Physico-mechanical properties of degradablepolymersused in medical applications:a comparativestudy Israel Engelberg and Joachim Kohn Department of Chemistry, Rutgers, The State University of New Jersey, New Brunswick NJ, USA (Received 9 January 1990; accepted 11 July 1990)

The physico-mechanical properties of degradable polymers used for medical applications have been characterized. The following polymers were included in this study: three samples of poly(ortho esters) derived from 3,g_bis(ethylidene 2,4,8,10-tetraoxaspiro[5,5]undecane) and various ratios of 1,8-hexanediol and traos-cyclohexane dimethanol, poly(glycolic acid), six samples of poly(t-lactic acid) and poly(~,~lactic acid) with mol wt from 21 000 to 550 000, poly(&-caprolactone), poly(j3-hydroxybutyrate) and three copolymers of /I-hydroxybutyric acid and various amounts of hydroxyvaleric acid, one sample each of two different types of poly(anhydrides), poly(trimethylene carbonate) and two different poly(iminocarbonates). For each polymer, the thermal properties (glass transition temperature, crystallization, melting and decomposition points) were determined by differential scanning calorimetry and by thermogravimetric analysis. The tensile properties (Young’s modulus, tensile strength and elongation at yield and break) were determined by tensile testing on an lnstron stress-strain tester. The flexural storage modulus as a function of temperature was determined by dynamic mechanical analysis. Keywords: Polymers, biodegradation, mechanical properties, thermal analysis

last 20 years, many degradable

Overthe suggested

as possible

application delivery range

of these

polymers Currently

devicele5. of new

important luminal

applications

trend

degradable

in

grafts,

coronary

the reblocking

implants

sophisticated

polymers

with

Particularly

important

strength

and

transition (storage

detail.

modulus),

the

A further

engineering

and

the

Correspondence to Dr J. Kohn.

selected

20

the mechanical

strength,

determined

(glass transition,

require

crystallization

range

of

temperature

analysis thermal

(glass

measured

point,

anical analysis (DMA).

important in

data

on the

is related

to the

facilitate

Biomaterials

199 1. Vol 12 April

(Young’s

The thermal

and melting scanning

(TGA)

stability

as a function

preparation

polymers

and conducted

was and

a

properties. modulus, were

properties

temperatures)

calorimetry

(DSC).

used to determine the

decomposition

( Td). Finally, the flexural storage modulus was

properties

properties

results,

at yield and break)

testing.

by differential

Thermogravimetric the

properties.

properties

and elongation

by mechanical

measured

as biomaterials

of temperature

of all test samples

the intrinsic

by dynamic

mech-

It stands to reason that the consistent by the same laboratory

variability

the direct comparison

may

of the test results and may of the properties

of different

polymers. Unfortunately

it is unavoidable

suffer from several limitations.

that such a study will

First, the number

polymers

is too large to allow a comprehensive

available

materials.

Second,

polymers

0 1991 Butterworth-Heinemann 292

degradable

Specifically, tensile

being investigated

or

reliable

polymers

therefore

(tensile

these

published

polymers.

We

decrease that

is in turn a function

study of some of their engineering

skin

not been investigated

in locating

of new

of different

were

melting

which

are prepared,

even if available, often cannot be used for a direct comparison

properties

viscoelastic

revealed

have often

difficulty

properties

thermal

of the sample

of the way the test samples

comparative

orthopaedic

material

on the morphology

since the mechanical

of polymers are strongly dependent

and

and tan 6).

review

properties

defined

of the test results;

properties

currently

or staples’-“. usually

variability

into

include

artificial

high-strength

(T,), softening

temperature)

literature

engineering

grafts,

are the mechanical

and loss moduli

A

vascular

intrinsic

and rheological

as intra-

after successful

applications

narrowly

temperature

degradation

example,

the collapse

of blood vessels

and degradable,

is an

are implanted

to prevent

such as bone nails, screws,

Such

For

investigated

that

drug

of a wide

‘* 7. Other advanced applications of temporary

for burn victims

studied

polymers

research.

devices

(restenosis)

the development

for degradable

in an attempt

balloon angioplasty

have been

widely

identification

are now being

stent-like

arteries

One

is as an implantable the

biomaterials

polymers

polymers

biomaterials.

of available study of all

of the same

Ltd. 0142-9612/91/030292-13

family

Physico-mechanical

have often tions

been prepared

that

differ

Although our

it has

molecular Finally,

not

within

as uniform

mechanical carefully

techniques

controlling

mechanical

polymers

USED

Poly(ortho Poly(ortho

reported

that

the

polymeric

IN THIS

are

more

hydrophobic

poly(lactic

investigated.

device

thinner

with

time

over

a period

of

acid)

names

were

the

intensively

acid and lactic acid have

sutures

Vicryl’”

of PGA with

(PLA)

of glycolic

as alternative

the trade

of PGA to a wider

copolymers

and are being

and Polyglactin

marketed

9 1 OTMzo,“.

number

devices

for drug

There Originally,

two

Chronome?’

Since

to

drugs

process,

esters)

esters)

Heller

of

were

use

prepared

Upon

products

upon hydrolysis

poly(ortho

The

rates

(t-CDM) with

type

with

2,4,8,1

with

various

hydrolysis soluble

the

by-

autocatalytically

included

in this

1,6-hexanediol

different

(1,6-HD).

ratios

(Structures

study

were

with trans-cyclohexane of t-CDM

Polymer

morphological

hydration

degrade

0,x;

Since distinct from

.+CHz~CHz+

+I

1.6.HI)

DETOSU 1 a. DETOSU 1b 1 c DETOSLJ

t-CDM

t-CDM : 1.6.HD = 100 : 35 : 65 t-CDM : 1.6-H,, = IO0 : 70 : 30 KDM 1.6.HD = IO0 : 90 : 10

in practice,

more

L-PLA

is an

amorphous

acid)

Poly(glycolic polyester

acid)

(PGA)

(Structure

melting was

used

and poly(lactic is the

2). Since

a monophasic

point in

and low the

simplest

solubility

development

orthopaedic linear

aliphatic

crystalline,

in organic of

and

the

it has

solvents.

first

totally

PLA, intensively applications. prehensively

PGA

stereocan

is not often

be

used

here. active

but

D and L

the

optically

Generally,

L-PLA

is

the hydrolysis

is the

naturally

of D,L-PLA

ramifications. it

is

delivery,

are

two

meso-PLA

crystallinity

Since

and

D,L-PLA

usually

considered

where

it is important

of the active

On the other

species

for to

within

hand, the semicrystalline where

required,

high e.g.,

mechanical sutures

and

’ their

copolymers

for a large

research

reviewed

In two

obtained

which

in applications

and

to

acid.

dispersion

investigated This

acid,

polymer,

the

D-PLA, since

of lactic

toughness

It exists

the optically

amorphous.

in the

devices*-’

tend

polymer

materials,

than

as drug

acid;

further

practical

matrix.

is preferred

strength

acid)

PGA is highly

such

are

meso-PLA

from

L(+)-lactic

differences

acid.

in the rates

copolymers

molecule,

L-lactic

is always

have important

the

crystallinity

acid and lactic

L-PLA

Since

frequently

yields

crystalline,

is the racemic

derived

L-PLA

L-PLA

and

and

stereoisomer

and

corresponding

give nse to four morphologically

are semicrystalllne D,L-PLA

relationship acid

the

Thus,

it is not considered

have a homogeneous

Structure 1: Polyforthoesters)

Poly(glycolic

D-

o,L-lactide.

The polymers

applications

DETOSIJ

D-PLA of

from

PLA is more

lead to an increase

is a chiral

D,L-PLA

a mixture

obtained

of thin

backbone

PGA or PLA20,21,23.

which

polymers.

occurring

X

acid

forms

polymers;

The !I+

lactic

than

of

lactic

of

hydrolysis.

rapidly

stereoisomeric

employed

AH2

and

more

to

of glycolic

changes

uptake

rate

is no linear

acid

PGA is highly

of ZZ

there

lost in copolymers

inactive

+,+

that

in

PGA.

of glycolic

Whereas

group

than PGA.

In addition,

than

copolymers. These

the

to PGA”.

solvents

ratio

methyl

the water

reduces

properties

monomers

Ctl,

and

physico-mechanical

to 1,6-HD

la-c).

of an extra

3) is more hydrophobic

as compared in organic

di-

acidic

2%”

It is noteworthy

of O-

presence

of PLA limits

about

is rapidly

of poly(ortho

do not release

of DETOSU

and

three

characterized

polymers

increase

to

regular

esters)

copolymers

specimens

a new

esters)

names

to the

hydrophobicity

between

rates.

poly(ortho

dimethanol

that

and do not exhibit

degradation

condensation

these

(DETOSU)

These

con-

the degradation

of 3,9_bis(ethylidene

tetraoxaspiro[5,5]undecane)

increasing

the trade

hydrolysis,

et a/.18 synthesized

the

and a dialcohol”.

that autocatalyse

based on the reaction

by

Owing

films

esters).

Jr, Poly(lactic acid)

lactic acid, PLA (Structure The

of poly(ortho

poly(ortho

under

in degradation

alcohols.

release

L Structure 3:

(PW

rate, poly(ortho

for controlled the

are known

by-products

resulting

release

that there are a significant

types

or Alzamer”.

acidic

the

crumbling.

of 2,2_diethoxytetrahydrofuran

poly(ortho

e.g.,

and will tend to

applications’4-‘6.

major

poly(ortho

densation

of

than

describing

delivery

are

erosion,

at a constant

It is not surprising

of publications

degradable

tend

useful

Poly(glycollc acid)

can be formulated

surface

to be particularly

drug delivery13.

PGA

to the

tend to lose their

(PGA)

for a number

esters)

rather

the polymer

within

synthetic

only at its surface

embedded

appear

of

undergoes

degrades slab-like

a high

Copolymers

been developed under

Owing

sutures

properties

the data on

the data collected

of PGA in Dexon

typically

materials

applications,

limitations

development

made of poly(ortho

device

become

were

the

of possible

are representative,

PGA

the trade

STUDY

a family

surface-eroding,

esters)

To adapt range

Structure 2:

esters) Devices

release

here

interpreting

that have been under

esters)

parameters,

Kohn

implantation”.

by

improved

under

of 46-52%“.

rapidly,

and J

Cyanamidlg.

The crystallinity

of PGA, Dexona

strength

wk after

the

1970.

I. Engelberg

available

in the range

nature

esters)

polymers

esters)

Since

by American

commercially

since

mechanical 2-4

suture

been

is typically

hydrophilic of

polymers:

l-3.

POLYMERS

years”.

be

best possiblevalues.These when

name Dexona sutures

of polymers.

polymer.

can

the processing

in mind

in

we have not optimized

for each test of

strength

be borne

in Tables

time.

family

cover

for the preparation

as possible,

properties

but not necessarilythe

Such

a given

to

have

all

samples

possible

of degradable

absorbable

sutures

properties.

representative been

synthetic

composi-

material

in order to keep our procedures

the processing

so

of molecular

respective

always

compositions

test specimen

must

in a variety

their

we have tried to include

study,

the

in

properties

by

effort

are

number has

Lewis24.

B~omatenal.5

also

recently PLA,

being

of drug-delivery PGA

199 7. Vol

been

com-

and

their

12 Awl

293

Physic@mechanical

copolymers degradable

are currently polymers

In view research,

properties of degradable polymers: I. Engelberg and J. Kohn

of the

the most widely

in human importance

six representative

used synthetic,

medicine.

samples

of PLA

and copolymers

with

in biomaterials

of PLAwere

included

our study. Table 1

Poly(j? -hydroxybutyrate) hydroxyvaleric acid

in

Poly(P-hydroxybutyrate)

(PHB)

recently been identified

(Structure

as a promising

#a)

biomaterialz5.

has

only

PHB is

Biodegradable polymers used in this study

MVdb

SOWX

Polymera

Poly(ortho esters) [ 1] t-CDM: 1,6-HD = 35:65 t-CDM: 1,6-HD = JO:30 t-CDM: 1,6-HD = 90: 10 Poly(glycolic acid) [Z] Poly(lactic actds) (31 L-PLA L-PLA L-PLA D,L-PLA D.L-PLA D.L-PLA Poly(B-hydroxybutyrate) [4] Homopolymer (0 mol% HV) Copolymer (7 mol% HV) Copolymer (11 mol% HV) Copolymer (22 mol% HV) Poly(e-caprolactone) [5] Polyanhydrides [6,7] Poly(CPP-SA-IS0 anhydride) Poly(SA-HDA anhydride) Poly(trtmethylene carbonate) [8] Polytminocarbonates [ 10,l 1] Poly(BPA-iminocarbonate) Poly(DTH-iminocarbonate)d

Sample characterizationC

WV

Ml?

[rll

19600 43 200 150 000 13400 66 300 163 500

0.6 1 1.65 3.08 0.25 0.64 2.01

SRI lnternattonal SRI International SRI lnternatlonal Polysciences Inc.

99 700 101000 131000 50 000

Polysctences Inc. Polysciences Inc. Polysctences Inc. Polysciences Inc. Stolle R&D Corp. Stolle R&D Corp.

50 100 300 21 107 550

000 000 000 000 000 000

64 800 139 600 375 100 16500 98 500 410 500

ICI ICI ICI ICI Aldrich Chemical Co.

370 450 529 227 44

000 000 000 000 000

212400 173 300 531 500 285 700 72 500

3 1 24 2 42

Nova Pharmaceuttcal Co. Nova Pharmaceutical Co. Amgen inc.

31000 142 000 48 000

147 900

55 100

0.42 1.13

Prepared in our lab Prepared rn our lab

N/A N/A

105 000 101000

62 000 70 000

0.40 0.31

1.49 1.04 1.97 1.30 0.79

400 400 900 800 500

aNumbers in square brackets refer to the structures provided in the text. bAbsolute weight average molecular weights as prowded by the suppliers of the polymer samples. ‘Data obtained by GPC in chloroform relative to polystyrene standards without further correction. The intrinsic wscostty [q] was determtned in chloroform at 30°C in an lJbbelohdetypeviscometer.The intrinsicviscosity [q] is indL/g. Owing tothe insolubilityof PGAin common organtc solventsand owingtothe limited availability of the poly(ortho esters) these polymer samples were not independently characterized. The polyanhydrides were too unstable in solutton to give reliable results. dDTH: Dat-Tyr-Hex, see Structure Il.

Table 2

Thermal properties of the biodegradable polymers

Polymera

M

T,(C)

W

Poly(ottho esters) t-CDM: 1,6-HD = 35:65 [ 1a] t-CDM: 1.6-HD = 70:30 [ 1 b] t-CDM:1,6-HD = 9O:lO [lc] Poly(glycolic acid) (21 Poly(lactlc acids) [3] L-PLA L-PLA L-PLA D,L-PLA D,L-PLA D,L-PLA Poly(fi-hydroxybutyrate) [4] Homopolymer (0 mol% HV) [4a] Copolymer (7 mol% HV) [4b] Copolymer (1 1 mol% HV) [4c] Copolymer (22 mot% HV) [4d] Poly(e-caprolactone) [5] Polyanhydrides Poly(CPP-SA-IS0 anhydride) [6] Poly(SA-HDA anhydride) [J] Poly(trimethylene carbonate) (81 Polyiminocarbonates Poly(BPA-iminocarbonate) [lo] Poly(DTH-tmmocarbonate) [l 11’

99 700 101000 131000 50 000

55 a4 95 35

50 000 100 000 300 000 21000 107 000 550 000

54 58 59 50 51 53

370 450 529 227 44

000 000 000 000 000

31 000 142 000 48 000 105 000 101000

-1 2 -5 ~62

-15 69 55

Jd(OC)

H,(Jg-’

210

358 362 338 254

Amorphous Amorphous Amorphous 71

170 159 178

242 235 255 255 254 255

41 20 39 Amorphous Amorphous Amorphous

171 160 145 137 57

252 243 235 251 350

51 32 12 7 34

46 49

297 292 261

1.2 2.5 Amorphous

135 138

Amorphous Amorphous

aNumbers in square brackets refer to the structures prowded in the text. bX, was calculated from H,. based on a calibration value of 72.3 J/g determined for PGA with a crystallinity of 52% (Reference 55) ‘DTH: Dat-Tyr-Hex.

294

Biomaterials

199 1, Vol 12 April

)

T,,,(“C)

XJWb

52 30 15 29

Physico-mechanical

Table 3

Mechanical

properties

of btodegradable

Polymer”

of degradable

polymers.

I Engelberg

and

J. Kohn

polymers

strength

modulus

Flexural modulus”

(MPa)

(MPa)

(MPa)

20 19 27 N/A

820 800 1150 N/A

28 50 48 N/A 29 35

Mb%

Poly(ortho esters) t-CDM:l.&HD = 35:65 [la] t-CDM:1,6-HD = 70:30 [1 b] t-CDM: 1.6.HD = 90: 10 [ 1c] Poly(glycollc actd) [2] Poly(lactlc acids) [3] L-PLA L-PLA L-PLA D,r-PLA D.L-PLA D.L-PLA Poly(/&-hydroxybutyrate) /4] Homopolymer (0 mol% HV) [4a] Copolymer (7 mol% HV) [4b] Copolymer (1 1 mol% HV) [4c] Copolymer (22 mol% HV) [4d] Poly(E-caprolactone) [5] Polyanhydndes PolyjCPP-SA-IS0 anhydride) 161 Poly(SA-HDA anhydrlde) [7] Poly(tnmethylene carbonate) 18) Polylmwxarbonates PolyjBPA-lmlnocarbonate) [lo] PolyjDTH-lmvwcarbonate) [ 1 11’

propertn?s

TellSlIe

Elongation Yteld (‘%,j

Break

1250 N/A

41 41 34 NA

220 180 7.0 N/A

1200 2700 3000 N/A 1900 2400

1400 3000 3250 N/A 1950 2350

37 26 18 N ‘A 40 35

6.0 3.3 20 N/A 6.0 5.0

36 24 20 16 16

2500 1400 1100 620 400

2850 1600 1300 750 500

142 000 48 000

N/A 4 05

N/A 45

N/A N/A N/A

105 000 101 000

50 40

2150 1630

2400 N/A

99 700 101000 131 700 50 000 50

000

100

000

300

000

21000

107 000 550 000 370

000

450

000

529

000

227

000

44

000

31

000

950 1000

wi

22 2.3 55 8.5 70 N

2.5 2.8 17 36 80

‘A

N/A 85 160

14 20 3.5 35

4.0 7.0

“Numbers KI square brackets refer to the structures provided an the text. bFlexural storage modulus as measured by DMA at room temperatures (23°C) ‘DTH- Dat-Tyr-Hex.

a degradable,

biocompatible,

by microorganisms”. whose

function

energy=?.

thermoplastic

is to

provide

constituent

made

polymer,

of carbon

by soil bacteria28,2g.

to o-3-hydroxybutyric

of human

storage

a reserve

PHI3 can be degraded

PHB degrades

polyester

It is an intracellular

acid which

blood. The low toxicity

PHB

In vivo,

is a normal

of PHB may at

Poly(&-caprolactone) polyester

that

can

degraded

be

:

4 a 4 b 4 c

d

4

homopolymer

of HB.

IHVI

Y = 0

copolymer of HB and HV.

: :

acid

(Structure

been

biomateria13’.

Initially,

by

microorganisms,

of PCL as a biodegradable

certain

circumstances,

enzymatically,

erosion33.

Low-molecular-weight

reportedly

taken

to

The

degradation

available

= 2’2

design

under the trade

PHB homopolymer the copolymers crystalline, potential

more flexible such

skin,

paramedical

as

as well

disposables.

can

be

surface

of

PCL

and degraded

are

intra-

of

long-term,

implantable

slower

most suitable drug-delivery

than

for the systems

contraceptive

device3’.

and

for the manuof sugars

by the structure

PHB and its copolymers

5: Poly(E-caprolactone)

acid are now commercially Biopol’M26.

is very crystalline

Since PCL is a semicrystalline and brittle whilst

about

acid (HV) are less

temperature.

and more readily processiblez6.

of these

by a

acid

process

of PH B with hydroxyvaleric

applications

applications artificial

name

PCL

of PCL IS significantly

Y (mole%i)

with up to 30% of 3-hydroxyvaleric

the

cellularly34.

of HB and HV.

eutrophus.

to

materia13’.

enzymatic

fragments

up by macrophages

a

conditions3*.

cross-linked

leading

copolymer

Alcaligenes

leading

physiological

that of PGA or PLA. PCL IS therefore

of PHB, based on the fermentation

bacterium

as

under

= 11

a biosynthetic

aliphatic that PCL

packaging

Y (mole%)

ICI developed

is an

that PCL can also be degraded

mechanism

such as CapronorTM, a 1 yr implantable

facture

4).

investigated

it was recognized

of HB and HV.

with hydroxyvaleric

5)

intensively

copolymer

copolymers

of 7,

(Structure

Later, it was discovered

Y [molen/o) = 7

Structure 4: Poly(f3-hydroxybutyrate)

HV contents

hydrolytic degraded

hydroxyvaleric

(PCL)

has

potential

Under . (HB)

with

were characterized

Poly(E-caprolactone)

evaluation

acid

copolymers

respectively,

and

least in part be due to this fact.

hydroxvbutyric

and three

1 1 and 22%,

polymers

controlled as industrial

drug

include release,

applications

The

biomedical sutures, such

-6O”C,

PCL is always Among

this is an unusual

polymer

the more common

property,

which

to the very high permeability

with a low Ts of

in a rubbery

state

allphatic

undoubtedly

at room

polyesters, contributes

of PCL for many therapeutic

drugs35.

as

Another form

interesting

compatible

blends

property with

of PCL is its propensity a

B/omatenals

wide

range

199 I, Vol

of

12 Apr//

to

other

295

Physico-mechanical

properties

polymers36. merized

In

with

oxide,

addition,

noteworthy

other

THF,

methyl

part of the evaluation non-toxic

be

(e.g.,

of Capronor”.

and lactic acid

38. extensively

and tissue-compatible

Drug Administration

materials.

has been

regarded

(FDA)-approved

as

US Food and

phase

I and phase

II

It is interesting has so far been

to note that despite

predominantly

drug-delivery

used as a biodegradable

reviewed

its versatility,

considered

applications. staple

blends and copolymers applications

aliphatic under

PCL

carbonate)

polycarbonate,

physiological

PCL is being

and it is likely that PCL or

with PCL will find additional

in the future. The current

addition,

a few reports

medical

merizations

(carbonate-ester)

and

found

were

to

applications.

carbonate

be

their

0

synthesis

hydrolytically potentially

limitation

who

of the

polyanhydrides

has

most

reactive

and The

Because

without

of their

degrade

erosion

and a

high rate of by a surface

the need to incorporate

into the formulation.

of polyanhydrides

surface

use of

used as biomaterials.

polyanhydrides

mechanism

the

A study

rate is both a blessing

of polyanhydrides.

catalysts or excipients

industrial

as a potential

suggested

the

polymers

when

various

This is a potential

over poly(ortho

only

esters),

various

which

additives

amines

have been shown

during

high-temperature

reactivity of the polymer

must therefore

be considered

controlled

release

reactive

Despite

amino

these

been approved clinical

controlled

trials

when

processing43.

The

using

of peptides,

aliphatic

carbonate)

research,

of aliphatic

use in the

however,

therefore

polycarbonates

industry.

points

have pre-

In biomaterials

of 40-60°C

are not necessarily PTMC

extremely

points and the low

polycarbonates

plastics

softening

strength included

become

The low softening

strength

their

mechanical

and low

disadvantages.

nucleophiles

polyanhydrides

proteins

The commercially derived

from

very stable

strength

used polycarbonate

Bisphenol

polymer

physiological carbonate)

A (BPA).

that is virtually

conditions.

Important

are its excellent

derived

is an aromatic non-degradable properties

processibility,

and its exceptional

shatter

group

modification

decreases

without

significantly

of poly(BPA-

its high mechanical

materia15’.

forms hydrolytically

degradable

in appearance

and

oxygen

stability of the polymer

the mechanical

Consequently,

is derived

the carbonyl

9 and 10). This backbone

the hydrolytic

affecting

properties

of malignant

anhydride),

bone structures,

films and fibres that are very

mechanical

strength

to those

made of poly(BPA-carbonate).

Biomaterials

characterized

Poly(CPP-SA-IS0

199 1, Vol

for agent)

the in

brain tumours44. anhydride)

two polyanhydrides

6:

in phase

devices

(a chemotherapeutic

poly(CPP-SA-IS0

were

Stmctu,e

delivery

12 April

anhydride)

CH3

Jn

and poly-

with different

(Structures

L

back-

6 and 7).

of

poly(BPA-iminocarbonate)

and sebacic acid have

are being tested

is a under

resistance47-4s.

by replacing

(Structures

by an imino

polymer

Poly(BPA-carbonate)

In a formal sense, poly(BPA-iminocarbonate)

the

or drugs

polyanhydrides

propane

of BCNU

We

in our study.

Polyiminocarbonates

similar

limitations,

polyanhydrides

In our study,

296

poly-

matrix toward

as implantable

release

the treatment (SA-HDA

n

by the FDA for clinical trials in a remarkably

short time. These III

to react with

groups.

from bis-p-(carboxyphenoxy)

in several

I-

Poly(trlmethylene

from poly(BPA-carbonate)

anhydrides

containing

mechanical vented

are

incorporated. Several

in copolyoxide. These

and Langer42.

among

high degradation many

for

biomaterials.

by Domb

are

unstable

degradation,

Generally,

soft at about 40-60°C.

1958

was later recognized

been published

8:

stability

high-molecular-weight

Polyanhydrides

In the

by Hill and possible

as degradable

of

in detail

for

et al.4’

by Langer

polyanhydrides

slow

describing

have been evaluated

of PCL was used in

in

major

extremely

as a monomer

an

degrade

communication).

lactide or ethylene

copolymers

Their low hydrolytic

considered fibres4’.

This feature

advantage

for the

albeit with personal

8).

to

status of PCL has been

sample

first investigated

as textile

potential

found

applications45.46.

Structure were

applications

show

(Structure

recently

II

Carothers3’

advantage

(PTMC)

(CH&-0-C-O

Polyanhydrides

erosion

anhydride)

have been published

with glycolide,

drug delivery

Polyanhydrides

limitation

was

conditions,

use of trimethylene

for controlled-

In Europe,

by Pitt3’. A commercial

recently

Poly(SA-HDA

carbonate)

this study.

was

7:

rates (C.G. Pitt and K.J. Zhu,

clinical trials3’.

release

Poly(trimethylene Poly(trimethylene

Consequently,

undergoing

Structure

as

Based on a large number

and PCL are currently

system

copolyethylene

Particularly

of c-caprolactone

extensively37,

and J. Kohn

4-vinylanisole,

vinylacetate).

of PCL has been studied

of tests, c-caprolactone the Caprono?’

can

S-valerolactone,

are copolymers

The toxicology

I. Engelberg

monomers

methacrylate,

that have been studied

polymers:

c-caprolactone

numerous

chloroprene,

styrene,

of degradable

Structure 9: Poly(Bispheno1 A carbonate)

Structure 10: Poly(Bispheno1 A iminocarbonate)

Physico-mechanical

Owing tothe and

mechanical

find some

combination strength,

applications

of degradability,

as a disposable

view of the growing

concern

degradable

plastics

in the environment,

degradable

materials

The

suggested5’,

physically

entrapped

pression moulded

within

poly( BPA-iminocarbonate) upon subcutaneous

biocompatibility

of various

dyes

films

com-

52. Although

in mice and rabbits5’,

the

of poly(BPA-iminocarbonate)

has

so far not been established. To reduce carbonate), tyrosine formed

the

we

potential

have

dipeptide5’,53. between

tyrosine

These

iminocarbonate-amide also be regarded

with

derivatives

iminocarbonate hydroxyl groups

polymers

(Structure

as pseudo-poly(amino

was

present at the

tyrosine-derived

copolymers

of

bond

are

7 1) that can

acids)54.

Films were prepared

0

by solvent casting and/or

depending

cast from

10%

temperature

glass

plates.

vacuum

on the specific

(w/v)

room

between

After

mm

drying,

were

For compression

thermostated

Polymers

were

placed

0.2

tonnes

were

were

A=0

1n

0

Structure

These

data,

Tab/es

l-3.

of

dynamic

In general,

pseudo-poly(amino

acids)

when amino acids are linked together

more

favourable

conventional The

poly(amino

tyrosine-derived resulting Based

properties

monomers

these

investigations,

(Structure

1 7)

promising

polymer

in the formulation devices

The carbonate),

of the

the

has

properties

been

of

investigated53.

poly(Dat-Tyr-Hex been that

currently

of high-strength

as

a

being

orthopaedic

polyiminocarbonates were 100

included and

synthesized

in

this

study,

poly(Dat-Tyr-Hex-imino-

in our laboratory

and had mol

000.

in this study

1. Polymers

were

and their used

to

sources

as received.

are The

standards. were

without

polymer

correction

in chloroform,

the

was used to determine

the degree a/,55 for polymers

were

thermal

determined

were

per

with indium

from the Hf

on a DuPont

The 951

Cohn et Td of all TGA

under an atmosphere

storage

made

of PGA and PLA.

of 52%.

as detected

heating materials

as determined

at a

of nitrogen.

onset

points

for

by TGA. The measure-

modulus

(E’) as a function

using a DuPont

mode (1 Hz) at a heating

AND

four

specimens

was calculated Jg-’

were

and the heat of fusion

in Tab/e 2 represent

of the flexural

fixed frequency

(X,)

a crystallinity

decomposition

temperature

(T,)

value of 72.3

reported

values

of at least

For crystalline

as well. For samples

rate of 20”C’min

The values

average

tensile

determined

the Tg and T,. The standard

temperature

with

were

9 10 DSC calibrated

of crystallinity

PGA

temperature

strength,

break

was 1 O”C/min.

(H,) were determined

were made using an at room

from four separate

A DuPont

and

relative

for the hydro-

In all cases, tensile

arithmetic

obtained

rate for all polymers

and

by GPC

Number

[q] of all polymers

Tensile

at yield

in

distri-

using an Ubbelohde

1122

D882-83.

conditions.

from sample.

983

DMA

of

in the

rate of 5”C/min.

DISCUSSION

characterization

The suppliers absolute

for

listed

calculated

viscosity

model

ASTM

measurements

Sample included

tester

are

weight

in our laboratory

averages

The intrinsic

elongation

Materials in Table

cut

of their samples.

the molecular

were analysed

standards

tensile

calculated

ments

were

suppliers,

Tensile measurements

heating

mm

weights

by the

at 30°C

RESULTS

shown

for

were asked to provide the

type viscometer.

EXPERIMENTAL

The polymers

0.3-0.6

molecular

weight

using a calibration

imino-

identified is

the

polymers

measurements.

relative to polystyrene

the crystallization

of several

such as bone pins and screws.

poly(BPA-iminocarbonate) wts of about

many

structure

has

particularly evaluated

the

and

carbonate)

fixation

than

acids)54. between

polyiminocarbonates on

acids) tend to retain

of the amino acids whilst exhibiting

engineering

relationship

bonds. lt

polymers

to crystalline

In order to obtain

under ambient

obtained

polymers).

was determined

modulus,

by non-amide

was found that such pseudo-poly(amino the good biocompatibility

are

(for crystalline

samples

as provided

volume.

according iminocarbonate)

and

or 10°C

to amorphous

about

average

molecular

lnstron

11: poly[Dat-Tyr-Hex

polymers)

(T,)

applied

of polymer

to polystyrene

CH,

used.

mould

characterization weight

weight

Icy5

steel

applied

tests and DMA

in chloroform

I

a stainless

press

was

a thickness

bution, all polymers

NH

laboratory

platens

with

absolute

O-&O_

a Carver

10 min. The mould then was rapidly cooled. Samples

All suppliers

u

about

tests.

about

Materials

0

under

and

length,

above Tg (for amorphous

of 2 tonnes

stored

40 mm

above the melting temperature Loads

were

heated

into

at

d). Strips of

moulding,

with

heated to 30°C

films

chloride

chloride-treated

was reached (2-3

cut for mechanical

equipped

Films were

in methylene

the

weight

compression

polymer.

trimethylsilyl

thickness,

mm width

mechanical

CH2-CH&H-CH-CH2

solutions

until constant

0.1 5-0.20

and

f

was

preparation

moulding,

5-7

of poly(BPA-imino-

BPA

The

the phenolic

side chains.

toxicity

replaced

by Li and

Trimethylsilyl

from Aldrich.

Sample

was found to be tissue compatible

implantation

grade.

of has

and

of HPLC

reported

(used to coat glass moulds for solvent casting)

obtained

were

was

chloride

of non-

solvents

and J. Kohn

In

material.

discs has been investigated5’,

of polyiminocarbonates

I fngelberg

All

as biomaterials

solvent-cast

polymers:

Kohn5’.

important.

5’ and the release

of degradable

may

the development

increasingly

use of polyiminocarbonates

also been

ultimate

plastic

about the accumulation

becomes

synthesis

low toxicity

poly(BPA-iminocarbonate)

properties

of polymer

weight

average

samples

were asked to provide the

molecular

Biomaterials

weight

of their samples.

199 1. Vol

12 April

297

Physico-mechanical

propwties

of degradable

polymers:

I. Engelberg

We assumed

these values to be correct and included

Tables

Since

7-3.

polymers

depend

on the

molecular

polymer

sample

the

physico-mechanical

by GPC, relative

The relative molecular

weights

in Tab/e 1. These

listed

hydrodynamic

volume

significantly by the

distribution,

were

from the absolute

suppliers.

calculatethe

Our

polydispersity

results weight were

with

polymer

samples

low polydispersity.

exceptions

e.g., the

and its copolymers more

detail

There

with

below.

we

(limiting

viscosity

samples.

The intrinsic viscosity

data are discussed

in

Since

the

(SSOC),

below

body

(1,6-HD)

esters)

having

dimethanol

were obtained

(t-CDM)

polymer

physico-mechanical

were

expected

observation unit

to

of t-CDM

can possibly the

increase

be explained

backbone.

to permit

The onset

sharply

the

by the restriction

thermal

molecular

dialcohols stability

with

similar

of the

stability of the poly(orthoesters)

polyesters The 1,6-HD.

thermal

mechanical were

The

strength,

should,

cleavage,

techniques

at the same

when designing

applications. readily

processible

moulding

with as

by

and formed between

decomposition suitable

be readily

such

and

70:30

the

indicates precautions

processible

injection

by melt

moulding

or

extrusion. We

noticed

that

over drying

poly(ortho

weight.

our observation

storage

at ambient

had

completely

esters)

molecular

after

agent

Although

for about

10

temperature, degraded

month all three

to

we did not investigate

may indicate during

that some prolonged

a

poly(ortho storage

is rigorously

low

further, esters)

at ambient

excluded.

PGA above are

reactivities, was

not

Since we were

unable to obtain high-molecular-weight

for our study,

we

Polysciences

had to use a commercial

Inc.) with

a nominal

sample

PGA (from

mol wt of only 50 000.

that

was significantly other

aliphatic

failed

to 9O:lO.

significantly

strength

of t-CDM.

of poly(ortho

degree

of copolymers

esters)

to 1,6-HD

small the A

copolymer

tensile

was

modulus

42%

than the

was that the 90: 10

elongation,

indicating

a

It thus seems

I

is the price for the increased containing

in the ratio of large

of the corresponding

Figure of

12 April

1

Determination

temperature

molecular B: ratio HD

199 1. Vol

60

100

80

120

,Temperature ("Cl

that in this type

will result in relatively

properties

40

a high proportion

small increases

above 70:30

in the mechanical

The between

the t-CDM/1,6-HD

our results indicate

relatively

of

not significant.

of brittleness.

copolymers.

Biomaterials

when

lower

in brittleness

Furthermore,

were

difference

at a much

increased

that an increase

elongation.

This

higher

Another

three

ratios

and modulus

only occurred

copolymer.

the

in terms of their tensile

copolymers

increased

of

t-CDM/1,6-HD

and

strength

and had a 44%

copolymer

changes

polymers

hydrolytic

even if moisture

esters)

(Tab/e 3)

having

modulus

change

ratio was

t-CDM

the

related to the ratio of t-CDM/

were very similar

in tensile

significant

tensile

than

films. The large safety margin

temperature,

and t-CDM

of most

properties

and the 35:65

70:30

stability

copolymers

tensile

differences

stronger

Con-

degraded

were

copolymers

ratio. It is noteworthy

not linearly

and 70:30

70:30

implantation.

after

may lose its stiffness

for practical

Ts

initial

drop

may be important

copolymers

low

(e.g. PLA) in this study.

copolymers 35:65

tested

tends to

service in viva.

circumstances

implantation

stability

was well

poly(ortho

thethermal

the

after

have limited

chemical

on the t-CDM/1,6-HD

than

of

motion.

decomposition

dependent better

faster

of water

must be heated to a higher

all three copolymers. Since 1,6-HD

300”Cfor

both aliphatic

certain

(37°C)

of the cyclic t-

Consequently,

extensive

of thermal

an

Ts

drug-delivery

has a relatively

copolymer

copolymers

these

of the

with

and the

into the polymer

during

even if both copolymers

fabrication

(Tab/e 2). This

by the presence

a larger ratio of t-CDM

temperature

298

of

function

in the polymer

motion caused in

containing

the

properties

temperature

exceeded

imbibition

Ts and the onset point of thermal against

Since t-CDM

is a linear flexible

to be a sensitive

found

portion

the molecular

temperature

rate. These considerations

sealed

Ts was

The

copolymer

the 65:35

copolymer,

that

1,6-hexanediol

and

1,6-HD

of trans-

composition.

increasing

CDM

whilst

the

copolymers

ratios

from SRI International.

is a rigid cyclic molecule, molecule,

different

and had a

copolymers

of drugs

its Tg may under

clear transparent

poly(ortho

the

in the formulated

either solvent casting or compression

esters)

cyclohexane

As

the temperature

the possible

65:35

much

All

Three

when

to the incorporation

value

specific

Poly(ortho

MPa).

for all three

reduce the Ts of the polymers

rigidity

studies.

E’ (1250 declined

After implantation,

polymer value

values of E’ (950

may be lower than the Tg of the pure bulk polymer.

[a] for most

used in our

similar and the

whilst the 90: 10 copolymer

matrix, the Ts of the polymer

sequently,

samples

yielded

copolymer

I).

intrinsic

[q] is an unambiguous

higher

sharply

the

the polymer

the 35:65

had nearly identical

E’ values

dropped

further

noteworthy

determined

number)

characterizes

In most

of poly(hydroxybutyrate)

HV. These

Finally,

viscosity

that uniquely

however,

rose, the

device

materials

of the E’ by DMA

MPa, respectively),

Owing

to

samples

distributions.

measurement

copolymer

1000

provided

it possible

well-defined

were,

ICI samples

70:30

(Figure

differed

of the polymer

and to assess their molecular

The

results. At room temperature,

significantly

are

for the

weights

made

(M,/M,)

cases,

the

standards.

and therefore

molecular

GPC

each

in our laboratory not corrected

of the polymer

of

but also

analysed

to polystyrene

obtained

values

weight

we

J. Kohn

them in

properties

not only on the molecular weight

and

by

compositions. of

= 35:65.

t-CDM

of the flexural

DMA

to

for Curve

1,6-HD

three A: rat:0 = 70:30;

storage

modulus

poly(ortho

estersJ

of t-CDM Curve

(E’J as a function having

to 1,6-HD C: ratio

of

different

= 90: 10; Curve t-CDM

to

1.6

Phywxwnechanical

Owing to the insolubility

of PGA in common

we did not obtain the GPC and viscosity The insolubility impossible

of PGA in chlorinated

to prepare

procedure.

strength.

specimens,

Owing

value

and

hydrocarbons

to the

highest

m.p.

close to the value of 72.3 PGA of similar

lack

with previously

made it

reliably for

of suitable

test

properties

(210°C)

results55,

among

all tested

Jg-‘, which is very

was 7 1

Jg-’

molecular

reported

PGA had the highest H,

to be semicrystalline.

the

that had been

reported

for r

weight55.

2(#

PIA difference

and the stereoregular whilst

between

L-PLA

of L-PLA could

illustrated

for a sample

(Figure

2).

Upon

heating,

observed

be readily

different

Thermograms

was quenched

resulting

in the

solid.

second

heating,

Upon

crystallization

exotherm.

be observed resulted polymer.

molecular melting

initial

transition,

test

B). Slow

178”C,

respectively;

000

and 300

had the lowest

inconsistent

is provided

samples

of

Likewise,

behaviour

had

distributions

significantly (f 1 O’C)

temperature

in the range of 50-59°C. In addition,

molecular

for any given

L-PLA was somewhat changes,

however,

irrespective versus

or the

were

unable

evaluation

= 21 000).

to obtain of

improved

weight.

D,L-PLA

mechanically

Compression

moulded testing.

samples

formed

with

Thus,

no

was allowed

run).

to slowly

crystallization.

the

thermogram

was

its strength strength

and modulus

degradable L-PLA.

tensile

increased

with

value

3000

of

the Tg of the

rather

insignificant.

A

to be 55°C

or

strength,

suitable

increasing and

storage

for the

of this polymer

by solvent strips.

too brittle for reliable

quantitative

data

for

the

surpassed

(+26%). increased

polymer

for high-

implants

(e.g.,

weight

Also

and reached No

in terms is

of tensile

one

available.

a

other

of tensile

in terms

L-PLA

of

moduli

of

the

Among

the

in our study, only the polyiminocarbonates strength

of L-PLA. Devices

moulding

or solvent

made of

casting

were

on the degree of crystalllnlty

during

processing.

Our results

of good mechanical

properties

of either D,L-PLA or L-PLA requires a minimum

mol wt of about

100

A limitation weight

000.

of all samples

Although

there

(irrespective

of

was their pronounced

all specimens

behaviour

L-PLA showed stress-strain

of PLA

and stereoregularity)

low elongations,

tended

were

subtle

break

at

differences

to

in

of L-PLA versus D,L-PLA. Whilst

a purely elastic deformation

for most of the

curve, D,L-PLA was more ductile and exhibited

a significantly

larger

3). These

can be attributed stereoregular

storage

respectively.

currently

to turbid, depending

from samples

(Figure

the

increase

to D.L-PLA. Based on

L-PLA

modulus.

by the specimen

relatively

and

significant

flexural

MPa,

indicate that the achievement

brittleness.

D,L-PLA

and

molecular

3250

polymers

the tensile

transparent

weight samples

module

by compression

molecular

casting Increasing

as orthopaedic

high-molecular-weight

of the polymer of the

as compared

a

that

by solvent

and modulus

such

in our study

obtained

was

polymer

bone nails). In our series of three test samples

the

L-PLA

000

moulding.

of

molecular

of L-PLA very significantly

applications

modulus

for Tg

107

these results, L-PLA is clearly the preferred

polymer

of the polymer.

of

processible

in a further

(+20%)

D,L-PLA are properties

increasing

wt

films

resulted

strength

included

weight,

strong

000

polymers

weight

mol

discs by compression

mol wt to 550 in tensile

a

with

yet readily

transparent,

transparent

approached

molecular

were

1 OO”C/min.

a spontaneous

the mechanical

dramatically

strong,

(Tab/e 1). Overall,

low-molecular-weight

Films prepared

at

showmg

m spontaneous

(third

= 50 000) A: First run of

is semicrystalline.

melt

of low-molecular-weight

D,L-PLA

is a representative

casting were sticky and could not be cut into uniform mechanical

properties

the stress-strain

mechanical

re-analysed

in Tab/e 3. However,

medical

of the stereoregularity

L-PLA)

the

C: The polymer

resulting

(M,

run.

strongest

value for the Tg of PLA appeared

representative

mechanical

for the

higher than that of D,L-

were

from

amorphous.

Curve

5”C/min,

was

first

was

at 89°C.

at

material

to the

mol wt

molecular

There was a small tendency molecular

specimen. We

000

of D,L-PLA and L-PLA were

to increase with increasing

(D,L-PLA

100

000 of the

of L-PLA.

The Tg of all tested samples

(+5”C),

the 100

different

and polydispersities that 1 70°C

value for the melting

PLA. These

a mol wt of

of crystallinity

of the

and

by our GPC results, which indicate that all

L-PLA

our results indicate

stereoregular

and their

L-PLA samples

of L-PLA (Tab/e 2). An explanation

three specimens apparently

the

had m.p. of 170

degree

melt

acid)

by DSC. Curve

Inc. The material

quenching

the material

The crystallinity

between

of L-PLA with

had a lower m.p. at 159°C.

mol wt sample

of the

to the first

specimens

000

the sample

cooling

state

found

points or their degree of crystallinity.

mol wt of 50 000

the

rapid

included

only (Curve C). was

of the three

the could

during cooling and in is identical

endotherm

the

Polysciences,

after

exotherm

from

of poly(L-lactic

as determmed

be

molten

endotherm

semicrystalline

no correlation

weights

could the

of an amorphous

(Curve

from

run

to quenching

When

histories

semicrystalline.

glass

crystallization

the melting

For L-PLA,

weight

the

Thus, the third thermogram

and shows

sample

formation

as obtained 6: Second

identical

by rapid cooling at a rate of

in the thermogram of the

cool

by DSC, as

From

and the melting

in spontaneous

the regeneration

A).

Curve

of samples

thermal

c~stallization

a mol wt of 50 000 endotherm

(Curve

100”C/min,

(M,

2

having

Owing

The crystallization

was

melting

D,L-PLA

is amorphous,

observed

the polymer

only the

in the thermogram

state, the polymer

100

material.

of L-PLA with

As obtained,

first

the racemic

is that D,L-PLA

L-PLA is a semicrystalline

behaviour

with

Figure

polymer

The most important

J. Kahn

solvent-casting

for the mechanical

The H, of our sample

materials.

and

in Table 3.

included

In correspondence PGAwasfound

I Engelberg

of PGA yielded compression

noquantitativedata

of PGA were

polymers:

organic solvents,

discs that were too brittle to be tested

mechanical

of degradable

data for this sample.

films by our standard

The available sample

moulded

properties

proportion

differences

of

plastic

deformation

in the stress-strain

to the presence

of a crystalline

behaviour phase in the

L-PLA.

B~omater/als

199 1, Vol

12 Apnl

299

Physico-mechanical

propetiies of degradable polymers: I. Engelberg and J. Kohn

Molecular

60 1

Weight 120

475

(weight average) 17 7.6

1

3.8

D ‘..._,

10

0

2

1

3

4

6

5

Elongation

(%I

Figure 3 Stress-strain cwves for various samples of PLA, Curves A and 6 were obtained from samples ofpoly(L-lactic acid) with mol wt of (A) 300 000 and (R) 100 000. The cwves indicate mostly elastic deformation. Curves C and D were obtained from pOiy(D,L-lactic acid) with mol wt of(C) 550 000 and(D) 107 000. These curves show both elastic and plastic deformation.

PBH and copolymers GPC analysis

with

(up to 35% (Figure

fraction

by weight) to

be

molecular-weight calculated from curve were

consisted

weights

the

provided

molecular

fractions. the entire

significantly

The true molecular values

The

low

viscosity

7) was

significant test

intrinsic

a further

amount

samples.

found for all ICI samples biosynthetic

origin

significant different

lots

limitations, about among

average

of the

several

increasing

content

copolymers

(Table 2). systems.

decreased, This

A qualitatively

copolymer

composition

had been

glycolic

reported

and

modulus

HV

elongation

was

of 2.8%,

made

highest

ductility.

all other

and

solvent-

polymers.

The

with HV decreased

with

with

optimum polymers

of HV

would

of the

defined

many

relationship

for copolymers

as

well

cantly

copolymer

between and

the

melting

of lactic acid and

DMA.

with

the

onset 252”C,

point

of the

as determined

199 1, Vol 12 April

when

thermal

decom-

by TGA, some

HV content

that

molecular

polymer

weight

PH B was kept in the

similar

about

had the brought

reduction

of

Our results indicate

in the

as the

DMA

polymers

for a wide range properties

in polydispersity,

samples

with

more

of one

narrowly

would exhibit signifi-

properties. results

were

E’, as a function

E’ was significantly

temperature.

of 22%

tensile

distributions

mechanical of the

the

to variations

improved

seen

occurred

reached

and toughness

Since

Qualitatively

gradually

at a low

improvement

the better ductility

and tensile modulus.

obtained

from

of temperature

higher in the homopolymer

than in the three copolymers. were

failed

of HV led to a significant

are sensitive

measurement

and

of the copolymer

applications.

expect

brittle

in this group of polymers

balance of strength

of possible

MPa) and the

but it was very brittle

(Tab/e 3). The copolymer

(2.5%) quite

HV the homo-

(36

with HV content of about 1 1% may have the

that copolymers

22%

reduced

MPa),

Unfortunately,

the tensile strength

As the crystallinity for

(2500

the HV content

about by the presence (Table2)

that the Tg

of the molecular

similar to PHB. A significant

were

PGA

strength

also

The copolymer

its crystallinity

of PHB was observed

Biomaterials

tensile

7%

or

with 3-HV were

with

tensile

Since the measurements

taken above the Tg of the four polymers,

of PHB was

degradation

to the copolymers

had the highest

and failed at low elongation with

for

moulding

of the copolymer.

As compared

13.5%.

T,,, were

similar

composition

lower

suited

to 2°C. This result indicated

these

of H, after

such as injection

was rather independent

of

by the standard

is typical

range -5

In

acid”.

Although position

the

behaviour

in a narrow

of these copolymers

highest

to be better

The Tg of PH B and its copolymers

extrusion.

polymer

HV have substantially

therefore

techniques

in ductility and toughness

of HV. The copolymer amorphous.

melt processing

only when

spite

with

points and appear

between

value

of copolymers

The copolymers

melting

variation

in this study for

are not

HV.

highest films

of

for about 1 h56. Thus, the melting temperature

that there may be a

batch

with

of the

samples

valid observations

employed

was almost completely

300

polymer.

included

degree of crystallinity

point

same

to form

procedure

distribution

weights

stability.

of a in the

be a reflection

molecular

to

samples

material

weight

we assume

had the second

the polymers

ICI

high.

presence

In polymer

batch

generally

too crystalline

casting

extremely

of all

could possibly

PHB and its copolymers PHB

was

of

were

molecular

In addition,

degree

high-

molecular weights, weight distribution

of the

of the polymer.

this kind, conventional very meaningful.

indication

bimodal

melt at 190°C

of PHB at 17 1 “C is very close to the upper limit of its thermal

of the

of low-molecular-weight

The

Time (min)

Figure 4 GPC of the copolymer of hydrowybutyric acid with 7 mol% of HV. Both retention time (lower axis) and the relative weight average molecular weight (X 1000) based on polystyrene standards (upper axis) are given. The chromatogram shows a bimodal molecular weight distribution with a high molecular weight fraction and about 36% (by weight) of low molecular weight material. Similar molecular weight distributions were found for all ICI samples tested (homopolymer of hydroxybotyric acid, Lot No. BX G04; copolymer of hydroxybutyric acid and 7 mol% of HV. Lot No. BX PSM4: copolymer of hydroxybutyric acid and 13.5 mol% of HV. Lot No. BX PO 10: copolymer of hydroxybutyric acid and 22 mol% of HK Lot No. BX PSM5/1).

amount

(Table1) and in all samples

lower

polydispersity

relatively

Retention

Z’O

material

by the supplier

weights

the calculated (Table

18

is

essentially

and a significant

of low-molecular-weight

4). The molecular found

14

of PHB and its copolymers

that all four samples

of a high-molecular-weight

were

HV

of the ICI samples

with HV revealed

li

7

the by

(PHB) were

no sharp transitions

curves.

Instead,

became

softer

E’ decreased with

increasing

Physico-mechanical

PC1

compression 0.5

PCL exhibited

several

the other tested exceptionally Another 235 typical

property

all other

The sample weight

to reason

increase weight

than

aliphatic

modulus

us

with

increasing

the mechanical than

leaves

PLA.

Although

nearly

90°C

that

observation

most of the other

polyesters

were

a

in the glassy

be

state at PLA and

state at room

were

unable

solvent,

the

phenomenon polymer. films.

to

Overall,

films

polymer

layer

was

to the other

a

broke

aliphatic

by

our

evaporation

into

pieces.

were

tested.

opaque,

unusual

flexible

polymer

as

suitable

Contrary

Despite

films

molecular

weight.

are therefore

was

The

second

more

stable

The

although weight

at the time

the tests

some

qualitative were

crystalline

conclusions.

HDA

anhydride)

was a pliable break.

analogue

of about

material Because

bonate)

and

of

and formed

clear, was

the

testing,

135°C

for

position

temperature

with

the

Transparent

the

known

ease.

between

the two

stability

against

of

a Td of

indicate

a decom-

for poly( BPA-carbonate).

obtained

from

FT-IR spectro-

samples,

we assume

of poly(BPA-iminocarbonate)

of

the

at temperatures group

indis-

amorphous

exceptional

degraded

tendency

to

virtually

of the thermal

evidence

is due

of

iminocarbonate about

and an organic

‘$”

--(=&k-o+

130-l

cyanate

bond 50°C

(Scheme

to

into

a

1).

nrQ-O-C=N + HO+

Z

thermal

to derive

similar

and

at yield

strength

polyanhydrides

and tested

applications.

properties

of aliphatic

was

found

to be an extremely

films

were

readily

obtained

by

relatively

present

low

imposes

thermal

of

property

Polycarbonates,

on the imino

to

and an

stability

to be an inherent

lacking

group,

cannot

and are consequently

by

melt

stability

more

spectroscopic

by TGA

polymer

sample

avoided

under

during carefully

or injection temperatures,

occurred

analysrs

thermal

compression controlled moulding, would

only as

about

some 100°C.

80°C

for

of

the

degradation moulding

conditions. which

clearly

at about

that

as low

requires

the

of

Although

revealed

at temperatures

moulding,

poly(BPA-

techniques.

poly(BPA-iminocarbonate)

compression

of

on the processibility

fabrication

as measured occurred

thermal limitations

IR

degradation Since

limited

in general.

loss

135”C, It

is known group

stable.

material

weight

modulus.

type

iminocarbonate) this

Poly(SA-

the

of reaction

this

reaction

to a hydroxyl

appears

undergo The

Glass transitrons to 50°C.

Thus,

atom

thermally

small

had

function.

leading

the extra hydrogen

polyanhydrides with

dissociation

in polyurethanes,

higher

58, PTMC

with

of over 350°C

of partially

a

particularly

completely

Our TGA results

decomposition

hydroxyl

was

poly(BPA-iminocarbonate)

analysis

as

poly(BPA-iminocar-

differences

reduction

that the thermal

some

In correspondence

be

materials

regarded

were

films

of polyiminocarbonates

PTMC polycarbonates5’,

brittle

be

polymer

were

poly(BPA-iminocarbonate).

occur

molecular

materials

mechanical

two

this

striking

a sharp

isocyanate

two

to drug-delivery

however,

used poly(BPA-carbonate),

appearance,

strong

One of the most

poly(BPA-iminocarbonate)

it is possible

-50

can

polymers

weight

large elongations

low

in too

for adhesion

may, with

poly(BPA-carbonate) Both

formed

strength

that exhibited of their

or blends

physical

polymer residual

45-50°C.

tensile

reactivity,

to be limited

material.

By

molecular

polyanhydrides

in the range from had low

hydrolytic

two

by

PTMC

to

performed. The

except

material

of the widely

characterization

extrusion

soft

copolymers

for

be mechanically

application, The

weight

obtarned

after

anhydride)

for mechanical their

amorphous

The

temperatures

not observed

The

in mind,

may

of

poly(CPP-SA-IS0

initial

used

molecular values

volume

PTMC

surgery.

A similar

about

limitations

fractions.

of

unable

poly(SA-HDA

were

predominantly

were

high

were

not certain

tested

appear

which

sample amorphous.

of well-defined

for

anhydride).

the absolute

poly(BPA-iminocarbonate)

degradable

poly-

atmosphere

we were

results

tested

after

together

without

immediately

anhydride)

and had a higher

films

these

tested

polyanhydride,

we were

With

melting

Since

dissociate

and

polymers,

an inert

precautions,

test

recoil

Polyiminocarbonates

incomplete.

poly(CPP-SA-IS0

transparent

test specimens

were

these

most

for medical

processibility

to all other

of poly(CPP-SA-IS0

anhydride)

their

cast under

and specimens

preparation.

investigated

to prepare solvent

compositions

are the hydrolytically being

limited

were

dry nitrogen

than

molecular

property

degradation.

anhydrides

obtain

currently

This

it difficult

massive

different

The

of

as PLA or PHB.

polymers

polyesters:

The polyanhydrides

polymers

applications. made

that

Based on preliminary with

other.

load deformed

to stick

and the relative

any practical after

in block

scopic

polyanhydrides

unstable

to find

of the

Polyanhydrides Two

each

low

no elastic

hydrodynamic

It seems

tinguishable.

This

crystallinity

yielded

rather

PCL

upon

due to the high moulding

PCL

of

procedure;

is probably

Compression

compared

obtain

solvent-casting

virtually

had a tendency

between

a large

interesting.

We of the

such

the

temperature. standardized

a

up and

PCL is can

its Tg whilst

above

to

prevention useful

weight,

in part by the fact that PCL is in the rubbery

room temperature,

using

and J. Kohn

of low-molecular-

little doubt

This

point

weak it

of PCL would

molecular

properties

= 50 000)

weaker

strength

I. Engelberg

be rolled

was

by Amgen

chloroform.

little tensile

(Table 3).

There against

as determined

polyesters.

and exhibited

= 44 000)

tensile

pressed

40°C

could

and the films

The large difference

is more

(IV,

at

films

breaking.

polymers:

PTMC had a low Tg (- 14°C) and was completely

had Td between which

The

deformation when

stability.

to us was of intermediate

L-PLA (M,

explained

T,,, of 57°C.

low

polyesters

that the mechanical

with

significantly

its

of degradable

moulding

tonnes.

without

are its

of PCL available

somewhat

comparison

aliphatic

esters)

and a low

stands

and

among

noteworthy

PCL had a Td of 350°C

of poly(ortho

molecular

not found

Most

of PCL is its high thermal

tested

255”C,

strength

properties

polyesters.

Tg of -62°C

low

and

unusual

aliphatic

unusual

Whereas

and

propelties

could

only be

Processing

would

require

be impossible

by even

without

degradation. The replacement

isosteric

imino

strength

of

the

group

of the carbonyl had

polymer:

little

effect

group

by the nearly

on the

mechanical

poly(BPA-iminocarbonate)

Biomaterials

199 1, Vol

12 April

was

301

Physico-mechanical properties of degradable polymers: I. Engelberg and J. Kohn

60

SUMMARY

1

AND CONCLUSIONS in Tab/es

The data collected to compare widely

2 and 3 represent

the engineering

investigated,

large number necessity

properties

degradable

of available

be

biomaterials.

polymers,

incomplete.

In

addition,

that cannot

example,

the need to keep the experimental

is in direct

L

012345678

parameters

specimens

that exhibit

be readily

we

Figure 5 Stress-strain curves for two different polyiminocarbonates. Curve A was obtained from a sample of poly(BPA-iminocarbonate) with a mol wt of 105 000. The curve indicates that this polymer is brittle with mostly elastic deformation. Curve B was obtained from poly/Dat-Tyr-Heximinocarbonate) with a mol wt of 10 1 000. Poly(Dat-Tyr-Hex-iminocarbonate) is less brittle and exhibits both elastic and plastic deformation. (First published in reference 53 and reproduced here with permission).

and

as strong

as poly(BPA-carbonate)

poly(BPA-carbonate) its

tensile

bonate),

against

most striking two

of similar

modulus,

was

modulus

under

stress-strain

the

sharply

failed

at 4%

bonds

optimized

that the possible

thereby

reducing

relative

to

general conclusions: poly(L-lactic

showed

the highest

was

found

mechanical

properties

in the

were

unchanged,

poly( BPA-imino-

somewhat

processing

and

Consequently,

reminiscent

required

the

onset

compression-moulded extrusion

Under

Although represents

a very of

modification polymer excellent

the

film

strength

increased

Biomaterials

BPA

change

the

effect

by

de-

properties

Dat-Tyr-Hex chemical

this

structural

of the resulting

polymers

are

the polymers

very

range and

available

polymers

cover a wide

95°C).

making

degradable

soft

to obtain virtually

futile search

Thus,

biomedical

screws,

applications

or scaffolds

of strength

(from -62”

to

any desirable

Tg

it has been implied

as

for

of severed

bone nerve

of material and biological

in many cases the biological

Although

instance

drug-releasing

for the reconnection

fibres require unique combinations

nontoxic

goal. Unfortunately,

such

grafts,

high-

or blends of the

for just one more

advanced

vascular

as

materials

the Tg of the tested

Likewise,

is no longer a valid research stents,

shades

range of over 160°C

material’5s intraarterial

such

from copolymers

or blending.

polymers properties.

and weak

all intermediate

materials.

by copolymerization

the poly(ortho

and its copolymers,

materials

to very

it possible

that ‘the generally

available,

strong

are accessible

currently

in our study,

aliphatic polyesters.

of physico-mechanical

L-PLA virtually

usually

all fall into this category.

the currently brittle

challenge.

related to aliphatic

PLA, PGA, poly( hydroxybutyrate)

From

the

mech-

is that the most widely

polymers

included

medical

devices)

with improved

research

of all

in terms of

inert polymers

bone fixation

observation

would

and tensile

strongest

were clearly inferior

esters),

molecular-weight

high-molecular-

strength

Among

Finally,

the

poly(BPA-iminocarbonate)

Thus, for many possible

degradable

PCL and PTMC

with

that had been fabricated

of tensile

or are structurally

properties.

in the of

properties

properties

(toxicity, degradation profile in viva, cell adhesion, blood compatibility, etc.) have not been determined, it appears to be unlikely

that the currently

be able to cover all desirable

available

materials

will indeed

combinations.

Poly(Dat-Tyr-Hex-imino-

amorphous

and

exhibited

retained

the

by poly(BPA-

ACKNOWLEDGEMENT

to poly(BPA-iminocarbon-

and tensile were

noticeable

be

as well.

of

In comparison

could

conditions,

limited.

completely

forming

ate), the tensile was

decomposition.

controlled

fundamental polymer,

thermal

may be possible

replacement

Tyr-Hex-iminocarbonate)

to

margin of

for

without

carefully

surprisingly

was

iminocarbonate).

ductility

in a wider

thermal

on the mechanical

was

carbonate)

of

moulding

the

of

of 14°C

relative

temperature

at 65-70°C

or injection

structure

in Ts resulted

the

investigated

and

strength

in agreement

to some of the advanced

general

such as PTMC

a derivative

7 7). led to a reduction

values

is an important

Another

and ductility

poly(Dat-Tyr-Hex-iminocarbonate)

composition.

polymer

and

of degradable

anical strength

preparation

conditions.

polymers

cover a very wide

(Table 2). Since the Td remained

the reduction

between

is we

sample

(such as degradable

development

controlled

even the mechanically

strength

applications

mobility,

but brittle

of BPA by Dat-Tyr-Hex,

(Structure

poly( BPA-iminocarbonate)

302

Overall,

mechanical

polyesters

hydrogen

chain

Tg of poly( Dat-Tyr-Hex-iminocarbonate)

safety

5,

L-PLA.

The replacement dipeptide

of

of poly(BPA-iminocarbonate)

to be a strong

of high-molecular-weight tyrosine

limit

degradable

individual

strictly

in mind it is possible to draw a few

acid)

However,

for tensile

between

Of all tested polymers,

weight

by the

point,

of interchain

could

poly( BPA-carbonate).

carbonate)

of the

poly(BPA-carbonate)

presence

the ductility

The

(Figure

At this

processing

test

in this study to

our data on tensile

not necessarily

such as PEEK or Kevlar”.

poly(BPA-imino-

100%47-4g.

in polyiminocarbonates

whose

shown

data. Whilst

elongation,

to fail only at about

of

brittleness

is clearly

curve of poly( BPA-iminocarbonate)

carbonate) speculate

in terms

properties

increased

This

A) and the elongation

known

weight

are

With this limitation

tested

poly(BPA-iminocar-

in the mechanical

poly(BPA-iminocarbonate). Curve

for

surpassed

M Pa for poly(BPA-carbonate)).

difference

polymers

molecular

(21 50 MPa

2000

and

during

Consequently,

as the

obtain

values

and

values obtained from test specimens

modulus. about

conditions

measurement.

For

and measureto

the best possible

uniform

certain

to optimize

polymer

Since we attempted

had to use

are

conditions

the desire

each

to the

addressed.

preparation

collect data that would allow comparisons experimental

(%I

with of

and modulus.

polymers

Elongation

conflict

processing strength

OIr

there

limitations

uniform as possible during sample

group of

Owing

any such study will by

practical

ment

a first attempt

of a diverse

modulus

slightly

(Figure

199 1. Vol 12 April

5, Curve

reduced, B).

of poly(Dat-

The authors

whilst

Incorporated,

its

Research

would

like to express

Nova

their gratitude

Pharmaceutical

and Development

Corporation,

to Amgen

Corporation,

Stolle

SRI International,

Phvsico-mechanical

and to Dr S. Lrn for contributing study.

In addition,

acknowledge

the

the helpful

manuscript

free polymer

authors

comments

samples

like

to

for this

and corrections

and J. Heller

Huang

(University

(MIT),

Dr

D.

(Stolle

Incorporated).

the viscosity

their help with the preparation 8902468,

by National

by Zimmer Focused

Development and Dr C.G.

measurements

and

and Mr S. Pulapura

for

of the manuscript.

Science

Foundation

Incorporated

23

24

This work and

A.M.

20,

and

25

D.K.,

26

of

Patent

3.839.297.

Miller,

R.A.,

Brady,

Biodegradable

changes

Mater.

Res.

1977.

11,

Lews,

D.H..

polymers,

Systems,

(Eds

NY,

1990,

release

and

pp. l-4

synthesis 1987,

2:

an In

catalystin

octoate

copolymer

sutures,

Degradation

rates

US

and

of oral

polyglycolates):

copolymer

ratios.

Rate

J. Biomed.

of

bloactlve

agents

Polymers

M. Chasln).

from

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