Amphiphilic chitosan derivatives as multifunctional ... · Coefficient of Friction - Reciprocating...

ZBTM • Polymer Institute • //www.zbtm.zut.edu.pl

DIVISION OF BIOMATERIALS AND MICROBIOLOGICAL TECHNOLOGIES

Amphiphilic chitosan derivatives as multifunctional coatings for catheters

Agata Niemczyk*,

Steve E. Franklin**,Mirosława El Fray*

Understanding Interactions of Human Tissue with Medical Devices

FP7-IAPP-286174

* **

POLAND THE NETHERLANDS

2

Biomaterials – surface and tissues infections

INTRODUCTION

biomaterial surface

THE INTERACTIONBETWEEN THE BIOMATERIAL SURFACE AND THE HUMAN BODY

human body

SUCCESSof medical procedures

or Health-related complications:• tissue trauma, • inflammation• infection,

3

biomaterial surface

human body

biological response of living cells





INTRODUCTION

4

biomaterial surface

human body


chemical stability or degradability of material





INTRODUCTION

5

biomaterial surface

human body


chemical stability or degradability of material mechanically-induced damage

to both the human tissue and the medical device





INTRODUCTION

6

biomaterial surface

human body


chemical stability or degradability of material mechanically-induced damage

to both the human tissue and the medical device





INTRODUCTION

7

MEDICAL DEVICES – the catheters

Cardiovascular catheter Urinary catheter

Catheterization procedures• Cardiovascular catheters

• Urinary catheters

blood lumen

catheter

contact area

INTRODUCTION

8

Cardiovascular catheter Urinary catheter

Catheterization procedures• Cardiovascular catheters

• Urinary catheters

mechanically-induced damage to the human

tissue

MEDICAL DEVICES – the cathetersINTRODUCTION

9

SOLUTION - Lubricious coatings

APPLICATION OF THE COATING

CONTACT AREA

blood lumen

catheter

contact area

catheter

coating

blood vessel wall

INTRODUCTION

10


CONTACT AREA

blood lumen

catheter

contact area

catheter

coating

blood vessel wall

Human bloodContain about 50% of water

Hydrophilic coatingThe water cushion reduces wet friction acting as a layer of gel-like lubricant

Biomaterial

Blood vessel wall

Hydrophilicity hydrophilic coatings are especially indicated to work in the humid environment significantly reducing the wet friction

THE LUBRICATION PROCESS

catheter

coating

blood vessel wall

blood


INTRODUCTION

11


CONTACT AREA

blood lumen

catheter

contact area

catheter

coating

blood vessel wall

Human bloodContain about 50% of water

Hydrophilic coatingThe water cushion reduces wet friction acting as a layer of gel-like lubricant

Biomaterial

Blood vessel wall

Hydrophilicity hydrophilic coatings are especially indicated to work in the humid environment significantly reducing the wet friction

Bio and hemocompatibility

Antimicrobial activity

Biodegradability

THE LUBRICATION PROCESS

catheter

coating

blood vessel wall

blood


INTRODUCTION

12

Chitosan-fatty acid derivatives

MATERIALS

PROPERTIES OF CHITOSAN:• natural polysaccharide• non-toxic• biocompatible in vitro and in vivo• antimicrobial • hydrophilic

O

H2NHO

O

CH2OH

OO

NH

CH3

O

HO O

O

CH2OH

HO

CH2OH

NH2

A. Niemczyk, M. El Fray, Novel Chitosan Derivatives as Films with an Antimicrobial Effect, PCACID, 2013.

13

Chitosan-fatty acid derivatives

MATERIALS

PROPERTIES OF CHITOSAN:• natural polysaccharide• non-toxic• biocompatible in vitro and in vivo• antimicrobial • hydrophilic

O

H2NHO

O

CH2OH

OO

NH

CH3

O

HO O

O

CH2OH

HO

CH2OH

NH2

MODIFICATION WITH FATTY ACID

LINOLEIC ACID (LA)

A. Niemczyk, M. El Fray, Novel Chitosan Derivatives as Films with an Antimicrobial Effect, PCACID, 2013.

PROPERTIES OF FATTY ACIDS:

• natural origin• non-toxic• antimicrobial • hydrophobic

14

Synthesis of N-acyl chitosan-fatty acid derivatives

CHITOSAN MODIFICATION

N-acyl derivative

CHITOSAN[NH2 mol]

LA [mol]

LA [wt%l]

1 0,16 17%

1 0,52 40%

1 1,00 56%

STAGE 1:

STAGE 2:

FA FA-EDC•HClEDC•HCl+

CH-FACH + +FA-EDC•HCl EDC•HCl

Reaction time: 24h

Reaction time: 3h

A. Niemczyk, M. El Fray, B. Pabin-Szafko, Progress on Chemistry and Application of Chitin and Its Derivatives, 2012, 17, 29

FTIR spectra of chitosan and its LA-derivatives Nexus with Golden Gate (ATR), 32 scans, spectral range of 400-4000 cm-1

500 1000 1500 2000 2500 3000 3500

Wavenumbers (cm )-1

Tra

nsm

itta

nce

CH

CHLA

4000

15

Biotribology system

EXPERIMENTAL PART

blood lumen

catheter

contact

area

CATHETERIZATION PROCESS

16

Biotribology system

EXPERIMENTAL PART

blood lumen

catheter

contact

area


COATING LUBRICITY

17

EXPERIMENTAL PART

blood lumen

catheter

contact

area


FRICTION BEHAVIOUR

Biotribology system

COATING LUBRICITY

18

Biotribology system – The test set

EXPERIMENTAL PART

blood vessel

polymeric probe

Blood analogue

coating

stroke: 10 mmvelocity: 0.5 mm/s

load: 100mN

TEST SYSTEM

CETR (Brüker) UMT Multi-Specimen Test

POLYMERIC PROBE:

• polyether block amide with medical grade

ARTIFICIAL BLOOD VESSEL:

• Chemically crosslinked PVA hydrogel(non-commercial - synthesized for test system)

BLOOD ANALOGUE:

• Glycerol/water solution (44/56 wt/wt) viscosity 4.25 mPas

COATINGS:

• Chitosan derivative coatings

• Commercial coatings

19

RESULTS

Test conditions:

load: 100mN

time: 1800s (30 min)

stroke: 10 mm

velocity: 0.5 mm/s

Coefficient of Friction - Reciprocating sliding friction test

NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

Co

effi

cie

nt

of

Fric

tio

n

Chitosan-LA derivatives

PA 69

chitosan

chla 0.16

chla 0.52

chla 1.00

20

RESULTS

Test conditions:

load: 100mN


stroke: 10 mm

velocity: 0.5 mm/s


NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

Co

effi

cie

nt

of

Fric

tio

n


PA 69

chitosan

chla 0.16

chla 0.52

chla 1.00

21

RESULTS

Test conditions:

load: 100mN


stroke: 10 mm

velocity: 0.5 mm/s


NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

Co

effi

cie

nt

of

Fric

tio

n


PA 69

chitosan

chla 0.16

chla 0.52

chla 1.00

22

Molecular structure of chitosan

• Stabilized by intra and inter H-bonds

• Occurrence of bound water

RESULTS

23

RESULTS


24

RESULTS


25

𝑊𝑈 =𝑊𝑠 −𝑊𝑑

𝑊𝑠

WATER UPTAKE

57 87 81 870

10

20

30

40

50

60

70

80

90

100

WAT

ERU

PTA

KE

[%]

After 4 days

CH000 CHLA17 CHLA40 CHLA56

Swelling and water uptake of chitosanderivatives

NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

RESULTS

134 685 444 4490

100

200

300

400

500

600

700

800

900

SWEL

LIN

G [

%]

After 4 days

CH000 CHLA17 CHLA40 CHLA56

𝑆 =𝑊𝑠 −𝑊𝑑

𝑊𝑑

SWELLING

𝑊𝑑 − 𝑑𝑟𝑖𝑒𝑑 𝑠𝑎𝑚𝑝𝑙𝑒 𝑤𝑒𝑖𝑔ℎ𝑡

𝑊𝑠 − 𝑠𝑤𝑜𝑙𝑙𝑒𝑛 𝑠𝑎𝑚𝑝𝑙𝑒 𝑤𝑒𝑖𝑔ℎ𝑡

Incubation in SBF, 37°C

26

RESULTS


NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

COMMERCIAL ONES

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

Co

effi

cie

nt

of

Fric

tio

n

Chitosan-LA derivatives vs commercial

PA 69

chitosan

chla 0.16

chla 0.52

chla 1.00

PA69_C1

PA69_C2

PA69_C3

27

RESULTS


NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

COMMERCIAL ONES

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

Co

effi

cie

nt

of

Fric

tio

n

Chitosan-LA derivatives vs commercial

PA 69

chitosan

chla 0.16

chla 0.52

chla 1.00

PA69_C1

PA69_C2

PA69_C3

• Antimicrobial activityA. Niemczyk, M. El Fray, Novel Chitosan derivatives as films with

an antimicrobial effect, Progress on Chemistry and Application of Chitin

and Its Derivatives, 2013, 18, 59-66

28

RESULTS

Cytotoxicity

ISO 10 993 Biological evaluation of medical device

Part 5: Tests for in vitro cytotoxicity

Fibroblasts, L 929 (ATCC), Medium 199+ 10% FCS

Grade: 1

Reactivity: slight

Not more than 20% of the cells are round, loosely attached and without intracytoplasmatic granules, or show changes in morphology; occasional lysed cells are present; only slight growth inhibition observable

0

1

2

3

4

5

6

polyurethane polyester CH000 CH 000-LA17

% o

f n

etr

oti

c ce

lls i

n v

iew

are

a

Cytotoxicity

29

RESULTS

Hemocompatibility

Test Conditions:

• EtO sterilization• 24 h incubation with whole human blood

0.0

0.4

0.8

1.2

1.6

2.0

negativecontrol

polyurethane polyester CH 000 CH000-LA 17

Hemolysis [g/L]

0.0

0.4

0.8

1.2

1.6

2.0

negativecontrol

polyurethane polyester CH 000 CH000-LA 17

Haemolytic index [%]

ASTM F 756-0

I. HI = 0-2% - non haemolytic

II. HI = 2-5% -slightly haemolytic

III. HI > 5% - haemolytic

30

Hydrolytic degradation

NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

We

igh

t lo

ss [

%]

Days

RESULTS

Samples:

round disks (diameter – 5 mm) from chitosan/derivatives films

Incubation: simulated body fluid (SBF),37°C, 25 days

31

Enzymatic degradation

Samples: Chitosan and chitosan derivatives (0.26 g/100cm3)

Incubation: sodium acetate buffer solution (pH 4.5), 37°C, 8 hours

Enzyme: Lysozyme from chicken egg white (SigmaAldrich)

Determination of the intrinisic viscosity changesof polymer solution over the time:Every 10-20 minutes @2hThen every 30 minutes @ 6h

RESULTS

32

Enzymatic degradationRESULTS

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 50 100 150 200 250 300 350 400 450

Red

uct

ion

of

the

intr

insi

cvi

sco

sity

[a.u

]

Time [min]

𝑅 𝜂 =(𝜂0 − 𝜂𝑡)

𝜂0

Reduction of the [ƞ]:

NAME LA wt%

CH000 -

CHLA17 17

CHLA40 40

CHLA56 56

The influence of Lysozyme on the intrinsic viscosity

33

Summary

Amphiphilic chitosan derivatives as multifunctional coatings for catheters

Highly potential material for catheter coatings

Development of fatty acid – chitosan derivatives

o Lubricious

o Hemocompatible

o Non-toxic

o Biodegradable



This work was supported by EU Marie Curie Industry-Academia Partnerships and Pathways: UNITISS, Understanding Interactions of Human Tissue with Medical Devices, FP7-PEOPLE-2011-IAPP/286174. Authors AN and ME would also like to acknowledge the Polish Ministry of Science and Higher Education for financial support for the research within the co-financed international project in the years 2012-2016

Thanks for:

• Philips Research Group• Biomaterials and Microbiological Technologies Group

• Agnieszka Piegat• Piotr Sobolewski• Marek Mazurek• Krzysztof Ulfig• Anna Blejson

• Foundation for Cardiac Surgery Development• Magdalena Kościelniak-Ziemniak• Piotr Wilczek • Małgorzata Gonsior• Roman Kustosz



THANK YOU FOR YOUR ATTENTION

Amphiphilic chitosan derivatives as multifunctional ... · Coefficient of Friction - Reciprocating...

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