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CHAPTER

Biomaterials

Myron Spector

AB in other surgical specialties, plastic surgery has been Synthetic calcium phosphate materials were introduced as bone
revolutionized by implantable devices. These advances have graft substitute materials. Research was also initiated on carbon
been largely based on biomaterials science and engineering. fiber-reinforced polymer composite materials to replace metals
Materials have been used for the fabrication of permanent in devices with even lower stiffness. Absorbable polymers were
implants to replace diseased, injured, or congenitally absent developed to produce biodegradable devices for fracture fixa-
tissues and to restore tissue function. tion and other applications.
In the future, however, materials will playa different role in Also during these decades, however, the limitations of
plastic surgery. Materials will also be used for the fabrication of permanent biomaterials and devices became apparent, largely
temporary, absorbable implants to facilitate the regeneration as a result of clinical experience and follow-up. Device failure
of tissue. This new role for materials is associated with novel from specific deficiencies of materials prompted the search for
therapeutic approaches associated with tissue engineering. new substances that might improve the performance and
extend the longevity of these devices.
More recently, a new class of the absorbable materials has
HISTORYAND OVERVIEW been developed to augment or replace graft materials for
defects in bone and certain soft tissues. These materials include
The changing role for materials in plastic surgery can be con- different forms of absorbable polymers used in devices for
sidered through the various eras of the discipline. The 1930s fracture fixation, as well as calcium phosphate substances and
through the 1970s might be considered the "Age of Devices." collagen materials. In many respects these absorbable sub-
During these years a wide variety of implants were developed stances and the experience with transplants in many surgical
for treating myriad problems. These devices revolutionized specialties have served as the foundation for the imminent
plastic surgery and were fabricated from relatively few mate- "Age of Tissue Engineering." Currently, porous absorbable
rials: stainless steel, cobalt-chromium alloy, polymethyl- synthetic and natural polymers are being investigated as
methacrylate (PMMA), and silicone. scaffolds to be seeded with cells in vitro for the production of
Selection criteria for materials in implants were (1) strength, tissue in the laboratory or for the preparation of implants to
(2) biocompatibility, and (3) degradation resistance. The latter facilitate tissue regeneration in vivo.
two specifications were often combined and referred to as We also seem to be on the threshold of the "Age of Gene
"inertness." Materials proposed initially for implants in plastic Therapy." Although experiments are investigating the efficacy
surgery and for other surgical applications were generally of injecting gene fragments alone, it is likely that absorbable
shown to display this property in nonmedical uses, especially materials may be effectively employed as delivery systems for
metallic materials. Advantages and disadvantages of materials these genes. Also, the ex vivo transfection of cells with selected
for specific applications often were determined only after their genes is certain to combine gene therapy with tissue engineer-
introduction into the clinic. Materials commended for a partic- ing. Laboratory findings have been promising, but much work
ularclinical application because of one favorable property were remains before the benefit/risk ratio of gene therapy for specific
found to fail because of a deficiency in another property. indications can be assessed.
The 1980s and 1990s might be considered the "Age of Selection and development of a material for a specific
Biomaterials." New materials were introduced for the refabri- indication are based on the following (Figure 19-1):
cation of devices already in clinical use to improve their perfor- 1. The device's function
mance. Also, the development of other materials led to new 2. The device's effect on the body
typesof implants. 3. The body's effect on the implant
Titanium alloy was introduced as an alternative to cobalt- Issues related to the attachment of tissue to the implant
chromium alloy for fabrication of components with lower (i.e., incorporation of the device into the body) also are
stiffness to reduce bone loss associated with stress shielding. important.

239
240 PART I PRINCIPLES AND TECHNIQUES

Implant Selection or Design

Function of device Effects of body on implant


Effects of
Mechanical device on Resistance to degradation?
Chemical body Yes(permanent);No (absorbable)
Electrical Surface Bulk Mechanical
Thermal Fracture (strength)
Optical Wear (abrasive,fatigue)
Chemical
Wear (adhesive)
Bioadhesion(i.e., tissuebonding)? Corrosion
(Surface) Oxidation
Yes No Hydrolysis
Enzymolysis
Dissolution/precipitation

Mechanical Nonreactive
Interpenetrating ("inert")
(tension, shear, compression) Hydrophobic
Chain entanglement Hydrogel
ECM in interconnecting
pores (porosity)
InterCligitating Chemical
(shear, compression) Proteinadsorption/
ECM in surface
binding
irregularities (rugosity) Mineral deposition

Figure 19-1. Issues related to selection or design of materials for fabrication of implantable
devices. ECM,Extracellular matrix.

This chapter provides a framework for understanding the metals most often used for the fabrication of implantable
composition and properties of the wide variety of materials devices are stainless steel, cobalt-chromium alloys, and tita-
used for implantable devices in plastic surgety as they impact nium and titanium alloy. The specific members of these
the biologic response to these implants. Additional back- families used as biomaterials are usually identified by a desig-
ground on biomaterials science and engineering can be found nation provided by the American Society for Testing and
in a recent text.89 Materials (ASTM).
The stainless steels, as with all steels, are iron-based alloys.
Chromium is added to improve the corrosion resistance
COMPOSITION AND PROPERTIES through the formation of a chromium oxide surface layer; at
least 17% chromium is required for the term stainless to be
The term biomaterials generally refers to synthetic and treated used. Carbon and nickel are employed as alloying elements to
natural materials employed in the fabrication of implantable increase strength. The most common type of stainless steel
devices that are used to replace or augment tissue or organ used for implants is 316L (American Iron and Steel Institute
function. An understanding of the physical properties of these designation; ASTM F-138), containing 17% to 19% chro-
materials is important for the judicious implementation of mium, 13% to 15.5% nickel, and less than 0.03% carbon.
implants and provides for a realistic expectation of clinical Surgical cobalt-chromium alloy is a cobalt-based system with
performance. chromium added for increased corrosion resistance. Its compo-
The physical properties of materials result from their sition contains 27% to 30% chromium and 5% to 7% molyb-
chemical makeup. Therefore an understanding of the molecu- denum. Tungsten is added to the wrought alloy to enhance
lar structure and chemical bonding ofbiomaterials can provide ductility.
the basis for understanding the physical properties.63 Titanium and its alloy, with 6% aluminum and 4%
vanadium (Ti-6Al-4V), are used for their excellent corrosion
Metals resistance and their modulus of elasticity, which is approxi-
In metals, closely packed arrays of positively charged atoms are mately one-half that of stainless steel and cobalt-chromium
held together in a loosely associated "cloud" of free electrons. alloys. This lower modulus results in devices with lower
The essential features of the metallic bond are that (1) it is stiffness, which may be advantageous in certain applications,
nondirectional and (2) the electrons are freely mobile. The such as implants in bone because they will result in less stress
CHAPTER 19 Biomaterials 241

shielding of bone. The alloy of titanium has much better mate- alloy crystal interfaces, the resultant corrosion occurs selec-
rial properties than the pure titanium. Problems with titanium tively in the intercrystalline paths. Certain grades of stainless
are its severe notch sensitivity and poor wear resistance. steel (e.g., F-138) have a maximum of only 0.03% carbon to
The mechanical properties of any material are linked to its reduce the formation of these carbides.
ultrastructure. Any processing treatment that alters the phase Another feature of the stainless steels relates to the presence
structure, grain size, or grain orientation of a metal will affect of inclusions, which can serve as Raws or cracks that can be
the material properties. Mechanically deforming a metal be- propagated by cyclic loading-the process offatigue failure. To
yond its yield stress will produce, in addition to a shape change, increase resistance to fatigue failure, certain grades of steel are
a material with increased yield and ultimate stresses and a available with smaller and more widely spaced inclusions.
higher endurance limit. Because this process, called cold work-
ing, results in permanent deformation, the resultant material is COBALT-CHROMIUM ALLOYS. As with stainless steels, the
lessductile than the initial material. chromium content of this alloy generates a highly resistive,
Casting is the pouring of molten metal into a mold to passive film that contributes substantially to corrosion resis-
produce a specific shape on cooling. Voids and other Raws are a tance. The cobalt-chromium-molybdenum (Co-Cr-Mo) alloy
major problem with casting. Forging is a process by which a (F-75) has superior corrosion resistance to the F-138 stainless
blank of metal is heated and pressed into a die by the applica- steel, particularly in crevice corrosion, and has ari extensive
tion of a large, single force. This produces a part with fewer history ofbiocompatibility in human implantation.
defects than a casting. Annealing is essentially heating for pro- Co-Cr-Mo devices are currently produced by hot isostatic
longed periods to allow stress relaxation and grain reorganiza- pressing, which results in parts with more favorable strength
tion and growth. Hot isostaticpressing is a newer technology characteristics than results from casting processes. In the hot
involving the consolidation of metal powder into a fine-grained isostatic pressing process the liquid alloy is atomized to
material under high temperature and pressure. These and other powder. Loose powder is consolidated to a void-free solid,
processing methods have been developed to produce parts of resulting in a part reasonably close in shape to the ultimate
complex shape with the highest degree of mechanical integrity. device. The preformed part is finished by machining and
Metallic materials have certain properties that make them polishing. The resulting structure has a very fine, alloy crystal
ideal for load-bearing applications. They can maintain very size and very fine, uniform dispersion of carbide particles. The
high strength under the aggressive aqueous environment in the availability of the high-strength varieties and their superior
body. The biocompatibility of metallic materials is related to corrosion resistance and biocompatibility make them excellent
their corrosion resistance. choices for high-stress applications.
Cobalt-chromium-titanium-nickel {Co-Cr- Ti-NOalloy
STAINLESS STEELS. Many alloys and grades of alloys are (ASTM F-90) is very different from the F-75 alloy, with which
identified as commercial stainless steels. Only the iron- it is often confused. This alloy can be hot forged and cold
chromium-nickel alloys are used as biomaterials. Unalloyed drawn and is not used in the cast form. In clinical practice it is
iron, carbon steels, and alloyed carbon steels cannot be used used to make wire and internal fixation devices (e.g., plates,
becausethey corrode in oxygenated saline solutions. intramedullary rods, screws).
Despite their very good corrosion resistance, stainless steels
are subject to several other corrosion processes, including UNALLOYED TITANIUM AND TITANIUM ALLOY. Tita-
crevice, pitting, intergranular, and stress corrosion. These nium and its alloys are of particular interest for biomedical
processescan profoundly degrade the mechanical strength of applications because of their outstanding biocompatibility. In
the alloy and can lead to the release of metallic ions into the general, their corrosion resistance significantly exceeds that of
surrounding tissue, with undesirable biologic consequences the stainless steels and the cobalt-chromium alloys. In saline
(seelater discussion). solutions at near-neutral pH the corrosion rate is extremely
Alloying with chromium generates a protective, self- small, with no evidence of pitting, intergranular, or crevice
regenerating oxide film that resists perforation, has a high corrosion. Data from in vivo animal experimental models and
degree of electrical resistivity, and thus provides a major from human sources indicate superior biocompatibility.
protection against corrosion. Formation of the chromium. So-called unalloyed titanium actually is alloyed by the
oxide "passivation" layer is facilitated by immersion of the level of oxygen dissolved into the metal. In large amounts,
alloyin a strong nitric acid soliltion. The nickel imparts more oxygen embrittles titanium and its alloys, but in small,
corrosion resistance and outstanding fabricability. The molyb- regulated amounts it helps control the yield strength of
denum addition provides resistance to pitting corrosion. Other the materials. ASTM F-67 is a specification for oxygen
alloyingelements facilitate manufacturing processes. providing 345 megapascals (MPa) of yield strength in grade
The presence of carbon in stainless steel is undesirable. III and 485 MPa of minimum yield strength in grade IV.
Under certain conditions the carbon segregates from the major Other elements in unalloyed titanium include nitrogen,
elements of the alloy, taking with it a substantial amount of 0.07% (maximum); carbon, 0.15% (maximum); hydrogen,
chromium in forming chromium carbide precipitates. Local 0.015% (maximum); and iron, 0.35% (maximum). Any
depletion of chromium deprives those zones of corrosion excess of these elements may degrade the performance of the
resistance,and since the carbides form most frequently at the basic material.
242 PART I PRINCIPLES AND TECHNIQUES

Unalloyed titanium is used less frequendy than the alloy for important benefit. Because of the limited strength and wear
implants but is available in various configurations, such as resistance of polymers, the load-bearing requirements of the
plain wire for manufacturing purposes. In addition, it is used applications must be considered.
to produce porous coatings for certain designs of total joint
replacement prostheses. POLYMETHYLMETHACRYLATE. PMMA is used in a self-
ASTM F-I36 specifies a titanium alloy with a content of curing form as a filling materials for defects in bone and as a
5.5% to 6.5% aluminum, 3.5% to 4.5% vanadium, 0.25% grouting agent for joint replacement prostheses.35 It can be
iron (maximum), 0.05% nitrogen (maximum), 0.08% carbon shaped in vivo while in a dough stage before complete polymer-
(maximum), 0.0125% hydrogen (maximum), and 0.1% other ization, and thus a custom implant is created for each use. Its
(maximum 0.4% total). Oeveloped by the aircraft industry as purpose is more even redistribution of stress on the surround-
one of several high-strength titanium alloys, this particular for- ing bone.
m ulation has a yield strength reaching 1110 MPa. The ASTM Often referred to as "bone cement," when PMMA is em-
F-I36 specification limits the oxygen to an especially low level ployed for joint arthroplasty, it acts as a grout to support the
of 0.13% maximum. This is also known in the industry as the prosthesis rather than a glue; it has minimal adhesive proper-
extra low interstitial (ELI) grade. Limiting the level of oxygen ties. The time-dependent properties of PMMA during curing
improves the mechanical properties of the material, particularly require an understanding ofits handling characteristics. Imme-
increasing its fatigue life. diately after mixing, the low viscosity permits interdigitation
One interesting feature of titanium and its alloys is the low with cancellous bone. Viscosity rises quickly once the chemical
modulus of elasticity of 100 gigapascals (GPa), as compared setting reaction begins, requiring that the prosthesis be accu-
with 200 GPa for the cobalt-chromium alloys. This feature rately positioned and stationary to achieve maximum fixation.
leads to their use in plates for internal fixation of fractUres. The chemical toxicity of the methylmethacrylate monomer
Some have found that the lower stiffness of these plates may and the heat generated during polymerization must be consid-
decrease the severity of bone stress shielding, which results in ered when using PMMA. Its britde nature after curing and low
osteopenia under these devices. fatigue strength make PMMA vulnerable to fractUre under high
One of the weaknesses of titanium is poor wear resistance. mechanical loading. Also, wear debris is produced when other,
This problem ~'parendy relates to the mechanical stabiliry harder materials rub ~ainst PMMA.
of the passive film covering the alloy's surface. On a carefully Although the adjunctive use of PMMA to stabilize patho-
polished surface, the film is highly passive but mechani- logic fractures of diaphyseal bones has become routine, its
cally weak. implantation about the cervical spine has been limited because
of the exothermic reaction during the curing process. Bone-
Permanent and Absorbable Synthetic cement interfacial temperatUres of 600 to 650 C (1400 to
and Natural Polymers 1490 F) during total knee arthroplasty and of 800 to 900 C
Polymers consist of long chains of covalendy bonded mol- (1760 to 1940 F) during total hip arthroplasty have been
ecules characterized by the repeated appearance of a mono- reported. These temperatures are of sufficient magnitUde to
meric molecular unit. They can be produced de novo by the cause degradation of protein. The adverse effects of such tem-
polymerization of synthetic monomers or prepared from peratures on the cerebrospinal fluid and spinal cord can be
natural polymers isolated from tissues. Most synthetic and avoided by the following:
natural polymers have a carbon backbone. Bonding among 1. Precooling the soft tissues and bone
polymer chains results from the much weaker secondary forces 2. Placing the cement on the dorsal aspect of the intact
of hydrogen bonds or van der Waal' s forces. Covalent bonding lamina
among chains, referred to as cross-linking, can be produced in 3. Applying precooled Gelfoam over exposed dura
certain polymer systems. In this way, acrylic cement and wire fixation of pathologic
Physical entanglements of the long polymer chains, the fractures of the cervical spine can be performed safely to allow
degree of crystallinity, and chemical cross-linking among early mobilization of patients with limited life expectancies.
chains play important roles in determining polymer properties.
The molecular bonding of the backbone of the polymer can be SILICONE. Silicones are polymers with a backbone comprised
designed to undergo hydrolysis or enzymatic breakdown, thus of alternating silicon and oxygen atoms and organic side groups
allowing for the synthesis of absorbable, as well as permanent, bonded to the silicon through covalent bonding with the car-
devices. bon atom.61 One form of silicone typically used for the fabrica-
Polymeric materials are generally employed for the fabri- tion of implants is polydimethylsiloxane (POMS). In POMS,
cation of implants for soft tissue applications that require a methyl (CH3) side groups are covalendy bonded to the silicon
greater degree of compliance than can be achieved with metals. atom. POMS can be used in the following three forms:
They have also been shown to be of value as implants in bone 1. A fluid comprising linear polymers of varying molecular
for indications that would also benefit from their lower modu- weight (i.e., chain length)
lus of elasticity, as well as the ability of some to be polymerized 2. A cross-linked network referred to as a gel
in vivo and adapt to defects of complex shape. For some 3. A solid elastomer comprising a highly cross-linked gel
indications the radiolucency of polymeric materials may be an filled with small particles of silica.
CHAPTER 19 Biomaterials 243

Silica is another silicon-containing molecule, silicon diox- ABSORBABLE POLYMERS


ide. PDMS elastomers contain a nonctystalline silica particle 7 Synthetic. Absorbable polymers have been used in plastic
to 22 nm in diameter that has been surface-treated to facilitate surgety for decades in the form of absorbable sutures.4 More
chemical bonding of the particle to the PDMS gel. Addition of recently this class of materials has been investigated for the
the silica particle to a highly cross-linked PDMS gel is done to application of resorbable devices, including fracture fixation
modify the mechanical properties of the elastomer. In certain implants and scaffolds for tissue engineering. The principal
cases, such as the PDMS elastomeric shell for silicone-filled issues associated with the implementation of absorbable
breast implants, the elastomer may contain side groups of polymers as implants include the following:
phenyl (C6Hs) or trifluoropropyl (CF3CH2CH2) instead of 1. Mechanical properties (e.g., strength)
the methyl groups to better contain the PDMS fluid. 2. Degradation rate
In evaluating the performance of silicone implants, the role 3. Biologic response to the degradation products.
of each form of PDMS in the device must be considered. One of the classes of polymers used frequently for the
Attributing specific biologic responses to individual compo- fabrication of absorbable implants is the alpha-hydroxy acids,
nents of a silicone device is complicated by the implant's many including L-Iactic acid, glycolic acid, and dioxanone. These
molecular forms of silicone. molecules normally are used in their polymeric forms: polY-L-
lactic acid (PLLA), polyglycolic acid (PGA), and polydiox-
POLYETHYLENE. Ultrahigh-molecular-weight polyethylene anone. Copolymers of lactic and glycolic acids are also fre-
(UHMWPE) has a vety low frictional coefficient against metal quently employed.
and ceramics and is therefore used as a bearing surface for joint A particular class of polyester undergoes breakdown as a
replacement prostheses.13,62 Moreover, the wear resistance of result of the hydrolytic scission of the ester bond. The access of
UHMWPE is lower than that of other polymers investigated water to this bond in PGA is much greater, resulting in a more
for this application. Low strength and creep, however, present rapid degradation rate compared with that occurring with
potential problems. PLLA, which has a bulkier CH3 side group instead of the H
The term polyethylene refers to plastics formed from poly- atom in PGA. The copolymer of polylactic and polyglycolic
merization of ethylene gas. The possibilities for structural vari- acid can be designed to have an intermediate degradation rate.
ation in molecules formed by this simple repeating unit for Although most breakdowns of these polymers are caused by
different factors (e.g., molecular weight, ctystallinity, branch- hydrolytic scission, nonspecific enzymatic action is also
ing, cross-linking) are so numerous and dramatic with such involved.
a wide range of attainable properties that polyethylene truly Factors that affect the rate of breakdown of these polymers
refersto a subclass of materials. The earliest type of polyethyl- include (1) the relative amount of monomers composing the
ene was made by reacting ethylene at high (20,000 to 30,000 copolymers, (2) the degree of ctystallinity, and (3) the surface
pounds per square inch) pressure and temperatures of 2000 to area. These polymers are normally broken down to natural
4000 C with oxygen as a catalyst. Such material is referred to as body components excreted in the urine or exhaled. The process
conventional or low-density, polyethylene. of degradation involves the gradual decrease in the average
Much polyethylene is produced now by newer, low- molecular weight of the polymer as hydrolysis proceeds. At
pressure techniques using aluminum-titanium (Ziegler) cata- some point the molecular weight decreases to the extent that
lysts.This is called linear polyethylene due to the linearity of its the polymer becomes soluble in the aqueous environment, and
molecules, in contrast to the branched molecules produced by a bolus release of the molecules occurs. Depending on the mass
high-pressure processes. The linear polymers can be used to of the implanted device, the concentration of the molecules
make high-density polyethylene by means of the higher degree may elicit an inflammatoty response. 108
of ctystallinity attained with the regularly shaped molecules.
Typically, molecular weight is not significantly different NaturaL Myriad devices are fabricated from collagen, the
between the low-density and high-density varieties (e.g., principal structural protein of the body. 117The collagen mole-
100,000 to 500,000). cule comprises three tightly coiled helical polypeptide chains.
If the low-pressure process is used to make extremely long In vivo the collagen molecule, tropocollagen, is assembled to
molecules (i.e., UHMWPE), however, the result is remarkably form fibrils, which in turn assume various orientations and
different. This material, with a molecular weight of 1 to 10 configurations to form the architecture of various tissues. The
million, is less ctystalline and less dense than high-density wide array of properties of tissues that make up collagen, from
polyethylene and has exceptional mechanical properties. It is dermis to musculoskeletal tissues and including articular carti-
extremely tough and is remarkably wear resistant; a 0.357- lage, meniscus, and ligament, is caused by differences in the
magnum bullet fired from 25 feet bounces back from a chemistty, density, and orientation of the fibrils formed from
l-inch-thick slab of UHMWPE. The material is used in vety the collagen molecule.
demanding applications (e.g., ore chutes in mining equip- Collagen is soluble in specific solutions in which the chains
ment) and is the most successful polymer used in total joint can become disentangled to produce gelatin. Collagen can be
replacements. It far outperforms the various actylics, fluorocar- isolated from tissue and purified through the use of several
bons, polyacetals, polyamides, and polyesters tried for such agents: acids, alkalis, enzymes, and salt. Treatment in acid
purposes. results in the elimination of acidic proteins and glycosami-
.
244 PART I PRINCIPLES AND TECHNIQUES

noglycans, which cause dissociation of the collagen fibrils. A able and is used in both dense and porous forms as a perma-
similar effect can be achieved using alkaline extraction with the nent implant. Tricalcium phosphate is bioabsorbable to
removal of basic proteins. Proteolytic enzymes that cleave the varying degrees, depending on formulation and structure.
telopeptides, which serve as natural cross-linking agents for Many calcium phosphate materials are currently under-
collagen, allow for the dissolution of collagen molecules and going investigation as bone graft substitute materials (see later
aggregates in aqueous solutions. Salt extraction leads to the discussion).
removal of newly synthesized collagen molecules and cenain
noncollagenous molecules, thus facilitating the disaggregation Composite Materials
of collagen fibrils. Composite materials are combinations of two or more materials
Collagen's solubility in an acidic medium facilitates its ex- and usually involve more than one material class (e.g., metals,
traction from tissues and reprocessing into biomaterials. Several polymers, ceramics). They are used to achieve a combination
factors are critical determinants of the propenies of reconsti- of mechanical propenies for specific applications. Composite
tuted collagen biomaterials. The degree of denaturation or technology, much of it developed for the aerospace industry, is
degradation of the collagen structures isolated from tissue will beginning to make its way into biomedical materials. Carbon
affect the mechanical properties. These properties will also be fiber-reinforced polymers are being investigated as substitutes
affected by the degree to which the material is subsequently for metals. The advantage is that devices with comparable
cross-linked. strength but with significantly lower stiffness can be produced.
An imponant biologic property related to collagen's molec- Moreover, these types of composite devices are radiolucent.
ular structure is the collagen-induced blood platelet aggregation.
The quarternary structure of collagen resulting from the per-
iodic aggregation of the collagen molecules has been well docu- BIOLOGIC RESPONSE TO BIOMATERIALS
mented. Methods for isolating and purifying collagen fibrils
result in the preservation or destruction of this quarternary The biological processes composing the tissue response are
structure and are used to produce either hemostatic or throm- affected by the following implant-related factors99:
boresistant biomaterials. Another factor relates to the removal 1. "Dead space" created by presence of the implant
of soluble components that might serve as antigens. The immu- 2. Soluble agents released by the i"!plant (e.:J1;.,
metal ions,
nogemclty can be reduced' to clinica.l1yinsignifiCant levels by polymer fragments)
chemically modifying the antigen molecules. 3. Insoluble paniculate material released from the implant
A wide variety of methods have been employed for the (e.g., wear debris)
fabrication of collagen sutures, fleeces for hemostasis, and 4. Chemical interactions of biologic molecules with the
spongelike materials for scaffolds in tissue engineering. implant's surface
5. Alterations in the strain distribution in tissue caused by
Ceramics (a) mismatch in the modulus of elasticity between the
Ceramics are typically three-dimensional arrays of positively implant and surrounding tissue and (b) movement of
charged metal ions and negatively charged nonmetal ions, often the implant relative to adjacent tissue as a result of the
oxygen. The ionic bond localizes all the available electrons in absence of mechanical continuity
the formation of a bond. Network organization ranges from Study of the tissue response to implants requires methodol-
highly organized, crystalline, three-dimensional arrays to amor- ogy capable of measurements at the molecular, cellular, and
phous, random arrangements in glassy materials. tissue levels (Figure 19-2). Time is an impottant variable be-
Ceramics may be the most chemically inert implant materi- cause of the critical temporal relationship between the molecu-
als currently in use. Their relatively low tensile strength, high lar and cellular protagonists of the biologic reactions. Also,
modulus, and brittleness, however, limit their applications. implant-related factors act on the biologic responses with dif-
Current techniques allowing the formation of ceramic coating ferent time constants. The dynamic nature of implant-tissue
on metallic substrates have revitalized interest in ceramics for interactions requires that the final assessment of tissue compat-
hard-tissue applications. ibility be qualified by the time frame in which it has been
evaluated.
ALUMINUM OXIDE. Aluminum oxide has been found of The tissue response to an implant is the cumulative physio-
value for the aniculating components of total joint arthroplas- logic effect of the following 10°:
ties because ofits high wear resistance and its low coefficient of 1. Modulation of the acute wound healing response to the
friction when prepared in congruent, polished geometrics. The surgical trauma of implantation and presence of the
brittle nature of alumina remains a detriment. implant (Figure 19-3)
2. Subsequent chronic inflammatory reaction associated
CALCIUM PHOSPHATES AND HYDROXYAPATITE. with presence of the device
Calcium-based ceramics, closely related to the naturallyoccur- 3. Remodeling of surrounding tissue as it adapts to pres-
ring hydroxyapatite in bone, have generated great interest in ence of the implant
recent years. Their ability to bond directly to bone and their In addition, the healing and stress-induced adaptive remod-
osteoconductive capability promise to enhance biologic fixa- eling responses of different tissues to the same implant can vary
tion of implant devices. Hydroxyapatite is only slightly resorb- greatly.
CHAPTER 19 Biomaterials 245

Biomaterial Cell and Tissue Response


Size scale
Protein adsorption/
nm mm
I flm
conformational change/
:: !
desorption
h
i: ~
Bone
icr Proteins i M"'mp age ~I
~~
~
: :
Osteoblasts
ic:;::
Wear
Particles
c D<J
o D:
,/---;!

'
:,%
: . ~
~~
Metal corrosion
Polymer degradation
0,,68

.:::
:
\ !.. ~

.
i

Ion,: .; '"a,leoda,'
Fibroblast
..'...... i~ibrous
@; :lis sue (sea r)
: '
...co.+.+ agen:.;;;?'".
11

Figure 19-2. Interactions among moieties released by implants, biologic molecules, cells, and
tissues.

Vascular response

~cute .
InRammahon
C
Tissueof labile
~
Clotting
Phagocytosis
Neovascularizati~
New collagen synth~~is
------- Tissuesof
~
.
<?ranulahon
hssue

or stable cells permanentcells


~ ~-Imprantmovement f.
Framework Framework Scarring
intact destroyed Fibrousencapsulation
~ ~ .. ~R
Chromc .
Regeneration Scarring In ammahon
(incorporationof Fibrousencapsulation
implantintotissue) ~
ChronicinRammation
(synovium,granuloma)

Figure 19-3. Biologicprocesses initiated by surgicaltrauma of implantation that determine tissue


response to implantable devices.

The biologic response elicited by an implant involves the Surgical wounds in avascular tissue (e.g., cornea, inner third
healingand remodeling characteristics of the four basic types of meniscus) will not heal because of the limited potential for
oftissue:connective tissue, muscle, epithelium, and nerve. The the proliferation and migration of surrounding parenchymal
characteristicsof the parenchymal cells in each type of tissue cells into the wound site. Gaps between an implant and sur-
canprovide a basis for understanding the tissue response to an rounding avascular tissue will remain indefinitely. Implant sites
implant. The following characteristics of an implant site are in vascular tissues where the parenchymal cell is incapable of
determinants of the biologic response: mitosis (e.g., nerve tissue) will heal by scar formation in the gap
1. Vascularity between the implant and surrounding tissue. Moreover, adja-
2. Nature of the parenchymal cell with respect to its capa- cent cells that have died as a result of the implant surgery will
bility for mitosis and migration, because these processes be replaced by fibroblasts and scar tissue.
determine the regenerative capability of the tissue
3. Presence of regulatory cells, such as macrophages and Normal Local Tissue Response
histiocytes WOUND HEALING. The tissue that forms around implants
4. Effect of mechanical strain, associated with deformation is the result of the influence of the device on (1) the wound
of the extracellular matrix, on the behavior of the healing response initiated by the surgical trauma of implanta-
parenchymal cell tion (Figure 19-3) and (2) subsequent tissue remodeling.
246 PART I PRINCIPLES AND TECHNIQUES

Implantation of a medical device initiates a sequence of cellular FIBROUS TISSUE INTERFACE. The implant creates a dead
and biochemical processes that lead to healing by secondary space in tissue that attracts macrophages to the implant-tissue
intention, that is, healing by the formation of granulation tissue interface.96 These cells are attracted to the prosthesis as they are
within a defect, as opposed to the healing of an incision, or, to any dead space (e.g., bursa, joint space), presumably because
healing by primary intention. of certain microenvironmental conditions (e.g., low oxygen,
The first phase of healing in vascularized tissues is inflamma- high lactate). In this regard it is not clear why macrophages are
tion. This is followed by a reparative phase, the replacement of absent from the surface of osseointegrated implants (see follow-
the dead or damaged cells by healthy cells. The pathway of the ing discussion).
reparative process depends on the regenerative capability of the Macrophages and the scar's fibroblasts form synovial tissue,
cells composing the injured tissue (i.e., the tissue or organ into which can be considered the chronic inflammatory response to
which the implant has been placed). implants, unless the device is apposed by osseous tissue (i.e.,
Cells can be distinguished as labile, stable, or permanent osseointegrated).101 This process is often termed fibrous encap-
based on their capacity to regenerate. Labile cells continue to sulation.27,54The presence of regulatory cells such as macro-
proliferate throughout life, replacing cells that are continually phages at the implant-tissue interface can profoundly influence
being destroyed. Epithelial and blood cells are examples of the host response to a device because these cells can release
labile cells, as are cells of splenic, lymphoid, and hematopoietic proinflammatory mediators if irritated by the movement of the
tissues. device or substances released from the biomaterial.3 The in-
Stable cells retain the capacity for proliferation, although flammatory response of the synovial tissue around implants is
they do not normally replicate. These cells can undergo rapid comparable to the inflammation that can occur in the syn-
division in response to a variety of stimuli and can reconstitute ovium lining any bursa (e.g., bursitis); thus the response to
. . .. 101
the tissue of origin. Stable cells include the parenchymal cells Imp Iants has b een terme d Imp Iant burslns.
of all the glandular organs of the body (e.g., liver, kidney,
pancreas), mesenchymal derivatives (e.g., fibroblasts), smooth RESPONSE TO IMPLANTS IN BONE. Wound healing
muscle cells, osteoblasts and chondrocytes, and vascular governs the makeup of the tissue that forms around implants.
endothelial cells. Because it can regenerate, bone should be expected to appose
Permanent cells cannot reproduce themselves after birth. implants in osseous tissue and form within the pore spaces of
Examples are nerve cells. porous coatings. Is this bone bonded in any way to the
Tissues comprised of labile and stable cells can regenerate implant? Bonding of a prosthesis to bone would enhance its
after surgical trauma (Figure 19-3). The injured tissue is stability, limiting the relative motion between the implant and
replaced by parenchymal cells of the same type, often leaving bone. In addition, bonding might provide a more favorable
no residual trace of injury. Tissues comprised of permanent distribution of stress to surrounding osseous tissue.
cells, however, are repaired by the production of fibrocollag-
enous scar. Despite the capability of many tissues to undergo Bonding and Osseointegration. Bonding of bone to an
regeneration, destruction of the tissue stroma remaining after implant can be achieved by mechanical or chemical means.
injury or constructed during the healing process will lead to Interdigitation of bone with PMMA bone cement or with
formation of scar. The biologic response to materials therefore irregularities in implant topography and bone ingrowth into
depends on the influence of the material on the inflammatory porous surfaces can yield interfaces capable of supporting shear
and reparative stages of wound healing. and tensile as well as compressive forces. These types of
The following types of questions need to be addressed when mechanical bonding have been extensively investigated and are
assessing the "biocompatibility" of materials: reasonably well understood.
Does the material yield leachables or corrosion products that Chemical bonding of bone to materials may result from
interfere with the resolution of inflammation initiated by molecular (e.g., protein) adsorption and bonding to surfaces
the surgical trauma? with subsequent bone cell attachment. This phenomenon has
Does the presence of the material interfere with the stroma undergone intensive investigation in recent years but is not yet
required for the regeneration of tissue at the implant site? as well understood as mechanical bonding.
A number of systemic and local factors influence the The term osseointegration has been used to describe the
inflammatory-reparative response. Systemic influences include presence of bone on the surface of an implant with no histologic
age, nutrition, hematologic derangements, metabolic derange- intervening nonosseous (e.g., fibrous) tissue. All implants in
ments, hormones, and steroids. Although the prevailing "con- bone should become osseointegrated unless the bone regenera-
ventional wisdom" is that elderly persons heal more slowly than tion process is inhibited.
young people, few control data and animal experiments sup-
port this theory. Nutrition can have a profound effect on the Bone Ingrowth. The bone ingrowth into a porous-surface
healing of wounds. Prolonged protein starvation can inhibit coating on an implant leads to an interlocking bond that
collagen formation, and high-protein diets can enhance the rate can stabilize the device. In order for the porous material
of tensile strength gained during wound healing. Local influ- to accommodate the cellular and extracellular elements of
ences that can affect wound healing include infection, inade- bone, the average pore diameter should be greater than
quate blood supply, and presence of a foreign body. about 100 ~m.
CHAPTER19 Biomaterials 247

The bone ingrowth process proceeds in two stages. First, immobilization-induced atrophy of certain tissues resulting
surgical trauma of implantation initially leads to the regenera- from the decrease in mechanical strains. Loss of bone mass
tion of bone throughout the pores of the coating. Second, around stiff femoral stems and femoral condylar prostheses of
mechanical stress-induced remodeling leads to resorption of total hip and knee replacement devices has been associated
bone from certain regions of the implant and continued with the reduced strains resulting from stress shielding.
formation and remodeling of bone in other regions. Hyperplasia and hypertrophy of tissue have also occurred, in
which mechanical strains have increased due to the presence of
Chemical Bonding of Bone to Biomaterial Previous an implant.
investigations have provided evidence of bone bonding to
many different types of calcium phosphate materials, calcium CRITERIA FOR TISSUE RESPONSE. The in vivo assessment
carbonate substances, and calcium-containing "bioactive" of tissue compatibility of biomaterials requires that certain
glasses.Chemical bonding was evidenced by the high strength criteria be implemented for determining the acceptability of
of the implant-bone interface, which could not be explained by the tissue response relative to the intended application of the
a mechanical interlocking bond alone. In addition, electron material or device. The biomaterial or device should be
microscopy has shown that no identifiable border exists be- considered biocompatible only in this context. Every study
tween these calcium-containing implants and adjacent bone. involving the in vivo assessment of tissue compatibility should
Many recent studies have investigated the bonding of bone provide a working definition ofbiocompatibility.
to one particular calcium phosphate mineral, hydroxyapatite. Biomaterials and devices implanted into bone can become
This was chosen because of its relationship to the primary apposed by the regenerating osseous tissue and thus can be
mineral constituent of bone; natural bone mineral is a calcium- considered compatible with bone regeneration. Altered bone
deficient carbonate apatite. Experiments have been performed remodeling around the device caused by stress shielding, with a
on both hydroxyapatite-coated metallic implants and on partic- net loss of bone mass (i.e., osteopenia), could lead to the
ulate and block forms of the mineral used as bone substitute assessment that the material or device is not compatible with
materials. Histology of specimens shows that a layer of new normal bone remodeling. When the implant is surrounded by
bone approximately 100 ~m in thickness covers most of the fibrous tissue, macrophages appearing on the material's surface
hydroxyapatite sutface within a few weeks of implantation and are the expected response to the dead space produced by the
remains indefinitely. This layer of bone is attached to the implant. The synovial tissue thus produced might be consid-
surrounding osseous tissue by trabecular bridges. ered an acceptable response relative to the material's chemical
In studying the mechanism of bone bonding, researchers compatibility. Using the thickness of the scar capsule around
have found that within days of implantation, biologic apatites implants alone as a measure of biocompatibility is problematic
precipitate (from body fluid) onto the surface of the calcium- because it can be influenced by tissue movement at the site
containing implants. These biologic apatites are comparable to relative to the implant.
the carbonate apatite of bone mineral. Proteins probably adsorb The cellular and molecular makeup of tissue and the inter-
to this biologic mineral layer, thereby facilitating bone cell actions among these components are complex. Criteria for
attachment and the production of osteoid directly onto the assessing certain features of the biocompatibility ofbiomaterials
implant. This osteoid subsequently undergoes mineralization, and devices should focus on specific aspects of the biologic
as it does normally in osteogenesis, thus forming a continuum response. Importantly, materials yielding acceptable tissue
of mineral from the implant to the bone. The bone cell re- compatibility in one site of implantation might yield unfavor-
sponds to the biologic apatite layer that has formed on the able results in another site.
implant and not directly to the implant itself.
Recent studies have shown that this biologic apatite layer Degeneration of Biomaterial-Tissue Interface
forms on many different calcium phosphate substances, ex- As noted earlier, the wound healing response initially estab-
plaining why bone-bonding behavior has been reported for lishes the tissue characteristics of the implant-tissue interface.
many different types of calcium phosphate materials. The clin- Several agents can initiate degenerative changes in the interface
ical value of this phenomenon will depend on the following: tissue. Other agents probably act as promoters to stimulate the
1. For coatings, how well these substances can be bonded production of proinflammatory mediators that stimulate tissue
to implants degradation and potentiate the failure process.
2. For bone graft substitute materials, their strength, Of the many factors affecting the implant-tissue interface,
modulus of elasticity, and ability to be resorbed two of the most important are motion of the prosthetic compo-
The finding that bone can become chemically bonded to nent and particulate debris. It is difficult, however, to deter-
certain biomaterials, however, is a significant advance in under- mine the causal relationships between these factors and implant
standing the implant-bone interface. failure from studying only the end-stage tissue. Other histo-
pathologic findings and laboratory studies indicate that metal
IMPLANT-INDUCED ALTERATIONS. The presence of the ions and immune reactions might play roles in the degenerative
implant can alter the stress distribution in the extracellular processes leading to prosthesis loosening in certain patients.
matrix and thereby reduce or increase the strains experienced Systemic diseases and drugs used to treat the disorders could
by the constituent cells. Many studies have demonstrated also contribute to the breakdown of the implant-bone interface.
248 PART I PRINCIPLES AND TECHNIQUES

Finally, interindividual differences in genetically determined histopathologic studies of tissues from human subjects have
cellular responses might explain why prostheses fail in some suggested that titanium alloy is more "biocompatible" than
patients with a low mechanical risk factor for failure. cobalt-chromium alloys. Therefore researchers assumed that
titanium particulate debris would be less problematic than
EFFECTS OF IMPLANT MOVEMENT. Movement of the particles of cobalt-chromium alloy. Histology of pigmented
implant relative to the surrounding tissue can interfere with the tissue surrounding titanium implants has generally revealed
wound healing response by disrupting the granulation tissue. considerably fewer macrophages and multinucleated foreign
With bone implants this relative movement, if excessive, can body giant cells than around cobalt-chromium alloy particles
destroy the stroma required for osseous regeneration, and a and polymeric particulate debris. However, titanium alloy
fibrous scar results. particles generated by the abrasion of femoral stems against
Another important effect of implant motion is the forma- bone cement in human subjects can cause histiocytic and
tion of a bursa within connective tissue, in which shearing and lymphoplasmacytic reactions to the metallic particles. 1 Tita-
tensile movement has led to disruption of tissue continuity and nium particles have also been found to cause fibroblasts in
formation of a void space or sac (lined by synovial-like cells). culture to produce elevated levels of prostaglandin £2 (PGE2).
Therefore the tissue around prosthetic components that are These findings show that adverse effects may occur with the
removed because of loosening might display features of biologic response to titanium particles as well as to cobalt-
synovial-like tissue. The presence of synovial cells (macrophage chromium alloy particulate debris.
and fibroblast-like cells) is important because they could be Many investigations evaluating the histologic response to
activated by other agents, such as particulate debris, to produce polyethylene and PMMA particles in animals and in tissue
proinflammatoty molecules. The process of activation of this recovered from revision surgery have revealed the histiocytic
tissue might be similar to that occurring in inflammatory joint response to these polymer particles. This macrophage response
synovium or bursitis. can also lead to bone resorption.
Previous studies explain how prosthetic motion leads to the Synovial cells also respond to calcium-containing ceramic
formation of the synovial-like tissue by showing that "synovial particles.79 Local leukocyte influx, proteinase, PGE2, and
lining is simply an accretion of macrophages and fibroblasts tumor necrosis factor (TNF) levels have been measured after
stimulated by mechanical cavitation of connective tissue.,,36 injection of calcium-containing ceramic materials into the
These findings are based on experiments in which the mechan- "air-pouch model" described earlier. TNF was detected in
ical disruption of connective tissue was produced by injection significant amounts after injection of the ceramics. These
of air and fluid into the subcutaneous space of animals.94 The substances also caused elevated leukocyte counts and increased
resulting sac was initially described as a "granuloma pouch." levels of proteinase and PGE2. Substances with surface chemis-
Later studies demonstrated that the membrane lining the tries that elicit a beneficial tissue response (e.g., bone bonding)
pouch displayed the characteristics of synovium, and this tissue when implanted in bulk form can cause destructive cellular
was referred to as "facsimile synovium."36 reactions when present in particulate form.
Prosthetic motion can also contribute to wear of the pros- Investigations indicate that most biomaterials, when pre-
thetic component abrading against the bone cement sheath or sent in particulate form in a size range small enough to be
surrounding bone. This generates increased amounts of partic- phagocytosed (less than 10 11m), can elicit a biologic response
ulate debris, which might contribute to activation of the mac- that could cause the bone resorption that initiates and promotes
rophages and synovial-like cells at the implant-tissue interface. the loosening process. This degenerative process has been re-
ferred to as small-particle disease.
EFFECTS OF IMPLANT-DERIVED PARTICLES. Particu-
late debris can be generated from the abrasion of the implant METALLIC IONS. Animal and human investigations have
against surrounding tissue. The potential for wear is greater revealed elevated levels of metal ions in subjects with certain
with materials or devices rubbing against a hard surface such as types of implants (e.g., total joint replacement prostheses). The
bone and with the articulating components of joint replace- mechanisms of metal ion release are still being studied, and
ment prostheses. This particulate debris can induce changes in results often vary when determining the concentration of
the tissue around the implants. Adverse responses have been specific metal ions in tissues and fluids. Metal in ionic form is
found to both metallic and polymeric particles. often not distinguished from that present as particles, which
The biologic reactions to particles are related to (1) particle confounds interpretation of results.
size, (2) quantity, (3) chemistry, (4) topography, and (5) shape. Serum and urinary chromium levels increase in patients
Although the role that each of these factors play in the biologic who have undergone conventional cemented cobalt-chromium
response is unclear, particle size appears to be particularly alloy hip replacement.6 An attempt to determine the valency of
important. Particles small enough to be phagocytosed (less chromium as either +3 (III) or +6 (VI) from the metal ion
than 10 11m) elicit more of an adverse cellular response than concentration in a blood clot was not successful. This experi-
larger particles. ment was based on erythrocytes displaying a unidirectional
Particulate metallic particles (e.g., cobalt-chromium alloy) uptake of Cr (VI) while effectively excluding Cr (III). The
can induce rapid proliferation of macrophages and focal distinction of the valency of chromium is important because Cr
degeneration of synovial tissues.49 Animal investigations and (VI) is much more biologically active than Cr (III).
CHAPTER19 Biomaterials 249

Unfortunately, our knowledge of the local and systemic lymph nodes and many organs. The spread of particles from
biologic and clinical sequelae of metal ion release has not silicone elastomer and liquid droplets (e.g., from breast
significantly advanced over the past several years. Addition implants) is well documented.104 The translocation of these
of cobalt ions in the form of cobalt fluoride solutions to the particles results from the following:
media of synovial cells can stimulate their production of 1. Migration through soft tissues
neutral proteinases and collagenase.37 These findings may be 2. Entry into the lymphatic system
relevant to tissue degradation (e.g., osteolysis) around im- 3. Direct entry into the vascular system.
plants, since metal ions could activate synovial cells in the Silicone particles have been found to migrate from breast
surrounding synovial tissue to produce agents that promote implants through soft tissue to sites as distant as the groin.20
tissue degeneration. The finding of silicone lymphadenopathy in axillary lymph
nodes is common in patients with breast implants.105 The
DISEASES AND DRUGS. Implant failure has not been well hematogenous dissemination of silicone to viscera has also been
correlated with disease states and drugs used to treat the reported as a result of soft tissue injection of the material. 104In
disorders. Some observations indicate that antiinflammatory the orthopedic literature, silicone lymphadenopathy has be-
agents, as well as certain anticancer drugs, can reduce the come a common finding in patients receiving finger joint
amount of bone formation around devices in the early stages of prostheses made of silicone elastomer.24
wound healing after implantation. Little is known, however, Reports documenting dissemination of particles in the
about the role of these and other agents on tissue remodeling lymphatic system from total joint prostheses are mounting,
and degeneration at the biomaterial-tissue interface. suggesting that this phenomenon may be more common
than previously thought. Several animal studies have docu-
Systemic Response to Particulate Debris mented lymphatic spread of polyethylene particles to regional
Local and regional lymphadenopathy caused by wear particles nodes.69.112 Bos et al14 recently provided evidence from
released from implants is becoming increasingly recognized human autopsies that polyethylene, PMMA, and metal
as a possible complication with certain prostheses. Particles particles released from stable total hip replacements spread to
generated by mechanical wear of prostheses can leave the site of inguinal, parailiac, and paraaortic lymph nodes as early as
the implant via the lymphatics and become engulfed by 1112years after implantation of the prosthesis.
macrophages within local and regional lymph nodes. Accumu- Sinus histiocytosis in association with wear particles of
lation of cells containing particles causes enlargement of the polyethylene has been an incidental finding in lymph nodes
lymph node and the characteristic histologic appearance of biopsied at revision arthroplasri9 and in the staging of pros-
sinus histiocytosis.44 tate7.44 and breast cancer.86 Adenopathy related to an implant
Distension and prominence of the lymphatic sinuses result is not limited to total hip and knee replacement prostheses.
from large numbers of (1) histiocytes derived from the cells that Axillary histiocytic lymphadenopathy was reported in associa-
line the sinuses or (2) macrophages derived from circulating tion with polyethylene wear particles from a total shoulder
monocyres. Multinucleated giant cells, resulting from the fu- replacement.86
sion of macrophages or histiocytes, may also be found in the
dilated sinuses. CliNICAL IMPliCATIONS. Lymphadenopathy secondary
Accumulation of polyethylene, PMMA, and metal particles to the accumulation of wear particles in sinus macrophages
in lymph nodes draining joints replaced with prostheses has may make the appropriate diagnosis difficult, especially when
been found in animal69.112and human studies.7.14.47.57Some malignancy is suspected. For example, a 19-year-old man had
have reported lymphadenopathy in surgical patients.44.86.95 right inguinal pain and a 3-cm2 palpable mass 3 years after
With joint replacement prostheses, synovial macrophages a right total knee replacement following resection of an
readily engulf particles released into the joint space. When the osteosarcoma.95 The lymph node was biopsied to evaluate for
production of particulate debris exceeds the phagocytic capac- suspected metastatic recurrence of osteosarcoma. Histologic
ity of synovial macrophages, excess particles enter lymphatic examination revealed sinus histiocytosis caused by metal par- '
vessels.1l4 Evidence indicates that macrophages laden with ticles released from the knee prosthesis. The patient had no
particles can also gain entry to the lymphatics.46 Macrophages evidence of malignancy.
present within lymph nodes endocytose free particles traveling The ultimate fate of particles released from total joint
within the lymphatic system. A steady influx of wear debris prostheses is unknown. A recent report suggests that metallic
causesthese macrophages to accumulate within the sinus of the particles from orthopedic prostheses may pass through the
lymph node.14 Over several years, macrophages with particles lymphatics and gain a systemic distribution. 57
may become so abundant that they cause dilation of nodal
sinusesand nodal enlargement. As mentioned, accumulation of Immune Reactions and Genetic Determinants
histiocyres or macrophages within lymph node sinuses is de- Two patients matched for gender, age, weight, activity level,
scribedpathologically as sinus histiocytosis. and other factors that might affect prosthesis performance
often have very different outcomes. This suggests that immune
SYSTEMICMIGRATION OF PARTICLES. Numerous stud- reactions or genetically determined responses might playa role
iesreport the migration of particles, released from implants, to in the failure of prostheses in some patients.
250 PART I PRINCIPLES AND TECHNIQUES

Immune responses include antibody and cell-mediated Fortunately, reports of neoplasms around implanted devices
reactions and activation of the complement system. Certain (e.g., total joint replacement prostheses) have been few.
metal ions can behave as haptens, which can trigger an Although no causal relationship has been shown, the index of
immune response when complexed with serum proteins. The suspicion is high enough to warrant serious investigation
cell types that might be expected to occur at sites of antibody through epidemiologic and other studies. The use of porous
and cell-mediated reactions, however, are not otten found in coated metallic devices (e.g., noncemented total joint replace-
tissue retrieved. These cells include lymphocytes and plasma ment prostheses with large surface area) in younger patients has
cells. The finding of occasional lymphocytic infiltrates in tissue added to the concern aboUt the long-term clinical conse-
around implants does not provide enough information. quences of metal ion release.
Immune reactions to polymeric materials (e.g., silicone) have The relationship of metallic ion release to oncogenesis1z and
also been suggested as the cause of certain systemic diseases, reports of neoplasms around orthopedic implants have been
but mechanisms for such a response, as well as its prevalence, reviewed.68 Differences in the tumor types, time to appearance,
remain in question. Much more work is necessaty to determine and type of prosthesis confound attempts to associate the
the role of immune reactions in the response to implantable neoplasm with the implant materials and released moieties.
devices. In an epidemiologic investigation in New Zealand, more
Previous studies have demonstrated that many biomateri- than 1300 total joint replacement patients were followed to
als can activate (cleave) certain molecules (C3 and C5) in the determine the incidence of tumors at remote sites.43 The inci-
complement system and thereby stimulate the alternative path- dence of neoplasms in the lymphatic and hemopoietic systems
way of the immune response. Complement activation by bio- was found to be significantly greater than expected in the
materials may playa role in adverse reactions to certain devices. decade after arthroplasty. Importantly, the incidence of cancer
Again, however, additional studies are required. of the breast, colon, and rectum was significantly less than
One form of cell-mediated immune reaction associated expected. The investigators acknowledged that although the
with implants that has been studied is the delayed hypersensitiv- association might be an effect of the prosthetic implants, other
ity response."Metal allergy" has been incriminated as the cause mechanisms, particularly drug therapy, require consideration.
of failure in certain patients,72 but results are not yet definitive. Somewhat similar results were obtained from another study
"The incidence of metal sensitivity in the normal population is of the cancer incidence in 443 patients who had total hip
nlgn, witn up to 1'5% o{tne population sensitive to nicKel'and' repl'acement (McKee-Farrar) oerween 1967 ana 1973 ana were
perhaps up to 25% sensitive to at least one of the common followed through 1981. The risk ofleukemias and lymphomas
sensitizers Ni, Co, and Cr. The incidence of metal sensitivity increased, whereas the risk of breast cancer decreased. The
reactions requiring premature removal of an orthopedic device authors concluded that the local occurrence of cancer associ-
is probably small (less than the incidence of infection). Clearly ated with Co-Cr-Mo prostheses indicates that "chrome-cobalt-
there are factors not yet understood that caused one patient but alloy plays some role in cancerogenesis (Sic).,,109
not another to react. "71
A similar situation exists with respect to sensitivity reactions Bacterial Infection
to polymeric materials, including bone cement (PMMA). The Under certain circumstances, biomaterial surfaces can provide
monomer of PMMA is a strong skin sensitizer.7o Failure of favorable substrates for the colonization of bacteria. The adher-
cemented devices, however, has not yet been correlated with a ence of bacteria to solid surfaces is facilitated by their produc-
hypersensitivity response in patients. tion of a biofilm. The biofilm is a complex structure comprising
No clear etiology exists for prosthesis loosening in some bacterial cells encapsulated in a polymeric matrix. The detailed
patients, and in others with multiple risk factors for failure the composition of the matrix has yet to be determined. Cettain
prosthesis functions well. Therefore some suggest that genetic biomaterials may favor the production and adherence of a
determinants may be responsible for loosening. biofilm, and certain material characteristics may predispose to
One investigation has shown interindividual differences in bacterial colonization. Studies are underway to understand
the in vitro cytokine and PGEz production by lipopolysac- these processes.
charide-stimulated macrophages.77 HLA-DRz-positive indi-
viduals and first-degree relatives were found to be low respond-
ers. Such studies suggest that in certain individuals, genetic BIOMATERIALFAILURE
determination might affect the degree to which cells in the
tissue around prostheses can be activated to produce proinfIam- Potential causes of failure of implanted devices include the
matory agents that stimulate tissue degradation. Additional following:
studies could help identify patients who might be high re- 1. Deficiencies in design of the device for a particular
sponders to prosthetic motion and particulate debris and there- patient
fore at high risk for prosthesis failure. 2. Surgical problems (e.g., problematic orientation and
excessive surgical trauma leading to problems in wound
Carcinogenicity healing)
Chromium and nickel are known carcinogens, and cobalt is a 3. Host abnormalities and diseases
suspected carcinogen. Therefore the release of these metal ions 4. Infections
into the human body from implants might raise some concern. 5. Biomaterial fracture, wear, and corrosion
CHAPTER19 Biomaterials 251

In what cases has the failure of the biomaterial initiated the strength of the atomic bonding in one of the two contact-
failure of the device? It is difficult to determine whether ing materials. When the two surfaces separate, fracture
breakdown of one or more biomaterials used in the fabrication occurs within the material, leading to loss of a transferred
of a particular prosthesis was the primary cause of the system fragment.
failure or secondary to other factors. Diagnostic imaging In adhesive wear the amount of material lost is generally
methods such as radiography and computed tomography directly proportional to the applied load and to the distance
rarely provide evidence of biomaterial failure early enough slid. In many material systems the amount of wear is inversely
for it to be identified as the primary cause of implant failure. proportional to the hardness of the surface being worn away.
Recovery of the device and surrounding tissue at revision These relationships are incorporated in the following equation:
surgery provides limited information about the initiating kWL
causes of failure.
V.dh= H
All the materials used to fabricate devices have finite "fatigue
lives" (i.e., failure as a result of cyclic loading). Unfortunately, v..dhis volume of adhesive wear, and k is a dimensionless wear
the endurance limit for many implantable devices or the mag- coefficient related to the probability of particle formation, or
nitude of the applied stress is not known. How does the device's the fraction of adhesive junctions that eventually produces
serviceable life relate to the patient's longevity. wear particles; k is generally less than 0.1 (i.e., only one of 10
The introduction of the "supermetals" virtually eliminated adhesive junctions results in a wear particle). W is the load
concerns about breakage of metallic devices. Corrosion can perpendicular to the surface; L is the distance through which
occur, but only rarely is it the initiating cause of device failure. the surfaces slid; and H is the indention hardness of the softer
Wear, however, is clearly the principal cause of failure in material.
certain articulating devices (e.g., joint replacement prostheses) Abrasive wear results when asperities on one material plow
and can occur to some extent in soft tissue implants. material from a softer contacting surface (Figure 19-4). The
Breakdown of a biomaterial does not necessarily cause the loss of material that occurs as two surfaces contact is referred
immediate failure of a device. In fact, biomaterial failure might to as two-body wear. When a third substance is interposed
be considered an ongoing process. It becomes clinically between the two surfaces, the process is three-body wear. The
important when it is the initiating cause of failure or accelerates following equation has been used to evaluate the volume of
a degenerative process initiated by other factors. material lost in abrasive wear:
WL
Wear
V.br= H p tan e
Wear is generally defined as the loss of material from solid
surfaces as a result of mechanical action. Several mechanisms
can contribute to wear. In each case, fracture through the
substance (i.e., loss of cohesive bonding) must occur for a
fragment of the material to be removed from the surface. The
Table 19-1.
three main mechanisms of wear are (1) adhesive wear, Wear Processes
(2) abrasive wear, and (3) fatigue wear.
Adhesive wear occurs when the force of adhesion between TYPE MECHANISM PART SIZE

contacting surfaces exceeds the cohesive force within one of Adhesive Chemical
the materials. When two surfaces come into contact, atomic nm to !!m
adhesion
bonding can occur between the materials (Figure 19-4 and
Table 19-1). Generally, when the surfaces separate, this bond is Abrasive (two Plowing of
broken. In some cases, however, this bond strength exceeds the body) asperity
through
softer
Harder material material

Abrasive (three Entrapment and


body) plowing of
particle
Fatigue Propagation of !!m to mm
(delamination) subsurface
cracks to
surface by
Softer material cyclic
Crack propagated by
fatigue {delamination} wear compression.
tension, or
Figure 19-4. Processes in adhesive, abrasive. and fatigue shear
(delamination)wear.
252 PART I PRINCIPLESAND TECHNIQUES

v..br is the volume of abrasive wear, and e is one-half the The following reaction describes the ion transfer
included angle of the asperity of the harder material plowing Mn+aqueousinto solution (i.e., the corrosion) that occurs when
through (i.e., abrading) the softer material. Tan e is very small a metal is immersed in an electrolyte solution. Electrons, freed
for sharp aperities, leading to high wear volume. as the metal ions enter solution from one region of the speci-
Fatigue wear results from repeated loading of contacting men (the anode), travel to other regions of the same specimen,
surfaces. The cyclic stresses initiate or propagate surface or making those areas cathodic. If the metallic sample is connected
subsurface cracks (Figure 19-4). This process eventually leads to (e.g., touching) another metal specimen with less of a ten-
to the loss of relatively large fragments of material. dency for corrosion, the second metallic specimen becomes the
The term fretting wear is used to describe the loss of material cathode (Figure 19-5). Corrosion of the anode can be acceler-
&om contacting surfaces undergoing oscillatory tangential ated by increasing the rate of reaction at the cathode.
displacement of small magnitude (micrometers). The loss of
material from fretting wear is the result of adhesive or abra- Anodic reaction
sive wear.
M ~ Mn+ aqueow + ne- metal
Another form of wear involves the process of corrosion. The
oxide passivation layer on metals may be lost as a result of a Cathodic reactiom

wear process. The removal of this film may accelerate the Reduction of dissolved oxygen
corrosion process and lead to alterations in the oxide layer. n (I n
These alterations may include an increase in rugosity (surface 1: \2 O2 + 1: H20 + ne-metal ~ nOfr
) aqueous
roughness), which can promote abrasive wear of the opposing
surface.
Reduction of hydrogen ions
n
Corrosion nW+ne- ~-H2
2
Whereas wear is the loss of solid fragments from surfaces as a
result of mechanical action, corrosion is release of ions and
compounds as a result of chemical action. Relatively little is
known about the mechanisms underlying the corrosion of
u'CItlMecan\\:;-sao'sram:es.-
tfi'e r611~wlligalSCUSSll'mtocuses on Table 19-2.
corrosion of metallic substances.
Electrochemical Series of Metals with Normal
Although they are relatively inert, metals are soluble in
Electrode Potentials*
aqueous solUtions. Metal leaves the solid metallic state to form
aqueous cations in electrolyte solutions (Mn+aqueousin follow- METAL ELECTRODE POTENTIAL (V)
ing reaction). Passivation, the formation of an insoluble salt
(oxide) on pure metals and metal alloys, inhibits metal egress NOBLE END
and thus inhibits corrosion. This layer selVes to protect the Gold +1.45
metal by insulating it from the electrolyte solution. A chro-
mium oxide passivation layer forms on stainless steel and Platinum + 1.20
cobalt-chromium alloy. A titanium oxide layer forms on tita- Silver +0.80
nium and titanium alloys.
The electrochemicalseries(or galvanic series) of metals rates Copper +0.34
the relative tendencies of metal ions to go into solution (Table Hydrogen 0.00
19-2). This classification of metals, however, does not consider
the effect of an oxide layer on the metal's surface. The electro- Molybdenum -0.20
chemical series shows that metallic elements such as gold are Nickel -0.25
relatively insoluble, whereas substances such as titanium and
aluminum, when present in pure elemental form, are relatively Cobalt -0.28
soluble (and active). When these same reactive metallic ele- Iron -0.44
ments are covered by their oxide layers, however, these metals
tend much less to go into aqueous solution. Chromium -0.73
Titanium is a more active element than chromium; titanium Titanium -1.63
and its alloys form oxide passivation layers more rapidly than do
substances containing chromium (i.e., cobalt-chromium alloy Aluminum -1.66
and stainless steel). Although an active metal such as titanium Magnesium -2.37
forms its oxide passivation layer spontaneously in any environ-
ment containing oxygen, however, the strength of adhesion of Lithium -3.05
the oxide layer to the underlying titanium metal is not as great ACTIVE END
as that of the chromium oxide layer to its metal substrate. In
addition, the chromium oxide passivation film is more dense *Measured in volts at 25° C (77° F). referred to hydrogen as zero.

than the titanium oxide layer.


CHAPTER 19 Biomaterials 253

The mechanisms controlling corrosion processes relate to The mechanisms of corrosion referred to as pitting, crevice,
factors that favor either the anodic reaction or the cathodic and depletion relate to situations in which oxygen is relatively
reactions. Factors that assist electron transfer from the metal depleted at certain sites on a metal implant (Figure 19-6).
would facilitate the anodic reaction, whereas changes in oxygen These sites take on an anodic character, favoring metal ion
concentration at sites along the metallic surface would facilitate release. Salts can accumulate at the sites of scratches produced
the cathodic reaction. by instruments at insertion. The depletion of oxygen at these
sites can lead to corrosion, resulting in pitting of the surface.
The low oxygen concentration at the bottom of the pits favors
continuing corrosion.
Crevices formed at the sites where components are joined
(e.g., in modular components of prostheses or at screw-plate
junctions) also create a microenvironment favorable to corro-
sion as a result of depleted oxygen (Figure 19-7). The depletion
00 of oxygen can also occur under plaques of biologic debris on the
00
surface of devices, thus also predisposing to a so-called concen-
+ tration cell corrosion mechanism.
Active
+ ~n How -0~1 Passive
"0 Another basic mechanism of corrosion can occur when
metal + metal
dissimilar metals touch. The tendencies of electrons to move
(anodic, + _0 (cathodic,
0- reduction) from the more active metal to the more noble metal causes the
oxidation)
+ former to become anodic, thereby producing conditions that
+ +
would favor accelerated corrosion. This mechanism of corro-
Electrolyte
sion has been referred to asgalvanic, two-metal, mixed-metal, or
couple corrosion. The degree of galvanic corrosion depends on
Figure 19- 5. "Concentration cell" depicting types of reactions the electrochemical nature of the tWo metals and the relative
incorrosion of metals.
areas of contact and surfaces exposed to the solution.
The term galvanic corrosion is derived from an observation
made by Galvani in 1791 as he was investigating the suscepti-
Depletion
bility of nerves to irritation. He found that if a rod of brass
contacted the frog's foot while a silver rod contacted the spinal
cord, the leg muscles contracted when the free ends of the rods
toucned. In 1800 Vofta confirmed that the force that provoked
I the contraction was electrical in nature. The electric current
- /" - \ Anodic ),'- '" I" generated by contact of dissimilar metals in an electrolyte
" -
"- solution is referred to as galvanic current.
1

/ /
" I In certain situations the breakdown of material is caused by
/
1

Metal I / mechanical and chemical processes acting in concert. These


/ -
" / - "I
mechanochemical processes include (1) fretting corrosion,
(2) stress corrosion, and (3) metallic transfer (with subsequent
galvanic corrosion).
Figure 19-6. Propensity of oxygen-deleted regions to corro- Fretting corrosion is a process in which abrasive wear is
sionon metallicsurfaces. accompanied by corrosion. The protective oxide layer on the

Crevice
'\ /
\
/
I Metal
/' , - -
~'- ' 'I ~""'ofh;gh
A,,,,,of low 0 ~ ><yge"","","trot;O" 0
oxygen concentration 0 0 0 0 0 0o0 8 000
0

.
"-

~O . "--
,
/ ~00000008
' , (') 000 0" n
"-

....
"
\ Metal \ / \
/
, /
/ '\
"-

"

Figure 19-7. Crevices in which oxygen concentration is lower than that around metallic device
are predisposed to corrosion.
254 PART I PRINCIPLES AND TECHNIQUES

metal is removed by abrasive wear. The new passivation layer cades of investigation of wound healing and treatments imple-
that forms after abrasion is not as durable or chemically inert as menting absorbable implants.
the original layer, thereby making the metal more susceptible
to corrosion. Stainless steel and cobalt-chromium alloys are In Vivo Versus In Vitro Strategies
susceptible to fretting corrosion. This form of corrosion often Just as they are the three components of tissue, the matrix,
occurs between screw heads and bone plates. cells, and soluble regulators are primary elements in strategies
Stress corrosion is the process by which the presence of an to engineer tissue in vivo or in vitro for subsequent implanta-
electrolyte decreases the strength of the metal. Microcracks tion. Decisions aboUt which elements might be required for
develop at anodic areas of the metallic device as the result of regeneration of tissue in vivo can be guided by an understand-
corrosion processes. These cracks propagate under applied ing of the deficits of the natural (i.e., spontaneous) healing
stress. The tips of these microcracks are at a more highly processes that prevent regeneration.
strained state than surrounding metal and are more susceptible An advantage of tissue synthesis in vitro is the ready ability
to corrosion, which contributes to crack propagation. to examine the material as it is formed and to make certain
.ABdissimilar metals come in contact, metallic tramfer of measurements to establish its functions before implantation. A
small fragments of the softer metal can occur to the harder one. disadvantage, particularly in the production of tissues that
.AB these two metals remain in contact, galvanic corrosion must playa load-bearing role, is the absence of a physiologic
processes may develop. Therefore implants should be handled mechanical environment during the formation of the tissue in
with instruments made of the same metal as the device. vitro. Mechanical force serves as a critical regulator of cell
Several methods are available to assess the predisposition of function and can profoundly influence the architecture of
metals to corrosion. A simple method involves weighing the tissue as it is forming.21.93 Because the mechanical environ-
specimen after exposure to corrosive environments and assay- ment extant during formation of most load-bearing tissue in
ing the bathing electrolyte solution for corrosion products. An vivo is not well understood, it is not yet possible to recreate
electrochemical method that has been valuable in characteriz- such an environment in vitro during the engineering of most
ing the potential of metals to corrode is anodic polarization. In tissues.
this experimental procedure the test metal is the anode of an Another disadvantage in the formation of load-bearing tis-
electrolytic cell. An increasing voltage is applied between it and sue oUtside the body is the necessary incorporation of the tissues
a reference cathode (usually platinum). The current demity after implantation, which requires that the engineered tissue be
(current divided by cross-sectional area of the anode) is a mechanically coupled to the surrounding structures. Union of
measure of the corrosion rate of the anodic metal in the partic- the implanted tissue with the host organ requires remodeling
ular electrolyte used. (degradation and new tissue formation) at the interfaces of the
Table 19-2 shows the electrochemical potentials and ten- implant with the host tissues. Remodeling of implanted tissue
dency for corrosion (i.e., current density) for the orthopedic engineered in vitro is essential for its functional incorporation.
alloys. The current density for titanium alloy is significantly less This demonstrates the benefit of de novo regeneration in vivo,
than that of the cobalt-chromium alloy and stainless steel, with the incorporation occurring as the tissue is being formed.
indicating that titanium and its alloys have much less of a Thus, for certain tissues, an effective strategy may be to
tendency for corrosion. Because the release of metal depends on facilitate tissue formation in vivo, under the influence of the
surface area, a greater amount of metal is released from porous physiologic mechanical environment. One disadvantage of
metal specimens. this approach, however, is that the regenerating tissue may be
dislodged or degraded by the mechanical forces normally
acting at the site, before it is fully formed and incorporated.
BIOMATERIALSFOR TISSUE ENGINEERING
Matrices
The wound healing process in many types of lesions in Matrices for engineering bone and soft connective tissues have
connective tissues does not lead to spontaneous regeneration; included synthetic and natural calcium phosphates51.60 and
the end result is often a dysfunctional scar. Recent research has many synthetic (e.g., polylactic acid,25.76 PGA,40.56) and
shown that some cells can proliferate and maintain their natural polymers (e.g., collagen,81.102 fibrin48,52). Material
phenotype when cultured on certain two-dimensional sub- used in the fabrication of matrices for engineering tissue in
strates or in specific three-dimensional porous matrices and vitro or used as implants to facilitate generation in vivo must
gels in vitro. This has formed the basis for tissue engineering, have the necessary microstructure and chemical composition
with the promise of forming tissues in vitro for subsequent to accommodate parenchymal cells and their functions. In this
implantation. regard a porous structure is generally needed. The required
Initially, "tissue engineering" was used principally to de- percentage of porosity and the pore diameter, distribution, and
scribe tissue produced in culture by cells seeded in porous orientation may vary with tissue type. Moreover, because the
absorbable matrices. 55 More recently, however, the scope of objective is the regeneration of the original tissue, the scaffold
tissue engineering has been widened to include the implemen- needs to be absorbable.
tation of porous matrices, alone or seeded with cells, as implants The chemical composition of the matrix is important with
to facilitate tissue regeneration in vivo. This enfranchises de- respect to its influence on cell adhesion and the phenotypic
CHAPTER 19 Biomaterials 255

expression of the infiltrating cells. The degradation rate of the logic demands of the tissue. For scaffolds in regeneration of
material generally may be determined based on the rate of new bone, this approach has led to the use of natural bone mineral
tissue formation and the normal period for tissue remodeling produced by removing the organic matter of bovine bone. *
at the implantation site. It is important to consider the effects The calcium-deficient carbonated apatite, which constitutes
of moieties released during matrix degradation on the host and the mineral phase of bone, and the unique microstructure
regenerating tissue. of the ECM of bone are determined by the organic template
A matrix can play the following roles during the process of of collagen and the initial release of calcium phosphate-
regeneration in vivo: containing vesicles from osteoblasts. This largely explains why
1. The matrix can structurally reinforce the defect site to bone mineral cannot be replicated in the laboratory.
maintain the shape of the defect and prevent distortion Several synthetic and natural polymers have been used in
of surrounding tissue. For example, cysts that form in the development of implants for the treatment oflesions in soft
the subchondral bone underlying the articulating sur- connective tissues. For example, with cartilage defects, PGA
faces of joints can lead to collapse of the joint surface. and PGA-polylactic acid blends30.106 and natural polymers,
2. The matrix can serve as a barrier to the ingress of including fibrin,48 collagen gel 110and sponge,102 and hyaluro-
surrounding tissue that may impede the process of nan, 58 have been seeded with chondrocytes in studies in vitro
regeneration. The concept of guided tissue regeneration and in vivo.
is based in part on the prevention of overlying gingival The approach of using analogs of ECM as implants for the
tissue from collapsing into the periodontal defect.32 regeneration of the soft connective tissue and nerve has
3. The matrix can serve as a scaffold for migration and employed porous collagen-glycosaminoglycan (GAG) copoly-
proliferation of cells in vivo or for cells seeded in vitro. mers. Regeneration of dermis in animals and human sub-
4. The matrix can serve as an insoluble regulator of cell jectsI8.115.116.118
. and reconnection ofaxons of cells in ruptured
. 23 II6 120 . .. .
function through its interaction with certain integrins penp h eraI nerves m rats' . reqUire certam tIssue-specl fic
and other cell receptors. pore characteristics and degradation rate. To produce these
One class of properties that is likely to play an especially materials, collagen is precipitated from acid dispersion in the
important role in the engineering of load-bearing tissues is presence of chondroitin-6-sulfate.II9 The suspended copre-
mechanical properties. Design specifications for several bone cipitate suspension is injected into a silicone tube (3.8 mm
graft substitute materials have included the strength of the inside diameter), or it is spread on a pan for immersion into a
matrix material, with the principal objective of employing coolant bath and freeze-dried, to produce a porous architec-
high-strength substances for immediate load bearing. Syn- ture. The matrices are then exposed to a dehydrothermal
thetic calcium phosphate ceramics were implemented as matrix treatment or to ultraviolet light for cross-linking and steriliza-
materials to facilitate bone regeneration in vivo. 17.33 tion. Additional cross-linking can be achieved using aldehydes
Besides possessing high strength, however, some of these or other cross-linking agents. These collagen-GAG matrices
materials also have a high modulus of elasticity, making them are nominally 95% porous and can be produced with an
extremely stiff structures. The disadvantage of this extreme average pore diameter of 30 to 120 ~m.
stiffnessis that the presence of the material greatly alters the
distribution of mechanical forces in surrounding tissue and CALCIUM PHOSPHATE AND BONE GRAFf SUBSTI-
thus adversely affects the stress-induced remodeling of neigh- TUTE MATERIALS. Although some polymers have been in-
boring bone. Because many materials of this class of matrix are vestigated as matrices to be used as implants to facilitate bone
essentially nonresorbable, the adverse effects on remodeling regeneration, most materials comprise calcium-containing sub-
will persist indefinitely. This remodeling can result in os- stances. Calcium sulfate88 and tricalcium phosphateI9.31.78.84
teopenic regions around the implanted site, increasing the risk were two of the calcium-containing substances first imple-
of fracture. Further complications can arise because conven- mented as bone graft substitute materials. These materials
tional methods for treatment of such fractures are likely to be undergo physiochemical dissolution relatively quickly, disap-
difficult, since the high density of the material precludes dril- pearing in days to weeks in some cases.
ling and sawing procedures. Revision surgical procedures at Some question remains, however, about the rate at which
sites implanted with these substances may require their com- these materials become absorbed by the body. Differences may
pleteremoval. be related to variations in the composition and structure and
Based on these considerations, the materials used should the different physiologic characteristics of the implant sites and
match the modulus of elasticity of the tissue at the implant site. animal models. Tricalcium phosphate often undergoes physi-
Thus the makeup and properties of the extracellular matrix cochemical dissolution at a rate that precludes the precipitation
(ECM) should be considered in selecting or designing a of biologic apatite and subsequent bone formation on its
scaffoldfor tissue engineering. surface. The dissolving surface does not allow for protein
One design approach has been to employ matrices that adsorption and cell attachment.
serveas analogs of the ECM of the tissue to be engineered. 119 Work with hydroxyapatite began in the mid-1970s.34.50
This concept recognizes that the molecular composition and Many studies focused on the use of hydroxyapatite in dense
architecture of the ECM display chemical and mechanical
properties required by the parenchymal cells and the physio- 'References 10. 11.26.51.53.75.83.98.113.
256 PART I PRINCIPLES AND TECHNIQUES

and porous forms of block and panicles.45 The increasing employed to facilitate regeneration of certain connective tis-
interest in bone graft substitute materials has advanced our sues, including bone,8° periodontium,32 and tendon.64 The
understanding of the bone response to these substances. lesion is isolated from the negative influence of surrounding
Mechanisms underlying the bone bonding associated with in- tissues, particularly as they collapse into the defect, while
corporation of these substances in osseous tissue are beginning wound-derived trophic factors are maintained in the lesion site.
to be revealed (see earlier discussion). With nerve the tube also serves as a guide for axonal elongation.
The mechanism of breakdown of calcium phosphates in Many synthetic and natural resorbable tubes, as well as silicone,
vivo is not fully understood. The appearance of macrophages have been investigated for this application. 8
and multinucleated foreign body giant cells around some types Silicone tubulization of nerve gaps has been the standard
of calcium phosphates suggest that particles might provoke the experimental model for many years59.65and has been shown to
activation of phagocytes, which in turn might stimulate other improve regeneration compared with defects that were not
cells and an inflammatory response. Agents produced by these contained with a tube. In clinical use, however, the silicone
cells could accelerate the degradation process. tubes have presented problems for long-term recovery. Silicone
Although generally considered a nonresorbable material, tubes typically have become encapsulated with fibrous tissue,
synthetic hydroxyapatite has also been found to undergo phys- which has led to constriction of the nerve, necessitating surgery
icochemical dissolution, albeit at a very slow rate. Because it is to remove the tube.
only slightly soluble in biologic fluid, synthetic hydroxyapatite Several previous studies have investigated the performance
substances can functionally be considered as long-lasting im- of biodegradable tubes fabricated from type I collagen.
plants, especially when they are incorporated into bone. Archibald et al5 obtained the most extensive longitudinal data
for nonhuman primate peripheral nerve repair. Their 31h-year
CARTILAGE ENGINEERING. Natural and synthetic materi- study demonstrated that repair of a 5-mm gap in the monkey
als have been employed as scaffolds for implantation in defects median nerve with a collagen tube had similar results to
of cartilage. With articular cartilage defects, matrices have been autograft repair.
used alone or seeded with cells before implantation. Nonre- Despite the promising results obtained using tubular nerve
sorbable materials that have been studied include carbon fiber guides, incomplete regeneration and the desire to accelerate the
mesh15.74 and spongelike constructs of polytetrafluoroethyl- process have prompted the investigation of soluble factors and
ene2.73 and polyester.73 insoluble regulators (matrices) placed within the tubes before
Concern about the effects of the permanent scaffold on the implantation.8 It has been hypothesized that these substances
mechanical performance of regenerated cartilage has focused may (1) provide more specific directional orientation for the
on resorbable substances as matrices. These include fibrin,48.87 axons, (2) enable haptotaxis, and (3) act as growth and trophic
collagen gels,111 collagen sponges,9.41,42.85.102PGA,39.97.107 factors.38 Materials investigated as promoters of nerve regener-
and polylactic acid.25.30.97 ation in tubes include laminin,8.67 gelatin with ACTH4-9,90
Questions remain as to the most suitable chemical compo- type I collagen precipitate,66.92 fibronectin,66 and skeletal
sition and pore structure in the fabrication of a cell-seeded muscle basal lamina grafts.16 The results of these efforts have
implant to treat defects in the anicular surface. The substance been mixed; some substances did improve regeneration,
should have a composition that maintains the chondrocyte whereas others actually impeded it. A recent study reported
phenotype and a pore structure that accommodates cell infiltra- results of a collagen-GAG-filled tube that were comparable to
tion. Furthermore, the scaffold must be mechanically stable an autograft in a rat model. 22
enough to be surgically manipulated for implantation. Because
of the poor surgical handling characteristics of gels, spongelike Future of Biomaterials for Tissue Engineering
matrices may be preferred. Tissue engineering may solve a number of compelling clinical
Insoluble type I collagen matrices have been successful in problems in dentistry not adequately addressed using perma-
animal models to improve healing of cartilage defects.9.85.102 nent replacement devices. The challenge will be to select the
Complete regeneration was not achieved, however, and the optimal combination of matrix, cells, and soluble regulators for
reparative tissue consisted of fibrous and fibrocartilaginous a particular clinical problem.
substances, with some hyaline cartilage. Recent work has For many connective tissues of the musculoskeletal system,
investigated the behavior of adult canine anicular chondro- with microstructures that reflect the mechanical environment,
cytes in vitro in matrices comprising collagen-GAG copoly- it may be more advantageous to regenerate the tissue in vivo
mers made from types I and II collagen.82 than to engineer the tissue fully in vitro for subsequent implan-
tation. The porous material that will serve as the matrix to
PERIPHERAL NERVE REGENERATION. One focus of ex- facilitate this regeneration must have certain pore characteris-
perimental efforts to promote and improve peripheral nerve tics, chemical constituents, and mechanical properties. One
regeneration across gaps has been guiding the axonal growth approach has been to employ substances that serve as analogs of
cone to the distal stump. The proximal and distal nerve ends are the ECM for the tissue to be regenerated.
encased in a tubel03-a nerve guide or nerve channel-in a With bone, natural bone mineral (anorganic bone) has been
procedure referred to as "fascicular tubulization"28.91 and "en- efficacious in several experimental animal and clinical studies.
tubulation repair.,,67 This approach is analogous to strategies For selected indications in which the supply of endogenous
CHAPTER19 Biomaterials 257

precursor cells has been compromised by disease or prior 16. Btyan DJ, Miller RA, Costas PD, et aI: Immunocytochemistry
surgical procedures, it may be necessary to seed the matrix of skeletal muscle basal lamina grafts in nerve regeneration,
before implantation with exogenous cells or to use the matrix Pfast Recomtr Surg 92:927-940, 1993.
as a delivery vehicle for growth or differentiation factors. 17. Bucholz RW, Carlton A, Holmes RE: Hydroxyapatite and
tricalcium phosphate bone graft substitutes, Orthop Clin North
Am 30:49-67,1987.
18. Burke JF, Yannas IV, Quinby WC, et al: Successful use of
REFERENCES a physiologically acceptable artificial skin in the treatment of
extensive burn injury, Ann Surg 194:413-428, 1981.
1. Agins HJ, Alcock NW, Bansal M, et al: Metallic wear in failed 19. Cameron HU, Macnab I, Pilliar RM: Evaluation of a
titanium-alloy total hip replacements, ] Bone Joint Surg biodegradable ceramic,] Biomed Mater Res 11: 179-186, 1977.
70A:347-356, 1988. 20. Capozzi A, DuBou R, Pennisi VR: Distant migration of
2. Ahfeld SK, Larson RL, Collins HR: Anterior cruciate silicone gel from a rupture breast implant, Pfast Reconstr Surg
reconstruction in the chronically unstable knee using an 62:302, 1978.
expanded polytetrafluoroethylene (PTFE) prosthetic ligament, 21. Career DR, Orr TE: Skeletal development and bone fimc-
Am] Sports Med 15:326-330,1987. tional adaptation,] Bone Miner Res 7:389-395, 1992.
3. Anderson JM, Miller KM: Biomaterial biocompatibility and 22. Chamberlain LJ, Yannas IV, Hsu H-P, et al: Collagen-GAG
the macrophage, Biomaterials 5:5-10, 1984. substrate enhances the quality of nerve regeneration through
4. Andriano KP, Pohjonen T, Tormala P: Processing and collagen tubes up to the level of autograft, Exp Neurol
characterization of absorbable polylactide polymers for use in 154:315-329, 1998.
surgical implants,] Appl Biomat 5: 133-140, 1994. 23. Chang AS, Yannas IV, Perutz S, et aI: Electrophysiological
5. Archibald SJ, Shefner J, Krarup C, Madison RD: Monkey study of recovery of peripheral nerves regenerated by a
median nerve repaired by nerve graft or collagen nerve guide collagen-glycosaminoglycan copolymer matrix. In Gebelein
tube,] Neurosci 15:4109-4123, 1995. CG, editor: Progressin biomedical polymers, New York, 1990,
6. Bartolozzi A, Black J: Chromium concentrations in serum, Plenum.
blood clot and urine from patients following total hip 24. Christie AJ, Weinberger KA, Dietrich M: Silicone lymphade-
arthroplasty, Biomaterials 6:2-8, 1985. nopathy and synovitis: complications of silicone elastomer
7. Bauer TW, Saltarelli M, McMahon JT, Wilde AH,: Regional finger joint prostheses,]AMA 237:1463-1464, 1977.
dissemination of wear debris from a total knee prosthesis: a 25. Chu CR, Coutts RD, Yoshioka M, et aI: Articular cartilage
case report,] Bone Joint Surg 75A: 106-111, 1993. repair using allogeneic perichondrocyte-seeded biodegradable
8. Bellamkonda R, Aebischer P: Tissue engineering in the porous polylactic acid (PLA): a tissue-engineering study,
nervous system. In Bronzino JD, editor: Biomedical engineering ] BiomedMater Res 29:1147-1154,1995.
handbook, Boca Raton, Fla, 1995, CRC Press. 26. Clergeau L, Danan M, Clergeau-Guerithault S, Brion M:
9. Ben-Yishay A, Grande DA, Schwartz RE, et al: Repair of Healing response to anorganic bone implantation in periodon-
articular cartilage defects with collagen-chondrocyte allografts, tal intrabony defects in dogs. Part I. Bone regeneration: a
Tiss Engr 1:119-133, 1995. microradiographic study,] Periodontol67: 140-149, 1996.
10. Benezra V, Hobbs LW, Spector M: Ultrastructure and 27. Coleman DL, King RN, Andrade JD: The foreign body
architecture of bone mineral and synthetic bone substitutes reaction: a chronic inflammatory response,] Biomed Mater Res
revealed by low-voltage high-resolution SEM. Presented at the 8:199-211,1974.
23rd Annual Meeting of the Society for Biomaterials, New 28. Colin W, Donoff RB: Nerve regeneration through collagen
Orleans, 1997. tubes,] Dent Res 63:987-993, 1984.
11. Berglundh T, Lindhe J: Healing around implants placed in 29. Corrin B: Silicone lymphadenopathy,] Clin PathoI35:901-
bone defects treated with Bio-Oss, Clin Oral Implants Res 902, 1982.
8:117-124,1997. 30. Coutts R, Yoshioka M, Amiel D, et aI: Cartilage repair using
12. Black J: Metallic ion release and its relationship to oncogene- a porous polylactic acid matrix with allogenic perichondrial
sis. In Fitzgerald RHJ, editor: The Hip, Proceedings of the cells. Presented at the 40th Annual Orthopedic Research
Thirteenth Open Scientific Meeting of the Hip Society, St Louis, Society Meeting, New Orleans, 1994.
1985, Mosby. 31. Cutright DE, Bhaskar SN, Brady JM, et al: Reaction of bone
13. Bobyn JD, Spector M: Polyethylene. In Encyclopedia of materi- to tricalcium phosphate ceramic pellets, Oral Surg 33:850-
als, science, and engineering, New York, 1987, Pergamon. 856, 1972.
14. Bos I, Johannisson R, L6hrs U, et aI: Comparative investiga- 32. Dahlin C, Linde A: Bone formation by guided tissue
tions of regional lymph nodes and pseudocapsules after regeneration. In Glimcher MJ, Lian JB, editors: The chemistry
implantation of joint endoprostheses, Path Res Pract 186:707- and biology of mineralized tissue, New York, 1988, Gordon and
716, 1990. Breach Science.
15. Brittberg M, Faxen E, Peterson L: Carbon fiber scaffolds in the 33. Damien q, ParsonsJR: Bone graft and bone graft substitutes:
treatment of early knee osteoarthritis, Clin Orthop 307:155- a reviewof current technologyand applications,] Appl Biomat
164, 1994. 2:187-208,1991.

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