Tantalum-loaded polyurethane microspheres for particulate embolization: preparation and properties

Tantalum-loadedpolyurethanemicrospheres for particulate embolization: preparation and properties B. Chithambara Tbanoo, M.C. Sunny and A. Jayakrishnan Polymer

Chemistry

Satelmond

Division,

Palace

(Received

29

January

Polyurethane

Biomedical

Campus, 1990;

accepted

microspheres

polymerization

Technology

Trivandrum

695

28 August

powder

Microspheres

radiation lumen.

These

Keywords:

Polyurethanes physical

Microspheres,

in

found

recent

a large

and fabrication

thanes

form

the

of

membranes

and tapes

knowledge,

polyurethane

any attention

number

have been

late embolization. nature

with

radiopaque

polyure-

tubings,

foams,

properties

in general

properties

of Ta7, polyurethane

deals with the preparation

acid (MA)

Teflon@ catheters embolization

without

emboli,

suspension

Methacrylic reduced

acid (MA)

pressure

In a 100

ml beaker

centration

Fluka were used without

The solution

PTMG

of such micro-

succinate

(DOS)

Company,

USA. Clinical-grade

was

diisocyanate

purchased

from

Ta powder

obtained

was (TDI) from

Dioctyl sulpho-

Aldrich

Engineering,

0

1991

to Dr A. Jayakrishnan, MAE

31 7. University

Butterworth-Helnemann

Department

of Florida,

water

was

of required

con-

PTMG

of Materials FL 3261

Science

Et

(i: 10%).

medium.

The

and finally

was introduced 60 min at 60°C.

admixed

with

several

times

60°C

and

India)

Polyurethane of MA

distilled

sieved

using

into different

modification

water,

of two different

The

micro-

were filtered dried

standard

of microspheres (0.5

TDI.

In the

was mixed off,

in an air

test

sieves

fractions.

slipperinesswasachieved

microspheres

slowly

for 30 min at

the Ta powder

washed at

it in

for 1 min. 5 ml

continued

at the end of the reaction

oven

of

of the two

dispersing

the contents

microspheres,

with

A mixture

mixing

1 min before

solution of DABCO

it was

at half-

ratio was then added and dis-

and the stirring

before

Surface

1, USA.

rev min-’

formed

was from Ingenor,

Gainesville,

using a motor-driven

spheres

(Filterwel,

Chemical

stirred

After stirring

30 min at 50°C

hydrophilicityand Correspondence

was distilled

was taken and thermostated

was done exactly

the DOS solution.

with

was

in the dispersion

ingredients

emboliza-

of a 10% aqueous

purification.

water

and TDI in the desired

persed

microspheres

(DABCO)

further

USA) Distilled

45 ml of DOS solution

in distilled

moon paddle stirrer at 200

having mol wt 990

Inc., USA. Toluene

used.

METHODS

4O”C,

Chemicals

(Aldrich,

and

throughout.

case of Ta-loaded

and 1,4-diazabicyclo[2.2.2]octane

and

the catheter

polymerization

and elasto-

MATERIALS

from DO.

obstructing

40°C.

properties.

glycol) (PTMG)

on to them using y-

agents.

into the system

Poly(tetramethylene

Technology,

of average mol wt

for particu-

and the excellent

with Ta could be useful for particulate of their

and that

on the use of poly-

radiocontrast

and some

and

have not received

encapsulated

tion. This report

methacrylic

employed

‘. While

In view of the biocompatible

of polyurethanes

glycol) (PTMG)

France.

used, to the best of our

reported

Sciences

into its sodium salt imparted hydrophilicity

under

biocompatibility

fibres,

microspheres

for Medical

500 ,um were prepared by condensation

embolization,

excellent

so far. Research from our laboratory3-5

meric microspheres

spheres

encapsulation,

their

good

MA

as radiopaque

of biomedical

of

versatility’,

sheets,

of Horak et A6 have recently

meric

tantalum,

because

properties,

and formulation in

by grafting

them to pass through

may find application

years

and mechanical

enabling

polyurethane,

Institute

containing dioctyl sulphosuccinate (DOS) as the suspension (DABCO) as the catalyst for polymerization. Incorporation phase led to the formation of Ta-loaded microspheres with good

were surface-modified

microspheres

have

applications

in the polymerizing

to the microspheres

Tirunal

with poly(tetramethylene

from a Co”’ source. Conversion of the grafted

slipperiness

Chitra

in the range 150-l

(TN)

990 in an aqueous dispersion medium stabilizer and 1,4-diazabicyclo[2.2.2]octane of tantalum

Sree

1990)

having diameters

of toluene diisocyanate

radiopacity.

Wing,

0 12. India

to impart

high

bygrafting

MA.

g) wereequilibrated

concentrations

(5 and

in 5 ml

10%)

over-

12 July

525

Ltd. 0142-9612/91/050525-04

B/omater/als

199 1, Vol

Po~orerhane

microspheres: B.C. Thanoo et al.

night and subjected to various radiation doses (0.1 to 1 .O Mrad). After irradiation, beads were washed for 7 d with several changes of water to remove all ungrafted material and dried. The grafted beads were further treated with 5% NaOH to convert the carboxylic acid functions into its sodium salt. Scanning electron micrographs of the microspheres were taken using a Jeol instrument (JSM 35C) after vacuum coating with gold. X-ray images were recorded using a Mimer III skull X-ray unit. Haemolytic potential of the microspheres was examined by incubating 5 mg of beads swollen to equilibrium in PBS (0.15 M, pH 7.4) with 1 ml of heparinized calf blood for 1 h at 37°C. Haemoglobin released was assayed according to the method of Raphael*.

RESULTS AND DISCUSSION Polyurethane microspheres Attempts were first made to prepare microspheres by a solvent evaporation process. A commercially available biomedical-grade polyurethane such as Tecoflex@ 80A (Therm~ics Inc., USA) was employed because of its solubility in volatile organic solvents such as di~hloromethane (DCM). Evaporation of a DCM solution of the polymer from an aqueous dispersion medium containing poly(vinyl alcohol) or DOS as the stabilizer gave rise to microspheres which were partially agglomeratory and sticky. Aromatic polyurethanes could not be used since they were soluble only in high-boiling solvents. It was therefore considered worthwhile to conduct the urethane formation reaction in suspension, directly leading to the formation of microspheres in one step. Reaction of TDI with PTMG in an aqueous suspension medium at 40°C without catalyst resulted in an uncured heter~eneous white mass due to the almost complete consumption of TDI for urea formation leaving the PTMG unutilized. Reaction at elevated temperatures resulted in the formation of large rigid foamy particles devoid of any spherical shape. Introduction of a catalyst such as DABCO into the dispersion medium after the reactants were dispersed led to a surface hardening of droplets preventing further contact of TDI with water. Further reaction at elevated temperatures (50 and 60°C) was predominantly urethane formation inside the droplets leading to the formation of elastomeric beads with good transparency and spherical geometry. The amount of TDI required to obtain beads having good transparency, elasticity and sphericity was found to be nearly twice the stoichiometric equivalent of PTMG, as the reaction of TDI with water was unpredictable and depended on several factors. TDI below this amount resulted in microspheres with poor mechanical properties.

Particle size control The particle size distribution of microspheres formed at three different concentrations of DOS as the stabilizer is shown in Figure 1. In general, a higher concentration of the stabilizer resulted in a larger fraction of smaller beads. The ratio of the amount of dispersed phase to the dispersion medium also influenced the particle size distribution of the final product. Table 7 shows the distribution pattern at three different ratios of the dispersed phase to the dispersion medium. An increase in the ratio of the dispersed phase to the dispersion medium resulted in a larger proportion of

526

Biomaterials

199 1. Vol 12 Ju/y

SIZE

RANGE (PM)

Figure 1 Particle size distribution ofpolyurethane microspheres formed at three different concentrations of dioctyl solphosuccinate in the dispersion medium. A 0.2%. 8: 0.550, C: 1.0%. Dispersed phase consisted of 1.5 g of poty(tetramethylene glycol) and 0.75 g of toluene diisocyanate.

Table t Percentage weight fraction ofpolyurethane microspheres formed at different weight ratios of the dispersed phase to the dispersion medium’ Percentage weight fraction at wt ratio 0.044 1200- 1500 1000-l 200 850-1000 710-850 600-710 425-600 355-425 300-355 250-300 180-250 150-180 go- 150

8.4 18.2 34.6 5.4 8.2 9.6 7.9 5.6 2.4

wt ratio 0.088 1.8 11.5 8.6 34.6 16.3 17.4 1.9 3.3 2.6 1.6 0.5

wt ratio 0.176

3.4 4.4 36.7 19.6 22.0 2.3 4.2 3.7 2.5 1.1 0.3

*Dispersed phase is poly(tetramethylene glycol) and toluene diisocyanate at a weight ratioof 0.5. Dispersion medium is 50 ml aqueous solution having 1% dioctyl sulphosuccinate and 1% 1.4-diazablcyclo[2.2.2]octane.

bigger particles. Experiments were conducted in duplicate and triplicate to assess the reproducibility of the particle size distribution data. A 20-30% deviation in data was observed in some cases. Such variation could be attributed to the lack of control of the extent of reaction between diisocyanate and the polyol during themixing process which results in unpredictable viscosity changes in the polymerizing phase before dispersion was effected. Particle size distribution could also be altered to a significant extent by incorporating a low-viscosity inert solvent in the dispersed phase. Size distribution of microspheres prepared in the absence and in

Polyurethane mIcrospheres: B.C. Thanoo et al.

c

I I

I

200

--I LOO PARTICLE

600 SUE

800

501

O-2

0, L

0.6

08

IRRADIATION

1000

‘0 DOSE

(Mrod)

Figure 3 Effecr of radiarion dose on the grafr yield of merhactylic acid (MA) and rhe equilibrium water content (EWC(%)J of the grafred MA in rhe sodium salt form. With 5% MA (eJ and 10% MA (mJ.

( pm)

Figure 2 Effect of 20% bury1 acetate in the dispersedphase on the pamcle size disrnburion of polyurerhane microspheres: ( -J with 1.5 g of poly(rerramerhylene glycolJ (PTMGJ and 0.75 g of roloene diisocyanare (TDIJ, (- - - -J wlrh 1.5 g of PTMG, 0.75 g of TDI and 0.55 g of bury1 acetate Dispersion medium is 50 ml aqueous solurion having 1% diocryl sulphosuconare and 1% 1,4-diazabicyclo[Z.Z.Z]ocrane

_____~

-I

the presence of 20% butyl acetate in the dispersed phase is shown in Figure 2. This could be attributed to a viscosity and surface tension lowering effect.

Surface

modified

microspheres

While the polyurethane microspheres prepared were soft and elastomeric, they were not sufficiently hydrophilic for their smooth and unhindered transit through hydrophobic microcatheters. Therefore, attempts were made to surface modifythem by grafting MA. Whilethegraftyield was highly dependent on the concentration of MA employed in the grafting medium, the dependence on irradiation dose was not found to be that high (Figure 3). The conversion of the grafted MA into its sodium salt improved the hydrophilicity and slipperiness of the particles remarkably. The extent of swelling as determined by the equilibrium water content (EWC) of the grafted beads in their Na+ form is proportional to the graft yield at low radiation doses (Figure 3). However, at high doses the swelling was found to level off at 5% MA concentration whereas at 10% the swelling was found to actually decrease beyond a dose of 0.25 Mrad. This could be attributed to the fact that at higher doses, along with grafting, cross-linking of the polyurethane matrix also occurred which impeded the swelling of the particles.

I__-_

_ _._. ‘:, ril n

-7

r--

:

1

1

_._l

_:

.

200

LOO

PARTICLE

600

SIZE

800

1000

(pm)

Figure 4 Effect of Ta encapsularlon on rhe pamcle sue disrriburion ofpolyJ wirh 1.5g of PTMG and 0.75g of TDI, urethane microspheres: ((- _- -) with 1.5 g of PTMG, 0.75 g of TDI and 0.9 g of Ta. Dispersion medium is 50 ml aqueous solurion containing 1% DOS and 1% DABCO. PTMG. poly(rerramerhylene glycol): TDI, roluene diisocyanare; DOS, diocryl sulphosoccinare; DABCO, 1,4-diazabicyclo[Z.Z.ZJocrane.

B/omarenals

199 1. Vol 12 July

527

Polyurethane microspheres: B.C. Thanoo et al.

Table 2 Blood haemolysis potential of polyurethane microspheres using heparinized calf blood Sample

Haemoglobin released (mg%)*

Control Polyurethane Polyurethane Polyurethane Polyurethane ~lyurethane

12.7 8.4 13.8 13.5 14.5 12.9

30% Ta loaded 7% MA grafted, Na+ form 17% MA grafted, Nat form 35% MA grafted, Na+ form

*Average of three values. MA, methacrylic acid.

formation of thrombus by interaction with the vascular endothelium and fix the emboli in the vascular lumen”.

Blood haemolysis by the microspheres Haemolysis studies showed that microspheres virgin, Ta loaded and MA grafted were all non-haemolytic. Plasma haemoglobin released in the presence of the particles was more or less close to the control value indicating their nonhaemol~ic nature in vitro (Table 2).

CONCLUSIONS

Figure 5 SEM of 30% Ta-loaded polyurethane microspheres. (a) At lower magnification and (bj At higher magnification showing Ta particles on the surface.

Reaction of TDI with PTMG in an aqueous dispersion medium containing DOS as the stabilizer generates polyurethane microspheres having good transparency, elasticity and spherical geometry. A small amount of catalyst such as DABCO is essential to facilitate the formation of microspheres. Grafting of MA imparts hydrophilicity and slipperiness to the microspheres. Encapsulation of Ta powder in the microspheres renders them radiopaque. In vitro tests show that the microspheres are non-haemol~ic.

ACKNOWLEDGEMENTS The authors thank the Director, SCTIMST, for permission to publish this manuscript and MS Janette Chesters of the University of Liverpool, UK, for the electron micrographs.

REFERENCES 1 2

3

Figure 6

X-ray images of 30% Ta-loaded polyurethane microspheres.

Tantalum-loaded

microspheres

4

5 6

Because of its high atomic number, Ta is highly radiopaque when compared with barium or iodine-based compounds. Moreover, Ta is well tolerated by the living tissue’. The particle size distribution of microspheres prepared in the presence of 30% Ta is shown in Figure 4. The presence of Ta does not modify the particle size distribution. The SEM and X-ray images of Ta-loaded microspheres are shown in Figures 5 and 6 respectively. The SEM at higher magnification clearly shows the Ta particles on the surface of microspheres. These particles are expected to impart a surface roughness to the microspheres which would help the

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Biomaterials

199 1, Vol 12 July

7 8 9 10

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