Clinical Applications of Surgical Adhesives and Sealants

Abstract

In the United States and Europe, the number of topical adhesives, surgical sealants, and hemostats approved for use in the surgical setting is ever expanding although no single device fills all medical and surgical needs to replace sutures. As more surgical procedures are performed through laparoscopic and robotic approaches, these devices are becoming more important, and current research is focused on solving the limitations of conventional wound treatments. This review article discusses clinical applications of various biologically derived and synthetic products that are currently available to surgeons and those that are in development.

I. INTRODUCTION

In operating rooms, lacerations and disruption of skin, visceral organs, muscles, tendons, and ligaments are commonly treated with sutures, staples, and wires.¹ Moreover, laser welding, a light activating technique that reconnects the extracellular matrix proteins to form a continuous molecular seal,^2–4 has shown promising results on thin or single-layer skin.^5–8 As more surgical procedures are performed through laparoscopic and robotic approaches, various surgical adhesives, sealants and hemostats are becoming more important, and current research is focused on solving the limitations of conventional wound treatments. Advantages of such devices include, but are not limited to, elimination of risk of needle-stick injury to surgeon, reduction of surgery time, decreased blood loss by the patient, mitigation of surgical complications and infections, and, no post-surgical removal requirements.⁹

A. Sutures and Associated Problems

Currently, there is not a universal solution for every type of wound because each treatment option has its individual advantages and limitations. However, surgeons predominantly choose sutures because of their great tensile strength and low failure rate despite the many shortcomings.¹ One of the main issues sutures present is traumatic punctures to surrounding tissue from the needle, which is especially detrimental for vital organs such as liver or lung, where stopping leaks of blood and air by suturing is difficult. In addition, the accuracy of positioning may be compromised when working in tight areas during laparoscopic and robotic surgeries.⁹ Incorrect suture positioning or tightness might lead to the development of fibrous scar tissue caused by epidermal ingrowth along the suture track¹¹ or loss of tensile strength before the intended degradation time of the suture.¹² In many situations, sutures are time-consuming for long or multiple lacerations. Although staples are an alternative to sutures for a faster application, they also cause damage to the surrounding tissue. Moreover, staples have been shown to create a greater risk of developing infections and a higher failure rate compared with sutures.¹³

B. Surgical Adhesives vs. Sealants

Often the terms “adhesives” and “sealants” are used interchangeably although their intended uses and functions are completely different. An adhesive exhibits characteristics that allow for in situ polymerization to cause adherence of tissue-to-tissue, or tissue-to-non-tissue surfaces.⁹ In general, tissue adhesives are meant to hold two sides of tissues together and support wound healing until regenerated tissue has enough mechanical strength. Sealants, on the other hand, are used as a barrier to leaks of fluids, such as blood, urine, or air. For example, sealants may be used to patch a puncture in the lung. Moreover, sealant devices may be applied to tissue wounds as hemostatic agents to control bleeding.¹⁴

1. Biologically derived adhesives and sealants

The two main types of biologically derived tissue adhesives and sealants are fibrin glue and matrix protein adhesives, which are effective in many applications, including graft attachment, colon, vascular and lung sealing, and as hemostatic agents in all surgery applications. Fibrin glues are the only material available in the United States that is approved by the Food and Drug Administration (FDA) for indications in adhesive, sealant, and hemostat.¹⁵ Fibrin glue has been shown to significantly decrease operating time and recurrence rate with no difference in complication rate compared with suture treatments.¹⁶ Although these biologically derived products are beneficial because of their good biodegradability, they involve risks of possible viral transmission and hypersensitive reactions.¹⁷ Moreover, because biologically derived glues exhibit limited tensile and adhesion strengths when used as adhesive or sealant, they are commonly used in conjunction with sutures.⁹ Because most fibrin and matrix-protein-based products are derived from animal and human tissues, they are more expensive and have limited availability compared with synthetics such as cyanoacrylates adhesives.^9,18

2. Synthetic adhesives and sealants

Cyanoacrylate and various polymer hydrogels represent the synthetic adhesives and sealants that have been proposed to make up for the weak mechanical strength of biologically derived glues. Although cyanoacrylates are known for their high adhesive strength and fast curing time (they polymerize in seconds at room temperature),¹⁹ potential risks for infection, cytotoxicity and tissue necrosis have been reported when they are used for internal applications.^20,21 For this reason, recent developments of synthetic glues for internal applications have focused on other polymer materials such as poly(ethylene glycol) (PEG), polyurethanes, and polyesters. These polymer-based glues provide attractive features based on their biocompatibility, degradability, and tunable mechanical properties. A common disadvantage of many of these polymer-based glues is significant post-polymerization swelling (range, 50–400%), which can potentially cause compression on surrounding tissues or nerves.²²

C. Purposes and Uses for Various Adhesives and Sealants

From the wide variety of wound treatment options, a clinician must choose the most appropriate approach with their main focus on the patient’s interests while optimizing the environment for which the wound can heal.²³ Not only the amount of products used but also the time spent during treatment determine the cost covered by the patient. Other factors include the availability, ease, and reliability of the procedure, and the local effects using a material, but more importantly, applicability to specific tissue site, robustness of treatment, time to heal, quality of repair, and patient acceptability.²⁴ This review article discusses clinical applications of various adhesive, sealant, and hemostatic products that are currently available to surgeons and those that are in development. The surgical uses are divided into the following categories: adhesives for topical wounds and internal tissue applications, sealants for puncture wounds, and hemostats to reduce blood loss.

II. ADHESIVES

Surgical adhesives are used to re-approximate wounded tissues in a variety of surgical applications including closure of lacerations, vessel and intestine anastomoses, and gluing skin flap to intestines to eliminate fluid accumulation. The most important characteristics of a durable surgical adhesive are appropriate mechanical properties while not hindering the natural healing process. The surgical adhesive needs to possess both high bulk and adhesive strengths to hold two ends of tissue together. However, if the adhesive is too strong and brittle, it can crack and break apart before the tissues heal properly. The materials for surgical adhesive products that are currently available include cyanoacrylates, albumin and glutaraldehyde, poly(ethylene glycol) (PEG), polyurethane, and fibrin.

A. Adhesives for Topical Applications

Cyanoacrylate adhesives were first used for wound closure as far back as in 1959 and are now becoming a common treatment choice in many accident and emergency situations.²⁵ They are a single-component adhesive that cures in the presence of anionic substances such as water or blood at room temperature within 30–60 seconds.²⁶ Cyanoacrylates offer tensile strength similar to that of absorbable sutures²⁷ for closure of skin wounds^28–30 and are capable of adhering to most tissue surfaces.¹⁸ It is suggested that these adhesives are not used in high-tension areas, across joints, on mucosal surfaces, at mucocutaneous junctions, or areas of dense hair growth³¹ because the pattern of failure for cyanoacrylate is based on the disruption of the skin–glue interface.²⁷ They should not be applied to wet wounds or those covered with water or alcohol to avoid acceleration of polymerization rate.¹⁸ Unlike conventional, nonabsorbable sutures, the surgical removal process is not necessary because cyanoacrylates will shear off during the process of normal skin exfoliation, and excess adhesive can be removed by acetone.¹⁸

Cyanoacrylates belong to a class of monomers consisting of the alkyl esters of 2-cyanoacrylic acid. To date, methyl, ethyl, n-butyl, isobutyl, isohexyl and octyl cyanoacrylates (Figure 1) have been investigated for surgical use.²⁶ While the basic structures of cyanoacrylates are similar, the length of the side chains and the presence of plasticizers and stabilizers vary among each cyanoacrylate surgical adhesive.³² The strength of the adhesive is determined by the length of the alkyl chain where the shorter chains (butyl) give stronger polymerized networks than the longer chains, and the longer alkyl chains give more flexible bonds resulting in a higher breaking strength.^33–35 The earlier clinical uses of methyl-2-and ethyl-2-cyanoacrylates in internal applications led to the discovery of negative side effects due to rapid release of toxic degradation products. For this reason, the use of the short side-chain cyanoacrylate products have diminished,^26,29 and only two types of cyanoacrylate adhesives, butyl-2-cyanoacrylate and octyl-2-cyanoacrylate, are currently approved by the FDA as topical skin-closure treatment options.

FIG. 1:

Chemical structures of (A) methyl, (B) ethyl, (C) butyl, and (D) octyl cyanoacrylates used as tissue adhesives.

1. Butyl-2-cyanoacrylate adhesives

Indermil^® (Covidien), Histoacryl^® and Histoacryl^® Blue (TissueSeal), and LiquiBand^® (Advanced Medical Solutions) are butyl-2-cyanoacrylate adhesives that are currently commercially available in the United States. All of these adhesives are approved for use in conjunction with deep dermal sutures to reapproximate skin edges caused by surgical incisions or trauma lacerations and wounds. Indermil^® and LiquiBand^® also act as a microbial barrier during the wound-healing process.^36–38 Studies using butyl-2-cyanoacrylate products for topical lacerations show encouraging results compared with sutures and fibrin glues. More specifically, no differences in wound complications or cosmetic results between LiquiBand and sutures were observed at 4–6 weeks or 3 months³⁹ with higher patient satisfaction reported for the cyanoacrylate adhesive.⁴⁰ Another study revealed that the application of Indermil on the cutaneous wound edges is a faster and easier procedure over sutures and did not delay or inhibit the healing process or its quality. Although Indermil adhesive induced edema and a mild acute inflammatory reaction, it resorbed almost completely within 2 months when applied to well-vascularized tissue.⁴¹ Moreover, a comparative study of Tisseel (Fibrin glue) and Histoacryl Blue^® (N-butyl-2-cyanoacrylate) showed that Histoacryl glue was a superior topical tissue adhesive over Tisseel for surface cutaneous wound closure with regard to safety, reliability, tensile strength, and cost-effectiveness. The researchers concluded that Tisseel should be used on the undersurface of skin flaps instead of surface cutaneous wounds in facial plastic and reconstructive surgeries because cyanoacrylate showed a more reliable tensile strength to hold the skin together.⁴²

When Indermil, Histoacryl, and Liquiband were compared, all of the butyl-cyanoacrylate adhesives exhibited similar immediate burst strengths, 150–175 mmHg.⁴³ However, after 1 day, the burst strength of Indermil and Histoacryl increased whereas that of the Liquiband decreased.⁴³ These findings were related to the curing of the adhesives, and the authors suggest that the increase in burst strength was related to the continuation of adhesive curing after application.⁴³ After application, Liquiband showed twice as high an incidence of fracturing (up to 85%) as Indermil (42%) and Hisoacryl (57%).⁴³ These results demonstrate that Indermil and Histoacryl performs better than Liquiband in terms of strength and flexibility. Despite encouraging results compared to sutures and fibrin glue, short bonds of butyl-2-cyanoacrylate tend to make the adhesive become brittle after polymerization and fracture before the wound can heal properly. Their tensile strength and flexibility properties usually limit their use to small, low-tension lacerations and incisions;³² thus, longer side chain, octyl-2-cyanoacrylate adhesives were introduced.

2. Octyl-2-cyanoacrylate adhesives

Dermabond^® (Ethicon), SurgiSeal^™ (Adhezion Biomedical), LiquiBand^® Flex (Advanced Medical Solutions), and OctylSeal (Medline Industries) are currently available octyl-2-cyanoacrylate tissue adhesives. These products are approved by the FDA for use in conjunction with deep dermal sutures to reapproximate skin edges caused by surgical incisions or trauma lacerations and wounds and to provide a microbial barrier during the wound-healing process.^38,44,45 Studies have demonstrated that the octyl-2-cyanoacrylate adhesives are stronger and more flexible than the butyl adhesives. For example, the bursting strength of incisional wounds closed with Dermabond is three times stronger than those treated with Histoacryl.⁴⁶ Moreover, a comparative study of butyl-2-cyanoacrylate adhesives, Indermil, LiquidBand and Histoacryl, and octyl-2-cyanoacrylate adhesives Dermond Advanced, derma-flex QS, and SurgiSeal, demonstrated that Dermabond Advanced was the strongest and most flexible, set in the shortest time, and was a fairly viscous adhesive, all of which are clinically desirable characteristics.⁴⁷ Unlike most adhesives tested, the wound bursting strength of Dermabond increased a day after application, which implies that the adhesive continued to cure over time. In addition, among the adhesives tested, Dermabond was the only one that did not fracture during the entire course of the study of 3 days.⁴³ Although clear differences among the various cyanoacrylate adhesives were observed in these studies, no data are available at this point to demonstrate the clinical impacts of their mechanical and physical characteristics.⁴⁷

3. Current research and future directions

In 2008, the FDA reclassified the topical cyanoacrylate adhesives from a class III to a class II devices. Because this change decreased the level of testing requirements for approval, it is anticipated that many new products will become available in the United States in the near future.³² One aspect that manufacturers and researchers are addressing is the viscosity of cyanoacrylates to improve the ease of application.^48,49 Namely, High Viscosity Dermabond (Ethicon/Johnson & Johnson), which is six times thicker than the original formulation, has been introduced to significantly reduce glue runoff.⁵⁰ Moreover, improvements in the flexibility and stiffness of these adhesives are being sought²⁴ by introducing butyl and octyl cyanoacrylate blends and incorporating other polymers within the adhesive system.^51–53 LiquiBand^® Optima, Surgical, and Surgical S (Advanced Medical Solutions) are adhesives containing a blend of butyl and octyl cyanoacrylates. When LiquiBand Surgical S was compared to sutures for closure of laparoscopic surgical port incisions, it was discovered that the mean wound closure time was significantly longer for sutures (an average of 2 minutes)⁵⁴ and that fewer dressings were required for patients treated with the LiquiBand. Results of a separate study revealed that, compared to Dermabond^® for the closure of topical skin incisions of laparoscopic port sites, LiquiBand^® Surgical S was significantly faster and easier to use.⁵⁵ Despite the fact LiquiBand combines the fast curing ability of butyl with the more flexible octyl cyanoacrylate, blinded evaluators and patients favored Dermabond in the healing of the incisions.⁵⁵ Currently, Dermabond is a standard tool frequently used by surgeons for small lacerations,⁹ although current research and advances in cyanoacrylate formulations to improve flexibility will further the use of these synthetic adhesives in larger wounds in various surgical applications.

While the issues with physical properties of the cyanoacrylate adhesives may be overcome, the main constraints that limit their use as topical applications are the toxic degradation effects, intense inflammatory response, and risk of cancer.⁵⁶ Current initiatives are aimed at developing implantable, absorbable cyanoacrylates or cyanoacrylate copolymers with no histotoxicity, causing minimal tissue reactivity and allowing for normal wound healing and tissue regeneration.⁴⁸ The longer alkyl chain molecules of cyanoacrylate provide a slower degradation process, releasing fewer toxic byproducts over time. A study examining the effect of side-chain length on synthesis yield, physical and mechanical properties, formaldehyde generation, cytotoxicity and biocompatibility were examined on skin incisions. Overall, longer carbon side-chain lengths yielded better flexibility and lowered toxicity both in vitro and in vivo without compromising biocompatibility, although the longer chains reduced adhesive strength when compared to widely used alkyl-cyanoacrylates and 2-octyl-cyanoacrylate (Dermabond).⁵⁷

4. Summary

Cyanoacrylate-based adhesives are used in skin wound reapproximations due to their strong adhesive strength, although their limited flexibility and toxic internal effects limit their use to topical applications. Cyanoacrylates are used in conjunction with sutures in small skin lacerations dues to their limited flexibility. Therefore, current research is aimed at reducing the brittleness or increasing the flexibility of the cyanoacrylate adhesives to eliminate the need for sutures. Further, researchers are working on slowing down the degradation of the adhesives to reduce the toxic effects.

B. Adhesives for Internal Applications

Very few adhesive products are currently approved by the FDA for internal use, and the ones commercially available in the United States are used in skin flap attachment and anastomosis procedures. Artiss is used to glue skin grafts to wounded skin caused by burns and skin-to-muscle tissue layer in rhytidectomy (facelift) surgeries to reduce fluid accumulation in the void. BioGlue^® is used as an adjunct to sutures or staples in cardiac and vascular repair. While it is only approved in Europe at this time, TissuGlu is a new adhesive product used in abdominal skin flap attachment.

1. Artiss

Artiss (Baxter) is approved by the FDA for adhering skin grafts to wounded skin caused by burns and for tissue flaps during facial rhytidectomy surgery.⁵⁸ This fibrin product of pooled human plasma is specifically intended as an adhesive and not as a hemostat because of the low thrombin concentration, which allows up to 60 seconds to position grafts or skin flaps prior to fixation.¹⁵ Clinical trials demonstrated that Artiss could be used to successfully attach skin grafts in burn patients with similar results to staples (71% of Artiss treated vs. 66% staple treated) in complete healing of the sites after 28 days. Additional analysis revealed the superiority of Artiss over staples for lower hematoma formation at day 1.⁵⁹ When used as an adjunct in rhytidectomy procedures, Artiss significantly reduced drainage volumes without increasing the incidence of hematoma or seroma.⁶⁰ The mean drainage volume was 7.7 (7.4) mL from the sides treated with the adhesive and 20.0 (11.3) mL from the sutures-only side, which suggests that Artiss eliminated dead space through improved flap adherence.⁶⁰ Overall, outcomes of using fibrin adhesive in individual patient reports have been positive, with benefits including reduced number of sutures, extent of swelling, amount of serous fluid secretions, hematoma formation, operating time, need for drains, and recovery time.¹⁵ Several investigators, however, have published data suggesting the lack of effectiveness of fibrin glues in rhytidectomy with less reproducible results being reported for the reduction of hematomas, ecchymoses, and edema.¹⁵ Variation in the results may be due to differences in products and application techniques.¹⁵

2. BioGlue

BioGlue^® (CryoLife) is a surgical adhesive approved by the FDA for use in vascular sealing of large blood vessels in conjunction with sutures for the purpose of hemostasis. In addition, BioGlue is used to assist in the repair of aortic dissection to provide a stronger vessel wall after vascular surgery.⁶¹ BioGlue is composed of a purified bovine serum albumin (BSA) and glutaraldehyde, which polymerizes in situ at the application site within 30 seconds with full strength achieved in 2 minutes.^62,63 BioGlue has shown mixed results from animal models and clinical testing in anastomosis applications. For example, in vitro testing demonstrated that BioGlue was effective in producing leak-free sutureless coronary artery anastomoses and capable of withstanding very high distention pressures of 300 mmHg.⁶⁴ Moreover, in vivo studies in goats showed no significant inflammatory response and animal growth for up to 1 year of follow-up suggested that any detrimental reactivity of the glue to the surrounding tissue was minimal.⁶⁵ In contrast, clinical tests showed that BioGlue failed to reduce leaks following pancreas resection⁶⁶ and exhibited a statistically lower bursting pressure with more inflammatory cell infiltration, intensive fibroblast development, and rich collagen production when compared with platelet-rich plasma.⁶⁷ Furthermore, an animal study using BioGlue as a reinforcement of aortic anastomoses resulted in a stenosis of the lumen (33.9% vs. 3.7% in controls) with tissue injury and fibrosis in all BioGlue animals versus none of the control animals.⁶⁸ The authors concluded that BioGlue reinforcement impairs vascular growth and causes stricture when applied circumferentially around an aorto-aortic anastomosis.⁶⁹ These results indicate that clinicians must determine when the benefits of using BioGlue outweigh the disadvantages on a case-by-case basis, and the inflammatory effects and long-term reaction to BioGlue need to be better described before the FDA approves expansion of its applications.⁹

3. TissuGlu

TissuGlu^® (Cohera Medical Inc) obtained a CE mark, i.e., European regulatory approval, in 2011 for use in abdominal tissue bonding to help reduce fluid accumulation under skin. TissuGlu^® is applied to the underlying abdominal layer to reapproximate the skin flap with the muscle layer and aids in the prevention of seroma, a pocket of clear serous fluid, under the skin after abdominoplasty (tummy tuck).⁶⁹ This product is a one-component adhesive composed of hyperbranched polyurethane with isocyanate end groups containing 50 wt% of lysine.¹⁹ The adhesive crosslinking takes place within 25 minutes, which gives surgeons time to reapproximate the abdominal skin to the underlying layer before the adhesive sets up.¹⁹ Clinical trials have shown no difference in adverse events and decreases in the amount of fluid accumulation compared to sutures in patients after abdominoplasty procedures.⁷⁰ Based on these results, it is expected that TissuGlu will receive FDA approval for use in the United States before long.

4. Current research and future directions

Current research on tissue adhesive is focused on improving the mechanical properties to achieve a sutureless treatment for internal applications.^71–74 To solve the strength issue, some researchers have looked at using dendrimers or hyperbranched polymers.^75–77 Dendrimers are polymers that consist of highly branched macromolecules of low polydispersivity and are well defined structures containing numerous functional groups.⁹ Due to their large number of functional groups at their periphery, dendrimers are attractive as crosslinkable building blocks for tissue adhesives.⁷⁵ In pursuit of stronger adhesives, other researchers have tried to mimic the natural adhesive abilities of the feet of geckos, beetles, and marine mussels. Research with biomimetic molecules has been a focus because these molecules are known to promote adhesion in a wet environment; the adhesive strength is not weakened in the presence of water.⁷⁸ For example, Gecko’s feet contain fibrillar arrays or setae that allow the gecko to adhere to rough or smooth surfaces when they are vertical or inverted through van der Waals and capillary forces.^79–81 Research is being conducted with this technology on waterproof sealants for hollow organ anastomoses; mesh grafts to treat hernias, ulcers and burns; hemostatic wound dressings;⁸² and air leak prevention in lung resection procedures.⁸³ Similarly, marine mussel molecules, such as L-3,4-dihydroxyphenylalanine (DOPA), have shown potential to provide advantages to adhesive systems.⁸⁴ In nature, mussels show impressive force needed to break the adhesive bonding when attached to plastic, glass, metals, and living body substances in wet environments. DOPA residues enable mussel adhesive protein molecules to cross-link by oxidative conversion to DOPA-quinone, where the quinone is thought to provide water-resistance characteristics of mussel adhesion.^85,86 DOPA adhesive research has looked at surgical applications including prosthetic mesh fixation⁸⁷, islet transplantation at extrahepatic sites,⁸⁸ repair of gestational fetal membrane ruptures.⁸⁹ Although DOPA research has shown promising adhesive data, the practical applications have been severely limited by the costly extraction process and unsuccessful large-scale production and have not been commercialized to date.^9,24

5. Summary

Tissue adhesives used in large flap attachments after abdominoplasty (tummy tuck) and rhytidectomy (face-lift) procedures have demonstrated positive results of strong tissue bonding that help reduce fluid accumulation between skin and underlying tissue. These products are used as an adjunct to sutures or staple and have not been tested as standalone adhesives. The need for a mechanically stronger internal tissue adhesive is growing due to the laparoscopic revolution of surgical procedures, and researchers are exploring multi-functional hyperbranched polymers and various biomimetic molecules. In addition to enhancing the performance of adhesives, future research should also carefully investigate the bio-mechanical properties of native tissues and organs to provide surgeons with a better understanding of why certain tissue adhesives tend to be more effective than others for different applications.

III. TISSUE SEALANTS

A tissue sealant can be used externally or internally for a protective barrier or for containment of fluids. Sealants may be applied to cover holes in a hollow organ or simply to close suture holes in tissues. The base materials of these sealants include both biologically derived and synthetics such as fibrin, gelatin, BSA, poly(ethylene glycol) (PEG), and cyanoacrylates.

A. Biologically Derived Tissue Sealants

The first biologically derived tissue sealant was collected from human blood plasma and used as a fibrin glue for nerve repair in 1940.²⁴ Since then, various fibrin glues (e.g., Tissucol, Biocol, Beriplast) became commercially available in Europe in 1972 and have been used for joining tissues in many surgical procedures.¹⁹ In the United States, Tisseel (Baxter) was the first biologically derived tissue sealant approved by the FDA in 1998; it is used for colostomy closures as a sealant and topical hemostat.¹⁹ Currently, two biologically derived tissue sealants are commercially available for internal applications, including Tisseel and ArterX^®.

1. Tisseel

Tisseel (Baxter) is used as an adjunct to sutures to prevent leaks from anastomoses to provide a barrier in various organ systems. This product is a two-component sealant containing pooled human plasma with sealer protein and thrombin.⁹⁰ When these components are combined, the glue mimics the final stage of the blood coagulation cascade. Tisseel has been used in a wide array of surgical applications, with beneficial effects noted on wound healing in colon, biliary tract, hernia repair, urologic, and thoracic surgeries.⁹¹ For example, Tisseel compared favorably with traditional methods of mesh fixation for hernia repair, evidenced by shorter operation times and hospital stays, and a lower incidence of chronic pain.⁹² Moreover, it was shown that the fibrin sealant was useful in preventing leaks at gastrojejunal anastomosis⁹¹ and for reducing the incidence of postoperative cerebrospinal fluid (CSF) leaks.⁹³ Others have cautioned, however, that persistent CSF leaks in patients who experienced durotomy during lumbar spine surgery be treated with direct suturing or augmentation with a mesh instead of the fibrin sealant⁹⁴ because the risk of fusion inhibition, extra time needed for material preparation, and added expense did not justify the use of Tisseel when primary repair was deemed adequate.⁹⁴

2. ArterX

ArterX^® Surgical Sealant (Tenaxis Medical, Inc.) has recently been approved by the FDA and is used to seal suture holes formed during surgical repair of the circulatory system and to reinforce sutured anastomoses. ArterX^® is composed of purified bovine serum albumin (BSA) and polyaldehyde and adheres to the native tissues as well as synthetic materials, including PTFE and Dacron grafts.⁹⁵ Clinical studies showed ArterX^® sealant resulted in superior, immediate hemostatic effectiveness compared with a gelatin-based hemostatic, Gelfoam Plus (Baxter), 60.5% vs. 39.6% at tissue anastomotic sites, and 62.5% vs. 34.0% with PTFE grafts.⁹⁶ Between the two products there were no significant differences noted in morbidity or mortality, but operative time was significantly less in the ArterX^® group compared with the Gelfoam Plus group (3.2 vs. 3.8 h). The investigators noted that no cost analysis was performed and that cost savings likely resulted from significantly decreased operative time.⁹⁶

3. Current research and future directions

Attempts have been made to address the limited mechanical strength that fibrin sealants offer. One approach to increasing the strength of the sealant is to include collagen in a fibrin matrix.¹⁸ Another approach is to increase the crosslink density of fibrin with genipin, which is a compound found in fruit extract.⁹⁷ The results of lap shear testing using pieces of annular tissue demonstrated that specimens created without genipin exhibited poor handling properties and readily delaminated, while genipin crosslinked fibrin gels remained adhered to the tissue pieces at strains exceeding physiological levels (15–30%), showing promise as a gap-filling adhesive biomaterial with tunable material properties.⁹⁷ In addition, gelatin (denatured collagen) has also been catching attention as a base material of biologically derived sealant. During in vivo testing on sheep lung, a photopolymerized gelatin effectively sealed wounds in lung tissue from blood and air leakage with no cytotoxic or inflammatory response.⁹⁸ The researchers concluded that the elastic properties, thermal stability, speed of curing, and high tissue adhesive strength of this photopolymerized gelatin offers considerable improvement over current surgical tissue sealants.⁹⁸

4. Summary

Fibrin-based sealants are well established, and newer biologically derived products are entering market, although their limited mechanical strength restricts their applications to use as an adjunct to sutures.⁹⁹ The main advantage biologically derived tissue sealants have over synthetic sealants is that they are composed of naturally occurring proteins, which make it easier to construct products that are fully biodegradable and biocompatible and do not induce an immune response.¹⁹ Despite the research to increase the mechanical properties of biologically derived sealants, many investigators believe that synthetic materials provide the most benefit for a tissue sealant.

B. Synthetic Tissue Sealants

To improve mechanical properties and other problems associated with biologically derived tissue sealants, synthetic materials are being explored as substitutes. Synthetic polymer sealants that are currently approved by the FDA and are commercially available for clinical use are made of PEG or cyanoacrylate. Products of polyurethanes and polyester-based sealants are currently in the research and development phase and are undergoing the FDA approval process.¹⁹ Most of these products are designed to form hydrogels in situ, with or without a UV light source, upon application on tissue surfaces with an injectable or sprayable delivery system.

1. PEG sealants

FocalSeal^® (Genzyme Biosurgery), Progel^™ (Neomend), Duraseal^™ and DuraSeal^™ Xact (Covidien), Coseal^® (Baxter), and ReSure Sealant (Ocular Therapeutix, Inc.) are commercially available PEG-based sealants currently approved by the FDA for clinical uses. While they are all categorized as PEG-based, differences exist in the polymers used and their indicated uses.

a. Lung treatment with FocalSeal and ProGel

FocalSeal^®, which is composed of PEG-co-trimethylene carbonate-co-lactide with acrylated end groups and eosin Y, and ProGel^™, which is composed of human serum albumin solution (HSA) and di-PEG-succinimidyl succinate, are both used as an adjunct to standard tissue-closure techniques for sealing or reducing air leaks incurred during pulmonary surgery.¹⁰⁰ Clinical studies demonstrated control of air leaks in 92% of FocalSeal^® treated patients, which was significantly higher than control patients (i.e., suture and staple patients) that controlled 39% of air leaks during hospitalization. In the FocalSeal^® treatment group, trends were observed for reduced time to chest tube removal and earlier discharge, with no significant differences in postoperative morbidity and mortality compared with standard lung closure only.¹⁰⁰ Another clinical study using FocalSeal^® showed that 100% of intraoperative leaks were sealed versus 18% of leaks in control patients. Further, 77% of the patients treated with FocalSeal^® remained leak-free from the end of the operation to chest tube removal versus 9% of control patients.¹⁰¹ One of the few disadvantages of FocalSeal^® is that the hydrogel uses photocrosslinking during the polymerization process that may cause damage to healthy tissue.

Compared with the cumbersome layering application and photocrosslinking process required to use FocalSeal, Progel^™ offers a simpler application process using a dual syringe and in situ chemical crosslinking upon application; it has shown equal or improved efficacy. A study showed significant reduction in air leaks intraoperatively and postoperatively with a decrease in 1 day of hospitalization using ProGel^™ as an adjunct to sutures in visceral pleural closure compared with sutures alone.¹⁰² Clinical trials established its safety and efficacy in the management of intraoperative pulmonary leaks showing 77% of air leaks were sealed in the ProGel^™ compared to 16% in the treatment with sutures only.¹⁰² Investigators concluded that the data reviewed favored the use of ProGel^™ in lung resection surgery in which air leaks that are difficult to close using standard suture and staple methods and that ProGel^™ reduces intraoperative and postoperative air leaks and length of hospital stay.¹⁰³

b. Cranial surgery with DuraSeal

DuraSeal^™, which is composed of tetra-PEG-succinimidyl ester and trilysine amine, is intended for use as an adjunct to sutured dural repair during cranial surgery to provide watertight closure.^104,105 Studies have demonstrated that DuraSeal^™ is significantly more effective for eliminating cerebrospinal fluid (CSF) leaks in 100% of patients compared with sutures in 64% of patients,¹⁰⁶ with few sealant-related adverse events, and clinical outcomes were consistent.¹⁰⁷ The use of DuraSeal^™ in patients was associated with two instances of paralysis, whereas Tisseel (fibrin) has been used in clinical studies without adverse events.¹⁰⁸ As discussed in section III.A Biologically Derived Sealants, however, Tisseel has been widely adopted in “off-label” use for dural repair.¹⁰⁸

c. Vascular recontruction with Coseal

Coseal^®, which is composed of tetra-PEG-succinimidyl ester and is tetra-thiol-derivatized, is used to manage anastomotic bleeding during aortic reconstruction after graft implantation¹⁰⁹ and to stop bleeding from anastomotic suture holes.¹¹⁰ Overall, 86% of patients treated with Coseal^® achieved immediate suture hole and anastomotic sealing at more than twice the rate of subjects treated with gelatin-based Gelfoam/thrombin (47% vs. 20%). Further, the time needed to inhibit bleeding in patients with no sealant treatment of suture holes was more than 10 times longer than for Coseal^® (16.5 vs. 189.0 sec).¹¹⁰ Biaxial tensile testing showed CoSeal (100.02 ± 67.⁶⁰ kPa) and fibrin-based Tisseel (102.59 ± 41.13 kPa) having no significant difference in stiffness while BSA-based BioGlue (3,122.04 ± 1,639.68 kPa) was much stiffer than aortic root replacement material. These results suggest that the high stiffness of BioGlue may restrict normal physiologic dilation and cause anastomotic strictures, whereas the compliant CoSeal and Tisseel allows for proper healing of the tissue.¹¹¹ The researchers concluded that the overall mechanical properties, including stiffness and sealant efficacy, should be considered in determining the choice of glue.¹¹¹

d. Ocular treatment with ReSure sealant

Recently approved by the FDA in 2014, ReSure sealant (Ocular Therapeutix, Inc.) is composed of PEG and trilysine; it is indicated for intraoperative management to prevent leakage from a cut or incision (up to 3.5 mm) in the cornea.¹¹² Clinical studies have demonstrated that ReSure Sealant may offer a better alternative to wound closure than sutures in cataract surgery with a premium intraocular lens. These claims are based on the reports that ReSure sealant–treated subjects leaked 5% under calibrated force gauge manipulation compared with 42% of suture-treated subject with no significant differences in overall wound healing or intraocular pressure.¹¹³ In another clinical study, 0 of 13 (0%) ReSure sealant–treated subjects and 3 of 7 (43%) suture-treated subjects leaked upon provocation with the calibrated force gauge. No ReSure sealant–related adverse events were experienced, and one suture-related adverse event was reported.¹¹⁴ When one-component PEG sealant ReSure^™ was compared to two-component OcuSeal^™ liquid bandage (Beaver Visitec International) composed of PEG and polyethylene amine (PEI) to reinforce closure of clear corneal incisions after cataract surgeries, patients treated with both sealants reported improved comfort compared to no reinforcement.¹¹⁵ However, Resure protected the wound by remaining localized over the de-epithelialized tissue for 24 hours, while Ocuseal^™ was absorbed within 12 hours.¹¹⁵

2. Cyanoacrylate sealants

Omnex^® (Ethicon/Johnson & Johnson) was the first cyanoacrylate device approved by the FDA for internal use and intended for use in vascular sealing to block the passage of blood, body fluids, and air¹⁸. This product consists of two monomers, n-octyl-2-cyanoacrylate and butyl lactoyl-2-cyanoacrylate, formulated to degrade in a slow and safe manner over 36 months so that only small amounts of toxic degradation products such as formaldehyde are produced at any given time.¹⁸ Omnex^® requires priming and mixing, unlike the “off the shelf” topical cyanoacrylate products (see section II.A. Adhesives for Topical Applications). Clinical studies showed that Omnex^® sealant significantly reduced time to hemostasis (119.3 vs. 403.8 s with sutures alone) when used as a sealant to treat anastomoses between PTFE bypass grafts and arteries in femoral popliteal bypass procedures.¹¹⁶ Furthermore, the proportion of patients requiring additional adjunctive measures was lower with cyanoacrylate surgical sealant than sutures alone, and the occurrence of adverse events was similar in both groups.¹¹⁶ Overall, it was concluded that Omnex^® surgical sealant was an easy-to-use internal sealant that significantly decreased anastomotic bleeding in vascular surgery.¹¹⁶

3. Current research and future directions

In general, all PEG-based sealants have the potential to swell and cause organ and nerve compression. Specifically, DuraSeal^™ has shown up to 50% hydrogel swelling after application, causing spinal cord and nerve compression in patients.^117,118 DuraSeal^™ Xact (Covidien) has been developed to minimize the possibility of spinal nerve compression due to swelling of the hydrogel by introducing a lower molecular weight PEG that provides a higher overall PEG concentration compared to the original formulation.¹⁸ Moreover, efforts are being made in development of new synthetic tissue sealants using materials beyond PEG and cyanoacrylates. For example, polyurethane and polyester-based sealants are attractive; they exhibit less swelling compared to PEG sealants and are thermally stable at physiological temperatures.¹¹⁹ Sylys^® (Cohera Medical, Inc.) is a single-component sealant composed of urethane and triethoxysilane that has been shown to provide support after anastomosis in combination with sutures in the prevention of leakage.¹⁹ TissuePatch^™ and TissuePatchDural^™ (TissueMed) are ester-based sealants consisting of PLGA and poly(vinylpyrrolidone-acrylic acid-NHS ester);¹²⁰ they are currently approved only in Europe. TissuePatch^™ is used to stop air leakage after lung surgeries or sealing and reinforcing soft-tissue adjunct to sutures during fluid leak and TissuePatchDural^™ has been shown to provide a watertight closure for fluid leakage after dural repair in cranial surgery.¹²¹ In addition, thermosensitive polymers, such as Pluronic or Tetronic, are being explored as viable solutions to overcome some of the limitations associated with PEG.¹²² By taking advantage of the rapid thermal gelation property of Tetronic T1107 and functionalizing the end group with acrylate for chemical crosslinking, researchers have developed a strong hydrogel network with limited swelling to be used as a tissue sealant/adhesive.¹²²

4. Summary

Currently, a number of synthetic sealant products, PEG and cyanoacrylates, are used in various surgical procedures including lung treatment, cranial surgery, vascular reconstruction and ocular repair. These products are highly biocompatible with no toxic effects on the tissue, although none of these sealants, except for the ocular applications, provide enough strength to completely eliminate the need for sutures. Another issue that many of the current synthetic PEG sealants have is the high swelling profile and the possibility of compression causing surrounding tissue or nerve damage. Current research is aimed toward finding a sealant that provides adequate adhesive strength to eliminate the need for sutures with limited swelling.

IV. HEMOSTATS

Hemostatic devices are generally used in combination with sutures or staples during surgery to control excessive bleeding.^123,124 With the exception of cyanoacrylate adhesives, Omnex^® and Trufill^® (Cordis Neurovascular, Inc.), which are approved for internal use to mechanically block blood flow, most commonly used hemostats are biologically derived and simulate the natural blood clotting process (Figure 2).

FIG. 2:

The natural blood clotting process represented by the coagulation cascade.

A. Fibrin

Fibrin hemostats that are approved by the FDA include Tisseel (Baxter),⁹⁰ Evicel (Ethicon/Johnson & Johnson) (previously known as Crosseal^®),¹²⁵ TachoSil (Baxter),¹²⁶ Evarrest (Ethicon/Johnson & Johnson), Vitagel (Stryker),¹²⁷ and Cryoseal (Thermogenesis).¹²⁸ Tisseel, Evicel, TrachoSil, and Evarrest are products of human pooled fibrin, whereas CryoSeal is from the patient’s own blood and Vitagel is bovine fibrin. All of these fibrin products are indicated for use as an adjunct to standard surgical methods (sutures, ligatures, cautery) to control bleeding. Fibrin products are made from components of plasma that enable the adhesive to mimic the final stages of blood clotting.²⁴ Fibrin glues generally contain fibrinogen (some with factor XIII and fibronectin) and thrombin with a small amount of calcium chloride to create a deliverable clot.⁹⁹ An advantage of these agents is that they do not require active bleeding and can function independent of the patient’s own fibrinogen.¹²⁹ Topical fibrin hemostats are often used in procedures such as skin grafting, dural sealing, bone repair, splenic injuries, closure of colostomies, reoperative cardiac surgery, urologic surgeries, plastic surgery, and total knee replacements.^129–132 These fibrin hemostats are offered in sprays, powders, sheets, and sponges with different fibrinogen and thrombin compositions.

B. Thrombin Hemostat

As fibrin hemostats, thrombin products are used to initiate and expedite the natural blood clotting process. Thrombin is a proteolytic enzyme that converts fibrinogen to fibrin, which is the basis of clot formation.¹²⁹ Currently, three kinds of thrombin hemostats are commercially available in the United States. Thrombin-JMI (King/Pfizer) is bovine thrombin;¹³³ Evithrom (Ethicon/Johnson & Johnson)¹³⁴ and FloSeal (Baxter)¹³⁵ are pooled human thrombin; and Recothrom (Zymogenetics/BMS) is recombinant thrombin from Chinese hamster ovary cells.¹³⁶ These products are approved by the FDA to be used as an aid to standard surgical techniques to control bleeding from capillaries and small venules. The thrombin products have shown efficacy in nephrectomy, and vascular applications although bovine products have been linked to life-threatening bleeding from allergic reactions. Human products have been known to carry risk of viral transmission.¹²⁹ To address these issues, a recombinant thrombin product has been developed recently that provides a potential alternative with equal efficacy to bovine thrombin without the attendant risk of antigenicity.¹³⁷

C. Collagen Hemostat

Collagen can be used to provide a matrix scaffold for the blood clot, to enhance coagulation, and to deliver blood clotting factors, like fibrinogen, to the wound area.^138,139 In the United States, commercially available hemostat products containing collagen include TachoSil^® (Takeda Pharaceuticals International GmbH),¹⁴⁰ Vitagel^™ (Orthovita),¹⁴¹ CoStasis (Cohesion Technologies, Inc), Proceed (Fusion Medical Technologies, Inc.), Avitene (Davol/Bard), Helistat and Helitene (Integra), Instat, and Ultrafoam (Ethicon/Johnson & Johnson). Collagen within the hemostats is used to adsorb blood and coagulation products on its fibers, trapping them in the interstices and effectively adhering to the wound. It further induces platelet adhesion and aggregation and activates coagulation factors to accelerate the blood clotting process.^142–144 However, the main issue with the collagen-based hemostats is that they can swell and potentially cause tissue compression. In addition, these products take a long time (roughly 10 minutes) to reach sufficient bonding strength, which is not an ideal characteristic for a hemostatic used under critical conditions.

D. Gelatin Hemostat

Gelatin is an irreversibly denatured collagen used as a base material for several hemostat products. Gelatin-based hemostat products, such as Gelfoam (Pharmacia), SurgiFoam and Surgiflo (Ethicon/Johnson & Johnson), are most commonly offered as gelatin-resorcinol-formaldehyde (GRF) or gelatin-resorcinol-formaldehyde-glutaraldehyde (GRFG).¹⁹ These gelatin-based products, delivered as sponge or powder, can be used to control small-vessel bleeding and bleeding from the bone.⁹ In a clinical study, thrombin hemostat FloSeal stopped bleeding in 94% of patients within 10 minutes, compared with 60% treated with the gelatin hemostat GelFoam-Thrombin.¹⁴⁵ The authors concluded that FloSeal demonstrated efficacy superior to that of Gelfoam-Thrombin when used as a hemostatic agent during cardiac surgery procedures.¹⁴⁵

E. Polysaccharide Hemostat

Hemostat products composed of naturally occurring polysaccharides are also commercially available. These sugar building blocks make it easier to construct hemostat products that are easily biodegradable and highly biocompatible because these materials are naturally found in plants and animals.¹⁹ Further, polysaccharide hemostats offer antimicrobial properties to reduce infections.¹⁹ Plant-derived polysaccharide-based hemostat products are Arista AH (Medafor),¹⁴⁶ Hemostase (CryoLife), Vitasure (Medafor, Inc.),¹⁴⁷ and Surgicel (Ethicon/Johnson & Johnson).¹⁴⁸ HemCon (HemCon Medical Technologies), Celox^™ (Medtrade Products Ltd), and QuikClot (Z-Medica) are all different family of products containing chitosan, deacetylated chitin (structural polysaccharide found in exoskeleton of crustaceans and cell walls of fungi) hemostat technology.¹⁹ These products are widely used in both military and civilian medical applications to stop blood loss in urgent hemorrhaging applications.¹⁹

F. Summary

Although all of these biologically derived products from fibrin, thrombin, collagen, gelatin, and polysaccharide may reduce or stop blood loss within minutes, they all have the main limitation of requiring that pressure be applied to the application site. In a swine model of uncontrolled penetrating hemorrhage, standard gauze dressings containing no hemostats performed similarly to the hemostatic agents tested.¹⁴⁹ Researchers conclude that proper wound packing and pressure may be more important than the use of a hemostatic agent in small penetrating wounds with severe vascular trauma.¹⁴⁹ The pressure needed is most commonly applied by the surgeon’s hands, which is not possible during laparoscopic and robotic surgeries. For this reason, the need for more advanced, fast-curing, mechanically strong hemostatic tissue adhesive and sealants is increasing.

V. CONCLUSIONS

In the United States and Europe, the number of topical adhesives, surgical sealants, and hemostats approved for use in the surgical setting is ever expanding (Table 1) although no single device fills all medical and surgical needs to replace sutures. In surgery rooms today, fibrin glues have the best range of applications as an adhesive, hemostat, and sealant and are the only material approved by the FDA for indication in all three categories.⁹⁹ Cyanoacrylates are also widely used not as a single product but in many different forms for topical wound applications, internal sealants, and hemostats. However, sutures are still the preferred clinical solution for closure of wounds in minimizing dehiscence and significantly faster to use compared with tissue adhesives,¹⁵⁰ and in many cases, fibrin and cyanoacrylates are used in conjunction with sutures. In addition, newer devices made from gelatin, collagen, and chitosan are also widely used for hemostatic properties, but they do not have the strength for many other applications. The limitations with the mechanical strengths have not been completely solved by the variety of commercially available PEG-based sealants, although the polymers give the flexibility to tune its swelling properties with various functional groups and molecular weights. Finally, dendrimers and biomimetics are not on the market yet, but they show good potential as future materials for surgical adhesives and sealants. While many technical challenges and regulation hurdles exist before commercialization and clinical use, an ideal tissue adhesive/sealant product should exhibit no adverse effects on the healing processes and patient comfort, precise biodegradability, high adhesive and bulk strengths, hemostatic properties, ease of use for surgeons, and applicability to various organ systems.

TABLE 1:

FDA Approved Adhesives, Sealants and Hemostats.

Category	Material Type	Trade name	Application
Adhesive: Topical Use	Butyl-2-cyanoacrylate	Indennil® (Covidien), Histoacryl® and Histoacryl® Blue (TissueSeal) and LiquiBand® (Advanced Medical Solutions)	Adjunct to sutures for re-approximation of skin edges caused by surgical incisions or trauma lacerations Indennil® and LiquiBand® provide a microbial barrier during wound healing
	Octyl-2-cyanoacrylate	Dennabond® (Ethicon), SurgiSeal™ (Adhezion Biomedical), LiquiBand® Flex (Advanced Medical Solutions), and OctylSeal (Medline Industries)	Adjunct to sutures to re-approximate skin edges caused by surgical incisions or trauma lacerations and provide a microbial barrier during wound healing
Adhesive: Internal Use	Pooled human plasma	Artiss (Baxter)	Adhering grafts to wounded skin caused from bums. Adhering tissue flaps during facial rhytidectomy surgery (face-lift)
	Purified bovine serum albumin (BSA) and glutaraldehyde	BioGlue® (CryoLife)	Vascular sealing of large blood vessels in conjunction with sutures. Assist in the repair of aortic dissection to provide a stronger vessel wall after vascular surgery
	Hyperbranched polyurethane with isocyanate end groups containing 50 wt% of lysine	TissuGlu® (Cohera Medical Inc)	Re-approximate abdominal skin flap with the muscle layer and aids in the prevention of seroma under the skin after abdominoplasty (tummy tuck)
Tissue Sealant: Biologically-Derived	Pooled human plasma with sealer protein and thrombin	Tisseel (Baxter)	Adjunct to sutures to prevent leaks from anastomoses and provide a barrier in various organ systems. Beneficial effects noted on wound healing in colon, biliary tract, hernia repair, urologic, and thoracic surgeries
	Purified bovine serum albumin (BSA) and poly aldehyde	ArterX® Surgical Sealant (Tenaxis Medical, Inc.)	Seals suture holes formed during surgical repair of the circulatory system and reinforce sutured anastomoses
Tissue Sealant: Polymer Based	PEG-co-trimethylene carbonate-co-lactide with acrylated end groups and eosin Y	FocalSeal® (Genzyme Biosurgery)	Adjunct to standard tissue closure techniques for sealing or reducing air leaks incurred during pulmonary surgery
	Human serum albumin solution (HSA) and di-PEG-succinimidyl succinate	Progel™ (Neomend),
	Tetra-PEG-succinimidyl ester and trilysine amine	Duraseal™ and DuraSeal™ Xact (Covidien)	Adjunct to sutured dural repair during cranial surgery to provide watertight closure
	Tetra-PEG-succinimidyl ester and tetra-thiol-derivatized	Coseal® (Baxter)	Stop bleeding from anastomotic sutures holes
	PEG and trilysine	ReSure Sealant (Ocular Therapeutix, Inc.)	Intraoperative management to prevent leakage from a cut or incision (up to 3.5mm) in the cornea
Tissue Sealant: Cyanoacrylate	n-octyl-2-cyanoacrylate and butyl lactoyl-2-cyanoacrylate	Omnex® (Ethicon/Johnson & Johnson)	Vascular sealing to block the passage of blood, body fluids, and air
Hemostats	Pooled human fibrin	Tisseel (Baxter), Evicel (Ethicon/Johnson & Johnson), TachoSil (Baxter), Evarrest (Ethicon/Johnson & Johnson)	Adjunct to standard surgical methods (sutures, ligatures, cautery) to control bleeding
	Bovine fibrin	Vitagel (Stryker)
	Patient’s own blood (fibrin)	Cryoseal (Thennogenesis)
	Pooled human thrombin	Evithrom (Ethicon/Johnson & Johnson) and FloSeal (Baxter)	Aid to standard surgical techniques to control bleeding from capillaries and small venules
	Bovine thrombin	Thrombin-JMI (King/Pfizer)
	Recombinant thrombin from Chinese hamster ovary cells	Recothrom (Zymogenetics/BMS)
	Collagen based	TachoSil® (Takeda Pharaceuticals International GmbH), Vitagel™ (Orthovita), CoStasis (Cohesion Technologies, Inc), Proceed (Fusion Medical Technologies, Inc.), Avitene (Davol/Bard), Helistat and Helitene (Integra), Instat and Ultrafoam (Ethicon/Johnson & Johnson)	Induces platelet adhesion and aggregation and activates coagulation factors to accelerate the blood clotting process and adsorbs blood and coagulation products
	Gelatin based	Gelfoam (Pharmacia), SurgiFoam and Surgiflo (Ethicon/Johnson & Johnson)	Control small-vessel bleeding and bleeding from the bone
	Plant-derived polysaccharide based	Arista AH (Medafor), Hemostase (CryoLife), Vitasure (Medafor, Inc.) and Surgicel (Ethicon/Johnson & Johnson)	Reduces blood loss in urgent hemorrhaging applications
	Chitosan based	HemCon (HemCon Medical Technologies), Celox™ (Medtrade Products Ltd), and QuikClot (Z-Medica)