At the recent International Symposium on Biopolymers, ISBP, in Stuttgart, scientists discussed the use of biobased plastics for applications in the field of medical technology. The majority of strategies presented at the symposium will only be ready for market in a few years’ time. However, they give an idea as to why bioplastics are likely to be applied to a greater extent in the field of medical technology.
Biodegradability is an expressly sought-after property in some medical technology applications. Biobased plastics that can be biologically degraded are already available; one such example is polylactide. However, Zhihua Gan from the Chinese Academy of Sciences in Beijing explained that bioplastics are not always as bioreactive as medical technology requires.
Gan and his team of researchers are working on drug delivery systems, tiny particles that transport drugs to their targeted destination in the human body and release them according to a predetermined kinetics. In order to be able to do this reliably, the transporter molecules need to be functionalised, which means that they need to have a three-dimensional structure that activates their biodegradability, target finding and migration into the cells. Functionalisation in biological systems requires amino (NH2) and carboxy (COOH) groups above all.
By combining hydrophobic polymers such as polylactide with water-soluble functionalised polymer fragments, Gan and his team were able to produce amphiphile co-polymers that develop micelles with tumour-specific surface structures. Since the co-polymer forms cysteine bridges in some regions, the micelles are also very sensitive to pH changes. At neutral pH, the micelles maintain their shape, but in acid environments they disintegrate. Therefore, the micelles are in principle suitable for transporting drugs through the blood and attaching to and migrating into tumours and tumour cells. Since the pH inside tumours is lower than that of blood, the micelles dissolve and release the drugs. Gan highlighted that the specific modification of polymers and the composition of functionalised co-polymers are the basis for applying biobased polymers in the field of medical technology.
Keiji Numata from the Department of Biomedical Engineering at Tufts University in Medford, USA, is also investigating bioactive transport systems with a particular focus on the use of spider silk as basic polymer.
Numata and his team use recombination methods to produce modified spider silk proteins in order to produce functionalised vehicles. To functionalise the vehicles, the researchers combine spider silk proteins with proteins that destabilise the membranes (so-called membrane destabilising peptides), or with RGD peptides that mediate cell adhesion. The scientists are particularly interested in peptide constructs which are used to transport DNA into cells. Specific viruses are normally used for such transfections, but Numata believes that silk protein-based vectors have greater advantages in terms of safety and biodegradability.
The researchers attach a polylysine peptide to one side of the silk protein and a functional peptide or a pharmaceutically active compound to the polylysine. Another function can be integrated at the other end of the carrier protein. With regard to the vectors used, the scientists attach peptides to facilitate the attachment of the vector to the target cells and the incorporation of nanoparticles. The multi-peptides are then used to produce nanoparticles that can take up plasmid DNA. Experiments have shown that the particles protect the integrated DNA molecules. Enzymes such as DNases are unable to degrade the vector DNA. Once a silk protein particle has reached the interior of the cell, enzymes destroy the particle structure and the content is released into the cell. The researchers assume that the release kinetics can be determined from the secondary structure of the silk protein. In other experiments, the researchers were able to show that, when equipped with specific functional groups, the particles could be guided into tumour cells.
Ekaterina Shishatskaya from the Institute of Biophysics at the Russian Academy of Sciences is investigating whether polyhydroxyalkanoates (PHAs) are suitable for application in medical technology. Shishatskaya uses polyhydroxybutyrate (PHB) and a co-polymer consisting of PHB and polyhydroxyvalerate (PHV) as PHA. The polymers were produced in the laboratory using the bacterium Wautersia (Ralstonia) eutropha. The biobased plastic is called Bioplastotan. Subsequent investigations focused on analysing the biocompatibility of Bioplastotan.
Shishatskaya investigated potential interactions between the polymer and biological systems using cell cultures and vertebrate animals. Short- and long-term studies were carried out over periods of seven days to six months involving mice, rats, rabbits and dogs to find out whether PHA led to adverse reactions in the animals. Suture threads made of PHA were used in the short- and long-term animal studies. Additional rapid tests involved the injection of polymer extracts into the animals. The cytotoxicity of the materials was also tested by cultivating cells on PHV/PHV foils.
The rapid tests showed that PHB/PHV did not cause any undesired reactions in the animals. The animals displayed no sensitive reaction to the substances nor did they develop allergies or other incompatibilities or sustain any tissue damage. The experiments involving wound suture threads showed that PHB/PHV did not compromise the animals' health. Shishatskaya therefore concluded that PHB and PHB/PHV are biocompatible and suitable for biomedical applications.
PHA might potentially be used for medical applications in the form of nanoparticles that transport and specifically release pharmaceutical agents. Xiaoyun Lu from the Xi‘an Jiaotong University in Xi‘an, China, presented such a system. She found that the system was able to block phosphoinositide-3 kinases (PI3K), at least in vitro. PI3K are enzymes that affect the differentiation of cells, cell division and cell migration. Intensive research focuses on PI3K inhibitors. However, many candidates that passed the test in preliminary in vitro tests, were shown to have no effect whatsoever in vivo. The reason for this was either that the substance's solubility or stability was too low, or that the inhibitors were removed from the blood too quickly. These problems can be solved by packaging the active compounds into particles and releasing them in a controlled way at their final destination in the body.
Xiaoyun Lu’s experiments have shown that PI3K inhibitors have a greater effect on cancer cells when applied by way of PHA nanoparticles. For drug developers, PHA nanoparticles are very promising systems which can be used to transport and release tumour-inhibiting drugs in the body. Researchers assume that nanoparticles are particularly suitable for drugs with hydrophobic domains.
The ISBP lectures showed that medical technology stands to benefit from the properties of biobased plastics. With their “biodegradable”, “functionalisable” and “biocompatible” features, biopolymers open up a plethora of applications in the field of medical technology. The event was held with the contextual and thematic support of BIOPRO Baden-Württemberg GmbH.