2013

Modified Polycarbonate-urethane Polymer to Rescue Hydrocephalus

BMA 513 PROJECT- BY MOHAMMAD ATIF FAIZ AFZAL

COURSE INSTRUCTOR- DR. ROBERT BAIER

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Contents

1. Introduction ................................................................................................................... 2

2. Hydrocephalus ................................................................................................................ 2

3. Treatment of Hydrocephalus .......................................................................................... 3

3.1 Silicone Shunt ................................................................................................................................ 4

3.2 Problems related to silicone shunt ............................................................................................... 4

3.2.1 Infection ................................................................................................................................ 4

3.2.2 Silicone Allergy ...................................................................................................................... 5

3.2.3 Market Issue of Silicone products ......................................................................................... 6

3.2.4 Ventricular shunt obstruction ............................................................................................... 6

3.2.5 Inflammatory reaction to cerebrospinal fluid shunt insertion ............................................. 6

3.2.6 Silicone shunt calcification and degradation ........................................................................ 7

4. New Shunt design based on Polyurethane ...................................................................... 7

4.1 Polyurethane ................................................................................................................................. 7

4.2 Chemical structure of polyurethane ............................................................................................. 8

4.2.1 Effect of diisocyanate monomers ......................................................................................... 8

4.2.2 Effect of polyols..................................................................................................................... 9

4.3 Surface modification of polyurethanes ........................................................................................ 9

4.3.1 Grafting techniques............................................................................................................... 9

4.3.2 Effect of protein adsorption on polyurethanes .................................................................. 11

4.4 Biodegradation and stress cracking of polyurethanes ................................................................ 11

5. Final Material Choice for designing shunts for treating hydrocephalus .......................... 13

6. Testing of the shunt ...................................................................................................... 14

6.1 Mechanical properties ................................................................................................................ 14

6.2 Surface Properties ....................................................................................................................... 14

6.3 Biocompatibility .......................................................................................................................... 15

6.4 Sterilization ................................................................................................................................. 15

7. Conclusion .................................................................................................................... 16

8. References ................................................................................................................... 17

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1. Introduction

The problem of hydrocephalus has been noted since centuries, but only has the problem been

understood in the late 19 century. Since then, constant efforts are being made to come up with effective

diagnosis for hydrocephalus. Silicone shunts were developed in early 1950’s which would rescue the

problem of hydrocephalus. But the problems related to mechanical and infectious complications, over

drainage of the cerebrospinal fluid and loculations were observed related to silicone shunts. There have

also been few reports of silicone allergy which were causing the shunt to fail [1]. Up to date there has

been numerous efforts and trials done with modified silicone shunts as well as other polymeric shunts

to overcome these problems. The hunt for the novel material for shunts which has no allergies and that

can overcome the noted deficiencies of silicone shunts is still going on.

In my report, I present a review on hydrocephalus, current treatments and their limitations and

a new material to be used as a shunt. I present a chemically modified polycarbonate-urethane (PCU) as a

potential polymeric material to be used in the development of shunts for treating hydrocephalus.

2. Hydrocephalus

Figure 1 shows the normal production and flow of CSF [2]. The CSF is produced by the choroid

plexus in the lateral ventricles and flows into the third ventricle and then drains into the fourth ventricle

through the cerebral aqueduct and then subsequently flows out into the subarachnoid space.

Hydrocephalus is the accumulation of the cerebrospinal fluid (CSF) inside the ventricular system in the

brain resulting in a raised intracranial pressure. There are two reasons for the accumulation of the CSF:

obstruction in the CSF flow or excessive production of CSF. In both the cases, the pressure builds in the

brain leading to clinical symptoms and signs. Obstruction to the CSF flow can be seen either inside the

ventricular system (Obstructive hydrocephalus) or outside the ventricular system (Communicating

hydrocephalus) [3, 4]. The cause of obstructive hydrocephalus can be midbrain tumors, congenital

causes, brain hemorrhage or infection. Whereas, causes of communicating hydrocephalus can be

scarring of subarachnoid space and arachnoid, intraventricular hemorrhage and as a complication of

childhood meningitis [4].

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Figure 1- Normal production and flow of cerebrospinal fluid (CSF) [2]

The signs of hydrocephalus and the rate at which hydrocephalus progresses is highly dependent

on the age of the patient. In children with hydrocephalus problem, show symptoms like increase in head

circumference, irritability, separation of cranial sutures, tense fontanelle and episodic apnoea [5].

Whereas in adults, the symptoms are not specific which include headache, vomiting, congenital

impairment, loss of concentration ability, gait disturbance, visual obscurations and altered levels of

consciousness [3]. All the above symptoms may reflect the increase in the intracranial pressure.

3. Treatment of Hydrocephalus

The problem of accumulation of water in the brain has been known since a long time. The

problem of hydrocephalus can be theoretically treated by three means: by deactivating the choroid

plexus and thus reducing the CSF production, by surgical removal of lesions to reopen the obstructed

pathways or by shunting the CSF into body cavities [6]. It is thought that Hypocrates, the father of

medicine, was the first to attempt a treatment to this problem of “water on the brain” in 5th century BC

[7]. Aleksander et al., described that the treatment of this problem, now known as hydrocephalus,

underwent three stages of evolution [8]. In first stage (prior to late 19th century), the hydrocephalus

problem was stated as “water on the brain” and the cerebrospinal fluid (CSF) circulation was not

understood. The second stage extends from the late 19th century to the mid-20th century, when the

concept of the CSF circulation in the brain was understood by the clinicians, but the surgical treatment

still was still not possible. The third stage (post mid-20th century) begins with the development of valve

regulated shunts and application of new bioavailable materials. Silicone shunts regulated with valves

were developed by Pudenz et al in 1957 for the treatment of hydrocephalus.

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3.1 Silicone Shunt

Primary requirement of the shunts for the hydrocephalus treatment include biocompatibility

and fatigue-free material that could withstand long term mechanical stress. Silicone shunts were

developed in the 1950’s and are proven to have good biocompatibility and resistant to mechanical

stresses. Thus, shunt operations using silicone shunts became the standard procedure later on. Current

treatment of hydrocephalus is the insertion of a silicone based catheter into the ventricular system and

then draining the CSF into other bodily cavities.

Silicone is a dimethyl polysiloxane and is considered to be biologically inert and stable material.

It is non-toxic, non-immunogenic and non-carcinogenic material, and therefore is considered an ideal

material for hydrocephalus shunting [9]. Silicone surface has very poor cell adhesion and thus do not

promote cell proliferation [10].

However, there have been many reports on the complications associated with silicone based

implants. The problems are mostly related to the surface properties of silicone which includes the blood

thrombi formation around the implant, scar tissue formation, infection, silicone allergy and other

problems related to the hydrophobic nature of silicone material.

3.2 Problems related to silicone shunt

3.2.1 Infection

Infection is the most frequent and serious complication in hydrocephalus shunting devices,

resulting in higher mortality and morbidity of the patients [11]. Silicone material is known to promote

bacterial adhesion, in particular staphylococcal species, therefore are more prone to causing infections

[10, 12]. The bacterial adhesion is dependent on the surface properties and is enhanced by microscopic

surface irregularities. Many efforts are being put into overcoming this problem of infection related to

silicone shunts. One of the initial efforts was to reinforce the silicone with silver particles [13-17]. The

silver particles release silver ions which diffuse into the cytoplasm of bacteria and cause impairment to

the DNA and RNA of the bacteria, thus inhibiting the bacterial growth [18]. Although silver impregnated

silicone show anti-bacterial activity, it has been shown that antibiotic impregnated shunts are more

effective for anti-microbial treatment [19]. In an another study on one of the patients, it was shown that

the patient was allergic to silver which resulted in a shunt failure [20].

In the last decade, more research is being done in developing shunts impregnated with antibiotic

materials. Silicone shunts are being impregnated with antibiotic materials like rifampicin, minocycline

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and clindamycin to reduce the complications related to infections [11, 16, 21-23]. These antibodies

particularly decrease the staphylococcal infection. It has been reported that these antibiotic

impregnated shunts also show anti-bacterial activity against the bacteria, Propionibacterium acnes,

which are the cause of 14% of shunt related infections [24]. Though these antibiotic impregnated shunts

have good resistance to infections, there are other complications related to these shunts which are still

not clearly understood. There are reports of allergic reactions occurring due to the antibiotics used and

thus leading to the shunt failure [25, 26]. Very high levels of CSF eosinophilia were observed in

conjunction with shunts impregnated with rifampin and minocycline [26].

These complications related to infections and other allergic reactions to antibiotics can be overcome by

using a new material for the shunt which does not promote bacterial adhesion compared to silicone

material. One such material is polyurethane which has been shown to have poor bacterial adhesion

compared to silicone. Thus, in terms of infections, polyurethane can be an ideal material for designing

shunts to rescue hydrocephalus.

3.2.2 Silicone Allergy

One of the less frequent complications related to the silicone shunts is the silicone allergy [27].

The role of silicone allergy has not been clearly understood and also there is not much research

published related to silicone allergy. Brownlee et al, reported a case of colonic perforation by a

ventriculoperitoneal shunt, which is attributed to the patients allergic reaction to the silicone material

[28]. The patient had three shunt revisions and in each time the patient’s skin breakdown would occur

over his shunt tubing and no evidence of infection or any other malfunction was observed. The patient

was eventually implanted with a polyurethane shunt and then no complications were observed,

confirming that the patient had silicone allergy.

Hussain et al, reported the distal ventriculoperitoneal shunt failure caused by the silicone allergy

[1]. The reported the case of silicone allergy in a 24 year old man who has to go through 9 shunt

revisions in a span of 3 years and no signs of infections or shunt obstruction was observed during these

revisions. They failure of the shunt multiple times is attributed to the allergic reaction of the patient to

the silicone material. The symptoms shown in the patient due to the silicone allergy are headache,

lethargy, abdominal pain, fever and erythema. After the problem of silicone allergy was identified, the

patient was implanted with polyurethane shunt and the patient did not show any adverse immune

reaction to the polyurethane material for next 8 years. Thus, polyurethane material acted like a rescue

material for hydrocephalus in cases of silicone allergy.

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3.2.3 Market Issue of Silicone products

In November 1991, FDA called a meeting to discuss several premarket approval applications

(PMAs) for silicone breast implants and concluded that the manufacturers could not provide sufficient

data on the safety of silicone based implants [29]. Therefore, following this meeting in January 1992,

FDA announced voluntary moratorium on silicone breast implants and requested the manufacturers to

take out their silicone breast implant products from the market and stop supplying them. This resulted

in the manufactures putting a halt on the production of medical grade silicone. As a result of no

production of silicone material, no silicone shunts were available for the treatment of hydrocephalus

and thus putting the life of 75,000 children born each year with hydrocephalus at risk. This action led to

development of non-silicone based shunts and immense research was invested into designing shunts

with other polymeric materials. One of the material that shares many properties similar to that of

silicone is polyurethane and therefore was emerged as an alternative to silicone material [30].

3.2.4 Ventricular shunt obstruction

Half of the shunt implants fail within 2 years of implantation due to the obstruction of the shunt

[31]. Blood and brain tissue come into contact with the shunt during insertion and then become

necrotic. In most of the cases, the ventricular wall collapse onto the shunt and result in the tissue

ingrowth and eventually blocks the shunt. Huge number of cases have been reported in the literature on

the tissue obstructing the shunts [32-39]. In most of these cases the catheters were found to contain

remnants of clotted blood, necrotic brain tissue, connective tissue, tumor cells and other foreign

materials. Silicone material has very poor cell adhesion and do not promote any cell proliferation, but

still silicone shunts have shown obstruction. This shows that, shunts of all physical designs are

susceptible to the obstruction even if the surface is highly bio inert. Recently, Ginsberg et al, have come

up with an idea to remove the obstruction by ultrasonic cavitation [38]. They showed that 90% of the

occluded blocks were unblocked within few minutes and were restored to normal flow.

3.2.5 Inflammatory reaction to cerebrospinal fluid shunt insertion

After the shunt is inserted, the initial events that occur is of vital importance to the long term

performance of the shunt. Platelets can adhere to the silicone surface and also some platelets can enter

the shunt and go into more distal components of the shunt and alter the functions of the valve

components [40]. Proteins also adsorb on the silicone surface, which stimulate the proliferation of cells

on material surface [41]. In spite of silicone being bio inert, silicone surface can evoke a inflammatory

reaction because of adsorption of serum proteins on silicone surface. Immense research has been done

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to alter the surface properties to reduce the inflammatory reactions. Some of the surface modifications

include coating the surface with hydrophilic molecules [42], surface grafting of carboxylic acid groups

[43], altering the surface charge [44] and altering the surface texture by reducing the microscopic

surface roughness [45]. Polyurethane is known to have minimal immunological reaction when implanted

in the body [1]. Therefore, in perspective of having minimal inflammatory response polyurethane is an

ideal material for shunt design.

3.2.6 Silicone shunt calcification and degradation

Late mechanical dysfunction of shunts is another major complication resulting in the shunt

failure. The silicone shunt starts to degrade with time especially that in contact with the subcutaneous

region, and become brittle and eventually lose the mechanical strength [39, 46]. During the course of

time, calcification (deposition of calcium phosphates) can occur on the surface of the silicone which is

the primary reason for making the material brittle in nature, and therefore more prone to cracking [34,

47]. Also, when these calcified silicone is subjected to mechanical stresses, the coating may detach and

result in an inflammatory reaction leading to the shunt failure [48]. Browd et al, showed that the silicone

material with a coating of gel can decrease cell adhesion and calcification, thus leading to less fractures

[39].

4. New Shunt design based on Polyurethane

Many other non-silicone based polymer materials have been used for designing shunts and have

been tested. For example, some of the polymers that have been tested for shunt applications are

polyurethane [17], polyethylene [49] and poly tetra fluoro ethylene (PTFE) [50]. In the following write up

I propose a new modified polyurethane based material to design shunts for hydrocephalus treatment.

4.1 Polyurethane

Polyurethanes refers to a very broad family of polymers which have limitless applications [51].

Polyurethanes have many unique biological properties which led to its wide use in biomedical

applications. These polymers have excellent mechanical properties like high tensile strength, abrasion

resistance and excellent tear strength. The attractiveness of polyurethanes comes from the fact that

their chemical structure can be tailored in such a way to meet structure property requirements of

various applications [52].

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Polyurethanes were first investigated as implant materials in late 1960’s by Boretos et al, and

since then polyurethanes have been widely used in various biomedical applications [53]. For example,

polyurethanes have been used in cardiovascular implants, oto-rhino-laryngology, esthetics, dentistry,

regulation, reproductive systems, orthopedics and biomechanics, tissue reconstructions and general

surgical applications.

A unique property of polyurethane is that the polyurethane surface do not interact with

proteins and do not allow for any cell adhesion to occur on the surface. Therefore, polyurethane surface

does not result in any immunological reaction when implanted in the body. It has been shown that

polyurethane coated materials result in a thicker and long lasting capsule formation when compared to

silicone based materials [54]. However, the thicker capsule shows more tissue injury near the implant,

but the long lasting nature of the capsule shows that the implant is stable and no immune reactions are

occurring.

4.2 Chemical structure of polyurethane

A diisocyanate, a polyol and a chain extender (diol or diamine) are reacted to form a

polyurethane elastomer. The resultant polymer has two segments: a soft segment consisting of polyol

and a hard segment consisting of the diisocyanate and the chain extender. Therefore, the physical and

chemical nature of the polyurethanes depends on these soft and hard segments.

4.2.1 Effect of diisocyanate

Two different classed of Diisocyanate are used for the preparation of polyurethanes: Aromatic

or aliphatic type diisocyanate. In the perspective of biomedical grade polyurethanes, manufactures

generally used 4,4’-diphenylmethane diisocyanate (MDI) (Figure 2). However, there is a possibility that

MDI may degrade to form carcinogenic product, methylene diamine. To overcome the problem of

potential carcinogenic product formation, manufacturers use hydrogenated version of MDI called as

HMDI. Though HMDI is safe to use in biomedical grade polyurethane, it has a limitation of poor

mechanical properties when compared to aromatic MDI.

My choice: Till date no case has been reported on the methylene diamine poisoning or tumor formation

when MDI is used in biomedical grade polyurethane. Also, shunts are required to have good mechanical

stability so that they can be implanted for a long periods of time. Therefore, I propose to use MDI as a

diisocyanate in the synthesis of polyurethane for shunts.

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Figure 2: Chemical structure of 4,4’-diphenylmethane diisocyanate (MDI)

4.2.2 Effect of polyols

The polyol selection for the synthesis of polyurethanes determines the mechanical

characteristics of the final product. Initially polyester-urethanes were used in biomedical applications

because these polymers have good mechanical properties as the ester groups form hydrogen bonding.

However, polyester-urethane are more prone to rapid hydrolysis because of presence of ester groups.

Therefore, polyether-urethanes were developed, which have good stability in presence of water and do

not get hydrolyzed. However, polyether-urethanes have poor mechanical properties when compared to

polyester-urethanes. Polycarbonate-urethanes have also been developed to overcome this problem of

hydrolysis. Polycarbonate-urethanes are shown to have excellent resistance towards hydrolysis,

environmental stress corrosion and metal ion oxidation.

My choice: As shunts will always be in contact with a moist environment, it is required that the material

has good stability and resistance towards hydrolysis. Therefore, I propose to use a polycarbonate

urethane for the synthesis of shunts. A more specific selection of the polycarbonate urethane will be

discussed in the following sections.

4.3 Surface modification of polyurethanes

It is well known fact that the surface chemistry of the material determines the biocompatibility.

Therefore, numerous studies on the surface modification of polyurethanes have been done in the past

to obtain an antithrombotic polyurethane surface. Most of the approaches for the surface modification

include coating processes, grafting techniques using oxidation, ionization, polymerization and surface

derivatization, and photo-chemical immobilization reactions.

4.3.1 Grafting techniques

Various grafting techniques have been used to modify the surface of polyurethane in the past

[55-61]. McCoy et al, have six different polyurethane graft materials and evaluated these materials as a

potential material in designing shunts [62]. Their findings revealed that the alkyl grafted polyurethane

showed the most thrombosis and whereas the sulphonated polyurethane showed least thrombogenic

behavior. Very recently, Zhou et al, studied polyurethane grafted with polyacrylic acid (PAA) to improve

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the hydrophilic and lubricious properties [63]. They showed that PAA can be firmly grafted on the

polyurethane surface activated by ozone and potassium peroxydisulphate. Their findings confirm that

surface ozonization is a better pretreatment for medical grade polyurethane to enhance surface

properties.

In an another study, Inoue et al, studied the biocompatibility of polyurethanes modified by

surface graft polymerization of acrylamide and dimethyl acrylamide (DMAA) [58]. They oxidized the

polyurethane surface with ozone before grafting DMAA on the surface. A firm layer of DMAA grafted

surface was obtained which is attributed to the technique of ozonization before grafting. There are

other reports of acryl amide grafting to the polyurethane surface using glow-discharge treatment to

produce ozone at the surface [57]. In all these studies, the ozonization of the surface of polyurethane

did not result in any deterioration of the bulk mechanical properties of the material. Inoue et al,

performed an ex-vivo evaluation of the DMAA-grafted polyurethane to determine the blood

compatibility of the material. They inserted the polyurethane tube as an anterio-venous shunt and

studied the platelet adhesion to the surface of the material and compared the results with that of a non-

modified polyurethane surface. Figure 3 shows the results obtained after 1 hour and 12 hours of

exposure to the blood [58]. It can be been seen that the DMAA grafted polyurethane surface do not

support any platelet adhesion even after 12 hours of contact with blood, whereas huge amount of cell

adhesion is observed on the non-modified polyurethane surface. Thus, a significant improvement in

blood compatibility of polyurethane is observed when grafted with DMAA.

Figure 3: SEM microphotographs of the virgin and the DMAA-grafted polyurethane tube with a graft

density of 30 mg/cm2 after 1 h (a) and 12 h (b) exposure to blood in the A–V shunt in a rabbit [58].

My choice- A shunt material designed with polyurethane and surface grafted with DMAA will have

excellent surface properties which does not support any cell adhesion or clot formation. Therefore,

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there is a very less probability of shunt obstruction which is the considered the major complications in

hydrocephalus shunts. I propose to use a DMAA grafted polycarbonate-urethane for designing shunts.

4.3.2 Effect of protein adsorption on polyurethanes

The surface of polyurethanes can be adsorbed by albumin proteins prior to implantation, which

mask the surface from the blood’s host defense activation, thus making the surface less thrombogenic

[64-67]. Once a material is implanted in the body, the first event that occurs is the adsorption of plasma

proteins. The composition of the plasma proteins adsorbed on the surface is highly dependent on the

material surface. Pre adsorption with albumins will prevent the adsorption of other plasma proteins like

fibrinogen and fibronectin which are known to promote thrombus formation. In contrast, a study by

Anderson et al, shows that the albumin adsorbed surface activates the growth of monocytes [68].

However, a huge amount of literature show that the immobilization of albumin proteins on material

surface exhibit significantly reduced thrombogenic activity.

My choice: Adsorption of albumin protein on the polyurethane surface have shown promising results in

the past. Therefore, I propose to immobilize the surface of DMAA-grafted polycarbonate-urethane with

albumin proteins before implantation.

4.4 Biodegradation and stress cracking of polyurethanes

Polyester-urethanes are more prone to degradation and are not suitable for long-term

biomedical applications due it its very poor hydrolytic stability [52]. To overcome this problem,

biomaterial scientists developed polyether-urethanes, which have good hydrolytic stability. However,

even polyether-urethane start to degrade and result in cracking. For example, the most common

macrodiol, poly (tetramethylene oxide) (PTMO), is prone to oxidative degradation in long term use. This

oxidative degradation leads to deep cracking in the surface, erosion and loss of mechanical properties

[52]. The degradation behavior of polyurethanes is not clearly understood and is assumed to be caused

because of oxidative pathways involving environmental stress cracking [52]. Figure 4 shows the

degradation on the polyurethane surface due to environmental stress cracking [52]. Stokes and Davis

from Medtronic, Inc. reported the failure of various polyurethane devices due to cracking [69]. They

discovered two mechanisms responsible for the failure of polyurethane devices: stress cracking and

metal catalyzed oxidation. Stress cracking is a phenomenon where the continuous stress/strain of the

polymer interacts with the tissue and subsequently resulting in cracks.

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Figure 4: SEM image showing environmental stress cracking on polyurethane surface [52].

McCarthy et al, were one of the first groups to study the in-vivo degradation of polyurethanes

using transmission-FTIR microscopy [70]. They studied the degradation of three different commercially

available polyurethanes implanted for 18 months. Their findings showed that the degradation of the

polyurethanes was associated with the oxidation of the soft segments and the breaking of bonds

between the soft and hard segments by hydrolysis. Since the phenomenon of stress cracking in

polyurethanes is known, immense research is being done to overcome this problem and to obtain long-

term stable polyurethanes by chemical modification techniques. Various degradation resistant

polyurethanes have been developed by changing the macrodiols. For example macrodiols based on

hydrocarbon [71], polyether [72], polycarbonate [73] and siloxane [74] were used to develop

polyurethanes. It was observed that the siloxane macrodiol based polyurethanes had the longest

biostability and followed by polycarbonate macrodiol based polyurethanes.

Polycarbonate urethanes have shown to have excellent resistance towards hydrolysis,

environmental stress corrosion and metal ion oxidation. Pinchuck et al, reported for the first time the

use of polycarbonate urethanes as long term medical implants [75]. Since then, many approaches have

been made to enhance the biostability of polycarbonate urethanes by chemical modifications [76, 77].

Recently, Lewandowska et al, synthesized a new polycarbonate urethane from polyhexamethylene

carbonate diol (PHCD) and HMDI [76]. The resultant polymer has good mechanical properties like tensile

strength, greater storage modules of elasticity at bending and lower glass transition temperature. This

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polymer also has very less toxicity and very less interaction with plasma. This modified polycarbonate-

urethane also showed excellent resistance to sterilization techniques like ETO and glow discharge.

My choice: Polycarbonate-urethanes have long term stability in-vivo along with excellent mechanical

and biological properties. Silicone based urethanes have superior properties than carbonate based

urethanes in terms of bio stability, but silicone based materials have other limitations as explained in

section 3.2. Therefore, I propose to use a polycarbonate urethane synthesized from polyhexamethylene

carbonate diol (PHCD) and MDI to design shunts for hydrocephalus treatment.

5. Final Material Choice for designing shunts for treating hydrocephalus

The final choice of material for designing shunts is dimethyl acrylamide grafted polycarbonate.

Following is a step wise approach to obtain the final product

a) Synthesis of polycarbonate urethane (PCU) polymer

The synthesis of the polymer will follow on the same protocols as mentioned by Lewandowska

et al [76]. Firstly a reaction between polyhexamethylene carbonate diol (PHCD) and 4,4’-

diphenylmethane diisocyanate (MDI) will be carried to obtain a prepolymer. This prepolymer is

dissolved in a solvent and a chain extender will be mixed in the solution. The chain extender in

this case will be 1,4-Butanediol. The reaction will be carried out at 70-80OC for 2-3 hours and

then subsequently dried at higher temperatures (about 120OC) to obtain a polycarbonate

urethane (PCU) polymer.

b) Extrusion in the shape of a tube

Obtained PCU polymer will be processed into the shape of tubes by extrusion technique. The

extrusion will be performed such that the final PCU tube will have an outer diameter of 2.5 mm

with a thickness of 0.5 mm. Great care should be taken during the process of extrusion to

prevent any cracks on the surface of PCU tube.

c) Impregnating with silver nano-particles

Impregnation of silver nano-particles will be obtained by following a novel method proposed by

Webb et al [78]. This method has not been used for impregnating silver particles into

polyurethane materials before. In this method, organic complexes of silver nano-particles will be

synthesized and dissolved in supercritical carbon dioxide. PCU will be placed in a high pressure

chamber and then the supercritical carbon dioxide containing organic complexes of silver is

vented into the chamber. The organic complexes of silver distribute homogenously inside the

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polymer matrix. Subsequently, hydrogen gas is vented to decompose the organic precursors and

then the residues of the organic precursors is removed completely by flushing super critical

carbon dioxide. The resultant material will have homogenous distribution of silver nano-

particles.

d) Surface grafting with DMAA

The surface of PCU tubes will be modified by grafting with dimethyl acrylamide (DMAA). The

grating will be done by following the protocol mentioned by Inoue et al [58]. The PCU tube will

be exposed to high ozone concentration to form peroxides on the surface of the tube. This tube

will then be immersed in a solution of DMAA. Then graft polymerization will be carried out at

35OC and then the grafted PCU will be washed with distilled to remove the homopolymers that

might have formed.

e) Immobilization of albumin proteins on the surface

Serum albumin proteins will be immobilized on the surface of the PCU tubes as mentioned by

Ryu et al [79]. PCU tubes will be grafted with serum albumin proteins by placing the tubes in a

phosphate buffer solution (PBS) containing 0.2 % (w/v) human serum albumin and 0.02%

sodium azide, for 12 hours at 4OC. the tubes will subsequently be washed with PBS and the dried

to obtain albumin immobilized PCU tubes.

6. Testing of the shunt

6.1 Mechanical properties

Polycarbonate urethanes in general have excellent mechanical properties compared to

polyether urethanes and polyester urethanes. Also, polycarbonate urethanes are known to have

excellent resistance to hydrolysis, environmental stress corrosion and metal ion oxidation. The proposed

PCU material will also have good mechanical properties and long term stability. However, experimental

studies like tensile strength and long term stability test should be performed to confirm the properties

(modulus, toughness, UTS etc.) of the proposed material.

6.2 Surface Properties

It has been shown that the polymeric surfaces when grafted with DMAA show a decreased

critical surface tension values. For example, polytetrafluoroethylene (PTFE) when surface grafted with

DMAA showed a decrease in the critical surface tension from 16 to 14 dynes/cm and polyethylene when

grafted with DMAA showed decrease in the critical surface tension from 22 to 20 dynes/cm [80]. The

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critical surface tension of various medical grade polyurethanes lie in the range of 22 to 29 dynes/cm

[81]. The critical surface tension of Chronoflex®, which is a polycarbonate urethane is evaluated as 28

dynes/cm [82]. Chronoflex® is synthesized from MDI (4,4’-diphenylmethane diisocyanate) and a

polycarbonate diol. Thus, it is hypothesized that the critical surface tension of the proposed material

(DMAA grafted PCU) will be in the range of 24-27 dynes/cm. Thus, the proposed material can serve as an

ideal material for shunt designing. However, experimental studies is required to confirm the critical

surface tension of the proposed material.

It has been shown that the grafting of medical device with DMAA results in a surface with very

low coefficient of friction. Ikeuchi et al, reported a value of 0.04 coefficient of friction for a DMAA

grafted polyurethane [83]. Such catheters with very less coefficient of friction are promising because of

ease in operation and also prevent tissue injury. The proposed material of PCU will also have a low

coefficient of friction as its surface will be grafted with DMAA.

6.3 Biocompatibility

An ideal shunt material should be compatible with the brain tissue, subcutaneous tissue,

cerebrospinal fluid (CSF) and have excellent blood compatibility. To test the proposed material, initially

in-vitro biocompatibility testing should be performed and also in-vitro metal-ion-induced oxidation

should be performed to evaluate long term stability. Then the material should be evaluated by ex-vivo

shunting. Following this the material can be evaluated for in-vivo biocompatibility by performing in-vivo

implantation in rabbits or dogs.

6.4 Sterilization

It has been shown that polycarbonate urethanes have resistance to sterilization techniques like

ethylene oxide (ETO) and glow discharge [76]. Also, polycarbonate urethanes have excellent resistance

to heat and therefore autoclave technique can also be used for sterilization. Therefore, the proposed

material can be sterilized with any of the techniques including ETO, glow discharge and autoclaving.

However, a detailed chemical analysis should be performed to confirm any chemical changes after

sterilization.

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7. Conclusion

A new material is proposed for the replacement of currently used silicone based shunts for the

treatment of hydrocephalus. The material proposed is a polycarbonate urethane synthesized from 4,4’-

diphenylmethane diisocyanate (MDI) and polyhexamethylene carbonate diol (PHCD), with a 1,4-

Butanediol as a chain extender. The proposed material is expected to have excellent resistance to

hydrolysis, environmental stress corrosion and metal ion oxidation. The proposed material will be

grafted with dimethylacrylamide giving appropriate surface properties to prevent platelet adhesion or

any thrombogenic activity after implantation. The proposed material will be impregnated with silver

nano-particles to impart antibacterial properties to prevent infection after implantation of the material.

The surface of the proposed material will then be immobilized with serum albumin proteins to further

improve the antithrombogenic property of the material. Given the unique properties the proposed

material will possess, it can serve as an ideal replacement for the currently used silicone based shunts

and rescue the problem of hydrocephalus.

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