Hydration of ultra-thin surface films and its role in enhancement of biocompatibility

of medical devices

Mike Thompson

Department of Chemistry and Institute for Biomaterials and Biomedical Engineering,

University of Toronto

9th Annual Conference on the Physics, Chemistry and Biology of Water

Pamporovo, Bulgaria, October, 2014

Topics• The core of our research – theranostics –

combined therapy and detection• Fouling and the sensor–biological fluid interface • Link between fouling and biocompatibility • Anti-thrombotic surface chemistry• Role of surface hydration• Neutron reflectometry of ultra – thin film water• Anti-fouling / anti-thrombogenetic effect -

concerted mechanism involving structured water• Questions

The Challenges of Critical CareSick Patients

Coagulopathy

Inflammation Organ Failure

Shock

In-line theranostics and medical bypass circuitry

Electromagnetic acoustic wave sensor

Fouling of Quartz by Serum

Sheikh, S.; Yang, D. Y.; Blaszykowski, C.; Thompson, M. Chem. Commun. 2012, 48, 1305

undiluted goat serum

12

Surface Modifier Structure

Anchoring function

Head function

Backbone

Substrate Quartz (piezoelectric), gold (electrical), stainless steel (implant), plastics (flexible), ...

Trichlorosilyl (Cl3Si), trialkoxysilyl ((RO)3Si), thiol (–SH), ...

Alkyl: –(CH2)n–

Oligoethylene glycol (OEG): –(O–CH2–CH2)n–

Perfluoroalkyl: –(CF2)n–

Functionalizable for subsequent biomolecule immobilization

X

Y Linkers for biosensors

5

Systematic Structural Modification

Sheikh, S.; Yang, D. Y.; Blaszykowski, C.; Thompson, M. Chem. Commun. 2012, 48, 1305

1/1 (v/v) H2O/MeOHroom temp., overnight

13

Antifouling Behaviour

Sheikh, S.; Yang, D. Y.; Blaszykowski, C.; Thompson, M. Chem. Commun. 2012, 48, 1305

Through the use of structurally simple surface modifiers, the frequency shift due to the adsorption of goat serum was substantially reduced from ~ -31 kHz for bare quartz to less than -3 kHz for MEG-OH films

14

BLOOD CONTACTING MEDICAL DEVICES

Blood Contacting

Medical Devices

Vascular Graft

Hemo-dialyzer

PPacemaker

Stents

Extracorporeal Circuits

Econous Inc. July 2012

Blood interaction and bypass circuitry

• Cardiopulmonary bypass (CPB) surgery is a common operation with

Over 1 million yearly worldwide1

• Has several undesired consequences including blood coagulation

• After surgery complications can occur for 20% for low risk patients with 12% result in multi organ dysfunction

syndrome2

• Multi organ dysfunction syndrome has a mortality rate of 40%3

1. Sphere medical statistics 2. Grover FL: . Ann Thorac Surg 1999;68:367-373; discussion 374-376.3. Kollef MH, Wragge T, Pasque C:. Chest 1995;107:1395-1401.

Biosensors Group IBBME

Collagen Coated Polycarbonate surfaces

MEG-OH coated Surfaces MEG-OH coated Surfaces

To investigate the hydration of ultra-thin films and gain insight into its anti – fouling mechanism.

1) Probe water density of water at MEG-OH and OTS-OH adlayers (normal to the surface)

‒ Examine interfacial water

2) Determine the effect of the internal ether oxygen atom on behaviour of water with adlayer

Bulk water

SiO

O n

Quartz

O

O

SiO

O n

H

O

H

Quartz

Wat

er d

ensi

ty p

rofil

e

MEG-OH OTS-OH

How?Neutron reflectometry

Purpose of Research

CNBC’s National Research Universal (NRU) Reactor

• Neutrons produced via fission of 235U (D2O moderator)• Largest global producer of medical isotopes (60Co, 99Mo, 131I)• > 85% neutron time to users (universities, research facilities)• Applications: Structural chemistry, soft materials, thin

films/interfaces (examples)

Canadian Neutron Beam Centre (CNBC)

Greetings from Chalk River!

D3 Neutron Reflectometer

6 Beam lines!!!

Ontario

Neutron Reflectometry (NR)

A neutron diffraction technique probing the specular reflectivity of surfaces and buried interfaces in layered systems

Functions and Features

• Structural and compositional information (e.g. oxide growth)• Atomic distribution (depth profiles)• High penetration depth

• Film thickness (up to 200 nm)• Sensitive to 1H and 2H

• Manipulation of contrast between media

NR Theory: Reflectivity Curve Anatomy

Addition of layer (film)N+1 interfaces

dCr

Air

Si

Kiessig fringes: Oscillations originate from constructive/destructive interference of reflected neutron waves

• Frequency depends on thickness of the layer

Δq= 2π/d• Amplitude depends on contrast

between adjacent media (ΔSLD)- Enhanced sensitivity with increasing contrast

Period of oscillation 1/α layer thickness (d)

Kiessig fringes

Amplitude α ΔSLD

9.42 x 10-6 Å-2

3.00 x 10-6 Å-2

2.07 x 10-6 Å-2

Dampened oscillations

z

σjj

koks

θo

θox

Surface Roughness

Diffuse scattering of neutrons ↓ R

Measurements in CMW: Si/SiO2

MEG-OH

OTS-OH

Si/SiO2

• Fringes on MEG-OH, OTS-OH reflectivity curves confirm presence of a ‘layer’ between SiO2 and CMW (interference of reflected neutron wave)

• MEG-OH: dampened oscillations (low amplitude)• OTS-OH : sharper minima, oscillations with higher

amplitude

FIT REFLECTIVITY DATA WITH MODEL

Measurements in CMW: Si/SiO2

SLD Profile: 2-Phase Fit

SiO2 Interfacial water BulkFilm

Reflectivity + Fits

SampleSLDSiO2

(x 10-6 Å-2)σSiO2 (Å)

d1

(Å)SLD1

(x 10-6 Å-2)SLDB

(x 10-6 Å-2)σB

(Å)

MEG-OH 3.67 14.3 21.7 2.97 3.66 16.5

OTS-OH 3.56 9.7 18.7 0.90 3.53 1.6

Low SLD(organic coating)

“Water Barrier”?

Si

O

O

H

OO O

Si

O

O

H

OO

Si

O

O

H

OO

Si

O

O

H

O

O

H

HO

H

H

OH

H

O

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

HO H

HO

H H O

H

H

O

H

HO

H

H

O

H

HO

H

H

O

H

H

OH H

OH

H

quartz

17MEG-OH

Si

O

O

H

OO O

Si

O

O

H

OO

Si

O

O

H

O

Si

O

H

OO O

Si

O

H

OO

Si

O

H

O

quartz

OTS-OH

6 Å

22 Å

BULK

BULK

5 Å

4 Å

- - - - - - - - - - - - -

- - - - - - - - - - - - -

not to scale

INTERFACIALWATER

Some questions

• What is the origin of the myth that high quality SAMs reduce adsorption + fouling?

• What is the precise role of the distal –OH in MEG-OH?

• Why is the chemistry so “robust” in terms of antifouling / antithrombogenesis?

• Can the surface chemistry lead to a quantum changes in medical device technology?

• Does hydration play a role in biochemical interactive selectivity – e.g. cell signaling?

Mike Thompson Research Group, October, 2014

Jack Sheng Jenise Chen

Dr. Sonia Sheikh Niall Crawley

Brian De La Franier Edmund Chan

Elaine Chak Ellie Wong

Kiril Fedorov Tairan Wang

Pat Benvenuto Rohan Ravindranath

Dr. Chris Blaszykowski Ruben Machado

Dr. Larisa Cheran Miguel Neves Victor Crivianu-Gaita

THANKS FOR LISTENING!mikethom@chem.utoronto.ca