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4 SPACE-FILLING BIOMATERIALS: BREAST IMPLANTS 1189

Fig. 9 Examples of saline-ﬁlled breast implants showing the silicone elastomer envelope. Sur-

faces can either be textured (upper) or smooth (lower). The textured design is thought to reduce

the incidence of capsular contraction.

of factors, including the chemical or electrical activity of the material. The initial

reaction of the body to a foreign object is to wall it off. A ﬁbrous capsule—a

result of the normal wound healing response of the body—will develop around

the structure, with the thickness of the capsule increasing in regions of high

chemical activity, high electrical activity, or sharp corners. The presence of this

ﬁbrous capsule formation can be taken advantage of to assist with implant ﬁx-

ation, however.

For objects with smooth surfaces, the ﬁbrous capsule will simply grow around

the outer surface of the material. If the surface of the foreign body is porous,

however, ﬁbrous tissue will begin to grow into the interconnected pores of the

structure. For bony implants, this tissue can become calciﬁed and develop into

a bony junction between the implant and the surrounding tissue. For soft tissue

implants, this ﬁbrous capsule can become integrated with the surrounding con-

nective tissue of the body to provide ﬁrm anchorage of the implant at a desired

location. Complete ﬁbrous tissue integration with the implant material will be

most efﬁciently achieved with a pore size ranging from 5 to 30

␮

m (Rose and

Litske, 1989; Wilkerson and Zalina, 1994).

The amount of desirable ﬁbrous capsule integration with the implant must,

however, be assessed and the area of porous surface determined as part of the

overall design. One breast implant design that failed because of an overabun-

dance of ﬁbrous capsule integration was the sponge design developed in the

1950s (Dukes and Mitchley, 1962; Edgerton and McClary, 1958). This implant,

1190 SELECTION OF MATERIALS FOR BIOMEDICAL APPLICATIONS

which met the space-ﬁlling requirements and was composed of polyvinyl alcohol

foam, was found to experience complete ﬁbrous ingrowth. Although the implant

was ﬁrmly ﬁxed in the correct anatomical position, the ﬁbrous capsule tended

to contract and calcify, resulting in a condition known as marble breast syn-

drome.

All breast implant designs have shown some incidence of capsular contrac-

tion, which in severe instances has required the implant to be removed. This has

led to the FDA requirement in the United States that all implant manufacturers

inform prospective patients of this potential complication and the fact that breast

implants should not be considered to be lifetime prostheses. While no implant

design has been developed that eliminates this phenomenon, the area of ﬁxation

patches on the posterior surface has been reduced, textured (though nonporous)

surfaces have been introduced for the silicone envelope, and clinical interven-

tions, including massage, have been prescribed in attempts to minimize the prob-

lem.

Carcinogenesis and Immunological Complications

For both carcinogenesis and general immunological considerations, it is impor-

tant to examine the response of not only the bulk material that is to be used but

also the components of the materials. This includes unreacted monomer, plas-

ticizers, ﬁllers, and any products that can result from the metabolic breakdown

of the bulk material in vivo. Any chemical compound that could be released by

an implant is a potential hazard. The complexity of this analysis becomes readily

evident.

The exact mechanism, or mechanisms, by which healthy cells in the body

mutate into malignant cells and cause cancer is not fully understood. However,

it is a well-accepted principal that all possible attempts should be made to avoid

implanting a material into the body that would increase the risk of cancer. As

cell mutations and tumor development can take many years to become evident,

how can this be done practically for newly developed materials?

Carcinogenesis, or the production of cancer, can occur in the immediate vi-

cinity of an implant, due to the presence of various chemicals, or at a remote

location in the body, due to the transport of released materials. Materials in the

body can act in one of three ways to cause cancer: (1) as a complete carcinogen,

resulting in cancerous changes by itself; (2) as a procarcinogen, a benign chem-

ical that is metabolically modiﬁed into a carcinogen by the body; or (3) as a co-

carcinogen that is not likely to itself cause cancer, but will increase the activity

of a complete or procarcinogen with which it comes into contact. It is hypoth-

esized that there is no threshold below which a carcinogen present in the body

is completely safe; however, as concentrations of a chemical increase, the prob-

ability that they will induce cellular changes that result in cancer also increase

(Black, 1999). A tumor may also develop in response to the presence of a solid

foreign body made of a noncarcinogenic material, due to the disruption of the

normal environment of the surrounding tissues (Black, 1999).

Testing of materials for their carcinogenic potential ranges from cell culture

studies that examine whether a material causes cells to mutate (Forster, 1986),

to in vivo animal tests and the development of databases to track the occurrence

5 SUMMARY 1191

of tumors in implant recipients. There are drawbacks to all of these tests, and

none, with the exception of a longitudinal study of tens of thousands of patients

with the same implant, can deﬁnitively determine if there is a link to cancer for

an implant or a material that does not initially appear to be carcinogenic. The

primary beneﬁt of these tests is to eliminate from consideration materials that

appear to have a high likelihood of causing tumors. General guidelines for basic

biocompatibility testing have been issued by the International Standards Orga-

nization and other regulatory agencies (ISO-10993, 1992–2000).

Similar problems exist for the documentation of other systemic or remote

tissue complications. Techniques have been developed to evaluate the immu-

nological response to a material (Marritt, 1986); however, the link between local

immunological sensitivity and a systemic autoimmune reaction may not be easily

discernable. It is important to determine whether the occurrence of a particular

disorder, whether it is lymphoma or rheumatoid arthritis, is occurring within the

implanted population at rate that is higher than the general population. One of

the difﬁculties in tracking the incidence of these occurrences is the fact that

many implant materials and combinations change on a time scale that is short

compared to the development of cancer and other immunological conditions. As

these material combinations change, it introduces another variable that requires

a higher number of subjects before a statistical determination can be made.

However, the establishment of databases at the national, or preferably interna-

tional, level for tracking of all complications associated with biomedical implants

will allow for a more complete analysis and more rapid understanding of the

problems associated with this imperfect science.

4.3 Current Material Selection

Prior to 1992, the most common form of breast implant involved a small bag of

silicone elastomer ﬁlled with silicone gel. Originally introduced in 1962 (Cronin,

1983), this implant was popular among patients and physicians alike. While the

silicone elastomer of the bag has been utilized in biomedical implants for many

years without signiﬁcant adverse effects, the breast implant scare of the 1990s

was based on rumors that the silicone gel had a tendency to leak from the

surrounding bag and cause adverse reactions at both local and remote locations.

Since that time, the majority of breast implants have utilized saline within the

same silicone rubber bag. If the saline does leak, or the implant does rupture,

the reaction with the tissue will be completely benign. This design has been an

option since 1965 (Rubin, 1983); however, most patients opted for the silicone

version due to its improved cosmetic appearance.

5 SUMMARY

There are few, if any, current implants that can be described as perfectly meeting

their design goals and constraints so that no further investigation of design or

material selection is warranted. As materials continue to be developed, whether

speciﬁcally for biomedical applications or in some different discipline, the se-

lection of biomaterials for implants will remain a challenge in the design of the

optimum implant. The evolution of tissue engineering from a bench-top science

to a clinically workable tool for new implant design will also open new doors

1192 SELECTION OF MATERIALS FOR BIOMEDICAL APPLICATIONS

for the development and use of biomaterials. In all of these cases, however, the

same principles apply to the selection of a material for a biomedical application.

The selection process can be summarized in the following way:

1. Determine the functional requirements of the material for the particular

application (preferably with an idea of the overall design in hand).

2. Select a group of materials that appear to meet those functional require-

ments and ensure that all conﬁrming tests are conducted in an environ-

ment that simulates human physiology.

3. Determine the biocompatibility of the materials in terms of material deg-

radation, tissue effects, blood compatibility, implant ﬁxation, and long-

term physiologic consequences.

4. Complete the design and approval process, with mechanisms in place to

obtain data on functional or material complications for many years after

clinical use is initiated.

As with all aspects of engineering design, selection of materials for biomedical

implants is like solving a puzzle—given all of the goals and constraints, what

is the one solution that best answers the question that has been posed? And if

a current solution does not exist, can one be developed? Some may argue that

careful selection of materials for medical applications is more important than

for other realms of engineering, due primarily to the overriding fear most people

have of disease or injury. Others may disagree. It is certain, however, that de-

velopment, evaluation, and selection of biomaterials is one of the most chal-

lenging areas of materials science. No two physiologic environments are exactly

the same; therefore, no two implants will respond in exactly the same way. It is

also much more difﬁcult to predict the loading, chemical, and biological envi-

ronment that an implant will see in a particular individual than it is to model

the potential variations in loading of a car or a building. The science of bio-

medical materials has improved tremendously since the days of George Wash-

ington’s wooden teeth—and the development of new materials has just begun.

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1195

CHAPTER 38

SELECTING MATERIALS FOR

MEDICAL PRODUCTS

Sherwin Shang

Baxter Healthcare Corporation

McGaw Park, Illinois

Lecon Woo

Baxter Healthcare Corporation

Round Lake, Illinois

1 INTRODUCTION 1195

2 CHALLENGES OF MEDICAL

PRODUCTS 1198

3 PRODUCT DEVELOPMENT

FUNDAMENTAL FACTORS 1199

3.1 Product Design 1199

3.2 Selecting Materials 1199

3.3 Newly Commercially Available

Polyoleﬁn-Based Materials 1210

3.4 Manufacturing Process 1213

4 MANUFACTURING PROCESS

ON MATERIALS PROPERTIES 1213

4.1 LLDPE Pelletization Processing

on Haze, Gloss, and Gel

Counts 1213

4.2 LLDPE Blown-Film Processing

on Mechanical, Haze, Gloss,

and Gel Counts 1214

4.3 Metallocene ULDPE Tubing

Extrusion Throughput Rate

Improvement 1216

4.4 PP Injection-Molding Processing

on Medical Product Clarity 1217

4.5 PP Compression-Molding

Processing on Medical Product

Clarity 1218

5 PRODUCT PERFORMANCE 1219

5.1 Correlating Product Performance

to Materials Characteristics 1220

5.2 Optimizing Product

Performance 1220

6 CONCLUSIONS 1221

REFERENCES 1222

1 INTRODUCTION

Medical device and medication delivery system products are critical sectors in

the medical, pharmaceutical, and health-care industries. Many medical devices

and solution drug delivery systems are disposed after a single use. These dis-

posable devices and delivery systems are generally produced from polymeric

materials. The disposable materials that host solution drugs or biological agents

are recognized as parts of drugs and biological agents. New drug applications

(NDA) to the Food and Drug Administration (FDA) and to foreign government

regulatory agents are required. In contrast, the materials used in many devices

HandbookofMaterialsSelection.EditedbyMyerKutz

1196 SELECTING MATERIALS FOR MEDICAL PRODUCTS

Table 1 Examples of Medical Products

Medical Product Product Characteristics

Angioplasty, hemo dialyzer,

and oxygenators

Medical device whose materials are compatible to blood and

blood vessel tissue.

Intravenous (IV) solution and

drug delivery system

Solution drugs stored in a medical container whose materials

are suitable to host solution drugs for long shelf life stor-

age without concerns of drug interaction and concentration

variation.

Blood collection, processing

into red blood cells (RBC),

platelets, and plasma, and

then storage for blood trans-

fusion

Anticoagulants are stored within blood collection bags to

prevent blood agglomeration. A breath container material

is a must for red blood cells and platelet storage. Low-

temperature ductile impact ﬁlm for plasma storage at sub-

ambient temperatures.

Nutritious solution and perito-

neal dialysis (PD) solution

containers and their delivery

system

Solution drugs stored in medical containers that can be steam

sterilized to meet sterility requirements. No drug degrada-

tion or harmful extractives from container materials during

autoclaving.

Pharmaceutical blister, bottles,

and containers

To host solid drug tablets whose packaging materials have

good barrier properties of moisture, O

, and CO

, and UV

exposure.

Syringe and drug preﬁlled sy-

ringe

Empty is a medical device that requires on 510K approval,

but preﬁlled syringe is a drug product that require New

Drug Application (NDA) approval.

and disposables that have short solution drug or human contacts require 510K

approval.

A new medical product must prove product safety and efﬁcacy to the FDA

before market launch. Material toxicology such as testing under U.S. Pharma-

copoeia (USP), European Pharmacopoeia (EP), or Japanese Pharmacopoeia XIV

(JPXIV) guidelines is used to ensure the safety of the materials for medical

product applications. The extractive contents and levels from poststerilized ma-

terials indicate the potential impact to solution drug or biological agent quality.

Solution stability is used to understand the interactions of polymeric materials

with the hosted medication ﬂuids during product shelf life. Examples in Table

1 of medical devices include angioplasty, hemodialyzer, syringe, and oxygenator.

Disposable sets and solution containers in medication delivery system include

those used to host intravenous (IV) solution, blood components, peritoneal di-

alysis solutions, parenteral nutritious solutions, and biological agents for infusion

and transfusion therapies.

Selecting materials for medical device and disposable products have stringent

guidelines. Table 2 lists the FDA International modiﬁed ISO 10993-1 test matrix.

The materials are tested after exposure to the desired sterilization modes. The

biological testing on the materials is dependent on the intended contact duration

and body contact. The contact duration is classiﬁed as limited (

⬍24 h), pro-

longed (24 h to 30 days), and permanent (

⬎30 days). The body contact is cat-

egorized according to surface devices, external communicating devices, and

implant devices.

Regardless of the applications of medical products, the health-care and med-

ical industries always attach a premium to medical product optical clarity. A

material’s ability to allow unimpeded light transmission is not just a desire to

be ‘‘clean’’ but is rather rooted in good clinical practice. For example, in nu-

1197

Table 2 FDA-Modiﬁed ISO 10093-1 Test Matrix

Device

Body Contact

Contact

Duration

Cytotoxicity Sensitization

Irritation /

Intracutaneous

Systemic

Toxicity

Subchronic

Toxicity Genotoxicity Implantation Hemocompatibility

Chronic

Toxicity Carcinogenicity

Repro. /

Devel. /

Biodeg.

Surface

devices

Skin Limited

Prolonged

Permanent

Mucosal

membrane

Limited

Prolonged

Permanent

䡩

—

䡩

— 䡩

Breached or

compro-

mised sur-

faces

Limited

Prolonged

Permanent

䡩

—

䡩

— 䡩

External com-

municating de-

vices

Blood path,

indirect

Limited

Prolonged

Permanent

䡩

—

䡩

—

䡩

XXX

Tissue / bone

/ dentin

communicat-

ing

Limited

Prolonged

Permanent

䡩

X—

䡩 X

Circulating

blood

Limited

Prolonged

Permanent

—

䡩

—

䡩

Implant

devices

Tissue / bone Limited

Prolonged

Permanent

䡩

X—XX

Blood Limited

Prolonged

Permanent

—

䡩

—

X-

XXX

Note: X ⫽ required; 䡩 ⫽ option.

Limited contact, ⱕ24 h; prolonged contact, 24 h–30 days); permanent contact, ⬎30 days).

1198 SELECTING MATERIALS FOR MEDICAL PRODUCTS

merous primary medical containers, prior to administration of the medical ﬂuid

to the patient, the nurse is required to inspect visually for particulate matter

(PM) contamination. This inspection is required to protect patients against the

danger of exposure to the visible contaminants.

In situations where medications in the powder form need to be mixed or

compounded prior to administration, the ability to visually inspect for the com-

pletion of dissolution is another important safeguard for patient safety. Recently,

transfusion therapies involving harvested, stored, and cultured cellular compo-

nents became widespread. During the in vitro phase, these cellular components

frequently need to be manipulated through separation, fractionation, and incu-

bation for diagnostic or therapeutic purposes. In many of the steps, the ability

to inspect contents visually or microscopically is crucial to the clinical protocol.

These are just a few reasons that optical clarity is a prerequisite criterion for

medical material selections.

Another attribute speciﬁc to the health-care and medical industries is the need

to deliver therapies in a sterile manner. As a consequence, compatibility with

common sterilization methods is a must. These methods include steam auto-

claving, ethylene oxide (ETO) sterilization, and ionizing radiation (either gamma

or electron beam.)

1,2

Steam autoclaving places a severe burden on the prospective

medical material with the use of high temperature (such as 121

⬚C) and pressure.

Ethylene oxide is currently being phased out due to worker exposure and en-

vironmental concerns, while long-term shelf life stability is an issue for the

material postradiation sterilization.

A third requirement that has received increasing attention is environmental

compatibility. As professionals concerned with health care, we obviously cannot,

in the course of mending our patients, destroy the environment that we live in

and our children will inherit. Of course, the quantitative ‘‘environmental score’’

is quite elusive and often subjected to passionate debate. However, some of the

basic tenets are very obvious; progressive companies have already adopted many

of the practices in this direction.

All these have urged the medical industry to select safe, clean, and environ-

mentally friendly materials to meet safety, manufacturability, and functionality

requirements for medical products. These requirements thus pose the constraints

and challenges on the materials selected during product development for medi-

cal, pharmaceutical, and health-care industry.

2 CHALLENGES OF MEDICAL PRODUCTS

Medical product challenges faced today are not only from technical advances

but also from business competition. Safety is the highest priority. Product clarity,

stability, biocompatibility, and low extractives are highly valued. Many medical

and health-care products require a speciﬁc level of oxygen (O

), carbon dioxide

(CO

), or water vapor transmtission rate (WVTR) at room temperature. These

products can be either very rigid or very ﬂexible, and for some drug delivery

systems and medical devices superior subambient impact is required. Further-

more, the selected medical materials should be compatible to the desired ster-

ilization mode and render no harmful damage to the packed devices, drugs, and

disposable systems.

Polymeric materials are part of the ﬁnished medical products. A lowest pos-

sible total system cost is used to direct product development and ﬁnished product