Jan Feijen

Phase separation processes in polymer solutions in relation to membrane formation

This review covers new experimental and theoretical physical research related to the formation of polymeric membranes by phase separation of a polymer solution, and to the morphology of these membranes. Two main phase separation processes for polymeric membrane formation are discussed: thermally induced phase separation and immersion precipitation. Special attention is paid to phase transitions like liquid-liquid demixing, crystallization, gelation, and vitrification, and their relation to membrane morphology. In addition, the mass transfer processes involved in immersion precipitation, and their influence on membrane morphology are discussed.

Stimuli-Responsive Polymersomes for Programmed Drug Delivery

In the past decade, polymersomes (also referred to as polymeric vesicles) have attracted rapidly growing interest based on their intriguing aggregation phenomena, cell and virus-mimicking dimensions and functions, as well as tremendous potential applications in medicine, pharmacy, and biotechnology. Unlike liposomes self-assembled from low molecular weight lipids, polymersomes are in general prepared from macromolecular amphiphiles of various architectures including amphiphilic diblock, triblock, graft and dendritic copolymers. Polymersomes exhibit very unique features highlighted with high stability, tunable membrane properties, versatility, and capacity of transporting hydrophilic as well as hydrophobic species such as anticancer drugs, genes, proteins, and diagnostic probes. Recently, much effort has been directed to the development of intelligent polymersomes that respond to internal or external stimuli, in particular, pH, temperature, redox potential, light, magnetic field, and ultrasound, either reversibly or nonreversibly. Stimuli-sensitive polymersomes have emerged as novel programmable delivery systems in which the release of the encapsulated contents can be readily modulated by the stimulus. The stimuli-responsive release may result in significantly enhanced therapeutic efficacy and minimized possible side effects. It is also feasible to form and disassemble polymersomes in water simply by applying an appropriate stimulus. In this article, recent advances in stimuli-sensitive polymersomes have been reviewed, and perspectives on future developments have been discussed.

Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery.

The past couple of years have witnessed a tremendous progress in the development of glutathione-responsive nano-vehicles for targeted intracellular drug and gene delivery, as driven by the facts that (i) many therapeutics (e.g. anti-cancer drugs, photosensitizers, and anti-oxidants) and biotherapeutics (e.g. peptide and protein drugs, and siRNA) exert therapeutical effects only inside cells like the cytosol and cell nucleus, and (ii) several intracellular compartments such as cytosol, mitochondria, and cell nucleus contain a high concentration of glutathione (GSH) tripeptides (about 2-10 mM), which is 100 to 1000 times higher than that in the extracellular fluids and circulation (about 2-20 μM). Glutathione has been recognized as an ideal and ubiquitous internal stimulus for rapid destabilization of nano-carriers inside cells to accomplish efficient intracellular drug release. In this paper, we will review recent results on GSH-responsive nano-vehicles in particular micelles, nanoparticles, capsules, polymersomes, nanogels, dendritic and macromolecular drug conjugates, and nano-sized nucleic acid complexes for controlled delivery of anti-cancer drugs (e.g. doxorubicin and paclitaxel), photosensitizers, anti-oxidants, peptides, protein drugs, and nucleic acids (e.g. DNA, siRNA, and antisense oligodeoxynucleotide). The unique disulfide chemistry has enabled novel and versatile designs of multifunctional delivery systems addressing both intracellular and extracellular barriers. We are convinced that GSH-responsive nano-carrier systems have enormous potential in targeted cancer therapy.

Interaction of cultured human endothelial cells with polymeric surfaces of different wettabilities

The in vitro interaction of human endothelial cells (HEC) and polymers with different wettabilities in culture medium containing serum was investigated. Optimal adhesion of HEC generally occurred onto moderately wettable polymers. Within a series of cellulose type of polymers the cell adhesion increased with increasing contact angle of the polymer surfaces. Proliferation of HEC occurred when adhesion was followed by progressive flattening of the cells. Our results suggest that moderately wettable polymers exhibit a serum and/or cellular protein adsorption pattern that is favourable for growth of HEC.

Porous polymeric structures for tissue engineering prepared by a coagulation, compression moulding and salt leaching technique.

A technique for the preparation of porous polymeric structures involving coagulation, compression moulding and particulate leaching has been developed. The technique combines the advantages of thermal processing methods and particulate leaching. A high molecular weight polymer solution in an organic solvent containing dispersed water-soluble salt particles is precipitated into an excess of non-solvent. The polymer-salt composite is then processed by thermal processing methods into devices of varying shapes and sizes, which can subsequently be extracted to give the desired porous structures. The porosities of the scaffolds could be varied between 70% and 95% by adjusting the polymer to salt ratio and the pore size could be controlled independently by varying the leachable particle size. This versatility provides for the optimisation of scaffolds used in medicine and in tissue engineering. Compared with commonly used porosifying methods such as sintering, compression moulding combined with salt leaching, and freeze-drying, this process allows excellent control over pore size and porosity and yields scaffolds with a much more homogeneous pore morphology. We have prepared porous structures from several relevant polymers in the biomedical field: poly(D,L-lactide), poly(epsilon-caprolactone) and 1000PEOT70PBT30, a segmented poly(ether ester) based on polyethylene oxide and polybutylene terephthalate.

Polymersomes for drug delivery: Design, formation and characterization

In the last past dozen years, polymersomes (Ps) have attracted tremendous attention as versatile carriers because of their colloidal stability, tunable membrane properties and ability in encapsulating or integrating a broad range of drugs and molecules. Relatively long blood circulation times of Ps can be accomplished when block copolymers with a poly(ethylene glycol) (PEG) are used for the formation of Ps. A number of Ps has been developed for new possibilities and applications in drug delivery, medical imaging, electronics and nanoreactors. In particular, Ps prepared by using biodegradable and/or stimuli-sensitive block copolymers that are responsive to various internal or external stimuli are of great interest for such applications. In this review, recent advances of Ps as drug delivery systems are discussed. Critical factors that influence the formation of Ps are also addressed. The review describes preparative methods and characterization techniques for Ps. Moreover, protein and cell interactions with Ps, in vivo circulation kinetics and biodistribution of Ps are addressed.

Adhesion of cultured human endothelial cells onto methacrylate polymers with varying surface wettability and charge

The adhesion of human endothelial cells (HEC) onto a series of well-characterized methacrylate polymer surfaces with varying wettabilities and surface charges was studied either in serum-containing (CMS) or in serum-free (CM) culture medium. HEC adhesion in CMS onto (co)polymers of hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) was found to be optimal on the moderately wettable copolymer (mol ratio 25 HEMA/75 MMA). Positively-charged copolymers of HEMA or MMA with trimethylaminoethyl methacrylate-HCl salt (TMAEMA-Cl), both with mol ratios of 85/15 and a negatively-charged copolymer of MMA with methacrylic acid (MAA), mol ratio 85/15, showed high numbers of adhering HEC. In CM, HEC adhered onto the three charged copolymers mentioned above, but neither onto the copolymer of HEMA and MAA (mol ratio 85/15) nor onto the HEMA/MMA co- and homopolymers. Complete cell spreading in CM was only observed on the positively-charged copolymers.

Glutaraldehyde as a crosslinking agent for collagen-based biomaterials

The formation of Schiff bases during crosslinking of dermal sheep collagen (DSC) with glutaraldehyde (GA), their stability and their reactivity towards GA was studied. All available free amine groups had reacted with GA to form a Schiff base within 5 min after the start of the reaction under the conditions studied (0.5% (w/w) GA). Before crosslinks are formed the hydrolysable Schiff bases initially present were stabilized by further reaction with GA molecules. An increase in shrinkage temperature (Ts) from 56°C for non-crosslinked DSC (N-DSC) to 78°C for GA crosslinked DSC (G-DSC) was achieved after crosslinking for 1 h. From the relationship between the free amine group content and the Ts during crosslinking it was concluded that higher GA concentrations and longer reaction times will result in the introduction of pendant-GA-related molecules rather than crosslinks. After 24 h crosslinking an average uptake of 3 GA molecules per reacted amine group was found. No increase in the tensile strength of the materials was observed after crosslinking, which may be a result of formation of crosslinks within the fibres rather than in between fibres. Aligning of the fibres by applying a pre-strain to the samples and subsequent crosslinking yielded materials with an increased tensile strength.

[(salen)Al]‐Mediated, Controlled and Stereoselective Ring‐Opening Polymerization of Lactide in Solution and without Solvent: Synthesis of Highly Isotactic Polylactide Stereocopolymers from Racemic d,l‐Lactide

Easily accessible [(salen)(iPrO)Al] exerts excellent molecular-weight and stereochemical control in lactide polymerization either in solution or in the absence of solvent. The R,R initiator shows a marked preference for L-lactide over D-lactide. Stereoblock copolylactides with high melting points can be prepared directly from d,l-lactides by using a racemic initiator.

Injectable chitosan-based hydrogels for cartilage tissue engineering

Water-soluble chitosan derivatives, chitosan-graft-glycolic acid (GA) and phloretic acid (PA) (CH-GA/PA), were designed to obtain biodegradable injectable chitosan hydrogels through enzymatic crosslinking with horseradish peroxidase (HRP) and H2O2. CH-GA/PA polymers were synthesized by first conjugating glycolic acid (GA) to native chitosan to render the polymer soluble at pH 7.4, and subsequent modification with phloretic acid (PA). The CH-GA43/PA10 with a degree of substitution (DS, defined as the number of substituted NH2 groups per 100 glucopyranose rings of chitosan) of GA of 43 and DS of PA of 10 showed a good solubility at pH values up to 10. Short gelation times (e.g. 10 s at a polymer concentration of 3 wt%), as recorded by the vial tilting method, were observed for the CH-GA43/PA10 hydrogels using HRP and H2O2. It was shown that these hydrogels can be readily degraded by lysozyme. In vitro culturing of chondrocytes in CH-GA43/PA10 hydrogels revealed that after 2 weeks the cells were viable and retained their round shape. These features indicate that CH-GA/PA hydrogels are promising as an artificial extracellular matrix for cartilage tissue engineering.