Novel Antibacterial Hydraulic Cement for Oral Biofilm Infection A

Terahertz(THz) chemical microscope(TCM) measurement system
for chemical reactions are proposed and developed.
・ In developed countries, the oral
health management of aging
society is one of important
national issues recently (Fig. 1).
・ Oral problems significantly
reduce Quality of Life (QOL).
・ Oral care reduces the risk of
systemic disease, like aspiration
pneumonia, however, the
completion of oral care is
extremely limited by the number
of dental professions.
Pat. US8710440 and US8300223.
The key component of TCM is a ‘sensing plate’ which consists of
Si and SiO2 film on the substrate. When ultra-fast lasers hit the
sensing plate, the THz pulses are radiated into free space. As the
amplitude of THz pulses is linked to the chemical reactions
on the sensing plate, the chemical reactions can be visualized by
scanning the laser across the sensing plate.
Fig. 1
To manage oral biofilm
infections is essential
for QOL.
Prototype TCM
Sensing Plate
Excitation Laser Pulse
Enzyme
・Our concept is very simple. Hydraulic cement is mixed with
bacteriocide and cetylpyridinium chloride (CPC).
Metabolic target
(LDH)
てんかん患者の約３割には、既存の治療薬が奏功しません。その難治性てんかん患
者に、食事療法（ケトン食療法）が有効です。つまり、ケトン食療法には、既存の
治療薬にはない作用機序があると想定されます。我々は、ケトン食療法に基づく治
療薬の開発方法を見出しました。
Tsuyoshi Inoue, Ph.D.
Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Kazuhiro Omori, D.D.S, Ph.D., Takashi Ito, D.D.S, Ph.D.
Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
0.45
0.40
400
600
0.1500
4
0.1200
3
0.09000
2
0.06000
Pump
Pump
Immune Assay
Avidin Immobilized Area
0
0.03000
1
12
0
2
0
4
X-Axis
6
10
8
(mm)
pH Imaging
44
4
3
33
22
11
00
2
00
11
22
33
X-Axis (mm)
(mm)
X-axis (mm)
X-Axis
44
3.7
3.7
2.5
1.3
4
2
4
6
X-Axis
1.3
8
10
12
(mm)
Biotin
3
1
0
-1
-3
Avatin
Silica
Sapphire
Terahertz
signal
Laser
T.Kiwa et al., APL 96, 211114 (2010)
T.Kiwa et al., Appl. Opt. 46, 3324-3327 (2008)
1
-0.2
6
Catalytic Metal
2.5
02.5
00
-0.1
8
2
5.0
5.0
5.0
流速制御
T.Kiwa et al., JJAP 46, L1052-L1054 (2007)
(mm)
(mm)
Y-Axis
200
5
0
・High antibacterial activity was observed on oral pathogens
including methicillin-resistant Staphylococcus aureus (MRSA)
(Fig. 3).
超高齢化社会を迎える先進国にとって、口腔バイオフィルム感染症は国家的な懸案
事項となります。今回、私たちは、既存の歯科用水硬セメント（Caviton®，GC 社）
に殺菌成分である塩化セチルピリジニウム（CPC）を配合した抗菌セメントを作製し、
口腔バイオフィルムを形成する代表的な菌（ミュータンス菌、カンジダ菌、肺炎球菌）
や MRSA に対する高い抗菌効果を確認しました。本抗菌セメントは、口腔バイオフィ
ルム感染予防に簡便に応用できる新たな技術です。
TCM 画像取得
0.50
Time (s)
T.Kiwa et al., SPIE newsroom, (2013)
K.Akimune et al., APEX, (2014)
Immobilized Urease Membrane
μ-TAS
0.55
0
・The cement mixture with 0.5% CPC keeps the performance of
original cement including hardness.
・It is ready to use. No mixing with powder and liquid is required.
Filling with fingers provides no air turbine or dental engine for
adjusting.
Ion Detection
0.60
(a.u.)
・Commercially available dental hydraulic cement (Caviton®,
GC corporation) is easy to use for temporary sealing of dental
treatment, however, the problem is intrusion of oral pathogens
during the hardening of cement.
THz amplitude
Fig. 3
Y-axis (mm)
Y-Axis
(mm)
Y-Axis (mm)
A clinically-used
antiepileptic drug
THz radiation
Y-Axis
Fig. 2
Y-Axis
Y-Axis (mm)
(mm)
Metabolism-targeting
antiepileptic drugs
Ultrafast laser
The TCM is a ‘multi-purpose’ system for various kinds of chemical
reactions, e.g. immune reactions, catalytic reactions and redox
reactions so far.
・No intrusion of oral pathogens were observed during the
hardening of the cement mixed with CPC (Fig. 2).
Stiripentol
Si Film (150 nm)
Sapphire Substrate
(600 μm)
(mv)
LDH is a metabolic enzyme to suppress seizures, and stiripentol
is a compound to act on the LDH. Metabolism-targeting
antiepileptic drugs can be developed by using LDH as the
drug target and stiripentol as the lead compound.
Sensing plate
Trigger Laser Pulse
For PC antenna
THz amplitude
Roadmap to new antiepileptic drugs:
SiO2 Film (275 nm)
Solution, Gas
THｚ
Advantages of Our Antibacterial Hydraulic Cement
2. Lactate dehydrogenase (LDH) is a metabolic enzyme mediating
this lactate shuttle, and its inhibition hyperpolarized neurons
and suppressed seizures in a mouse model of epilepsy.
3. Stiripentol, a clinically-used antiepileptic drug for Dravet
syndrome, was an LDH inhibitor. A stiripentol analog also
inhibited LDH, and suppressed seizures more strongly.
Schematic of how to measure
chemical reactions
Amplitude
We obtained the following three findings.
1. A metabolic pathway in the brain (astrocyte-neuron lactate
shuttle) contributed to antiepileptic actions by ketogenic diets.
Oral Biofilm Infection Threatens a Life in Elderly !
Shine on chemical reactions by terahertz pulses
(mv)
Our findings (Science 347, 1362-7, 2015):
A Terahertz Chemical Microscope　THzamplitude
amplitude (mV)
THz
(mv)
As epilepsy is characterized by hyperexcitation of electrical activities
in nerve cells, an antiepileptic drug suppresses the hyperexcitation.
Therefore, antiepileptic drugs were designed to act on the molecules
regulating electrical activities in nerve cells such as an ion channel.
However, these antiepileptic drugs are ineffective for one-third of
epileptic patients. On the other hand, drug-resistant epilepsy can be
controlled by diet treatment ( ketogenic diet ). We found a new
strategy to develop a metabolism- targeting antiepileptic drug by
exploring ketogenic diet treatment.
Novel Antibacterial Hydraulic Cement
for Oral Biofilm Infection
THz amplitude (mV)
New Strategy to Develop an Antiepileptic Drug
THz
THz amplitude (mV)
Targeting Metabolism:
T.Kiwa et al., Sens. Act.:B, 187, 8-11 (2013)
T.Kiwa et al., IEEJ Trans. Sens. Micromachines,
T.Kiwa et al., APL 86, 261102 (2005)
T.Kiwa et al., Opt. Exp., 22, 1330-1335 (2014)
129, 221-224 (2009)
T.Kiwa et al., Opt. Exp. 20, 11637-11642 (2012)
(Selected in Virtual J. Biomed.I Opt.)
0
0
1
2
3
4
我々の研究グループでは、化学反応の分布を可視化することができる新しい顕微鏡
X-Axis (mm)
「テラヘルツ波ケミカル顕微鏡」の開発を行っています。これまでに、抗原抗体反応、
触媒金属の反応など様々な反応の可視化に成功してきました。
Toshihiko Kiwa, Ph.D. in Eng.
Graduate School of Natural Science and Technology