new smart biomaterials: main properties and applications · 2020. 2. 4. · collapse of grafted...
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SMART BIOMATERIALS: Main Properties and Applications
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resp
on
se
external variable
“all-or-nothing”
“0”
“1”
critical point
resp
on
se
external variable
high non-linear behaviour
Chemical stimuli= pH, ionic factors, chemical agents
Physical stimuli= Temperature, electric or magnetic fields, mechanical stress
Biochemical stimuli= antigens, enzymes, ligands
STIMULI-RESPONSIVE POLYMERS
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+ stimulus
- stimulus
+ stimulus
- stimulus
+ stimulus
- stimulus
+ stimulus
- stimulus Based on: AS Hoffman, PS Stayton, Macromol. Symp. ‘04
solubility in aqueous solutions
adsorption control
collapse of grafted chains
swelling in hydrogels
STIMULI-RESPONSIVE POLYMERS
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- Water swollen crosslinked polymers - Crosslinks may occur:
- by reaction of one or more monomers - hydrogen bonds - van der Waals interactions
HYDROGELS
Classification (based on preparation method) - homopolymer hydrogels (one type of hydrophilic mer) - copolymer hydrogels (two types of mers, at least one hydrophilic) - multipolymer hydrogels (more than three types of mers) -interpenetrating polymeric hydrogels (swelling a network of polmer1 in mer2, making intermeshing network of polymer1 and polymer2)
- Crosslinks may be induced during polymerization or by radiation following polymerization - Interchain connections can be:
- a carbon atom - chemical bridge - van der Waals - hydrogen bonds - molecular entanglements
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- Crosslink structure:
A) ideal network with tetrafunctional
covalent crosslinks (rarely observed)
B) multifunctional junctions
C) molecular entanglements (could be
permanent or semi-permanent)
- Defects in crosslink structure:
D) unreacted functionality
E) chain loops
Mc: Molecular weight between crosslinks
HYDROGELS
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HYDROGELS
Hydrogels prepared by crosslinking copolymerization of 2-hydroxyethyl methacrylate (HEMA) and ethylene dimethacrylate (EDMA) (a) Homogeneous hydrogel (b) Example of popcorn formation (c) Heterogeneous (porous) hydrogel
Use of HEMA based hydrogels in rhinoplasty a) Patient before surgery, b) Patient after surgery
Soft contact lenses
J Biomed Mater Res 9, 675 (1975)
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Natural polymers and synthetic monomers used in hydrogel fabrication
Adv Drug Del Rev 58, 1379 (2006)
HYDROGELS
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HYDROGELS - APPLICATIONS
J Pharm Sci 96, 2197 (2007)
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LCST Lower Critical Solution temperature
coil structure collapsed structure
TEMPERATURE RESPONSIVE HYDROGELS
LCST 32-33ºC in water
nCH
C O
NH
CH
CH3CH3
CH2
poly(N-isopropylacrylamide) - PNIPAAM
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DESIGNS FOR LCST CONTROL
Acrylamide – more hydrophilic comonomer N-butylacrylamide – more hydrophobic comonomer
J Biomed Mater Res 52, 577 (2000)
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TEMPERATURE RESPONSIVE HYDROGELS
Gelatin gels at ~35 ºC
Gelatin
Carrageenan
Carrageenan gels at between 25-80 ºC
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Cellulose derivatives
MC gels between 40-50 ºC and HPMC between 75-90 ºC
TEMPERATURE RESPONSIVE HYDROGELS
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TEMPERATURE RESPONSIVE HYDROGELS
Polyethylene oxide (PEO) – hydrophilic Polypropylene oxide (PPO) - hydrophobic
Amphiphilic block copolymers: PEO-PPO-PEO (Poloxamers)
Depending on the ratio and distribution along the chain of the hydrophilic and hydrophobic subunits different gelation temperatures (from 20 to 85 ºC) can be obtained
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pH-RESPONSIVE HYDROGELS
H2
CHC
COOH
n
H2
CHC
COO-
n
-
+
OH
H
H2
CHC
C
n
H2
CHC
C
n
-
+
OH
H
CH2CH2N(CH2CH3)2
O
H
CH2CH2N(CH2CH3)2
O
+
LOW pH HIGH pH poly(acrylic acid) PAA
poly(N,N’-diethylaminoethyl methacrylate)
…consist of ionizable pendants that can accept and donate protons in response to the environmental change in pH.
POLYACIDICS SWELL AT HIGH pH
POLYABASICS SWELL AT LOW pH
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pH-RESPONSIVE HYDROGELS
a) Poly(acrylic acid) PAAc, b) Poly(methacrylic acid) (PMAAc), c) Poly(2-ethyl acrylic acid) (PEAAc), d) Poly(2-propyl acrylic acid) (PPAAc)
pH-responsive polyacids
pH-responsive polybases
a) poly(N,N’-dimethyl aminoethyl methacrylate) (PDMAEMA), b) poly (N,N’-diethyl aminoethyl methacrylate) (PDEAEMA), c) poly(4 or 2-vinylpyridine) (PVP), d) poly(vinyl imidazole )
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O
CH2OH
H
H
H
OH
NHCOCH3
HH
O
O
CH2OH
H
H
H
OH
NHCOCH3
HH
O
n
GlcNAc
O
CH2OH
H
H
H
OH
NH2
HH
O
O
CH2OH
H
H
H
OH
NH2
HH
O
n
CHITIN
Deacetylation
CHITOSAN
GlcNAc
+ CH3COONa
NaOH, temperature
pH-RESPONSIVE HYDROGELS
OH
H
HO
OH
H
H
C
O
H
H
O
H
HO
OH
H
C
H
OO
D-Mannuronic acid (M) residue
H
O
OH
O
OH
O
H
HC
H
HOH
H
O
HOH
OHH
O
H
H
C
O OH
OH
O
HOH
O
L-Guluronic acid (G) residue
n
1
1
1
1
4
4
4
4Alginic acid: source – e.g. brown algae (Phaeophyceae, mainly Laminaria)
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DESIGNS FOR CRITICAL pH
Source: Adv Drug Del Rev 58, 1655 (2006)
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DESIGNS FOR CRITICAL pH
Hydrogels of 1) PAAc and 2), 3), 4) copolymers with different fractions of acrylic acid and a n-alkyl acrylate (n=8)
Effect of the fraction of hydrophobic groups
Macromolecules 30, 8278 (1997)
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T-RESPONSIVE HYDROGELS FOR TE APPLICATIONS
Laminin functionalized methylcellulose hydrogels for neural TE
LCST of the MC hydrogels
MC- methylcellulose OXMC- oxidized methylcellulose OXMC-LN: Laminin functionalized methycellulose
The LCST of the LN-functionalized MC gels do not exceed 37 ºC
LN-functionalized MC gels support
neuronal cell attachment
Attachment of cortical neurons to MC hydrogels
JBMRA 77, 718 (2006)
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T-RESPONSIVE HYDROGELS FOR TE APPLICATIONS
Laminin functionalized methylcellulose hydrogels for neural TE
A significant increase in the
viability of cortical neurons
within the LN-functionalized MC
scaffolds when compared with
the unmodified MC scaffolds was
found Scale bar= 50 mm
Confocal Laser Microscopy Results
JBMRA 77, 718 (2006)
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Chitosan--glycerophosphate salt formulations with bioactive glass (BG) nanoparticles
T-RESPONSIVE HYDROGELS FOR TE APPLICATIONS
a) 0% BG, b) 10% BG, c) 30% BG and d) 40% BG
Gelation point decreases with increasing BG content (from 41 ºC to 36.9 ºC) and gelation time less than 5 min
TE Applications: as injectable scaffolds and to deliver cells/bioactive agents
Daniela Couto, Zhongkui Hong, João Mano Acta Biomaterialia 2009
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Enzyme-sensitive Hydrogels Enzymes= matrix metalloproteinases (MMPs)
AIM To guide tissue regeneration by mimicking the MMP-mediated
invasion of the natural provisional matrix Hubbell et al, PNAS 100 5413 (2003)
Polymer-Peptide Bioconjugates
ENZYME-RESPONSIVE HYDROGELS FOR TE APPLICATIONS
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Hubbell et al, PNAS 100 5413 (2003)
A) Fibroblasts were demonstrated to proteolitically invade these networks, a process
that depends on MMP substrate activity, adhesion-ligand concentration and network
crosslinking density. Invading fibroblasts typically assumed spindle-like shapes - A) and
B) (A-image obtained by phase contrast microscopy and B-CLM image).
ENZYME-RESPONSIVE HYDROGELS FOR TE APPLICATIONS
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Preparation of alginate+PNIPAAM semi-IPN Beads Preparation of alginate+PNIPAAM semi-IPN Beads with a Polyelectrolyte Complex Coating
Constant stirring
CaCl2
PNIPAAM +Alginate
Constant stirring
PNIPAAM +Alginate
CaCl2
Chitosan
Alginate+CaCl2
PNIPAAM-Alginate Core
Chitosan-Alginate complex coating
Uncoated beads
Coated beads
SEM
pH- and thermo-responsive semi-IPN Beads for Drug Release
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water uptake of the uncoated beads : effect of temperature and pH
0
10
20
30
40
50
60
Sw
elli
ng r
atio (
%)
A B C D E
at pH2.1, 37oC
at pH7.4, 37oC
at pH7.4, 25oC
Increasing PNIPAAm content
SWELLING RESULTS - UNCOATED BEADS
Jun Shi, Natália Alves, João Mano, Macromol. Biosc. 2006
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0 100 200 300 400
0
20
40
60
80
100
Sample C
Dru
g r
ele
ase
(%
)
time (min)
pH=2.1
pH=7.4
0 100 200 300 400
0
20
40
60
80
100
Sample B
Dru
g r
ele
ase
(%
)
time (min)
25 ºC
37 ºC
pH=7.4
37 ºC
EFFECT OF pH EFFECT OF TEMPERATURE
Jun Shi, Natália Alves, João Mano, Macromol. Biosc. 2006
DRUG RELEASE RESULTS - UNCOATED BEADS
T pHpH
PNIPAAMalginate
Ca2+
drug
Drug= indomethacin
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0
10
20
30
40
50
60
Sw
elli
ng
Ra
tio
(%
)
A B C
25oC, pH7.4
37oC, pH7.4
25oC, pH2.1
37oC, pH2.1
SWELLING/DRUG RELEASE RESULTS - COATED BEADS
0 100 200 300 400 500
0
20
40
60
80
100
Time (min)
Dru
g r
ele
ase(%
)
Sample A
Sample B
Sample C
pH 7.4, 37oC
Water uptake– effect of temperature and pH
Drug= Indomethacin
Drug release - effect of coating
Jun Shi, Natália Alves, João Mano, JBMRB 2008
A- uncoated bead B and C - coated beads
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DRUG RELEASE RESULTS – COATED BEADS
Release of Indomethacin previously incorporated into the beads
EFFECT OF pH
0 100 200 300 400 500
0
20
40
60
80
100
37 oC
Time (min)
Dru
g r
ele
ase (
%)
pH 7.4, Sample B
pH 2.1, Sample A
pH 2.1, Sample B
pH 2.1, Sample C
0 100 200 300 400 500
0
20
40
60
80
100
Time (min)
Dru
g r
ele
ase
(%)
37 oC, Sample B
25 oC, Sample A
25 oC, Sample B
25 oC, Sample C
pH 7.4
EFFECT OF TEMPERATURE
Jun Shi, Natalia Alves, João Mano, JBMRB 2008
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SMART BIOACTIVE SURFACES: T-RESPONSIVE
PLLA+BG
SBF NIPAAm solvent
casting
plasma activation (10 min, 30W)
Immersion in NIPAAm sol. (8h, 40 ºC) Immersion in
SBF (2 weeks)
bioactivity tests
Hypothesis: the change in roughness and surface energy across the LCST of surface modified substrates with PNIPAAM could influence the ability for apatite formation in SBF.
EXPERIMENTAL PROTOCOL
PNIPAAm grafting
PLLA+BG substrate grafted with PNIPAAM
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50 mm 50 mm
10 mm 10 mm
50 mm 50 mm
50 mm 50 mm
25 ºC 37 ºC
PNIPAAM grafted PLLA film with 20% of BG
T-RESPONSIVE SURFACES: BIOACTIVITY RESULTS
SEM images of control samples after immersion in SBF during 2 weeks
unmodified film with 10% of BG
PLLA/10%BG film after plasma modification
PNIPAAm grafted PLLA film.
[too much BG]
[sample with 10% BG not bioactive]
[plasma modification does not promote bioactivity]
[PNIPAAm modification without BG does not promote bioactivity]
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25 ºC
10 mm
37 ºC
50 mm 50 mm
50 mm
PLLA+10%BG+PNIPAAm modification n
o s
urf
. mo
d.
PN
IPA
Am
mo
dif.
CA=51.92.4º CA= 58.82.4º
T-RESPONSIVE SURFACES: BIOACTIVITY RESULTS
Jun Shi, Natalia Alves, João Mano, Adv Funct Mater 2007
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2000 2500 3000 3500 4000
10
20
30
40
50
60
70
80
90
Tra
nsm
itta
nce
wavenumber (cm-1)
PLLA
chitosan
grafted PLLA
82.4 ± 1.3 81.7 ± 0.5
82.6 ± 2.7 81.5 ± 2.5
67.6 ± 2.3 88.9 ± 4.1
non modif. PLLA
non modif. PLLA+30%BG
CHT modif. PLLA+30%BG
pH 7.4 pH 5.4
PLLA+BG
chitosan
solvent casting
Plasma activation (60 sec, 32W, Ar) Air for 30 min 1% cht sol.
2x
grafted chitosan
FTIR
SMART BIOACTIVE SURFACES: pH-RESPONSIVE
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50 mm 50 mm
10 mm 10 mm
Bioactivity results – PLLA+30%BG : no surface modification
pH 7.4 pH 5.4
7 d
ays
in S
BF
21
day
s in
SB
F
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Bioactivity results – PLLA+30%BG+chitosan modification
50 mm 10 mm
pH 5.4 pH 7.4
pH 5.4
50 mm 10 mm
7 d
ays
in S
BF
21
day
s in
SB
F
Catarina Dias, João Mano, Natália Alves J Mater Chem 2008
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50 mm
polycarbonate mask
PLLA/10%BG composite
PATTERNING THE APATITE FORMATION
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PATTERNING THE APATITE FORMATION
plasma activation
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activated surface
PATTERNING THE APATITE FORMATION
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polymerization
SBF
PATTERNING THE APATITE FORMATION
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500μm500μm
50μm50μm50μm
PATTERNED MODIFIED SURFACES: BIOACTIVITY RESULTS
Jun Shi, Natália Alves, João Mano, Adv Funct Mater 2007
T=37 ºC, immersion time in SBF= 2 weeks
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SMART BIOACTIVE SURFACES
Surface modification with pH- and T-responsive polymers can be used to
obtain a smart surface where the ability for apatite formation can be switched
depending on temperature or on pH. We thus propose the idea of “smart” or
”stimuli-responsive” mineralization. The concept could be extended to other
external stimuli and other kind of mineral deposited.
By patterning the modification of the surface, it is possible to combine
stimuli and spatial control of the biomimetic apatite formation.
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Films of Chitosan-graft-NIPAAm (GRAFT) and alginate (ALG)
(a) chitosan, (b) PNIPAAm (c) GRAFT.
Dual-responsive Coatings
FTIR
T<LCST T>LCST
GRAFT
pH 5.5, 0.15 M NaCl
QCM-D- GRAFT/ALG)5GRAFT films
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In-situ detachment of SaOs-2 cell sheets after 10 min (A) and 15 min (B) of incubation at 4 ºC from (GRAFT/ALG)5GRAFT films Microscope images of a
detached cell sheet re-cultured in a new tissue culture plate on time 0 (C) and after 45 min (D)
Dual-responsive Coatings – Cell behaviour
The developed dual-responsive films could be potentially used for cell sheet engineering:
[Okano] Gabriela Martins, João Mano, Natália Alves, Langmuir 2011
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Mussels are promiscuous fouling organisms and have been shown to attach to virtually all types of inorganic and organic surfaces (including PTFE – Fig. A) Clues to mussels’ adhesive versatility may lie in the amino acid composition of proteins found near the plaque-substrate interface (Fig. B to D), which are rich in 3,4-dihydroxy-L-phenylalanine (DOPA) and lysine amino acids. DOPA contains the ortho-dihydroxyphenyl –catechol- functional group In addition to participating in reactions leading to bulk solidification of the adhesive, DOPA forms strong covalent and noncovalent interactions with substrates
H. Lee (…) P.B. Messersmith, Science ‘07
Bioinspired adhesive coatings
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Hyaluronic Acid (HA) HA-DN
EDC Dopamine
PBS pH 5.5
2 hr
Hypothesis
Chitosan and hyaluronic acid (HA) are very popular biomaterials, and have been often combined using the LbL technique to form nanostructured coatings HA can be modified using the carbodiimide chemistry in order to incorporate dopamine domains that present catechol groups – HA-DN conjugate We hypothesize that the resulting conjugate can form LbL films with chitosan and produce surfaces with distinct properties with respect with the conventional CHT/HA ones, including improved adhesive properties and enhanced biological performance
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Mechanical tests of CHT/HA-DN films: adhesion
12,7mm
LbL film
127+L mm
177,8+L mm
25,4mm 25,4mm
25,4mm
2 mm
Area in
test
grips
standard procedure ASTM D1002 – tensile shear strength
The adhesion strength of the CHT/HA-DN film is significantly higher when compared with the control film
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Biological tests : direct contact tests using L929 cells
Biological tests : direct contact tests using L929 cells
HA-DN/CHT films presented enhanced cell response
These films could be potentially used as adhesive coatings of distinct implants in order to improve both cell response and adhesion strength in a simple and versatile way.
Isabel Neto,…, Natália Alves, João Mano, Small 2014