Hydrogels

1. Hydrogels
Antonio Di Martino
dimartino@tpu.ru
Исследовательская школа химических и
биомедицинских
Tomsk Polytechnic University

2. Introduction
1949 = First ever hydrogel for biomedical implant – PVA crosslinked with formaldehyde - IVALON
1960 = synthesis of poly (2-hydroxyethyl methacrylate) (pHEMA) gel for contact lenses by Witcherle and Lim
pHEMA
Revolution for present day hydrogels
 Cross-linked networks
 Swelling without dissolution
 Shape retain
1970 = hydrogels for biomedical applications gained popularity – particularly stimuli responsive hydrogels

3. Hydrogel Classifications
1st Generation (cc 1960) = cross-linked hydrogels with high swelling and good mechanical properties
2nd Generation (cc 1970) = responsive by swelling to defined stimuli such as pH, temperature, biological compounds
3rd Generation (cc 1980 to present) = stereo complexed materials (e.g. PEG-PLA cross-linked by cyclodextrin)
Present = Smart hydrogels with stimuli sensitive tunable properties
Great attention in the use for organ, tissue regeneration and regenerative medicine

4. What make hydrogels interesting?
 Soft and rubbery
 Low interfacial tension with water and biological fluids –> reduced cell adhesion -> Less negative immune response
 Natural hydrogels – similar to extracellular matrix (ECM) in living tissues
 Mucoadhesive and Bioadhesive properties
 Enhanced tissue permeability and drug residence
Bioadhesion = mechanism by which two biological materials are held together by interfacial forces
Mucoadhesion = refers to the attractive forces between a biological material and mucous membrane
 Membrane = barrier
 Mucus = Mucins + salts + enzymes+ immunoglobuline + glycoprotein + lactoferrin
 Mucins = family o high molecular weight glycosylated proteins
 Glycosylated proteins = carbohydrate covalently linked to proteins

5. Glycoconjugate

6. Hydrogels
3D materials able to adsorb large amounts of water while maintaining their dimension stability
Water permeability
Crosslinking point => SOLUBILITY IS BALANCED BY THE RETRACTIVE FORCE OF ELASTICITY

7. Crosslinking points : to maintain the 3D integrity of the hydrogel in the swollen state
-COOH
-OH
-CONH2
CONH-
-SO3H
 Limited use = > cannot be reshaped and/or resized
 Some of the crosslinking agents are toxic (e.g.
glutaraldehyde)
 Unreacted components have to be removed
• Chain entanglements
• Hydrophobic interaction
• Hydrogen bonds
• Ion complexation
• Reversible crosslinking point
• Weak mechanical properties in the swollen state

10. Photochemically crosslinkable hydrogels and potential applications
Gelatin methacryloyl- Chitosan
UV-light
Tissue engineering
Chitosan/methacrylated/PVA
Guar gum–methacrylate
Methacrylated glycol chitosan/hyaluronic acid
Cartilage tissue engineering
Tissue Engineering Scaffolds
Cartilage tissue engineering
Chitosan
Poly(ethylene glycol)
Cartilage regeneration
Riboflavin –UV light

12. Stimuli responsive hydrogels – Smart hydrogels
Stimuli responsive hydrogels undergo relatively large changes in their swelling behavior, network structure, permeability
and/or mechanical strength in response to small environmental changes

13. Temperature
Shift in temperature changes polymer-polymer and polymer-
water interaction responsible for swelling
Chitosan-Poly(acrylamide)
Pressure
Swelling under increased pressure and vice versa. This fact is
due to an increase in lower critical solution temperature (LCST)
value of hydrogels with pressure. LCST is the temperature below
which negative thermoresponsive hydrogels swell.
Poly(N-isopropylacrylamide) (PNIPAM)
Poly(N,N-diethylacrylamide) (PNDAC)
PNIPAM PNDAC
Light
Exposure to light (UV and visible light) reversibly changes the
hydrogel from its flowable (moving in one direction) form to
non-flowable form and vice versa.
Poly(trimethylenium iminium trifluorosulfonimide)
2,6-bis(benzoxal-2-yl)pyridine
Physical Stimuli

14. Electric field
Changes in electrical charge distribution within the hydrogels
matrix on the application of electric field cause swelling–
deswelling
Polythiophene (PTs) Polypyrrole (PPy)
Magnetic Field When a magnetic field is applied, it causes pores in the gel to
swell
Composite of magnetite nanoparticles and
Poly(acrylamide)
Ultrasound irradiation Exposure to ultrasound temporarily breaks the ionic cross-links
in the hydrogels but they are reformed after ending the
exposition
Calcium alginate
Poly(lactic acid)

15. Alginic Acid
‘egg-box’
Ordered Messy

16. Chemical Stimuli
pH “Shift in pH causes change in the charge on the polymer chains leading to swelling”
 Polyacids = Anionic polymers
 Polybases= Cationic polymers
Poly(acrylic acid) ; Dextran sulfate; Alginic acid;
Guar gum succinate etc….
-COOH; -PO4; -OH; -SO4
PEI = polyethylenimine
Linear Branched-NH2

17. Ionic strength “Change in ions concentration causes swelling”
A- anion
C+ cation
 The hydrogel exchange protons to the solution
 Electroneutrality
 Ionic strength of the solution is increased
 Exchange of ions with the solution.
 The concentration of free counterions inside the hydrogel increases
 Electroeutrality;
 Osmotic pressure arises which causes the gel to swell
 High levels of Ionic strength (1 M–10 M),
 The hydrogels shrink due to the loss of the osmotic pressure
 Solution has osmotic pressures in the range of those inside the gel

18. CO2
“On exposure to CO2, the pH of solution changes resulting in
swelling or deswelling of the hydrogel which causes a change in
pressure which is a measure of the partial pressure of CO2”
Glucose “Hydrogels show swelling in response to increased glucose concentration”

19. Biological stimuli
Enzyme “Enzymes cause hydrogel degradation”
Antigen “Hydrogels sense the free antigen and undergo swelling”
DNA “Single stranded (ss) DNA grafted hydrogel probes show swelling in the presence of ssDNA”

20. Hydrogels

21. Water in hydrogels – Swelling
Swelling depends on :
1) Network parameters
2) Nature of solution
3) Structure (porous or poreless)
4) Drying techniques
 Crosslinking density => Crosslinker concentration
 Distance between the two crosslinkers in the same polymer chain
 Higher crosslink density the shorter is the distance

22. Water in hydrogels - Swelling
 First step: The diffusion rate of the water into the network is determined at the beginning of the swelling process
Depends on: Molecular weight of the solvent; temperature and porosity of the hydrogel
 Second step: how fast polymer chains can relax – slower absorption process
High crosslink density = behavior like a metal mesh = constant rate
Low crosslink density = variable rate

23. Types of water in hydrogels
Physically trapped between the hydrated polymer chains
Easy to remove – mild conditions
Directly attached to the polymer through hydratation
Part of hydrogel structure – Very high temperature to remove
Intermediate properties between free and bounded
Free and interstitial water can be removed by centrifugation or compression

24. Multiple Hydrogels Systems
Hydrogels based on single polymer may not meet the requirements for the application (e.g high swelling but inferior mechanical
properties)

25. Hydrogel characterization
Solubility
 Wd = dried weight
 Wi = initial weight
Swelling  Ws = swollen weight
 Wd = dried weight
FTIR Investigation of the structural arrangement in hydrogel comparing with starting materials
SEM Morphology, network structure
GPC-MALLS (Multi Angle Laser Light Scattering) Determination of molecular distribution

26. Rheology Rheological properties are dependent on the types of structure
DSC
H-NMR
 Quantify the amount of free and bound water in hydrogels
 The proton NMR gives information about the interchange of water molecules between the so-
called free and bound states
 DSC is based on the assumption that only the free water may be frozen
 The bound water is then obtained by difference of the measured total water content of the
hydrogel test specimen, and the calculated free water content
X-ray diffraction (XRD) Formation of cross-linked network

27. Applications of hydrogels as biomaterials
Blood contacting hydrogel
Poly(vinyl alcohol)
Poly(acrylamide)
Poly(ethylene oxide)
Poly (ethylene glycole)
Cellulose
Artificial Kidney
Cellulose acetate
Poly(vinyl alcohol)
Poly (ethylene glycole) – Poly(ethylene terephthalate)
Artificial
cartilage
Poly(vinyl alcohol)
Poly(N-isopropyl acrylamide)
Poly(ethylene glycole)-Poly(propylene glycol)
Artificial skin
Poly(vinyl alcohol)
Poly(hydroethylmethacrylate)
Contact lenses
Poly(hydroethylmethacrylate)
Poly(N-vinyl pyrrolidone)
Poly(methacrilic acid)
Poly(butyl methacrylate)
Poly(methyl methacrylate)

28. Hydrogels for drug delivery applications

29. Hydrogels for cell encapsulation

30. Hydrogels for tissue engineering scaffolds

31. References
 Cheung et al., J Biotechnol Biomater 2015, 5:2
 J Appl Biotechnol Rep. 2018 Sep;5(3):81-91
 Trends in Biotechnology June 2015, Vol.33,No. 6
 Journal of Advanced Research (2015) 6, 105-121
 Material Science and Engineering C 57 (2015) 414-433
 Polymers 2017, 9, 137; doi:10.3390/polym9040137
 Talebian, Set al., (2019). Self-Healing Hydrogels: The Next Paradigm Shift in Tissue Engineering? Advanced Science, 6(16),
[1801664]
 Analyst, 2003, 128, 325–331