|Year : 2013 | Volume
| Issue : 2 | Page : 107-112
Tissue adhesives in ophthalmology
Sharadini Vyas1, Sheetal Kamdar2, Prateep Vyas1
1 Centre for Sight, Vijay Nagar, Indore, India
2 Lotus Eye Hospital, Mumbai, India
|Date of Submission||28-Dec-2012|
|Date of Acceptance||06-Mar-2013|
|Date of Web Publication||20-May-2013|
102, Sneh Nagar, Sapna Sangeeta Road, Indore - 452 001
Source of Support: None, Conflict of Interest: None
Tissue glue is increasingly becoming a choice of material as an adjuvant to surgical wound closure in ophthalmology. Each of the type of glue is unique in terms of its advantages as well as limitations and so is used in different indications. Although the presently available tissue adhesives are good enough for the procedures mentioned, there is still a demand for newer adhesives. The increasing acceptance of these adhesives by the clinicians promises this to be a standard procedure for surgical wound closure. The existing cyanoacrylate glue is mainly used as a corneal patch to seal acute corneal perforations and improve visual outcomes, with reduced enucleation rates and need for tectonic keratoplasty in many situations. Fibrin glue is a biological adhesive, which reduces the total surgical time. The multiple advantages has extended its use in all the superspeciality fields of ophthalmology like corneal and conjunctival surgeries; strabismus, cataract, refractive, glaucoma, and even retinal surgeries. A newer tissue adhesive like biodendrimers and photocrosslinkable ones has better biocompatibility, rapid sealing properties and increased binding forces. It promises to overcome the drawbacks and risks associated with the existing ones but still under research. The increasing acceptance of all these promises it to be a standard procedure for surgical wound closure and probably will introduce a newer modality for drug delivery. In this article, we tried to review the literature with internet and medlines search for the available adhesives, as well as the upcoming ones with promising applications in ophthalmology.
Keywords: Cyanoacrylate, fibrin glue, newer tissue adhesives, tissue glue
|How to cite this article:|
Vyas S, Kamdar S, Vyas P. Tissue adhesives in ophthalmology. J Clin Ophthalmol Res 2013;1:107-12
The use of tissue adhesives is emerging from its nascent stages. As of now they are used mainly for adhesive purpose though they could be engineered in future for drug delivery systems as well.  Tissue adhesives are group of synthetic or naturally occurring compounds, which helps in wound reconstruction either natural ones or intra and post-operative.  These are the compounds, which replace the need for sutures. This in turn reduces overall surgical time as well as inflammation thereby improving post-operative comfort without compromising wound strength. Moreover, economically also it is a more viable option. Each of the type of glue is unique in terms of its advantages as well as limitations and so is used in different indications. We tried to review the literature with internet and medline search for the available adhesives, as well as the upcoming ones with promising applications in ophthalmology.
| History|| |
The history of surgical wound repair dates back to millions of years when the first attempt of wound repair was carried out with muscle fibers or shreds of tendon. Later the first reported known use of suture was approximately in 1100 BC.  It was made popular by Egyptians, Ancient Greeks and Indians. The use of adhesive tapes and plant gum was traced back to 4000 years. The trial was carried out using ant sting as skin clips. Sutures by themselves had problems like irritation, increased inflammation, risk of infection, need for removal in certain cases etc. This was then modified with refinements in suture, materials, type of suturing, modification in needles like types and sizes of needles.
Keeping in mind a constant desire to improve upon the existing ones there was further refinements in repair techniques over sutures in the form of staples, clips, and adhesive tapes. All the methods had good acceptance due to reduced surgical time, reduced inflammation, and better comfort over sutures. The reason for non-acceptances was low wound strength leading to need for repeat applications and other surgical complication. In the modern era these all modalities are gradually getting replaced with the use of Tissue Adhesives.  This is not only true with ophthalmology, but in other surgical areas also.
Ideal glue should have enough working time before it solidify, should be biocompatible, have adequate tensile strength, should be permeable to fluids and metabolites to prevent necrosis, should have minimum induced inflammation, should not carry risk of disease transmission, and be easily accessible and affordable. ,
There are two basic types of tissue adhesives available:
- Synthetic: Cyanoacrylate glue.
- Bioadhesives : l0 ike fibrin glue.
Effective and early application of cyanoacrylate glue as a corneal patch adds in the management of small corneal perforations, melts, and wound leaks, though it is also extended to sealing clear corneal incisions in cataract surgery.  The use in corneal pathologies gives improved visual outcomes, with reduced enucleation rates ,, It also reduces the need for tectonic keratoplasty in many situations. ,
Cyanoacrylates are a type of synthetic glues that polymerize rapidly when come in contact with a wet surface. Application of cyanoacrylate leads to a mild eosinophilic reaction, which occurs within 24 h and the reaction is minimal by the 7 th day. After 1-2 weeks, the glue cast extrudes and it has significant bacteriostatic properties also. ,,
There are two variants of cyanoacrylate glues:
- N Butyl 2 cyanoacrylate which is mainly used in ophthalmology.
- 2-octyl cyanoacrylate (Dermabond) used mainly for external wound closure in plastic surgery, and dermatology. It is available in Indian Market as Dermabond (Ethicon Inc., Somerville, NJ). It is used in ophthalmology with paraben as a liquid bandage.
The mode of application of cyanoacrylate varies according to surgeon's preference. Some surgeons use insulin syringe, draw glue on it, and apply a small amount of glue over the area of perforation after complete drying of the surface. There is a quick polymerization of the glue which then leaves a brittle opaque piece of glue. It's rough on surface and needs bandage contact lens to avoid friction and discomfort. Other way of application is to use a special applicator. In both cases the tissue heals beneath the glue which is then extruded. In India, it is available as Amycrylate (Concord drug limited, A.P.)
Although effective in the indicated cases cyanoacrylate has its own limitations also. Its application is cumbersome. Too much of glue induces intolerance or extrusion before healing and too less will leave areas of leaking. Applied on moist surface it will not adhere, which happens in cases when the corneal wounds continuously ooze out aqueous. Its potential toxicity to the surrounding tissue also is a limiting factor. The major disadvantage of the glue is the associated inflammation leading to intense discomfort. Toxicity of the glue is mainly by direct contact of the glue with corneal endothelium, and lens. Vigilance in monitoring for secondary infection is also warranted especially when the glue has been in place for more than 6 weeks. ,
Corneal patching with cyanoacrylate glue is basically a temporary procedure. It helps in temporarily saving the eye anatomically, thus buying time for healing of the underlying pathology, control of associated inflammation. All this in turn calls for the need of visual rehabilitation in a quiet eye as an elective procedure improving the final visual outcome.
Human fibrin glue may be used in place of cyanoacrylate tissue adhesives in many conditions with the advantage of reducing the conjunctival and corneal inflammation to a large extent. It is a biological adhesive which mimics the final stage of coagulation cascade. Fibrin glue includes fibrinogen component and a thrombin content, both of which are prepared by processing plasma. It also can be prepared at a blood transfusion center or from patient's own blood also. ,,
In India, it is available as Tisseel Fibrin Sealant (Baxter AG Vienna, Austria), and as reliseal (from Relince life-sciences).
The kit contains the following in separate vials.
- Large Blue Bottle: Sealer protein concentrate (human), Freeze dried, vapour treated, containing:
- Clottable protein-75-115 mg
- Fibrinogen-70-110 mg
- Plasma fibronectin-2-9 mg
- Factor XIII-10-50 IU
- Plasminogen-40-120 μg (microgram)
- Small blue bottle: Aprotinin solution, bovine 3000 KIU/ml
- White bottle: Thrombin 4 (bovine), freeze dried reconstituted contains 4 IU/ml
- Large black bottle: Thrombin 500 (bovine), freeze dried reconstituted contains 500 IU/ml
- Small black bottle: Calcium chloride solution, 40 mmol/L
Before use, the syringes containing two components of fibrin glue, namely, Thrombin (black) and Fibrinogen (blue) are taken out from the deep freeze and thawed to room temperature.
1 + 2 (fibrin component)
3 + 5 (thrombin component)-Used for slow release
4 + 5 (thrombin component)-Used for rapid release
To slow the process of fibrin formation, only 0.1 ml of the thrombin-calcium chloride solution is withdrawn into a disposable syringe to which 0.9 ml of balanced salt solution (Acorn Inc., Decatur, IL, USA) is added to achieve a 1:10 dilution. This syringe is placed into the duplojet injector along with a parallel disposable syringe containing the fibrin sealer protein and fibrinolysis inhibitor.
The two components of fibrin glue can either be applied simultaneously or sequentially, depending on the surgeon's preference. In all cases, prior to application of the glue, the surgical field must be dried meticulously. After application, the tissue is pressed gently over the glue for 3 min for firm adhesion. At the end of the procedure, pad, and bandage is applied after instillation of antibiotic drops.
Fibrin glue reduces the total surgical time when compared to suturing. It is better tolerated, non-toxic and has antimicrobial activity when compared to the cyanoacrylate glue.
It also lowers the risk of post-operative wound infection, and is hypoallergenic. The smooth seal along the entire length of the wound edge results in a higher tensile strength, with the bond being resistant to greater shearing stress.
However, anaphylactic reactions following its application have been reported. This reaction has been attributed to the presence of aprotinin in fibrin glue. ,
The major drawback to its use is the risk of transmitted disease mainly viral from pooled blood donors.
Clinical applications of fibrin glue
In Pterygium surgery
Pterygium surgery is carried out with conjunctival auto transplant or with primary amniotic membrane. In both cases the graft needs to adhere to the recipient conjunctival margins.  This can be achieved either with sutures or with fibrin glue.
Fibrin glue is a safe and effective method for this purpose It reduces operating time, with reduction in post-operative inflammation, discomfort with ultimate reduction in the rate of recurrence in primary surgery. , When used in recurrent Pterygium its anti-inflammatory effect controls the post-operative fibrosis.
As early as 1986 the glue was used in conjunctival surgery utilizing pericardium. , Currently, its use has gained popularity for both conjunctival closure and transplant. Fibrin glue is one of the most popular tissue adhesive used for most of the conjunctival surgical procedure. It has promising results in traumatic conjunctival tear repairs, for conjunctival or amniotic membrane transplant; primary as well as recurrent pterygium surgery, mucous or amniotic membrane transplant after symblepheron release, for conjunctivochalasis repair, for primary and secondary surgeries in chemical injuries and Steven Johnson syndrome. It is also very effectively used as a substrate transplant after excision of large conjunctival tumors including ocular surface squamous neoplasia.
In strabismus surgery
Conjunctival closure with fibrin glue is a good alternative to suturing for conjunctival closure in strabismus surgery. It also results in a more comfortable post-operative course. Tonelli et al. in 2004  used glue in a rabbit model to find the efficacy of the glue in Faden operation. Though, the outcome was good in their study, they commented that in small muscle recessions, the glue was not strong enough to overcome the contractive strength of the muscle.
In Corneal surgery
a) Corneal perforation and melt
Tissue Glue is used commonly for perforated corneal ulcer and those with impending perforations, descemetocele and extremely thinned out corneas. Fibrin glue as well as cyanoacrylate tissue adhesives are both effective in the closure of corneal perforations up to 3 mm in diameter. ,,,,, Glue is also used in fixing the amniotic membrane in refractory and perforated corneal ulcers and found to be a viable option. Fibrin glue has the advantage of faster healing and significantly less corneal inflammation and neovascularization. In irregular corneal tears fibrin glue act as an adjuvant to seal leaks left due to poor approximation of the wound. The very advantage of replacing fibrin with cyanoacrylate lies in controlled post-operative inflammation, which in effect increases patient's comfort and reduces corneal neovascularization. Furthermore, there is no need for removal of the glue.
b) Amniotic membrane transplantation
Fibrin glue is the most effective and safe method for fixing the amniotic membrane to the ocular surface in almost all surgeries like partial and total limbal stem cell deficiency,  as a substrate for cultivation of limbal stem cells,  to fix a polymethylene methacrylate ring to amniotic membrane patch on the ocular surface.  Amniotic membrane graft (AMG) when used as a substitute transplant also works better with fibrin glue rather than with suture. All surgeries which needs substitute transplant on the cornea, conjunctiva or limbus are associated with use of fibrin glue for better comfort, controlled inflammation, and better cosmetics as well as for scarless tissue repair. Sekiyama et al.  evaluated the efficacy and safety of transplantation of fibrin glue coated freeze dried amniotic membrane (FD-AM) for ocular surface reconstruction. They found out that the FD-AM retained most of its biological characteristics indicating that it was safe and efficacious for ocular surface reconstruction.
c) Lamellar Corneal grafts
Use of sutures in corneal surgeries especially, lamellar ones increase the risk of interface infilterates through the suture track. Glue has also been used successfully in lamellar graft in highly vascularized and infiltrated corneas , reducing the risk to the graft. Narendran et al.  carried out deep lamellar keratoplasty using fibrin glue supported with overlay sutures. They found it to be a time efficient and effective technique. They concluded that fibrin glue is ideally suited when both recipient bed and donor buttons are of same size and thickness.
d) Penetrating keratoplasty (PKP)
Isolated use of fibrin glue is not a choice for obvious reasons of poor wound strength. Combined use of fibrin glue with 8-16 sutures proved to a good choice. In a laboratory situation Bahar et al.  concluded that the use of fibrin glue in top hat PKP was found to be more mechanically stable than traditional sutures.
e) Limbal cell transplantation
Fibrin glue has also been used effectively and safely to fix the donor limbal lenticule on the bed of the recipient in cases of limbal deficiency. As suturing the thin in limbal transplantation creates special problems related to tissue apposition, suture related inflammation, vascularization and patient discomfort to the exposed sutures on the ocular surface, the use of glue was a rational alternative. Pfister and Sommers did study of a cohort of 95 patients who underwent corneal stem cell reconstruction with use of fibrin sealant as the only method for stem cell adhesion and concluded that fibrin sealant alone is a safe and effective way of attaching corneal stem cell to the limbal niche. 
f) Tissue engineering
Kazuo Tsubota et al. and Hideyuki et al. have reported a novel method of engineering transplantable, carrier-free corneal epithelial sheets by using a biodegradable fibrin sealant and compared its characteristics with epithelial sheets cultivated on denuded amniotic membrane carriers and reported that tissue engineering with a commercially available fibrin sealant is effective means of creating a carrier-free, transplantable corneal epithelial sheet. Carrier-free sheets were more differentiated compared with AM sheets, while retaining similar levels of colony-forming progenitor cells. 
a) Treating epithelial ingrowth
In the refractive arena, it is for epithelial ingrowth that the product has gained the most ground, typically in recalcitrant cases of epithelial ingrowth. ,,, The glue forms a mechanical barrier and prevents the epithelial cells from growing underneath the flap, at least until the flap is healed. The glue typically dissolves gradually over a 2 weeks period and by then, the epithelial surface and stromal interface show complete healing with no cells in the interface. However, the major disadvantages of the use of fibrin glue for flap reattachment is that the glue is fairly opaque when it polymerizes. As a result, it is difficult to see through it to determine, if there are inflammatory cells in the interface. In addition, it is expensive and requires special equipment and preparation time.
Lingmin He, et al.  have used fibrin glue for management of buttonhole in flap with epithelial ingrowth.
b) As a temporary basement membrane
It is being used on photorefractive keratectomy (PRK) operated corneas to reduce corneal haze. In surface ablations like PRK covering the entire treated area with fibrin glue not only makes the surface smoother and regular reducing the post-operative discomfort, but the glue at the same time also acts as a temporary basal layer for corneal epithelium. This reduces the reepithelization time. The fibrin glue also forms a biochemical/mechanical barrier preventing the direct contact of mayo fibroblast activating fibers of tears and corneal epithelium to come in contact with treatment area preventing the post-treatment haze. Use of autologous fibrin additionally will reduce the risk of disease transmission. 
c) In flap tear/traumatic flap dislocation
Usually a flap tear occurs secondary to trauma, which induces some epithelial defect. In such scenario, the flap adheres better to the denuded surface on or around the flap and prevents epithelial ingrowth. 
A number of studies have been carried out both experimentally and clinically to prove its efficacy in glaucoma surgeries.  at multiple steps and in multiple types of surgery. It is used as an effective method of achieving conjunctival wound closure after all drainage procedure.  Its successful use has also been reported in the management of post trabeculectomy hypotony due to leaking bleb. ,, It is considered as a safe substitute for the sutures used in glaucoma drainage device [GDD] surgery. It does not alter intra ocular pressure control, reduces post-operative conjunctival inflammation and surgical time. However, further studies are needed to better understand the role of the glue in GDD implantation. 
Its use in cataract surgery to close the capsular perforation  and cataract incision , has been tried since 1987. It has also been used for the prevention of post-operative astigmatism , and to seal the wound in small incision cataract surgery. , Recently, the glue is being used to fix the haptics of intraocular lens (IOL) to the tissue in place of sutures in Glued IOL. 
Vitreo retinal surgery
As early as 1988, Zauberman and Hemo  have reported its use for conjunctival wound closure following retinal detachment surgery. Mentens et al. , in 2007 compared the efficacy of fibrin glue in comparison with conjunctival closure by sutures following 20 gauge needle pars plana vitrectomy in eyes. They commented that fibrin glue offers significantly better results than suturing for closure of conjunctival wounds.
Lid and adnexal surgery
The glue was used in eyelid surgery for fixing the free autologous skin transplants for covering skin defects and the procedure is advantageous as early fibrovascular ingrowth into the transplant is stimulated. It is also helpful in lid split procedure combined with free skin graft for severe upper eyelid entropion. In lower eyelid trichiasis, glue has been used for fixation of free autologous conjunctival transplants from the upper fornix after separation of the lashes from the posterior lamella with a lid split technique. ,
It has been used for reconstructing lacerated canaliculi; canaliculo cystotomy, canaliculoda cryocystorhinostomy, for the microanastomosis between canaliculi and lacrimal sac and for attaching lacrimal and nasal mucosal flaps. ,
Summary of fibrin glue
The main indication of cyanoacrylate tissue adhesive is in cases of corneal thinning and small uncomplicated perforations, which now has been proved to be equally effectively treated with fibrin glue also with the added advantage of biocompatibility as well as minimizing induced inflammation. This advantage is employed for its use in pterygium surgery where post-operative inflammations one of the important cause for recurrence. Similarly, It is also used to cover large area like substitute transplant as AMG or conjunctival graft. The increasing horizon of fibrin needs a word of caution over theoretical risk of viral transmission.
Glue with AMG
Cyanoacrylate prevents epithelization into the zone of damaged stroma and prevents the development of collagenase production that can lead to stromal melting. Combination of glue with the biological bandage in the form of amniotic membrane is highly indicated in these cases where the lesion is large or there is some amount of tissue melt seen. The membrane protects the glue as well as prevents further melt, reducing the inflammatory reaction induced by glue. ,
Glue with glue
Here, a combination of both cyanoacrylate and fibrin glue is used. In cases where a AMG is required to be used in corneal perforations, a layer of cyanoacrylate is used to seal the perforation and then fibrin glue is used for adhesion of the amniotic graft. In cases of infectious keratitis where a large area infiltrate is associated with a small actual or threatening perforation, a combined approach is used where in debulking of infiltrate is combined with application of cyanoacrylate glue over the area of perforation is followed by covering the entire pathological area with amniotic membrane adhered with fibrin glue. It serves purpose firstly sealing the perforation as well as biological bandage serves as a drug delivery system along with controlling the inflammation thereby preventing tissue melt.
Newer generations of tissue glue
The cyanoacrylate as well as fibrin glue are well-accepted with their limitations and risks. Risk include, scarring with induced astigmatism, tissue necrosis, cytotoxicity, viral-disease transmission and low bonding strength. There is a strong need for newer adhesives that eliminate these issues. Some of them are available while some are still in investigative stages. These newer glues not only will broaden the horizon of treatment, but will also increase the safety and efficacy of the procedure.  Some of these include: Biodendrimers, which are made of biodegradable as well as biocompatible material. Because of the unique chemical and structural composition they have promising application as drug delivery systems and photoactivated collagen cross linking. These include Photo-activated Dendritic Polymers and Chemical cross linking Linear Polymer Adhesives. The Photo-activated Dendritic Polymers have ocular applications like repair of central corneal lacerations, clear corneal cataract incisions, Laser assisted in situ keratomileusis (LASIK) flaps, scleral incisions and penetrating keratoplasties. Chemical crosslinking (two-component) Dendritic Polymers also called Chemically derived bioadhesive (CDB) have significantly improved bonding strength over commercially available fibrin glue. It is easy to handle and cause minimal to nil effect on the surrounding tissue. This group includes adhesives like Chondroitin sulphate-aldehyde Adhesive, Gelatin Resorcinol and Albumin-glutaraldehyde Adhesive.
The group includes Bovine Serum Albumin-based Bioadhesives. It is a photoactivated tissue adhesive and has been tried in squint surgery for muscle to muscle adhesions, for sclera to sclera and for muscle to sclera adhesions because of its very high bioadhesive properties. Another photocrosslinkable adhesive is a Riboflavin-based bioadhesive. It is cross likable polymer, which contains riboflavin. On exposure to ultraviolet A it results in collagen cross linking of cornea increasing the bio mechanical strength of the stroma. This property is used for treating corneal pathologies like Keratoconus, post-LASIK ectasia, post-infectious corneal melts to name a few. The third one in the series of crosslinkable bioadhesive is Hyaluronic Acid-based photocatalytic Glue. This is applied on a lacerated corneal wound and then activated with Argon LASER beam. The hydrogel polymerizes and seals the wound with minimal
| Conclusion|| |
Tissue glue is increasingly becoming a choice of material as an alternative or adjuant to surgical wound closure in ophthalmology. Each of the type of glue is unique in terms of its advantages as well as limitations and so is used in different indications. Although the presently available tissue adhesives are good enough for the procedures mentioned, there is still a demand for newer adhesives with better biocompatibility, rapid sealing properties and increased binding forces. These novel developing adhesives promises to overcome the drawbacks and risks associated with the existing ones. The increasing acceptance of these adhesives by the clinicians promises this to be a standard procedure for surgical wound closure.
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