Hum rigin™

A part of something great®

 Li-Te Chin
Adjunct Associate Professor, Inst. of Life Science, Fu-Jen Catholic University

Dept. of Immunotechnology, University of Lund,

Dept. of Microbiology & Immunology, National

Institute of Preventive Medicine, National

Defense Medical Center, Taipei, Taiwan, R O C
Defense Medical Center, Taipei, Taiwan, R O C
Dept. of Biology, Fu-Jen Catholic University,

Research Director, Chinese Blood Services Foundation

Adjunct PI, Chinese Blood Services Foundation
1. Assistant Professor, Dept. of Medical Technology,
National Cheng-Kung University
2. Technical and Quality Supervisor, The Blood Bank of
NCKU University Hospital

Technical Director, General

Biologicals Corp., Taiwan
Taipei, Taiwan, R O C

CCO, SCI Inc., USA

CEO, Apex Biotechnology Corp.,
Taiwan
Lund, Sweden

CEO, HumOrigin, Taiwan

Adjunct Associate Professor, Dept. of Medical
Technology, China Medical University
Broad Member, Hsinchu Biomedical Industrial
Park, National Taiwan University
1982 1985 1987 1990
~ ~ ~ ~ 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
1985 1997 1990 1994
 57%
24% 132.3

32.9 84.5
26.5
23% 50
17.5 40 42.3
14.2
30
20 50%
15,000 20.8
10 14.1
U$ 9.4
10,000 13,243
U$2,560 0
5,000
2000 2030
0 44%
Non-diabetic Diabetic 33%
22.5
2002 15.6
annual medical expenses
1 1.3
World 2004-11-09
2000=151 million
2010=221 million 中國糖尿病患者超過5000萬
Increase: 46% 患者數量世界第一
American Diabetes Association Economic Costs of Diabetes in the U.S. in 2002 Source:
Diabetes
SOURCE: S.Zimmet
DiabetesPCare,
Care 26(3):917-932,
Wild, et al.
2003. MayNature. 2001;414:782.
2004; vol 27: pp 1047-1053.
 Million people
with diabetes
300

150

2000 2025

Source: World Health Organisation

September 1998

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
The worldwide market for diabetes therapeutics and diagnostics in 2000
was estimated at $12.4 billion.
Fueled by
A. increasing prevalence of the disease
B. improved therapeutics, delivery systems, and diagnostics,
the market will grow at a compound annual growth rate (CAGR) of 12%
to reach approximately $27 billion in 2010.
For glucose monitoring, the world market was estimated at $3.7 billion in
2000, and Theta Reports projects this market to grow to nearly $10 billion
by 2010.
Market growth will also depend on manufacturers' abilities to meet
market needs, including patients' demands for
A. smaller blood test samples, B. less invasive and painful testing,
C. easy-to-use features like: D. more cost-effective consumables,
large display screens, larger E. patent integrity
test memory, and more rapid results.
June 15, 2004
 Market Size ($billions) 8

6
6.0B

4.9B
4
3.7B

1.1B

0
Blood Oral
Insulin Insulin
Glucose medication
delivery therapy
Monitoring therapy
By Li-Te Chin, Ph.D. in Engineering
copyright reserved Source: 2002
 2000
Rest of the world Meter: 1,478
1,635
1,37813%
1500 1,214

782 880 1,000

1000 660
14% 478 564
500
Strips: 87%
24% ($M) 0
USA 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Europe
62%
1000
800 880

600
Blood glucose self- 400
monitoring products 200 300
220
75.27% = $1.4 B 0
($M) Fingerstick HbA1c F ructosa-
The 2000 OTC market blood glu- mine, urine
cose testing testing and
worldwide = $3 billion others
By Li-Te Chin, Ph.D. in Engineering
Source: The US Market for Over-the-Counter Diagnostics , 2001
copyright reserved
 12,000

10,000
11.2% 9,732
8,915
8,106
($ millions)

8,000 6,553
7,316

5,826
6,000 5,140

4,000

2,000

0
2003 2004 2005 2006 2007 2008 2009
Year
By Li-Te Chin, Ph.D. in Engineering
copyright reserved Source: Diagnostics & Imaging Week；工研院經資中心ITIS計畫(2004/07)
醫療器材與檢驗試劑
功能 外科手術器械 項目
矯形整形用醫材
(Surgical) (Orthopedic and prosthetic)

體外診斷器材 醫療器材 牙科器械

(IVD) (Medical Device) (Dental)

電子醫療器材 放射器械
(Electromedical) (Radiological)
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 30,000 28,861

25,554 : 1979
25,000 938億美金 : 1989
Value of Shipments ($ millions)

≈474億美金
: 1999
20,624 : 2004
20,000 1.4% 歐洲其它地區
17,846
歐盟 九十三年度中央
政府總預算歲出
16,713

15,000 為1兆6,113億元 13,507

10,660
22.9% 12,166

9379 9567
10,000

56.3% 5298
4821
5,000 3888 3949

2254
3443 17.2% 2932 2325
1335 1926 1667
1080 681 717
美洲 矯形整形用 亞洲/太
電子醫療器材
外科手術器械 醫材(Ortho - 平洋地區
牙科器械 放射器械 體外診斷器材
(Surgical) 2.1%
pedic and (Dental)Source:
(Radiological)
(Electro-
(IVD)
中東與北非地區 prosthetic) Espicom Business
medical) Intelligence
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 福永生技 厚美德生物科技
www.epsbio.com.tw www.hmdbio.com

惠碁生技
www.eumed.com.tw www.oncoprobe.com.tw

台欣生物科技
www.tysonbio.com www.bestgen.com.tw

www.hdiasc.com.tw
勤立生物科技
www.gtm.com.tw/bi001_ch.html
聿新生物科技

生苙醫療器材 泰博科技
www.taidoc.com.tw
www.biotestsystems.com
翔國科技
myweb.hinet.net/home3/stcds-1/corp.htm
華廣生技
(www.bionime.com) http://www.wegene.com.tw/
By Li-Te Chin, Ph.D. in Engineering
Updated: Feb, 2005
copyright reserved
 邁迪科技 41.25
翔國科技 5
泰博科技 60
勤立生物科技 80
1988年1月13日
倍晶生技 10
末 梢神經病變、腳
榮睿生物科技 360
>25.58E
趾循環不良傷口感
厚美德生物科技 83.19
染壞死而截肢
聿新生物科技 366
玻璃體出血、視網
威今基因科技
膜 剝離並且完全失 72.89
生苙醫療器材
明 150
台欣生物科技研發 289
五鼎生物技術 717.68
福永生物科技 110
惠碁生物科技 113
華廣生物科技 100

0 200 400 600 800

By Li-Te Chin, Ph.D. in Engineering
Updated: Feb, 2005
copyright reserved
兩岸檢驗試劑(醫療器材)產業比較

進 2004 (910)

技術開發能力
+1.6%
口

商品化能力
2003 (896)

專利保護

醫療品質
品質穩定度
出

基礎科學研究
2004 (610)
-13.6%
口 2003 (694)
+23.0%

內需市場規模

自製品佔有率

生產成本
進 2004 (3283.0)

法規
口 2003 (2528.6)
出 2004 (2777.0)
+35.3%
口 2003 (1798.1)
0 500 1000 1500 2000 2500 3000 3500
1U$ = 33.4 NTD
U$ in million

By Li-Te Chin, Ph.D. in Engineering 2005

copyright reserved
Source: IT IS,
 50

40
% of Death

30

20

10

0
Ischemic Other Diabetes Cancer Stroke Infection
Infection Other
Heart Heart
Disease Disease
 Common
bile duct

Pancreatic duct
Small intestine
(duodenum)

Exocrine
cells
: α cell secrets glucagon
Endocrine
cells
Islet of : β cell secrets insulin & amylin
Langerhans
α cells : D cell secrets somatostatin
β cells
D cells

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Glycogen ' Glucose
Triglycerides ' Fatty Acids
Proteins ' Amino Acids

Glucose oxidation  Glycogenolysis 

Glycogen synthesis  Gluconeogenesis 
INSULIN GLUCAGON
Fat synthesis  Ketogenesis 
Protein synthesis 

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 {
Fatty acids 
Plasma Amino acids 
Glucose
Amino Glucose  Insulin
Insulin acids
(Pancreas) To receptors Insulin
receptor Fatty acids

(Brain)

(RBC)
Fatty acids

Promotes anabolic processes &

Inhibits catabolic processes

(Muscle) (Liver) (Adipose tissue)

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Insulin deficiency
Insulin secreted
into bloodstream Pancreatic β-cell
destruction
capillary
Insulin-dependent
diabetes mellitus (IDDM)
Children and
adolescents
: Insulin-produ- : Insulin-producing Ketoacidosis
cing cells cells destroyed
~5%

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Genetic
Acquired
Glucotoxicity Insufficient glu
People whose pancreas
Lipotoxicity makes insulin but not enough, or who have insulin
-cose disposal
resistance, or both
Insulin deficiency
Insulin resistance (decreased insulin receptor sensitivity)
Impaired
A progressive Glucose-
disease associatedHepatic
Glucose-induced
with a combination of risk factors,
beta cell
glucose
including: insulin secretion production
function
Post
Hyperglycemia receptor
1. abdominalTissue
obesity,
response defect
Glucose Basal hyper-
hyper-
to insulin
uptake
2. high triglycerides, low high-density lipoprotein (HDL-C) cholesterol
Glucose insulinemia
transport
levels,Insulin
and resistance
Insulin
binding
3. hypertension
Genetic
Genetic
~95%
Acquired
Obesity
Age
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 2.5 million years 50 years

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
Pulmonary disease Idiopathic intracranial
abnormal function hypertension
obstructive sleep apnea Stroke
hypoventilation syndrome
Cataracts
Nonalcoholic fatty liver disease Coronary heart disease
steatosis Diabetes
steatohepatitis
Dyslipidemia
cirrhosis
Hypertension
Gall bladder disease
Severe pancreatitis
Gynecologic abnormalities
abnormal menses Cancer
infertility breast, uterus, cervix
polycystic ovarian syndrome colon, esophagus, pancreas
Osteoarthritis kidney, prostate
Skin
Gout Phlebitis
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Acquired: Obesity, Aging &
Genetics Insulin resistance Sedentary lifestyle
遺傳性因素 胰島素抗性 外在因素: 肥胖、年齡老化、
缺乏運動
Hyperinsulinemia
胰島素分泌過多症

Compensated insulin resistance

(Normal Glucose Tolerance) Impaired glucose tolerance
補償性胰島素抗性 【血糖耐受 血糖耐受缺損
正常】

Genetics Increased hepatic

β-cell “failure”
遺傳性因素 glucose output
肝臟葡萄糖輸出
Type 2 diabetes 第二型糖尿病 增加
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Glucose  Macrovascular
The Heart
kidneysattack
filter(Cardiovascular
and
someMicrovascular
glucose outdiseases)
Complications
of the blood
Kidney
into the urine,
Vision failure,
may get needing
making dialysis
the person
blurred. or transplant
urinate
(Retinopathy) more.
(Nephropathy)
Cuts may not heal as fast.
Visionmore
Urinating loss makes the person thirsty, to re-
Peopledamage
may get more skin infections.
placeNerve
the fluid lost. (Neuropathy)
Women may get more
Sexual problems vaginallack
[impotence, yeast
of infections.
arousal, dry
vagina]
People may get drier skin.
Losing the problems
Dental glucose in [gumthedisease,
urine makes people
lossinoftheir
teeth]
People may feel burning
lose weight, without trying to do so. or tingling feet.

All these changes make people tired all the time.

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Plasmaglucose
Plasma glucoselevels
levels(mmol
(mg glucose/dL):
glucose/L):
FPG OGTT
Diabetes ≥126
≥7.0 or ≥200
≥11.1
Impaired fasting Glycaemia >110<126
Fastingglucose ≥6.1<7.0
Impaired glucose tolerance >110<126
≥6.1<7.0 >140<200
≥7.8<11.1

FPG = Fasting plasma glucose

OGTT = Oral glucose tolerance test at 2 hours (75 g glucose)
Report of Expert Committee on the Diagnosis and Classification of Diabetes Mellitus,
WorldAccepted
6/97. Health Organization 1999; WHO/NCD/NCS/99.2
by ADA, NIDDK, and CDC
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
Mother:
1.Gestational
Type 1Diabetes
diabetes* - previously known as
may be present in 12.3% of North American pregnancies
A.tojuvenile
Unable diabetes
maintain control of blood sugar through control of nutrition alone &
B. insulin-dependent
will progress to insulin injections diabetes mellitus (IDDM)

2.UpType
to 60% will develop “true” diabetes (Type II) within the first year after
2 diabetes* - previously known as
delivery
A. adult-onset diabetes
More pregnancies with GDM, more at risk for GDM in subsequent
B. non-insulin-dependent diabetes mellitus (NIDDM)
pregnancies
3.More GDM pregnancies,
Other specific more risk (includes
types for diabetes later in life
Secondary Diabetes)
Fetus:
4. Gestational diabetes
Baby mellitus
uses mother’s blood sugar(GDM)
Excess blood sugar  > 9 lb (4082 g) baby
Difficult
*Patients with any form labor
of &diabetes
delivery may require insulin treatment at
some stage ofDisproportionate
their disease.growthSuch – shoulders
use of insulin does not, of itself,
Excess fat – lethargic; not healthy
classify the patient.
Baby very low blood sugars at birth
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
American Diabetes Association http://care.diabetesjournals.org/
Diabetes Control and Complications Trial (DCCT)
– Type 1 diabetics
Insulin/Oral medication & Exercise Food intake BG
– intensive therapy to control glycemia slows the onset
and progression of retinopathy, nephropathy, and
neuropathy
BG Kingdom Prospective Diabetes
United Study
Constant Juggling
– Type 2 diabetics followed for average of 10 years
– showed same benefits of intensive therapy to control
glycemia in reducing risks of retinopathy, nephropathy,
and possibly neuropathy
Exercising at least 30 minutes a day reduces
Type 2 risk more effectively than medication

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Type 2 slope observations:
50%
• β-cell function only at
approximately 50% at
Typ
e
diagnosis
2-
sl o
pe • Insulin therapy is the
β-Cell function

ultimate treatment and is

typically initiated some
7-12 years after
Type 1 –
diagnosis
Immediate need for insulin

Time from diagnosis

By Li-Te Chin, Ph.D. in Engineering

copyright reserved Source: Novo Nordisk Type 2 diabetes market research
 Medtronic MiniMed, Inc.
1-800-MINIMED (646-4633)
www.minimed.com
Disetronic Medical Systems, Inc.
1-800-280-7801
www.disetronic-usa.com
Deltec Cosmo
1-800-826-9703
www.deltec.com
Animas Corporation
1-877-YES-PUMP (937-7867)
www.animascorp.com

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Diagnosis

Therapeutic Lifestyle Change

Insulin required in
Monotherapy 20-30% of patients

Combination Therapy - Oral Drugs Only

Combination Therapy - Oral Drug with Insulin

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Hepatic enzyme
activators/inhibitors

Genetic Glucose-sensitive Insulin mimetics DPPIV

insulin
Acquired NovoNorm®
Glucotoxicity Vaccination
Lipotoxicity NN2501
Insulin deficiency Liraglutide

NovoRapid® Impaired
Stem cells Hepatic
NovoMix30® Glucose-induced glucose
beta cell
LevemirTM insulin secretion function
production
Post
NN344
Hyperglycemia receptor
NovoMix 50 & 70 Tissue response defect
Glucose Basal hyper-
NN1998 AERx iDMS to insulin
uptake Glucose insulinemia
Protein Delivery Systems
transport
NN2344 Insulin resistance PPAR α, γ, δ Insulin
11βHSD1 NN414 binding
Genetic
Acquired NovoNorm®
Obesity Liraglutide
Appetite
Age
regulators Kinase/phosphatase
modulator
Note: Light blue indicates selected key products already marketed, Red indicates projects in development,
Grey indicates selected projects within research
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Rosiglitazone  α-glucosidase inhibitors
(AVANDIA®, GlaxoSmithKline) Acarbose (Precose®, Bayer)
 Pioglitazone Miglitol (Glyset®, mfd. by Bayer
(Actos®, Takeda) for Pharmacia & Upjohn )

Pancreas
(Impaired insulin secretion)
 Sulfonylureas
(Orinase®, Pharmacia & Upjohn;
Adipose tissue Glucotrol®, Pfizer and Amaryl®, Gut
(Glucose uptake) AVENTIS )
(Glucose output)
 Repaglinide
(Prandin®, Novo Nordisk)

± Thiazolidinediones Hyperglycemia  Thiazolidinediones

Metformin
(Glucophage®, BMS)

Liver Muscle
(Hepatic glucose output ) (Glucose uptake)
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 玉竹蒸魚 山藥猪肚粥
川七
苡仁百合蒸石斑
當歸
丹參 山梔子

五味子煲仔雞 菟絲子餅

豆品飲料 黃精蒸海參

葛根飲
番石榴
山梔子
石斛生地茶
淮山枸杞粥
百合粥
柚子 糙米、蔬菜
人參 胡蘿蔔

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
To observe effect of new food on blood glucose:
Diabetes is Managed,
check blood glucose 2 hours after meal for several
But
daysit Does Not Go Away.
substitute food containing
carbohydrate in meal
GOAL: sugar for other

check blood glucose 2 hours

after meal and compare To maintain target
blood glucose

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 by health care workers in acute and chronic care facilities,
Portable meters are used in physicians’ offices and
by patients.

Site
(clinic, hospital)

Provider
(physician)

i Patient
i i Indicators
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Any Diabetic Microvascular
Stroke DM Deaths
Endpoint Complications
0
% Reduction in Relative Risk

5%
10%
-10 12%

-20
24%
*
-30 32% 32%
*
* P < 0.05 compared to tight glucose control
37%
-40
44% *
Tight Glucose Control Tight BP Control (Average
* (Goal < 144 mg/dL) 144/82 mmHg)
-50
Bakris GL, et al. Preserving renal function in adults with hypertension and diabetes: A consensus approach.
American Journal of Kidney Diseases,Vol 36, No 3 (September), 2000: pp 646-661
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 30
24.0 25.2
20

10

0
1996 2000
<4% 4─4.9%mortality5─5.9%
Age-adjusted rate >6%
(per 100,000)
CDC data on prevalence of diabetes across the United States in
1994 (left) and in 2000 (right). The rise in diabetes rates is striking.
In the year 2000, no states had less than 4% of the population
with diabetes, and only 10 states had under 5%.
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Worldwide Sales
Company Market Share (%)
($ millions)
Roche 1065 28 42
Johnson & Johnson 975 26 28
Bayer 675 18 16
Abbott 495 13 11
Home Diagnostics 100 3
Inverness 90 2
Others 370 10
Total 3770 100
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
Source: Merrill Lynch (Boston)
 May, 1997: $11 billion

Jan, 1996: $880 millions

®

Jan, 2004: $1.2 billions

May, 1978: $215 millions

Ames Nov, 1986: $100 millions

May, 2001: $1.3 billions

1978 1983 1988 1993 1998 2003 2008

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 1960: The GOD method 1983: "Accu-Chek"

1974: "Reflomat"

1994: "Accu-Chek Advantage"

® 1986: Exactech

1969: The first portable 1992: Glucometer Elite

blood glucose meter

Ames 1985: Meter with memory

1997: consumer cartridge

1941: Urine glucose test -based biosensor

1992: OneTouch Basic

1941 1951 1961 1971 1981 1991 1997

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 電壓，用”V”代表，單位是伏特(Volts)
流電如流水！
一江春水向東流

水壓
1826
李煜
Georg Simon Ohm
937-978
(1789~1854)
阻抗 =
V 水流
阻抗
水壓

I R
電流，用”I”代表，單位是安培(Amperes)

電阻，用”R”代表，單位是歐姆(Ohms)
水流

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 (−)
越容易丟電子
-1.0
Zn  Zn+2 + 2e− (-0.763)
-0.5 Fe  Fe+2 + 2e− (-0.441)
Pb  Pb+2 + 2e− (-0.126)
Voltage

0.0 Fe  Fe+3 + 3e− (-0.040) H2  2 H+ + 2e−

2+ 6− 3+ 6−
−
Fe(CN)64−  Fe(CN) e-6 + e (0.360)
3−
Cl SO44-2-2-
SO

0.5 Cu  Cu+ + e− (0.520)

Cu
Ag
Zn
Ag  Ag + e (0.799)
+ −  Cu
Ag
Zn ++
2+
2+ + e− −−
2e
1.0 Ag
Cu + ++Cl
Zn2+ SO −  ZnSO
2− AgCl
CuSO4
+0.682 +1.7604
0 -1 -2 越容易撿電子
(+) O2  H2 O 2  H2 O
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 -0.763V
e- e- e-
e- e-
0.337V

John Frederic Daniell

English physicist and
chemist, invented
Daniell's cell in 1836.
SO42-
SO
K+4+2-
Na SO
K+4+2-
Na SO
K+4+2-
Na Cl4−32--
SO
NO Cl4−32--
SO
NO Cl4−32--
SO
NO
SO42-
e- e-

Cu2++Cu −
2e2+ + 2e
Cu− Zn  Zn2+ + 2e−
SO4
Cu2+2−+ SO42−  CuSO4 Zn2+ + SO42−  ZnSO4
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
Stratum corneum Hair follicle

(1) (2)
(3)
Epidermis
(1) Manipulate the barrier

Dermis (3~5 mm)

(2) Direct drugs to viable skin tissues

Subcutaneous tissue

Sebaceous gland
(3) Skin treatment for systemic conditions

Hair matrix Endocrine sweat gland

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Stratum corneum DC
(Constant current)
The transfer of ions across the skin (transdermal) by use
Drug Buffer
of continuous direct currentreservoir ions
Gel sponge A- D+ A-
Epidermis
Iontophoresis is based on the principle that an electrically
electrode charged
H+
Skin electrode will repel a similarly charged ion (first reported by LeDuc
in 1903).
Dermis (3~5
Delivers mm) High-amp DC current
a low-volt
Drug ions
Local blood flow is increased for 1 hour post-treatment
A-
Capillary &
blood flow
A-

D+
Drug to the blood stream
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Ground electrode on deltoid Plasma concentration profile
of R-apomorphine in a patient
with Parkinson Disease
3

Plasma conc.
(ng ml-1 )
2

0
0 1 2 3 4 5

Drug electrodes on 2 IV sites

Time (h)

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Vyteris® Lidocaine
Medications Pathology Dose Polarity

Acetic Acid Myositis 80 mA/min +

Dexamethasone Inflammation
41 mA/min –
& Lidocain & Pain control

Lidocain &
Pain Control 30 mA/min +
Epinphrine

Lidocain &
Pain Control 20 mA/min +
Epinphrine

Dexamethasone Inflammation 41 mA/min –

E-trans Fentanyl

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 e- e- e- 0.799V

1.229V e- e-
Pt

H2 or O2 bubbles

Cl-
e- e- e-
OH- K+

2e− + 2H2O  2OH− + H2 (-0.828V) Ag  Ag+ + e−

2H2O  4H+ + O2 + 2e− Ag+ + Cl−  AgCl
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 (-0.6V) e-
e- e- e- 0.799V
O2出現  增加鉑槽接受電子之能力
1.229V e-  溶液中[O2](pO2)和所得電流成正比
e-
Pt
Leland Clark

H2 bubbles
Ag+
e-
Cl-
e-
2e− + 2H2O  2OH− + H2 Ag  Ag+ + e−
O2  H2O2 (+0.682V) H2O (+1.760V) Ag+ + Cl−  AgCl
By Li-Te Chin, Ph.D. in Engineering Clark LC Jr: Monitor and control of blood and tissue oxygenation. TASAIO 2:41-45,
copyright reserved 1956.
 e− e−

A e− e− A e− e−
Polarographic
Blood Glucose pO 2 sensor
Sensor

GOD
Glucose + O2  Gluconic Acid
+ H2O2
KCl Ag
Pt
Oxygen permeable
membrane
O2 H2O2
Glucose Oxidase
By Li-Te Chin, Ph.D. in Engineering
copyright reserved Clark, L.C. Jnr. Ann. NY Acad. Sci. 102, 29-45, 1962
First launch 1973 by: YSI
Incorporated, Yellow Springs, Ohio

GOD
Glucose + O2 Gluconic Acid + H2O2

Hydrogen Peroxide Measurement:

Platinum Anode
H2O2 2H++O2+2e-

Anti-interference membrane
1975
Outer protective membrane
 YSI's success can be judged:
their sensors are used routinely in laboratory, near-point-of-care
and even point-of-care situations in many clinics and hospitals
and
many research groups working on other types of glucose
sensors use YSI readings as their reference method.

January 9, 2003

Malte vonMatthiessen moves on— Doing business

differently at YSI …… When he took over in
1985, YSI Incorporated — then Yellow Springs
Instruments — had 350 employees and sales of $15
million. Seventeen years later, YSI still has 350
employees but sales have quadrupled, topping $60
million and, in the last 12 years, its stock value has
Malte von Matthiessen risen 500 percent. ……
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Glucose + GO/FAD  δ-Gluconolactone + GO/FADH2

+3 +2
GO/FADH2 + 2[Fe(CN)6]3-  GO/FAD + 2[Fe(CN)6]4- + 2H+
FERROCYANIDE

δ-Gluconolactone + H2O  Gluconic Acid

Requirement:
LED 1. removal of excess sample (by wiping or blotting),
Detector 2. careful timing,
3. frequent cleaning to prevent contamination of the
meter
4. blood applied to individual strip outside meter
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
Glucose + GO/FAD  δ-Gluconolactone + GO/FADH2
Absorbing pad for the excess blood

GO/FADH 2 + O2  GO/FAD + H2O2

Application of a drop of blood.

δ-Gluconolactone + H2O  Gluconic Acid

H2O2 + 2H+ + 2I– → I2 + 2H2O

OneTouch
OneTouch Basic SureStep
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 600
Zone A represents accurate
glucose estimations (±20% & <70).
500 A
Values in zone E represent
Meter readings (mg/dL)

E C “erroneous treatment”.
400 A
<70: Glucose supplement
Values in zone D represent a
The target BG range is between 70 and 180, and patients
300 dangerous failure to detect and
will only attempt to correct values outside that range
treat
B ≥180<240: Medication required
200 Values in zone C might result in
over-correction of Insulin
≥240: the true glucose
injection
D B D level
100
Zone B represents acceptable
C 0 E
100 200 300 400
glucose estimations.
500 600
0
0 100 200 300 400 500 [blood
600 glucose] (mg/dL)
True [blood glucose] Values
140: Diabetes inatzones
criteria that timeC, D, or E are not
William Clarke,(mg/dL)
YSI readings M.D. acceptable
By Li-Te Chin, Ph.D. in Engineering Source: Cox DJ, Clarke WL, Gonder-Frederick L, Pohl S, Hoover C, Snyder A, Zimbleman L, Carter WR,
copyright reserved Bobbitt S, Pennebaker J: Accuracy of perceiving blood glucose in IDDM. Diabetes Care 8:529–536, 1985
 Glucose + GO/FAD  δ-Gluconolactone + GO/FADH2

+3 +2
GO/FADH2 + 2[Fe(CN)6]3-  GO/FAD + 2[Fe(CN)6]4- + 2H+
FERROCYANIDE
Fe3+
Conc.

δ-Gluconolactone + H2O  Gluconic Acid

Fe2+
Electric
Time flow
Voltage Supplied

Mediator Current Shuttle 2[Fe(CN)6]4-  2[Fe(CN)6]3- + 2e-

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Sample appli-
cation window Reagent window

Reagent

Dielectric layer

Electrodes

Substrate Compare to colorimetric:

• Faster
• No contamination
• More accurate.

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Electron

GO/FAD
H
H22O
O22

Glucose Gluconic acid

O2

Pt electrode

NBA

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 OH OH HO
UnderHOconditions for H2O2 detection
HO
atNHa
N N
O platinum electrode,
O
substances always O
N O OH
HO N or frequently found in the blood sample
such as
uric acid,
vitamin C and
paracetamol
break down electrochemically and thus
give interfering signals.
Uric acid Ascorbic acid Acetaminophen
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 The reaction of GOD with mediator is
much better defined- there is less
need to worry about variable oxygen
concentrations in the sample- just add
a known, constant amount of mediator.
Partially eliminates "electrochemical
interference"
[Fe(CN)6]3-

Fe3+
e- e-
Fe2+

[Fe(CN)6]4-
By Li-Te Chin, Ph.D. in Engineering
Working electrode Counter electrode
copyright reserved
H2O2 + GO/FAD  O2 +
Same amount of GO/FADH
glucose tested
2 by GO sensors:
Glucose
venous + GO/FAD
> capillary  δ-Gluconolactone + GO/FADH2
> arterial
Capillary: pO2 50-65
+3 +2
GO/FADH2 + 2[Fe(CN)6]3-  GO/FAD + 2[Fe(CN)6]4- + 2H+
Artery: pO2 83-108
FERROCYANIDE
Oxygen-dependent side
reaction in a GO/FAD- δ-Gluconolactone + H2O  Gluconic Acid
based biosensor

Vein: pO2 37-47 Electric

克拉克魔咒 flow
Voltage Supplied

Mediator Current Shuttle 2[Fe(CN)6]4-  2[Fe(CN)6]3- + 2e-

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
Glucose Dehydrogenase (GD)
Glucose + GD/PQQ  δ-Gluconolactone + GD/PQQH2

+3 +2
GD/PQQH2 + 2[Fe(CN)6]3-  GD/PQQ + 2[Fe(CN)6]4- + 2H+
FERROCYANIDE

No Oxygen Effect!! δ-Gluconolactone + H2O  Gluconic Acid

Electric
flow
Voltage Supplied

Mediator Current Shuttle 2[Fe(CN)6]4-  2[Fe(CN)6]3- + 2e-

By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Upper arm

Forearm

Thigh
Coulometry
FreeStyle™

Calf
Glucose dehydrogenase
Osmium-based mediator
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
BD Logic™
Blood Glucose Monitor BD Latitude™ Diabetes
Management System

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
Increasing Integration of Monitoring and Therapy

+ =
GlucoWatch® G2 BiographerTM
(GW2B) 1
AutoSensor Component
nd
– 2 cross-linked
generation device by
two polymeric Mask
Cygnus Inc.
hydrogel disks; must be
– FDA every
replaced approved in 2002 for
15 hr. Hydrogel
diabetics 7+ years old pads
disks contain electrolyte and
– performs noninvasive, trans-
glucose oxidase enzyme (GO).
dermal, near-continuous, BG
Electrode
analysis
Biographer Component assembly
– tracks BG vales at 10-min
bulkintervals
of devicefor 13 hr, stores
Electronic
stores, analyzes,
BG data, andBG
identifies displays
trends, component
dataalerts
from user of hypo-using
AutoSensor and Components of GW2B
hyperglycemia
mixture of experts algorithm (upside-down view)
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Biographer
Glucose selectivity
Oxidation reaction in cathodic hydrogel
Microprocessor, Data disk:
GO
memory, Display Glucose + O2  Gluconic acid + H2O2
IONTO(phoresis)
electronics
Size exclusion: skin’s MW
cutoff oxidation
Electrocatalytic is ~500 Da in Pt/C
Biosensor Glucose =adjacent
composite electrode 180 Da to
-
electronics hydrogel disk: HHb = 2H
2O2  64.5
++OkDa
2 +2e
AutoSensor
GOx Gel GOx
pads Electrons (current) are detected by Ag
(cathode)
(anode) Charge exclusion: current
and Ag/Cl electrodes
Skin is preferentially carried by
Na+, glucose in vivo Na+; uric acid and
ascorbic acid migrate to
Reverse Iontophoresis: apply 0.3 mA/cm2 current
across skin; electromigratory and electroosmotic anode
effects  interstitial neutral molecules (glucose)
migrate with cations to cathodic hydrogel disk
Electronics and structure of GW2B (CS view)
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Attract anionic compounds to the anode
Iontophoresis
Application of low level direct current will
Move drugs into blood stream
Attract using
cationic electricity
substances to the cathode

Reverse Iontophoresis
IONTO(phoresis)
electronics
Move something out of blood stream using electricity
Carry along other neutral compounds by
electro-osmosis, e.g., glucose

OH- Na+, H+

glucose

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
30

25
Target range
Blood glucose (mmol/l)

• Sensor inserted subcutaneously into

abdomen.
• Connected to small pager-sized monitor
5 (worn by patient)
• Continuous reading for up to 3 days to
0
determine direction or trend of blood
0:00 4:00 8:00 12:00 16:00 20:00 24:00
glucoseTime
levels.
of a day
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
Web Cam

Blood Pressure
Monitor

Glucose
Monitor

By Li-Te Chin, Ph.D. in Engineering

copyright reserved IDEATel Home Telemedicine Unit, Columbia University
 occurs exclusively in liver
prominent in starvation and diabetes (Lungs)
Epinephrine
FA NADH
not under direct hormonalGlucagon
Insulin control
HM Glutaryl CoA
Glucocorticoids Acetoacetyl CoA
Triglyceride
Acetoacetate (AcAc)
NADH NAD
Acetyl CoA
Fatty acids FA-albumin Acetone
H O H Oxaloacetate β−hydroxybutyrate (HB)
। ॥ ।
(Adipose tissue) H–C–C–C–H Acetone (Liver)
। ।
Glucose
H O H H H HB
। ॥ । ॥O α−ketoglutarate NADH
HB + AcAc
H–C–C–C–C Acetoacetate NAD
। । । Succinyl CoA AcAc
OH
H H Succinate
Krebs Cycle Acetoacetyl CoA
OH

H H
। । । ॥O Acetyl CoA
H–C–C–C–C β-hydroxybutyrate
। । । । OH
H H H Oxidation (Muscle)
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 OH
H H
। । । ॥O Ketones (acids) can build up and result in
H–C–C–C–C β-hydroxybutyrate (78%)
। । । । OH diabetic ketoacidosis (DKA).
15~20
H H H 20

Ketone bodies (mM)

H O H
। ॥ । ॥O 15
H–C–C–C–C Acetoacetate (20%)
। । ।
OH 10
H H
5.0
H O H 5
। ॥ । 0.2
H–C–C–C–H Acetone (2%) 0
। । lts o sis
H H adu atio
n id
oac etes
feed sta
rv k et
well
f diab
o
Acids that build up in body and cause patient to feel ill
Emergency state, can lead to coma, death.
Common symptoms include fruity odor to breath, nausea, vomiting, drowsiness
Number one reason for hospitalizing children with diabetes
Early detection and treatment of ketones prevents hospitalizations
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 Color chart
Negative Trace Small Moderate Large

mg/dL 5 15 40 80 160

Urine strip
Colorimetry

hydroxybutyrate
deshydrogenase
β-hydroxybutyrate acetoacetate

NAD+ NADH
Electrochemistry

red ox
mediator mediator

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
N-terminal Val
 CH2OH
CH2OH
H O OH Hemoglobin
Prehemoglobin A1c A1c
H H O OH
OH H H

HC
OH H
HO H Glucose + Hemoglobin A

HC
HO H H2O

HO

O
−R

H
H OH H2C−NH

CH
HCO R-NH
N=R 2 2

HC
H OH
HCOHβ2 β1

O
C=O

HC

H
O
H
HOCH
CH
2
O HOCH
CH2OH
H
HCOH HCOH
H O OH HCOH HCOH
H
OH H CH2OH CH2OH The IFCC working group
CH2OH
HO H has defined HbA1c as
H O OH Hb that is irreversibly
H H OH
glycated at one or both
OH H
N-terminal valines of
HO H α2 α1 the beta chains.
H OH
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 H2C−NH2 R R H2N − CH2

C=O β2
HbA1c MEAN BLOOD GLUCOSE
β1 C=O
test score mg/dL mmol/L
HOCH HOCH
14.0 380 21.1
HCOH action suggested HCOH HO
13.0 350 19.3 B
HCOH HCOH HO
12.0 315 17.4
CH2OH CH2OH
11.0 280 15.6
10.0 250 13.7Boronic acid
9.0 215 11.9
α2 8.0 α
180 10.0
good

7.0 150 8.2

6.0 115 6.3
excellent

HbA1c
5.0 80 4.7
☺ 4.0 50 2.6
HbA1a+b HbF HbA0
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 H2C−NH2 R R H2N − CH2

C=O β2 β1 C=O

HOCH HOCH

HCOH HCOH

HCOH HCOH
A1c epitope
CH2OH CH2OH
A1c epitope

Antigenic epitope

α2 α1

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Test result window
Sample well
Highly specific
Minimal number of reaction steps
Heterogeneous Reactions
Test
CaptureTestAntibody
line on Sensor Surface
Sample well Control Control line
Small volume of Labeled Ab Required
Housing
Sample pad

Conjugate pad
Absorbent pad
Membrane
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
公 司 Metrika Provalis / Biorad Bayer Axis Shield / Primus

產 品 A1cNow Glycosal / (Macromat II) DCA2000+ NycoCard HbA1c

價 格 70,000 87,500 45,000
525 / test
(新台幣) 245~420 210~350 210~350
免疫薄膜層
小型化boronate 免疫凝集分析、 boronate-conjugated
技術平台 析、微電子
親和管柱層析 半自動化操作 dye配合濾紙分析
光學分析

測量方法 光學分析 光學分析 光學分析 光學分析

檢測時間 8 min 5 min 6 min 4 min
測定範圍 3-15% 3-20% 2.5-14% 3-18%
需 血 量 DCA
10 μL 2000+ 10 μL < 40 μL 5μL

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Normal urine protein excretion : <150mg (20% of
this is albumin); therefore, normal urinary
albumin excretion is < 30 mg/day
Microalbuminuria :urinary albumin excretion 30-
300 mg/day

Microalbuminuria is the first clinical

sign of diabetic nephropathy

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 tetrabromophenol blue, pH 3.0.

For the measurement of proteins, a specific antibody

binds with albumin in the presence of polyethylene
glycol. The Ag-antibody complexes that are formed
cause increased turbidity which is measured as
absorbance at 531 nm.

HbA1c
DCA 2000+
Protein antigens: Albumin

Creatinine

By Li-Te Chin, Ph.D. in Engineering

copyright reserved
 Insulin & syringes

We are here
Drug (insulin)
delivery
Pumps
Pens
Wireless Closed Loop
Open Loop Connectivity
Data Management
Advice/Feedback

Home Monitors

Monitoring Portable meter

Clinic Monitoring
Hospital Self Management Automation
By Li-Te Chin, Ph.D. in Engineering
copyright reserved
 whole cost
test cost

Shorter hospital stays

Home healthcare

Reduce total healthcare costs

By Li-Te Chin, Ph.D. in Engineering

copyright reserved