Future directions in biomaterials

Future directionsin biomaterials Robert Langer,Linda G. Cima,Janet A.

Tamada, and Erich Wintermantel*

Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, MA 02 139, USA and *Swiss Federal Institute of Technology. Departments of Materials Science and of Mechanical Engineering, Zurich, Switzerland (Received 24 May 1990; accepted 1 June 1990)

Biomatarials have made a great impact on medicine. However, numerous challenges remain. This paper discusses three representative areas involving important medical problems. First, drug delivery systems; major considerations include drug-polymer interactions, drug transformation, diffusion properties of drugs and, if degradation occurs, of polymer degradation products through polymer matrices developing a more complete understanding of matrix degradation in the case of erodible polymers and developing new engineered polymers designed for specific purposes such as vaccination or pulsatile release. Second, cellpolymer interactions, including the fate of inert polymers, the use of polymers as templates for tissue regeneration and the study of polymers which aid cell transplantation. Third, otthopaedic biomaterials, including basic research in the behaviour of chrondrocytes, osteocytes and connective tissue-free interfaces and applied research involving computer-aided design of biomaterials and the creation of orthopaedic biomaterials. Keywords: Drug delivery, cell polymer interactions, orthopaedic biomaterials

Biomaterials play a role in the lives of most individuals. They are used in areas such as contact lenses, artificial kidneys and wound dressings. However, there are at least two major difficulties associated with biomaterials. The first is an incomplete understanding of the physical and chemical functioning of biomaterials and of the human response to these materials. Advances in polymer characterization and computer science and in cell and molecular biology will play a significant role in studies of biomaterials. A second difficulty is that many biomaterials do not perform as desirably as we would like. This is not surprising, since many materials used in medicine were not designed for medical purposes. For example, some of the materials used in the artificial heart and vascular grafts were originally used as clothing. A significant future challenge will be the rational design of human biomaterials based on a systematic evaluation of desired biological, chemical and engineering requirements. Among the numerous challenges in biomaterials, discussion is focused on three representative areas: (1) drug delivery systems, (2) cell-polymer interactions, and (3) or-thopaedic biomaterials. It should be noted that the examples discussed are representative of the research being conducted in our and several other laboratories; a comprehensive assessment of all future research in biomaterials is beyond the scope of this paper.

NEW

MATERIALS

FOR DRUG

DELIVERY

Amongst the most important areas for future research in drug delivery are the creation of new materials and the Correspondence

to Professor R. Langer.

improved understanding and utilization of existing materials. There are many types of drug delivery devices, each with its own particular requirements for its constituent material. For example, reservoir devices require a biocompatible membrane which will control the diffusion of drug through the system. Other devices control rate by the swelling properties of the polymer. Non-erodible matrix devices control diffusion through the polymer composition and pore structures created in the polymer. Osmotic devices generally require a selective osmotic membrane which will allow only certain substances to pass through. In this section, discussion primarily focuses on the future aspects of degradable drug delivery systems. Degradable materials are particularly important for many drug delivery applications because retrieval of the delivery device is avoided. However, because of their relative novelty for use in drug delivery devices, there is still much development to be done. The toxicity of degradation products can be a major difficulty. Clinical application of degradable polymers has, until recently, been limited to lactic/glycolic acid copolymers used principally for sutures. Controlled-release technology using erodible polymers may be particularly advantageous for delivery of proteinbased drugs. However, proteolytic enzymes in the blood, saliva and stomach acid can degrade proteins contained in conventional injectable or oral dosage forms in vivo before they reach the target area. Thus, the polymer dosage form can play a crucial role in protecting the protein during storage and administration. To realize the full potential of proteinbased drugs, numerous practical difficulties with formulation and administration methods must be addressed. Some of the challenges in the development and 0

738

Biomaterials

1990, Vol 11 November

1990

Butterworth-Hememann

Ltd. 0142-9612/90/090738-08

Future

application

of polymers,

for drug and protein

particularly

delivery

degradable

are discussed

polymers,

matrix

structure The

Drug-polymer

interactions

itself

resonance Drug-matrix lenges

interaction

to

systems.

formulation Proteins

functional

various

model

drugs

amide

bond

release

between

mixture. method,

polymers

will

have

many

undesired

side

hydroxyl,

Work

was

polymer

anhydride

a complete

without

rate-controlling.

and

amine of a of the

protein drugs. such

as

Proteins

with different controlled-

into

the

aggregation.

takes

matrices

insulin

from

solid-phase with

the matrix’.

minute

water

amounts

are likely

through

Recent

place with

polymer

catalysed

cracks and pores formed

for

aggregation.

methods limiting

which

The

protein-water

colyophilization

with

the

protein

can

water-soluble

in polymers

solution

via external

that

polymer solution.

amounts

of

minimized

reaction

of inorganic

polymers, create

by

including salts,

lyophilizing

or

of

monomer

reduces However,

not necessarily

material

itself is an important It has been

certain polymers,

that

(SEM)4.

Presumably,

through

the

the rate of drug

water

penetrates

e.g. lactic/glycolic

and

acid copolymer,

electron microscopy of the polymer

matrix must diffuse through this porous structure. Additionally, it dissolves the diffusion

of drug through

a solution-diffusion through

silicone

Diffusion by Saltzman coefficients was

porous

material

e.g. diffusion

allow

itself by

of steroids

materials

has been studied

et a/. 5. Using known solution-phase and mathematical

constructs

the overall effective

calculated.

means

Additionally,

the polymeric

polymers

rubber. through

diffusion coefficients or other

by the drug itself as

Finally, some

mechanism,

the matrix structure, particle

pores created

from the exterior.

are necessary

refinement

mass transfer

by quasi-elastic to make

of knowledge

diffusion

of the geometry

Concentration-dependent

measured

by simply

changing

the

For example,

by

can be designed

1 wk to 6 yr’. This

from

types

of monomers.

have shown that the monomers

from

the

matrix

at the

same

do rate.

et al.* have shown

any drug in the interior

drug can drssolve through

for copolymers.

rates and polymer

to the other.

ranging

in

lose the more soluble glycolic acid before the lactic

drug

leaving a porous matrix seen by scanning

erode

monomer

Linhardt

factor affecting

observed

complex Release

to just a few

recent findings

and diffusion.

of

ratios, polyanhydrides

testing

surface.

to the bulk

leads to the overall

appearance

controlled

over periods

toxicity

convection

If the

matrices

acidic

partially degraded matrix material and the matrix

release. degrades

and

often

solubility.

of the device,

to the polymer

is even more

monomer

to degrade

these

of

of the

solution

polylactic/glycolic that

acid and carboxyphenoxypropane

release

of sebacic

acid than

Weight

loss and appearance

acid

copolymers

of

(CPP) give more

the

less water-soluble

CPP. of monomer

have been the main tools for studying These will continue to be important. of

the

release

understand

of

both

Newer have produced

may

images of water

of 25 p and below’0“2 through

Additionally,

Development Another

progress

(MRI)

has allowed

of methanol

to image

the polymer,

(PMMA)13, the

profile

and 14. of a

or to follow the monomer

degrades.

in drug

polymers

in

particular,

calculations.

polymers

for

medical

involves degradable

to

Insight.

imaging

methacrylate)

of novel engineered

challenge

addrtional

resonance

it may be possible

as the polymer

essential

fully.

This type of technology

poly(methyl

model drug through profile

determrnatron

be

protons down to resolutions

the study of the time-dependent acetone

will

give

In magnetrc

degradation.

However,

of release

technologies

Recent developments

in solutions

polymer

monomers

the mechanism

light scattering

of the experimental

that

et al.’ have shown

D’Emanuele

rapid the

or small oligomers,

interior

advantages.

of

resulting

a localized

properties

diffusion

the

ratio of one monomer

changing

acid.

degraded

i.e.

have certain are

in the

step

The

aqueous

of these steps which

The situation

relative

local

mass transfer

erosion,

sebacic

The

bond.

and encapsulating

pH3.

Diffusion

place

It is the combination

due to contact

was responsible be

solutions

which

of

properties

addition

the protein from acidic aqueous

release

S-S bond formation

this interchange contact,

controlled-

materials.

aggregation

prevent

labile

must diffuse

their

the

conditions.

at the surface are removed

small

reaction

other additional

products

in the polymeric

interchange

or

the

products

These

via a thiol-disulphide

causing

Degradation

and

polymers

an intermolecular

basic

to the

to

For

units. This reaction

either monomers

according

hydrophobic

In the case of albumin,

products,

forces.

of the bonds,

involves

of the enzyme

or imbibition

by capillary

into smaller

by acidic,

degradation

the polymer

surface

degradation

with

have shown

Such

down

for

step is

actual polymer degradation

the hydrolysis

to be broken

be

polymer

polymers,

of steps,

which

takes

incomplete

even

is to determine

degradation

aggregation

of water3.

to penetrate

will

are different

particularly deamidation

studies

proteins can undergo

of which

dissolve

a variety of transformations

to cause

involves a number

can occur, even

of insulin in polymeric

is thought

of the

degraded

degradation

interactions,

cross-linking,

Aggregation

release

technology studies.

In the first step, water contacts

interior

hydrolytically

diffusion

the polymer

undergo

denaturation,

the

magnetic

of matrix

by direct access to the polymer

may

polymer-drug

typically

The challenge

either

the effect

of the active agent during storage specific

This

understanding

The erosion of polymers

suggested

investigating

of degradable

Developing degradation

Enzymatic

Instability

through

nuclear

for future

each polymer.

technology.

inside

important

by

processing

drug type and reactivity

Drug transformation

by

spectroscopy6.

the details and relative importance

thermal

be a vital aspect

(NMR) increasingly

of

group

studied

analyses

the

during

become

to describe

of mass transfer.

of substances

studied

et a/

carboxyl

of the -NH2

polyanhydrides

be triggered

polymer-drug formulation

interaction spectroscopic

formation

could

Sulphhydryl,

with

et al. ‘. Infrared

Leong

undergo

may all be reactive to a particular

For example,

chal-

been

models

predictions

coefficient

has

R. Langer

controlled-release

pharmaceuticals

can

with the polymer.

in question.

one of the greatest

degradable

other

which

and amine groups

that

of

and

groups

reactions

presents

may improve

diffusion

polymer

,n bnmaterrals:

and of mathematical

these structures

below.

drectlons

polymers

delivery

is the

more

applicatrons.

polymers

Biomaterials

and,

for

One

Vol

design

such-

that are composed

1990,

degradable

rational

of

example

of and will

1 1 November

739

Future directions

in biomatarials:

R. Langer et al

break down into naturally occurring substances. Thus, the synthesis of new polymers in which L-amino acids or dipeptides are polymerized by non-amide bonds (e.g. ester) involving functional groups located on the amino acid side chains was proposed’5. This approach permits the synthesis of biomaterials for drug delivery systems, sutures, artificial organs, etc., which are derived from non-toxic metabolites (amino acids and dipeptides) and also have other desirable properties. For example, the incorporation of an anhydride linkage into the polymer backbone could result in rapid biodegradability; an iminocarbonate bond may provide mechanical strength; an ester bond may result in better film and fibre formation. One application of this class of polymer system involves vaccine delivery. Many adjuvants such as alumin~um oxide and incomplete Freund’s adjuvant rely on a simple depot effect, releasing adsorbed antigen over periods ranging from several hours to a few weeks. In earlier studies with mice and rabbits16, the prolonged release of small amounts of antigen from a non-degradable polymeric antigen delivery device resulted in sustained production of serum antibodies over a period of 6 month in laboratory animals. Since the polymer was not degradable, the implant was surgically removed from the host after completion of the immunization process. However, it would be advantageous to use biodegradable devices for the controlled release of antigen. This concept is pa~icularly attractive considering that the polymer degradation products could be intentionally designed to have adjuvant properties; this is an example of an engineered polymer. In this case, the polymer would be used to construct a device capable of stimulating the immune response, simultaneously releasing antigen over prolonged periods of time. Because of the known adjuvanticity of t_-tyrosine and its derivatives, a polymeric antigen delivery system which would degrade into tyrosine or a tyrosine derivative was synthesized. Such a polymer could provide sustained adjuvanticity, simultaneously serving as a repository for antigen. To test this hypothesis, a poly(iminocarbonate), whose primary degradation product was ~-benzyloxycar~nyl-L-~rosyl-L-tyrosine hexyl ester (CTTH), was selected as a candidate material for a polymeric antigen delivery system. Poly(C~H-iminocarbonate) is a new, biodegradable polymer in which tyrosine dipeptide units are linked together by hydrolytically labile bonds via the tyrosine sidechain hydroxyl groups. In mice, the release of antigen from a single poly(CITH-iminocarbonate) pellet gave rise to higher antibody titres than release of the same dose of antigen from a comparable control poly(iminocarbonate) pellet or from two injections of the antigen over a 1 yr period17. Theoretically, it will also be desirable to have polymeric systems which can provide increased levels of drug to the body when needed. Several approaches have been studied. One set of approaches involves externally regulating polymerdrug release using forces such as magnetism18, ultrasound’g, light”, pH*’ , temperature” and electricity23. A second class are systems that possess internal feedback control. Several approaches are being developed using immobilized enzymes, such as glucose oxidase, which act as biosensors to regulate release rates. External glucose reacts with this enzyme causing gluconic acid to form. This causes a pH change which can alter the solubility of encapsulated insulin24 or the permeability of certain membranes25, causing more insulin to be released. Other self-triggered insulin delivery systems that involve modified insulins encapsulated in membranes are also being studied2”. Finally, self-triggered systems

740

Biomaterials

1990, Vol 11 November

involving polymers, enzymes and antibodies are being explored*‘* **. Other areas of future research in drug delivery-based biomaterials include novel bioadhesives for targeting drugs to certain segments of the gastrointestinal tract or other parts of the body”, 30, memory plastics that are biocompatible and possibly biodegradable and polymers that can be used to aid in cell-targeting approaches, e.g. for cancer treatments3’, 32.

FUTURE DIRECTIONS INTERACTIONS

IN CELL-POLYMER

Virtually every use of polymers in the human body is accompanied by some type of cell-~lymer interaction. Early uses of polymersin viva were primarily in applications where the polymer was intended to remain inert, and therefore much research in the area of cell-polymer interactions has focused on understanding how to prevent or minimize undesired cell interactions. Whilst these issues continue to be important for a variety of applications, design of new polymers to interact with cells in ways which provoke a physiological response, such as growth or differentiation, is becoming increasingly important. In the past decade, significant advances have been made in understanding the ways in which cells interactwith their natural environment of extracellular matrix proteins and this has laid the foundation for the rational design of polymers which play an active role in tissue regeneration and repair.

Inert polymers Prevention of cell-polymer interaction is an important issue in devices which contact blood and in soft tissue replacements, such as breast implants. The design of inert, biocompatible polymers for chemical and physical structures of the devices, remains important. Biocompatible, in this sense, means that the function of the polymer device is in no way impaired by reaction of the surrounding tissue. Ideally, the bio~ompatability of a polymer could be predicted from a series of in v&o tests. Currently, both in viva and in vitro tests are used to assess bi~ompatability because the essential components of the in viva environment, from a biocompatibility perspective, are not yet fully understood. Progress toward developing in vitro tests for biocompatability has been made using several approaches. Reconstruction of important events in the inflammation process was carried out in vitro by Miller and Anderson33, 34, who cultured human peripheral blood monocytes in the presence of several biomedical polymers and demonstrated that soluble factors produced by the monocytes in the presence of the polymers stimulated fibroblast growth and collagen synthesis and that the degree of fibroblast proliferation in the in vitro system was correlated with the degree of fibrous capsule formation in vivo. An in vitro system which mimics the enzymatic and oxidative environment of the implant site has also been developed and used successfully to characterize molecular changes in polymer devices during the inflammation process35; e.g. in the case of poly(ether urethanes), only certain molecular weight fractions are subject to enzyme attack. On a fundamental level, the physico-chemical determinents of cell-polymer interactions are being elucidated through in vitro studies of the interactions of cells with a series of welldefined model polymer surfaces, pa~i~ularly copolymers in

Future

the hydroxyethyl (EMA),

methacrylate

methyl

(MAA)

family.

Horbett

a linear correlation

(MMA)

from

a series

Polymers

of HEMA/

of the copolymer,

of the hydrophobicity

one physical

property,

by the studies which

of predicting

were

to give

the

of

negative

prediction

somewhat

empirical;

particular

polymer

changing

from

of

and MAA,

but

exhibited

0 to 70%

correlations

as techniques

MMA

Although

prostheses3*, mm)

much

progress

occlusion

vascular

prevents

their

combination ethylene

to growth

of cell types

in At

is

grafts

of the

are

surfaces

cells or immune polymers,

New

basement

a

is tumour

within

oxide

and

developed little

problem based

example

properties

and

with

one

polymer

a

of poly-

of other

polymers

characterized3’. with

Such PEO lifetime

The design of hybrid

acting

to

give

for future when

mechanical

synthetic

of the polymer

long-term

its

success of small diameter

with a porous wall structure ceils and blood vessels4*. p(HEMA)

device must also be

biocompatability.

elicit

that allows

In contrast,

a stronger

of the resulting

ingrowth

foreign

A major

of future

tissue

properties

polymers

of the polymer

or cross-linking

of polymeric

currently

may become

are in clinical

through

in use.

decreasing

to create

with

polyurethane

only

recently

released

foam-covered

been

from

techniques

apparent

use. For example,

the

linked

breast

to

a better

in the

polymer

environment45,4”.

the

cells

features

which

considered associated

prostheses

of the

have

products Use

spectroscopy

exposure

One area in which

with

be inap-

an impetus

to

the features

of

the desired

which

cell

have the safety

along with the chemical

cells in biologically

the key features give

rise

may be surface

in the natural to the

relevant

charge,

specific

sequences,

or gel-like

peptide

responsible

for the adhesion

fibronectin

is

the

activity. peptide

structure.

sequence

environment

desired

hydrate

specialized

of

These

or carbo-

For example,

the

of many cell types to

arginine-glycine-aspartate

transmembrane

receptor5*,

54. A

biologically

relevant property of a large (MW 500 000) protein has thereby been reduced to a size and chemical nature that can be incorporated

as a component

surfaces

concentrations

spreading

to the amount polymers

covalently

in a synthetrc

derivatized

of RGD peptide

cell adhesion,

of peptide

have been shown

present55,

of only those

Non-

to regulate

in culture

according

56. The design

of new

that Interact with a specific cell

type may possibly aid in the regeneration guidance

polymer.

with varying surface

and migration

with such moieties

Polymers

of tissue by contact

cells that are desired.

Whilst

for cell transplantation

some soft-tissue

of

(XPS)

chemical

to the

where

no healthy

plantation diabetes,

defects

in viva

the biocompatibility

of

can be repaired

tissue, diseases

tissue

of healthy where

alternative

covering44.

understanding during

materials

interact

which

technique,

molecular

degradation

foam

may thus

to achieve

polymers

e.g.

The first step in the rational design of such polymers is determining

Polymer

only after the devices

such as X-ray photoelectron

leading

which

and alter

defects

complications

to toxic

polyurethane

degradation

of toxic products,

cause the device to fail. The toxicity of polymers to be permanent

devices

is the lack of truly stable

of chains,

creating

of synthetic

Further-

fibrous

to provide suitable

on the long-term

may lead to release

the properties

properties

required

to

regeneration,

is thus

that incorporate

cells from the surrounding

in the design

replacement

of those

and

devices.

polymers and lack of information degradation

body

of the polymer and the microstructure

limitation

for permanent

of fibrous

forms43. Integration

device must be performed

compatibility

rubber tubes

porous forms of PTFE

tissue response than smooth, non-porous of the surface chemistry

For

vascular grafts

using silicone

matrix

difficult

substrates,

used in nerve There

of

Often

and can lead

desired.

protein

substrates

polymers

thereby

adhesive

research.

optimizing

Matrigel

and such

are

strength

than those

of some

repair

(RGD)52-54 and cells adhere to this moiety by means of a

reticuloendothelial

by the prolonged

in the blood4’.

in dogs has been demonstrated

are

tissue

and strength

and on

other

a damaged

and bone5’.

proteins

or

serve to

ways.

small diameter

a major

from

source

as collagen

include

cartilage

mechanical

for use in humans.

response,

polytetrafluoroethylene

interaction

The microstructure

changes

in under-

and another to impart the desired surface chemistry,

considered

weight

made

polymers

and the strength

enzymes

is important

tissue

only

membrane

propriate design

responsible for cell used for vascular

blood-compatible

cells, as evidenced

of PEO-grafted

and

the

still

but this is

show very low protein adsorption40,4’.

also show

strength

remains

use.

(PEO)

being

has been

of biomaterials-based

clinical

oxide

(PTFE) grafted

more,

derived

and

that

by using

templates

surrounding

diverse

tissue5’,

have insufficient

templates

such

These

tissue

are

demonstrated

to some extent

proteins

healthy

fabricate,

and cell characterization

mechanisms to materials

as polypropylene

grafts

from

applications

the extracellular

standing the biophysical and protein adsorption

such

cells The

such

differences

cell type,

area.

different

cells adhered.

can be drawn

of polymer

must be

regeneration have

membrane.

charges;

interactions

for a given

in viva of

of basement

nerves 47-4g, peridontal

improve.

(4-6

experiments constructed

extracts recruit

on cell

of surface

cell-polymer

family

is illustrated

hydrophobicity

charge

of cell adhesion

present,

of HEMA, a range

same

based on

and co-workers3’

copolymers

treated

with

magnitudes degree

such as hydrophobicity,

of van Wachem

to various

polymers

cell interactions

for tissue

many tissue types can be repaired templates

The complexity

implantation

et a/

design of new, more stable polymers.

as templates

Preliminary

on initial cell

attachment.

adhesion

is through

R. Langer

have demonstrated

with the hydrophobicity

little influence

improved

,n b~omater~als:

designed for permanent

futuredevices

acid

the critical shear stress required

of fibroblasts

EMA copolymers

ethyl methacrylate

and methylacrylic

and co-workers36

between

for the detachment but found

(HEMA),

methacrylate

direct:ons

is available,

cells.

Examples

cell transplantation

to

whole

organ

donor tissue support

two approaches, the immune porous

and transplanted

system

support

large proteins

such as antibodies.

to or encapsulated

in a

barrier

principally

diseases,

such as forms of diabetes,

or

exclude by a

treatment

which are considered

cells transplanted

for treatment

such as liver failure, can be protected

rejection

using

Biomaterials

will

protection

in the

diseases,

already

ingrowth,

which

Immune

physical

are from

of cells to a highly

vascular

in a membrane

the drugs

this

into indrvr-

into the host. There

attachment

of cells

be auto-immune;

and as an

In

dissociated

to allow

encapsulation

is critical

trans-

on the degree of protection

required:

designed

the

transplantation5’-“‘.

is removed,

depending

require

are liver disease

has been proposed

dual cells or groups of cells, attached polymer

by recruiting

of whole organs,

of other

from immune

in use for whole

1990,

Vol

of to

11November

organ

741

Future directions in biomaterials:

R. Langer et al

transplants. The issues in the design of polymers for these two approaches are different. For transplantation of cells attached to a porous matrix,the polymer design issues are similar to those for the guidance templates described above. The polymer must be designed to allow adhesion, growth and differentiation of the cells. Polymer degradation is another desired feature. The fibrous tissue deposits that accompany the implantation of permanent materials would be especially detrimental in the case of the liver, which depends on good access to the vascular system to transport materials rapidly to and from blood. Degradable polymers which have suitable processing characteristics, such as the polylactides and polyglycolides, do not possess side chains with functional groups amenable to covalent modification. A challenge for the future is to design new, degradable polymers with appropriate bioactive characteristics. In transplantation of encapsulated cells such as pancreatic islets, fibrous capsule formation around the transplanted microcapsules is observed tocausecell death6’ and at the very least prevents adequate transport of the substances secreted by the encapsulated cells to the blood. Highly charged polymers, such as polylysine and alginate, are used to form the capsules, because stable membranes can be formed from these polymers using processing techniques gentle enough to ensure cell survival. Two routes to improve the compatability of these devices are the development of processing techniques which use alternate polymers, or controlled release of steroids to prevent inflammatior?‘.

ORTHOPA~DIC

BIOMATERIALS

Orthopaedic tissue-replacement devices include minor or major joint prostheses, osteosynthesis implants, bone deformation correcting implants, bone replacement materials and artificial ligaments. Orthopaedic biomaterials are classified as either load transmitting implants or filler devices. Load transmi~ers, such as joint endoprostheses, are fully mechanically stressed early in the post-operative period. In contrast, fillers, such as homologous cancellous bone, must be integrated gradually into a recipient bone structure and require longer periods of no-load or low-load application before becoming fully stressed. A typical example of technology development in orthopaedic biomaterials are hip endoprostheses, which can be considered to have passed through four clinical generations. First-generation devices addressed only basic mechanical functions. These devices were made from cast metal alloys and were made only in a few standard designs”2. The second generation were constructed from forged metal alloys and offered a wider selection of designs63. Second-generation devices also include custom-made prostheses64 manufactured according to the individual geometry data of each patient and of prostheses offering elasticity similar to bone under bending stress@. 66. The clinical application of the third generation is currently being entered; this brings in the use of anisotropic materials, i.e. fibre compound materials, which are structurally tailored to meet the needs of the recipient tissue67. The fourth generation will provide biomaterials with higher specificity to mimic the natural requirements of biological tissue to effect complete tissue integration, e.g. extracellular matrix analogues which are known to regenerate certain tissues”‘, 6g. The first two generations of biomaterials can be

742

Biomaterials

1990, Vol 11 November

characterized by biocompatibility levels ranging from inert to temporarily biocompatible. They often have to be replaced by a second or a third surgical procedure due to malfunctioning, as in hip prostheses which must be replaced because of loosening of the stem or the acetabular cup7’. Thus hip endoprostheses have not yet proven to be permanent implants for the majority of patients. In the future, there is a promise that fully biocompatible implants can be developed. Future directions in both basic and applied orthopaedic research are now discussed.

Basic orthopaedic biomaterials

research

Through the acquisition and analysis of a large amount of morphology data from cells in tissue culture it may be possible to determine osseo- and ~hondr~ompatibili~. Cell growth on optimized surfaces can be used to establish biocompatibility indices and material qualifying test procedures. An example of the technology currently under development is the image-analysis-assisted determination of cytotoxicity (Figure 7) which classifies materials according to their degree of biocompatibility. This classification will assist in systematizing the approval procedures of the US Food and Drug Administration (FDA) and other regulatory agencies. It will also help shorten the development process for new implants, because materials which are not fully biocompatible will not be considered. A future step will be interfaces on the nanometer scale, such as scanning tunnelling and ion force microscopy. The need for predictability of biocompatibility will make it necessary to develop automated biocompatibility determination tests in tissue culture as part of the design and manufacturing process. This should be a major step in sho~ening the design process because the choice of the material is the first step in a complex manufacturing process. The behaviour of single chondrocytes and osteocytes under physiological and chemical stress needs to be characterized. This would allow the current knowledge about the behaviour of a living macrostructure (bone) under implant stress to be applied to understanding the behaviour of microstructures (cells), as well as to finite element modelling of molecular biomaterial/celI interfaces. It remains

Figure 1 Scanning electron micrograph processed by image analysis (Tracer Norther 8500 system). Shape factors and distribution patterns of cells grown on different osteo-or chondrocompatible surfaces ara anaiysed and typical form/function patterns are worked out. The power of the system allows the acquisition of a statis?i~al~ significant amount of data, even about rareoccurrences.

Future

to

be

determined

whether

load-transmitting

units formed

from a combination

bone

are

tissue

osteons

et al

R. Langer

each

and natural other

e.g. trabeculae,

as are lamellae,

and chondrons.

The development would

improve

transmitting

of connective-tissue-free

implant

performance.

orthopaedic

low-stressed undesired the

from

microunits,

in biomaterials:

anisotropic

of the implant

distinguishable

natural load-transmitting

directions

implants, barrier

implant

e.g.

against

and

determined

the

developed

which

substances,

prevent

excessive

fibrosis

around

materials could

which

will

natural

cartilage.

meet

the

the implant can be considered would

represent

in skin

of histotypical used

to develop

same

by synthetic

shown

If it were known tissue, of joint

as a resurfacing

An important

If complete

to

that can

specifications

and

joints.

be

systems site.

induction

the mechanical

be developed

to be can

agents,

matrix analogues

it is necessary

which

It remains

the implant

induce formation

meets

is an

between

implants

of regeneration

for diseased

whether

tissue.

have not yet been determined.

a graft which material

systems,

such as collagenolytic

e.g. extracellular

cartilage

delivery

and interaction

load-transmitting

The mechanisms

how these

drug

contact

load-

mechanically

will also act as drug delivery

release

regeneration,

around

and around

histotypical

whether

polymers,

implants

interfaces

Fibrosis

question

will be

a polymeric

scaffold

mechanical

specifications

regeneration

can be achieved,

to be physiologically

the

highest

as

integrated,

degree

of

biocom-

patibility. New polymerfibres tensile

strength

followed These

and

by degradation polymers devices

operation

for removal

either

be

used

currently

novel

integrity

to prevent

could

synthesis be

will be needed which mechanical

a second

to

replace

used which

of the implant.

high-strength

provide high for

8-10

metal

require

These

F/gum

osteo-

a second

polymers

degradable

wk

procedure.

3D-computer

and implantation

development. segment

could

polymers

2

tissues

Here,

lumbar

and

analysing

traumatic

The integration design

of

(Figure

increasing make

into a common

implant/tissue

modelling amount

2)

of individual the

on

site

production

of

appropriate

more

design (in

various

and

on

from individual

an LdLs

finite

element

cases.

trauma

joint

technrques replacing

to intact structures.

these

resurfacing

implantation

current

techniques

arthritic

are less would

For hip endoprosthetic

will

joints,

which

techniques

involve

keeping

other

desurfacing bone

and

structures

may

A wide from

manufacture.

(CADCAM)

demand

for

before

will exist and

and

made

tests

load

disc development. ,n CATIA

(cells, Implant

The

data

obtained

and manufacture

hospital)

implants

safety

variables

design

than

surgery,

element

complex.

reproducibility of

IS modelled

structures

tool for mdwidual

and the growing

and morphology

process

integration

Computer-aided

finite

important.

of materials

geometry

strict

by more

and parts design

the

computerized allow

become

reduce

of computer-aided

compounds will

manufacturing

require

research

database

degree of anisotropy

range of materials will

biomaterials

of an intervertebral

spine

for use in surgical

orthopaedic

recipient

or

composites.

Applied

of complex be an effrclent

as part

of the

modelling

modelling sitesJ will

may

(overnight)

preshaped

parts,

implants

can

if be

established. Biomaterials regulated

processing

by computer

specificity

and

compound implants,

reliability

materials recent

homogeneity processing

of the

for

results7’

of fibre/matrix

of ply-angles

can

to achieve future

demonstrate

and analysis

material

and of an implant part of a computer

and

and

highest In fibre

orthopaedic

that fibre

distribution

(Figure

durina _ .orocessina

the

implant.

load-transmitting

be automatically

aoolied . become

quality will be controlled

assistance

content,

and identification

determined

by image

3). All optical test methods manufacturina

will be quantified, integrated

of a bio-

automated

manufacturing

and (CIM)

infrastructure. Development

Figure

3

Processmg by Integrated

of

a fibre

compound

information

analysed

content

of

distributed allows

biomaterials

and implants

the

biomaterial

matenal

being

a/d. Here,

and

process,ng, how

of olv anoles ~,~, I procedure

processed

factor

of unknown allows

and

scanned

thereby

homogeneously

a homogeneity

control

manufactured

Biomater/als

of Implants

the microscopic

IS automattcally

by ,mage

by attributing

this

and manufacturing

computer

speomen

identificatton

infrastructure,

of orthopaedic

of biomatenals

controlled

1990,

The Image laminates. over Into

Vol

and

the

determining hbre

the

will be

cross-section

and

opt/Cal the

matnx

processmg As oalt quality

fibre are also

of a CIM of

the

an Implant.

11 November

743

Future directions in biomaterials: R. Langer et al.

(the femur’s neck and most of its head) intact. This could be referred to as a hot spot replacement. To reduce trauma further, endoscopic implantation procedures should be developed to perform partial replacement with highly specific materials rather than total replacement with nonspecific ones. Osteosynthesis of suitable closed fractures of superficially located bones might be performed by transcutaneous stapling or direct bone stapling after small skin incisions by application of high-strength steel staples. The current method of screwing and plating is a time-consuming procedure and causes additional trauma to the tissue surrounding the fracture site at the time of implantation and at the time of explantation, in the case of non-resorbable devices. Polymeric resorbable scaffolds with an osteocat-tilage compound, consisting of bone and of cartilage tissue in a functional unit similar to that present in human joints, might be developed for joint-resurfacing procedures. For implantation of these scaffolds, the orthopaedic surgeon will use familiar principles of osteosynthesis (bone to bone junction), but will not need to form the bone-cartilage interface during the surgical procedure. The bone-cartilage-interface would be prefabricated extracorporeally. Impressive results in growing cartilage from cell cultures7’ indicate that this will be a way of restoring normal joint function. Self-inspecting and instrumented devices will be developed for online sensing of in vivo load conditions and for transmittal of the data to an extracorporeal receiving device73-75. Applied to fibre compound materials, sensing devices may be laminated into the compound, either as part of a layer of fibres or in between such layers and would register the rupture of single fibres, an early indication of a failure of the whole implant. During regular clinical checkups, a patient carrying such a prosthesis may be tested under patterns of load conditions, providing data about the functioning of the implant/tissue interface. Acquisition of these data may indicate the necessity for additional therapy for the patient, as well as help improve future biomaterials and implants.

DISCUSSION

8

9

10

11 12

13

14

15

16

17

18

19

The areas of research discussed represent only part of the future directions of biomaterials. New methods of polymer analysis are expected, as well as improved approaches for assessing biocompatibility, new methods of altering the surfaces of materials and novel approaches for studying and modelling materials. New materials are expected to be created for such applications as vascular stents, artificial muscles, blood contacting applications and other medical indications. These advances in biomaterials will not be limited to medicine. Biomaterials will also play a role in materials used in the environment and in other areas. In the past century, biomaterials have played a major role in positively affecting human health. In the next century it is believed that the improved understanding of biomaterials and the creation of new biomaterials will become one of the most important areas where interdisciplinary science, e.g. chemistry, engineering, biology, will affect modern medicine.

20

21

22

23

24

25

26

REFERENCES 27 1

2

744

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Biomaterials

1990, Vol 11 November

28

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