Smart Polymers for Biomedical Applications (2014)

Smart materials have the ability to respond to changes in their environment by variations in their molecular structure or in their physicochemical properties.1 Shape-memory and shape-changing polymers are examples of this class of materials, whose capability of performing stimuli-induced active movements has inspired engineers to develop heat-shrinkable packing materials, smart textiles, and morphing structures for aerospace vehicles. In the last 15 years, these materials have created significant interest in the field of biomedicine, for example, in minimally invasive surgery for the insertion of self-inflating bulky medical devices.2 The progress in materials chemistry, physicochemical characterization techniques, assessment of biomaterial interaction with cells and tissues, and computer-assisted modelling motivates the exploration of knowledge-based approaches for the design of active polymer systems. However, these active polymers are not restricted to actively moving materials. They can offer a wide-spread spectrum of functions, including controlled release, swellability, and degradability, that may be controlled by suitable stimuli. The concepts for the design of smart polymers with the associated processes can be categorized by the targeted device (e.g., coating, particles) and the nature of the function. Besides shape-memory polymers,3 other material systems of interest are stimuli-sensitive hydrogels4 and nanocarriers for the targeted administration of drugs or genes.5 Polymeric materials offer various structural parameters on different levels to adjust their properties and functions:6 the chemical structure of the repeating units (i.e., the kind and number of chemical functions within the macromolecules), their chain segment length in polymer network architectures, the (self-)assembly of macromolecules on the supramolecular level, and the geometry of shaped bodies on the macroscopic level (i.e., layer thickness, particle size, geometric features, inner/outer shape of the material). In this special issue of Macromolecular Chemistry and Physics, which is inspired by the presentations held at the CIMTEC 2014 conference, organization motifs of polymers at the different hierarchical levels to evolve, enhance, and study the (multi)functionality of these materials, are discussed. The design of the molecular structure of the repeating units allows manyfold possibilities for influencing the properties of polymers. An example is the incorporation of different functional groups, whether integrated in the backbone or as a pendant group. This method was successfully applied to adjust the hydrolytic degradation route of polymeric biomaterials. The introduction of methyl groups, meaning the replacement of glycolide units by lactide units in poly(glycolide-co-lactide)s (PLGA) changes the thermal, mechanical, swelling, and degradation properties of these copolyesters. This strategy of replacement has been followed by Cui et al.7 in their paper “Dopamine-Based Coatings and Hydrogels: Towards Substitution-Related Structure–Property Relationships”. Herein, the authors describe an active hydrogel system on the basis of poly(catecholamine)s, which is able to respond to pH changes by uptaking/releasing water (swelling/deswelling). The hydrogel-forming polymer was synthesized by controlled oxidative polymerization of dopamine and norepinephrine and could be processed into coatings or covalently crosslinked self-standing bodies. It was shown that the macroscopic properties of the swollen hydrogel can be influenced by substitution at the catechol­amine 6-position with chloro- or nitro-functionalities. Due to strong inductive and mesomeric effects of the substituents, affecting the ionizability of the hydroxyl groups, a significant impact on the pH response or water uptake was observed. pH-, and thermoresponsive nanogels were obtained by crosslinking of N-isopropylacrylamide (NIPAM) and 2-dimethyl(aminoethyl) methacrylate with dendritic acrylated poly­glycerol. In their article “Positively Charged Thermoresponsive Nanogels for Anticancer Drug Delivery” Molina et al.8 present the manipulation of the molecular structure of the NIPAM-based system by incorporation of the positively charged comonomer. This enables a control over the lower critical solution temperature (LCST). At the same time, a pH-responsive material was obtained due to the presence of tertiary amino groups, which can be protonated in acidic solutions. Depending on the pH-value of the solution, different LCSTs were observed for the nanogels. Responsive nanogels containing 0.4 and 12 wt% of the charged comonomer could be loaded with two different anticancer drugs in separate experiments. In subsequent studies, these drugs were released at 25 and 45 °C. Generally, the cumulative release from the positively charged nanogels was higher, compared with uncharged material; however, a different release behavior of both drugs was observed. Such pH-sensitive release opens the possibility of targeted medication, as the release trigger can be adjusted to the conditions prevailing in cancer cells. The impact of the modification of the molecular structure on the macroscopic properties has also been demonstrated for shape-memory polyurethane foams intended for clinical use. A critical issue of shape-memory foams employed as a trans­catheter embolic device for aneurysm treatment is the time period, which is required for the depression of the glass-transition temperature (the switching temperature for the employed shape-memory effect) when moving from dry to aqueous conditions, due to the plasticizing effect of the water molecules that diffuse in the polymer network. Hasan et al.9 report in the article “Effects of Isophorone Diisocyanate on the Thermal and Mechanical Properties of Shape-Memory Polyurethane Foams” how this challenge was conquered. Premature foam actuation was avoided by the substitution of rather flexible trimethylhexamethylene diisocyanate with the stiff isophorone diisocyanate (IPDI) for the generation of the polyurethane networks. They showed that 10 wt% of IPDI within the networks is sufficient to prolong the surgical-operation time span to more than 20 min, thus providing sufficient time for the foam to be placed at an aneurysm site without actuation within the catheter. Polymer network architectures offer several parameters to tailor properties such as the chain segment length or the block weight ratio in multiphase materials. An example is the adjustability of the melting transition of shape-memory polymers based on covalently crosslinked poly(ε-caprolactone) (PCL) by the variation of the PCL chain segment length. An important design principle for dual-shape materials based on thermoplastic urethane elastomers (TPU) is the combination of two components, hard and switching domains with different thermal transitions, either a melting or glass transition, where the hard domain (the component with the higher transition temperature) provides the stability of the permanent shape, and the switching domain fixates the temporary shape. Sun et al.10 demonstrate the influence of the domains associated with the soft segments of TPU on its shape-memory properties in their paper “Heating-responsive shape memory effect in thermoplastic polyurethanes with low melt flow index”. The degradation behavior of copolyesterurethanes as multiblock copolymers is of high interest with respect to biomedical applications. Langmuir monolayer experiments to study the degradation, as a model system, for multiblock copolymers based on oligo(ω-pentadecalactone) and oligo(ε-caprolactone) segments (PDLCL) with different weight ratios of both segments are described by Schöne et al.11 in the article “Characterization of Langmuir Films Prepared from Copolyesterurethanes Based on Oligo(ω-pentadecalactone) and Oligo(ε-caprolactone) Segments”. Differences in the behavior of polymers containing oligo(ω-pentadecalactone) segments only, in contrast to PDLCL, are discussed and mainly attributed to the higher polarity and abundance of hydrogen bonds in the case of the oligo(ε-caprolactone) segments, which lead to a higher water content and layer thicknesses of the Langmuir films. Multiple-shape memory effects were realized by chemically linking different oligomeric blocks, whereby each oligomeric block forms domains associated with a distinct thermal transition. These thermal transitions determine the different switching temperatures of the multiple-shape-memory effect. Nöchel et al.12 present a triple-shape system with reprogrammable switching temperatures in the paper “Triple-Shape Effect with Adjustable Switching Temperatures in Crosslinked Poly[ethylene-co-(vinyl acetate)]”. Crosslinked poly[ethylene-co-(vinyl acetate)]s with different crosslink densities and very broad melting transitions enable tuning of the switching temperatures of both shape transitions by purely physical manipulation of these materials. The (self-)assembly of macromolecules to form particulate systems is a very successful design principle, e.g., the assembly of poly(ethylene glycol-block-propylene glycol) to micelles in aqueous environments serves as a template for the generation of responsive hydrogels. This principle was employed by Paiphansiri et al.13 for the generation of nanocapsules with a shell consisting of disulfide-linked DNA. In the contribution “Glutathione-Responsive DNA-Based Nanocontainers Through an Interfacial Click Reaction in Inverse Miniemulsion” the authors describe the assembly of droplets of thiol-terminated DNA, stabilized by a poly(ethylene glycol)-based block copolymer and subsequent polymerization of the shell by the disulfide exchange agent 1,4-bis(3-(2-pyridyldithio)propion­amido)butane in the presence of the dimaleimide-modified fluorescent dye BODIPY. The disulfide linkages of the shell could be selectively cleaved by glutathione, causing the release of the fluorescent dye. Such capsules could potentially be used as a biological sensor, which would allow for the examination of the cleavage and degradation of nanocarriers in an intracellular medium by fluorescent spectroscopy. In addition to the controlled release of dyes, nanocarriers are also considered as artificial vectors for gene delivery. Complex micelles for this application, consisting of a biodegradable poly(lactide-co-glyco­lide) core and a composite shell of poly(ethylene glycol) mixed with branched poly(ethylene imine) (PEI) chains, were also generated by the supramolecular organization principle. In the study “Self-Assembly of Polyethylenimine-Modified Biodegradable Complex Micelles as Gene Transfer Vectors for Proliferation of Endothelial Cells”, Lv et al.14 demonstrate that these nanocarriers have a considerably lower cytotoxicity due to the lower molecular weight of PEI applied for the composites, compared with PEI normally used as nonviral vectors. Despite the low molecular weight of PEI, the successful transfection of genes into endothelial cells could be demonstrated. The introduction of functionality at the macroscopic level in the context of biomedicine is often connected to topographical features of cell substrates, as cells respond to the structure of the surface to which they adhere, e.g., orientation of cells growing on ridged surfaces. In the manuscript “Near-Infrared-Irradiation-Induced Remote Activation of Surface Shape-Memory to Direct Cell Orientation”, Shou et al.15 show the programming of such ridged surface patterns on flat films from gold nanorods embedded in PCL using a nanopatterned silicon mold. A remote activation of the shape-memory effect during cell culture by application of near-infrared light (NIR) led to a spatially limited recover of the flat surface. Cell alignment in the NIR-irradiated region was lost and random cell migration was observed, while cells on the non-illuminated region were still aligned along the direction of the temporal pattern. Tissue substitutes or medical devices for specific therapies (e.g., intravascular stents) require specific macroscopic shapes from (bio-)materials. Patient-specific bone grafts should be provided if required, because of the shape of the bone defect. Moreover, depending on the site of the bone defect, the substitute should also mimic the trabecular structure of cancellous bone. In their contribution “Shape-Memory Performance of Thermoplastic Amphiphilic Triblock Copolymer Poly[(d,l-lactic acid)-co-(ethylene glycol)-co-(d,l-lactic acid)] (PELA)/Hydroxyapatite Composites”, Kutikov et al.16 demonstrate the fabrication of macroporous scaffolds by rapid prototyping, which fulfills the above-mentioned requirements. Moreover, it was shown that compounding of this material with polycrystalline hydroxyapatite powder as a calcium source has only minimal impact on the shape-memory capability of the material. This collection of articles demonstrates how different properties and functions of polymeric smart materials can be tailored by targeted material design: the choice of monomer, the combination of oligomeric blocks to macromolecules, their assembly to (multi-)functional materials, compounding them to formulations, and finally processing them into shapes optimized for a specific application. Moreover, it becomes apparent that the progress in translational research is driven by an interdisciplinary approach involving materials science, engineering, computer science, and (bio-) medicine. The editorial and administrative support by Dr. Stefan Spiegel, Wiley-VCH, and Sabine Benner HZG, is kindly acknowledged. This work was financially supported by the Helmholtz Association of German Research Centers. Stefan Baudis is post-doctoral scientist at the Institute of Biomaterial Science of the Helmholtz-Zentrum Geesthacht in Teltow, Germany. He received his doctoral degree in Macromolecular Chemistry from the Vienna University of Technology in 2011. Marc Behl is Deputy Director of the Institute of Biomaterial Science, Helmholtz-Zentrum Geesthacht in Teltow, Germany and Head of the Department “Active Polymers”. In 2004 he received his doctoral degree in Organic Chemistry from the Johannes-Gutenberg University Mainz. Andreas Lendlein is Director of the Institute of Biomaterial Science, Helmholtz-Zentrum Geesthacht in Teltow, Germany and serves on the Board of Directors of the Berlin-Brandenburg Center for Regenerative Therapies. He is Professor at University of Potsdam and Professor in Chemistry at Freie Universität Berlin, as well as Member of the Medical Faculty of Charité University Medicine Berlin. He completed his Habilitation in Macromolecular Chemistry in 2002 at RWTH Aachen University and received his doctoral degree in Materials Science from the Swiss Federal Institute of Technology (ETH) in Zürich in 1996.