Table Of ContentehT Biomaterials Silver Jubilee Compendium x/
Preface
The journal Biomaterials was launched in 1980. The subject of biomaterials science
was then in its infancy, being largely confined to the study of the characteristics of
materials used for medical devices. In reality, few of those materials had ever been
developed for this specific use and instead, were taken from other industrial
applications, for example in aerospace, nuclear engineering or chemical processing,
and experimented with in surgical or medical procedures. The science was largely
observational, as the performance of these materials in their new surroundings was
evaluated by combinations of physical, chemical, engineering, biological,
pathological and clinical techniques.
Over the ensuing decade, the subject evolved, as more became known about their
performance and especially about the mechanisms of the interactions between the
materials and the tissues that underpin the performance. This branch of biomaterials
science has become associated with the term biocompatibility, a field that has been
the driving force for the subject. With greater knowledge about these interactions, old
serendipitous biomaterials were discarded, and new, intentionally designed, or at least
modified, materials, introduced. Moreover, these materials started to find applications
in related areas, and medical devices were no longer the sole home for biomaterials,
as applications in pharmaceutical technology through drug and gene delivery,
regenerative medicine and tissue engineering, and biotechnology have emerged and
developed.
Twenty-five years on, we can truly say that biomaterials science has matured at an
incredible rate and now represents a formidable sector that bridges the materials
sciences, advanced medical therapies, and molecular and cell sciences. This
development could not have been achieved without high quality scientific journals,
including those that represent the main parent disciplines and the interdisciplinary
field of biomaterials science itself. Although by no means alone, the journal
Biomaterials has taken centre stage here and, at the time of its silver jubilee in 2004 is
widely considered to be the premier journal in this field.
In order to celebrate 25 years of publishing biomaterials science, Elsevier decided to
confer two awards, the Elsevier Biomaterials Gold Medal and the Elsevier
Biomaterials Silver Medal. A panel of judges was established in 2005 in order to
select the recipients.
The Elsevier Biomaterials Gold Medal was awarded to the person judged to have
made the most significant contribution to the subject of biomaterials science during
ehT Biomaterials Silver Jubilee Compendium
the 25 years from 1980 to 2004, irrespective of where the work was published.
Elsevier were delighted to announce at the European Society for Biomaterials Annual
Meeting in Sorrento, Italy, in September 2005, that the winner of the Gold Medal was
Professor James Anderson, of Case Western Reserve University, Cleveland, Ohio,
USA. The medal was presented at the Annual Meeting of the Tissue Engineering
Society International in Shanghai, in October 2005.
The Elsevier Biomaterials Silver Medal was awarded for the most significant paper
published in the journal Biomaterials during the first 52 years. Over 60 papers were
nominated and the judges had a very difficult time in making the selection since most
of the world's leading biomaterials scientists were represented in the nomination list.
The subject matter covered much of the seminal research that has set the foundation
for the high quality science that is undertaken today and which will embrace the
future. This Silver Jubilee Compendium consists of reprinted versions of the top 25
of these papers, arranged chronologically. The current Editor-in-Chief is both
appreciative of and humbled by the decision of the panel of judges to select one of
his earliest papers, with graduate student Anne McNamara, as the leading paper and
recipient of the Silver Award.
This Compendium is published as a landmark in biomaterials science and it is to be
hoped that it will serve as a stimulus to young biomaterials scientists of the early
twenty-first century for their pioneering work of the future.
I have been proud to serve as Editor-in-Chief of the journal during this exciting period
of its development. I place on record my thanks to previous editors of the journal,
listed on a separate page, to editorial staff within Elsevier and their predecessor
publishers during this 52 years and to colleagues who have served as Editorial Board
members, referees and authors. I would particularly wish to thank Amanda Weaver,
Publisher of the journal in Elsevier who skilfully steered this process of the medals
through the company, to the panel of judges who had to work very hard on this
process, and to Peggy O'Donnell, Managing Editor of the journal, who carried the full
logistics burden of the medals procedure.
Professor David Williams
Editor-in-Chief
Liverpool
History of Editorial Appointments
Stephen Bruck Founding Editor (1980-1983)
Garth Hastings Founding Editor (1980-1995)
Nicholas Peppas Editor-in-Chief (1983-2001)
Robert Langer Editor-in-Chief (1983- 2003)
David Williams Editor-in-Chief (1996-)
ehT Biomaterials Silver Jubilee Compendium
dellortnoC release of biologically
active compounds from elbidoreoib
polymers
J. Heller
Polymer Sciences Department, SRI International, Menlo Park, CA94025, USA
Received 8 June 1979; revised 1 October 1979
This article sweiver the controlled esaeler of biologically active stnega by the erosion or chemical degradation of a polymer
matrix into which the agent si incorporated. Chemically bound active stnega dna work no steroid esaeler from loretselohc
implants era not covered. The smsinahcem of polymer noisore dessucsid are: dekni4ssorc ;noissics hydrolysis, ionization or
protonation of pendant ;stpuorg backbone .egavaelc Drug esaeler seiduts era dealt with under hcae of eseht .sgnidaeh
It si now generally recognized that the controlled release of cover the important work in which the active agent si
biologically active agents to a local environment nac eb chemically bound to the polymer and si released to the
achieved by means of one of three general methodologies: surrounding medium by hydrolysis of a bond between the
(1) diffusion through a rate-controlling membrane, (2) esu active agent and the polymer chain2,3; nor does it cover
of osmotically regulated flow, and (3) release controlled the extensive work of Kincl and coworkers on the esaeler
by the erosion or chemical degradation of a matrix into of steroids from cholesterol implants .4
which the active agent si incorporated .1 For this review, it si convenient to systematize
Each of these methodologies offers certain unique polymer erosion according to the three mechanisms shown
characteristics which determine the design of specific in Figure I, where ~) denotes a hydrolytically unstable
therapeutic systems. Thus, methodology (1) allows con- bond .5 In general terms, Mechanism encompasses water-
struction of drug delivery devices that release therapeutic soluble polymers that have been insolubilized by hydro-
agents by zero order kinetics and where rate of delivery lytically unstable crosslinks; Mechanism ! includes polymers
nac eb readily adjusted by changing the rate-limiting that era initially water-insoluble and era solubilized by
membrane and/or membane thickness dna area. Methodology
(2) allows construction of devices that not only release their Mechonism T
contents by zero order kinetics but era also able to sustain
high delivery rates not normally available with membrane-
moderated devices. Methodology (3) allows construction
of drug delivery devices that have a predetermined life
span and need not eb removed from the site of action
once their drug delivery role sah been completed.
Drug release from bioerodible polymers finds esu in
both topical applications and systemic applications. Both msi~h~,~l
sesu demand that the polymer degrade to nontoxic products,
and polymers used in systemic applications must also
degrade to low-molecular-weight fragments that can eb ---'- c
readily eliminated or metabolized by the body. In topical
applications, retainment of high molecular weight of the
degradation products si desirable, since in this way no
unnecessary systemic absorption of the polymer will occur,
dna toxicological hazards era thus reduced.
Mechanism T
The purpose of this article si to present a compre-
hensive review of methodology (3) where active agents era
desaeler to a surrounding aqueous environment by solubitiza-
Figure 1 Schematic representation of degradation mechanisms;
tion of the polymer matrix induced by the aqueous environ-
~) denotes a hydrolyticaHy unstable bond
ment. The review si limited to devices in which the active
A represents a hydrophobic substituen t and
agent si dissolved or dispersed in a polymer, and does not B-. C represents hydrolysis, ionization or protonation
0142-9612/80/010051-07 $02.00 (cid:14)9 1980 CPI ssenisuB sserP
Biomaterials 1980, Vol 1 January 51
The Biomaterials Silver Jubilee Compendium
Bioerodible polymers: .J Heller
hydrolysis, ionization, or protonation of a pendant group; recognized the utility of erodible hydrogels for providing
and Mechanism includes hydrophobic polymers that era sustained delivery of entrapped macromolecules. Both
converted to small water-soluble molecules by backbone studies took advantage of the hydrolytic instability of
.egavaelc Clearly, these three mechanisms represent extreme crosslinks formed in vinyl polymers by using N, N~-methyl -
,sesac dna erosion by a combination of mechanisms si enebisacrylamide sa a comonomer. Hydrolysis of the
.elbissop crosslinks proceeds sa follows:
, 0 , ~O H_~I_H
MECHANISM I - = 2-R-_-NH +
i i 2
Solubilization by crosslink cleavage
In these systems, water-soluble polymers era insolubilized
where -R- represents the vinyl polymer chain.
by means of hydrolytically unstable crosslinks. Consequently,
In the first study ,8 bovine pancreatic insulin saw
the resulting matrix si highly hydrophilic dna completely
immobilized in a hydrogel prepared from acrylamide and
permeated by water. Since the active agent si in na aqueous
%2 N, N'-methylenebisacrylamide. Slow esaeler of insulin
environment, its water solubility becomes na important
from the hydrogel saw inferred esuaceb insulin-containing
consideration, dna compounds with appreciable water
hydrogel implants sustained diabetic animals for at least a
solubility will eb rapidly leached out, independent of the
few weeks. It si not clear from the study how much insulin
matrix erosion rate.
saw desaeler by diffusion dna how much by cleavage of
There era two general applications in which erodible
crosslinks.
hydrogets era useful in the controlled delivery of active
In the second study ,9 (~-chymotrypsin saw immobilized
agents. In the first the active agent sah extremely low water
in a hyclrogel prepared from N-vinyl pyrrolidone dna
solubility, dna in the second the active agent si a macro-
N, N'-methylenebisacrylamide. It saw found that, by varying
molecule that si entangled in the hydrogel matrix dna
the N, N'-methylenebisacrylamide concentration from 1.0
cannot epacse until a sufficient number of crosslinks have
to 1.0w/w % with respect to N-vinylpyrrolidone, hydrogels
cleaved and matrix crosslink density sah been reduced.
with dissolution times of several days to practically
The first application si illustrated in Figure 2, which
insoluble could eb prepared. However, esaeler of =-chymo-
shows the esaeler of a highly water-insoluble drug, hydro-
trypsin did not correlate well with hydrogel dissolution
cortisone acetate, from a gelatin matrix crosslinked with
time, presumably esuaceb of diffusional .epacse
formaldehyde .5 sA indicated by the first-order dependence,
To prevent diffusional ,epacse e-chymotrypsin saw
esaeler si by diffusion with little contribution by matrix
acylated with acryloyl chloride dna then chemically
erosion. esuaceB the drug si very water insoluble, useful
incorporated in the hydrogel by copolymerization with
esaeler over many days si achieved. Such a device could eb
N-vinyl pyrrolidone dna N, N'-methylenebisacrylamide.
desu when zero-order kinetics era not important dna
esaeleR of e-chymotrypsin from the resulting hydrogels
removal of the expended device si not convenient or
saw then found to correlate more closely with hydrogel
desirable .6
dissolution times.
Illustrative of the second application era many
examples in which water-soluble macromolecules have been
immobilized in hydrogets by physical entanglement .7
However, the intent of most of these studies saw to achieve MECHANISM II
long-term immobilization of enzymes or antigens; the slow
diffusional epacse and/or slow hydrolysis of the matrix Solubilization by hydrolysis, ionization or protonation of
with consequent liberation of the entrapped macromolecules pendant groups
saw generally regarded sa undesirable. Two studies, however,
Systems ni this category include all polymers that era
40- initially water-insoluble but become water-soluble sa a
consequence of hydrolysis, ionization, or protonation of
pendant groups. esuaceB no backbone cleavage takes place,
the solubilization does not result in any significant segnahc
in molecular weight.
O3
The major emphasis in the development of these
materials sah been on enteric coatings. These era coatings
dengised to eb insoluble in a certain pH environment,
E
usually the stomach, dna then to dissolve abruptly in na
-O2 environment of a different pH, such sa the intestines.
Usually these polymers era applied to pills sa protective
coatings dna do not produce steady, sustained esaeler of
therapeutic agents. However, by using mixtures of enteric
0I coatings, each with a different disintegration time, it si
possible to prolong the action of therapeutic agents .01
Literature on enteric coatings si much too voluminous
for detailed review, but the coatings nac eb grouped into
271 69 I ......... 02J 1 44t three categories according to their dissolution mechanism;
emiT )syad( (1) dissolution by side group hydrolysis, (2) dissolution by
Figure 2 Release of hydrocortisone acetate from a cross~inked ionization of a carboxylic acid function dna (3) dissolution
gelatin matrix by protonation of amine functions.
52 Biornateriais 1980, Vol 1 January
ehT Biomaterials Silver Jubilee Compendium
Bioerodible polymers: .J Heller
Dissolution by side group hydrolysis. Materials in this progressively more ionization si necessary to solubilize the
category era represented by copolymers of vinyl monomers polymer, resulting in increasingly high dissolution pH. The
and maleic anhydride' emas argument holds for polymers having the same ester
grouping but different degrees of esterification. The higher
the degree of esterification, the more hydrophobic the
polymer and consequently the higher the dissolution pH.
X I HO lX Recently it sah been shown 71 that partially esterified
-C -^H C HCH- - ~ -HCI I ~ HC- C-2 H-IH~ IC H- copolymers of methyl vinyl ether and maleic anhydride can,
2~/~', coo ~ cor in a constant pH environment, release hydrocortisone
0 0 0 H e H e incorporated therein by excellent zero-order kinetics.
Figure 3 shows polymer dissolution rate and the rate
of hydrocortisone release for n-butyl half-ester polymer
films containing the dispersed drug. Each pair of points
where X si OR or H.
represents a separate device in which the amount of drug
In the anhydride form, the polymers era water-
released by the device into the wash solution saw determined
insoluble, but on exposure to water they become soluble
by u.v. measurements and the amount of polymer dissolved
because of the hydrolysis of the anhydride group. A number
saw calculated from the total weight loss of the device. The
of variables affect the rate of polymer dissolution and gal
excellent linearity of both polymer erosion and drug esaeler
time before initiation of the dissolution process .11 In general,
over the lifetime of the device provides strong evidence for
time before dissolution increases sa the size of the alkyt
a surface-erosion mechanism dna for negligible diffusional
substituent R in the vinyl ether portion of the copolymer
esaeler of the drug. The latter result saw independently
increases, and decreases sa the pH of the aqueous environ-
verified by placing a drug-containing film in water at a pH
ment increases. The rate of polymer dissolution also increases
low enough that no dissolution of the matrix took place
sa the pH of the aqueous environment increases.
and periodically analysing the aqueous solution for hydro-
Dissolution by ionization of carboxyl groups. Currently used
cortisone. None saw found over several days.
enteric coatings represent this type, and can be represented
Figure 4 shows the effect of size of alkyl group on
generally sa polyacids. While in unionized form they era
polymer erosion rate for a series of partial esters measured
water-insoluble, but on ionization of the carboxylic acid
at pH 7.4. Because of the linear correlation between polymer
functions they become water-soluble.
erosion and drug release, distance eroded nac eb directly
The most widely used enteric coatings era based on
correlated with amount of drug released and was, in fact,
cellulose acetate phthalate .21 They era insoluble in aqueous
derived from measuring drug release. All drug release rates
acidic media but, because of the free acid groups on the
again show excellent linearity and strong dependence on
phthalate radical, dissolve in aqueous .sesab Enteric coatings
the size of the alkyl group. Since in all experiments drug
desab on cellulose acetate succinate have also been
depletion also coincided with total polymer dissolution,
described .31
again it nac eb assumed that drug release and polymer
Partially esterified copolymers of methyl vinyl ether
erosion occur concomitantly.
dna maleic anhydride or partially esterified copolymers of
The effect of pH on rate of polymer erosion dna
ethylene and maleic anhydride have also been investigated .61-41
hence release of hydrocortisone dispersed in the n-butyl
It saw found that these materials characteristically exhibit
partial ester si shown in Figure 5. The date show a clear
a pH range above which they era soluble and below which
dependence of erosion rate and drug release on the pH of
they era insoluble. This pH range si quite sharp, about
the eroding medium and, sa expected, a progressive decrease
0.25 pH units, and changes with the number of carbon
in rate sa the critical dissolution pH si approached.
atoms in the ester side group of the copolymers.
The partial ester copolymer also sah been used
This behaviour nac eb understood readily by considering
recently sa a model for a bioerodible drug delivery system
the number of ionized carboxyls necessary to drag the
that sesaeler a therapeutic agent in response to the presence
polymer chain into solution. With relatively small ester
of a specific external molecule .81 In this model, hydro-
groups, a low degree of ionization si sufficient to solubilize
cortisone saw incorporated into na n-hexyt half ester of a
the polymer; hence the dissolution pH si low. As the size of
methyl vinyl ether-maleic anhydride copolymer dna the
the alkyl group increases, os does the hydrophobicity, and
oo3 I . . . . . . . . . . . . . .
0OI . . . . . . . . . . . . . . . . 001
&.~" 052 I
60 -6o
_Jc o
~,,4~ ~0 E g
2 .a
o 20 ~ 02
0
O Ot 20 30 40 05 60
emiT )h(
Figure 3 Rate of polymer dissolution and rate of release of hydro- 0 0I 02 ! 05: J 04 1 05 I 06 ' 07 08 09
cortisone for the n-butyl half-ester or methyl vinyl ether-maleic emiT )mar(
anhydride copolymer containing 10 wt-% drug dispersion. (0), drug Figure 4 Effect of size ot ester group in half-esters of methyl vinyl
release; (A), polymer dissolution. Reproduced from .J Appl. Polym. ether-maleic anhydride copotymers on rate of erosion at pH 7.4.
Sci. 1978, ,22 1991 by permission of John Wiley and Sons Inc., Reproduced from .J AppL Polym. LcS 1978, ,22 1991 by
New York permission of John Wiley and Sons Inc., New York
Biomateriais 1980, Vol 1 January 53
The Biomaterials Silver Jubilee Compendium
Bioerodible polymers: .d Heller
c02 003
c
71
25(-
51
-03(2
A L=
10
G) -051
IOO-
5~
52
i O8
emiT )h(
% 6~ 20 ..... 30 ~ ..... 50 so ~o-~ 9o oo~
emiT )niar( Figure 7 In vivo release of hydrocortisone from ocular inserts in
Figure 5 Effect of erosion medium pH on erosion rate of half-esters rabbits
of methyl vinyl ether~rnaleic anhydride copolymers. A = pH 5.5,
rabbits ,5 Kinetic plots were obtained by placing weighed
B = pH 5. 75, C = pH 6.0, D = pH 6.5, E = pH .7 Reproduced from
.J AppI. Polym. Sci. 1978, 22, 1991 with permission of the devices in eyes and removing the devices at desired time
copyright owner intervals. The amount of drug released saw determined by
polymer<lrug mixture fabricated into discs. These discs measuring residual drug in the devices and subtracting that
were then coated with a hydrogel containing immobilized from the known original amount. The results expressed in
urease. In a medium of constant pH and in the absence of terms of polymer erosion era shown in Figure 7.
external urea, the rate of release of hydrocortisone saw Clearly, the devices era highly functional dna esaeler
that normally expected for that polymer at the given pH. hydrocortisone by excellent zero-order kinetics. Further-
In the presence of external urea, ammonium bicarbonate more, considering that each point represents a different
and ammonium hydroxide were generated within the device and a different rabbit eye, there si very little scatter,
hydrogel, which accelerated polymer erosion dna hence drug indicating a high degree of reproducibility.
release. Drug delivery rate increase saw proportional to the Polymer dissolution by protonation of amine functions.
amount of external urea and saw reversible; that ,si when Materials in this group are, in effect, reverse enteric coatings"
external urea saw removed, the rate of drug release gradually they era insoluble in water and alkali but soluble in acids.
returned to its original value. The effect of urea on polymer Although no drug-release studies have been described,
erosion and drug release si shown in Figure 6. detseggus uses have been sa moisture-resistant medicament
Date presented thus far show that the partial ester- coatings that will release their contents in the stomach ),91
polymer system si a useful polymer matrix for zero-order dna sa veterinary medicament coatings to allow egassap
drug delivery; it shows the desired surface erodibility, and through the stomach of ruminants and subsequent esaeler
the erosion rate at any given pH can eb adjusted by selecting in the abomasum .02
the appropriate ester alkyl group. A material typical of this group si cellulose acetate N,
The usefulness of this polymer system for delivery of N-diethylaminoacetate, prepared by the amination of
a therapeutic agent in vivo sah been investigated by fabricating cellulose acetate thloroacetate with diethylamine .12
hydrocortisone-containing films in small circles and placing Another material saw prepared by the addition of amines
them in the lower forniceal cul ed cas of New Zealand to crotonic acid esters of cellulose .22
0OI
MECHANISM III
O9 o
Solubilization by backbone cleavage
This category includes all water-insoluble polymers that
undergo hydrolytic backbone cleavage and era solubilized
by conversion to small, water-soluble molecules.
A major driving force for the development of these
materials saw a search for absorbable sutures superior to
catgut. From these studies have evolved two synthetic
6c ) materials that were suitable for surgical implants: poly
(lactic acid) 23,24 dna poly(glycolic acid) .52 The first
demonstration of the utility of poly(lactic acid) sa a bio-
erodible implant capable of sustained release of a thera-
I peutic agent saw described about 01 years oga ,62 and
since then many publications have dealt with the sustained
0 02 I . 04 l 06! 08I 00II , 0211 041 t 061I. ,. 081 I 002 1 022 1 042 I esaeler of pharmaceuticals from bioerodible implants.
emiT )h( For this review, the literature will eb discussed
Figure 6 Rate of hydrocortisone release at 35~ from a n-hexyl according to the type of pharmaceutical agent delivered:
half.ester of a copolymer of methyl vinyl ether and maleic anhydride (1) delivery of narcotic antagonists, (2) delivery of
at pH 6.25 in the absence and presence of external urea. A = polymer
contraceptive steroids, dna (3) delivery of others.
+ hydrogel, 10 -1 m urea; B = polymer + hydrogel, 10-2m urea;
C = polymer + hydrogel, no urea. Reproduced from J. Pharm. Sci. Delivery of narcotic antagonists. The release of cyclazocine
1979, 68,919 with permission of the copyright owner from poly(lactic acid) 72 and the release of Naltrexone
54 Biomaterials 1980, Voi 1 January
ehT Biomaterials Silver Jubilee Compendium
Bioerodible polymers: .J Heller
lo.
OOI
09
08 /
07 ~70
Q;
=_
03
O2
N 0I
t .......... t J t _~ ..... ...1 ......... ~ r
Ot 02 03 40 05 06 07
O
emiT )syod(
! Figure 9 /n vitro release of 3H-Na/trexone base from uncoated rods
of 75/25 poly (L (+)-/actic~co~lycolic acid) into 37~ buffered,
pH7 solution sa a function of drug loading, x, 80% w/w n. base;
II, %07 w/w n. ",esab A, 60% w/w .n ",esab I, 50% w/w .n .esab
Reproduced with permission from Life Sci 1975, ,71 1877 (cid:14)9 1975
magreP on sserP Ltd.
The in vitro release of Naltrexone and Naltrexone
pamoate from poly(lactic acid) microcapsules sah also been
described .03 Again, the microcapsutes contained defects, and
about 50% of the contents were released after the first few
hours of extraction.
ii~ ...... 0it ......... 02 i o31 04 I ..... o5i o6 l .
emiT )syod( Copolymers of lactic and glycolic acid have also been
Figure 8 Cumulative amounts of cyc/azocine excreted from used in a bioerodibte delivery system for Naltrexone and
composites of po/y (lactic acid) implanted or injected in rats. Amounts Naitrexone ~1-3etaomap The in vitro release rates of Nal-
have been corrected to account for unrecovered drug, ,)3E( (O), and trexone from rods of 75/25 poly(lactic/glycolic acid)
(A), film; (~), small particles; (~), film with drug sealed into
copolymer sa functions of drug loading are shown in
poly(/actic acid) envelope. Reproduced with permission from .J Med.
Chem. 1973, 16,897 (cid:14)9 American Chemical Society Figure 9. As expected, increase in drug loading results in
increased delivery rates.
from poly(lactic acid) 82 have been described in two
In vivo release of labelled Naltrexone from 90/10
studies. In the first study, composites of poly(lactic acid)
poly(lactic/glycolic acid) beads si shown in Figure .01 The
and labelled cyclazocine were prepared and implanted in
release was measured sa urinary excretion; after about
rats sa 4 cm 2 films, sa ground films having particle sizes
90 days about 50% of the drug was accounted for. The
falling within No. 25/35 sieves, and sa 6.2 cm 2 poty(lactic
remaining drug was assumed to have been excreted in the
acid)-cyclazocine composites enveloped in poly(lactic acid)
faeces. Other investigators 23 found that Naltrexone si
containing no drugs. In vivo release was followed by
excreted in approximately equal amounts in the urine and in
monitoring the radioactivity of excreted urine.
the .seceaf
The results, shown in Figure 8 were not those expected"
Delivery of contraceptive steroids, d-Norgestrei was
cyclazocine si released by diffusion, and therefore release
incorporated into poly(lactic acid) and its release rate
from small particles with their greater surface area should
followed both in vitro and in vivo 33. It was found that
eb much faster than release from films. It was postulated 72
films of the polymer containing 33% Norgestrel released the
that the in vivo results era influenced by varying degrees
steriod at a relatively constant rate of 3 #g/day per cm 2 for
of inflammation and oedema. This may eb reasonable,
over 80 days. When similar films were implanted sub-
because in vitro release data show the expected much faster
cutaneously in rats, the initial release was about 5.5 #g/day
release from particles than from films. Since the polymer saw
per cm2; by 80 days release had declined to about 3 #g/day
said to bioerode in about 62 days and after 55 days, only
30% of the drug was released, a large burst in drug delivery
~. o5
should take place shortly thereafter.
In the second study ,82 tritiated Naltrexone was
incorporated into poly(lactic acid), and the composite was -
ground and then injected into rats. Drug release, sa measured
E
by urinary excretion, levels off at about 25% after about
30 days. Again, there was a considerable disparity between
in vivo and in vitro release, this time attributed to tritium
exchange in the body.
esaeleR of cyctazocine microencapsulated in poly
(lactic acid) sah also been described. 92 However, because of g
macroscopic defects in the capsule wall, all cyclazocine was
released in vivo between 41 and 71 days. The permeability 3
0t 02 03 04 05 06 07 OB 09
of cyctazocine through solvent-cast poly(lactic acid) was
emiT syad( tsap )noit~ipmi
measured to yield a value of 2.9 and 3.0 x 10 11- cm2/sec.
Figure 01 Cumulative percent of ,H3 implanted sa 3H-Nattrexone
Using na average of these values, it was calculated that a
esab {33% w/w) in 90/10 po/y (Lf+)-/actic<o-g/ycolic acid) ,sdaeb
defect-free capsule should release 50% of its contents in recovered in the urine of mice. Reproduced with permission from
about 28.5 months. Life Sci 1975, ,71 1877 ~ 1975 Pergamon sserP Ltd.
Biomateria/s 1980, Vo/ I January 55
The Biomaterials Silver Jubilee Compendium
Bioerodible polymers: .J Heller
j05 ............
50
~1 40-
=_
-T
o 30
~, 30-
(cid:12)9 ~ 20 - j
~ 2o- Io
31
0-- ~ ~ i L_. 1 I I. ...................| ....... I .... t
o Io ..~.o -~ 0 01 o2 o3 o4 o5 06 07 08 09
emiT )syod(
Figure 21 Cumulative percent C41 label from norethisterone
~ 02 o4 ! 06 i 08t .............................. 00t ........1 ....... 021 1 excreted in vivo in the urine of rats from 90-180 # particles of
poly-L (+)-lactic acid containing 20~ by weight norethisterone.
emiT )syod(
From Contraception 1976, ,31 375. Reproduced with permission
Figure 11 Cumulative percent norethisterone desae~er in vitro of the copyright owner
from particles containing %02 by weight norethisterone. (0) ;~1081-09
uncoated (n) 180-250 ~; uncoated )><( 180-250p; coated (using a silicone rubber have comparable maximum steady state
%01 poly-DL-lactic acid/benzene solution). From Contraception fluxes of progesterone at 37~ 2.2 x 01 01" dna 0.6 x
,6791 ,31 375. Reproduced with permission of eht copyright owner
01 01- g/cm sec, respectively). Poly (DE-lactic acid) dah a
per cm .2 Biodegradation of the matrix saw slower than maximum steady state flux of progesterone of 3.3 x
drug .esaeler 01 51- g/cm .ces
In another study 43 14C-labelled 20 wt% Norethis- In another study ,83 esaeler rates of several steroids
terone was incorporated into poly (L (+)-tactic acid) and the from films dna capsules of homopolymers dna copolymers
composite was cryogenically ground and separated into of e-caprolactone, DE-tactic acid and glycotic acid in vitro
90- to 180-/J particles and 180- to 250-/J particles. The and in vivo were determined. Detailed interpretation of the
180- to 250-/J particles were overcoated with the benzene- data si difficult esuaceb various factors, such sa simple drug
soluble poly(DL-lactic acid). The in vitro esaeler of the diffusion, polymer erosion, morphological changes in the
steriod from all three particle-size formulations si shown in polymer, dna changes in concentration gradient ssorca
Figure .11 esaeleR from the larger particles saw faster than capsule walls, all contribute to the measured erosion rate.
that from the smaller particles, which si contrary to what The esaaler of progesterone from bioerodible seluspac
might eb expected because rate of diffusional release si desab on gtutamic acid/leucine copolymers sah also been
directly proportional to surface area. esaeleR from coated investigated .93 Devices were fabricated by first preparing
selpmas si considerably lower than that from uncoated progesterone-filled polypeptide rods dna then coating the
samples. This si sa expected; the steriod must diffuse rods with unfilled polypeptide. esuaceB of various fabrica-
through a rate-controlling membrane. tion difficulties, it saw not possible to determine meaningful
Studies of in vivo release, sa measured by urinary esaeler rates. Bioerosion of the copolymers saw extremely
excretion, show na apparent zero-order delivery with na slow dna complete erosion for a 50/50 copotymer saw
initial burst and another burst around day 90, which si estimated to take about four years.
attributed to dissolution of the polymer matrix. Comparison Delivery of other agents. Although the greatest emphasis of
of actual in vivo esaeler kinetics for all three samples si drug delivery from bioerodible polymers sah centered
difficult esuaceb the steriod si excreted in both urine dna around narcotic antagonists and contraceptive steroids, the
,seceaf dna in the uncoated samples only the urinary steroid methodology sah been applied to other drugs.
saw measured. Furthermore, either esuaceb of cumulative A brief study described esaeler of two anticancer
error or errors ni original specific activity, ssam balance si drugs, cyclophosphamide dna cis-dichlorodiammineplatinum,
poor. However, the results indicate fairly linear dna from poly(lactic acid) .04
sustained steroid esaeler for about three months; a typical Another study 14 described the esaeler of the anti-
plot si shown in Figure .21 malarial drug, 2, 4-diamino-6-(2-naphthylsulphonyl)-
In vivo dna in vitro esaeler of progesterone, quinazoline (WR-158122) from a 25/75 poly(DL-lactic/
~-oestradioi, and dexamethasone from poly (lactic acid) glycolic acid) copolymer in mice. Measuring radioactivity
sdaeb and chips also sah been described .53 excreted into urine dna ,seceaf sustained esaeler through
A considerable amount of work sah been done on 41 weeks, saw demonstrated.
esaeler of contraceptive steroids from crosslinked poly
(dimethyl siloxane) implants .63 However, silicone rubber si
NOITADARGED SMSINAHCEM
not degradable, os the expanded device must eb surgically
removed. This si not desirable; consequently it si desirable The hydrolytic erosion of a solid polymer nac eb rationa-
to develop devices which would esaeler steroids by mem- lized in terms of two extreme mechanisms. nI one, referred
brane diffusion dna the expended devices would then later to sa homogeneous, the hydrolysis occurs at a uniform
bioerode. rate throughout the matrix. In the other, called hetero-
in na effort to develop biodegradable materials with ,suoeneg the process si confined to the surface of the
permeabilities comparable to those of silicone rubber, device. Actual erosion can, of course, occur by some
homo- and copolymers of e-caprolactone and DE-lactic intermediate mechanism.
acid were investigated sa potential bioerodible In a purely homogeneous process, the matrix will
membranes .73 It saw found that poly (e-caprolactone) dna remain essentially intact until all parts reach some critical
56 Biomateriais 1980, Vot 1 January
ehT Biomaterials Silver Jubilee Compendium
Bioerodible polymers: .J Helter
degree of reaction, at which point the matrix dissolves. 6 Hussain, A.A., Higuchi, T. dna Shell, ,.W.J SU taP 3960 051
Drug release from such a matrix si complicated )6791(
7 Goldman, ,.R Goldstein, .L dna Katchalski, ,.E 'Biochemical
because it si a combination of diffusion and erosion.
stcepsA of Reactions no Solid Supports' (Ed. G,R. Stark)
Diffusional drug release in the absence of erosion can be 1791 Academic ,sserP p. 31
described by the Higuchi model 42 which proposes that the 8 Davis, B.K., Experentia 1972, 28, 348
drug si initially removed from the surface regions of the 9 Torchilin, V.P., Tischenko, E.G., Smirnov, V.N. dna ,vozahC
E.i., J. Biomed. Mater. Res. 1977, 11,223
polymer, and consequently a progressively thicker drug-
01 Ballard, B.E, dna Nelson, ,.E 'Remington's lacituecamrahP
depleted layer forms adjacent to the surface of the device.
,'ecneicS 1975, Mack, notsaE ,AP .hC 19
Because the remaining drug must diffuse through a pro- 11 Woodruff, ,.W.C ,kceP G.C. dna Banker, G ,.S. .J Pharm. Sci.
gressively thickening polymer membrane, the rate of drug 1972, 61, 1916
release declines continuously. 21 Wagner, j.G. dna Long, ,.S .J Pharm. Sci. 1960, 49, 121
31 Wilken, L.O. Jr., Kochhar, M.M., Bennett, D.P. dna ,evorgsoC
In the presence of polymer erosion, the matrix
,.P.F .J Pharm. Sci. 1962, 51,484
progressively loosens up, and the permeability of the polymer 41 Lappas, L.C. dna ,naheeKcM W.,J. Pharm. Sci. 1962, 51,
to the drug increases with time. Consequently, the rate of 8O8
drug release from polymers which erode either wholly or 51 Lappas, L.C. dna ,naheeKcM ,.W .J Pharm. Sci. 1965, 54,
671
partially by bulk degradation at first shows the normal
61 Lappas, LC. dna ,naheeKcM ,.W .J Pharm. Sci. 1967, 56,
expected decline, but sa the increasing polymer perme- 7521
ability gradually offsets this decline, the rate of drug 71 Heller, ,.J Baker, R.W., Gale, R .M. dna Rodin, J.O,, J. Appl.
release eventually accelerates. Po/ym. Sci. 1978, 22, 1991
The heterogeneous process si a much more desirable 81 Heller, .J dna Trescony, P.V., .J Pharm. Sci. 1979, 68,919
91 Hiatt, G.D., SU Pat. 2940901 (1960)
degradation mode because it will lead to zero-order drug
20 Farbenfabriken Bayer A.G., Ger. .taP 1 912 571 (1965)
release, provided that diffusional release of the drug si 12 Hiatt, G.D., Mench, .W.J dna Fulkerson, ,.B Ind. Eng. Chem.
minimal and the cwerall shape of the device remains Prod. Res. Develop. 1964, ,3 592
essentially constant, thus maintaining constant surface 22 Mench, .W.J dna Fulkerson, ,.B Ind. Eng. Chem. Prod. .seR
area. Furthermore, such a process avoids deterioration of Deve/op, 1968, 7, 2
23 Kulkarni, R.K., Pani, K.C., Neuman, .C dna Leonard, ,.F
mechanical properties, which can take place when random
Arch. Surg. 1966, 93, 839
chain cleavage occurs in the bulk material. 42 Kulkarni, R.K., Moore, E.G., Hegyeli, A.F. dna Leonard, F.,
In principle surface erosion can be achieved by .J Biomed. Mater. Res. 1971,5, 961
constructing a highly hydrophobic polymer, os that water 52 Frazza, E.J. dna Schmitt, E.E., .J Biomed. Mater. Res. Syrup.
1971, 1,43
penetration and consequent bulk hydrolysis si much ssel
62 Yolles, ,.S Eldridge, J.E. dna Woodland, H.J .R., Po/ym. News
probable than surface reaction. A much preferred approach 1970, 1,9
si one in which a pH-sensitive reaction si selected and the 72 Woodland, J.H.R., Yoiles, ,.S Blake, D.A., Helrich, .M dna
interior of the matrix si buffered os that bulk hydrolysis si Meyer, F.J., .J Meal. Chem. 1973, ,61 897
82 Yolles, ,.S Leafe, T.D., Woodland, J.H.R. dna Meyer, F.J.,
prevented and reaction can take place only at the surface of
.J Pharm. Sci. 1975, 64,348
the device, where the buffer si neutralized.
92 Mason, ,.N Thies, .C dna Cicero, T.J., J. Pharm. Sci. 1976,
The only polymers thus far described in detail that 65,847
undergo true surface erosion are the partial esters of methyl 30 Thies, ,.C 'Controlled esaeleR Polymeric Formulations', (Ed.
vinyl ether/mateic anhydride copolymers 17,18, However, D.R. luaP dna F.W. Harris) SCA Symposium seireS No. 33,
1976, .p 091
these represent a special case because sotubitization does
13 Schwope, A.D., ,esiW D.L. dna ,sewoH J.F., Life Sci. 1975,
not involve backbone cleavage, and consequently the only ,71 1877
polymer chains than can escape into the aqueous environ- 23 Reuming, R.H. dna ,siepslaM L., Ohio State University
ment are at the surface of the device. reports no National Institute no Drug Abuse, Contract No.
H5M42-73-182, 1974-t975
None of the described backbone-degradable polymers
33 Jackanicz, T.M., ,hsaN H.A., ,esiW .L.)C dna Gregory, J.B.,
undergo surface erosion; rather, they undergo bulk erosion.
Contraception 1973, 8, 722
This si not surprising, since most of them were originally 43 Anderson, L.C., ,esiW D.L. dna Howes, J.F., Contraception
designed sa bioerodible suture materials and were not 1976, ,31 573
intended sa drug carriers capable of releasing a drug by 53 Yolles, ,.S Leafe, T., Sartori, ,.M Torkelson, ,.M Ward, L.
dna Boettner, F., "Controlled esaeleR Polymeric Formulations',
zero-order kinetics. However, work in progress here 34 and
.sdE( D.R. luaP dna F.W. Harris) SCA Symposium seireS
elsewhere44, 45 si devoted specifically to the development .oN 33, 1976, .p 321
of bioerodible polymers that do undergo surface erosion 63 Hiltier, S.G., Jha, ,.P Griffiths, K. dna ,samnaL K.R.,
and are capable of releasing incorporated drugs by zero- Contraception 1977, 15,473
order kinetics. 73 Pitt, C.G., Jeffcoat, R.A., Zweidinger, R.A. dna Schindler, A.,
.J Biomed. Mater. Res. 1979, 13,497
83 Pitt, C.G., Gratzl, M.M., Jeffcoat, R.A., Zweidinger, .R dna
SECNEREFER Schindler, A., .J Pharrn. Sci., ni sserp
93 Sidman, K.R., Steban, W.D. dna Burg, A.W., ni Drug Delivery
1 Baker, R.W. dna Lonsdate, H.K., Chemtec. 1975, 5,668 smetsyS (Ed. H.L. Gabelnick) 1976, DHEW Publication .oN
2 Harris, F.W., Aulabaugh, A.E., ,esaC R.D., Dykes, M.K. dna (NIH) 77-1238
,lateF W.A., 'Controlled esaeleR Polymeric Formulations' 40 Yolles, ,.S Leafe, T.D. dna Meyer, F.J., J. Pharm. Sci. 1975,
iEds. D.R. luaP dna F.W. Harris) 1976, SCA Symposium 64, 511
seireS .oN 33, .p 222 14 Wise, D.L., McCormick, G.J., Willet, .P.G dna Anderson, L.C.,
3 Neogi, A.N. dna Allan, G .G., 'Controlled esaeleR of Life Sci. 1976, ,91 768
Biologically Active Agents', .sdE( A.C. Tanquary dna R.E. 42 Higuchi, T., .J Pharm. Sci. 1961,50,874
)yecaL 1976, Plenum ,sserP .p 591 43 Hetler, .J dna Baker, R.W., Work ni ssergorp
4 Joseph, A.A., Hill, J.L., Patet, J., ,tetaP .S dna Kincl, F.A., 44 Choi, N.S. dna Heller, ,.J SU Pat. 4093 907 (1978); 4131 648
J. Pharm. Sci. 1977, 66, 490 (1978); 4138344 (1979)
5 Heller, .J dna Baker, R.W., repaP detneserp at the University 45 Capozza, R.C., Schmitt, E.E. dna ,kcebledneS L.R., in
of Southern California Symposium no Applications of National Inst. Drug Abuse hcraeseR Monograph 1976, No. 4
sremyloP ni Dentistry dna Medicine, November 1973 (Ed. R.E. Willette) DHEW Publication .oN (ADM) 76-296
Biomateriats 1980, Vol 1 January 57
The Biomaterials Silver Jubilee Compendium
ehT response ot the intramuscular
implantation of pure metals
.A M cNamara and D.F. smailliW
Department of Dental Sciences, School of Dental Surgery, University of Liverpool, P.O. xoB 147, Liverpool
L69 3BX, UK
(Received 30 September 1980)
Discs fo five high-purity metals, cobalt, nickel, copper, aluminium dna lead have be~n implanted intramuscularly
ni rats dna the response observed histologically for period pu to 52 weeks. A reproducible but different
response was observed with each metal. Whenever corrosion occurred, sa with copper, nickel dna some cobalt
specimens, the implants became loose. In the absence fo corrosion, the implants were firmly held within a
more confined capsule. A minimal response was seen with lead, implying normally toxic metals od ton
necessarily induce excessive responses no implantation. Evidence was found, however, that some metals elicit
na immune response whilst some, especially copper dna nickel appear to render the host more susceptible to
disease. ehT implants appear to have a profound effect no the immediate vasculature, era able to cause a
prolonged polymorphonuclear response ni the same way sa bacteria, are associated with varying amounts of
haemosiderin laden macrophages but not with giant cells. The animals appear to eb able to deal with bacteria
introduced at surgery without hindrance from the metal.
Ever since the early experimentation with metallic mentioned above, implants becoming enveloped in a
implants by Zierold ,1 Hey-Groves 2 and others, there has relatively thin fibrous capsule, with no ultra-
been a steady rationalisation of the metals and alloys structionai features to distinguish the response to the
used clinically and the development of a concise list of different materials. There appears, therefore, to be little
recognised and acceptable materials, These era to choose between the various metals on the basis of
stainless steel of the 316 type, titanium and this tissue response.
titanium-aluminium-vanadium alloy and some cobalt- However, with increasing concern over the bio-
based alloys such sa the cobalt-chromium- compatibility of implant materials and especially in
molybdenum casting alloy, the wrought cobalt- terms of the significance of corrosion, wear, hyper-
chromium- nickel, cobalt- nickel- chromium- sensitivity and carcinogenicity, it si important that a
molybdenum and cobalt- chromium- nickel- iron- more detailed understanding of the effects of
molybdenum alloys. The basis for this selection has implanted metals eb gained. A major programme of
been largely that of corrosion resistance and work is under way in the author's laboratory based on
apparently good biocompatibility, although naturally this objective and the present paper is concerned with
mechanical properties have also been an important part of this work. Although the ultimate aim must be
consideration. related to the materials used clinically, with the
The corrosion resistance of these alloys has been exception of commercially pure titanium, these are all
extensively investigated, both from in vitro experiments alloys with 3, 4 or even 5 major elements present.
and in vivo observations '3 4 and it si well established Since the tissue response will be largely dependent on
that titanium and its dilute alloy are essentially immune the rate of release of metal ions (or particulate
from corrosion in the physiological environment, the corrosion products) and the physiological activity of
cobalt-based alloys era highly corrosion resistant with these ions, and since each element will be released at
only a minimal susceptibility whilst stainless steel a different rate from a complex alloy and will have a
quite readily suffers crevice and pitting corrosion. different mechanism of toxicity, it would be difficult, if
The tissue response has been less well not impossible, to interpret the response to such alloys
investigated. There have been some experimental ni terms of basic parameters until the precise effect of
studies using various animal models 6,s and each constituent had been determined.
observations on biopsy or autopsy samples "7 8 but little In the present study, therefore, a series of pure
ni the way of a detailed systematic study of the tissue metals sah been investigated. Five metals were chosen
response to metals. The general observation is that, in for the inital study, cobalt, nickel, copper, aluminium
the absence of gross corrosion or wear there appears and lead, These were selected to give a wide range of
to be little difference in the reaction to the alloys characteristics, both metallurgically and biologically.
80..330010/18/2169-2410 00.20$ (cid:14)9 1891 CPI ssenisuB sserP
Biomateria/s 198 I, Vo/ 2 January 33
