Polymers in Biomedicine and Electronics (2010)

The versatility of polymeric materials originates from the broad variety in their chemical structure and in their hierarchical organization as well as from the possibility to realize a wide spectrum of functions. Often such functions result from a combination of a molecular architecture/morphology with a physical process and therefore require integration in a suitable system (e.g. medical device, electric circuit) or environment (e.g. physiological environment). Frequently, research in the area of functional polymers is motivated by applications. This special issue focuses on two application areas, in which polymer research as well as product development are progressing rapidly: Biomedicine and Electronics. Here (multi)functional polymers are an enabling technology and in this way create substantial and sustainable value. The significance of this topic is also 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 (BVP). Topics of the conference cover the design and the synthesis of functional polymers, physical principles underlying the function, the characterization of such functions within a system as well as product-oriented industrial research. Smart biomaterials, biocompatible coatings and their applications in controlled drug delivery systems or in regenerative therapies will be discussed in the biomedicine-oriented sessions of the conference. Photovoltaic, charge transport, light emission as well as sensors and actuators will be subjects in the area of electronics. This special issue comprises eleven papers covering different facets of current research performed in this area, which will also be presented at the above mentioned conference and thus demonstrate the vitality and the increasing interest in the field of (multi)functional polymers. Most polymeric biomaterials established in clinical application today have not been developed primarily for medical applications. Polymers synthesized in large scale production for engineering applications still form the predominant material basis of medical devices including implants and components of extracorporeal systems. To date blood bags are manufactured from polyvinylchloride containing a low molecular weight softener, hernia meshes are prepared from poly(propylene) and vascular prostheses as large diameter vessel substitutes are fabricated from expanded polytetrafluoroethylene, whereby this list just gives a few examples. The concept of degradable implants supporting wound healing leads to the targeted development of hydrolytically degradable aliphatic copolyesters, which have been successfully applied for several decades in surgical implants such as sutures, pins or clamps. Another application field for degradable polymers was developed in pharmaceutical technologies. Controlled drug release systems are implants, which reliably deliver a drug locally with a predefined kinetic ensuring therapeutically appropriate drug concentration. Copolyester-based systems can release low molecular weight drugs diffusion controlled from the bulk. Porous copolyester beads are able to delay the release of peptides entrapped in the pores by physical interactions. Hydrophobic polyanhydrides are polymers, which are eroded from the surface and can release drugs controlled by matrix degradation. They exhibit only very limited water uptake in physiological environments, but contain easily hydrolysable bonds. Hydrolytic degradability is an example of how material functions can be designed and how the availability of novel biomaterials can impact medicine. Modern therapeutic strategies require biomaterials with specific combinations of their functions and properties, which cannot be sufficiently fulfilled by the clinically established biomaterials. Examples can be found in regenerative therapies, where biomaterials are essential for inducing autoregeneration, especially in case of critical size defects.1 Biomaterials can be applied as well in combination with cells in tissue engineering and somatic cell therapy. Often the polymer shall act as a temporary substitute of the extracellular matrix enabling the ingrowth of tissue by attracting cells from surrounding tissue, providing a suitable microenvironment for the desired cells and degrading in a predetermined time period adjusted to the formation kinetics of the neotissue. Ideally, such devices should be implantable minimally-invasively, which requires a shape changing capability of the implant material, so that it can unfold or extend from a compressed temporary shape. In this way a bulky implant could be inserted in the body through a small incision.2 Properties and functions of biomaterials, especially their compatibility and biofunctionality, must fulfill regiospecific requirements. An example of this challenge are biofunctional implants supporting the endogenous regeneration of blood vessel walls. The initial direct contact with blood immediately after implantation requires hemocompatibility. The compatibility with endothelial cells or smooth muscle cells is essential for the regeneration process.3 The growing scientific interest in materials for regenerative medicine becomes apparent when paying attention to the number of chemistry related scientific publications containing the term “regenerative medicine”, which has grown substantially over the past ten years reaching values over 1 000 publications/year (see Ref. 1). Macromolecules are also intensively explored as medicinal products, in the area of polymer therapeutics.4-6 This research area has been stimulated in recent years by advances in nanotechnology and is often referred to as nanomedicine. An example is the conjugation of polymers with proteins for solubilization and stabilization of the bioactive molecule (Figure 1). As transport vehicles nanocarriers enable the crossing of barriers, e.g. cell membranes by multi-component polyplexes as non-viral vectors, or enable the targeted delivery of drugs to certain cells or tissues, e.g. inflamed tissue guided by multivalent interaction through negative charges of multiple sulfate groups on the surface of dendritic polymers.6 Polymeric micelles, to which a drug is covalently bound, dendritic polymers and nanogels form further transporter vehicles, which are sized in the nanometer scale (Figure 2). Schematic representation of polymer therapeutics taken from Ref 4: A) polymeric drug, B) polymer-protein conjugate, C) polymer-DNA complex, D) polymer-drug conjugate. Reprinted by permission from Macmillan Publishers Ltd. Different polymer architectures for polymer therapeutics taken from Ref 6: A) polymeric micelle, B) dendritic polymer-drug conjugate, C) multifunctional nanogel. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. Amphiphilic diblock copolymers forming micelles are a versatile molecular architecture to implement multifunctionality. Each block-forming polymer can contribute a function. In addition the block located in the core of the micelles can be functionalized by chemical modification. Barz et al. (DOI: 10.1002/marc.201000090) present amphiphilic poly[N-(2-hydroxypropyl)-methacrylamide]-block-poly(L-lactide) [P(HPMA)-b-P(LLA)], which were designed to combine the hydrolytic degradability of P(LLA) and the biocompatibility of P(HPMA). This novel combination of blocks was achieved by a three-step synthesis route. P(LLA) was obtained by ring-opening polymerization of L,L-dilactide and subsequently reacted with 4-cyano-4-((thiobenzoyl) sulfanyl)pentanoic acid to link a chain transfer agent to the hydroxy-endgroup of P(LLA). Chain extension with pentafluorophenol methacrylate by RAFT polymerization resulted in a second block, whose side chains were chemically modified in a polymer analogous reaction with 2-hydroxylpropylamine. This polymer modification step can also be used to covalently link chromophores for labeling, drugs or target moieties. The diblock copolymers built micellar structures with a hydrodynamic diameter of 17 nm. The materials proved to be non-toxic in vitro and a cellular uptake was observed for human cervis adenocarcinoma cells. Biopolymers are also investigated as drug carrier forming macromolecules. An example is the plasma protein human serum albumin (HSA). HSA conjugates with drugs and proteins have already entered clinical development. Eisele et al. (DOI: 10.1002/marc.201000176) address cell specific drug targeting, which is essential for many drug based therapeutic strategies, such as tumor treatment where the bioactive substance should only hit cancer cells. For this purpose multifunctional albumin-based copolymers were synthesized and characterized, which carry folic acid groups for targeting cancer cells, poly(ethylene glycol) (PEG) chains for improving water solubility and metabolic stability as well as a carboxylic acid groups to reduce non-specific cellular uptake. The folic acid receptor is up-regulated and over-expressed in a number of rapidly-growing malignant tumor cells and therefore folic acid has been identified as a potential target molecule of various cancer cells. The cellular uptake of chromophore loaded micelles was investigated with two cancer cell types (with and without folic acid receptor) to explore cell specific effects. A significantly higher uptake was determined for the cell type expressing folic acids receptors (KB cells) compared to the other cell type (A-549 cells). It has been concluded that this higher uptake of KB cells is caused by receptor mediated endocytosis. Besides the formation of nanotransporters, their degradation or drug release are also relevant factors. Liu et al., (DOI: 10.1002/marc.201000337) describe the degradation behavior of water-soluble, positively charged, amphiphilic hyper-branched poly(ethylene imine)-graft-poly(ε-caprolactone)-block-monomethoxyl poly(ethylene glycol) (hy-PEIPCL-mPEG), which was investigated under in vitro conditions with a special emphasis on elucidating the effects of polymer compositions and degradation environments on the degradation rates. The changes of micelle sizes and pH values were in good agreement with the molecular weight decays, suggesting that the degradation of water-soluble hy-PEI-PCL-mPEG can be described as the degradation of their micelles in aqueous solution. Also, these copolymers degraded within a reasonable time period that was sufficiently long to enable gene transfer. These degradation patterns suggest that hy-PEI-PCLmPEGs could be a promising candidate for in vivo gene delivery. Besides the complexation and transport of DNA, the hydrophobic nature of many modern drugs, requires new drug delivery systems for their solubilization in aqueous environments. In the paper from Kurniasih et al. (DOI: 10.1002/marc.201000112) hyperbranched polyglycerol was functionalized to design a hydrophobic core for specific polymer–drug interactions. The core was modified by different hydrophobic functional groups, like biphenyl and perfluorinated chains, and by different degrees of core functionalization to achieve a better transport ratio of drug or dye molecules. The high complex stabilities of these water soluble dendritic architectures and their suitable particle size for endocytosis (20–200 nm) make them ideal candidates for cellular uptake. Alternatively, a nanotransporter can also be a hybrid system between a metal core and a biocompatible polymeric shell. The high biocompatibility of aliphatic polyether structures, such as PEG and polyglycerol, make them also attractive for the coating of metal nanoparticle probes.6 In the paper from Kumagai et al. (DOI: 10.1002/marc.201000341) high density PEG was used to coat iron oxide-gold core-shell nanoparticles (AuION) to develop T2-weighted magnetic resonance imaging (MRI) contrast agents for cancer imaging. They have demonstrated that AuION of controlled sub-50 nm size and coated with a dense PEG brush can be used as an MRI contrast agent for a variety of tumors, including pancreatic tumors. The relatively small hydrodynamic diameter along with a high PEG density allowed the PEG-AuION to show prolonged circulation. These results imply that, with proper control of nanoparticle structural and surface properties, it is feasible to develop effective MRI contrast agents for the diagnosis of intractable tumors, such as pancreatic cancer. The tumor targeting is achieved even without attachment of cell-targeting ligands by the enhanced permeation and retention of these nanoparticle probes. In general two approaches are pursued for biomaterials (temporarily) substituting the extracellular matrix (ECM): hydrophobic materials with a relatively low water uptake and hydrophilic polymer networks forming hydrogels. The first strategy is derived from the development of surgical implants requiring a certain mechanical strength of the biomaterial. The latter is following a biomimetic approach with regard to the natural ECM. Advances in hydrogel developments are reported in this special issue for biohybrid materials from star-shaped PEG and ECM fragments (Tsurkan et al., DOI: 10.1002/marc.201000155) as well as gelatine functionalized with tyrosine derived aromatic moieties (Neffe et al., DOI: 10.1002/marc.201000274). Tailoring of implant materials to the requirements of specific applications is exemplified for the adjustment of mechanical properties (Weichelt et al., DOI: 10.1002/marc.201000317) and shape-memory properties (Wagermaier et al., DOI: 10.1002/marc.201000122). PEG-diacrylates can be crosslinked by radical polymerization induced by a photoinitiator. The resulting polymer networks are forming hydrogels when exposed to aqueous environments, which have been studied comprehensively as biomaterial. This hydrogel system was extended to biohybrid hydrogels by crosslinking peptides containing two cysteine residues with star-shaped PEG modified with acrylate groups in a Michael-type reaction. The peptide segments can be used to incorporate biofunctionality in the material by mimicking fragments of the ECM. Tsurkan et al. (DOI: 10.1002/marc.201000155) have further extended the functionality of such networks. An apopeptide was prepared containing the RGD sequence to promote cell adhesion and a MMP sensitive sequence enabling enzymatic degradation. This peptide only contained one cysteine residue so that the Michael addition reaction with the star-shaped PEG modified with acrylate groups resulted in oligomeric telechelics with four terminal amino groups. The crosslinking occurred by reacting these terminal amino groups with carboxylic groups of herapin, which was selected as crosslinking segment because of its high affinity to various signaling molecules such as the vascular endothelial growth factor (VEGF). In this way the hydrogels could be loaded with growth factors, whose controlled release over time can be used to influence cell behavior and tissue formation. A promising result was obtained in vitro when primary endothelial cells were cultivated on VEGF loaded degradable hydrogels. After one day of culture enhanced 3D cell migration was observed. This could be an early step in the formation of new blood vessels growing into the hydrogel scaffold, which is highly important for the creation of 3D tissues. Gelatin is the starting material for a physically crosslinked hydrogel system, which should allow the systematic tailoring of the hydrogel properties (Neffe et al., DOI: 10.1002/marc.201000274). This aim is challenging because of the inherent variability between different production batches of biopolymers. A side chain functionalization with tyrosine-derived moieties desaminotyrosine (DAT) and desaminotyrosyl tyrosine (DATT) should inhibit the formation of collagen-type triple helical structures by sterical hindrance. At the same time physical netpoints should be formed by π-π interactions and hydrogen bonds. Molecular models of the gelatine-based materials were developed and validated with experimental data. They formed the basis for the knowledge-based material design. A relatively small number of DAT or DATT side groups lead to a clear reduction of helicity, and a dramatic reduction of the swelling capacity was determined for the DATT functionalized gelatine. At the same time the mechanical properties of the hydrogels were influenced by the functionalization, e.g. an increase of E modulus was determined. The scope of biomedical applications for gelatine-based materials might be expanded by this knowledge-based approach. Improved mechanical strength demanded for hard tissue reconstruction was achieved by incorporating CaCO3 nanoparticles in scaffolds based on polymeric monoliths (Weichelt et al., DOI: 10.1002/marc.201000317). Porous polymeric monoliths were prepared by ring-opening metathesis polymerization from norborn-2-ene and a 7-oxanorborn-2-ene-based crosslinker using a third generation Grubbs-initiator in presence of the inorganic particles. The CaCO3 particles were surface-modified with norborn-2-enephosphonate to increase their compatibility with the matrix material. In cell culture tests the number of adipose tissue-derived stem cells increased by almost a factor of four within eight days. A detailed knowledge of structure-property/function relationships is a prerequisite for tailoring polymers to the specific application relevant requirements. In situ characterization by combining X-ray scattering with thermomechanical analysis is a versatile method to investigate dual and triple-shape effects in multiphase polymer networks (Wagermaier et al., DOI: 10.1002/marc.201000122). This integrated approach enables systematic investigation and interpretation of relevant structural features during the programming procedures and the thermally-induced recovery process. The investigated polymer network contains two different crystallizable switching segments. Poly(ε-caprolactone)-segments (PCL) connect two netpoints in the network structure, while PEG is linked to the network as a side chain with one dangling chain end. One result of the study concerns the orientation of crystallites formed under macroscopic deformation of the polymer network. A clear trend of orientation in the deformation direction was determined for the PCL crystallites, while PEG crystallites revealed only a minor preferential orientation perpendicular to the respective stretching direction. Consequently, a two-step deformation procedure is required to create a triple-shape capability for this polymer network system. Ten years ago Alan J. Heeger, Alan G. MacDiarmid and Hideki were the in for the and development of polymers. was explored as the first for example and the soluble are the studied of the polymers. 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