Polymers in Biomedicine

Polymer research in the field of biomedicine is driven on the one hand by the high clinical need for multifunctional biomaterials as an enabling technology for modern therapies and on the other hand by the fundamental scientific interest to understand and mimic functions of biological materials such as the extracellular matrix (ECM).1 The broad clinical application of polymer-based implants and extracorporeal systems, in which tissues or body fluids are extensively exposed to polymers, e.g. in haemodialysis, for many decades lead to insights into the great potential of biomaterial-based therapies but also demonstrated limitations of the polymeric biomaterials established in clinical applications today. Modern medicine is aiming at regenerative therapies providing a causal treatment of damaged or non-functional cells, tissues or organs, which would be beneficial for the patient and also might be socio-economically attractive compared to palliative treatments. Therefore the next generation of biomaterials should not only temporarily substitute tissue or organ functions but also induce and guide endogenous regeneration in vivo. Lessons learnt from immunology, wound healing and long-term in vivo behavior as well as concepts derived from developmental biology, angiogenesis, biological signalling, (stem) cell biology and matrix biology need to be considered in the design of next generation biomaterials. Macromolecules are also explored as nanocarriers for drugs, which should recognize a biological target, e.g. inflamed tissue, and only release the drug at this site to ensure a local treatment. Bioactive compounds like DNA/RNA molecules should even be transported into cells and delivered at specific cell organelles.2 The significance of polymer-based biomaterials is highlighted at the conference "Polymers in Biomedicine and Electronics", which takes place from Oct 3rd to 5th, 2010 in Berlin combining the biannual meetings of the Gesellschaft Deutscher Chemiker (GDCh) Division "Macromolecular Chemistry" and of the Berlin-Brandenburgischer Verband für Polymerforschung e.V. (BVP). Design and synthesis of functional polymers, physical principles underlying the function, the characterization of such functions within a system as well as product-oriented industrial research are the topics of this conference. Biomedicine-oriented research will be discussed in several sessions covering smart biomaterials, biocompatible coatings and their applications in controlled drug delivery systems or in regenerative therapies. This special issue of Macromolecular Bioscience comprises a selection of ten papers, which will also be presented at the above mentioned conference. Recombinant spider proteins (Spiess et al.; DOI:10.1002/mabi.201000071) and depsipeptide-based polymers (Feng et al.; DOI:10.1002/mabi.201000076) are comprehensively reviewed as promising candidates for the next generation biomaterials. The successful synthesis of polysialic acid derivatives described by Su et al. (DOI:10.1002/mabi.201000094) makes interesting building blocks for multifunctional polymers available. Especially the N-acyl derivatives of polysialic acid providing functional groups suitable for Cu-free "click" chemistry could be promising starting materials. Further focal topics of the special issue are polymers for controlled/targeted delivery of bioactive molecules and biointerfaces. A challenge in designing biomaterials is the complexity of properties and functions, which need to be tailored to the specific requirements of an application.1 Mechanical properties on macro- and microlevel, thermal properties, permeabilities, e.g., for water and oxygene, are examples for material properties to be considered. Biocompatibility comprising non-toxicity and biofunctionality, (bio)degradability, drug releasing capabilities as well as stimuli-sensitivity are examples for functions, which might be required singularly or combined. At this point the question arises, which property or function should be addressed first when designing a new polymeric biomaterial. Many of the clinically applied biomaterials were selected from the list of commercially available plastics based on their structural properties. On the contrary degradable synthetic biomaterials were developed intentionally to fulfil this specific function in surgical sutures. Therefore they are briefly discussed in the following as an example for targeted biomaterial design and starting point for the development of polymer systems, whose properties and functions can be varied in a wide range by only small changes in their chemical structure. The cleavage of chemical bonds by hydrolysis was selected as reaction for degradation of linear polymer, because water is ubiquitous in the human body. Another design criterion is degradation products, which should be dissolvable in water, non-toxic and ideally metabolizable analogously to compounds naturally occurring in the cell metabolism. Polyglycolide, an aliphatic polyester, and copolyesters with improved processability prepared by copolymerization of diglycolide with L,L-dilactide or ε-caprolactone were the result of this development. They form the material basis for degradable surgical sutures to date. The hydrolysis rate of these copolyesters could be adjusted by their comonomer ratio, but also by variation of the sequence structure in case of poly[(ε-caprolactone)-co-glycolide]. A glycolide unit is accelerating the hydrolysis of ester bonds if involved in the ester bond as the hydroxy- or the carboxy- group providing component. Therefore ester bonds connecting two glycolide units are the most easily hydrolysable bonds (see Scheme 1). A copolyester with a blocky sequence structure degrades faster than a copolyester with the same comonomer ratio but a random sequence structure.3 Chemical structures of the four different ester bonds, which can occur in poly[(ε-caprolactone)-co-glycolide] regarding diads consisting of two repeating units and their relative reactivity in hydrolysis.3 Changing the sequence structure or the comonomer ratio also influences the thermal and mechanical properties of copolyesters. A polymer system, in which degradation rate and mechanical properties could be adjusted almost independently from each other, are phase-segregated multiblock copolymers with oligo[(3-R-hydroxybutyrate)-co-(3-R-hydroxyvalerate)] hard segments and oligo[(ε-caprolactone)-co-glycolide] soft segments.3 While the mechanical properties of this physically crosslinked polymer system are determined by the hard segment content, the degradation rate could be adjusted by the glycolide content and the sequence structure of the soft segment. Polymer networks are also advantageous in their degradation behavior with regard to the changes in elasticity with progressing hydrolytic degradation.4 While linear copolyesters can exhibit an abrupt loss of elasticity during hydrolytic degradation, polymer networks consisting of copolyester segments are becoming more elastic with proceeding degradation. The elasticity of polymer networks in their viscoelastic state is determined by the network chain segment length. The cleavage of a chemical bond in one segment weakens the polymer network, but its integrity is maintained as long as a sufficient number of neighboring and via netpoints connected segments still are intact (see Scheme 2). As the segment chain length in the network increases in this way, the polymer becomes more elastic. Molecular changes of polyester urethane network during hydrolytic degradation. (A) Initial network. (B) Uptake of a small amount of water () leads to first bond cleavages. (C) Subsequently, increased hydrolysis, production of further dangling chains and decrease in Tg of the network is observed. (D) Entanglement of non-linear fragments formed by random cleavage of ester bonds on different chains with remaining parts of the network has a strengthener effect, resulting in an increase of the elongation at break εb. (E) Further bond cleavages result in the formation of soluble fragments, leading to mass loss and change of network composition. (F) Finally, the network disintegrates. Reproduced with permission.4 The copolyester based materials discussed so far are bulk degrading polymers. They initially take up a few weight percent of water and then degrade homogeneously, at least in their amorphous domains. More hydrophobic polymers containing easily hydrolysable bonds like polyanhydrides or polyorthoesters are surface eroding materials as the diffusion of water into the materials is a much slower process than the hydrolysis of the cleavable bonds. The geometry of shaped bodies strongly influences the degradation rate of such surface eroding materials. The larger the surface to volume ratio the faster is the sample degradation in terms of mass loss. The degradation behavior of a polymeric biomaterial might also be different in aqueous buffer solution, cell culture medium or in vivo. The presence of enzymes, cells/tissues, mechanical stimulation and many other factors need to be taken into consideration here. Computational simulation and Langmuir monolayer experiments for exploring degradation mechanisms are promising methods towards a knowledge-based approach for the development of degradable polymers.5 A common strategy for gaining biofunctionality is equipping polymers with bioactive molecules, e.g., antibiotics for treatment of bacterial infections or cytokines for inducing tissue regeneration. For each polymer system a suitable loading technique for incorporation of bioactive compounds needs to be explored and the maximum load capacity must be determined. A major challenge is to ensure that drug loading does not negatively affect other material properties and functions. AB-polymer networks from oligo[(ε-caprolactone)-co-glycolide]dimethacrylates and n-butyl acrylate exhibit a shape-memory capability and can be applied in self-deploying and anchoring implants. Wischke et al. explored this polymer network system as multifunctional matrix for controlled drug release (DOI:10.1002/mabi.201000089). Drug loading ratios for hydrophilic or hydrophobic drugs depended on the hydrophilicity of the polymer matrix. The kinetics of the drug release was influenced by its glycolide content, which affects the polymers' crystallinity at body temperature. Material properties determined for in vivo degradation agreed well with results from in vitro degradation studies for an unloaded AB-polymer network. A key biofunctionality of nanocarriers is their uptake into cells. A set of polymethacrylate nanoparticles were prepared by miniemulsion polymerization technique to systematically study the influence of particle hydrophobicity and softness on the cellular uptake, while the particle diameter was kept constant (Lorenz et al.; DOI:10.1002/mabi.201000099). Hydrophobicity of the nanoparticles was altered by variation of the alkyl-chain of the monomer. Poly(benzylmethacrylate) was studied as well. The nanoparticles were loaded with a fluorescent dye so that cellular uptake could be investigated quantitatively by flow cytometry. The cellular uptake of nanoparticles was favoured for more hydrophobic particles, whose Tg was lower than body temperature. A versatile polymer system to study the nucleic acid transfection capability of hyperbranched polymers with different endgroup functionalizations is presented by Germershausen et al. (DOI:10.1002/mabi.201000077). In this modular system hyperbranched poly(ethylene imine) (Pei) or polyglycerol (PG) served as the polymer scaffold. Two different endgroup modifications were performed in order to mimic the histidine binding motives of naturally occurring histones as DNA complexing proteins. Either imidazole or 3-dimethylamino propyl groups were linked to the polymer endgroups. Dye labelled oligonucleotides or DNA were tested in interaction with the pure polymers and the different end group functionalized materials. In vitro transfection experiments resulted that imidazol-modified Pei had the same transfection efficiency as pure Pei, but is less toxic. Pure PG and moderately modified PG showed only low transfection rates. This finding suggests that both complexation and buffer capacity are playing an important role to reach high transfection efficiencies. Mimicking the function to complex DNA is a nice example illustrating how a concept for equipping polymers with a specific biofunctionality can be derived by learning from nature. The ECM structure and its diverse functions are the starting point for different strategies exploring polymeric scaffolds as ECM substitutes (see Figure 1). Extracellular matrix and biomaterial-based temporary substitutes: A) Schematic drawing of the ECM (collagen fibers: purple; hydrogel forming components containing proteoglycans and glycosaminoglycans: blue; adhesion molecules: dark brown) in contact with integrin receptors (ocher) located in the bilayer cell membrane and cytoskeletal filaments (light brown), Copyright GKSS. Scanning electron microscopic picture of B) nanofibre mesh prepared by electrospinning from poly(p-dioxanone), Copyright GKSS C) porous structure prepared by CO2 foaming from poly(ε-caprolactone) from Ref. 6, D) hydrogel film prepared by crosslinking of gelatin with a diisocyanate in water in presence of a tenside from Ref. 6. Considering the ECM geometry motivated the creation of porous structures from polymers.7 Design criteria include high porosity and interconnected open pores, whose diameter should be chosen to amongst others enable attachment and migration of cells as well as ingrowth of blood vessels. Salt-leaching, freeze-drying, phase-separation processes, and foaming by use of inert gases are examples for suitable processing technologies.6 Also nonwovens have been extensively explored as ECM substitutes whereby especially nanofibre-based nonwovens and meshes prepared by electrospinning are promising.8 While the macroscopic three-dimensional structure of a scaffold should guide morphogenesis and address surgical requirements, the pores have to provide a suitable microenvironment for the cells, e.g., by fulfilling the micromechanical requirements. The interaction of cells with the ECM by focal adhesion is an example for a function, which is controlled on the molecular level. Here integrins bind to extracellular proteins via short amino acid sequences such as the RGD sequence. Hybrid systems combining synthetic macromolecules with ECM fragments have been explored to integrate ECM functions determined by the molecular structure. The incorporation of peptide motifs into synthetic hydrogels was greatly pioneered by Jindrich Kopeček,9 who used oligopeptide segments for making synthetic hydrogels enzymatically degradable9 or for directing the self-assembly of hydrogels.9 A combination of two different functionalities in a hydrogel was obtained by incorporating an integrin-binding oligopeptide and a highly metalloproteinase-sensitive amino acid sequence, which enabled fibroblasts to proteolytically invade this hydrogel.10 Biomacromolecule-based functions have also been achieved in scaffolds by modifying the interface of a synthetic polymer-based matrix. Electrospun fibers with reactive isocyanate groups could be chemically modified with peptides. By combining a collagen IV segment and a RGD-motif the number of adherent keratinocytes could be increased (Grafahrend et al.; DOI:10.1002/mabi.201000068). Layer-by-layer assembly is a versatile method to build up polyelectrolyte multilayers (PEM) with potential applicability in biomedicine.11 Liu et al. explored growth and differentiation of human mesenchymal stem cells (hMSC) on different PEM deposited on poly(L-lactide) surfaces (DOI:10.1002/mabi.201000086). The strong influence of the cell culture medium on the in vitro cell behavior became apparent in this study. Only a weak osteogenic differentiation of hMSCs was observed for one type of PEM if cells were cultivated in normal cell culture medium. However, application of an osteonic differentiation medium in combination with a specific PEM variant promoted differentiation of hMSCs towards osteoblasts. This finding was discussed by the authors as synergistic effect of the PEM and the cell culture medium. Different PEM were also investigated with regard to their ability to influence mineralization of calcium carbonate or calcium phosphate, which both have high relevance in biological systems. Junginger et al. investigated the mineralization of calcium phosphate beneath a polycationic monolayer at the air-water interface in Langmuir monolayer experiments to gain a better understanding of the underlying mechanism (DOI:10.1002/mabi.201000093). Variation of the monolayer charge density by changing the subphase's pH value influenced the architecture of the formed calcium phosphate. Biofunctional surfaces also have a high application potential in bioanalytics, e.g., in protein microarrays. In order to study the function of proteins their tertiary structure should be maintained when they are immobilized. Thus any kind of interaction leading to a denaturalization of the protein structure should be avoided. Pippig and Holländer developed hydrogel coatings, which could be covalently linked to polyethylene substrates (DOI:10.1002/mabi.201000052). First, the polyethylene surface was functionalized with an oxidative plasma treatment and subsequent coupling of a low molecular weight diamine. The amine groups on the surface were anchors for the polymer network, which was prepared from a poly(ethylene glycol)diamine and a trifunctional epoxide or trifunctional acid chloride. This method for creating a polymer network layer, which is covalently linked to the substrate, is versatile as the crosslink density as well as the kind and the density of functional groups could be varied systematically. The high level of complexity in the design of multifunctional polymers for biomedicine becomes apparent in all articles of this special issue of Macromolecular Bioscience, which emphasizes the fundamental scientific challenge in the development of next generation biomaterials. I thank all authors for their interesting and stimulating contributions to this special issue as well as Dr. Kirsten Severing from Wiley-VCH, Dr. Karolin Schmälzlin and Sabine Benner, both from GKSS Research Center, for their valuable editorial and administrative support. Andreas Lendlein is Director of the Institute of Polymer Research at GKSS Research Center in Teltow, Germany and Member of the Board of Directors of the Berlin-Brandenburg Center for Regenerative Therapies. He is Professor at University of Potsdam and Honorary Professor 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. His current research interests include (multi)functional polymer-based materials and their interaction with physiological environments.