Japanese Dental Science Review (2011) 47, 5—12

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

journal homepage: www.elsevier.com/locate/jdsr

Review article

A review: Biodegradation of resin—dentin bonds

Masanori Hashimoto *, Futami Nagano, Kazuhiko Endo, Hiroki Ohno

Division of Biomaterials and Bioengineering, School of Dentistry, Health Sciences University of Hokkaido, 1757 Kanazawa,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Received 17 August 2009; received in revised form 28 December 2009; accepted 15 February 2010

KEYWORDS Summary Resin—dentin bonding was first achieved through mechanical hybridization between
Adhesion; resin and collagen fibrils using a functional monomer containing resin system. In the last decade,
Hybrid layer; new adhesive resin systems were frequently released onto the market within a short-period of
Degradation; time. Before and after commercialization, the bond integrity has been tested by bond tests, and
Electron microscopy; leakage evaluation by researchers, but it is very difficult for clinicians to obtain a comprehensive,
Polymer; up-to-date understanding of their nature and degradation. Although newly developed adhesive
Resin adhesive resins have attempted to improve the bond strength at least in the first 24 h after bonding, the
long-term durability of the bonds has not yet been established analytically. However, numerous
recent studies have shown micromorphological evidence of biodegradation of resin—dentin
bonds, due to hydrolysis of the resin and collagen fibrils within the bonds. This review mainly
summarizes the most recent work in biodegradation of resin—dentin bonds based on micromor-
phological analyses of data obtained by scanning and transmission electron microscopy.
# 2011 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2. Bond degradation of total-etch (etch-and-rinse) adhesives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3. Bond degradation of self-etching adhesives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4. Bond degradation of one-bottle self-etching adhesives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

* Corresponding author. Tel.: +81 133 23 1211; fax: +81 133 23 1960.
E-mail addresses: masanori-h@mue.biglobe.ne.jp,
has@hoku-iryo-u.ac.jp (M. Hashimoto).
1. Introduction
Many resin adhesive systems and types have been developed
and marketed in dentistry over the last two decades (Fig. 1).
The initial attempts at adhesion of resin concentrated on
enamel, the first successful attempts to achieve a micro-
mechanical interlocking of resin tag formation with acid

1882-7616/$ — see front matter # 2011 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.jdsr.2010.02.001
6 M. Hashimoto et al.

Figure 1 Classification of adhesive resin systems. E: etchant;

P: primer; B: bonding resin (adhesive).

pretreatment being reported by Buonocore [1]. However,

resin bonding to dentin could not be achieved due to its
complicated structure involving surface moisture and the
collagen network. Nakabayashi et al. reported micromecha-
nical bonding of a functional monomer containing resin
system (4-META/MMA-TBB) to collagen fibrils in deminera-
lized dentin in 1982 [2]. Since a smear layer created during
tooth preparation has an adverse effect on dentin bonding
[3,4] due to weak adhesion to underling dentin [5], its
removal by an acidic agent prior to application of a bonding
resin require to gain stronger bond strength. Acid-etching of
etch-and-rinse systems (total-etching system) demineralizes
the dentin surface to expose a few-micron-thick collagen
network providing space for resin infiltration. The following
application of a primer and/or adhesive penetrates into the
interfibrillar spaces of the collagen web, leading to the
formation of a hybrid layer composed of collagen fibrils
and adhesive resin (Fig. 2). Wet bonding leaves the dentin
surface visibly moist after acid etching. This leads to
increased resin infiltration into the exposed collagen network
as a result of increasing bond strength [6,7]. However, the
degree of dentin surface wetness (i.e. moist, wet or over-
wet) greatly affects the bond strength in both the laboratory
and clinical situations. The depth of demineralization and
completeness of monomer diffusion affect the quality of the
hybrid layer. When the former exceeds the latter, a region of
naked collagen fibers is left exposed as a bond defect (Fig. 3).
For the first system of self-etching adhesives, an acidic
monomer of phenyl-P diffuses through extant smear layers to
reach the underlying calcium-rich dentin as a result of for-
mation of a hybrid layer where the smear layer remains in the
lower half of the hybrid layer [8,9]. The hybridization occurs
among resin, collagen fibrils, and inorganic matter of the
smear layer (Fig. 2). Theoretically, there are no deminera-
lized dentin zones in the bond face because of the lack of acid
pretreatment [8—10]. This system is attractive to clinicians
because it is thought the application step is simple and easy
compared with total-etching systems with separate etching
and water rinsing step.
Newly marketed one-bottle self-etching systems, have
been developed with a view to further simplifying the bond-
ing procedure, combining etching, priming, and bonding
Figure 2 Schematic illustration of bond structure of a self-
etching system and etch-and-rinse system (total-etching sys-
tem). The structure of the hybrid layer of total-etch adhesives
consists of resin and collagen fibrils. The combination of resin,
collagen fibrils and inorganic matter (the smear layer) is a typical
hybrid layer of self-etching adhesives. The hybrid layer of self-
etching systems is thinner than that of total-etching adhesives,
due to the mild acidic effect of their acidic monomers on dentin.
steps into one component (Fig. 1). These adhesives can be
categorized as a self-etching system.
If the hybridized layer is impermeable to water or various
chemical stimuli, it could make dentin stable for long-term
clinical use. However, many studies have reported the long-
term water storage testing of resin—dentin bonds to measure
bond strength [11—23]. Most adhesives had decreased bond
Figure 3 Schematic illustration of demineralized dentin zone
of total-etch adhesives. Inadequate resin infiltration into colla-
gen fibrils leaves nano- or microspaces within the adhesive
interface. This zone is not common for self-etching adhesive
systems. Collagen hydrolysis of the demineralized dentin zone is
one of the degradation patterns for total-etch adhesives. In the
absence of a demineralized dentin zone within the bonds, this
collagen hydrolysis does not occur because the encapusulation of
cured adhesive resins or protection of the mineral matrix of
dentin prevents chemical degradation of the collagen fibrils even
after long-term function.
A review: Biodegradation of resin-dentin bonds 7

strength to various extents after long-term water storage

such as for 6 months or 1 year. All such degradation is
accelerated in the presence of water [24,25]. The hydrolytic
effect of water on the adhesives itself is of great importance
when considering the bond degradation. Although the extent
of the bond strength reduction is similar for all types of
adhesives after aging, micromorphological examination is
able to demonstrate the various degradation phases for each
adhesive system in in vivo and in vitro. Since the bond
structure of the resin—dentin bond depends on the type of
adhesive, micromorphological analysis reveals various degra-
dation patterns of bonds after aging.
The objective of this article is to provide a critical review
of the degradation of resin—dentin bonds for all types of
adhesive systems.

2. Bond degradation of total-etch

(etch-and-rinse) adhesives
Acidic solutions (i.e. 35% phosphoric acid) are used to demi-
neralize the smear layer and the underlying intact dentin to
expose the collagen network. The incomplete impregnation
of the exposed collagen space by subsequent application of
bonding resin is due to imperfect resin monomer infiltration
(Fig. 3). The discrepancy between the depth of the collagen
layer and resin infiltration creates an exposed demineralized
dentin zone under the hybrid layer (Fig. 3) [26—35]. These
zones correspond with the sites of different modes of silver
nitrate staining within the hybrid layer. Spencer and Wang
reported resin monomer distribution in the demineralized
dentin zone, especially evaluating the heterogeneity of the
Figure 4 Scanning electron micrographs of fractured surface
monomer—collagen interaction, using micro-Raman spectro-
of resin—dentin bonded beams. A three-step total-etch adhesive
scopy [34,35]. In their publications, the differentiation of
were used for both specimens. Fractured surface were obtained
resin monomer diffusion was reveal to depend on the mole-
in the dentin side of specimen after microtensile bond test. A
cular weight of the monomer at the collagen network of the
fractured surface of control specimens (after 24 h of bonding) (a)
hybrid layer [34,35]. Using atomic force microscopy (AFM),
and that had been functioning in human oral cavity for 10 months
Marshall et al. observed in situ collagen morphology before
(b). The presence of lateral branches of dentinal tubules is
and after dentin surface treatment [36—38]. The zone of
morphological symptom of collagen depletion.
demineralized dentin and the degradation phase were found
morphologically using AFM analysis [29]. The exposed col-
lagen fibrils here underwent structural deterioration due to tion has also been morphologically found using SEM and TEM
hydrolytic degradation, resulting in decreasing bond strength in in vitro testing of a total-etching system with resin—dentin
[12,14—16]. In vivo morphological evidence of collagen bonded beams after 1 year of water storage [12,14—16].
hydrolysis was first obtained using extracted human primary Several in vitro studies using morphological analysis have
teeth with resin restorations [12,39]. Fig. 4 shows collagen shown hydrolytic degradation of the collagen mesh in the
degradation within the demineralized dentin in the fractured resin—dentin interface in specimens stored in water for over
surface of a resin—dentin bonded specimen (Scotchbond 1 year [29,39,40]. Transmission electron microscopic exam-
Multi-Purpose) that functioned in the human oral environ- inations have shown the deformation of less stainable col-
ment for 10 months (Fig. 4b). Although an intact hybrid layer lagen fibrils as an indicator of collagen chemical degradation
is visible in the control specimen at 24 h after bonding [16,41]. This hydrolysis of collagen greatly affects the long-
(Fig. 4a), hydrolytic degradation of collagen fibrils term bond stability of total-etch adhesive systems. One
(Fig. 4b) is clearly observed after aging. There are many reason for this collagen hydrolysis may be the effects of
lateral branches of dentinal tubules at the fractured surfaces saliva or oral bacteria [42,43] in the human oral environment.
of the dentin side of a specimen in the aged specimen However, little information is available on the mechanism of
(Fig. 4b), whereas there are none in the control (Fig. 4a). collagen degradation in vitro.
The peritubular matrix of the dentinal tubules is richer in Recently, Pashley et al. established a different concept,
inorganic compounds than the lateral branches and the degradation of naked collagen fibrils by host-derived matrix
lateral branches are readily widened by collagen hydrolysis metalloproteinases (MMPs) in the dentin matrix [44—50].
[12,39]. The degradation of the collagen suggests that the Matrix metalloproteinases are a family of zinc-dependent
resin—dentin bonds made with this adhesive system proteolytic enzymes that are capable of degrading the
remained a demineralized dentin zone due to the incomplete organic dentin matrix after demineralization [51]. Although
encapsulation of the dentin by the resin. The same degrada- collagenolytic or gelatinolytic activity identified from oral
8 M. Hashimoto et al.
bacteria [52] may contribute to the hydrolysis of organic
matter of the dentinal matrices in the caries process, recent
studies have reported host-derived proteinases in the form of
different types of MMPs present and released from the dentin
matrix [51,53,54]. When a region of naked collagen remains
in the demineralized dentin zone, the gradual and slow
release of active MMPs dissolves the collagen during the
long-term, even in in vitro conditions. In addition, by SEM
and TEM micromorphological evidence of self-destruction of
collagen has been found in the human dentin matrix in vivo
and in vitro [44—50].
Elution of resin from hybrid layers due to hydrolysis of the
resin is a further possible explanation for the bond degrada-
tion of total-etching adhesives [17,55—58]. This degradation
phase has been found in all type of adhesive systems.
3. Bond degradation of self-etching
adhesives
The combination of an etchant and primer into a self-etching
primer is advantageous in that it eliminates one application
step. For etch-and-rinse systems, factors affecting sensitivity
include the surface wetness of the acid etched dentin, acid-
etching time, light irradiation time, thickness of the bonding
resin layer, consecutive coating methods, and the method of
air blowing for the adhesive-coated dentin surface, etc.
[6,7,59—61]. For self-etching adhesives, the surface wetness
of acid-etched dentin can be theoretically eliminated
because there is no water rinsing or dentin moisture reten-
tion. The fewer application steps of self-etching adhesives
are thought to require less skill by the operator and be easier
to implement.
Self-etching primer adhesives differ from the etch-and-
rinse systems in that the self-etching adhesives partially
involve original smear layers in the hybrid layer [8,9]. The
acidic monomer penetrates into the smear layer, smear plug
or underlying intact dentin but can be neutralized to stop the
demineralized reaction due to pH change [62]. Therefore,
the hybrid layer of self-etching systems is a combined struc-
ture of resin, collagen fibrils, and minerals. The strong acid of
etch-and-rinse systems (i.e. 35—40% phosphoric acid) com-
pletely dissolves the matrix of the dentin surface, including
the smear layer, exposing the collagen network approxi-
mately 3—7 mm in depth. For self-etching adhesives, the
smear layer is completely or partially enveloped into the
bond structure, providing simultaneous demineralization and
infiltration during the application of the acidic monomer,
resulting in formation of a hybrid layer. The market-driven
simplification of adhesive systems of self-etching primers
that combine the conditioning and priming is thought to have
overcome the shortcomings of the formation of an exposed
collagen network within the bonds of the total-etching
adhesives. However, incomplete infiltration was also found
as nanoleakage within the hybrid layer [63,64]. Therefore,
there is a route for water impregnation into bond faces of
self-etching systems after bonding.
One of the beneficial characteristics of a microtensile
bond test is that the bond strength measurement can be
done for specimens with small adhesive areas (i.e. 1 mm2).
Using a microtensile bond test, Sano et al. measured resin—
dentin bond strengths in in vivo specimens after long-term
function in monkeys [11]. This small adhesive area of the
microtensile bond test allowed them to make specimen
beams from resin—dentin bonded teeth that had functioned
orally. The study revealed evidence of hydrolysis of bonding
resin within the hybrid layer of a self-etching adhesive after 1
year of functioning. Later, similar morphological evidence of
degradation was confirmed by in vitro tests [13,14]. How-
ever, hydrolysis of collagen fibrils is not common as a degra-
dation phase with self-etching adhesive systems. Regions of
incomplete resin infiltration or incomplete resin polymeriza-
tion within the hybrid layer or bonding resin termed nano-
leakage have been shown by silver tracer deposition.
Although nanoleakage can theoretically be eliminated by
using self-etching adhesives, many studies have shown that
all self-etching adhesives had a spot- or reticular-mode of
nanoleakage within the hybrid layer [63—67]. Although a
naked collagen zone was absent within the interface of
the self-etching adhesives, it is possible that a loss of resin
may initiate and promote proteolytic hydrolysis of collagen.
However, this aging pattern is uncommon and which of the
structures (collagen or resin) contributes to the bond degra-
dation is unclear. According to the results of these previous
studies, resin hydrolysis may be more damaging to long-term
bonding effectiveness than collagen hydrolysis in the case of
the hybrid layer of self-etching adhesives.
4. Bond degradation of one-bottle self-
etching adhesives
Recently, one-bottle self-etching adhesive systems are
widely used in clinics because of their simple and easy
application. Self-etching adhesive systems are currently
available as two-step and single-step types. The single-step
self-etching systems can be further divided into two types,
the all-in-one and one-bottle types, depending on whether
they require mixing or not. The recently introduced all-in-
one adhesives are supplied as two-bottles that are mixed
together immediately before use. One-bottle self-etching
adhesives that combine the etchant, primer, and bonding
resin into one bottle with single-step application have been
developed, allowing simultaneous etching and priming with
one adhesive component. One drop of the adhesive is applied
to the dentin/enamel surface with the smear layer covered,
resulting in the combination of resin, collagen, and hard tissue
as a bonding substrate. This system is generally thought to be
less technique-sensitive and time-consuming than traditional
adhesive resins (two-step self-etching and etch-and-rinse
adhesives). This system is thus attractive for clinicians because
of its easy handling and short application time.
Nanoleakage was first visualized in SEM interfacial obser-
vations in 1995 [68] and a water tree was first found as an
indicator of a leakage pathway by TEM analysis in 2003 [63].
Several studies have shown unfavorable bond defects such as
nanoleakage, water trees, bubbles, and phase separation in
the bond faces of all-in-one and one-bottle adhesives due to
their characteristically high amounts of water [69,70], which
is needed for demineralization of dentinal hard tissue by the
acid-effect of the monomers of self-etching systems. The
hydrophilic nature of bonding resins easily induces water
absorption as a result of replacement of the hydrophilic resin
monomers even after curing, leading to hydrolytic degrada-
tion in the long term [71—77]. Several studies have shown an
A review: Biodegradation of resin-dentin bonds 9

increased amount of silver staining in the hybrid layer or

bonding resin layer as a function of time using total-etch and
self-etching adhesives [78,79]. Recent studies have shown
water sorption of adhesive resin to be proportional to the
hydrophilic characteristics of the resin [71—77]. The self-
etching ability is commonly achieved by incorporation of
water in resin monomers that enables ionization of acidic
monomers. In addition to the water in the compounds, the
ionizable moieties of acidic monomers are also hydrophilic
[80]. The presence of such a hydrophilic layer may thus
induce water sorption and uptake, in turn, plasticizing the
polymer network [17,55—58]. Phase separation of the adhe-
sive or micro-size bubble formation in the bonding resin layer
is a typical morphology in one-bottle self-etching adhesive
systems [69,70]. A recent study has shown the effect of
dentinal surface wetness before bonding on the bond
strengths of one-bottle adhesives [81]. In that study, the
bonding strengths of resins to dentin were measured using
two different surface wetnesses for the dentin substrate
before bonding, wet-dentin with short air blowing and dentin
dried in a desiccator for 24 h. The hydrophilic one-bottle
adhesives with high contents of solvents and water exhibit
high water sorption. This water sorption further contributes
to a large decrease in the bond strength in wet-dentin
compared to dry bonding. An interesting finding was that
this result indicated the adverse effect of etch-and-rinse
systems on surface wetness. Fig. 5 shows nanoleakage
expression (silver staining) in a two-step self-etching speci-
men (Fig. 5a) and one-bottle self-etching adhesives (Fig. 5b
and c) using the back-scatter electron mode of SEM. Although
silver staining was observed in the bonding resin layer of one-
bottle self-etching adhesives, there is no silver tracer present
in the bonding resin when using two-step self-etching adhe-
sives, as shown in Fig. 5a. Based on this, it may be concluded
that the nanoleakage expression in bonding resin layers is a
special characteristic of one-bottle self-etching adhesives
(Fig. 5b and c).
Recently, a typical type of degradation of one-bottle self-
etching adhesives was found at the border between adhe-
sives and the resin composite border [82,83]. Although,
there was little or no silver staining after 24 h (not shown)
of bonding in one-bottle self-etching adhesive specimens,
silver particles were present around filler particles of the
resin composite between the bonding resin and resin com- Figure 5 Longitudinal cross-section of the resin—dentin inter-
posite border after more than 300 days (Fig. 6) in water. face of control specimens that stained silver tracer (a: back-
Fractured surface observations also showed a similar degra- scatter electron mode of two-step self-etching adhesive; b and
dation pattern (detached filler particles and gap formation) c: back-scatter electron mode one-bottle self-etching systems).
at the same region (adhesive/composite border) in in vitro There is an electron lucent layer bonding resin with no silver
tests using one-bottle adhesives, despite the fact that simi- staining in the specimens of two-step self-etching systems. Spot-
lar morphology cannot be found in other adhesive systems mode of silver impregnation (b) and balloon-shaped staining (c)
[82,83]. A schematic illustration of the region of typical are visible within the hybrid layer or adhesive layers for one-
degradation at the adhesive/composite border is shown in bottle self-etching adhesives. White arrows in (c) indicate a
Fig. 7. Oxygen inhibits free radical polymerization and yields balloon-shaped nanoleakage at the hybrid layer/bonding resin
a thin unpolymerized and/or hydrogel layer on cured sur- junction. These regions are enough large for water infiltration.
faces [84—86]. Large amounts of water and/or solvent are The degree of silver staining of bonding resin layer of one-bottle
responsible for a decrease in viscosity, and lead to oxygen self-etching system is greater than the other type of adhesive
transport to the top surface of the cured adhesive layer, and systems. B: bonding resin; C: composite resin; D: dentin.
the depth of the uncured layer with one-bottle adhesives
may be more severe than for hydrophobic adhesives. the bulk polymer, leading to hydrolysis of the filler-adhesive
Furthermore, the remaining monomer around the filler junction after aging. This poorly polymerized hydrophilic
around inadequately polymerized monomers will become polymer domain is deteriorated rapidly by environmental
a pathway for environmental water invasion and entry into water and thus is sensitive to interfacial attack by water.
10
Figure 6 The resin—dentin interfacial aspects of specimens (a
one-bottle self-etching adhesive) after 300 days of water storage
(back-scatter electron mode of silver staining specimen). There
were filler particles of resin composite stained at the border of
bonding resin and composite resin. A continuous crack formation
was visible within the interface due to the high vacuum chamber
of electron microscope. The region of crack formation is in
accordance with weakest portion of adhesive interface. White
arrows indicate silver staining around filler particles of resin
composite. This silver staining pattern is typical for aged speci-
mens, but uncommon in control group or other type of adhesive
systems. B: bonding resin; C: composite resin; D: dentin
Figure 7 Schematic representation of typical bond degrada-
tion of one-bottle self-etching adhesive. Some filler particles of
resin composite are occasionally floated in the upper part of
bonding resin layer. This morphological phase suggested that the
imperfect polymerization layer was presented onto the top
surface of bonding resin, the filler particles can penetrate.
The degradation at the adhesive/composite border is common
for most one-bottle self-etching adhesives, but none or very rare
for other type of adhesives. The staining pattern could not be
clearly observed in control specimens such as 24 h bonding.
However, in vivo test results are required in further
research.
5. Summary
Although clinical performance depends on the respective
adhesive systems, recent long-term clinical trials of resin
composites in non-carious cervical lesions demonstrated
good clinical performance [87,88]. However, laboratory stu-
dies of bond degradation will open the way for the develop-
ment of new adhesive resin systems that are more stable and
have compatible components from the chemical polymer
M. Hashimoto et al.
aspect [89—91] and morphological nature in the future.
Degradation of the resin composite at the filler—matrix
junction (hydrolysis of the silane coupling agent) was easily
observed in teeth that functioned in vivo in monkeys and in
humans over 1 year [11,12], though the same morphological
results are not available for in vitro aging tests such as long-
term water storage or thermal cycling. Many studies have
reported the enzyme-catalyzed hydrolysis of ester linkage in
metharylate-based monomers of resin composite [43,92—
94]. It is well known that esterases (i.e. cholesterol esterase,
salivary esterases, or porcine liver esterases) induce ester
hydrolysis. In contrast to resin or collage hydrolysis, careful
comparison between in vivo and in vitro resin composite
degradation is needed. In addition, analysis of the degrada-
tion of bonding resin by esterases in vitro will be an important
research topic in the future.
A variety of chemical and physiological factors affect the
durability of resin—dentin bonds. This review article concen-
trates on the morphological evidence of bond degradation.
The long-term durability and degradation patterns of resin
adhesives have changed with the types of adhesives during
the last two decades. There are clear differences among
total-etching systems (etch-and-rinse system), self-etching
system, and one-bottle self-etching systems. Typical mor-
phological evidence of degradations is provided by collagen
hydrolysis of total-etch adhesive systems, resin elution from
the hybrid layers of all systems, and hydrolytic degradation at
the border between the adhesive/composite junction of one-
bottle self-etching adhesives. In addition, the results in many
previous studies give promise for the translation of in vitro
into in vivo results for bond testing and morphological ana-
lysis of resin and collagen hydrolysis. This biodegradation
research will provide an avenue of progress for newly devel-
oped resin adhesives.
Acknowledgements
This work was supported, in part, by Grants-in-Aid for Scien-
tific Research No. 20592384, and for High-Performance Bio-
medical Materials Research from the Ministry of Education,
Science, Sports and Culture, Japan.
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