There are a large number of substances that help the adherence of opposing surfaces of various types of materials. Adhesives or glues as they are called can be of several types -- epoxies, polyurethanes, polyamides, etc. The nature of adhesion the mussels, tubeworms, and barnacles form with non-self surfaces and how geckos hang from the ceiling always intrigued people. Molecular bondings, the hydrophobic nature of complex binding agents, and the electrostatic forces all play significant roles. A man could never produce such a bond underwater, and this remained the major difference from the natural animal also can Glues in medical practice be found in various forms -- paste, liquid, pellets, films, tapes, etc. Physically, structural adhesives or pressure-sensitive adhesives and small localized deformation may be necessary to bring about a join. Usually, an elastomeric material is needed which causes the adherence. Thermosetting adhesives are usually available in two parts and in addition to the heat, some time is necessary for the adhesion to occur. The basic principle of adhesion is the strength of the join, which should at least be equal to the least strong material to be joined.
Surgical glues have a different concept and these are mainly used for stopping troublesome bleeding and bridging regions not accessible to surgery. The concept of glues in surgery creeps into the mind of a practising surgeon in difficult hemostatic situations once in a while. Glues and adhesives were always explored in surgery as an alternative to sutures. Personally, I, believe that the correct placement of sutures is the best way of achieving hemostasis in anastomoses. However, once in a while, troublesome bleeding happens, and the source cannot be pinpointed. Also the budding surgeons, not sure about their handiwork, often will go for the available sealants as security. Sometimes they do not properly adhere to the proper directions of use.
Rapid hemostasis means clean and efficient surgery in a reasonably quick and acceptable time. Better visualization and an improvement in recovery also is a consideration. An honest effort is made to find out how such things evolved. Major vascular anastomoses in aortic aneurysms, arch and hemi-arch replacements, carotid endarterectomy, etc., require such agents for reducing bleeding from suture holes and also strengthening suture lines. The gelatin-resorcinol-formaldehyde glue has been in use from the earliest times in aortic surgery and there have been improvements in the understanding of such products. This writing tries to simplify the agents used as such agents in cardiothoracic surgery.
The mystery of barnacles sticking to various objects is complex and has not been solved yet. A substance is said to be ‘bio-adhesive’ when it comes to sticking to biological material. Bio-adhesion is the property of a compound that helps a substrate adhere to the biological tissue for a long time. When the biologic tissue is represented by a mucosa, the phenomenon is called ‘muco-adhesion’. The mucoadhesive materials interact with the glycoproteins in the mucus covering the epithelia of the mucosae. The generally accepted idea is that the mucoadhesion process involves several stages: wetting and swelling of the hydrophilic polymer which allows its contact with the biological tissue and the inter-penetration of the polymer chain with the molecules in the mucin, which leads to an adequate substrate and creates a semi-permanent adhesive bonding. Other theories explain the forces that underpin bio-adhesion: van der Waal's forces, hydrogen bondings, disulfide bridges, hydration forces, hydrophobic interactions, steric forces, covalent bonds, etc.
The agents used can be broadly subdivided into three types---hemostats, sealants, and adhesives. There is considerable overlap between the types and the norm is the usage of one that is effective and readily available.
The hemostats can again be subdivided into:
Gelatins - Porcine in origin and are partially hydrolyzed hydrocolloids that swell up by absorbing blood also can expand 200% of their volume and seal the pores of the capillaries and small vessels. It is affordable and can be stored at normal room temperatures and absorbed into the system. May be whipped into a foam or dried. One should remember that if the origin is considered, then gelatin is a hydrolyzed derivative of collagen.
Collagens - Derived from bovine skin and provides a matrix for clot formation. It also promotes platelet aggregation, degranulation, and release of clotting factors. The product is available as sheets or in powder form and is costly. Compared to gelatin, less time is taken for hemostasis (1 to 5 mins). Removal requires copious irrigation only and a lesser amount is needed for re-application. It takes about 8 to 10 weeks to get absorbed.
Oxidized Regenerated Cellulose (ORC) - As these are plant-based alpha celluloses, chances of immunogenicity allergic reactions are rare and the mechanism of action includes 7 to 10 times swelling by absorption of surrounding tissue fluids to seal the mouth of open capillaries and small vessels. They are available as high or low-density knitted fabrics and are commonly used as small square pieces with tail cotton to combat troubling intra-operative bleeding during neuro-surgery. These can be used immediately and the effects are obvious.
The main disadvantage of these products is that they can not be used in small confined spaces as chances of tamponade are there. In all these products, there is some degree of increase in volume (of the product used). Again these are passive agents of hemostasis. The fact that direct joining with glue made the issue more attractive, and led to the search and development of bio-acceptable adhesives.
The sealants lead to the effective obliteration of the suture holes and other minor bleeding points. This facilitates visualization of and completion of subsequent steps of surgery. The final goal is to create a strong and stable clot that fills up the spaces through which the flowing blood is seeping out. A sealant is a matrix really and are agent that, not only hastens the formation and stabilizes the clot, it also helps in strengthening a joint or anastomosis. The scaffolding is added to a combination to make it remain in place. The time spent in the process may be useful in the long run.
The active agents are usually thrombin in some form, pooled from the blood of a donor (Human, Bovine, or recombinant) and dried. It requires mixing with calcium chloride. Initially, bovine thrombin was used as the availability of human blood was limited. The use of recombinant thrombin has not only eliminated the possibility of immune-related reactions but also the probability of zoonotic diseases. To understand the role of thrombin one should realize that this agent only hastens the conversion of fibrin from fibrinogen in the last step of the coagulation cascade. So in fibrinogen-depleted situations, it is not going to work, and, keeping cost considerations in mind, these should be used in the right conditions. Evithom and Gelfoam Plus are human thrombin. The recent commonly used product is Recothrom which is recombinant thrombin.
Next comes the flowable categories where a combination of two different types of hemostats is done. The resultant efficacy is increased as there is more than one type of mechanism. Gelatin (Porcine) is mixed with thrombin (preferably recombinant) or collagen (bovine) is combined with pooled human plasma. The porcine gelatin products such as SurgiFlo or the Floseal have been marketed after trials and FDA approval. SurgiFlo is a sterile, absorbable porcine gelatine matrix combined with a thrombin calcium chloride complex. FloSeal on the other hand is comprised of a gelatine matrix, calcium chloride, and an amount of thrombin derived from human plasma. When applied to a superficial wound or surgical site, the gelatin granules absorb the blood and swell (20% within 10 min) to form a tamponade, which conforms well to the geometries of wounds. High concentrations of thrombin serve to rapidly react with the patient’s fibrinogen in the formation of a ‘mechanically stable clot,’ which is reabsorbed within 6 – 8 weeks. A unique characteristic of Floseal is its requirement for the presence of blood for activation. In addition, it may hypothetically initiate thromboembolic events if injected directly into medium to large vessels.
These are the other sealants used in aortic surgery trials and have yielded a statistically significant reduction in bleeding. These sealants are capable of blocking the needle holes with stable clots and the presence of flowing blood is helpful promotes the ongoing process. FloSeal was compared with a freshly concocted combination of Gelfoam and thrombin and the results favored FloSeal. The fibrin-containing sealants, also known as the fibrin glues contain fibrinogen or fibrin in some form. The on-table mix of a freeze-dried protein (fibrinogen) with thrombin from a separate vial is used. So some time is required for preparation. Fibrin sealants, though in use in Japan or Western Europe, received FDA clearance only in 1988. These were also tried mainly in aortic and other vascular procedures. The recommendations are the application of the glue before the release of vascular cross-clamps so that the build-up of pressures is gradual. The available one in the market was Evicel (fibrin extracted from pooled human plasma + thrombin, in separate vials) and Tisseel. Evicel was previously known as Crosseal and was extensively used in major vascular surgeries. Tiseel is now better known due to its aggressive marketing policies and contains fibrinogen, thrombin, aprotinin, and calcium chloride in separate vials. The preparation is elaborate involving the engagement of a person knowing the process and a specific temperature-warming device. The resultant fibrinogen and thrombin preparations in liquid form are filled are drawn in two syringes in a contraption that has a single driving plunger. The mix of the two happens at the region of the application when the plunger is pushed. A stable fibrin clot is formed and consolidated by aprotinin in the preparation.
Tiseel-like preparations have some disadvantages. First, they are costly. The various components are derived from pooled plasma of humans or other animals and hence the chances of transmission of zoonotic diseases are always a probability. Elaborate preparation requires prior planning and is hence used only in elective cases where major vascular anastomosis is required. They have no use in emergent situations and flowing blood washes away the sealant complex. A next-generation, freeze-dried, ready-to-use, virus-inactivated Tiseel VH/S(solvent)D(detergent) preparation is now available and is replacing the older preparation. The product is equally efficacious and the indications expanded to include congenital defects in children.
The other notable products in the market in various countries include Vitalgel, TachoSil, and Bolheal. Collagen in the microfibrillar form is used in Vitalgel. In TachoSil, a two-layer patch/sponge material with one side comprised of equine collagen and the other of human fibrinogen and thrombin is present. The collagen is seated on the wound, whereas the fibrinogen and thrombin serve to complete the normal coagulation cascade.TachoSil is a two-layer patch/sponge material with one side comprised of equine collagen and the other of human fibrinogen and thrombin. The collagen is seated on the wound, whereas the fibrinogen and thrombin serve to complete the normal coagulation cascade. Bolheal consists of freeze-dried liquids stored in two refrigerated vials and needs an application that requires a rub and spray technique. The agent is considered as effective as the other ones and is mostly used in aortic or hemi-arch replacement surgeries. The product, used only in European markets, is not FDA-approved and not for sale or use in America.
TachoSil has been approved for adult use only to date. The other product requiring a mention is Grifols with trial reports yet to come.
CryoSeal is the first sealant to be produced from single units of human plasma, thus eliminating the risks that are associated with pooled plasma products. CryoSeal components are 100% human (cryoprecipitate and thrombin) and contain no animal products or synthetics. It is produced from single-donor, fresh-frozen quarantine apheresis plasma units that are obtained from healthy, voluntary, nonremunerated donors. CryoSeal is a good alternative to multi-donor and autologous fibrin sealants and contains higher amounts of plasminogen than other products. Earlier clot degradation and absorption of materials occurred. We still are not sure whether this is an advantage as is claimed by product developers. CryoSeal is used in hepatectomy cases.
Now comes the story of the synthetic sealants. Almost all are based on poly-ethelyn-glycols. It is a ubiquitous plastic and the molecular size or the isomeric form determines the final appearance or shape of the desired product. Thus PEGs are found in paint bases, pharmaceutical products, glues, etc. A polymerized hydrogel is formed which seals the openings through which blood seeps out. This form cross-links with the surrounding tissue and a mechanical barrier to fluids is created. These are devoid of any animal or human tissue and thus the chances of immunogenicity and allergic reactions are not there. Complete breakdown and re-absorption occur within 30 days. In most cases, a mix of macro-and micro-molecules of PEG is used and the preparation is supplied as two components, a primer, and the active substance. Preparation is less cumbersome and the adhesive is produced at the region of application. Some use a two-syringe system driven by a plunger, while others prefer the spray application process where even distribution and accessing remote regions become easier. CoSeal, DuraSeal, and Progel are the brands worth mentioning. DuraSeal imparts a blue hue and the distribution of the adhesive is visible. As the name suggests the agent is preferred by neuro-surgeons and may even be used for the creation of an artificial dura. Progel is mainly used for combating intra-operative air leaks (IOAL) in lung surgery.
At present research is on the photoreactive aspects of these materials. However, wound closure ensures light rays can not enter and the currently usable ultraviolet waves have the power to penetrate 3 mm at the most. So the effect of photo-reactivity plays no role at all in emergencies and where the wound is covered. The minimum time taken to control bleeding is most cardiac surgeons' goal and is still considered the ideal property of glue.
Adhesives both seal and join by creating a cross-link with the surrounding tissue. Most are compound products with more than one action. Ideally, they are called adhesive hemostatics and are used as adjuncts in cardio-vascular practice. Sealants are more flexible and when compared, adhesives have a basic difference in the fact that these are stronger and at least will try joining two or more structures or surfaces. Sealants, on the other hand, fill up spaces left behind and speed up a natural ongoing process to complete a fluid seal. As satisfactory hemostasis has been the goal, sealants in most cases serve the surgeon's need, the rest is taken care of by natural processes. The role of adhesives as adjuncts comes to mind mainly in aortic and similar massive vascular procedures when, in addition to joining two surfaces and security of the suture anastomosis plays a part.
As stated earlier Gelatin-resorcinol-formaldehyde (GRF) glues have been used since time immemorial in aortic replacement surgeries, aortic dissections, and/or other major vascular surgeries al. Later, due to concerns about toxicity, glutaraldehyde replaced formaldehyde. However, these are moribund conditions and on-table mortality is very high. The survival, even if the surgery is successful, is questionable and long-standing involvement of other organs, the age of the patient, and the involvement of other unrecognized regions all play important roles. That Michael Debakey survived such a procedure, even after the time that was wasted due to their hesitancy in decision-making, should be considered an exception.
Recently Bioglue, containing purified bovine serum albumin and glutaraldehyde, has become popular. Marketed by CryoLife, it is claimed to be the strongest available bioadhesive material. The solutions, 5 and 10 ml in the syringe are dispensed with a controlled delivery system, composed of a reusable delivery device, applicator tips, and applicator tip extenders. Once dispensed, the adhesive solutions (in a pre-defined ratio) are mixed in the applicator tip where cross-linking begins. The glutaraldehyde molecules covalently bond (cross-link) the BSA molecules to each other and, upon application, to the tissue proteins at the repair site, creating a flexible mechanical seal independently of the body’s clotting mechanism. The delivery device-mediated application is designed to provide reproducible mixing of the components in vitro. BioGlue begins to polymerize within 20 to 30 seconds and reaches its bonding strength within 2 minutes. BioGlue also adheres to synthetic graft materials via mechanical interlocks within the interstices of the graft matrix. The BioGlue component has a shelf life of 3 years if stored at 25 °C. It has become a routine to spray Bioglue, wait for some time, and then release the cross-clamp in aortic surgery now.
Baxter has introduced PEG-based CoSeal in the market. CoSeal has been clinically proven to provide a rapid seal at vascular suture lines. It consists of two synthetic biocompatible polyethene glycol polymers that rapidly crosslink with proteins in tissue and mechanically adhere to the synthetic graft material. Compared to Bioglue, the parent company Baxter claims fewer adhesions and synechiae formation, and additionally, the chances of transmission of zoonotic diseases and immune reactions are minimized.
Cyano-acrylates have also been tried in the reinforcement of anastomotic lines. The apparent disadvantage was the exothermic nature of the reaction, lack of flexibility after application, and the inability to create joints in the presence of flowing blood.
There is ongoing research in the quest for an ideal glue and the recent interest may be silicone-based. The silicone- silicone links appear to be an alternative to similar carbon-carbon bonds and till now a pressure sensitivity adhesive skin apposition patch is on the market.
Adhesives are extensively used in dentistry and orthopaedics. In the latter case, methyl-methacrylate cement is used mainly for the restoration of shape, glueing together the lost bone grafts and/or prosthetic materials till they get integrated into the body. In dentistry, there is a system of adhesives and they play a big role principally in sealing carries cavities of reconstruction of dentine crowns, and otherwise. Since the introduction of the “Sevitron Cavity Seal” system in 1951, there has been a systematic search and no less than 4 generations of resin-based adhesives have been developed. These characteristically interact with hydrophilic and hydrophobic bonds to fill up the microtubules in the dentine material and fuse chemically with it.
To conclude, glue is a loose term that includes hemostats, sealants, and adhesives, either singly or in combination. These help in joining surfaces or structures and ensure hemostasis at the same time. There is a difference between the Industrial and other needs, and the surgical requirement. Most important the material has to be biocompatible and absorbed ultimately. The surgical requirements are specific and the nature where hemostatic bonds are created is especially looked for. All of these make the search and inventive research for such substances within a narrow zone exciting.
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