Penny J. Martens

In situ forming degradable networks and their application in tissue engineering and drug delivery

Multifunctional macromers based on poly(ethylene glycol) and poly(vinyl alcohol) were photopolymerized to form degradable hydrogel networks. The degradation behavior of the highly swollen gels was characterized by monitoring changes in their mass loss, degree of swelling, and compressive modulus. Experimental results show that the modulus decreases exponentially with time, while the volumetric swelling ratio increases exponentially. A degradation mechanism assuming pseudo first-order hydrolysis kinetics and accounting for the structure of the crosslinked networks successfully predicted the experimentally observed trends in these properties with degradation. Once verified, the proposed degradation mechanism was extended to correlate network degradation kinetics, and subsequent changes in network structure, with release behavior of bioactive molecules from these dynamic systems. A theoretical model utilizing a statistical approach to predict the cleavage of crosslinks within the network was used to predict the complex erosion profiles produced by these hydrogels. Finally, the application of these macromers as in situ forming hydrogel constructs for cartilage tissue engineering is demonstrated.

Conducting polymer-hydrogels for medical electrode applications

Abstract Conducting polymers hold significant promise as electrode coatings; however, they are characterized by inherently poor mechanical properties. Blending or producing layered conducting polymers with other polymer forms, such as hydrogels, has been proposed as an approach to improving these properties. There are many challenges to producing hybrid polymers incorporating conducting polymers and hydrogels, including the fabrication of structures based on two such dissimilar materials and evaluation of the properties of the resulting structures. Although both fabrication and evaluation of structure–property relationships remain challenges, materials comprised of conducting polymers and hydrogels are promising for the next generation of bioactive electrode coatings.

Conductive Hydrogels: Mechanically Robust Hybrids for Use as Biomaterials

A hybrid system for producing conducting polymers within a doping hydrogel mesh is presented. These conductive hydrogels demonstrate comparable electroactivity to conventional conducting polymers without requiring the need for mobile doping ions which are typically used in literature. These hybrids have superior mechanical stability and a modulus significantly closer to neural tissue than materials which are commonly used for medical electrodes. Additionally they are shown to support the attachment and differentiation of neural like cells, with improved interaction when compared to homogeneous hydrogels. The system provides flexibility such that biologic incorporation can be tailored for application.

Structural and functional characterisation of poly(vinyl alcohol) and heparin hydrogels

Synthetic scaffolds show great promise for use in tissue engineering due to their ability to mimic some aspects of the extracellular matrix, however, their use has been hindered by the lack of inherent recognition sites that are required for protein and cell interactions. Heparan sulfate (HS), a glycosaminoglycan polysaccharide present in the basement membrane and on the cell surface, binds growth factors and cytokines and enhances the signalling of these ligands by forming complexes with their receptors. This study focuses on the formation of photopolymerised hydrogels derived from methacrylated macromers of poly(vinyl alcohol) (PVA) and heparin, with the aim of imparting the growth factor activation property of heparin to the synthetic scaffolds. It was shown that the methacrylate group attachment on heparin did not result in the fragmentation of heparin molecules, and that the biological activity of the methacrylated heparin was preserved as determined by tests on its anticoagulation properties and ability to signal fibroblast growth factor-2 (FGF-2). The addition of heparin into the PVA hydrogels resulted in an increase in mass swelling ratio from 5.8 for pure PVA to 6.5 and 6.6 for PVA/heparin co-hydrogels of 19/1 and 17.5/2.5 (w/w) compositions, respectively. It is believed that heparin molecules can be added into a synthetic PVA scaffold without adversely affecting the structural and mechanical stability of the PVA scaffold. The tensile moduli of the co-hydrogels remained close to that of PVA hydrogels (61 kPa), even up to 2.5% heparin composition (PVA/hep 17.5/2.5). Finally, the co-hydrogels were found to retain the growth factor signalling activity of heparin at equilibrium.

Immunoisolating semi-permeable membranes for cell encapsulation: focus on hydrogels.

Cell-based medicine has recently emerged as a promising cure for patients suffering from various diseases and disorders that cannot be cured/treated using technologies currently available. Encapsulation within semi-permeable membranes offers transplanted cell protection from the surrounding host environment to achieve successful therapeutic function following in vivo implantation. Apart from the immunoisolation requirements, the encapsulating material must allow for cell survival and differentiation while maintaining its physico-mechanical properties throughout the required implantation period. Here we review the progress made in the development of cell encapsulation technologies from the mass transport side, highlighting the essential requirements of materials comprising immunoisolating membranes. The review will focus on hydrogels, the most common polymers used in cell encapsulation, and discuss the advantages of these materials and the challenges faced in the modification of their immunoisolating and permeability characteristics in order to optimize their function.

Silk fibroin/poly(vinyl alcohol) photocrosslinked hydrogels for delivery of macromolecular drugs.

Hydrogels are three-dimensional polymer networks widely used in biomedical applications as drug delivery and tissue engineered scaffolds to effectively repair or replace damaged tissue. In this paper we demonstrate a newly synthesized cytocompatible and drug releasing photo-crosslinked hydrogel based on poly(vinyl alcohol) methacrylate and silk fibroin which possesses tailorable structural and biological properties. The initial silk fibroin content was 0%, 10%, 20%, 30%, 40% and 50% with respect to the weight of poly(vinyl alcohol) methacrylate. The prepared hydrogels were characterized with respect to morphology, crystallinity, stability, swelling, mass loss and cytotoxicity. FITC-dextrans of different molecular weights were chosen as model drugs molecules for release studies from the hydrogels. The hydrogels containing different silk fibroin percentages showed differences in pore size and distribution. X-ray diffraction analysis revealed that amorphous silk fibroin in poly(vinyl alcohol) methacrylate is crystallized to β-sheet secondary structure upon gelation. The sol fraction increased with increasing fibroin concentration in the co-polymer gel (from 18% to 45%), although the hydrogel extracts were non-cytotoxic. Similarly, the addition of silk fibroin increased water uptake by the gels (from 7% to 21%). FITC-dextran release from the hydrogels was dependent on the silk fibroin content and the molecular weight of encapsulated molecules. The study outlines a newer type of photo-crosslinked interpenetrating polymer network hydrogel that possess immense potential in drug delivery applications.

Synthesis and characterization of degradable hydrogels formed from acrylate modified poly(vinyl alcohol) macromers

Poly(vinyl alcohol) was modified with pendant acrylate groups to create a multifunctional macromer that is crosslinkable via photopolymerization and degradable through hydrolytically cleavable ester groups within the crosslinks. The chemistry and functionality of the macromer, as well as the polymerization conditions, were varied to produce hydrogel networks with a wide range of physical properties and degradation behavior. The resulting networks were characterized by measuring the volumetric swelling ratio and mass loss profiles with degradation time. Experimental results show that the volumetric swelling ratio increases exponentially during degradation of these gels, and this increase can be predicted through a pseudo-first order reaction depending only on the kinetic constant for hydrolysis and the number of degradable links in the crosslinker. Coupled to the hydrolytic degradation, the network structure also influences the mass loss or erosion profile and, ultimately, the overall time for degradation.

The effect of elastin on chondrocyte adhesion and proliferation on poly (ɛ-caprolactone)/elastin composites

The aim of this study was to demonstrate the effect of elastin on chondrocyte adhesion and proliferation within the structure of poly (ɛ-caprolactone) (PCL)/elastin composites. The homogenous 3D structure composites were constructed by using high pressure CO(2) in two stages. Porous PCL structures with average pore sizes of 540 ± 21 μm and a high degree of interconnectivity were produced using gas foaming/salt leaching. The PCL scaffolds were then impregnated with elastin and cross-linked with glutaraldehyde (GA) under high pressure CO(2). The effects of elastin and cross-linker concentrations on the characteristics of composites were investigated. Increasing the elastin concentration from 25mg/ml to 100mg/ml elevated the amount of cross-linked elastin inside the macropores of PCL. Fourier transform infrared (FTIR) analysis showed that elastin was homogeneously distributed throughout the 3D structure of all composites. The weight gain of composites increased 2-fold from 15.8 ± 0.3 to 38.3 ± 0.7 (w/w) % by increasing the elastin concentration from 25mg/ml to 50mg/ml and approached a plateau above this concentration. The presence of elastin within the pores of PCL improved the water uptake properties of PCL scaffolds; the water uptake ratio of PCL was enhanced 100-fold from 0.030 ± 0.005g liquid/g polymer to 11.80 ± 0.01g liquid/g polymer, when the elastin solution concentration was 50mg/ml. These composites exhibited lower compressive modulus and energy loss compared to pure PCL scaffolds due to their higher water content and elasticity. In vitro studies show that these composites can support primary articular cartilage chondrocyte adhesion and proliferation within the 3D structures. These results demonstrate the potential of using PCL/elastin composites for cartilage repair.

Conductive hydrogels with tailored bioactivity for implantable electrode coatings.

The development of high-resolution neuroprosthetics has driven the need for better electrode materials. Approaches to achieve both electrical and mechanical improvements have included the development of hydrogel and conducting polymer composites. However, these composites have limited biological interaction, as they are often composed of synthetic polymers or non-ideal biological polymers, which lack the required elements for biorecognition. This study explores the covalent incorporation of bioactive molecules within a conducting hydrogel (CH). The CH was formed from the biosynthetic co-hydrogel poly(vinyl alcohol)-heparin and the conductive polymer (CP), poly(3,4-ethylene dioxythiophene). Adhesive biomolecules sericin and gelatin were covalently incorporated via methacrylate crosslinking within the CH. Electrical properties of the bioactive CH were assessed, and it was shown that the polar biomolecules improved charge transfer. The bioactivity of heparin within the hybrid assessed by examining stimulation of B-lymphocyte (BaF3) proliferation showed that bioactivity was retained after electropolymerization of the CP through the hydrogel. Similarly, incorporation of sericin and gelatin in the CH promoted neural cell adhesion and proliferation, with only small percentages (⩽ 2 wt.%) required to achieve optimal results. Sericin provided the best support for the outgrowth of neural processes, and 1 wt.% was sufficient to facilitate adhesion and differentiation of neurons. The drug delivery capability of CH was shown through incorporation of nerve growth factor during polymer fabrication. NGF was delivered to the target cells, resulting in outgrowth of neural processes. The CH system is a flexible technology platform, which can be tailored to covalently incorporate bioactive protein sequences and deliver mobile water-soluble drug molecules.

Combining submerged electrospray and UV photopolymerization for production of synthetic hydrogel microspheres for cell encapsulation

Microencapsulation within hydrogel microspheres holds much promise for drug and cell delivery applications. Synthetic hydrogels have many advantages over more commonly used natural materials such as alginate, however their use has been limited due to a lack of appropriate methods for manufacturing these microspheres under conditions compatible with sensitive proteins or cells. This study investigated the effect of flow rate and voltage on size and uniformity of the hydrogel microspheres produced via submerged electrospray combined with UV photopolymerization. In addition, the mechanical properties and cell survival within microspheres was studied. A poly(vinyl alcohol) (PVA) macromer solution was sprayed in sunflower oil under flow rates between 1–100 µL/min and voltages 0–10 kV. The modes of spraying observed were similar to those previously reported for electrospraying in air. Spheres produced were smaller for lower flow rates and higher voltages and mean size could be tailored from 50 to 1,500 µm. The microspheres exhibited a smooth, spherical morphology, did not aggregate and the compressive modulus of the spheres (350 kPa) was equivalent to bulk PVA (312 kPa). Finally, L929 fibroblasts were encapsulated within PVA microspheres and showed viability >90% after 24 h. This process shows great promise for the production of synthetic hydrogel microspheres, and specifically supports encapsulation of cells. Biotechnol. Bioeng. 2012; 109:1561–1570.