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138 Surface Modification of Magnesium and its Alloys for Biomedical Applications
Figure 4.9 Two-dimensional reconstruction of explanted femura containing an AZ91D rod
(a) and a LAE442 rod (b) after 18 weeks of implantation. Corrosion morphology and direct
contact with newly formed bone can be observed for both magnesium alloys (a, b). Bar 1/4
1.5 mm (Witte et al., 2006).
part of the compact portion of the specimen; rather, they reflect the corrosion progress.
An acid-cleaning process using chromic acid or hydrofluoric acid is a suitable means
of removing corrosion products without causing damage to the magnesium component
(Song & Atrens, 1999). Following this treatment, the specimen should be carefully
rinsed in ethanol and left to air-dry.
4.4.4 Scanning electron microscopy and energy-dispersive
X-ray analysis
Scanning electron microscopy (SEM) is a well-established procedure for evaluating
the surface structure and degradation behaviour of magnesium implants (Duygulu,
Kaya, Oktay, & Kaya, 2007; Li et al., 2008; von der H€oh, von Rechenberg, Bormann,
Bioabsorbable behaviour of magnesium alloys e an in vivo approach 139
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Figure 4.10 Three-dimensional reconstruction of remaining magnesium alloy (red) segmented
from the bone matrix (grey) by voxel growing method. (a) AZ91D, (b) LAE442; Bar 1/4 1.5 mm
(Witte et al., 2006).
Lucas, & Meyer-Linderberg, 2009; Zhang, Xu, Yu, Pan, & Yang, 2009). SEM, which
can be performed before and after the acid-cleaning process, allows examination of the
corrosion layer, i.e., the implant surface. Degradation in magnesium implants typically
occurs in the form of pitting corrosion (Song & Atrens, 1999; von der H€oh et al.,
2009), which is identifiable under a scanning electron microscope as a hole-like inden-
tation on the implant surface. However, the morphology of the magnesium alloy surface is inhomogeneous. The production process, alloy qualities, and coating properties
may play a role in this.
Energy-dispersive X-ray (EDX) analysis makes use of electromagnetic radiation to
investigate the implant and its interfaces with regard to the composition of the individual
layers (Acarturk et al., 2008). This method may additionally indicate that the implant
has an osteoconductive effect (Witte et al., 2005). In terms of evaluating the outcome,
however, one disadvantage is the fact that merely the elements and their concentration
can be displayed, and not any compounds of these elements.
The literature contains multiple descriptions of the formation of a corrosion layer on
the surface of magnesium implants during the degradation process (Witte et al., 2005;
Li et al., 2008; von der H€oh, 2009; Zhang et al., 2009; Krause et al., 2010; Thomann
et al., 2010) (see Figure 4.11). Krause et al. (2010) and Thomann et al. (2010)
140 Surface Modification of Magnesium and its Alloys for Biomedical Applications
(a)
(b)
O
Element Wt% At%
C K 34.11 42.41
N K 04.87 05.19
O K 48.30 45.09
C
Mg
MgK 10.01 06.15
P K 01.03 00.49
S K 00.37 00.17
CaK 01.33 00.49
N
1.00 2.00 3.00 4.00 5.00 6.00 7.00
Figure 4.11 (a) SEM image of the screw thread part of the retrieved Mge1Ca alloy pin after
1 month implantation; (b) EDS spectra corresponding to the rectangular area in (a) (Li et al., 2008).
P
Ca
S
investigated the composition of the degradation layer of intramedullarily implanted
magnesium alloys and were able to detect elements such as magnesium, oxygen, calcium, and phosphorous. Other studies found magnesium oxide, magnesium hydroxide,
hydroxyapatite, and complex magnesium-calcium-phosphate compounds on the surface of corroded magnesium implants in vivo and in vitro (Li et al., 2008; Witte
et al., 2005; Zhang et al., 2009).
4.5 In vivo biocompatibility of magnesium alloys
4.5.1 Biocompatibility e general considerations (acute, chronic,
and foreign-body reaction)
Implants are generally to be regarded as foreign bodies. To test their biocompatibility, the methods to be used must first be defined. Biodegradable implants need
Bioabsorbable behaviour of magnesium alloys e an in vivo approach 141
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to satisfy p articular requirements for biocompatibility, because all implant components remain within the body or are progressively expelled. Pizzoferrato, Vespucci,
Ciapetti, and Stea (1985) coined the terms “biocompatibility” and “biofunctionality”
in the context of cell culture. The former term has been defined by various groups
(Gradinger & Gollwitzer, 2006; Wintermantel & Ha, 1996). According to Gradinger
and Gollwitzer (2006), the quantity, form, and nature of the substances released
from the implant are crucial determinants of biocompatibility, a distinction being
made between biocompatibility and bioactive implants. A material’s b iocompatibility is a func tion of its compos ition, form, and surface properties, the implantation
site, the condition of the implant bed, the interface between implant and tissue, and
the degradation of the material, as well as the surgical technique and the mechanical
loading to which the implant is subjected (Bergsma, Rozema, Bos, & De, 1993;
Epple, 2003; Rosengren, Bjursten, Danielsen, Persson, & Kober, 1999; Thull,
2003). Epple (2003) describes in his work that the properties of the interface be-
tween implant and tissue e such as chemical processes involving release of ions,
pH value, adsorption of proteins and cells, and surface morphology e play a vital
role. One basis for in vivo testing is that of successful in vitro outcomes. Various
means of verifying biocompatibility are described in the literature, largely based
on the recommendations of International Organization for Standardization (ISO)
10,993-6:2009 (ISO 10993-6:2009). This standard describes three test methods: epicutaneous testing, bone testing, and implantation in muscle. A prerequisite for
testing biocompatibility is that the implant is not subjected to any mechanical and
functional stress (ISO 10993-6:2007). Histological sections may be analysed semiquantitatively, quantitatively, or morphometrically (Be thmann & Knofler, 1987).
Several authors discuss the possibility of using micro-CT images of tissue
morphology to assess biocompatibility in bone (Wachter et al., 2001). The ISO
10,993-6 standard requires that the histological preparation of specimens take account of the following parameters: formation of a connective-tissue capsule, occurrence of inflammatory cells, signs of degeneration, presence of necrosis, and
particulate material. At the cellular level, implanted foreign material always leads
to an immune response. In the first instance, the innate immune defence system delivers the body’s defence response, in particular involving the formation of macro-
phages, neutrophil granulocytes, and natural killer cells. The macrophages respond
chemotactically and also act as a link between the innate and adaptive immune responses. They also have the ability to form foreign-body cells (Anderson, Rodri-
guez, & Chang, 2007). The adaptive immune response is mediated primarily by
B and T lymphocytes. Biodegradable magnesium implants give rise to degradation
products that need to be eliminated by the body, so that a greater incidence of macrophages should not necessarily be regarded as indicating a rejection reaction
(Doernberg et al., 2006). Anderson et al. (2007) describe the body’s response to
implanted biomaterial over time. During the initial phase, a blood-based matrix
forms at the implant site, wh ich is the basis not only for wound healing, but also
for foreign-body reactions. The next phase, i.e., that of acute inflammation, is characterised in particular by neutrophil granulocytes and is not expected to exceed 7
days. Mast cells, which secrete histamine and interleukins, perform an important
142 Surface Modification of Magnesium and its Alloys for Biomedical Applications
regulatory function during this phase. The chronic inflammatory phase is distin-
guished by monocytes, lymphocytes, and plasma cells and tends to be of short duration. The foreign-body reaction involves a mix of different constituent cells, and,
while similar to the chronic reaction, it is the occurrence of macrophages and
foreign-body giant cells that is characteristic here. Once the inflammatory phase is
over, granulation tissue is formed in conjunction with macrophages, fibroblast infiltration, and new vessel formation. Granulation tissue is regarded as the precursor
stage for the formation of a fibrosis layer. It is, primarily, the quantity and time
of occurrence of immune cells that are crucial in assessing the body’s immunological reaction (Anderson et al., 2007)(seeFigure 4.12; 4.13 and 4.14). A strong layer
of connective tissue with numerous immune cells indicates the encapsulation of the
implant and, indirectly, insufficient biocompatibility (Freeman & Brook, 2006; Tsai,
Ruey-Mo, Chien-Ping, & Jiin-Huey Chern, 2008; Witte et al., 2007b).
Injury, implantation
Inflammatory cell infiltration
PMNS, monocytes, lymphocytes
Exudate/tissue
Acute inflammation
Mast celIs
PMNs
Chronic inflammation
Monocytes
Lymphocytes
Granulation tissue
Fibroblast proliferation
and migration
Capillary formation
Fibrous capsule formation
Biomaterial
IL-4, IL-13
Th2: IL-4, IL-13
Monocyte adhesion
Macrophage differentiation
Macrophage mannose
Receptor up regulation
Macrophage fusion
Foreign body giant
cell formation
Figure 4.12 Sequence of events involved in inflammatory and wound healing responses leading
to foreign body giant cell formation. This shows the potential importance of mast cells in the
acute inflammatory phase and Th2 lymphocytes in the transient chronic inflammatory phase with
the production of IL-4 and IL- 13, which can induce monocyte/macrophage fusion to form
foreign body giant cells (Anderson et al. 2007).
Bioabsorbable behaviour of magnesium alloys e an in vivo approach 143
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Monocyte Macrophage Foreign body giant cell
Blood Tissue Tissue/biomaterial
Chemotaxis
migration
Chemotaxis
migration
adhesion
differentiation
Adhesion
differentiation
signal transduction
activation
Biomaterial
Activity
phenotypic
expression
Figure 4.13 In vivo transition from blood-borne monocyte to biomaterial adherent monocyte/
macrophage to foreign body giant cell at the tissue/biomaterial interface. There is ongoing
research to elucidate the biological mechanisms that are considered to play important roles in the
transition to foreign body giant cell development (Anderson et al. 2007).
(a) (b)
(c)(d)
Figure 4.14 Scanning electron microscopy images of an Elasthane 80A Polyurethane surface
from an in vivo cage study showing the morphological progression of the foreign body reaction.
The sequence of events at the Polyurethane surface includes (a) monocyte adhesion (0 days),
(b) monocyte-to-macrophage development (3 days), (c) ongoing macrophageemacrophage
fusion (7 days), and (d) foreign body giant cells (14 days) (Anderson et al., 2007).
144 Surface Modification of Magnesium and its Alloys for Biomedical Applications
4.5.2 Pharmacophysiology of magnesium and selected
alloy components
Magnesium is among the elements that are essential to the body and has, using the
29 Mg isotope, been detected in small mammals (Rogers & Parker, 1959; Rogers,
Haven, & Mahan, 1960). Magnesium implants are generally characterised in clinical
experiments by good biocompatibility (Lambotte, 1932; Verbrugge, 1934; McBrideB,
1938; Nicole, 1947; Witte et al., 2005; von der H€oh et al., 2006; Witte et al., 2007; Xu
et al., 2007; Li et al., 2008). Most in vivo studies also describe the formation
(to differing extents) of hydrogen gas (Lambotte, 1932; Verbrugge, 1934; McBrideB,
1938; Nicole, 1947; Witte et al., 2005; von der H€oh et al., 2006; Witte et al., 2007b; Li
et al., 2008). However, the degradation products of corrosion exhibit different pharma-
cophysiological properties.
Because of unsuitable enzymatic conditions, hydrogen is not formed in the cells
(Staiger et al., 2006). It is known, however, that hydrogen e an antioxidant e has a protective effect on cells. It also shows antiinflammatory properties in in vivo investigations
(Atsunori, 2011; Buchholz et al., 2008; Haung et al., 2010). This formation process is
described as being an important co-factor in gas production (Li et al., 2008). In vivo,
the gas formed is resorbed by the surrounding tissue (Witte, Hort, et al., 2008).
The OH- ions that also form during the degradation process would, without regulatory mechanisms, lead to strong alkalinisation of the tissue around the implant
(Heublein, 2003; Song, 2007). Magnesium chloride (MgCl
salt, which may lead to slight acidification of the liver and is toxic at high concent rations (Franke, 1934). Magnesium ions (Mg
2þ
) that do not contribute to the formation
of salts and apatites may in principle be involved in physiological metabolism. It has
been suggested that magnesium ions promote bone-remodelling processes (Janning
et al., 2010; Rude et al., 2006). Apatites containing magnesium are similar to the min-
eral phase of bone, namely, hydroxylapatite Ca
(OH)(PO4)3. It is therefore likely that
5
apatite is involved in normal bone-remodelling processes. Several authors postulate
that calcium phosphates exhibit osteoconductive properties (Li et al., 2004, 2008;
Witte et al., 2005; Xu et al., 2007).
Alloy compo nents also play a significant role in biocompatibility; they have, in
recent years, assumed an important function in the fabrication of magnesium implants
in relation to their mechanical and corrosive properties. The influence of alloy components on tissue is not fully known (Yuen & Ip, 2010) (see Table 4.5).
) is a rapidly resorbable
2
4.5.2.1 Aluminium
The total quantity of aluminium in the human body is (depending on weight) 0.295 g,
with most of it stored in bone (Skalsky & Carchman, 1983). Aluminium is regarded as
a strong neurotoxin and is thought to be one of the causative factors in Alzheimer’s
disease (El-Rahman, 2003; Mj€oberg, Hellquist, Mallmin, & Lindh, 1997).
4.5.2.2 Calcium
Calcium is the most abundant element in the human body (which contains around 1 kg)
and is hormonally regulated (Civitelli & Ziambaras, 2011). Disruption of the calcium
Table 4.5 Toxicological critical values and derived toxicological critical values for common alloying elements in magnesium
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alloys
Al Mn Zn Cu Ni Fe Sr Zr Ce
c
Source ATSDR
[11]
Type of
exposure
limit
Potential
adverse
a
NOAEL-a N0AEL-h/
Neuro-
toxicity
systemic
effects at
initial
overdose
Exposure limit
(mg
bw
UF for
1
1
b
26 0.14 0.83 0.042 0.02 0.28 140 n/a n/a
kg
day)
10 1 1 1 1 1 10 n/a n/a
interspecies
variation
UF for inter-
10 1j 3 3 1 1 3 n/a n/a
individual
variation
IRIS [17] ATSDR [10] ATSDR [24] ATSDR [25]
and IRIS
[25]
NOAEL-h NOAEL-h EPA RfD Guidance
RfD
CNS
effccts
Reduced
erythrocyte
superoxide
dismutase
level
Changes in
blood
protein and
enzyme
levels
Reduced
body and
organ
mass
UK FSA [28] ATSDR
[23]
NOAEL-a Insufficient
level
Reduction in
serum zinc;
possible
increased
risks of
Abnormal
bone
mineriali-
sation
cardiovascular
disease and
cancer
Not found
in FSA/
ATSDRI/
IRIS
data
Allergic
hyper
sensitivity.
Dialysis
osteomalacia accumulates in
the brain
similar to
Al [42,43]
IRIS [41]
Insufficient data
Cardiac toxicity
and reduction
of haemoglobin
oxygen affinity
Continued
Table 4.5 Toxicological critical values and derived toxicological critical values for common alloying elements in magnesium
alloys e cont’d
Al Mn Zn Cu Ni Fe Sr Zr Ce
c
Oral absorption
efficiency
(%)
Modifying
factor for
100%
absorption
(¼l/oral bioavailability)
UF/absorption
adjusted
exposure
limit (mg
1
kg bw
day)
Daily exposure
limit for a
60-kg adult
(mg/day)
Annual
exposure
limit for a
60-kg adult
(mg/year)
0.63 5 20 36 27 15 20 n/a n/a
158.7 20 5 2.78 3.703 6.6 5 n/a n/a
1.64Ee03 7.00Ee03 553Ee02 5.04Ee03 5.40Ee03 4.24Ee02 9.33Ee01 n/a n/a
9.83Ee02 4.20Ee01 3.32Eþ00 3.02Ee01 3.24Ee01 2.55Eþ00 5.60Eþ01 n/a n/a
35.88 153.30 1211.80 110.29 118.28 929.09 20.440 n/a n/a
a
h, human data; a, animal data NOAEL (no observed adverse effect level). RfD, reference dose; n/a, not available.
b
Inhalational and gastrointestinal effects excluded.
c
Data deficit for rare-earth metals; cerium was the sole one identified from the database, and is only listed as an example.
Yuen and Ip (2010).
Bioabsorbable behaviour of magnesium alloys e an in vivo approach 147
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level in the blood leads to various functional disorders of certain organs (the heart,
gastrointestinal tract, and kidneys) as well as the nervous system and muscles.
4.5.2.3 Lithium
Lithium, which is present in the body only in negligible amounts, may enter the cell via
sodium channels. Even a mild overdose leads to muscle weakness and vegetative
symptoms. A severe overdose results in damage to the lungs and kidneys (Bichet,
2006; Giles & Bannigan, 2006; Timmer, 1999).
4.5.2.4 Zinc
Zinc is among the important trace elements and is also involved in immune system
function (Lastra, Pastelin, Camacho, Monroy, & Aguilar, 2001). It is regulated in
the body chiefly via the gastrointestinal tract. At high concentrations, it has a neurotoxic effect, and it is believed to be involved in development of amyotrophic lateral
sclerosis (ALS) (Post, Eibl, & Ross, 2008).
4.5.2.5 Rare-earth elements
Rare-earth elements are present in the body only in very small quantities, with cerium
apparently the most abundant in terms of weight (Inagaki & Haraguchi, 2000). Their
half-life period within the body shows considerable fluctuation and may be as much as
10 years (Hirano & Suzuki, 1996 ). These metals’ possible antiproliferative effect on
cancer cells is also discussed in the literature (Kostova, Momekov, & Stancheva,
2007). They also have a similar ionic radius to that of calcium and may act as an antag-
onist to calcium in the body (Feyerabend et al., 2010; Nakamura, Tsumura, Tonogai,
Shibata, & Ito, 1997). Gu et al. (2009) report that the rare-earth elements may also in-
fluence haemolysis, chromosomal aberrations, and liver function.
A number of techniques are available for verifying in vivo biocompatibility.
As these differ in the approach involved, they work together synergistically in clarifying the issue of biocompatibility.
4.5.3 Histology
To provide information about the tissueeimplant compound and, therefore, to assess
biocompatibility, histological examinations are essential (An, 2003). The specimens
obtained must initially be fixed. Depending on the types of tissue, decalcification
may be carried out prior to the further preparation of osseous and cartilaginous specimens, so sections of appropriate thickness can be created. After the specimens are
embedded, the sections are produced and then stained. However, owing to the decalcification of the bone, the fine morphology and the dynamic processes in the bone are
assessable only to a limited extent. A suitable method of processing decalcified samples is embedding in plastic (Wolf, R€oser, Hahn, Welkerling, & Delling, 1992). The
cutting-grinding technique is one of many methods that make preparation of noncalcified bone possible (Donath, 1998).
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