Living Radical Polymerization: Progress ... - ACS Publications

Chapter 13

Downloaded by UNIV OF ARIZONA on January 6, 2013 | http://pubs.acs.org Publication Date: August 13, 2009 | doi: 10.1021/bk-2009-1023.ch013

Design of Thermoresponsive Materials by ATRP of Oligo(ethylene glycol)-based (Macro)monomers Özgür Akdemir,1 Nezha Badi,1 Sebastian Pfeifer,1 Zoya Zarafshani1 André Laschewsky,2 Erik Wischerhoff,1 and Jean-François Lutz*1 1

Fraunhofer Institute for Applied Polymer Research Geiselbergstrasse 69, 14476 Potsdam-Golm, Germany. 2University of Potsdam, Department of Chemistry. *Corresponding author: [email protected]

It was recently demonstrated that synthetic polymers containing a hydrophobic backbone and short hydrophilic oligo(ethylene glycol) side-chains may exhibit a lower critical solution temperature (LCST) in aqueous medium. In particular, polymers constructed with oligo(ethylene glycol) acrylates or methacrylates seem particularly promising. Indeed, these oligo(ethylene glycol) (macro)monomers are often commercially available and can be easily polymerized by reversible addition-fragmentation transfer polymerization (RAFT) or atom transfer radical polymerization (ATRP). The latter technique is very versatile and allows the rational design of a wide variety of stimuli-responsive materials. For example, in the present chapter, some examples of thermoresponsive hydrogels, polymeric micelles and planar substrates are presented.

© 2009 American Chemical Society In Controlled/Living Radical Polymerization: Progress in ATRP; Matyjaszewski, K.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

189

190

Introduction


Synthetic macromolecules undergoing rapid conformational change in response to an external stimulus such as pH, temperature, ionic strength or irradiation became lately very important in applied materials science.1 For example, thermoresponsive polymers exhibiting a lower critical solution temperature (LCST) in aqueous medium are very promising materials for bioapplications such as enzyme recycling, protein chromatography, controlled bioadhesion, hyperthermia-induced drug delivery or tissue engineering.2 Such polymers are soluble in water below the LCST but precipitate at temperatures above it. Hence, temperature can be used as a simple external trigger for controlling the hydrophilicity and therefore the structural shape of these macromolecules.

Poly(N-isopropylacrylamide)

Linear poly(ethylene glycol)

O

O

NH O

NH O

O O

NH

non-linear PEG-analogue O O

O n

Polymerizable PEG side chain methacrylate n= 2, 3, 4, 8, 20

O

O O

O O

O

O O

O n

O O

O n

O

O n

O n

n

Scheme 1. Molecular structure of various biorelevant polymers.

Classic examples of synthetic polymers exhibiting an aqueous LCST include poly(N,N’-diethyl acrylamide), poly(dimethylaminoethyl methacrylate), poly(N-acryloylpyrrolidine), poly(2-isopropyl-2-oxazoline), elastin-like artificial polypeptides, poly(vinyl methyl ether) and poly(N-isopropylacrylamide) (PNIPAM, Scheme 1). The latter has been by far the most studied and applied thermoresponsive polymer and therefore can be considered as the “gold standard” in this field of research.3 During the last decades, several thousands of research articles and patents described the synthesis, the properties and the applications of this fascinating macromolecule.

In Controlled/Living Radical Polymerization: Progress in ATRP; Matyjaszewski, K.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.


191 However, despite its widespread popularity in material science, PNIPAM has inherent disadvantages such as an irreversible phase transition and, for short polymers, a significant influence of end-groups on the thermal behavior.3 Moreover, strictly speaking, PNIPAM is not a bio-inert polymer. Indeed, the presence of multiple secondary amide functions in the molecular structure of PNIPAM may lead to the formation of cooperative H-bonding interactions with other amide polymers, in particular with proteins. Thus, the design of new types of thermoresponsive polymers is a crucial topic in contemporary polymer chemistry. In this context, graft (co)polymers with oligo(ethylene glycol) side-chains emerged lately as a promising new class of thermoresponsive polymers.4 Indeed, these macromolecules exhibit, for the most, a defined LCST in aqueous or physiological medium.5-9 This thermoresponsive behavior is believed to be related to the amphiphilic character of these polymers.10, 11 Indeed, the hydrophilic oligo(ethylene glycol) side-chains form H-bonds with water, whereas the backbones, which are usually less polar in nature, lead to a competitive hydrophobic effect. For instance, oligo(ethylene glycol)-grafted polymers based on poly(vinyl ether)-,5 poly(norbornene)-,12 polyester-,13 polystyrene-,14 poly(acrylate)-,15, 16 or poly(methacrylate)-17-21 backbones were all reported to exhibit a LCST in water. Still, the latter category has been progressively more studied in recent years. Indeed, most of the oligo(ethylene glycol) methyl ether methacrylates are commercially available and moreover can be readily polymerized using versatile polymerization techniques such as atom transfer radical polymerization (ATRP) or reversible additionfragmentation transfer polymerization (RAFT).22-25 For example, we recently reported that the atom transfer radical copolymerization of two oligo(ethylene glycol) methacrylates of different chain-lengths, namely 2-(2methoxyethoxy)ethyl methacrylate (MEO2MA, Scheme 2) and oligo(ethylene glycol) methyl ether methacrylate (OEGMA475, Mn = 475 g·mol-1, Scheme 2), leads to the formation of thermoresponsive copolymers with a precisely tunable LCST in water.18 The phase transitions measured for the copolymers P(MEO2MA-co-OEGMA) were found to be reversible and relatively insensitive to important parameters such as concentration of the copolymer in water, ionic strength and chain-length.17 Moreover, the resulting polymers are certainly promising for bio-applications as they are principally composed of biocompatible oligo(ethylene glycol) segments. Indeed, PEG (Scheme 1) is an uncharged, water soluble, non-toxic, non-immunogenic, FDA-approved polymer, and thus is probably the most widely applied synthetic polymer in biotechnology and medicine in recent years. Hence, these novel polymers appear as promising candidates for building advanced stimuli-responsive materials. For example, the present chapter summarizes our recent efforts to prepare biorelevant materials such as hydrogel scaffolds, thermoresponsive polymeric micelles and switchable planar surfaces.


192

Thermoresponsive Hydrogels


Thermoresponsive macroscopic copolymer hydrogels composed of MEO2MA and OEGMA475 were prepared using ethylene glycol dimethacrylate (EGDM, Scheme 2) as a crosslinker.10 Although such hydrogels can be easily synthesized by conventional radical polymerization, the ATRP method was selected to insure a homogeneous comonomer composition in each region of the macromolecular network. Indeed, in the ATRP process, all the chains constituting the network grow simultaneously and therefore consume homogeneously the comonomers. Such precaution would not be necessary if one is only interested in the swelling of the hydrogel at room temperature. However, if a thermoresponsive gel is targeted, a defined composition of the network is probably essential. MEO2MA

OEGMA475

BMDO

O O

O

O

O

EGDM

O

O O

O O

O O

O 9

Scheme 2. Molecular structure of the monomers used for preparing hydrogels.

Two macroscopic gels with different MEO2MA/OEGMA475 compositions were prepared: 90/10 and 80/20. The polymerizations were conducted in the presence of 1 molar equivalent of initiator and 1 molar equivalent of crosslinker. The hydrogels were molded into capillary tubes having an internal diameter of 4 mm. Figure 1 shows the swelling/deswelling behavior measured for these two samples. Dried hydrogel cylindrical monoliths with a length of 10 mm and an initial weight Wd of approximately 100 mg were placed in an excess of deionized water at room temperature. The weight of the swollen hydrogels Ws was then measured as a function of time. Prior to each measurement, the surfaces of the monoliths were shortly dried with a hygroscopic filter paper. The swelling ratio Q was then calculated according to equation 1. Q = (Ws - Wd)/ Wd

(1)

Both hydrogels exhibited a satisfying swelling capacity in pure water and appeared as homogeneous transparent materials in the swollen state. However, the swelling rates and the maximum swelling ratios were found to be proportional to the fraction of OEGMA475 grafts in the network, which is a logical behavior previously observed for PEG grafted hydrogels.26


193

4

Swelling 25°C

Deswelling 60°C

3

Swelling ratio (g/g)


Moreover the hydrogels were found to be thermoresponsive. Their phase transitions were visually evaluated (i.e. the formation of a skin layer on the surface of the hydrogels was examined as a function of temperature) and found to be in the range 42-45°C for the gel with 10 mol% OEGMA475 and 51-53°C for the gel with 20 mol% OEGMA475, which roughly correspond to the phase transitions previously observed for their single-chain counterparts.18 Preliminary evaluation of the deswelling kinetics of these thermoresponsive hydrogels indicated that their thermally induced shrinkage is extremely fast (Figure 1). Such a behavior could be a consequence of the presence of the long OEGMA grafted chains, which can potentially act as water release channels within the network and therefore boost the deswelling kinetics.27

2

1

0 0

1000

2000

3000

4000

Time (minutes)

Figure 1. Evolution of the swelling ratio as a function of time for macroscopic hydrogels P(MEO2MA-co-OEGMA) containing either 10 mol% (empty symbols) or 20 mol% (full symbols) of OEGMA per chain. At t = 3000 minutes, the temperature of the aqueous medium was quickly raised from 25°C to 60°C.

Additionally, degradable versions of these smart networks were also prepared. These degradable hydrogels were prepared via atom transfer radical tetrapolymerization of MEO2MA, OEGMA475, EGDM and 5,6-benzo-2methylene-1,3-dioxepane (BMDO, Scheme 2). The latter monomer is a cyclic ketene acetal, which ring-opens in a radical process to form labile ester functions in the polymer main-chain.28 The formed gels swelled in pure water (swelling trends were roughly comparable to those displayed on Figure 1), displayed a thermoresponsive behavior and furthermore were fully degradable. Indeed, the gels disintegrated completely after one day in KOH solution. However, these macroscopic objects could not be fully degraded in the presence of enzymes.


194


Besides covalently crosslinked hydrogels, we recently designed a series of thermoreversible physical hydrogels.29 The building-blocks of these networks were synthesized by ATRP of MEO2MA and OEGMA475 in the presence of either linear- or star-shaped PEG macroinitiators. The formed copolymers possess permanently hydrophilic PEG inner-blocks and thermoresponsive P(MEO2MA-co-OEGMA) outer-blocks. Below the LCST of the thermoresponsive segments, these (star)-block copolymers are doublehydrophilic (i.e. fully soluble in aqueous medium), whereas above LCST, P(MEO2MA-co-OEGMA) chains precipitate, thus resulting in the formation of a defined hydrogel network.29

Thermoresponsive micelles Macromolecular amphiphiles and their aggregates in water are an increasingly important aspect of modern colloidal science.30, 31 Indeed, macromolecular surfactants such as amphiphilic block-copolymers or polysoaps spontaneously self-assemble in selective solvents into a variety of interesting and useful nanoscale morphologies. For example, amphiphilic diblock copolymers composed of distinct hydrophilic and hydrophobic segments selforganize in water into spherical micelles, cylindrical micelles or vesicles, depending on their hydrophilic-hydrophobic balance.32 More complex morphologies (e.g. multicompartment micelles, toroids, crew-cut micelles, nanotubes, pearl-necklace structures) may be obtained by using surfactants with more elaborate molecular design (e.g. miktoarm stars or triblock copolymers) or by varying the experimental conditions for self-assembly (e.g. using co-solvents, cosolutes, temperature or pH variations).33 Many of these polymeric micellar aggregates have been shown to be very promising for applications in cosmetics, food-industry, medicine and biotechnology. In this context, we recently studied the synthesis and the aqueous selforganization of a new family of biocompatible surfactants composed of a cholesterol hydrophobic moiety and various poly(oligo(ethylene glycol) (meth)acrylate) hydrophilic segments.34 The choice of cholesterol was motivated by the fact that this biological molecule and its esters are generally easily metabolized. Hence, cholesterol-based surfactants and their aggregates in water could be potentially used for drug-delivery or diagnostics applications. The cholesterol-based ATRP initiator cholesteryl-2-bromoisobutyrate (CBI) was synthesized by esterification of cholesterol in the presence of 2-bromoisobutyryl bromide and used for initiating the controlled radical polymerization of various monomers such as OEGMA475, MEO2MA, oligo(ethylene glycol) methyl ether acrylate (OEGA, Mn = 454 g·mol-1) and 2-(2-ethoxyethoxy)ethyl acrylate (EEO2A) (Table 1).


195 Table 1. Molecular description of the surfactants prepared by ATRP.a

1 2 3 4 5 6 7

M1

M2

OEGMA OEGMA OEGMA OEGMA OEGA OEGA OEGA

MEO2MA MEO2MA MEO2MA MEO2MA EEO2A

M1/M2/CBI/ Cu(I)/Bipy 3/17/1/1/2 6/34/1/1/2 4/16/1/1/2 8/32/1/1/2 40/-/1/1/2 40/-/1/1/2 8/32/1/1/2

t (h)

conv.b

Mn c

Mw/Mn c

17 14 14 14 3 1.5 3

0.99 0.98 0.97 0.99 0.29 0.21 0.46

8500 10700 8500 12000 4900 3300 4000

1.20 1.19 1.19 1.20 1.14 1.21 1.49


a

Experimental conditions: copolymerization of methacrylates (Entries 1-4) 60°C, in ethanol solution (monomer/ethanol = 1:1.25 (v/v)) and in the presence of Cu(I)Cl ; homopolymerization and copolymerization of acrylates (Entries 5-7) 90°C, in bulk and in the presence of Cu(I)Br. b overall monomer conversion measured by 1H NMR. c measured by SEC in THF.

The ATRP of the methacrylate monomers was performed at 60°C in ethanol solutions and in the presence of the catalyst copper(I) chloride/2,2’ bipyridyl (Bipy) (Table 1, Entries 1-4).18 Copolymers P(MEO2MA-co-OEGMA) of various chain-lengths and comonomer compositions were prepared and isolated in high yields. After purification, 1H NMR analysis confirmed that the formed polymers exhibit a terminal cholesterol moiety. Additionally, as previously demonstrated, the molar fraction of OEGMA in the copolymers was found, in all cases, to be almost equal to the fraction of OEGMA in the initial comonomer feed.18 Furthermore, SEC measurements in THF indicated that all the copolymers are rather well-defined (Table 1, Entries 1-4). Oligo(ethylene glycol) acrylates generally polymerize rather slowly if the experimental conditions described above are used. Thus, as previously optimized, acrylate monomers were polymerized at 90°C, in bulk, and in the presence of a combination of copper(I) bromide and Bipy (Table 1, Entries 57).16 Either homopolymers of OEGA (Table 1, Entries 5 and 6) or copolymers of OEGA and EEO2A (Table 1, Entry 7) could be successfully synthesized by ATRP using CBI as an initiator. After purification, 1H NMR measurements in acetone-d6 confirmed that all the formed (co)polymers contain an α-terminal hydrophobic cholesterol moiety. The aqueous self-organization of the formed macrosurfactants was studied by dynamic light scattering (DLS) and turbidimetry. Figure 2A shows typical size distributions measured by DLS for various acrylate-based surfactants (Table 1, Entries 5-7). The aggregation behavior of these surfactants in pure deionized water depends indeed on their hydrophilic-hydrophobic balance (i.e. on the volume fractions of the hydrophilic and hydrophobic segments).32 For instance, cholesterol-b-POEGA macrosurfactants (Table 1, Entries 5 and 6) did not lead to the formation of large aggregates in pure water (Figure 2A). We previously reported that POEGA is a very hydrophilic homopolymer, which is soluble in pure water at any temperature up to 100°C.16 Hence, POEGA segments, even with a theoretical degree of polymerization DP as short as 11 (Table 1, Entry 5) or 8 units (Table 1, Entry 6), probably lead to surfactants with a too high


196 hydrophilic volume fraction to observe aggregation. Therefore, the small objects (5-6 nm in diameters) observed by DLS for cholesterol-b-POEGA surfactants are most likely random coils (i.e. unimolecular micelles, in which the cholesterol hydrophobic moiety is protected from water by the POEGA coil).

A

B 80

Transmittance (%)

Volume % (normalized)


100 80 60 40 20 0

1

10

100

Diameter (nm)

1000

60

40

20

0

40

60

Temperature (°C)

Figure 2. (A) Size distributions measured by dynamic light scattering at room temperature for individual solutions (10 mg·mL-1) of either cholesterol-bPOEGA samples (dashed line = Table 1, Entry 5 ; dotted line = Table 1, Entry 6) or cholesterol-b-P(EEO2A-co-OEGA) (full line = Table 1, Entry 7) in pure deionized water. (B) Plots of transmittance as a function of temperature measured for an aqueous solution (1 mg·mL-1) of cholesterol-b-P(EEO2A-coOEGA) (Table 1, Entry 7). Solid line: heating, dotted line: cooling. Reproduced with permission from reference 34. Copyright Wiley-VCH Verlag GmbH & Co KGaA.

Random copolymers of EEO2A and OEGA are typically less hydrophilic than POEGA. Due to its short oligo(ethylene glycol) side-chain (i.e. only two EO units) and its terminal ethyl ether, the monomer EEO2A is less hydrophilic than OEGA. Thus, we previously demonstrated that well-defined copolymers P(EEO2A-co-OEGA) exhibit a LCST in water, which can be precisely adjusted by varying the comonomer composition.16 For example, copolymers P(EEO2Aco-OEGA) containing 20 mol% of EEO2A exhibit a LSCT in pure deionized water at approximately 40°C. Hence, the surfactant cholesterol-b-P(EEO2A-coOEGA) (Table 1, Entry 7) is probably having a lower hydrophilic/hydrophobic balance than POEGA-based surfactants and therefore self-organized in pure water into rather monodisperse aggregates with an average hydrodynamic diameter Dh of approximately 100 nm (Figure 2A). 1H NMR measurements in D2O confirmed the aggregation of the surfactants as the protons of cholesterol were undetectable in that solvent (data not shown). Moreover, as expected, these aggregates were found to be thermoresponsive and precipitated at higher temperatures. Turbidimetry measurements (Figure 2B) indicated that their LCST


197 is around 45°C, which is slightly higher than the value observed for the unbounded copolymer P(EEO2A-co-OEGA).16 Other reports indicated that PEG-based thermoresponsive micelles can exhibit higher LCST than the corresponding hydrophilic segments.20, 35 Moreover, the measured phase transition was relatively broad. This behavior is generally observed for thermoresponsive copolymers with a short DP (i.e. DP below 25 units) and is due to chain-to-chain deviations in comonomer composition.17


Switchable bioactive surfaces Surfaces coated with PEG or oligo(ethylene glycol) are generally regarded as materials of choice for preventing bioadhesion.36 For instance, numerous publications described the protein-repellency of PEG-modified substrates.37 Such anti-fouling behavior is mainly due to the steric repulsion between hydrated neutral PEG chains and proteins.38, 39 Furthermore, as cell-adhesion mechanisms are generally protein-mediated, PEG-modified surfaces were also reported to be efficiently cell-repellent.40 Thus, PEG-coated materials have been extensively studied in various bio-applications such as blood-compatible materials, implants and stealth carriers for either drug- or gene- delivery. Yet, although very useful, bio-repellent PEG surfaces remain, on the whole, passive materials. Several emerging areas of biosciences and biotechnology certainly require “smarter” surfaces with more sophisticated properties. For instance, switchable surfaces capable of performing reversible bio-interactions are highly relevant for modern applications such as bioseparation, biosensors, bio-assays and cell engineering. Such smart surfaces can be, for example, constructed with stimuli-responsive polymers.41 For instance, the thermoresponsive polymer PNIPAM and closely related polyacrylamides have been widely investigated for preparing biorelevant switchable surfaces.42-44 Exhibiting a LCST at 32°C, PNIPAM is the currently most studied material for inducing surface changes between room- and body- temperature. However, as discussed in the introduction, PNIPAM is not a bio-inert polymer. This polymer may interact with biological objects such as proteins or cell. Thus, the development of efficient switchable surfaces based on polymers of other chemical nature is certainly a topical matter. For instance, surfaces exhibiting thermoresponsive properties comparable to those of PNIPAM and the biorepellent behavior of hydrated PEG would be of high interest for numerous applications in modern biosciences.


198


T=37°C adhesion

T=25°C rounding-up

Figure 3. Phase contrast microscopy images of L929 mouse fibroblasts on P(MEO2MA-co-OEGMA)-modified gold substrates after 44 hours of incubation at 37°C (left) and 30 minutes after cooling down the sample to 25°C (right). The surface presented in this figure was prepared using the macroinitiator “grafting-from” approach. Scale bars correspond to 100 µm. Cartoons (top panel) show a schematic view of the polymer coatings at 37 and 25°C. Reproduced with permission from reference 51. Copyright Wiley-VCH Verlag GmbH & Co KGaA.

In this context, the P(MEO2MA-co-OEGMA) thermoresponsive polymers are particularly relevant. Indeed, polymer brushes of oligo(ethylene glycol) methacrylates can be easily prepared on flat substrates via either surfaceinitiated ATRP or surface adsorption of well-defined polymers with anchor moieties.45, 46 Yet, brushes prepared with long PEG methacrylates (i.e. sidechains of 5 ethylene oxide units or longer) behave somewhat like standard biorepellent PEG coatings.47-49 However, thermoresponsive polymers with shorter oligo(ethylene glycol) side-chains might behave differently. For instance, Huck and Jonas recently demonstrated that surface initiated P(MEO2MA-coOEGMA475) brushes exhibit LCST values, which coincide with those observed for free copolymers in aqueous solution.50 The partial dehydration and the change of conformation of these surface brushes above LCST may be of practical interest for tuning bio-adhesion. In the present work, P(MEO2MA-co-OEGMA475)-modified gold surfaces were evaluated for their ability to control cell adhesion.51 In such an application, temperature variations should be relatively mild as mammalian cells may be



199 damaged by extreme temperature fluctuations. Thus, the surfaces should ideally mediate cellular adhesion at physiological temperature and abandon it at room temperature. To attain such properties, a copolymer P(MEO2MA-co-OEGMA) containing in average 10 mol% of OEGMA475 units per chain was selected. This copolymer exhibits a LCST of about 39°C in pure water,18 whereas in phosphate buffer saline solution, due to a weak salting-out effect, the LCST is around 35°C, rendering it ideal for the present application. To explore the potential of these thermoresponsive copolymers, three different strategies were investigated for modifying the surfaces. First, welldefined copolymers P(MEO2MA-co-OEGMA) were prepared by solution ATRP in the presence of a low molecular weight disulfide ATRP initiator, purified and subsequently adsorbed on clean gold substrates (“grafting-onto” approach).51 Alternatively, the disulfide initiator was first adsorbed on gold surfaces, which were used to initiate the atom transfer radical copolymerization of OEGMA475 and MEO2MA in ethanol/H2O mixtures (“grafting-from” approach). In the third strategy, pristine gold surfaces were first modified via layer-by-layer polyelectrolyte deposition and subsequently functionalized by a polyanionic ATRP macroinitiator (i.e. macroinitiator “grafting-from” approach).52, 53 P(MEO2MA-co-OEGMA) brushes were then grown from the surfaces using either standard- or AGET- ATRP protocols.54 The three different types of P(MEO2MA-co-OEGMA)-modified gold surfaces were used for cultivating L929 mouse fibroblasts at 37 °C. The fibroblasts adhered efficiently and spread well on all types of substrates (Figure 3), indicating that the P(MEO2MA-co-OEGMA)-modified surfaces are bioadherent at physiological temperature. The maximum of adhesion was typically observed after 40 h of cultivation. Such kinetics of adhesion are roughly comparable to those generally observed on PNIPAM-modified surfaces. However, when the temperature of the cultivation medium is decreased to 25 °C, a rapid cell rounding is observed within approximately 30 minutes (Figure 3), allowing their facile detachment and harvesting. No cell rounding of spread fibroblasts occurs on plain gold surfaces upon a temperature decrease from 37 °C to 25 °C. Thus, the P(MEO2MA-co-OEGMA)-modified gold substrates can be tuned from cell-attractive to cell-repellent (i.e. standard PEG repellency). Importantly, this behavior is reversible and successive cycles spreading/rounding can be triggered by temperature switches. Ultimately, the cells may be washed-off from the surface by gentle rinsing at room temperature.

Conclusion Thermoresponsive polymers based on oligo(ethylene glycol) acrylates or methacrylates can be easily prepared by atom transfer radical polymerization under straightforward experimental conditions (i.e. in bulk or in ethanol solution and in the presence of commercially available catalysts). Thus, these stimuliresponsive macromolecules can be exploited for preparing a wide range of smart advanced materials such as thermoreversible hydrogels, thermoresponsive block-copolymer micelles and switchable surfaces. Hence, some of the results


200 presented in this chapter are anticipated to be highly relevant for biotechnological applications such as protein chromatography, cell cultures, stem-cells differentiation, DNA bioseparation in PCR, tissue engineering, and implants.

Acknowledgments


Fraunhofer society and Max-Planck society (joint project bioactive surfaces) and the Federal Ministry of Education and Research (BMBF programs NanoforLife and NanoChem) are acknowledged for financial support. Additionally, J.F.L. thanks Katja Uhlig, Dr. Andreas Lankenau and Dr. Claus Duschl (Fraunhofer IBMT, Potsdam) for the cell experiments.

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