1. Biomaterials and Protein Adsorption

2. Examples of Biomaterials
Medical implants
Contact lenses
Drug delivery systems
Scaffolding for tissue regeneration

3. Proteins are amphiphilic molecules in an aqueous milieu
Polypeptides are amphiphilic molecules
BUT -- The human body is 90% water!
SO : hydrophobic regions of proteins seek refuge in supramolecular configurations that minimize their exposure to water

4. Hydrogen Bonding Depends on the Electronegativities of the Donor and Receptor Groups
Blue = hydrogen donors
Red = hydrogen acceptors
Black = non-hydrogen bonding

5. Proteins adhere to hydrophobic surfaces
“Foot Model” of protein adhesion
Self-propagating
First step in the humoral response against foreign materials in the body

6. Design of Biomaterials Surfaces
Hydrophilicity inhibits protein adsorption, however:
Some cell adhesion may be desirable
Compliance is a key consideration
Solution? Polymers, of course! s

7. Techniques for Coating Biomaterials
Physisorption
Adhesion to biomaterial surface is of hydrophobic and/or electrostatic origin
Chemisorption
Polymer is chemically attached to the surface, usually via reaction of the surface with a specific end-group on the polymer
Often referred to as a “self-assembling monolayer” (SAM)
example: an –SH terminated polymer covalently binds to a Au3+ surface

8. Polymer Brushes
A “brush” is formed when the spacing d between end-grafted polymers is less than twice the Flory radius, RF, where RF ~ aN3/5 and a is the monomer size

9. Fundamentals of Protein-Surface Interactions
Large free energy gain associated with protein adhesion to hydrophobic surfaces
Attraction due to long-range van der Waals forces, as well as specific and hydrophobic interactions, and the electrostatic double layer (all short-range)
Repulsion due to steric and osmotic factors (short range)
Proteins will stick if
Ubare(0) < kT

10. Steric and Osmotic Factors
Atoms and molecules take up a finite amount of space which cannot be occupied by other elements – i.e. they introduce an excluded volume
Dense packing, rotations, and/or rearrangements may therefore not be energetically allowed: i.e. steric hindrance
Crowding leads to an increase in the internal energy and thus the osmotic pressure

11. The Free Energy Profile of the Brush has Two Minima
a) brush potential, Ubrush(z)
b) attractive [primarily] van der Waals
potential UvdW(z)
c) net interaction potential

12. Modes of Protein Adsorption
(I.) adsorption of proteins to the
top boundary of the polymer brush
(II.) local compression of the
polymer brush by a strongly
adsorbed protein
(III.) protein interpenetration into
the brush followed by the non-
covalent complexation of the
protein and polymer chain
(IV.) adsorption of proteins to the
underlying biomaterial surface via
interpenetration with little
disturbance of the polymer brush

13. What do the The Primary and Secondary Minima Correspond to?
Secondary minimum: Uout
Adsorption at the outer brush surface
Primary minimum: Uin
adsorption at the solid surface

14. Osmotic vs Entropic Forces
The brush thickness, L depends on
a balance of forces:
Osmotic Force
Elastic Force
At Equilibrium or
Brush thickness:
where
Monomer volume fraction:
Variables:
So the corresponding
force and free energy per chain:
And the corresponding osmotic pressure:

15. Secondary Adsorption Occurs when Uout < -kT
Since there is no energy barrier, it is only possible to control Uout thermodynamically
Uout  UvdW(L)
Because penetration of the brush requires chain compression, large proteins will preferentially undergo secondary adsorption so long as UvdW(L) < -kT
For a rod-like protein (fibrinogen, e.g.) of radius R and length H, suppression of secondary adsorption may only be achieved if:
Where A is the Hamaker constant, A ~ J
for proteins interacting with organic materials

16. Primary Adsorption Occurs when Uin < -kT When Rp << L :
** The presence of an energy barrier enables both thermodynamic and kinetic control
When Rp << L :
There is negligible effect on 
When Rp >> L :
Approach to the surface results in compression of the brush
and an increase in osmotic pressure
where
and
Where  is the width of the energy barrier
and D is the diffusion coefficient
The rate constant for adsorption:
And the free energy barrier, U* for primary adsorption:
Where Uads is the interaction potential of
the adsorbed protein at the bare surface
Finally:

17. Methods for Counteracting Protein-Surface Interaction with Polymer Coatings
Dense polymer coatings (low s)
Long polymer chains (large N)
Uout may be manipulated by varying N or s
Uin is primarily controlled by varying s
R a N
d a s

18. Poly(ethylene oxide) (PEO) in Biomaterials
The most extensively used polymer for biomaterial surface coatings, because:
Completely water-soluble
Creates an extensive H-bonding network
Helical conformation
Proven to be extremely protein resistant
Capable of being functionalized for ligand-receptor specificity
However:
Poor mechanical stability
Protein adhesioin reported under certain conditions