Research Express@NCKU - Articles Digest

Research Express@NCKU Volume 8 Issue 7 - May 1, 2009 [ http://research.ncku.edu.tw/re/articles/e/20090501/1.html ]

An exploratory model of knowledge flow barriers within healthcare organizations Chinho Lin1,*, Bertram Tan2, Shofang Chang3

1Department of Industrial Management Science & Institute of Information Management, National Cheng Kung University, Tainan, Taiwan, ROC 2Institute of Business Administration, Kun Shan University of Technology, Tainan, Taiwan, ROC 3Institute of Health Information & Management, Chia Nan University of Pharmacy & Science, Tainan, Taiwan, ROC linn@mail.ncku.edu.tw Information & Management, 45(5), pp. 331-339, 2008

1.Introduction

Healthcare IS today are mainly knowledge-based and the diffusion of

medical knowledge is imperative for optimal treatment of patients. Our

study of the industry explored barriers to knowledge flow using a

Cultural Historical Activity Theory (CHAT) framework. Our work was

exploratory and qualitative in nature, and consisted of three phases: in-

depth interviews to explore medical knowledge flow barriers resulting in

a model; a case study using a survey approach to test and modify the

model; and a Delphi study to validate the generalizability of the model.

Figure 1 CHAT applied to knowledge flow

2.Determinants of and barriers to knowledge flow

Knowledge flow barriers into the categories shown in Table 1:

Table 1 Barriers to medical knowledge flow

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3.Research process

In phase I. 25 physicians from 7 different hospitals were involved;

In Phase II, 129 physicians from a medical center were used; and

In Phase III, 20 experts or middle medical managers were interviwed. The research process is shown

in Figure 2.

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Figure 2 Research process

4.Analysis

In Phase I, we classified medical knowledge barriers and derived two propositions which are as follows:

Proposition 1: Medical knowledge flow barriers can be classified into five categories: knowledge source

barriers, knowledge receiver barriers, characteristics of the knowledge transferred barriers, contextual

barriers, and insufficient mechanisms.

Proposition 2: The five categories of medical knowledge flow barriers are not independent; they affect

one another.

In Phase II, we revised proposition1 is as followed: ”Medical knowledge flow barriers can be classified

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into five categories: knowledge source barriers, knowledge receiver barriers, knowledge transferred

barriers, knowledge flow context barriers, and organizational context barriers;” and tested of proposition

2 which is supported.

In Phase III, we derived the final model which is depicted by Figure 3:

Figure 3 Final model: revised CHAT applied to medical knowledge flow

5.Conclusion

Our approach was the first to emphasize the importance of context between “knowledge sources” and

“receivers”, since previous studies concentrated only on the organizational context. It complemented the

original CHAT theory and is the first to propose a holistic model concerning medical knowledge flow in

terms of five knowledge flow barriers. It allowed for the complexity of the context and diversity of

stakeholder perspectives.

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Research Express@NCKU Volume 8 Issue 7 - May 1, 2009 [ http://research.ncku.edu.tw/re/articles/e/20090501/2.html ]

Liquid Phase Deposition of Al2O3 Thin Films

on GaN Sarbani Basu, Pramod K. Singh, Jian-Jiun Huang, and Yeong-Her Wang*

Institute of Microelectronics, College of Electrical Engineering and Computer Science, National Cheng Kung University yhw@eembox.ncku.edu.tw Journal of The Electrochemical Society, 154 (12) H1041-1046 (2007)

Much attention has been focused on replacing SiO2 with Al2O3 as

a dielectric insulation film for semiconductor device applications due

to the latter’s large band gap (~9 eV), higher dielectric constant (k =

10), high breakdown electric field (5 -10 MVcm-1), good thermal

stability (amorphous up to 1000o C), chemical stability against

AlGaN (without inter-diffusion and interaction of Si and Al), and

lower lattice mismatch to GaN. Because of these properties, ultra

thin alumina films of nanometer scale are widely used as high-k

material to replace SiO2 in microelectronic devices such as dynamic

random access memories (DRAMs) and metal-oxide semiconductor

field effect transistors (MOSFETs) based on both Si and III-V

compound semiconductors.

Many conventional methods for fabricating Al2O3 films are described in different papers, including

thermal oxidation, metal organic chemical vapor phase deposition (MOCVD), direct current reactive

magnetron sputtering, photo luminescent alumina films by pyrosol process, and atomic layer deposition

(ALD) process. The growth of Al2O3 thin films as achieved by the above-mentioned techniques involves

high substrate temperatures (>750). This causes thermal strain and defect states in the semiconductor

oxide interface, which in turn degrade device performance. In this study, our aim was to deposit the thin

Al2O3 insulating layer for GaN MOSHEMT device application to reduce the gate leakage current.

This LPD deposition system contains a temperature-controlled water bath that offers a uniform

deposition temperature with ± 0.1 accuracy, a substrate holder, a Teflon beaker, a magnetic stirrer for

the high homogeneity of the growth solution, a pH meter. Aluminum sulfate (Al2(SO4)3.18H2O) was

placed in a Teflon beaker, and a small amount of water was added to form a nearly saturated solution of

Al2(SO4)3 as a source liquid. After the addition of NaHCO3, the hydrolysis of Al3+ particles and the

concentration of Al(OH)3 colloid particles increased. As soon as the reaction was completed, de-ionized

water was immediately added in order to increase the pH value to 3.80, which is the optimized pH value

used for the deposition of an alumina film. The growth solution was transparent, and all the parameters

were optimized with Al2(SO4)3 = 0.0834 mol/L and NaHCO3 = 0.211 mol/L (final concentrations). The

chemical reaction of film growth can be described in the following:

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Fig. 1 film thickness vs deposition time

Fig. 1 shows the film thickness of Al2O3 with

deposition time at different growth temperatures.

It was observed that after more than 3 h, the pH

value decreased from 3.80 to 3.67, and the

solution slowly started to become turbid due to

the precipitation phenomenon of Al(OH)3. The

slight decrease in pH value was caused by the

consumption of NaHCO3 in the reaction.

Temperature was also a big factor in controlling

film growth quality and deposition rate. At a

higher temperature (i.e., 40), film quality

became poor, and the growth solution quickly

became turbid. For different oxide thicknesses,

the refractive index of the deposited samples varied from 1.50 to 1.65.

Fig. 2 displays the surface morphologies of oxides on GaN for different annealing temperatures. The

AFM data (the scan rate was 1.3 Hz, and the set point was 0.158 V) shows that the root mean square

surface (RMS) roughness of a 50 nm-thick Al2O3 film was (height modulation in the 2×2 μm2) only

1.025 nm after high-temperature annealing at 750, which was very low as compared to SiO2 on a GaN

substrate (5.2 nm). The surface morphology was improved after high-temperature annealing. Therefore,

this smooth surface result provides potential for GaN MOS-HEMT device applications.

Fig. 2 AFM (3D image) surface morphology of Al2O3 oxide deposited on a GaN substrate for different

annealing temperatures in N2 ambient for 30 mins.

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Fig. 3(a) shows the typical leakage current density of LPD-grown Al2O3 thin film on GaN annealed at

150 for 30 mins. At an electric field of 1 MV/cm, the corresponding leakage current densities ranged

from 10-4 to 10-5 A/cm2. The breakdown electric field was more than 10 MV/cm for a 50 nm oxide

thickness. Furthermore, the leakage current density could be improved by a high-temperature annealing

of oxide films. Fig. 3(b) shows the improvement of leakage current density with a higher annealing

temperature in N2 ambient. After annealing at 750, the leakage current density was reduced to the

order of 10-6 to 10-7 A/cm2 at an electric field of 1 MV/cm. This leakage current density of thin Al2O3

film on GaN was quite comparable or better than that of SiO2 on GaN and Al2O3 on Si by sputtering.

However, the result shows that the breakdown field was higher.

Fig. 3 (a) The log I-V characteristics for the 50 nm-thick Al2O3 on GaN annealed at 150 for 30 mins.

(b) The improvement of leakage current densities with varying annealing temperatures.

Fig. 4 The measured and ideal C-V characteristics

at 1 MHz.

Fig. 4 shows the typical C-V characteristics measured by 4280A at frequency 1 MHz. The thin

line and thick solid lines in Fig. 8 represent the

experimental results of the as-grown and

annealed films at 150 for 30 mins in N2

ambient, respectively. The approximate curve of

ideal C-V characteristics based on theoretical

calculation is also shown in broken lines. The

interface charge density (Dit) and flat-band

voltage (VFB) can be determined by employing the

equation Dit = Cox/q [(d¢s/dV)-1-1] - CD/q, where

Cox and CD are the oxide and depletion

capacitance, respectively. The surface potential (¢

s) is the potential difference across the space

charge layer. At ¢s = 0, the applying bias voltage represents the VFB. According to the plot and calculated

results, the VFB was +2 V and +0.2 V for the as-grown and annealed samples, respectively. The

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calculated interface trap densities were 3.89×1011 cm-2eV-1 for an oxide thickness of 50 nm on GaN

annealed at 150 (30 mins) and 5.59×1011 cm-2eV-1 for the as-grown oxide film. Thus, after annealing,

the average Dit near the mid gap of the LPD-grown oxide was reduced from 5.59×1011 cm-2eV-1 to

3.89×1011 cm-2eV-1.

In summary, we have achieved a low-cost, more efficient, and low-temperature (~30) liquid phase

deposition of Al2O3 thin films on GaN. The refractive index and relative permittivity of oxide were 1.55

and 9.7, respectively. Moreover, the results showed that in terms of AFM pattern, leakage current

density, breakdown electric field, and interface trap charge density, this LPD-Al2O3/GaN method

provides a unique opportunity to make high-quality gate dielectrics for GaN MOSFET applications.

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Research Express@NCKU Volume 8 Issue 7 - May 1, 2009 [ http://research.ncku.edu.tw/re/articles/e/20090501/3.html ]

Contact measurement of internal fluid flow within poly(n-isopropylacrylamide) gels Wei-Chun Lin1,*, Kenneth R. Shull1, Chung-Yuen Hui2, Yu-Yun Lin3

1Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA 2Department of Theoretical and Applied, Mechanics, Cornell University, Ithaca, NY 14853, USA 3Department of Civil Engineering, National Cheng Kung University, Tainan 701, Taiwan *w-lin5@northwestern.edu

3cyylin@mail.ncku.edu.tw Journal of Chemical Physics, 127(9), 2007, Art. No 094906

Associate

Professors, Yu-

Yun Lin

Gels are porous materials composed of subunits that are able to bond with each other

to form a macroscopic network. An important characteristic of gels is that their

mechanical behavior depends on the time scale of the measurement used to probe the

material. At sufficiently short times a gel behaves as an incompressible material

because there is no time for fluid to flow out of the network. At extended times,

however, the gel acts as a compressible material. Polymer gels, consisting of a network

of cross-linked polymer chains, swollen with a small molecule solvent, are another

important class of gels, with widespread applications in medicine and biomedical

engineering. In the eye, for example, the lens and the vitreous body, the large space

behind the lens, are gels. Changes in the viscoelastic properties of the lens can lead to

the loss of accommodation, or its refractive power, while changes in its permeability can create the onset of

a mature cataract. Liquefaction of the vitreous body—i.e., when the gel deteriorates to a liquid phase—is

believed to play an important role in retinal detachment. Measuring the transport properties and

mechanical properties of these gels could therefore have potential clinical applications. Additionally, an

understanding of bulk properties in gels is applicable to the development of controlled drug delivery

systems that are used in pharmaceutical, and cosmetic applications. Quantifying the bulk transport

properties of gels is essential in each of these situations.

Measurement of the transport properties of polymer gels has traditionally been accomplished by light

scattering or by direct mechanical measurement. However, the nature of these measurements is limited to

transparent samples since light scattering is not possible for opaque gels, such as in the case of a cataract

that affects the lens of the eye. These types of gel can be tested using mechanical method. For extremely

flexible samples (moduli of several kilopascals), this study utilizes a flat, circular punch, in addition to flat,

rectangular punch, to characterize the transport and mechanical properties of a polymer gel. These

geometries are depicted in Figs. 1(a) and 1(b), respectively.

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Fig. 1(a), 1(b) Fig. 2

The model system chosen for this study is a poly(N-isopropylacrylamide) (pNIPAM) gel. pNIPAM is used

because of its unique phase behavior and physical properties. These gels have generated much interest in

the medical community, largely because of their phase behavior. pNIPAM gels undergo a reversible phase

transition at a lower critical solution temperature (LCST) of ~33 in aqueous solutions, a temperature

close to the human body. Below the LCST the polymer networks swell with solvent, resulting in clear,

homogeneous gels, with water molecules forming cagelike structures around hydrophobic groups of the

pNIPAM macromolecules. Above the LCST, the gel dehydrates and the phase separates, forming a

heterogeneous, opaque structure. Phase separation occurs when the structure of the water molecules

around the hydrophobic groups is disrupted, causing these hydrophobic groups to associate. The collapse of

the network leads to polymer-rich and solvent-rich regions throughout the gel. The transition from a

swollen, homogeneous gel at T=22 to a shrunken, heterogeneous gel at T=39 is depicted in the

photographs in Fig. 2.

In the indentation experiments an indenter is brought into contact with a thin layer of a pNIPAM gel, using

a probe tack apparatus that is shown schematically in Fig.3. We subject the gel to a two-step displacement

history in the linear elastic regime. Figure 4 illustrates the time dependence of the load and displacement

for a typical experiment.

Fig. 3

Fig. 4

First, the rigid indenter is brought into contact with the sample until a predefined maximum compressive

load is reached. The displacement is then fixed for 1000 s as the gel relaxes due to solvent flow and

viscoelastic relaxation of the gel network. Immediately following this period of stress relaxation,

displacement oscillations with a 20µm amplitude are applied at frequencies ranging from 1.0 to 0.002 Hz.

Elastic moduli obtained from oscillatory tests performed at 22 and 39are shown in Fig. 5. The shear

moduli plotted in Fig. 5 were approximated by neglecting the effects of solvent flow, i.e., by taking veff=0.5.

This is a very good approximation when the phase angles are small, as is indeed the case in our

experiments. These phase angles are plotted in Fig.6.

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Fig. 5 Fig. 6

In the case where the energy dissipation is entirely due to the solvent flow, a predictive model for the phase

angles can be developed. We begin by defining the following response function Y(t), which describes the

response of the material to an instantaneous displacement increment δ0:

where Y0 describes the instantaneous response and λ describes the fractional relaxation due to the solvent

flow. The specific functional form of the unit force response Y(t) depends on the loading geometry and is

not generally available. However, for an indenter with circular cross section against a porous half-space (a/

h«1, a is the punch dimension and h is the gel thickness), Lin and Hu have obtained the following

expression for Y(t):

where and the normalized time T=Dct/a2.

If we consider the following steady state oscillatory displacement functionδss(t)=δωeiωt, the resulting steady

state force is

where Y∞=Y0(1-λ). The phase angle is given by

Combination of the above equations leads to the following approximate expression for the phase angle for a

flat circular punch,

(*)

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Where Ω as the normalized angular frequency,

We define an effective pore size , Dpis the permeability of the gel. Equation (*) is a central

theoretical result of this paper, which relates a measurable phase angle to relaxed Poisson’s ratio (through

λ) and the pore size (through Ω).

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Research Express@NCKU Volume 8 Issue 7 - May 1, 2009 [ http://research.ncku.edu.tw/re/articles/e/20090501/4.html ]

Development of a Novel Conditionally Replicating Pseudorabies Virus for HER-2/neu-Overexpressing Bladder Cancer Therapy Ai-Li Shiau1,*, Wen-Luan Wu2, Ming-Derg Lai3, Chao-Liang Wu3

1Departments of Microbiology and Immunology, 2Department of Biology, 3Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan alslhiau@mail.ncku.edu.tw Molecular Therapy 15: 131–138 (2007)

Conventional therapies for transitional cell carcinoma of the bladder

often result in poor prognosis. HER-2/neu is a cell surface proto-

oncogene that is often overexpressed in various cancers. Higher

frequency of HER-2/neu overexpression has been observed in muscle-

invasive bladder cancer, which correlates with enhanced metastasis and

a poor clinical outcome. Overexpression of HER-2/neu enhances

invasion, angiogenesis, and increased survival of cancer cells, leading to

increased cancer metastases. Therapeutic strategies to targeting HER-2/

neu-overexpressing cancer cells have shown promise for cancer

treatment. Pseudorabies virus (PrV), a herpesvirus of swine, may be

exploited as an oncolytic agent for human cancer. Herein, we generated

a novel conditionally replicating glycoprotein E-defective PrV mutant carrying glycoprotein D and

herpes simplex virus type 1 thymidine kinase genes, which are essential for viral entry and replication,

under the transcriptional control of the HER-2/neu promoter (Figure 1).

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FIGURE 1. (A) Schematic presentation of the strategy for generating YP2 virus, a gE-defective PrV

carrying gD and HSV-1 TK genes driven by the human HER-2/neu promoter. The CW1 virus is a gD/gE/

TK-defective PrV mutant carrying HSV-TK gene inserted in the place of the gD gene. The bicistronic

expression vector pDgD/HER2pr-gD-IRES-TK contains the human HER-2/neu promoter and the

coding regions of gD and HSV-TK linked by an IRES sequence. MBT-2 cells were transfected with pDgD/

HER2pr-gD-IRES-TK plasmid followed by infection with CW1 virus, yielding YP2 virus. (B) Detection of

gD and HSV-TK sequences from YP2 by PCR. (C) Southern hybridization of YP2. DNA from CW1 (Lane

1), TNL (Lane 2), and YP2 (Lane 3) were digested with BamHI.

First, we examined the expression levels of HER-2/neu protein in a panel of cancer cell lines and mouse

NIH3T3 fibroblasts by immunoblot analysis. HER-2/neu was highly expressed in TSGH-8301, MBT-2,

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and HCDB-1 cells, with the highest levels in TSGH-8301 cells. The lowest levels of HER-2/neu

expression were found in NIH3T3 and TCC-SUP cells. Furthermore, to compare the transcriptional

activity of the HER-2/neu promoter among these cells, HER-2/neu promoter activity was determined

with the luciferase reporter assay. The cytomegalovirus (CMV) early promoter was active in NIH3T3,

MBT-2, and HCDB-1 cells, with highest activity found in NIH3T3 cells. However, the HER-2/neu

promoter activity was detected only in MBT-2 and HCDB-1 cells, but hardly detectable in NIH3T3 cells.

Thus, the ratio of HER-2/neu to CMV promoter activity was higher in MBT-2 and HCDB-1 cells than in

NIH3T3 cells. In human bladder cancer cells, the ratio in TSGH-8301 cells was higher compared with

that in J82 and TCC-SUP cells. Notably, the human HER-2/neu promoter activity was weaker in non-

human cancer cells than in human cancer cells, as compared with the CMV promoter. Taken together,

these results indicate that TSGH-8301 cells possessed significantly higher HER-2/neu promoter activity

and expressed more HER-2/neu proteins than J82 and TCC-SUP cells. In non-human cells, MBT-2 and

HCDB-1 cancer cells exhibited much higher HER-2/neu promoter activity than NIH3T3 fibroblasts

(Figure 2).

FIGURE 2. Expression of HER-2/neu proteins and transcriptional activities of HER-2/neu and CMV

promoters in various cells. (A) Expression of HER-2/neu proteins in various cancer cells and NIH3T3

fibroblasts examined by immunoblot analysis. Expression of β-actin served as the quantitative control.

(B) HER-2/neu and CMV promoter activities were assessed by the luciferase reporter assay. Cells were

transfected with pGL-HER-2-Luc or pGL-CMV-Luc and the transfection efficiency was standardized to

the cotransfected plasmid pTCY-LacZ expressing β-gal driven by the β-actin promoter. Relative

promoter activity is expressed as a ratio of relative luciferase activity driven by the HER-2/neu promoter

divided by that driven by the CMV promoter in (C) MBT-2, HCDB-1, and NIH3T3 cells, and (D) TSGH-

8301, J82, and TCC-SUP cells.

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We then examined YP2-induced CPE in various cell lines through light microscope and crystal violet

staining. Either YP2 or TNL caused CPE in MBT-2 cells that overexpress HER-2/neu, whereas CW1, as

expected, did not induce CPE in the cells. TNL dose-dependently lysed all the cell lines examined at 3

days postinfection, whereas YP2 exerted differential cytolytic effects on these cells. YP2 caused CPE in a

dose-dependent fashion in HER-2/neu-overexpressing TSGH-8301 and MBT-2 cells. Notably, neither

non-HER-2/neu-overexpressing cancer cells nor NIH3T3 fibroblasts showed CPE when infected with

YP2. Nevertheless, TCC-SUP cells were as susceptible as TSGH-8301 cells to TNL infection, while J82

cells were more resistant to TNL-induced cytolysis. Interestingly, CPE in HCDB-1 cells infected with YP2

appeared more pronounced than that infected with TNL. In a separate experiment, cell viability was also

measured by trypan blue exclusion 4 days after infection with YP2, TNL or CW1 at 2 × 104 TCID50. The

viability of YP2- or CW1-infected NIH3T3 cells did not differ significantly from that of the mock-infected

counterpart, whereas viable cells in TNL-infected cells were scarcely detected. By contrast, the viability

of MBT-2 cells decreased dramatically after YP2 or TNL infection, but remained unchanged after CW1

infection when compared with mock-infected cells (Figure 3).

FIGURE 3. CPE in various cell lines after infection with YP2, TNL or CW1. (A) CPE in MBT-2 cells

infected with YP2 or TNL, but not CW1. MBT-2 cells were infected with YP2, TNL or CW1 and monitored

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for CPE. (B) CPE in MBT-2, NIH3T3, TSGH-8301, TCC-SUP, J82, and HCDB-1 cells after infection with

TNL or YP2. Cell were infected with varying doses of TNL or YP2, and monitored for CPE by crystal

violet staining at 3 days postinfection. Cell viability in (C) NIH3T3 and (D) MBT-2 cells after infection

with TNL, CW1 or YP2.

Because YP2 replication was dependent on the production of gD and TK, which was under the

transcriptional control of the HER-2/neu promoter, we investigated whether difference of the HER-2/

neu promoter activity in MBT-2 cells influenced the cytolytic effect of YP2. MBT-2 cells exerted higher

HER-2/neu promoter activity when treated with TPA and retinoid acid, which rendered MBT-2 cells

more susceptible to YP2-induced cytolytic effects (Figure 4).

FIGURE 4. Modulation of HER-2/neu promoter activity affected YP2-induced cytolysis in MBT-2 cells.

MBT-2 cells were transfected with pTCY-E1A and pGL-HER-2-Luc. (A) Cell lysates were harvested after

transfection and their luciferase activities were determined. (B) Cells were infected with various doses of

YP2 and monitored for CPE by crystal violet staining. (C) MBT-2 cells were transfected with pGL-HER-2-

Luc and pTCY-LacZ. After 24 h, cells were treated with TPA and retinoic acid and their luciferase

activities were determined. (D) MBT-2 cells were infected with various doses of YP2.

YP2 treatment significantly retarded MBT-2 bladder tumor growth compared with CW1 or PBS

treatment. Increased survival was also observed in YP2-treated mice in comparison with CW1-treated or

PBS-treated. Immunofluorescent staining with swine antiserum against PrV demonstrated that PrV

proteins were detected within MBT-2 tumors after intratumoral injection with either YP2 or TNL,

whereas only background expression was observed with the tumor of PBS-treated animals. Furthermore,

hematoxylin-eosin staining revealed that the intratumoral infiltrate of mononuclear cells was more

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pronounced in the tumors injected with YP2 or TNL than those injected with PBS (Figure 5).

FIGURE 5. Antitumor effects of YP2 on immunocompetent mice bearing bladder tumors. Groups of

C3H/HeN mice that had been inoculated s.c. with MBT-2 cells at day 0 were treated intratumorally with

of YP2 or CW1, or with PBS daily from days 7 to 13. (A) The mean tumor volume is shown and the data

are presented as mean ± SD. (B) Kaplan-Meier survival curves. (C) Detection of PrV proteins within

MBT-2 tumors in vivo.

Taken together, our results suggest that YP2 may have therapeutic potential for the treatment of invasive

bladder cancer. Furthermore, because HER-2/neu is overexpressed in a broad spectrum of cancers, this

conditionally replicating PrV may be broadly applicable.

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Research Express@NCKU Volume 8 Issue 7 - May 1, 2009 [ http://research.ncku.edu.tw/re/articles/e/20090501/5.html ]

A portable potentiostat for the bilirubin-specific sensor prepared from molecular imprinting Chun-Yueh Huang1, Mei-Jywan Syu2,*, Yong-Shuen Chang2, Chih-Hung Chang3, Tse-Chuan Chou2, Bin-Da Liu4 1Institute of Communication Engineering, National University of Tainan, Taiwan, ROC 2Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan 70101, ROC 3Department of Electronic Engineering, Kun Shan University of Technology, Taiwan, ROC 4Department of Electrical Engineering, National Cheng Kung University, Taiwan, ROC syumei.bioeng@gmail.com Biosensors and Bioelectronics 22 (2007) 1694–1699

Bilirubin is an end product from hemoglobin metabolism. Total and

direct bilirubins are usually measured to screen or to monitor liver and gall

bladder disfunctions. The bilirubin test can be used to judge a liver disease

or a blocked bile duct. Owing to the physiological importance of bilirubin, it

was chosen as the target molecule to be investigated in this work. The

electrochemical sensor for bilirubin was prepared from molecular

imprinting in this work. The molecular imprinting technique is an

important tool for the measurements particularly for biosensors because it

has the advantages of high selectivity, sensitivity, and lowcost. In 1997, the

MIP for sensor technology was discussed. A review on the application of

molecularly imprinted polymer to the biomimetic sensors was published.

Based on molecularly imprinted polymers (MIP), the electrochemical

sensors for a variety of applications can be made.

Electrochemical biosensors, which can show the detected data by means of potential or current, are

commonly applied in DNA identification, protein classification, neural recording, glucose determination, or

pH variation detection. In the signal processing, each electrochemical sensor needs a potentiostat to

maintain the electrochemical stability for the sensor and to convert the sensor’s output into an analog

signal. So, the potentiostat is an indispensable device for the electrochemical sensors. Many researchers

devoted themselves to develop the single chip potentiostat so that the chip size and cost can be both

reduced. The emphasis from these researchers was focused on the integration of potentiostats and sensors.

A potentiostat designed with portability would be described and implemented in this work. Additionally, an

SOC-based chip was further used for the portable potentiostat to improve the system performance as well as

to reduce the cost. As a result, the measurement of the proposed potentiostat can be carried out in daily life.

Consequently, a potentiostat was designed and assembled for the electrochemical detection of bilirubin by

the electrode coated with imprinted poly(methacrylic acid-co-ethylene glycol dimethacrylate) thin film. The

performance from the proposed potentiostat was investigated from the cyclic voltammogram, current

signals, calibration sensitivity, reset time and steady response time.

Fig. 1 shows the circuit diagram of a portable potentiostat. The proposed potentiostat is mainly constructed

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by a C8051F020 mixed-signal microprocessor, a current-to-voltage converter, three inverter amplifier, two

low-pass filters, and an RS232 serial data transfer interface. The C8051F020 chip is an 8051 based CPU

with 12-bit digital-to-analog converters, 12-bit analog-to-digital converters, and digital peripherals. A

personal computer (PC) is used to control the experimental process and collect the experimental data of

potentiostat.

Fig. 1 The circuit diagram of the portable potentiostat.

The fabrication of the MIP onto the substrate is illustrated in Fig. 2. The bilirubin electrode was prepared by

synthesizing a thin layer of bilirubin imprinted poly(methacrylic acid-co-ethylene glycol dimethacrylate)

onto the Au layer. With the molecularly imprinted polymer (MIP) film, specific detection of bilirubin was

successfully achieved. The cyclic voltammetry profile of the MIP electrode obtained from the bilirubin

solution by this proposed assembled scan-mode potentiostat is shown in Fig. 3. The profile shows a

significant oxidation current around the potential of 0.4V. The scan rate was set to be 7.5 mV/s. In fact,

even without the MIP film, bilirubin can be oxidized into other compound. However, the binding specificity

of bilirubin toward this MIP film can be further helpful to reduce interference problem. The performance

from a commercial potentiostat was considered rather stable and was used as a reference to examine and

evaluate the performance of the assembled potentiostat. The detected current signals by the bilirubin

sensing were obtained. Linear calibration with a sensitivity of 1.344 ± 0.38 µA/mg/dl was achieved while

the one obtained from the commercial potentiostat was 1.600 ± 0.194 µA/mg/dl. It should be noticed that

the deviation might be a combined result from either the potentiostat or the MIP modified electrode. The

response signals by the AD-mode potentiostat were evaluated from the aspects such as the reset time and

steady-response time. Gathered the data from several batches (not shown here), the times required to reach

a steady state before the measurement were 1,983 ± 126 s (6.34%) from the proposed potentiostat.

Although the proposed potentiostat was slightly slower than the commercial potentiostat, they could reach

similar performance. For the steady-response time, it was 41.33 ± 2.15 s (5.21%) from the proposed

potentiostat. Similarly, the deviation on the reproducibility of the MIP electrode also contributed to the

standard deviation of the comparison made between the potentiostats.

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Fig. 2 Schematic illustration of the fabrication of the MIP film onto the electrode.

The calibration curves were further compared to those obtained from a 2.0 cm x 2.0 cm MIP electrode, the

coincidence amon g the data was rather high. The detection was performed by an MIP electrode of 1.0

cm x 1.0 cm. The detection area of 1.0 cm x 1.0 cm achieved a detection sensitivity of 1.344 µA/mg dl while

5.685 µA/mg dl (with a standard deviation (S.D.) of 0.393 and a relative standard deviation (R.S.D.) of

6.91%) for a corresponding area of 2.0 cm x 2.0 cm. The detection sensitivity was 4.23-fold with respect to a

detection area increment of four-fold. Therefore, within the experimental range of detection, the sensitivity

is almost linearly proportional to the electrode surface area. In conclusion, the detection precision

performance was rather good. To further achieve the limit of detection (LOD), the current signals were

measured at a lower bilirubin concentration range within 1.0 mg/dl. The surface area of the MIP modified

electrode was 1.0 cm x 1.0 cm. A calibration parameter of 0.950 ± 0.041 µA/mg/dl with an R.S.D. of 4.26%

was obtained. Therefore, the LOD at this range was confirmed. With this LOD, the detection of bilirubin

concentration from the serum of a normal adult can be expected. In addition, the noises of the detected

current signals were calculated. Therefore, the signal-to-noise ratio can be obtained as shown in Table 1.

Obviously, judging from the S/N ratio in the table, the detected current signal was significant enough for

measuring the bilirubin concentration.

Our experimental results showed that the proposed potentiostat’s performance could achieve sufficient

performance. The evaluation was also made from the aspects such as reset time and steady-response time.

The self-assembled potentiostat thus demonstrated its ability in precise detection of bilirubin from an

electrode layered with the imprinted polymer film. The calibration of bilirubin concentration from 0.1 to 1.0

mg/dl is also excellent, which is then feasible for the detection of the bilirubin concentration for a normal

adult. Although the performance from the assembled potentiostat may not be as equally good as the

commercial one, the ability to achieve precisely amperometric detection of bilirubin by the MIP modified

electrode was confirmed.

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Fig. 3 Cyclic voltammograms measured from the

proposed potentiostat in scan mode.

Fig. 4 The detected current signal profiles of the

bilirubin concentration from the proposed

potentiostat.

Table 1 The signal-to-noise-ratio data calculated from the detection current signals.

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