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This paper describes the synthesis and characterization of new bivalent folate-targeted PEGylated doxorubicin (FA2-dPEG-DOX2) made by modular chemo-enzymatic processes using Candida antarctica lipase B (CALB) as a biocatalyst. Unique features are the use of monodisperse PEG (dPEG) and the synthesis of thiol-functionalized folic acid yielding exclusive γ-conjugation of folic acid (FA) to dPEG. The polymer-based drug conjugate is built up by a series of transesterification and Michael addition reactions all catalyzed be CALB. In comparison with other methods in the literature, the modular approach with enzyme catalysis leads to selectivity, full conversion and high yield, and no transition metal catalyst residues. The intermediate product with four acrylate groups is an excellent platform for Michael-addition-type reactions for a wide variety of biologically active molecules. The chemical structures were confirmed by nuclear magnetic resonance spectroscopy (NMR). Flow cytometry analysis showed that, at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 were taken up by 99.9% of triple-negative breast cancer cells in 2 h. Fluorescence was detected for 5 days after injecting compound IV into mice. Preliminary results showed that intra-tumoral injection seemed to delay tumor growth more than intravenous delivery.

Hernia is a defect of the abdominal wall. Treatment is principally surgical mesh implantation. Non‐degradable surgical meshes produce numerous complications and side‐effects such as inflammatory response, mesh migration and chronic pain. In contrast, the biodegradable, poly (vinyl alcohol) (PVA) based polymers have excellent chemical, mechanical and biological properties and after their degradation no chronic pain can be expected. The toxicology of PVA solution and fibers was investigated with Human dermal fibroblast‐ Adult cell line. Implantation tests were observed on long‐term contact (rat) and large animal (swine) models. To measure the adhesion formation, Diamond and Vandendael score were used. Macroscopical and histological responses were graded from the samples. In vitro examination showed that PVA solution and fibers are biocompatible for the cells. According to the implantation tests, all samples were integrated into the surrounding tissue, and there was no foreign body reaction. The average number of adhesions was found on the non‐absorbable suture line. The biocompatibility of the PVA nanofiber mesh was demonstrated. It has a non‐adhesive, non‐toxic and good quality structure which has the potential to be an alternative solution for the part of the hernia mesh.

The effect of reaction conditions on the structure of poly(3,6-dioxa-1,8-octanedithiol) (polyDODT) made by Reversible Radical Recombination Polymerization (R3P) using triethylamine (TEA), H₂O₂ and air was investigated. 800 MHz (1 and 2D) NMR was used to investigate the polymer structures. Sensitivity analysis provided direct evidence for high purity cyclic polyDODT up to M_n ∼ 100 000 g mol⁻¹. Comparative analysis by High Resolution Multidetector Size Exclusion Chromatography (SEC) using integrated data showed that the cycles had lower viscosity and were more compact (both for R_g and R_h) than linear samples of similar molecular weight. However, differential data revealed unusual behavior. While lower molecular weight cyclic polymers eluted later and had lower intrinsic viscosity than their linear counterparts at the same molecular weight, at higher molecular weights the polymers showed strange behavior: both the diffusion coefficient measured by Quasielastic Light Scattering (QELS) and Mark–Houwink–Sakurada plots of intrinsic viscosity for linear and cyclic polyDODT were found to converge. R3P, an aqueous based “green” method is capable of producing polymers at the 10–100 g scale in the lab, which will allow more detailed studies of this new class of biodegradable elastomers so further experimentation can be performed to elucidate the reasons for the unusual findings.

This paper focuses on preliminary in vitro and in vivo testing of new bivalent folate-targeted PEGylated doxorubicin (DOX) made by modular chemo-enzymatic processes (FA2-dPEG-DOX2). A unique feature is the use of monodisperse PEG (dPEG). The modular approach with enzyme catalysis ensures exclusive γ-conjugation of folic acid, full conversion and selectivity, and no metal catalyst residues. Flow cytometry analysis showed that at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 would be taken up by 99.9% of triple-negative breast cancer cells in 2 h. Intratumoral injection to mice seemed to delay tumor growth more than intravenous delivery. The mouse health status, food, water consumption, and behavior remained unchanged during the observation.

This paper presents the results of the first part of testing a novel electrospun fiber mat based on a unique macromolecule: polyisobutylene (PIB). A PIB-based compound containing zinc oxide (ZnO) was electrospun into self-supporting mats of 203.75 and 295.5 g/m2 that were investigated using a variety of techniques. The results show that the hydrophobic mats are not cytotoxic, resist fibroblast cell adhesion and biofilm formation and are comfortable and easy to breathe through for use as a mask. The mats show great promise for personal protective equipment and other applications.

This paper investigates liquid chromatography at critical condition (LCCC) for polymer analysis. Based on controversial claims on the separation of cyclic polymers from linear analogues in the literature, the efficiency of LCCC for separation and purity analysis is questioned. Polyisobutylene (PIB) and poly(3,6-dioxa-1,8-octanedithiols) (polyDODT) were used for the study. The structure of low molecular weight cyclic and linear polyDODT was demonstrated by MALDI-ToF. NMR did not show the presence of thiol end groups in higher molecular weight PIB-disulfide and polyDODT samples, so they were considered cyclic polymers. When a low molecular weight polyDODT oligomer with only traces of cycles, as demonstrated by MALDI-ToF, was mixed with an M_n = 27 K g/mol cyclic sample, LCCC did not detect the presence of linear oligomers at 6 wt%. Based on the data presented here, it can be concluded that the LCCC method is not capable of measuring

This chapter of the book dedicated to Professor Kennedy’s 90th birthday discusses medical applications of polyisobutylene (PIB)-containing materials. The PIB-components are made by living carbocationic polymerizations. The first living system yielding high molecular weight PIB with narrow polydispersity led to the thermoplastic elastomer (TPE) polymeric coating of the Taxus drug eluting coronary stent. The chapter will discuss subsequent generations of PIB-based TPEs: block copolymers with arborescent PIB cores with polystyrene (or derivatives) hard blocks, and triblocks and multiblocks with PIB-soft segments and polyalloocimene hard segments. Biodegradable PIB-disulfides are also discussed, made by living Radical Redox Recombination Polymerization (R3P) of PIB-dithiols. These and other reactive PIBs made by enzyme-catalyzed polymer functionalization will also be discussed. The modular surface functionalization technology yielding “smart” stimuli-responsive surfaces has high potential for future medical applications. Finally, PIB-based polyurethanes will be discussed.

This study investigated cell viability in the presence of allylamine-modified and plasma-treated electrospun polysuccinimide fiber mats (PSI-AAmp). Low pressure non-equilibrium plasma was used for crosslinking the PSI-AAm. Comparison of FTIR and XPS analyses demonstrated that crosslinking occurred on the surface of the samples. Cell viability was investigated using the MG-63 osteosarcoma cell line and WST-1 viability reagent. Since PSI hydrolyzes to poly(aspartic acid) (PASP), PASP was used in addition to the regular controls (cells only). Phase contrast showed normal morphology in all cases at 24 h, however, in the presence of PSI-AAmp at 72 h, some rounded, dead cells could also be seen, and proliferation was inhibited. Since proliferation in the presence of PASP alone was not inhibited, the cause of inhibition was not the final product of the hydrolysis. Further investigations will be carried out to pinpoint the cause.

Abdominal hernia is a purely surgical disorder where due to a defect in the abdominal wall, tissues or organs can extrude out of the abdominal cavity. The only conclusive treatment is surgical making a mesh implantation indispensable. Tissue engineering is now a promising method for creating scaffolds that provide an adequate support for tissue ingrowth. Our purpose was to develop a non-adhesive hernia mesh, which could be used in the repair of abdominal wall hernias but concurrently a scaffold for abdominal tissue regeneration. Poly(vinyl alcohol) bulk hydrogels are promising materials in wound dressing hence, interest in electrospun poly(vinyl alcohol) meshes has emerged in the past few years for different biomedical applications. In the present paper, preparation of electrospun poly(vinyl alcohol) fiber membranes and their in vitro and in vivo behaviors were followed to study the adhesion, biocompatibility, and biodegradability of the meshes. Our results showed that the surface of PVA meshes does not favor cell adhesion in vitro. During the animal experiments, PVA meshes demonstrated good integration into the surrounding tissue with minimal inflammatory reaction and minimal adhesions to intra abdominal structures.

In tissue engineering a permeable 3D fibrous macrostructure with high surface area is desired for cell attachment and growth. In this paper novel experimental technique is reported to prepare 2D and 3D fibrous scaffolds by reactive electrospinning as a potential matrix for cell culturing. The sub-micrometer sized fibrous scaffolds were synthesized from chemically cross-linked poly(succinimide) molecules (anhydrous form of poly(aspartic acid)). Magnetically active particles of what the size distribution was determined by small- and wide angle X-ray scattering were incorporated into the fibers. The morphology of loaded and unloaded fibers was studied by light- and atomic force microscopy. It was found that coupling elastic and magnetic properties within the 3D flexible scaffold enables continuous non-contact mode of mechanical agitation by external magnetic field. These unique properties can be exploited in cell culturing or in magnetic hyperthermia in solid-like matrix.

Electrospinning is a widely investigated and used technique for creating nano and microfibres which has a wide range of medical and pharmaceutical applications. For cell culturing and tissue engineering, it is a greatly investigated method because it resembles the extracellular matrix. Changing the electrospinning parameters we affect the properties of these systems to fine-tune it for our needs. To create a high porosity fibrous mesh for culturing different cells in a suitable three-dimensional way, we need to step forward from conventional electrospinning. In this paper, we are presenting a strategy involving the addition of inorganic salts to electrospinning solution to reproducibly synthesize nano and microfibrous fluffy 3D structures from polysuccinimide (a biocompatible and biodegradable polymer). Effect of different concentrations of LiCl, MgCl2 and CaCl2 on fibre properties are presented. Results show that the 3D structured fibrous meshes were produced in the presence of LiCl, MgCl2 or CaCl2 in a narrow concentration range. To understand the effect of salt on the resulting meshes characterization of the ion-ion and ion-solvent interactions were carried out using vibration spectroscopy and density functional theory calculation.

This paper focuses on reviewing recent developments in folate-targeted cancer diagnostic agents. First clinical trials involving Small Molecule Diagnostic Conjugates (SMDCs) are discussed, followed by Polymer-based Folate-targeted Diagnostic Conjugates (PDCs). Specifically, the advantages of multivalent targeting are discussed. Finally, recent results of a new chemo-enzymatic approach for the synthesis of bivalent folate targeted, PEGylated PDCs is discussed. Unique feature is the use of monodisperse PEG (dPEG). This modular approach with enzyme catalysis ensures exclusive γ-conjugation of folic acid, full conversion and selectivity, and no metal catalyst residues.

Electrospinning is a versatile method for the preparation of polymer fiber networks. From the medical application point of view, the stability of the fibrous structure in water is crucial. The aim of this research was to explore the possibility to induce crosslinking by treatment with non-equilibrium low pressure plasma to give structural stability to fibrous meshes. Low pressure plasma treatment was studied to induce crosslinking in allylamine-modified polysuccinimide nanofibers. Polysuccinimide was first modified with allylamine (PSI-AA) to attach the reactive allyl groups to the polymer chain. Allylamine-modification degrees varied between 10 and 100%. Then PSI-AA meshes were created by electrospinning followed by low pressure plasma treatment to allow the allylamine groups to establish crosslinks in the meshes. The crosslinked structure was confirmed by immersing both the plasma-treated, and untreated PSI-AA meshes in dimethyl sulfoxide, which is a good solvent of the non-crosslinked PSI-AA. Plasma-treated meshes kept their integrity, while the untreated samples dissolved almost immediately, which proved the formation of crosslinks due to plasma treatment. Structural changes in the meshes were studied with infrared spectroscopy (IR). X-ray photoelectron spectroscopy (XPS) investigates the structural changes on the surface of the samples and proved the presence of crosslinks. PSI-AA meshes were then hydrolyzed into poly(aspartic acid) (PASP) meshes and with the right choice of synthesis parameters (allylamine grafting degree, plasma treatment duration and power) PASP hydrogel meshes retained their fibrous structure, which was observed in SEM images of PSI-AA meshes.

Electrospinning is a well-known technique for the preparation of scaffolds for biomedical applications. In this work, a continuous electrospinning method for gel fiber preparation is presented without a spinning window. As proof of concept, the preparation of poly(aspartic acid)-based hydrogel fibers and their properties are described by using poly(succinimide) as shell polymer and 2,2,4(2,4,4)-trimethyl-1,6-hexanediamine as cross-linker in the core of the nozzle. Cross-linking takes place as the two solutions get in contact at the tip of the nozzle. The impact of solution concentrations and feeding rates on fiber morphology, proof of the presence of cross-links as well as pH sensitivity after the transformation of the poly(succinimide)-based material to poly(aspartic acid) is presented.

Biocompatible synthetic polymer gel scaffolds for tissue engineering and regenerative medicine were prepared by reactive electrospinning. Protein-like nano- and microfibres from chemically crosslinked polysuccinimide were obtained. Fibrous poly(aspartic acid) gels with size similar to that of extracellular matrix were obtained by hydrolysis of the polysuccinimide gel fibres. The effects of process parameters on fibre morphology (diameter, swelling degree) and chemical structure were investigated. Sub-micrometre-sized biocompatible fibrous scaffolds from a poly(amino acid) is a novel approach with great promise in several biomedical applications due to the tailor-made synthetic nature, extreme purity and possibility of production on a large scale. © 2014 Society of Chemical Industry

Kinetics of hydrolysis induced swelling as well as pure swelling of a novel class of pH responsive biocompatible polymer gels was studied. Poly(aspartic acid) gels were prepared by hydrolysis of chemically cross-linked poly(succinimide) networks. The volume change of spherical gels of different size, measured at constant pH, proceeds in three distinct processes: solvent exchange, hydrolysis and swelling. It turned out that pure swelling as well as the swelling coupled with hydrolysis can be described by the Tanaka-Fillmore-Peters-Candau theory. The relaxation times as well as the cooperative diffusion coefficient of the network chains were determined. It was found that the initial condition of the swelling makes its influence felt neither on the relaxation time, nor on the cooperative diffusion coefficient.