GLUE AS SEALING AGENT OF WOUND AFTER

SURGERY

A REVIEW SUBMITTED TO THE COUNCIL OF THE COLLEGE OF

DENTISTRY AT HAWLER MEDICAL UNIVERSITY IN PARTIAL
FULFILMENT OF THE REQUIREMENT FOR BACHELOR
DEGREE IN DENTISTRY

PREPARED BY:
WRYA NASRADIN MUHEDIN

SUPERVISED BY:
ASSISTANT LECTURER. DILSHAD HAMAD CHOMANI
M.B.CH.B, M.SC (GENERAL SURGERY)

April 2019 A.D Newroz 2719 K Shaaban 1440 A.H

 QUOTATION

“In order to be irreplaceable, you must always be different”

Coco Chanel

ii
 DEDICATION

It is my genuine gratefulness and warmest regard that I dedicate

my work to my beautiful mother Adhima, Source of life and
happiness.

To my beloved dad Nasradin, who is always helping me, I’m

always in owe for his encouragement and anchorage in the study.

To my siblings Dunya, Hiwa, Darya, Dalya, Lanya, and Lvin, I

can’t forget their help and support.

iii
 ACKNOWLEDGMENT

At the beginning, I want to thank Allah, for all of his support and
helping throughout my life. Everything I do is for the pleasure of
Allah.

Then, I appreciate the help of my college for their kind

opportunity to gain knowledge throughout those years and guiding
us for gaining further knowledge.

After that, special thanks to dear Dr Dilshad for his kind support
and encouragement, Appreciate his help.

Finally, great respect and appreciation to our dean of college Dr

Dara hamarashid for his support and facilities that he gave to us.

Also to our beloved head of department Dr Othman abubakir, as

he always give his hand to all students and his encouragement.

iv
 TABLE OF CONTENTS

Title Page Number

Quotation ii
Dedication iii
Acknowledgment iv
List of contents v
List of tables vii
List of figures ix
List of abbreviation x
Introduction 1
Chapter 1: Literature review 3
1.1 Overview of wound 3
1.1.1 Surgical wound and Its types 3
1.1.2 Wound healing 4
1.2.1 Local Hemostatic Measures 6
1.2.1.1 Mechanical Methods 6
1.2.1.2 Thermal 7
1.2.1.3 Chemical Methods 7
1.2.2 Systemic agents 9
1.3.1 Glue as sealing agent 9
1.3.2 Adhesive and Adhesion; Theory and Mechanisms 11
1.3.2.1 Mechanical interlocking 11
1.3.2.2 Intermolecular bonding 11
1.3.2.3 Chain entanglement 12
1.3.2.4 Electrostatic bonding 12
1.4 Types of sealants(glues) 13
1.4.1 Naturally Derived Tissue Adhesives 13
1.4.2 Synthetic Tissue Adhesives 17
1.5 Recent Developments in Tissue Adhesive 20
Technology
1.5.1 Urethane-Based Adhesives 21
1.5.2 Nature-Inspired Adhesives 22
1.6 Uses And Restrictions Of Glue 24
1.7 How to Seal A Cut With Surgical Skin Glue 26
1.8 Inflammatory Response After BioGlue Application 27

28
1.9 In vivo cutaneous incisional wound healing study
1.10 Latest Development Of Glue 30
1.11 Adhesive use in oral and maxillofacial surgery 31
1.11.1 Efficacy of hemocoagulase as a topical hemostatic 31
agent after dental extractions

v
1.11.2 Application of fibrin sealant in periodontal surgery 32
1.11.3 Use of the surgical glue in the cutaneous closure 37
of cheiloplasties for cleft lip
1.12 Surgical glue removal 38
1.13 Comparison between surgical sealant and 39
conventional sealing agent
39
1.13.1 Tissue adhesives
1.13.2 Adhesive tapes 40
1.13.3 Sutures 40
1.13.4 Stapler 41
1.13.5 Surgical zipper 42
1.13.6 Laser tissue bonding 43
1.14 Healing of oral surgical wounds using 3/0 silk 45
suture and n-butyl cyanoacrylate tissue adhesive
2 Conclusion 47
3 References 48

LIST OF FIGURES

Figure Page number

Figure 1: Types of wound 3
Figure 2: Wound healing process 5
Figure 3: Mechanical hemostatic agents 6
Figure 4: Electrocautery 7
Figure 5: Chemical hemostatic agent 8
Figure 6: Ethamsylate 9
Figure 7: The Dusky Arion slug 10
Figure 8: A new, flexible adhesive material can stick to 10
biological tissues even when wet
Figure 9: Schematic illustration of mechanical 11
interlocking
Figure 10: Schematic illustration of intermolecular force 12
Figure 11: Schematic illustration of electrostatic force 12
Figure 12: Surgical glue application 13
Figure 13: Diagram showing the preparation of fibrin 14
glue
Figure 14: Fibrin glue syringe 15
Figure 15: Fibrin sealant usage on penic incision 16

vi
Figure 16: Cyanoacrylate sealant 18
Figure 17: Cyanoacrylate sealant applied on skin wound 19
Figure 18: PEG-based hydrogel sealant 20
Figure 19: Urethane based adhesive device 21
Figure 20: Mussels adhesive proteins 22
Figure 21: a) Gecko foot hairs, b) Gecko inspired 24
adhesive
Figure 22: Sealant application on heart and arterial 25
wounds
Figure 23: Scarless wound healing with glue 25
Figure 24: Wound dehiscence 26
Figure 25: Ragged edge wound 26
Figure 26: Approximating wound edges 27
Figure 27: Inflammatory Response after BioGlue 28
Application
Figure 28: Morphological comparison of fibrin glue, 29
CPAA glue, and suture
Figure 29: H&E and masons trichrome staining of wound 29
at D 28
Figure 30: Metro application on lungs 30
Figure 31: Hemocoagulase applied on extracted socket 31
Figure 32: a) incision in lower wisdom tooth region 32
before using cyanoacrylate. B) one week follow up
Figure 33: Fibrin glue application 34
Figure 34: Periodontal flap suturing 34
Figure 35: Fibrin glue application after 3 days 35
Figure 36: Periodontal flap suturing after 3 days 35
Figure 37: Fibrin glue application after 7 days 35
Figure 38: Periodontal flap suturing after 7 days 35
Figure 39: Periodontal flap suturing after 7 days 35
Figure 40: Fibrin glue application after 20 days 35
Figure 41: Periodontal flap suturing after 20 days 36
Figure 42: Fibrin glue application after 3 months 36
Figure 43: Periodontal flap suturing after 3 months 36
Figure 44: Surgical glue application around implant 36
Figure 45: a) 6 months, left cleft lip and palate, 37
preoperative appearance. b) Surgical glue used after
primary cheilorhinoplasty
Figure 46: a) Adhesive at time of usage and before 38
drying. b) Adhesive after one minute of drying and

vii
application of nasal conformator
Figure 47: a) Scar appearance at 10 days postoperatively. 38
b) Scar at 6 months postoperatively
Figure 48: Dermal stapler 41
Figure 49: Medzip surgical zipper 42
Figure 50: Cyanoacrylate usage at lower 3rd molar area 46
Figure 51: Cyanoacrylate usage at lower 3rd molar area 46
Figure 52: Cyanoacrylate usage at upper 2nd molar area 46

LIST OF TABLES

Table Page number

Table 1: Tissue adhesive 39
Table 2: Adhesive type 40
Table 3: Surgical stapler 42
Table 4: Surgical zipper 43
Table 5: Laser tissue bonding 44
Table 6: Different wound closure materials 44

LIST OF ABBREVIATIONS

Abbreviation Meaning
TAFI Thrombin activatable fibrinolysis inhibitor
GRF/ GRFG Gelatin-resorcinol-formaldehyde/glutaraldehyde
MAPs Mussel Adhesive Proteins
L-DOPA L-3,4dihydroxyphenylalanine
viii
iCMBAs injectable citrate-enabled mussel-inspired bioadhesives,
PDMS Poly dimethylsiloxane
PGSA Poly(glycerol-co-sebacate acrylate)
CPAA Catechol containing poly amidoamine
MeTro Methacryloyl-substituted tropoelastin
PHEMA Poly(hydroxyethyl methacrylate)
FITC-chitosan Fluorescein isothiocyanate-labeled chitosan
GTR Guided tissue regeneration
PEGS Polyethylene glycols
LTB Laser-assisted tissue bonding
OCA Oxidized regenerated cellulose
HVOCA High-viscosity oxidized regenerated cellulose
PTB Photochemical tissue bonding
ICG Indocyanine green
NBC n-butyl cyanoacrylate
OCA Octylcyanoacrylate
FFSS Fibrin-Fibronectin Sealing System

ix
 1

INTRODUCTION
Bleeding entanglements arising from injury, surgery, as well as inherited,
disease-associated or drug-induced blood disorders can cause serious morbidities
and mortalities in civilian and military populations. Therefore, stoppage of bleeding
(hemostasis) is of paramount clinical significance in prophylactic, surgical and
emergency cases. A fundamental principle of good surgical technique is reduction
of blood loss, and nowadays surgeons have a wide variety of agents and tools to aid
them in this endeavor (Sundaram and Keenan, 2010).

To fix torn or severed organs and tissues, surgeons commonly employ staples,
sutures and wires to bring and grip the wound edges together so that they can heal.
However, these procedures can be difficult to perform in hard-to-reach areas of the
body and wounds are often not completely stamped directly. They also come with
the risk that tissues are further harmed and infected (Khademhosseini, 2017).

A special challenge is posed by wounds in fragile or elastic tissues that

continually dilate or contract and relax, like the breathing lung, the beating heart
and pulsing arteries. To cure some of these troubles, biomedical engineers have
established a range of surgical sealants that can bond tissues to lock leakages. Yet,
"currently available sealants are not good enough for most surgical applications and
they do not work solely without the need for suturing or stapling because they lack
an optimal combination of elasticity, tissue adhesion and strength (Annabi, 2017).

Surgical glues and adhesives are needed to attach organs, structures, or tissues
to each other. These may include single components, such as cyanoacrylates or
fibrin glue, or may boost by incorporating additional hemostatic or sealant
properties, (e.g., a combination of collagen and thrombin, or a combination of
thrombin, collagen and fibrin). Although "surgical sealants" and "surgical glues" are
sometimes used synonymously (Louis, 2018).

Scientists have developed new surgical glue that’s based on the proteins of sea
mussels and other animals. The material is capable to stick to objects while placed
in an aqueous environment, has recently been tested and shown to work better than
current commercially available products. Tissue adhesives or glues are
 2

progressively used in place of stitches or staples to close wounds. It has been

suggested that tissue adhesives may be faster and easier to use than sutures for
closing surgical wounds. Tissue adhesives bear no risks of sharp injury dissimilar
needles that are used for sutures and are thought to afford a barrier to infection. This
may mean that they also improve healing and the obligation for removal of sutures
is avoided. (Scott, 2007).

The aim
The aim of this review is to answer these questions:-
 Are there any substitutes for sutures to reestablish tissue continuity?
 Are there alternatives to clamps, ligatures, or cautery for control of bleeding?
 3

Chapter 1: LITERATURE REVIEW

1.1 Overview of Wound

Wound is breaking in the continuity of any bodily tissue due to violence,

including, for example, surgery. The evidence indicates open wounds are those in
which the guarding body surface (the skin or mucous membranes) has been
collapsed, allowing entrance of foreign bodies into the tissues. A wound is exposed
to additional hazards, since the tissues may be invaded by foreign bodies such as
bacteria, dirt, and piece of cloth, which may give rise to significant local or general
problems from infection (fig.1) (Sorg et al, 2017).

In closed wounds, by contrast, the distracted tissues are not exposed to the
external environment. Slight blow may collapse the skin and underlying soft tissues,
as dictated by bruising, which results from the infiltration of blood into the tissues
from pierced small vessels and by swelling caused by the passage of fluid through
the walls of damaged capillaries (fig.1) (Lotha, 2017).

Figure 1: Types of wound (Lotha, 2017)

1.1.1 Surgical Wounds and Its Types

A surgical wound is a laceration or incision in the skin that is usually made by a
scalpel during surgery. They are usually closed with sutures, but are sometimes left
open to heal. It is believed that surgical wounds can be classified into four
categories. These categories rely upon how dirty or tidy the wound is, the risk of
infection, and where the wound is located on the body (Augestyn, 2019).
 4

 Class I, These are considered clean wounds. They present no signs of

infection or inflammation. They often involve the eye, skin, or vascular
system.

 Class II, These wounds are considered clean-contaminated. Although the

wound may not display signs of infection, it is at risk of becoming infected
because of its position. For example, surgical wounds in the gastrointestinal
tract may be at a great risk of becoming infected.

 Class III, A surgical wound in which an external object has come into
contact with the skin has a great risk of infection and considered as a
contaminated wound. For example, a gunshot wound may contaminate the
skin around where the surgical repair occurs.

 Class IV, This class of wound is considered dirty-contaminated. These

include wounds that have been exposed to fecal material. (Augestyn, 2019).

1.1.2 Wound Healing

Many researchers have noted, the final healing of a wound is the result of array
of complex biological events taking place over a long duration. The process is as
follows (fig.2): When tissues are traumatized, blood from the injured blood vessel
fills the cavity of the wound and overflows its borders. The blood clots and
eventually the surface of the clot dries out and becomes hard, forming a scab.
During the first 24 hours the scab shrinks, drawing the borders of the wound closer
together. Gradually a pearly, grayish, thin membrane extends out from the skin
edge; eventually it covers the whole surface. The actual area of the wound,
meanwhile, is steadily reduced by a process of contraction finally, there is no raw
surface to be seen (Mercandetti, 2017).
 5

Figure 2: Wound healing process (Lotha, 2017)

Today, urgent postoperative closure of the wound is simply termed “primary

wound closure.” Closure of a “clean wound” is commonly accomplished by a
primary closure technique in healthy patients undergoing an uncontaminated wound
repair, such as closure of a biopsy, plastic reconstructive surgery, or closure of a
clean surgical wound. The goal is to have an operative closure that creates a
functional scar with complete healing. However, there is only a small window of
opportunity to close the wound by primary intention, usually 4 to 8 hours. An
additional factor is the potentiality of the clinician to approximate the wound edges.
Reason for wound closure delay includes contamination or simply a significant
lapse of time. In these cases, healing by secondary intention is the next best option
(Sacido, 2017).

Most incised surgical wounds will heal by primary intention, but some must
heal by secondary intention, usually because the wound has been deliberately left
open as a delayed primary closure staging technique. It is not extraordinary for the
wound margins to dehisce because of high wound margin tension, in spiece over
joints where there is a significant functional range of motion (Lotha, 2017).

Patients who are medically insecure, have wounds that are dirty or infected, or
have secondary wound dehiscence are candidates for tertiary intention of wound
closure. Tertiary intention (delayed primary closure) occurs when a wound is
primarily left open after debridement of all nonviable tissue. Tertiary intention can
also refer to subsequent surgical repair of a wound at first left open or not
previously treated. This method is indicated for infected or dirty wounds with high
 6

bacterial content, wounds with a prolonged time lapse since trauma, or wounds with
a severe crush component (Hodgetts et al, 2015).

1.2.1 Local Hemostatic Measures

During any surgical process, complete hemostasis must be obtained before

closure of the wound. Direct control of bleeding at the area of trauma is the best
method to obtain hemostasis. The techniques for local hemostasis may be classified
as (i) mechanical, (ii) thermal or (iii) chemical (Malik, 2008).

1.2.1.1 Mechanical Methods

There is a speech say employment of compression basically counteracts the

hydrostatic pressure inside the bleeding vessel until such time, that a clot can form
and seal the bleeding orifice (fig.3). Compression is usually able to control most of
the hemorrhages. Serious maxillofacial bleeding due to facial fractures may be
stopped with temporary or definitive reduction and fixation of the fractures. Use of
Hemostat is uniquely designed to clamp bleeding points in the surgical site. Usually
electrosurgical thermocoagulation is done after grasping the bleeding point with
artery forceps, if the vessel is small. The large vessels are ligated with suture. With
the help of angiography, the correct bleeding point can be confined. Vessels that are
usually investigated and catheterized for treatment of oral and perioral lesions
include the facial, lingual, transverse facial and internal maxillary arteries (Piñeros-
Fernandez, 2016).

Figure 3: Mechanical hemostatic agents (Malik, 2008)

1.2.1.2 Thermal
 7

Many researchers have noted that, heat attain hemostasis by denaturation of

proteins which results in coagulation of large areas of tissue. Electrocautery is an
effective and favorable way of controlling hemorrhage (fig.4). Electrocautery can
be applied directly to bleeding point or after grasping the bleeding point with
hemostat. It will be argued that (Cryosurgery) extreme cooling has been used for
hemostasis. Temperature ranging from –20C to –180C is used. At these
temperatures, the tissues, capillaries, small arterioles, and venules undergo
cryogenic necrosis. This is caused by dehydration and denaturation of lipid
molecules (Coulthard, 2013).

Cryosurgery is specially applied to treat superficial haemangiomas. Argon-

beam coagulator, it expresses a new form of electrocautery, shown to be more
effective than standard electrocautery. This let on bleeding from vessels that are
smaller than 3 mm in diameter to be controlled without the exertion of hemostats or
ligatures. Lasers usually result in bloodless surgery, as these effectively coagulate
the small blood vessels during incising of tissues. (Malik, 2008).

Figure 4: Electrocautery (Malik, 2008)

1.2.1.3 Chemical Methods

Monsel’s solution comprises ferric subsulphate and it acts by precipitating

proteins. It is actually effective in capturing the capillary bleeding and post-
extraction bleeding in medullary bone (fig.5). Tannic acid also aids in precipitating
proteins and causes clot formation. This is more helpful as a home remedy or
prescription over phone until patient reaches the clinician. Patient inquired to bite
over a folded tea bag in case of post-extraction bleeding. Mann hemostatic, silver
 8

nitrate and ferric chloride are other agents, which can be employed in case of
minimal capillary bleeding (Derici et al, 2012).

When bleeding is take place from a bony canal, it can be handled by small
quantity of bone wax adapted to the bleeding bone. It acts by mechanical occlusion
of the bony canal. Large quantity of bone wax can induce foreign body granuloma
and infection. Topical use of thrombin acts by transforming fibrinogen into fibrin
clot. It is delicate to tissues and quite effective. It is employed to the bleeding
surface via a pack, gelatin sponge or surgicel. Oxycel, it is oxidized cellulose and
on application releases cellulosic acid, which has notable attraction for hemoglobin,
inducing formation of artificial clot. Surgicel; Its local hemostatic mechanism rely
on binding of hemoglobin to oxycellulose, allowing the dressing to expand into a
gelatinous mass, which in turn acts as scaffold for clot formation and clot
stabilization (Frost et al, 2016).

Fibrin glue; It is a biological adhesive containing thrombin, fibrinogen, factor

XIII and aprotinin. Thrombin change fibrinogen to insecure fibrin clot, factor XIII
stabilizes the clot and aprotinin avoid its degradation. During wound healing,
fibroblasts move through the fibrin meshwork forming more durable framework
contain of collagen fibers. Adrenaline or epinephrine, applied topically lead to
vasoconstriction and thus aids in attaining hemostasis (Coulthard, 2013).

Figure 5: Chemical hemostatic agent (Malik, 2008)

1.2.2 Systemic Agents

 9

When there is serious blood loss due to hemorrhage, and there are
manifestations of hypovolemic shock, whole blood transfusion may be indicated.
Fresh whole blood consists of all the factors for coagulation. Fresh whole blood
refers to blood that is given within 24 hours of its donation. Platelet rich plasma, It
is recommended to raise the platelet levels to the range of 50,000 to 1, 00,000
cells\mm3 to afford persisted security. Platelets can be collected from donated whole
blood or directly from the patient via plasmapheresis (Piñeros-Fernandez, 2016).

Fresh frozen plasma is usually collected from one donor and contains all
coagulation factors. Fresh frozen plasma is reserved at –30C and should be infused
within two hours once dissolved. A 15 ml vial of cryoprecipitate comprise nearly
100u factor VIII, 250 mg fibrinogen, factor XIII and von Willebrand factor and is
reserved at –30C. Adrenochrome monosemicarbazon and ethamsylate (fig.6), these
systemic chemical agents are of unclear efficacy. Ethamsylate reduces capillary
bleeding in the existence of normal number of platelets. It probably acts by
adjusting abnormal platelet adhesion (Hick et al, 2010).

Figure 6: Ethamsylate (Nelima anil Malik, 2008)

1.3.1 Glue as Sealing Agent

It is believed that surgical glues and adhesives are applicated to adhere
structures, or tissues to each other. Although "surgical sealants" and "surgical glues"
are sometimes used synonymously. Tissue adhesives or glues are used with
acceleration in place of stitches (sutures) or staples to close wounds. It has been
suggested that tissue adhesives may be quicker and easier to apply than sutures for
closing surgical wounds. Tissue adhesives bear no risk of sharps trauma dissimilar
needles that are employed for sutures and are thought to afford an obstacle to
 10

infection. The slug known as Dusky Arion (Arion subfuscus) coats itself with
mucus to keep moist (fig.7). It can add certain proteins to its mucus to make glue.
With this glue, the slug can attach so strongly to a surface (Li et al, 2017).

Figure 7: The Dusky Arion slug (Li et al, 2017)

Surgical glue that has two layers. One layer is a sticky surface that comprises a
polymer. Like the proteins in the slug’s glue, the polymers create strong chemical
bonds to the underlying tissue. The other layer is a rubbery, strong hydrogel, such
as alginate-polyacrylamide. It’s found that the adhesion could be as powerful as
natural cartilage binding to bone. The glues adhered so well because they are
flexible rather than fragile like currently available medical adhesives (fig.8). This
flexibility allows them to spread out the forces that normally cause adhesives to fail
(Piazza, 2018).

Figure 8: A new, flexible adhesive material can stick to biological tissues even when wet, and can be
formed into sheets (teal blue) and custom shapes (dark blue) (Li et al, 2017)

1.3.2 Adhesion; Theory and Mechanisms

1.3.2.1 Mechanical Interlocking

Adhesive material is believed to penetrate into the pores and roughness’s of

adherends surfaces and mechanically locks into the microscopic surface
 11

irregularities of the substrates that induce binding to the surface (fig.9). However,
there are some uncertainties about how significant role this mechanism plays in
adhesion (Mehdizadeh and Yang, 2014).

Figure 9: Schematic illustration of mechanical interlocking (Mehdizadeh and Yang, 2014)

1.3.2.2 Intermolecular Bonding

This is the main mechanism of adhesion between adhesive materials and

substrates, which arises from interatomic/intermolecular forces and the bonds
between atoms/molecules of adhesives on one side and the surficial atoms/
molecules of substrates on the other (fig.10). These forces involve primary
interactions or chemical bonds as well as secondary forces. Although the energy of
secondary forces is much lower than that of the primary bonds, in many adhesion
systems only the secondary forces are liable for bonding strength, in spiece when a
large number of sites for secondary forces are accessible in the interface between
adhesive and substrates. Chemical bonding is the dominant adhesion mechanism in
bioadhesion, where the bonding between adhesive materials and tissue surface
arises from primary chemical bonds, secondary forces, or a combination of both
(Ebnesajjad, 2008).
 12

Figure 10: Schematic illustration of intermolecular force (Ebnesajjad, 2008)

1.3.2.3 Chain Entanglement

In this mechanism polymer macromolecules spread out reciprocally over the

polymer polymer contact interface, which typically has a thickness of 1-100 nm,
and forms a layer of interpenetrated polymer chains (Valbonesi, 2006).

1.3.2.4 Electrostatic Bonding

When the surface of two materials with unlike electronic band structures are
brought to a close proximity, the attainable transfer of some electrons, which occurs
to balance the Fermi levels, might form a double layer of electron charge in the
interface area (fig.11). These charges are believed to induce electrostatic forces,
which may play a significant role in the intrinsic adhesion of the two contacting
surfaces. This mechanism is believed to have an attainable role in bioadhesion
(Spotnitz and Prabhu, 2005).

Figure 11: Schematic illustration of electrostatic force (Spotnitz and Prabhu, 2005)

1.4 Types of Sealants

1.4.1 Naturally Derived Tissue Adhesives

The main components of the bioadhesive systems discussed in this section are
either directly extracted from biological sources, such as human blood, or are based
on proteins isolated from animals, such as porcine or bovine. These products can
function without involvement of any other chemical reagents. Fibrin-based glues
are one of the most widely employed tissue adhesives in clinical applications
 13

(fig.12). The application of fibrin as a scaffold for tissue regeneration and local
hemostatic agent was first reported as early as 1910’s (Joch, 2013).

Figure 12: Surgical glue application (Joch, 2013)

It has been suggested that fibrin glues simulate the last stage of blood clotting,
during which fibrinogen is converted to fibrin clot through a complex coagulation
cascade (fig.13). The fibrin glue typically comprise of two major components
including concentrated human-derived fibrinogen and human or bovine thrombin in
combination with calcium chloride solution as the second component. Upon
blending the two components, fibrinogen is transformed to fibrin monomers by
thrombin which consequently forms a polymer (Shalaby and Burg, 2014).

In the intervening time thrombin activates factor XIII (in presence of calcium
chloride) into factor XIIIa, which reinforce the network through the crosslinking of
fibrin molecules by creating amide bonds and developing an insoluble clot. In order
to avoid fibrinolysis, an antifibrinolytic agent (such as aportinin) is applied in some
formulations. The utmost adhesion strength is usually attained within 3 to 5 minutes
and is directly equivalent to the concentration of fibrinogen. There are many reports
on employing fibrin glue as hemostatic agent and sealant in cardiovascular surgery,
specifically to avoid bleeding from suture line and graft area, which is a common
issue in this kind of operations. Fibrin sealants are also utilized in neurosurgery to
seal cerebrospinal fluid after operation on the central nervous system and peripheral
nerve repair and grafting (Tatehata et al, 2011).
 14

Figure 13: Diagram showing the preparation of fibrin glue (Mehdizadeh and Yang, 2014)

The employment of fibrin glues (fig.14) in treatment of gastrointestinal tract

diseases such as in patients suffering from bleeding peptic ulcers has also been
investigated with the purpose of replacing surgical procedure by noninvasive
endoscopic injection of fibrin sealant. There are also many reports on the utilization
of fibrin sealants in a diversity of medical disciplines such as plastic surgery and
skin grafts, ENT and head and neck surgery, trauma surgery, urology (fig.15), and
ophthalmology (Annabi, 2017).

Disregard of having many advantages, such as fast curing, biocompatibility,

and biodegradability, using fibrin glue might be associated with some risks and
safety concerns. The thrombin from bovine source can trigger allergic reactions in
some patients. Additionally, in reaction to factor V or thrombin from bovine source,
some antibodies are produced that might cross-react with human clotting factor
causing significant hemorrhage. There is also a danger of conveyance of infectious
agents to human when bovine-source thrombin is used. Thrombin of human-source
can be used in order to overwhelm these safety concerns (Messersmith et al, 2017).

Another issue in using fibrin sealant is the risk of blood-borne disease

conveyance, such as HIV and hepatitis A, B and C, as the result of using pooled
human plasma for pulling out fibrinogen and thrombin. To remove this concern
some fibrin sealants make use of fibrinogen and/ or thrombin that are derived from
patient’s own blood plasma. The adverse effects of using antifibrinolytic agents are
another suspicion associated with using fibrin glue. Moreover, introduction of the
glue into large blood vessels can result in thromboembolic event and impede with
blood stream (Joch, 2013).
 15

One more weakness of fibrin glues is their lacking adhesion to tissue when
compared to other adhesives such as cyanoacrylates and GRF/ GRFG glue. Other
disadvantages of fibrin glues are their lengthy preparation time, which takes
approximately 20 minutes need for ancillary equipment’s, and their incompetency
in high pressure hemorrhage. Bovine products have the theoretic danger of
transmission of bovine spongiform encephalitis .Finally; fibrin sealants do best
when utilized to dry surfaces, which is a limiting factor when wet tissue adhesion is
demanded (Shalaby and Burg, 2014).

Figure 14: Fibrin glue syringe (Baxter, 2019)

Some of the challenges facing urologists during a partial nephrectomy include

control of bleeding and repair of the collecting system. Several groups have
exhibited the usefulness of fibrin glue during partial nephrectomy, where fibrin glue
is applied to the incised surface of the kidney. Delayed bleeding was not reported,
proposing that fibrin sealant is effective for renal hemostasis (Traver and Assimos,
2006).

Figure 15: Fibrin sealant usage on penic incision (Traver and Assimos, 2006)
 16

Another group of commercially valid adhesives and sealants for clinical

application is based on proteins or protein-like compounds that go through
crosslinking reaction upon exposure to proper crosslinking agent, while
simultaneously form covalent bonds with the tissue surface. Unlike fibrin glue,
these adhesives do not look like the physiological coagulation mechanisms
(Mehdizadeh and Yang, 2014).

One of the adhesives of this type is a gelatin-based glue called Gelatin-Resorcin

Formaldehyde/Glutaraldehyde (GRF or GRFG), which was developed in Europe in
1960’s. Gelatin, a naturally occurring protein, is extracted from collagen of bovine
or porcine skin or bone. Relying on production method gelatin is categorized into
type a, prepared by using acid extraction, or type B, which is conditioned by a base
followed by acid extraction. Gelatin is a biocompatible and bioabsorbable material
that can form strong, transparent, and flexible gels and films, fulfilling its suitable
properties for medical application (Traver and Assimos, 2006).

However, due to its solubility in water and consequently low stability in

aqueous environment, gelatin network need to be stabilized through crosslinking in
order to be used within physiological systems. Gelatin can be cross-linked by
reacting with aldehydes, which decreases its solubility and increases the cohesive
strength. The combination of gelatin and aldehyde was primarily proposed as a
tissue adhesive, but due to its poor performance in aqueous environment, a phenolic
component (1,3-benzenediol), namely resorcinol or resorcin, was added to develop
its strength through decreasing the negative effect of water (Couthard, 2013).

GRF/GRFG glue also known as “French glue”, is two-component glue

comprising of gelatin and resorcinol mixture. Due to their strong linking, even in
the existence of moisture, this type of adhesive has been used in medical
applications, especially in Europe for the treatment of aortic dissections, liver
surgeries, gastrointestinal tract surgeries, and urinary tract surgeries (Ogle et al,
2011).

In spite of being used for many years, some researchers have noted that
presence of formaldehyde, as a residue of unreacted aldehydes or as a degradation
 17

product, is a major point of concern due to its possible mutagenicity and

carcinogenicity. Therefore, some investigations have centering on using less toxic
glutaraldehyde glyoxal. Additionally, developing other crosslinking techniques
rather than using chemical agents can remove the danger of using aldehydes.
Researchers reported synthesis of a tissue sealant that was prepared based on a
photo-crosslinkable gelatin (Mehdizadeh and Yang, 2014).

1.4.2 Synthetic Tissue Adhesives

Various classes of synthetic adhesive polymers have been widely used as soft
and hard tissue adhesives. Synthetic polymers are attractive because their structure
and consequently material properties including adhesion, degradation, mechanical,
etc., can be controlled, tailored, and processed accordingly to suit specific
applications. Cyanoacrylate-based adhesives, also called Superglue, have been one
the strongest and multipurpose adhesives available (fig.16). They have wide
applications from general household uses to medical applications. The general
structure of cyanoacrylates is (alkyl-2-cyanoacrylates) monomer (Lih et al, 2012).

The first cyanoacrylates adhesive used in clinical application for skin incision
closure in Europe and Canada, was n-butyl-2-cyanoacrylates in 1980’s. In the
United States FDA approved the first cyanoacrylate adhesive with indicated
application of topical skin approximation in 1998 (Dermabond), an adhesive based
on 2octyl-2-cyanoacrylate, which also contains plasticizer, radical and anionic
stabilizers and colorant. Another available medical adhesive from cyanoacrylate
family is based on nbutyl-2-cyanoacrylate (Indermill), which was approved by FDA
for closure of the topical skin incisions (Silvestri, 2016).
 18

Figure 16: Cyanoacrylate sealant (Mehdizadeh and Yang, 2014)

Cyanoacrylate adhesives properties concluded as strong adhesion, rapid setting

time, immediate adhesion to tissue and their ease of use with simple preparation
make them very attractive for clinical uses and are widely used in emergency
rooms, dermatology and plastic surgery (fig.17). There are some other reported
applications, such as endoscopic intervention for gastric varices outside the United
States (Xavier, 2017).

They are also become popular in dentistry applications, as tissue adhesive, in

bonding orthodontic brackets, for dentures repair, etc. On the other hand exothermic
reaction, i.e. heat formation during polymerization, and concerns about toxicity of
degradation products, namely cyanoacetates and formaldehyde, has imposed
restriction in medical use of cyanoacrylate adhesives. Furthermore, despite of
having rapid polymerization and strong adhesion, it might lack demanded
stretchibility particularly when used for soft tissue adhesion (Wilker, 2003).

There are also some other issues associated with cyanoacrylates adhesives
including difficulties in accurate delivery due to its low viscosity, weak shear
strength of joint area especially in the existence of water, high rigidity that can
cause unwanted consequence such as adhesion failure and tissue irritation, and
infection due to presence of nonabsorbable polymer. These disadvantages have
restricted the usage of cyanoacrylate adhesives to topical skin approximation in the
United States (Jacob and Nash, 2015).

Figure 17: Cyanoacrylate sealant applied on skin wound (Jacob and Nash, 2015)
 19

Recently, multiple brands and formats of cyanoacrylate adhesives are available,

and are broadly applied for corneal perforation repair, skin laceration repair,
esophageal and gastric variceal repair, skin grafting, and vascular repair. Testini et
al. informed seriously decreased morbidity when using human fibrin glue or N-
butyl-2-cyanoacrylate adhesive for mesh fixation during inguinal hernia repair
when compared with suture. Elmore et al. report the use of 2-octyl-cyanoacrylate in
sutureless circumcision with good result, negating the risk of suture tracks or
sinuses. Cyanoacrylates are becoming increasingly popular for the sutureless
closure of small skin incisions, and as surgeons from all fields become more
comfortable with the properties of these adhesives, cyanoacrylates are likely to be
put to increasingly innovative uses (Xavier, 2017).

However, its use was restricted due to the intense local inflammation it
generated. Several studies have since demonstrated that n-butyl2-cyanoacrylate and
Dermabond have low toxicity and produce limited local inflammation. One more
sort of artificial tissue sealants are polymeric hydrogels developed based on PEG
(fig.18). PEG is a famous nontoxic, non-immunogenic, biocompatible and FDA
approved material, which has found many applications in modern medicine
including surface modification of materials for enhanced biocompatibility and
hydrogel for drug delivery. One of the FDA approved PEG-based adhesives
(Coseal). The principal indicant of this adhesive is to stamp suture lines and
vascular grafts (Giano et al, 2014).

Another FDA approved PEG sealant (Duraseal) is employed as an auxiliary to

dural closure for sealing CSF leakage following a neurosurgery. Although PEG-
based tissue adhesives propose numerous benefits such as fast gel formation,
adhesion to biological surface, biocompatibility of polymer and degradation
products and bring about mild to moderate inflammatory response, there are some
concerns associated with them including a swell ratio of up to 40% of novel
volume, which desire more precaution when applying to closed spaces to prevent
pressure build up on surrounding tissues (e.g. nerve compression).additionally, it
needs a relatively dry surface for better outcomes (Wilker, 2003).
 20

Figure 18: PEG-based hydrogel sealant (Giano et al, 2014)

1.5 Recent Developments In Tissue Adhesive Technology

As debated earlier, a number of tissue adhesive systems have already been

approved by FDA for indicated applications and are commercialized. However,
many researchers have noted the execution incompetency, safety inquiry and
impediment associated with the use of each of these adhesive and sealants have
driven researchers to address those problems by grow new adhesives, which have
better performance in biological environment, broader applications and fewer
disadvantages (Mehdizadeh and Yang, 2014).

1.5.1 Urethane-Based Adhesives

This sort of adhesives typically comprise of isocyanate-terminated pre-

polymers, which form a polymer network in reaction with water molecules upon
touch with wet biological environment (fig.19). At the same time, these pre-
polymers will covalently adhere to tissue through formation of urea bond between
existed isocyanate groups and protein amines available in physiological body.
However, they believed that there are three main challenges associated with
application urethane adhesives, lengthy set time, ether-based polyurethanes are not
readily biodegradable, and toxicity and carcinogenicity of degradation products
(Kim et al, 2014).

Isocyanate-terminated pre-polymers usually present long set time when no

catalyst is used, which makes them unsatisfiable as tissue adhesives. In another
 21

effort researchers used linear and multi-armed pre-polymers capped with more
reactive Isocyanate groups. They synthesized Lysine di- and tri-isocyantes (LDI and
LTI) that reacted with glucose and PEG with different molecular weight to yield
isocyanate-capped pre-polymers. These pre-polymers are reportedly cross-linked
within 30 sec to 2 min upon applying to tissue surface. Employing this sort of
isocyanates also reduced the safety concerns associated with aromatic isocyanates
(Mahdizadah and Yang, 2014).

To tackle the challenge of lengthy in-vivo biodegradability of polyether based

polyurethanes, hydrolytically-degradable ester components were included into the
structure of polyurethanes, which resulted in polymers with accelerated rate of
degradation. In spite of all these progression and other improvements in urethane
chemistry and raw materials to address presenting safety concerns, there is no FDA-
approved tissue adhesive based on polyurethane to date (Coulthand, 2013).

Figure 19: Urethane based adhesive device (Coulthand, 2013)

1.5.2 Nature-Inspired Adhesives

Adhesive materials are widely used by many organisms. The evidence indicates
that one of the most distinguishable characters of the adhesive polymers produced
by sea creatures is their capability to forcefully adhere to any substrates in wet
condition. Moreover, these adhesives present strong resistance against rubbing
effect of water, which often adversely affect the strength of many chemical bonds
and hence, the strength of adhesives (Hickman et al, 2018).

Many researchers have suggested that tissue adhesives must effectively act in
watery environment in order to be able to form strong adhesion to wet biological
surfaces. One of the creatures that have been widely studied, mostly through the
works of H.J. Waite, is mussel. Mussels, such as Mytilus edulis , secrete adhesive
materials (MAPs) that let them to firmly attach to varies underwater surfaces such
 22

as sea rocks and ship hulls, and challenge detachments even in marine’s harsh and
wavy condition (fig.20). Studies have presented that this strong wet adhesion is
primarily due to the presence of a catechol-containing amino acid called L-
3,4dihydroxyphenylalanine (L-DOPA), a post-translational hydroxylation of
tyrosine, in the structure of secreted mussel’s adhesive proteins (Frost et al, 2016).

Figure 20: Mussels adhesive proteins (Messersmith, 2017)

Considering the matchless properties of mussel adhesives such as rapid curing

even in wet condition, and strong adhesion to surfaces, many researchers have tried
to simulate the adhesion strategy of mussels to make bioadhesives that can stoutly
work in wet/dry condition. Since isolation and purification of MAPs from mussels
is a complicated procedure with relatively low yield (10,000 mussels to obtain 1g of
MAP), there have been many investigations concerning synthesis of polymer
adhesive mimetic of MAPs (Mehdizadeh and Yang, 2014).

In a current improvement, we have successfully synthesized a novel family of

biodegradable and strong wet-tissue adhesives based on mussel adhesive strategy
with 2.5-10 times stronger adhesion strength than commercial fibrin glue. These
injectable citrate-enabled mussel-inspired bioadhesives, iCMBAs, were synthesized
using a facile polycondensation reaction using FDA-approved and cheap materials
including citric acid, PEG, and dopamine/ L-DOPA. Including catechol group in the
structure of iCMBAs causing them strong adhesion to wet tissue surface as well as
crosslinking capacity for bulk cohesive strength. Additionally, the presence of
hydrolytically degradable ester bonds in the back bone of iCMBA polymers made
this family of adhesives readily biodegradable without needing any further
modifications (Patel et al, 2010).
 23

In vivo study showed that iCMBA rapidly and effectively ceases bleeding and
closed open wounds created on the dorsum of a rat animal model without the aid of
other wound closure tools such as stitches or staples. Geckos are able of ascending
and strongly attaching to vertical and reversed surfaces (fig.21, a). Yet, temporary
nature of this adhesion enables geckos to detach and reattach to the surface with
high pace, making it potential for them to run quick over vertical and reversed
surfaces. Researchers formulated a gecko-mimetic adhesive based on
micropatterned pillars that were made of stretchable polyimide films using electron-
beam lithography and dry etching in oxygen plasma (fig.21, b). They reported that
the adhesion strength these adhesives is directly proportional to the number of foot-
hairs sticking to the surfaces and the flexibility of the pillars, which is needed for
attaching to rough surfaces (Takaharah, 2013).

However, the adhesion is inversely affected when the micro-patterned pillars

are immersed in water. To treat this problem, researchers took advantage of the
combination of the sticking mechanisms of gecko and the adhesion power of
mussels. They prepared nanoscale pillars, similar to gecko foot hairs, out of poly
(dimethylsiloxane) (PDMS) that was then dipcoated by a mussel-mimetic polymer
film to create an adhesive with the ability of reversibly adhering to different
surfaces in dry and wet condition. By combining these two adhesion strategies,
mechanical and chemical, they reported a significant rising in the adhesion strength
between an individual pillar and the residing surface in dry and specifically in wet
environment (Wei, 2016).
 24

Figure 21: a) Gecko foot hairs, b) Gecko inspired adhesive (Mehdizadeh and Yang, 2014)

1.6 Uses and Restrictions of Glue

Tissue adhesives have been employed for abundant years in major and minor
procedures of skin closure. They have broad indications and usage, and have been
used for fixation of implants, tissue adhesion, and closure of cerebrospinal fluid
leaks and embolization of blood vessels (fig.22). Additionally, tissue adhesives are
currently used for facial wounds, groin wounds, hand surgery, blepharoplasty,
laparoscopic wounds, hair transplantation and lacrimal punctum closure (Toriumi
et al., 1998; Dowson et al., 2006; Sterling, Skouge, 2008).

There are numerous benefits of tissue adhesives over suturing and other means
of wound closure, such as a lower infection rate, less operating room time,
favorable esthetic results, ease of use, immediate wound sealing, faster return to
athletic and work activities, removal of needle-stick injuries and exclusion the need
for post-operative suture removal. Tissue adhesives are also easier and friendlier for
use in children. It is also believed, it is an acceptable mean for wound closure in
patients who are at danger for keloid or hypertrophic scar formation (Lin et al,
2004; Ridgway et al, 2007; Scott et al, 2007; Sterling et al, 2008).

Figure 22: Sealant application on heart and arterial wounds (Mehdizadeh and Yang, 2013)

Tissue glues afford faster wound closure, no further trauma, less inflammation,
and decreased scar formation (fig.23). The decreased scar length and morbidity
make this technology especially appealing in cosmetic surgeries, such as facelift
surgery. Many researchers believed that glue has to use in place of bandages when
 25

have shallow incision/cuts exist. It has been suggested glue should only utilized
when the flow of blood is less. Paper cuts and light cuts from sharp knives are the
best candidates for glue. Also use glue only when you are relaxed doing so. Cuts
can become infected and infected cuts are risky (Takaharah, 2013). 

Some noted that glue only should apply on cuts less than 5 cm long and that
happen to be straight. Irregular cuts or tears, like the types often made by falling or
incising you on a dull knife, are not viable for sealing shut with glue. It has been
concluded glue should never use on face, anywhere near eyes, deep wounds,
wounds that are bleeding, wounds that are over joints or body parts that flex,
infected wounds, wounds as a result of an animal or insect bite, puncture wounds in
general (Hickman et al, 2018).

Figure 23: Scarless wound healing with glue (Peng et al, 2017)
There is restriction in the use of glue due to its high price, which may be more
than four times as expensive as sutures. Additionally, glue requires proper patient
selection. Furthermore, glue use demand a meticulous technique, as there should be
no space between the skin margins or bleeding. Even with very small gaps, the
tissue adhesive may seep through and limit normal epithelialization (fig.24), finally
disrupting the wound healing (Kim et al, 2014).
Contraindications to tissue adhesives include the presence of infection,
gangrene or ulceration, bleeding or oozing from the incision, incisions under
tension need sutured approximation or edematous wound edges, partial-thickness
skin loss, burns, animal bites, mucosal surfaces or across mucocutaneous junctions,
areas of high moisture or dense hair, and areas of high tension, such as joints
(fig.25). Tissue adhesives are also contraindicated in patients at risk for delayed
wound healing (diabetics or patients with collagen vascular diseases) and in those
sensitive to glue (Al-Mubarak and Al-Haddab, 2013).
 26

Figure 24: Wound dehiscence (Mehdizadeh Figure 25: Ragged edge wound (mehdizadeh
and yang, 2013) and Yang, 2013)

1.7 How to Seal a Cut with Surgical Skin Glue

Cease the bleeding by holding pressure. Attempting to line up the edges of the
wound as best you can (fig.26). This is easiest with a tidy cut like from a knife.
Carefully disclose one end of the cut while still holding pressure. As you reveal the
cut, apply glue, and wait until it dries. Carefully disclose more of the cut and repeat
the process until the cut is entirely sealed. As you disclose the cut, it will probably
start to bleed in spite your best efforts. The blood will blend with the glue, forming
hardened bubbles and lumps. This is normal, and while it may not look attractive,
the major goal is to cease the bleeding (Oldani, 2018).

Figure 26: Approximating wound edges (Oldani, 2018)

1.8 Inflammatory Response after BioGlue Application

Hewitt and associates concerning the potency and histopathology of the

adhesive BioGlue in aortic surgical procedures, they used this adhesive to control
hemorrhage after end-to-side bypass grafting of the abdominal aorta in a sheep
 27

model. Histopathologic evaluation showed only “a relative paucity of prominent

inflammatory response”. Chronic granulomatous inflammation as a possible foreign
body reaction was seen only seldomly, and multinucleated giant cells were not
found in any sample. These results were proved by histologic study of specimens
from 2 patients. There was a chance to examine a specimen from a dissecting
descending thoracic aortic aneurysm that necessitated replacement of that section of
the aorta 3 months after replacement of the ascending aorta and reconstruction of
the arch with BioGlue for type a dissection. They found a 0.5cm glue remnant in the
false lumen of the aneurysm adherent to the dorsal aortic wall (Erasmi, Sievers and
Wohlschl, 2002).

Opposed to the findings of Hewitt and colleagues, histologic study of the

specimen showed a serious active inflammation surrounding the glue remnant with
multiple granulocytes and histiocytes and a massive foreign-body reaction with
many multinucleated giant cells (fig.27). These findings as a possible variation in
the response to this kind of biological glue. Whether this major inflammatory
response has any adverse effects over time remains unclear. Nevertheless, the
reaction to biological glues such as BioGlue seems to rely on the individual and
require further evaluation (Hewitt et al, 2011).

Figure 27: Glue remnant surrounded by granulocytes (small arrow), histocytes (big arrow), and
multinucleated giant cell (curved arrow) indicates severe active inflammation (Erasmi, Sievers and
Wohlschl, 2002)

1.9 In Vivo Cutaneous Incisional Wound Healing Study

 28

The wound healing process could be divided into four overlapping but well-
defined phases: hemostasis, inflammation, proliferation, and remodeling and scar
formation. The excellent tissue glue should be capable to obtain immediate wound
closure and hemostasis. During the animal study, the CPAA tissue glue or fibrin
glue was applied to the wound openings on the dorsum of Sprague Dawley rats after
cleaning the blood. In the control group, the wounds were closed by sutures.
Application of the fibrin Glue and the CPAA glue could attain both wound closure
and hemostasis (Peng et al, 2017).

On day 14, the fibrin glue and the CPAA glue show a same wound recovery,
outperforming the suture group. On day 21, the wounds in the CPAA glue group
almost fully recovered, whereas the wound scar could be clearly seen in the fibrin
glue group and the suture group. On day 28, all groups exhibited full recovery of
the wound, and the CPAA glue group showed a lesser degree of scar formation
compared with the fibrin glue group. Detailed wound healing process analysis was
performed on day 28 through hematoxylin and eosin (H&E) staining. For normal
wound healing, day 28 should be the end of the proliferative phase and in the
middle of remodeling and scar formation process (fig.28). H&E staining film
exhibit (fig.29) serious immune cell infiltration in the suture-treated group, whereas
the CPAA glue and fibrin glue both exhibited little immune cell infiltration (Xavier,
2017).

Figure 28: Morphological comparison of fibrin glue, CPAA glue, and suture in Sprague dawley rat
model (Peng et al, 2017)
 29

Whereas the collagen fibers in the suture-treated group and the fibrin glue-
treated group were still in an admixed packed state, more organized collagen
(brighter blue) fibers were present in the CPAA glue-treated group at day 28. These
in vivo results indicated that the application of the CPAA glues induce a scarless
wound closure in the cutaneous incisional wound model (Olbrich, 2017).

Figure 29: H&E and masons trichrome staining of wound at D 28 (Peng et al, 2017)

1.10 Latest Development of Glue

Scientists have improved elastic, adhesive surgical glue that could convert
emergency treatments by sealing up critical wounds in the skin or the organs,
without the demand for staples or sutures. The gel is based on methacryloyl-
substituted tropoelastin (MeTro), a hybrid elastic protein, and can be squirted onto
internal and external wounds to seal them up and encourage healing (fig.30). In
accordance with the international team of researchers behind the glue, it could quite
literally be a lifesaver, sealing up wounds in 60 seconds without stopping the
natural expanding and relaxing of the organ or the skin it's applied. "The beauty of
the Metro formulation is that, as soon as it comes in contact with tissue surfaces, it
solidifies into a gel-like phase without running away," (Annabi, 2017).

Once in place, the sealant is put under ultraviolet light to secure it. This allows
the sealant to be very accurately placed and to tightly bond and interlock with
structures on the tissue surface. Wounds treated with MeTro can heal up in half the
time compared with stitches or staples and if surgery is needed then Metro can
simplify that procedure. In emergency situations where speed is critical, MeTro
 30

could make a huge difference in sealing wounds or lung punctures. In fact it works
a little like silicone sealants you might use on tiles in the kitchen or bathroom. The
potential applications are powerful – from treating severe internal wounds at
emergency sites such as following car accidents and in war zones, as well as
promoting hospital surgeries (Nield, 2017).

Figure 30: Metro application on lungs (Nield, 2017)

1.11 Adhesive Use in Oral and Maxillofacial Surgery

In oral and maxillofacial surgery, closure of soft tissue wounds is chiefly done
with mechanical devices, such as sutures and staples. To close larger soft tissue
wounds or develop large soft tissue flaps in esthetic and reconstructive procedures,
clinicians employ mechanical devices and apply drains that help evacuate dead
spaces to limit hematomas. The emerging adhesives and sealants are likely to have
clinical applicability in oral and maxillofacial surgery soon and accelerate this
clinical change (Buckley and Beckman, 2010).

1.11.1 Efficacy of Hemocoagulase as a Topical Hemostatic Agent after

Dental Extractions

Hemocoagulase is a fractional isolate of poisonous Bothrops jararaca or

Bothrops atrox and is an enzyme complex, with coagulative and anti-hemorrhagic
properties being a topical form, it also work fast and is atoxic. Hemocoagulase has
enzymatic actions like thromboplastin and thrombin, and thereby boost rapid blood
coagulation and wound healing (fig.31) (Gupta, M R and Kumar, 2018).
 31

Figure 31: Hemocoagulase applied on extracted socket (Gupta, M R and Kumar, 2018)

Aslam et al. conducted a study on 20 subjects to evaluate the potency of local

application of hemocoagulase solution as compared to a placebo in wound healing
following dental extraction (fig.32). The differences between the hemocoagulase
site and control site were too much. Pain was also evaluated at the sixth hour, and
the amount of pain in the hemocoagulase group was less compared to the placebo
group, and the results were statistically significant (Sumanth et al, 2016)

Figure 32: a) incision in lower wisdom tooth region before using cyanoacrylate. B) one week follow up
(Khalil et al, 2009)

Accelerated hemostasis with the uneventful healing of extraction wounds with

the use of hemocoagulase was observed in all these studies and they emphasize that
hemocoagulase plays a valuable role as a promoter of wound healing. Based on the
clinical evidence, topical hemocoagulase is a potent hemostatic agent after dental
extractions. It also decrease pain and swelling and promotes wound healing by rapid
formation of healthy tissue (Kumar, 2016).

1.11.2 Application of Fibrin Sealant in Periodontal Surgery

 32

Many products have been applied to help in periodontal surgical procedures

which could promote early wound healing and augment tissue regeneration. It is
believed fibrin glue has been used to hold gingival grafts and mucoperiosteal flaps.
The adhesive property effectively seals tissue and remove potential spaces. In
addition to binding tissues, fibrin sealant acts as a natural wound bed. This bed act
as a scaffold facilitating the proliferation and differentiation of mesenchymal and
endothelial cells. Fibronectin as one of its main constituents has the potential for
regeneration of periodontal supporting structures. A temporary shield is formed for
the safe population of potential periodontal ligament cells capable of regeneration
of functional periodontium. This barrier limits the entry of cells of epithelium and
gingival connective tissue from reaching the potential regenerative space (Jacob and
Nath, 2015).

Fibrin sealant proves to be a better substitute for fixation of tissues compared to

sutures. There is close approximation with better hemostasis. This induces early
wound healing as oral hygiene can better maintained in a patient. The clinical signs
of inflammation were less. The grafts and flaps were more rigid and stable which
results in a better healing at 1 or 2 weeks after surgery. There is a smooth adaptation
of flaps to the tooth surface resulting in lesser accumulation of plaque. Fibrin
sealants provoke early wound healing and connective tissue growth by accelerating
revascularization and facilitating the migration of fibroblasts. It is able to induce
angiogenesis, highly stable epithelium-connective tissue interface and connective
tissue more resistant to proteolytic enzymes (Reynolds, 2010).

Immobilization of free gingival grafts and coronally displaced flaps by fibrin

sealant exhibit more advanced healing compared to sutures. Fibrin sealant improved
the clinical outcome when used for gingival recession coverage. The presence of a
stable thin fibrin sealant facilitated clot could be the reason for the improved results.
Fibrin sealant has been shown as a better substitute to suturing of flaps during
implant placement, especially in the esthetic zones. There is also stronger and
greater peri-implant bone contact interface. When used with bone alloplastic
materials, fibrin fibronectin system exhibited regeneration of peri-implant defects. It
 33

has also been used to preserve the alveolar ridge following tooth extractions (Jacob
and Nath, 2015)

There is better healing with good quality of bone formation seen. There is
improvement in the survival of the stem cells due to the presence of a suitable local
microenvironment. Fibrin sealant has been shown as a better scaffold for stem cell
proliferation and reservoir. Fibrin sealant material saturated with antibiotics can be
considered as a better substitute to the local drug delivery agents in use for
periodontal infections (Peng et al, 2017).

Osteomyelitis could be resolved by antibiotic impregnated fibrin sealant

implant. The antibiotic is released by dissolution of the fibrin sealant. The
controlled release of antibiotic at the appropriate concentration along with wound
healing property of fibrin sealant would be well suited for early resolution of
periodontal infections by inhibiting the microbial etiology and assisting the host.
Fibrin sealant has been recently used for odontogenesis, which can regenerate tooth
tissue by tissue engineering (Mader et al 2002).

There is a report of patients in whom flaps were closed using fibrin glue in
the first patient and sutures in the second (fig.33-44). The goal was to check the
fallout of fibrin sealant as an alternative to sutures. There was a definite ease of
usage on the part of clinician of the fibrin glue, while there was painless and early
recovery of the glued area in the first patient as compared to the sutured area in
the second patient (Radosevich, Goubran and Burnouf, 1997).

Figure 33: Fibrin glue application; Case 1: After debridement, fibrin glue being applied on bone and
both facial and lingual flaps followed by flap approximation for 3 minutes under finger pressure (Bimal
Jathal et al, 2008).
 34

Figures 34: Right side flap approximation with fibrin glue is compared with sutures on left side. Note
the stoppage of bleeding immediately after 30 seconds on fibrin glue side (Bimal Jathal et al, 2008).

Figure 35: after 3 days, case 1 Figure 36: After 3 days, case 2 (Bimal
Jathal et al, 2008).

Figure 37: after seven days, case 1 Figure 38: After seven days, case 2 (Bimal
Jathal et al, 2008).
 35

Figure 39: (after seven days, case 2, and plaque retention Figure 40: after 20 days, case 1
Below sutures. At the time of suture removal bleeding (Bimal Jathal et al, 2008).
Points are clearly seen at the site of needle insertion

Figure 41: after 20 days, case 2. Figure 42: After three months, case 1(Bimal
Jathal et al, 2008).

Figure 43: After three months, case 2 (Bimal Jathal et al, 2008).
 36

Figure 44: [Surgery (A, B, C) Flapless extraction of the tooth after root hemisection to preserve the septal bone. (D,
E, F) Guided implant surgery. (G, H) Fibrin glue was applied on the surgical wound all around the healing abutment.
(I) Post-operative intraoral radiograph. (Francesco_Mangano, 2018)]

1.11.3 Use of the Surgical Glue in the Cutaneous Closure of

Cheiloplasties for Cleft Lip

A remaining scarring of a cleft lip may be responsible for a psychological

impact. Primary repair must guarantee surgical closure and then secondary healing
as excellent as possible .Primary cheilorhinoplasty was done on six-month-old
children. The similar technique could be accomplished in a secondary cheiloplasty.
A muscle suture performed with non-resorbable Prolène1 4/0 or 5/0 sutures. The
mucosa closure made by absorbable Vicryl1 4/0, 5/0 or 6/0 type sutures. The suture
of the subcutaneous plane is done by Monocryl1 6/0 absorbable sutures. There are
no skin sutures (Pouzet et al. 2018).

First, the wound is cleared up with water and dried carefully, afterwards
Liquiband surgical glue is applied; it is a mixture of 90% n-butyl and 10% 2-octyl
cyanoacrylate. The dried scar had to be forced between thumb and forefinger to
confront the edges of the wound (fig.45-47). Distinct concentration is paid so that
the glue is not placed in the wound. The application is made largely on both sides of
the scar. No postoperative care is needed in the glued area (Pouzet et al. 2018).
 37

Figure 45: a) 6 months, left cleft lip and palate, preoperative appearance. b) Surgical glue used after
primary cheilorhinoplasty (Pouzet et al. 2018)

Figure 46: a) Adhesive at time of usage and before drying. b) Adhesive after one minute of drying and
application of nasal conformator (Pouzet et al. 2018)

Figure 47: a) Scar appearance at 10 days postoperatively. b) Scar at 6 months postoperatively (L. Pouzet
et al. 2018)

1.12 Surgical Glue Removal

Surgical glue ultimately shed off on its own several days after surgery. Leave
the incision site alone, do not draw the surgical glue covering the incision, and do
not scratch at the incision site if it itches. Doctors can prescribe anti-itch medication
 38

to soothe a prolonged itch. Scratching at your surgical glue makes it peel off faster
and may interfere with the healing process. Hold the wound away from sunlight.
Incisions revealed to sunlight get red and painful. Redness and swelling owe to
sunburn at the incision site may avoid the wound from healing properly. The wound
shouldn’t be washed, Avoid immersing incision site in water for several days
because water can make glue come off faster. Prevent putting lotions or ointments
on top of surgical glue because these substances may lessen its adhesive properties.
Surgical glue on incisions typically takes 2 - 3 weeks to fall off (Hammoudeh,
2018).

1.13 Comparison between Surgical Sealant and Conventional Sealing

Agent

Ideally, a wound closure method should be inexpensive, time-efficient, and

easy to carry out, and produce the optimal esthetic result. The basic aims of treating
wounds in general and skin incisions in particular are rapid closure with the
formation of a functional and esthetic scar (Ridgway et al, 2007).

1.13.1 Tissue Adhesives

Newer substitutes have been announced currently, such as adhesive paper tape
and tissue adhesives (table.1). Glue usually begins to work upon application within
10 seconds. Interestingly, the glue breaking strength is about five times the strength
of monofilament nylon sutures. Within 5-10 days, as the wound re-epithelializes,
the adhesive generally sloughs off. Wounds must be assessed before adhesive usage
for placement of subcutaneous sutures to reduce wound tension, remove
subcutaneous dead space and maximize skin edge eversion (Al-Mubarak and Al-
Haddab, 2013).

Table 1 Tissue adhesive (Toriumi, O’Grady, Desai and Bagal, 1998)

Uses Advantages Disadvantages Contraindications
Fixation of implant Lower infection rates Cost Infection

Lacrimal punctum Reduce operating time Proper patient selection Wound under tension
closure
Hair implantation Good cosmetic results Limitation on internal Edematous wound edges
 39

use

blepharoplasty Lower cost Partial thickness skin

loss

Laparoscopic wound Ease of use Burns

Tissue adhesion Immediate wound Animal bites

sealing
Closure of CSF leaks Fast return to routine Delayed wound healing
activities
Embolization of blood No need for
vessel postoperative suture
removal
Facial wounds and groin No risk of needle stick
wounds injury

1.13.2 Adhesive Tapes

Surgical adhesive tapes usually consist of an adhesive backing contain iso-octo-

acrylate and n-vinyl-pyrolidone (table.2). A perfect surgical adhesive tape should be
non-allergenic, non-irritating, water resistant, vapour permeable and must firmly
adhere to skin. Adhesive tapes are applied most frequently as adjunctive wound
support after staples or sutures are eliminated, in combination with buried dermal
sutures, or with absorbable running subcuticular sutures in low-tension wounds.
There are numerous critical factors in tape employment, including dry skin,
accurate apposition of edges, strict homeostasis, and the use of an adhesive adjunct;
additionally, the tension should be distributed along the entire tape to avoid blisters
(Sarifakioglu et al, 2006).

Table 2 Adhesive type (Sarifakioglu et al, 2006)

Uses Advantages Disadvantages
As adjunct wound support Prevent the local skin tension Unacceptable variability

In conjugation with buried dermal Less wound infection Poor reliability

suture

With absorbable running Avoid scar Loose their adhesiveness overtime,

subcuticular suture lead to dehiscence

In low tension wounds Maintain faster restoration of Difficulty to achieve appropriate

tensile strength edge approximation

Low cost Injury during removal

Less operating time

 40

1.13.3 Sutures

Sutures or staples are used most frequently because they give the required
mechanical support. A broad choice of suture materials is available to surgeons
today. Absorbable sutures are distinguished by the loss of most of their tensile
strength within 60 days after placement. They have to be absorbed with little or no
tissue reaction for the duration of the desired tissue support. They are applied
basically as buried sutures to close the dermis and subcutaneous tissue and to
decrease wound tension. Non-absorbable sutures are identified by their defiance to
degradation by living tissues, and they are most beneficial in percutaneous closures.
Artificial non-absorbable monofilament sutures are most frequently used in
cutaneous procedures. Artificial non-absorbable multi-filament sutures consist of
nylon and polyester are used uncommonly in dermatologic surgery (Parell et al,
2013)

Generally braided sutures potentiate more infections than non-braided sutures.

Unlikely, contaminated wounds closed by non-braided sutures presented a
significantly decreased incidence of wound infection. Many surgeons favor non-
absorbable monofilament sutures for their easy gliding through tissue, easy
handling, minimal inflammatory response and unlikeliness to break prematurely.
Other surgeons favor absorbable sutures owing to exclusion for suture removal, and
they save time and reduce patient anxiety and discomfort. The major drawback of
non-absorbable sutures is the need for their removal between 5 and 10 days after
being placed (Al-Mubarak and Al-Haddab, 2013).

1.13.4 Stapler
Disposable mechanical skin staplers are a fast and potent mean for closing long
skin incisions (fig.48). There is a believe that three- to four-fold reduction in the
time for skin closure was observed with staple use for wound closure. However,
more time is required for their removal post-operatively (Fick et al, 2015).
 41

Figure 48: Dermal stapler (Al-Mubarak and Al-Haddab, 2013)

Absorbable staples were invented as a substitute to sutures for closure of

surgical wounds (table 3). It was suggested that it preserve 40% of its strength at 14
days and is totally absorbed within a period of months. These skin staplers are
placed in the sub-cuticular tissue to hold the wound together without puncturing the
epidermis and are designed to join the cosmetic result of absorbable sutures with the
rapid closure times in addition to eliminating the need for metal staple removal
post-operatively (Al-Mubarak and Al-Haddab, 2013).

Table 3 Surgical stapler (Parell et al, 2013)

Uses Advantages Disadvantages
Contaminated wounds Rapid and effective method for long skin skin Unacceptable scar formation
incision

Long wounds Three to four fold reduction in time of wound Skin irritation
closure

Discomfort

Painful removal

Risk of wound contamination

1.13.5 Surgical Zipper

A new form of non-invasive skin closure system, the Medizip surgical zipper,
was announced to the field (fig.49). Rookler et al. reported no significant
differences in the cosmetic consequences or complications of the scar in
comparison with sutures. The zipper could be a safe substitute to conventional
suture material for skin closure (Luck et al, 2008).
 42

Figure 49: Medzip surgical zipper showing the method of puncture-free skin closure (Al-Mubarak and
Al-Haddab, 2013)

The zipper is ineffective in high-tension or wet wounds, wounds with

substantial curves of more than 20 degrees and in obese patients. Concluded
advantages presented as, it can be opened for wound inspection, comfortable for the
patient, reduce the time for skin closure in the operating room and does not require
removal, and therefore potentially promoting the cosmetic outcome (table.4). This
mean is very beneficial in pediatric patients and adults affected by neoplastic
disease (Bastian et al, 2013).

Table 4 Surgical zipper (Luck et al, 2008)

Uses Advantages Disadvantages

Wounds require multiple inspection Can be opened for wound Useless in high tension
inspection
Oncology patients Comfortable for patient Not used in wet wounds

Reduce operating time Not used in highly curved wounds

Useful for children Not used in obese patients

Adults with neoplastic lesion

Ease of handling

Good cosmetic result

1.13.6 Laser Tissue Bonding

Different types of laser welding/soldering techniques were tried to raise the

quality of healing for skin incisions. The use of wavelength-specific dye-absorbers
such as indocyanine green (ICG) and adhesive proteins such as albumin to laser
welding process may lead to faster and stronger close up of tissues than the
 43

traditional suture technique. A rapid and potent mean for wound closure, laser-
assisted tissue bonding (LTB) was currently improved. This method can be
subdivided into two main sub-phases: (1) photochemical tissue bonding (PTB) and
(2) photothermal tissue bonding. (Simhon et al, 2007)

Bass and McNally suggested that laser heating of collagen strand fibers on both
sides of the wound margins will lead them to intertwine and generate an immediate
wound seal followed by immediate integration of the extracellular matrix network,
therefore resulting in faster re-epithelialization and decreased granulation tissue
formation and fibroplasia, as demonstrated by scar width and macroscopic
appearance. Laser-assisted tissue bonding (LTB) offers a rapid and potent mean for
incision closure, thereby reducing scar formation and development of complications
(table.5). Experimental and clinical data have accumulated to support the concept of
accomplishing laser tissue soldering for improved wound healing after
reconstructive surgery (Al-Mubarak and Al-Haddab, 2013).

Table 5 Laser tissue bonding (Simhon et al, 2007)

Advantages Disadvantages
Minimal tissue handling Impaired wound healing

Maximal tissue alignment Low initial tensile strength

Water tightness Decrease long term tensile strength

Early re-epithelialization
Minimal scar

No foreign body reaction

Needle free technique

Many factors are associated in the choice of the skin closure material (table.6),
Including the type and place of the wound, available materials, physician expertise
And preferences, patient age and health (Al-Mubarak and Al-Haddab, 2013).

Table 6 Different wound closure materials (Al-Mubarak and Al-Haddab, 2013)

Tissue adhesive Adhesive tapes Suture Staples Zipper Laser
bonding
Lacerations Adjunctive Skin grafts Contaminate Wound need Repair of
wound support d wounds frequent inspection hypospadias

Pediatric patients lacerations blepharoplasty Long wounds Oncology patients

 44

Laparoscopic Clean
wounds contaminated
wounds
Lacrimal punctum
closure

Closure of CSF
leak

1.14 Healing Of Oral Surgical Wounds Using 3/0 Silk Suture and N-
Butyl Cyanoacrylate Tissue Adhesive

This study was performed to assess the clinical healing of the intraoral incision
sites after closure with silk suture or cyanoacrylate (Glubran 2) and also the
difference in their employment during the incision closure procedure (fig.50-52).
Cyanoacrylate is a biocompatible tissue adhesive and has good working features
like flow and fast setting. Cyanoacrylate is a good hemostatic agent. It has good
bonding properties and strength to hold tissue edges together (Greer, 1975 and
McGraw and Gaffesse, 1978).

Patient comfort is also important when comparing alternative incision closure

devices providing that the primary efficacy variable of dehiscence, infection and
cosmetic appearance are satisfactory. The present study exhibit that patient approval
was more when using cyanoacrylate rather than suture, because of lack of need for
its removal and less irritation during healing than suture reported by Greene (1999)
and Shamiyeh (2001). As a conclusion the use of N-butyl Cyanoacrylate (Glubran
2) in closure of intra-oral surgical incisions is an easy and potent method in tissue
adhesion. The wound healing is not different from using suturing but with better
clean margins. On the other hand, it greatly decreases the patient psychological
 45

stress and anxiety during suturing. The only drawback of this material is its high
cost in comparison to black silk sutures (Khalil et al, 2009).

Figure 50: a) incision in lower wisdom tooth region before using cyanoacrylate. B) one week follow up
(Khalil et al, 2009)

Figure 51: a) 2 weeks follow up, show complete healing. b) 4 weeks follow up (Khalil et al, 2009)
 46

Figure 52: a) an incision in upper right 2nd premolar area before closure using cyanoacrylate. b) 4 weeks
follow up after wound closure (Khalil et al, 2009)

2 Conclusions
Classical techniques of surgical incision closure have been used for many years.
Nevertheless, these methods are not without some problems and it is therefore
important to regard new developments - such as tissue adhesives - which may
provide some advantages for patients. An observable finding in this review was that
when compared tissue adhesives with sutures, a higher risk of dehiscence associated
with tissue adhesives. However, a faster wound closure technique may gain surgeon
satisfaction with glues and may also be charming to patients when surgery is
undertaken using only local anesthetic.

Tissue adhesives and sealants bear many advantages over classical wound
management techniques, such as potent and quick bleeding control, ease of
handling, and overall cost-containing potential. Tissue adhesives are also
demonstrated to have significant potential in many off-label applications,
particularly in tissue engineering and regeneration, enhancing integration between
biomaterials and tissues, and drug delivery. Considering their promising
performances, new tissue adhesives developed based on different adhesion
strategies, mussel-inspired glues for instance, might be the solution to many of
existing issues.
 47

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