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Natasha Agustin Ikhsan (13013082)
Eric Hansel (13014076)

Dr. Johner Sitompul
Dr. Dendy Adityawarman

SEMESTER I 2017/2018
1. Need identification, Ideas, and Selection

Blood loss due to battlefield, vehicle accidents, violence, wilderness accidents, construction
accidents, even nosebleed can be life threatening if not handled quickly and properly. Uncontrolled
blood loss is the major cause of death in battlefield. Haemorrhage, blood loss due to ruptured blood
vessel, cause 15-25% of trauma deaths in civilian hospital. Because of that, rapid hemostasis is
required to decrease mortality and also to achieve optimal recovery.

Injury of blood vessel will trigger the process of hemostasis with a certain sequence. First,
vessel will constrict to reduce blood flow. Next, platelets will adhere to the blood vessel wall at
the trauma site. Finally, platelets will activate and aggregate, along with a series enzymatic
reactions involving coagulation proteins that produce fibrins to form a hemostatic plug (Galanakis
et al., 2011). Hemostatic agents are used to imitate and promote or bypass specific steps of
coagulation process. Hemostatic agent can be classified into several categories which is physical
agents, absorbable agents, biologic agents, synthetic agents, and hemostatic dressings.

a. Physical agents

Physical agents consist of bone wax and ostene. Bone wax is a nonabsorbable mixture of
beeswax, paraffin, isopropyl palmitate, and a wax-softening agent. Bone wax can stop bleeding
almost instantaneously and is easy to handle. However, it cannot be absorbed by the body, making
bone healing harder to accomplish. Ostene is thought to be more superior than bone wax as it does
not hinder osteogenesis. While ostene can achieve hemostasis without promoting infections, no
studies on human have been published.

b. Absorbable agents

Another type of hemostasis agents is the absorbable agents including:

1. Gelatin foam
Gelatin foam is made from animal skin gelatin and can be applied as film, sponge or
powder. It provides physical matrix for clotting initiation and can be used for small vessel
bleeding and control bleeding from bone. It is also nonantigenic and works in neutral pH.
However, it cannot be used in closed spaces as it can swell and may compress nerves.

2. Oxidized cellulose
Oxidized cellulose has very good handling properties such as cotton-like consistency, does
not stick to instruments and used in dry condition. It also has low pH which can inhibit the
growth of microorganism. However, low pH can also hinders the activity of other
biological agents and cause inflammation.
3. Microfibrillar collagen
Microfibrilllar collagen (MFC) is a white, fluffy, dry material that can conforms well on
irregular surfaces. MFC does not cause significant swelling and can control wide areas of
parenchymal bleeding. The downside of using MFC is that it can stick to operators gloves,
may bind to neural structures and may pass through filters of blood scavenging system.

c. Biological agents

Another idea is to use biological agents for hemostasis. Biological agents come from the body
of living organism. Some materials that are classified as biological agents includes:

1. Topical thrombin
In the human body, thrombin is an enzyme that has roles in cell signalling, homeostasis,
and inflammation. Currently, thrombin is derived from bolvine plasma. Although it is easy
to apply and fast acting, it is not recommended due to immunologic response.
2. Fibrin Sealants
Fibrin sealants are 2 component products that combine thrombin and fibrinogen. The
components are mixed on the site of application, leading the thrombin to cleave fibrinogen
to fibrin that form clots. Wounds must be cleaned of antiseptic such as alcohol, metal ions
or iodine as thrombin and fibrinogen may be denaturated in the presence of these
3. Platelet Gel
This platelet gel contains the patients plasma so it can strengthen clot. It also has proteins
in gel that facilitate tissue regeneration. Another advantage of platelet gel is that it can be
used in surgery. However, centrifugation and pre use processing is needed before obtaining
this hemostatic agent.

d. Synthetic agents

Some hemostatic agents are synthetized from chemicals. Several hemostatic are included as
synthetic agents:

1. Cyanoacrylates
Cyanoacrylates are liquid monomers that forms polymer in the presence of water and
quickly glue surrounding surfaces together. It can form waterproof barrier and can achieve
full binding strength rapidly. It cannot be used for bites, puncture, and crush wounds.
2. Polyethylene Glycol Hydrogel
This agent consists of two solutions of high molecular weight of polyethylene glycol in
sodium phosphate buffer that can be sprayed on tissue to form a synthetic, hydrogel matrix.
It does not cause inflammation as well as bacterial infections but it can cause huge swelling.
3. Glutaraldehyde Cross-linked Albumin
This agent consists of glutaraldehyde solution and bovine serum albumin. Glutaraldehyde
covalently cross-links lysine residues of proteins in the albumin, and in extracellular
matrices and cell surfaces at the wound site to form a tough scaffold. It can achieve full
binding power rapidly and good for arterial bleeding. On the other hand, this agent can
cause serious problems such as inhibit cell growth, nerve dysfunction, may cause
hypersensitivity reaction and may have mutagenic effects.

e. Hemostatic dressings

Finally, there are some that are classified as hemostatic dressings. Those materials include dry
fibrin dressings, chitin and chitosan, mineral zeolite. Dry fibrin dressing is created by adding
freeze-dried fibrinogen and thrombin on gauze dressing. It has longer shelf-life than fibrin sealants
and does not need mixing at site application. However, it needs a strong packaging because it is
very brittle. Chitin is a polysaccharide that is produced by algae during fermentation. It can also
be found in the skeleton of antrhopod animals. It is effective for minor wounds and intended as
first-aid. Chitosan has the same properties as chitin. It also has antimicrobial properties. On the
other hand, chitosan shows varied results for severe wounds and cannot be used for patients with
shellfish allergies.

Mineral zeolite hemostatic agents are granular powders consisting of molecular sieves made
of inert minerals like oxides of silicon, aluminum, magnesium, and sodium. It can absorb liquid at
the site of the wound, thus increasing the concentration of clotting factors, platelets, and
erythrocytes to stimulate homeostasis. It is stable, easy to use, and only cost $10 per packet. It is
very effective on handling low pressure bleeding. The product now is also modified so that it can
absorb water less exothermically, making it less damaging to tissue and decrease the chance of
inflammation. It is achieved through embedding zeolite to surgical mesh so it can be used as a
compress, and pre-hydrating the zeolite. Recently, it is also used in emergency situation as first-

Blood loss due to various reasons has led an ongoing need to have a quick acting, safe, and
cheap homeostasis agent. Based on the advantages and disadvantages of the various ideas and
products, the selected homeostasis agent that has the most potential is the mineral zeolite,
specifically alumina silica nanoparticle. This agent is cheap as it only cost $10, does not cause
inflammation, infection, allergies, or swelling, and it can be used in emergency situation.

2. Product Manufacturing

One of products applying aluminasilica nanoparticles to stop bleeding is Quikclot

Nosebleeding . Main component of Quikclot is synthetic zeolite 5A with Linde Type A (LTA)
structure (Price, 2017). Currently, there are some 40 different natural zeolites and approximately
150 synthetic zeolites, including zeolites A. The pore diameter of zeolite 5A is around 5 or 0.42-
0.44 nm. Typical chemical composition of wet and dry zeolite 5A are:

0.7CaO-0.3Na2O-Al2O3-2SiO2-70H2O (wet)

0.7CaO-0.3Na2O-Al2O3-2SiO2-4.5H2O (25 wt% water)

Two processes applied in industry to produce zeolite 5A are hydrogel process and kaolin
process (Farag & Zhang, 2012) which are elaborated in the followings:

a. Hydrogel process

A zeolite gel is a hydrous metal aluminosilicate which is prepared from aqueous solution,
reactive solids, colloidal sols, or reactive aluminosilicates such as meta-kaolin and glasses. Starting

Figure 1. Hydrogel process flow diagram for manufacturing of 4A zeolite from hydrogel

materials for this process include an aqueous solution of sodium silicate (Na4SiO4), water, Al2O3-
3H2O to generate NaAlO2 and NaOH. All starting materials are mixed mixed with water in a tank,
followed by gel makeup reactor, then gel aging and crystallization, as displayed in Figure 1. After
wet zeolite 4A crystals are formed, zeolites are filtered to remove water. Afterwards, final product
zeolite 4A is obtained. All reactions involved are:
Sodium Aluminate formation
2NaOH + Al2O3-3H2O 2NaAlO2 (Sodium aluminate) + 4H2O (1)
Zeolite 4A gel formation
Na4SiO4 (Sodium silicate) + NaAlO2 (Sodium aluminate) + H2O 2Na2O-Al2O3-1.75SiO2-
70H2O (Zeolite 4A Gel) (2)
Water removal
2Na2O-Al2O3-1.75SiO2-70H2O (Zeolite 4A Gel) 2Na2O-Al2O3-1.75SiO2-6H2O (Zeolite 4A dry)
+ 64H2O (3)

b. Kaolin conversion process

Apart from hydrogel process, starting material for this process is kaolin (Al2Si2O5(OH)4) that
is usually dehydroxylated to become metakaolin (Al2Si2O7). The dehydroxylated process is
performed by air calcination at 500-600C, to form meta-kaolin according to the reaction:
Al2Si2O5(OH)4 (kaolin) Al2Si2O7 + 2H2O (meta-kaolin) (at 550C) (4)
At higher temperature, (1000-1100C) meta-kaolin breaks down to calcined kaolin which
is called mullite (Si2Al6O13) and SiO2 called cristobalite through this reaction:
3Al2Si2O7 Si2Al6O13 + 4SiO2 (at 1000-1100C) (5)
Afterwards, mullite and cristobalite are reacted with caustic soda and water in a gel make-
up tank to form zeolite 4A gel. The reaction of this process is written below:
12NaOH + 204H2O+ Si2Al6O13 + 4SiO2 (200F) 3(2Na2O-Al2O3-2SiO3-70 H2O) (zeolite 4A
gels) (6)

Figure 2. Process flow diagram for producing zeolite 4A and 5A via kaolin conversion process

To produce zeolite 5A, zeolite 4A gel is fed to an ion exchanger to mix it with calcium
chloride and water. The main process is to replace Na+ ions in zeolite 4A with Ca2+ ions to produce
zeolite 5A which is described in this reaction:
(2Na2O-Al2O3-2SiO2-70H2O) (Zeolite 4A Gel) + 0.7 CaCl2 (200F) 0.7CaO-0.3 Na2O-Al2O3-
2SiO2-70H2O (Zeolite 5A wet) + Na2O + 1.4 NaCl (7)

Process flow diagram is shown in Figure 2.
Zeolite 5A which is still wet will get dehydrated while passing through dryer to remove
water and produce dry zeolite at 1000F. The dehydration reaction is written below:
0.7CaO-0.3 Na2O -Al2O3-2SiO2-70H2O (1000F) 65.5 H2O + 0.7CaO-0.3 Na2O -Al2O3-2SiO2-
4.5H2O (Zeolite 5A dry) (8).
Inside dryer, there are screens to remove undersize and oversize particles. In other words,
there is particle size distribution (PSD) to control the homogeneity of product particle size. The
final zeolite 5A product exits from the screens.
These are two ways to produce zeolite 5A. The next step it to manufacture the commercial
product of this invention. The zeolite particles are packed into surgical mesh and then packaged
into ready-sell products as shown in Figure 3.

Figure 3. Commercial product of hemostatic gauze

3. References
Farag, I. H., & Zhang, J. (2012). Simulation of Synthetic Zeolites-4A and 5A MAnufacturing or
Green Process. IRACST-Engineering Science and Technology: An International Journal
(ESTIJ), 2(2), 188-195.

Price, G. L. (2017, October 3). Zeolite. Retrieved from TU Chemical Engineering:

Li, Y., Li, H., Xiao, L., Zhou, L., Shentu, J., Zhang, X. and Fan, J. (2012). Hemostatic Efficiency
and Wound Healing Properties of Natural Zeolite Granules in a Lethal Rabbit Model of
Complex Groin Injury. Materials, 5(12), pp.2586-2596.

Achneck, H., Sileshi, B., Jamiolkowski, R., Albala, D., Shapiro, M. and Lawson, J. (2010). A
Comprehensive Review of Topical Hemostatic Agents. Annals of Surgery, 251(2), pp.217-

Kudela, D., Smith, S., May-Masnou, A., Braun, G., Pallaoro, A., Nguyen, C., Chuong, T., Nownes,
S., Allen, R., Parker, N., Rashidi, H., Morrissey, J. and Stucky, G. (2015). Clotting Activity
of Polyphosphate-Functionalized Silica Nanoparticles. Angewandte Chemie International
Edition, 54(13), pp.4018-4022.