INTRODUCTION:

Bio adhesives mostly refer to natural polymeric substances, which functions as adhesives and are a loose term to describe synthetic glue made for biological substances. The terms like ‘bio adhesives’ or biological adhesives and surgical adhesives are often used for biocompatible substances capable of forming temporary/permanent attachment between two native tissue surfaces, or could be between a tissue surface and a non native tissue surface/implant .Bio adhesives have gained importance over last two decades showing beneficial effect by acting as a glue in various surgical applications ,especially involving skin, soft tissue, bone, as well as other body tissue. In fact, with steadily improving methods in surgery their demand is increasing in surgical arena and are being used to replace the use of sutures/staples, or join silt parts or reconstructive surgery¹. Ideally a bio adhesive should offer a combination of high bond strength, ability to cure in moist environment and biologically compatibility/minimal toxicity.

Various adhesives from different origin have been developed over last two decades and are indicated in a wide variety of conditions. Some of the compounds are true adhesives while others are cements with some adhesive properties which help the surface bond by interlocking². Though various substances like epoxy resins, mixture of fibrous and collagen protein, Poly urethane foam, Cyanoacrylates, zinc poly carboxyl ate, polymethyl methacrylate and fibrin adhesives have been used as bio adhesive, Cyanoacrylates have been shown good efficiency in a variety of surgical conditions. Further Cyanoacrylates have not been seen to produce allergy or simulate tumor genesis and hence offer safer approach.

CYANOACRYLATES:

Cyanoacrylates were developed long back in 1950s and their remarkable bonding strength and ability to bond in wet environment brought them to attention in medical field. A large variety of useful 2-cyanoacrylate esters were available by varying the length of the alkyl chain. Rapidly decomposing methyl and ethyl Cyanoacrylates produce higher concentration of toxic substances, but increasing the length of the alkyl chain has been seen to reduce the toxicity, as seen in isoamyl Cyanoacrylates. Several in vitro studies have shown that Cyanoacrylates lead to cortical bone adhesion and soft tissue and skin adhesion approaching as high as 6.5MPa (942psi) with cortical bones. Demonstrating the efficacy of Cyanoacrylates as bio adhesives, a comparative study on bovine ribs showed that ‘Champy’ system mini plates and bio adhesives had equivalent bond strength³. In another study comparison of sub articular tissue with tissue adhesive for closer of flank ovariohysterectomy skin incision showed more complete and straight epithelialization with bio adhesive than suture on 7^th post operative day , with around 20% experimental model showing fully developed glands and hair follicles with bio adhesives than none with sub articular suture⁴. The advantages of Cyanoacrylates in skin wound closer and scar healing hold considerable promise in suture less surgery with better cosmesis along with improved wound healing. The advantages of Cyanoacrylates are as follows in Table-1

CYANOACRYLATE

Table-1: Cyanoacrylates In Skin Closure And Surgical Wound Healing.

1. Cyanoacrylates are bio adhesives that have been used to treat skin lacerations with favorable results.

2. Cyanoacrylates are alternative to suture , have been gained increasing clinical popularity due to the case of application decreased scarring decreased pain and they are more effective in providing fine cosmesis compared to sutures.

3. Cyanoacrylates are bactericidal, chemically stable easily stored and marking them useful clinically⁵

4. Clinical studies shows a low rate of wound dehiscence , fewer wound infections and improved cosmetic outcomes for wound approximated with Cyanoacrylates tissue adhesives.

5. No Discomfort is seen with Cyanoacrylates compared to sutures which adhere or snag to the clothing and dressing⁶

6. Histological evaluation of tissue healed in the presence of Cyanoacrylates showed normal wound healing characteristics⁷

7. Cyanoacrylates have been advocated for low tension surgical incision in the pediatric population

8. Cyanoacrylates were seen to be efficacious as sutures with no statistical significant difference terms of efficacy including the rate of wound inflammation, infection, bleeding of incision repaired with Cyanoacrylates than with sutures⁸.

9. Cyanoacrylates shows decreased scaring and no lumpy contour, stitch mark associated with sutures are also absent further they obviated the use of traditional dressings like tincture benzoin, paraffin tulle or sofra tulle many of which are incorporated within the suture to keep them in place and hence associated with pain during their removal⁹

EFFICACY OF CYANOACRYLATES:

A larger number of surgical situations exist where bio adhesives like Cyanoacrylates have shown efficacy include; general surgery, ophthalmology, gynecology, ENT surgery, neurosurgery and dental surgery¹⁰. Though Cyanoacrylates have been used for variety of transcatheter embolising techniques of vessels/ tubular sutures their beneficial effect in bonding various tissue have been explored in surgical wound cure and healing and they have shown to be quite effective. Good bioadhesion and fracture healing In experimental studies lead to clinical trials and benefits have been seen in variety of orthopedic surgery. Importantly Cyanoacrylates have been reported to be completely biodegradable and permit good healing with minimal tissue reactions¹¹. Cyanoacrylates used to stabilized osteochondrial fragments were found to be nontoxic to adjacent bone and cartilage and did not have any apparent deleterious effect on adjacent fracture healing¹²

EVOLUTION OF LESS TOXIC AND SAFER CYANO ACRYLATES:

Though shown to have good efficacy and relatively more safer in some experimental and clinical studies increased local reaction in spite of good bonding effect lead to a question mark on the use of short chain Cyanoacrylates (ethyl and methyl Cyanoacrylates). But development of Cyanoacrylates with larger alkyl chain (butyl and isobutyl Cyanoacrylates) led to revival of Cyanoacrylates as they showed much lesser toxicity and benign tissue reaction than their earlier counterpart¹³

Evolution of isoamyl-2 Cyanoacrylates (IMC) led to further diminished side effect, while maintaining the bond strength and the compound has over last few decades shown considerable efficacy and relative safety. Not only it has been successfully used in bone surgeries / bone fragment bonding , muscle sclera bonding in ophthalmological surgeries¹⁴ but has also shown good result in good result In offering non- suture skin closer in operative procedure thus enhancing wound healing in good condition. Various applications where IMC has shown better result discussed in table-2.

Table 2: Various applications of IMC in Surgery

1. Suture less surgery: Rejoining veins, arteries and intestines sealing and reinforcing suture lines.

2. Ent Surgery: To rejoin Jones in the middle ear in mastoid surgery and to stop nose bleeding

3. Vascular surgery : In bonding skin and bones or teeth to tissue or the bone in the mouth

4. Cosmetic surgery: To replace or to supplement sutures thus reducing scaring.

5. Dental Surgery: Tooth sockets can be sealed after extraction.

6. Periodontal surgery : To reduce post operative pain

ISOAMYL-2-CYANOACRYLATES:

IMC is a gamma sterilized, non pigmented non-toxic and non allergic and biostatic tissue adhesives. It serves as an alternative to conventional sutures for closing surgical incisions caused by surgery. IMC help in rapid wound closer with minimal scarring and reduces the risk of post surgical complications and trauma, apart from being simple to use, and showing a demonstrable safety¹⁵ thus providing effective wound healing with minimal risk. The mechanism with which IMC act as by getting converted into a polymer in contact with a moisture and though by itself it is an inert material it solidifies rapidly within 5-10 sec. Importantly IMC does not show any potential to get absorbed into the blood stream and react with the tissue fluid apart from the being pathogen (bacteria) free IMC can be used in various applications of different surgery (refer table no 1) .various useful properties of IMC as an osseous adhesive include

1. Self stability

2. Sterilizability

3. Ease of application to form bonds of reasonable strength

4. Minimum production of heat

5. Biodegradability

6. No apparent carcinogenicity

However IMC has other advantageous features over other bio adhesives which are as follows in table 3

Table 3: Salient Features and Advantages of IMC

1. On coming in contact with moisture the monomer form of IMC gets converted to polymeric form and it solidifies within 5 to 10 seconds. The process of solidification is faster I alkaline media and slower in acidic media.

2. In the presence of small quantity of weak base such as water IMC undergoes a catalytic exothermic polymerization. This anionic polymerization facilitates bonding action and there by the adhesiveness can be maximized by spreading the monomer into a very thin film

3. IMC is sterile, nontoxic homeostatic and bactreostatic.

4.In comparison to octyl Cyanoacrylates IMC has faster tissue bonding capacity and also cures faster

5. Since IMC does not brittle in fracture on long laceration it is regarded superior to N- butyl Cyanoacrylates

6. The toxicity of IMC is much reduced owing to its longer molecular chain moreover longer molecular chain. More over longer molecular chain lengthens the time for polymerizing and spares a longer time for the surgeon to close the incision effectively after aligning the cut edges.

7. IMC is not absorbed in the blood and is inert to tissue fluids.

8. Compared to sutures IMC is associated with less edema formation and Granuloma

9. The free flowing nature of IMC facilitates easy spread in between the two skin lesions of the wound and also hold it tightly and permanently

10. IMC is simple and safe to use as it reduces the risk of post surgical complications

11. Importantly the biodegradable nature of IMC helps it eliminating it from the body via urine and faces¹⁶.

EFFICACY OF IMC:

The documented efficacy of IMC has been seen in experimental as well as clinical trials especially in several orthopedic procedures requiring bonding and in non-suture skin closer demonstrating enhanced healing effects post-surgically. IMC offers advantage over conventional metal osteosynthesis in the treatment of fractures. Use of IMC improves the ease and speed of fixation, as IMC can automatically adhere and fit tight with In the small fragment and prevents the necessity of any hardware removal

BONDING IN CORTICAL BONE WITH IMC:

In vitro bonding strength of cortical and cancellous bone help to evaluate any bio adhesive for osteosynthesis with most investigating using tensile testing to evaluate bonding strength. Though sheer testing may have been more clinically relevant but since shear stress is very dependent on orientation on bonded surface relative to the bonded surface relative to the force applied. It is not a reliable test and tensile testing minimizes this aspect and was hence used to evaluate efficacy of IMC in cortical bone bonding

Cyanoacrylates, fibrinadhesive, and PMMA (polymethylmethacrylate) were tested on fracture induced on bovine femur. Result of tensile testing in cortical bone showed large standard deviations probably due to significant variability in bonding seen with each adhesive. Isoamyl Cyanoacrylates showed one of the highest bonding strength (2.35mPa) as compared to other adhesives. Figure no 1

Figure No 1: Bonding Strength of Cyanoacrylates Adhesives To Cortical Bone Tested In Tension

STABILSATION OF OSTEOCHONDRIAL FRAGMENTS AND FRACTURE HEALING USING IMC:

Stabilization of relatively small osteochondrial fragments can be done by temporary internal fixation with bio adhesives though would need to use the adhesive in limited amounts and in limited areas to allow the normal healing process to occur between the areas of adhesives placement. Though bonding In such cases require need not be high the adhesive should have minimum hepatic toxicity for minimal interference with normal healing process and allowing effective stabilization of small fragments. Stabilization of osteochondrial fragments with complete osseous bridging possible was shown to efficaciously occur with.

GOOD UNION ACHIEVED WITH IMC:

A study utilizing viscous IMC monomer was conducted in this respect which evaluated its ability to maintain its reduction of unstable osteochondrial fragments while allowing for healing around the sites of adhesive replacement. Experimental models with unstable osteochondrial osteotomics created on both medial femoral condyles were studied after applications of IMC, In 96% knees in which IMC was used , osteotomy fragments firmly united in proper anatomical position with normal appearing joint fluid being evident and no gross synovitis was found in these knees . However only 50% of these knees were able to achieve union of fragments in non adhesive control group, with the difference being statistically significant Figure-2

Figure 2: Percentage Union of Osteotomy Fragments Achieved.

Histologicallly IMC group showed a non continuous layer or retained adhesive on osteotomy surface and bridging across the osteotomy surface was noted to occur by reparative tissue in various stage of maturity adjacent to IMC adhesive. Repair across the articular surface was continuously present in spite of retained in close proximity

Further no inflammatory response was noted adjacent or involving synovium in IMC group. Thus IMC was shown to serve as a temporary mean of internal fixation while allowing for normal healing process to occur relatively unimpeded. Histological findings affirmed that IMC was relatively innocuous to adjacent bones and cartilage as compared to toxicity seen in lower homologues of Cyanoacrylates (methyl and ethyl derivative). The study hence clearly demonstrated the efficacy as well as safety potential of IMC as bone adhesive for small fragments

UNIMPAIRED HEALING IN ADJACENT TISSUES WITH IMC:

An in vivo study of viscous IMC used in limited amount evaluated the ability of IMC as an osseous adhesive and was to be effective. The study also observed in the ability of IMC to allow for healing around the site of adhesive replacement by histological evaluation of any inflammatory reactions in the adjacent bone, cartilage, or synovium. Osseous/cartilaginous healing was observed apparently unimpaired around the site of adhesive and no inflammatory reaction involving adjacent viable tissue was evident¹⁷.

EFFICACY IN DENTAL PROCEDURES/ RESTORATION:

Strong, permanent bonding by adhesive between bone and dental tissue pose a problem in dental restoration. Lack of chemical bonding between synthetic material and hard tissue I.e. bone and tooth, in a humid environment as seen in clinical conditions is probably the major shortcoming of bone cements and dental restorations with a need of increased tensile strength¹⁸.

BONDING STRENGTH WITH IMC IN MANDIBULAR TOOTH BONE

A study was conducted to determine adherence to bone or dentin by 2-cyanoacrylate and to assess the durability and stability of the bond. The bond strength of dentin cemented to poly methyl methacrylate in an experimental model was determined by using mandibular anterior teeth embedded in resin. One day bond strength of ethyl, isobutyl, n and isoamyl Cyanoacrylates showed excellent adhesion after one day water storage (Table-3). Viscous isoamyl homologues showed maximum 1 day tensile strength of smooth surface bone cemented together however non viscous isoamyl Cyanoacrylates also adhered well to bone. Interestingly the bond strength achieved with ethyl 2 Cyanoacrylates rapidly decreased on prolonged water storage with nearly complete destruction of bond occurring within 30 days. However such greater stability was seen with IMC on long term and isomeric Cyanoacrylates showed smallest decrease in bond strength (table-4) After 6 months storage in water the isoamyl and viscous IMC retained 70% and 72% of their 1- day bond strength respectively (figure-3 and table-4)¹⁸

Table: 4 Tensile strength of alkyl Cyanoacrylates bonded dental bone at 1-dayand after 3and 6 month storage in water (37⁰c)

2-cyanoacrylates	1Day	3 Months	6 Months
Ethyl	6.60	-	-
N-Butyl	2.86	-	-
Isobutyl	6.62	4.62	2.01
N-Amyl	6.62	3.80	4.84
Isoamyl	6.27	4.98	4.39
Viscous isoamyl	7.18	6.33	5.14

Figure 3 Good Retention of Bond Strength (%) Seen After 6 Months of Water Exposure

Further effect of temperature on bond strength and bond stability also showed viscous IMC to have one of the highest one-day tensile strength values. Viscous IMA was seen to be the most hydrolytically stable bio adhesive with least deterioration of bond strength to bone in aqueous environment. It was felt that IMA had an advantage of being more suitable for application requiring filling of gaps by bio adhesives and was less toxic than the lower homologous of 2-cyanoacrylate series. Conclusively the study showed that bonding of 2-cyanoacrylate to mineralize tissue in aqueous environment appears to be superior to that of other adhesives with higher homologues of alkyl-2-cyanoacrylates (isoamyl Cyanoacrylates) being useful clinically when an intermediate term bone adhesive was needed.

EFFICACY IN SKIN ADHESION IN OPERATIVE SKIN CLOSER:

Since day care surgery in pediatric age group is increasing as it required short intra-operative period and less post operative complication, Tissue adhesives are being enthusiastically considered leading to better surgical wound closer and healing. Advantages with adhesives has been prominently seen with results showing almost equivalent tensile strength and rather improved cosmetic appearance of the scar along with lower infection rate when compared to sutures, staples and adhesive tape, with lesser risk of disadvantages¹⁹

EFFECTIVE SKIN CLOSER WITH IMC IN PEDIATRIC DAY CARE SURGERY:

A study was conducted using IMC as a tissue adhesives for skin closer in day care surgery in pediatric age group (age of the patients varying between 1 to 12 years) , as IMC is almost considered as an ideal adhesives being sterile inert and non toxic biocompatible and bactreostatic liquid topical skin adhesies²⁰

The study was conducted in India from 2007 to2009 and all the surgeries were performed as a day care procedure. The procedure include herniotomy , appendectomy, orchidopexy and superfacial skin cuts with skin margins approximated within 1-2 minutes.IMC glue used in 100 pediatric patients and the length of the skin incision varied between 28 cm though the glue was not used in case of infected wound. Appropriate preoperative blood investigation was done and the glue was applied with the syringe /niddle/dropper with care taken to prevent spillage. The result showed that average healing period and falling of hardened glue was 5-10 days. Minor wound separation was observed in 3% of the cases and the raw wound was seen to heal without any surgical intervention .Importantly the study did not find any hypersensitive reaction after the applications of IMC .The skin margins were held together by means of skin hook for 1-2 min. and better cosmesis was observed with no suture mark or lumpiness after healing²⁰

Further no major complications were seen and even the wound separation which occurred in the early part of the study was due to the faulty application of the glue. The later cosmesis was better as there were no suture mark or lumpiness and being suture less also increased the acceptance of the procedure cost wise with cost only being marginally higher to the sutures. The herniotomy wound before skin closer and final appearance of the scar application of IMC.

The study concluded that IMC is a feasible alternative to sutures and is more suited to day-care surgery. Not only is it easier to apply and is associated with less pain and being less time consuming, but it avoids the need of stitch removal along with less nursing care required in the post operative period. Moreover no risk of needle stick injury to the surgeon or assistant is additionally advantageous²⁰

Further lower complication rate and the excellent cosmesis achieved makes it a better option in suture less wound closer with enhanced wound healing. However it is importantly felt that care should be taken to approximate the edges well before the application of IMC. IMC can be considered as an alternative to sutures in the pediatric day care surgery. Though the efficacy and safety of using IMC in suture less surgery have been clearly documented , more trials in skin closer especially in larger surgical wounds are needed to exactly quantify the efficacy of IMC in larger /longer incisional cuts required in some surgical procedure²⁰

BETTER COSMESIS WITH IMC IN SKIN CLOSER

Another study compared sub cuticular sutures with IMC as a tissue adhesive for closer of flank ovariohysterectomy skin incision Though the repair time for skin incision was slightly more with IMC than sub cuticular suture ,cosmesis score with IMC was better than sub cuticular group²¹ Indicating better healing with IMC as compared to sutures in low tension skin incisions.

CONCLUSION:

Bio adhesive are biocompatible substance used in temporary or permanent adhering of different tissue and has application in surgery with documented efficacy in orthopedic. Dental and ophthalmologic surgery along with efficacy in non-suture skin closer associated with surgical incision wound in various operative surgeries. Though a variety of substances have been used, Cyanoacrylates have shown considerable efficacy in several surgical applications and is quite popular in skin closer and suture less surgery. Cyanoacrylates with short alkyl chain shows lots of toxicity; However evolution of long chain alkyl derivative like IMC has shown higher safety as compared to short chain ethyl and methyl derivatives. IMC has several advantageous properties and has an edge over other bio adhesives. Efficacy of IMC has been demonstrated in temporary bone internal fixation by its adhesive effect with the body repair process taking care of permanent fixation. Dental bone adhesion has shown promising and efficacious result with IMC. More recently IMC was shown to be quite efficacious in pediatric day care surgery, with suture less wound closer effectively achieved and better cosmesis seen, leading to overall better wound healing. Considering the wide spectrum of application IMC can be beneficially used in various surgeries including ocular surgery, neurosurgery, ENT surgery and dental surgical procedure.IMC offers promising potential in technology advancement of the surgical process in terms of better wound healing and improved cosmesis and need to be essentially explored due to potential benefits.

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Received on 01.11.2013 Modified on 02.12.2013

Asian J. Research Chem. 7(3): March 2014; Page 349-354