Advanced Functional Polymers Addressing the Needs of Modern Medicine

There is no doubt: Biomaterials need to be designed as to be multifunctional to be able to fulfill the complex requirements of medical applications.1, 2 The function arises from the favored behavior of a material depending on a certain application scenario (system). So far, the implementation of the desired function of a material in a biological environment, so-called biofunctionality, realized by a knowledge-based approach into a design concept for functional materials, is limited. The challenge is to reveal the influence on biological systems of chemical and physical properties of a material, especially related to processes like the degradation, diffusion, or adsorption of biomacromolecules. For this, different material functions and their combinations are implemented into polymers and their effects are investigated in vitro and in vivo. A function of a material can be realized by the combination of a molecular structure and a physical manipulation (treatment). For example, for the shape-memory effect, a polymer needs to provide on the molecular level permanent and temporary netpoints, as well as chain segments providing elasticity, and only by applying a programming step will the shape-memory effect be implemented as a function. Besides this example, stimuli-sensitivity, degradability, and controlled drug release are other important functions. For biomedical applications, often a combination of these functions is required. This special issue is therefore dedicated to advanced functional polymers for medicine. An elegant method to simultaneously synthesize a large number of porous polymeric scaffolds with the aim of obtaining a wide range of physical properties such as water uptake or macroscopic compressive moduli is realized in this issue by combinatorial mixtures of six different telechelics. The reactive precursors are oligomers/polymers with low molecular weight and methacrylate end groups. They are dissolved in ethylene carbonate (EC), placed in wells, and subsequently cooled below the melting temperature of EC: EC crystallizes and phase separation occurs. After photocrosslinking, EC is removed, resulting in 63 different porous polymeric scaffolds with relatively low porosities. Water uptake ranges from 3 to 1532 wt% and macroscopic compressive moduli in the wet state from 0.01 to 60 MPa. Precursors are selected from a group of polymers relevant for biomedical applications [marc.201500229]. The realization of new functions demands, in some cases, the application of innovative chemical structures for hydrogel synthesis. One example is the use of biomaterials as a source of biochemical in-situ processes. Nitric oxide (NO) is a relevant active agent in cancer treatment as a signal transduction molecule for cellular apoptosis. L-arginine is a substrate for NO synthase and therefore plays a crucial role in the generation of NO in situ, however, it metabolizes in vivo too fast to be used directly for NO generation. A strategy reported here by Nagasaki et al. allows the controlled synthesis of PEG-b-poly(L-arginine) (PEG-b-PArg) on a multigram scale, reported here for the first time, to form particles functioning as arginine carriers. The block copolymer is synthesized in two main steps. First, a ring-opening polymerization of N-carboxybenzyl-protected L-ornithine N-carboxyanhydride with methoxy-PEG-amine, followed by quantitative guanidinylation. Different guanidinylation reagents are investigated but only N,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine can quantitatively and under mild conditions convert the amino group in the side chain to a guanidino group. Moreover, polyion complex micelles are prepared from positively charged PEG-b-PArg and negatively charged hyaluronic acid or chondroitin sulfate, which could act as an arginine carrier [marc.201500224]. Besides linear polymers, star-shaped precursors could in this context be of interest in the future, in order to build up more complex polymer network structures. The synthesis of star-shaped polypeptides by N-carboxyanhydride polymerization and their relevance as delivery systems for therapeutics is reviewed here by Heise et al. [marc.201500300]. Especially in release systems, the degradation behavior of polymer matrices or macromolecular carriers is of high significance. A Langmuir monolayer technique can be used to determine the degradation behavior of polymers in vitro in a timely manner. An example of the application of this set-up is the investigation of the influence of three different diurethane linkers in oligo[(rac-lactide)-co-glycolide]-based polyesterurethanes, in view of their hydrophilicity and packing motifs, at the air–water interface compared to poly[(rac-lactide)-co-glycolide]. No influence of the linker is observed in the Langmuir film behavior in terms of the π-A isotherm. However, the evolution of morphological structures at intermediate compression levels under isobaric conditions is retarded by the linker compared to the PLGA, independent from the chemical structure of the diurethane linker [marc.201500316]. On-demand triggered release of bioactive substances is one challenge in drug delivery research. Microgels composed of crosslinked poly[(N-isopropylacrylamide)-co-(vinyl imidazole)] (P(NIPAM-co-VIm)) are thermosensitive due to the PNIPAM and, by copolymerizing it with VIm, pH-sensitivity is implemented. It is shown in this issue that these microgels can be fragmented by ultrasonication, which can be used for on-demand release. The fragmentation is highly dependent on the swelling degree, which is in turn dependent on pH and temperature. Only at maximum swelling, when the polymer chains are expanded, can the microgels be mechanically destroyed by ultrasound. Additionally, two different lipases as model compounds are encapsulated, which have different isoelectric points as the diffusion rate depends on electrostatic interaction. Release is only observed when the isoelectric point of the lipase is near the pH at which the fragmentation of the microgels is feasible. This work shows a general principle for how ultrasound-triggered on-demand release can be realized, and shows the opportunity to be transferred to other copolymer/protein systems [marc.201500311]. The thermosensitivity of PNIPAM can also be used to switch between cell-adherent and protein-repellent surfaces. This principle can be applied for the cultivation of stem cells, which are important players for regenerative therapies. However, the challenge in the cultivation of human mesenchymal stem cells (hMSCs) is to maintain their proliferation capacity and stemness over a long cultivation time. Nash et al. present here advances in the development of thermoresponsive substrates based on PNIPAM for hMSC expansion. A solvent-casting method is used to make 1 μm thick films of PNIPAM: the perfect thickness of films for cell attachment and proliferation, as the same group reported in a previous study. Seeding and harvesting the hMSCs several times from the PNIPAM films, they are compared to hMSCs seeded on conventional tissue culture plastics and harvested by trypsinization. It is proven that hMSCs from PNIPAM films can better maintain their ability for multilineage differentiation and, therefore, this approach represents an attractive alternative for stem cell cultivation [marc.201500234]. Especially with regard to remote healthcare, bioanalytic approaches are of pivotal interest. Biosensors can be conceived by applying gold nanaoparticles (AuNPs). A new method for the formation of stable AuNPs is explored in this issue using suckerin proteins. These suckerins are very robust proteins derived from the sucker ring teeth of squid, showing a silk-like architecture, good solubility in weak acidic conditions, and a high tyrosine content within the sequence. This latter characteristic is used to induce the formation of AuNPs through redox activity. It is shown that AuNPs can grow either with spherical or plate-like morphologies, depending on the concentration of the protein. Moreover, it is possible to form AuNPs on nanostructured solid substrates by a simple dipping method, opening up their application in solid-state biosensors [marc.201500575]. Conductive polymer microfibers can also be of interest for bioanalytical applications. The preparation of a conductive polymer mat consisting of electrospun polycaprolactone with an interpenetrating network of polypyrrole and polystyrene sulfonate is reported in this issue. By using electrical stimulation, bone marrow-derived MSCs placed on the polymer mats show enhanced differentiation towards osteogenic outcomes, determined by increased alkaline phosphatase activity and calcium deposition. Besides applications in bioanalytics, such conductive materials are interesting candidates for bone tissue engineering [marc.201500233]. Nanoreactors or artificial organelles can be realized by the formation of polymersomes. The design of polymersomes is challenging, as their stability and the permeability of their membranes need to be well-balanced. The mechanical stability of such synthetic membranes increases with increasing molecular weight of the copolymer used for their formation, due to increasing membrane thickness. However, this might lead to a reduced permeability. Mechanistic studies are undertaken here to explore whether increasing membrane thickness affects the transport of calcium ions mediated by the ionophor ionomycin. Polymersomes with increasing membrane thickness bearing ionomycin as calcium ionophores inside the membrane are compared. In the inner cavities, a calcium-sensitive fluorescent dye is encapsulated to prove calcium transport by spectroscopic analysis. It is shown that Ca2+ transport is not blocked in thicker membranes, but markedly decreased compared to thinner membranes [marc.201500289]. Polymersomes bearing heparin on their surfaces have shown antimalarial activity. This is due to the interaction of heparin with the surface protein of malaria parasites. In this approach, the polymersomes function as nanomimics, whereby the parasites attach to the polymersomes instead of invading red blood cells, and reproduction is inhibited. Now in the follow-up study reported here, the interaction between the parasite surface protein and heparin is investigated in-depth by using an antimalarial assay. The concentration and length of the heparin is varied, and it is shown that fewer heparin molecules exposed at the polymersome minimize the potency of the nanomimic and, when using shorter heparin, more chains on the polymersome had to be introduced to show similar activity compared to using long heparins [marc.201500267R1]. The design of functional polymers for medicine is a broad research field, as the contributions in this special issue display. With the progress made for biomedical applications, such as regenerative medicine, drug delivery, or bioanalytics, a lot of new ideas for applications are generated, which provide future demands on material functionality. Therefore, this is an interdisciplinary research field which is developing dynamically. We would like to thank all authors for contributing to this interesting and inspiring special issue. Dr. Kirsten Severing from Wiley-VCH and Sabine Benner from HZG are acknowledged for their appreciated editorial and administrative work. We hope you enjoy reading this special issue! Dr. K. K. Julich-Gruner Prof. A. Pandit Prof. A. Lendlein