extremely complicated. The product consists of two components, which must be stored differently and applied very quickly by the practitioner via a syringe due to the short drying time. Cohesion is rather poor and the substance quickly becomes brittle. In addition, these products are very expensive. Due to their numerous undesirable side effects, these adhesives are not yet suitable to replace sutures entirely [5].
Polyurethane (PU) can be employed for different tissue adhesive or sealant purposes. This synthetic polymer represents excellent thermal stability at physiological temperature and is also being applied for bone fixation, hemostasis, and sealing of vascular grafts in several surgery procedures [29][30]. The most recognized commercial polyurethane-based adhesive is TissuGlu® Surgical Adhesive, which is biodegradable and used for abdominal tissue bonding. This adhesive consists of a hyperbranched polymer with isocyanate end groups containing about 50 wt.% of lysine. A frequently experienced side effect after using this adhesive for abdominal or breast surgery is fluid accumulation under the skin, resulting in a so-called seroma [31].
Aliphatic polyesters, such as poly(Ɛ-caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA), have also been applied as tissue adhesives. A recently commercialized example of a tissue adhesive based on PLGA is TissuePatchTM. This tissue adhesive and sealant is applied in the prevention of air leakage after lung surgery or avoiding fluid leakage after surgery on soft tissue [32].
Dendrimers are a type of synthetic, fully branched polymers with a central core. The addition of a branching layer develops different types containing large number of functional groups around their perimeter. Because of this unique structure, dendrimers are appropriate cross-linkable building blocks for tissue adhesives [33]. The first dendritic tissue adhesive was reported for ophthalmology in 2002 [34]. These dendritic structures were fabricated by a poly(glycerol succinic acid) dendrimer (PGLSA) and a PEG linear polymer. It was suggested that the developed adhesives are as effective as traditional sutures in closing a corneal incision in in vitro studies.
Other synthetic tissue adhesives are mainly considered in a scientific context and have not yet been able to establish themselves in clinical settings. However, several synthetic tissue adhesives are commercially available by now.

3.2. Polysaccharide-Based Adhesives

Polysaccharide-based tissue adhesives have the advantage that their natural occurrence makes it easier to develop materials that are biodegradable, biocompatible, and less immunogenic. Chitin and chitosan are present in the exoskeleton of invertebrates and in the cell wall of fungi and exhibit the above-mentioned properties. It has been reported that chitin and chitosan gel-based substances have inhibitory effects on tumor angiogenesis and metastasis [35][36], and by inducing apoptosis, can prevent tumor cell proliferation [36]. In addition, they potentially have antimicrobial activity and attract red blood cells due to their positive charge, thus accelerating local coagulation [37]. Research to date has focused particularly on the development of wound dressings, tissue engineering, and drug delivery systems [38]. Commercially, biopolymers are produced from shrimp shell residues. The process is particularly complex and the extraction is costly [39]. Due to their dense crystal structure, previous products are extremely poorly soluble. Alternative wound adhesives based on polysaccharides, such as dextran, chondroitin sulfate, and hyaluronic acid, are also being investigated in studies. At the current time, no polysaccharide-based tissue adhesives are commercially available.

3.3. Protein-Based Adhesives

As the most common protein-based representatives, fibrin glues are biocompatible due to their natural ingredients, degrade within a few days to weeks depending on their composition, and can, therefore, be used both locally and internally. Since these products are considered to be relatively safe in terms of their biocompatibility, infectivity and natural degradation, they are used in numerous specialist disciplines. In vascular surgery, they are now regularly used to control unstoppable bleeding [5]. As a sealant, targeted air- and fluid-tight closure can be achieved in lung and neurosurgical procedures [40]. In plastic and aesthetic surgery, bleeding from burn wounds can be treated after debridement and flapoplasties can be adapted [41]. Furthermore, liver and spleen injuries have been successfully treated in visceral surgery with tissue adhesives [42]. Fibrin is a physiological component of human blood and an essential factor in secondary hemostasis [12]. Products have been commercially available in Europe since 1972 [43][44]. Adhesives consist of two separate components: Thrombin (Factor IIa) and Calcium (Factor IV) as well as Factor VIII and Fibrinogen [12].
First, cleavage of fibrinogen by factor IIa to fibrin monomers and subsequent cross-linking via covalent bonds of lysine and glutamine residues by factor VIIIa and calcium form an insoluble thrombus. This bond is further stabilized by natural fibrinolysis inhibitors (a2-P inhibitor, a2 macroglobulin, plasminogen activator inhibitor 2) [12]. However, the use of fibrin glues is relatively complicated because fibrinogen and thrombin must be kept separately and refrigerated. Prior to application, the components must then be warmed and dissolved before transferring them to a dual-chamber syringe. Consequently, the preparation time is relatively long [5]. Since human blood products are involved, contamination with infectious agents, such as HIV or hepatitis, cannot be completely excluded. Alternatively, material can be derived from porcine blood, but this may lead to allergic or autoimmune reactions. Compared to synthetic Polycyanoacrylates, the adhesion ability is significantly inferior, especially under humid conditions [5].
Gelatin and albumin are two naturally occurring proteins and can be used in combination with other components as tissue adhesives. The best-known product is gelatin-resorcinol-formaldehyde-glutaraldehyde, GRFG (BioGlue, CryoLife Inc., Kennesaw, GA, USA) [5]. Under dry conditions, adhesion strength is significantly superior to fibrin adhesives and comparable to cyanoacrylates, but decreases significantly in humid environments [12]. The cytotoxic properties of formaldehyde and glutaraldehyde can cause inflammation and increase scarring, which is why further research is needed to investigate alternative drug combinations.

3.4. Biomimetic Adhesives

Artificially produced adhesives have not yet come close to substances found in nature in terms of properties such as biocompatibility. The knowledge of natural adhesion systems is far from producing innovative tissue adhesives for commercial use [45]. Therefore, it is essential to explore the individual composition of these materials and understand their mode of action and function in order to transfer them to biomedical use [45][46]. From an evolutional perspective, animals have been able to develop multiple mechanisms to walk, climb, or adhere to different surfaces [45]. This phenomenon is being exploited in bioadhesive research. However, there are still difficulties in developing tissue adhesives that form sufficiently stable bonds even under humid conditions [47]. Therefore, great efforts have been made in the past two decades to explore synthetic adhesives based on mussel proteins [12][46].
Some mussel species are capable of adhering securely to a wide variety of surfaces under extreme conditions. By secreting so-called byssus, a protein-rich secretion produced in the animals’ foot glands, they can survive in waters with strong currents, salty environments, and pH and temperature fluctuations with ease. These mussel foot proteins (MFPs) are rich in catecholamines such as L-3,4-dihydroxyphenylalanine (DOPA), and form fibers that connect the mussel to a contact surface via electrostatic interactions, hydrogen bonds, and covalent cross-links [12][47]. Moreover, it is indicated that oxidation of DOPA by metal ions or enzymes is mandatory to adhere to surfaces or tissue [48].
Numerous attempts have been made to extract these mussel proteins. One challenge is that several thousand mussels are needed to extract just one gram of protein, which is why one has to rely on synthetic production [47]. The artificial mussel proteins show little antigenic activity and function well under dry conditions [12]. However, in humid environments or water, the binding strength strongly decreases. This is because catecholamine groups are particularly responsive to oxidation under neutral and alkaline conditions, which weakens the adhesion ability [46][47]. Furthermore, the long drying and degradation time of some adhesives is another drawback, which has limited clinical applications to date. Therefore, nowadays, biomaterial researchers have been trying to fabricate biomimetic synthetic polymers comprising DOPA moieties [49][50].
Yin et al. fabricated a DOPA-modified silk fibroin-based bioadhesive and chemically cross linked the structure using genipin [51]. Furthermore, metal ions have also been utilized to modify the adhesion properties of adhesive (dopamine modified). The results demonstrated that the DOPA-modified silk fibroin-based composite shows a greater stickiness except slow gelation speed. In addition, they proved the doping of cationic metal ions can hasten the gelation of the bioadhesive.
Other examples of biomimetics include adhesives based on gecko proteins, endoparasites, and worms. These also show good biocompatible properties, but again, the extraction of the substances is problematic and the adhesion strength in water is limited [45].
The primary concerns of applying mussel adhesive protein mimics are their long degradation times and the utilization of harmful oxidizing agents such as periodate and iron (III). Although DOPA-functionalized polymers show high potential as tissue adhesives, no clinical studies have been performed to date [34].

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Subjects: Medicine, Research & Experimental
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ralf Smeets
,
Anders Henningsen
,
Simon Burg
,
Tobias Vollkommer
,
Rico Rutkowski
,
Audrey Laure Céline Grust
,
Sandra Fuest
,
Martin Gosau
,
Farzaneh Aavani
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Revisions: 2 times (View History)
Update Date: 01 Aug 2022
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