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An intelligent system for the storage and controlled release of pharmaceutical substances

It is no longer a pipe dream – a sophisticated reservoir that sits under the skin and dispenses precise quantities of drugs locally and at a particular point in time now exists. What's more, it is also biocompatible. A junior research group from the University of Freiburg’s BrainLinks-BrainTools excellence cluster led by Dr. Maria Asplund and her doctoral student Christian Böhler from the Department of Microsystems Engineering (IMTEK) has developed a small storage system made of organic-inorganic hybrid material that can be implanted and used for the controlled release of pharmaceutical substances. The system was developed in cooperation with a team led by Prof. Dr. Margit Zacharias at the IMTEK's Laboratory of Nanotechnology. The researchers hope that the system will be suitable for curbing the inflammatory reactions commonly associated with the implantation of electrodes for controlling prostheses. The system also has the potential to be used in numerous applications for tumour treatment.

Doctoral student Christian Böhler hopes that the newly developed miniature pharmacy will help control inflammatory reactions associated with implanted electrodes. © private

A brain-machine interface can be used in many ways, for example helping paralysed patients to control a wheelchair, computer or prosthesis. Arm or leg prostheses are connected directly to existing nerves by way of implantable electrodes, a process that often leads to inflammatory reactions because the body identifies the electrodes and prostheses as foreign. As the inflammation progresses, the signal measured at the electrode gets worse and may be lost completely. If an anti-inflammatory drug could be released at the delicate interface, the system could be kept stable and frequent surgical interventions would therefore no longer be required. Christian Böhler, a doctoral student in a junior research group from the University of Freiburg’s BrainLinks-BrainTools excellence cluster and the Department of Microsystems Engineering (IMTEK), came up with the idea of integrating a drug storage system into a multifunctional electrode.

20 times thinner than a strand of hair

Existing drug storage systems are less compact and cannot simultaneously and effectively control and store pharmaceutical substances. Many drug storage systems have drawbacks such as size, risk of infection or lack of controllability. The innovative storage system developed by the team from the University of Freiburg is a promising approach for overcoming the drawbacks of an implantable drug delivery system. The ingenious thing about the new system is that it is separated into two units, one for storage and one for controlled release of molecules. The biocompatible construct is made from hybrid materials and conducting polymers and, with its compact and minimalist architecture, enables simultaneous storage of molecules with different charges. The miniature pharmacy consists of a storage layer made from organic-inorganic hybrid material, a mixture of polyethylene glycol (PEG) and zinc oxide, in which drugs can be stored. Above this is a release layer made from PEDOT, a conducting polymer that coats the hybrid material with a thin film and changes its pore size when the voltage changes. The system is like a net with holes that release the substance when electrical signals cause the holes to open. It is a layered system that is no more than five micrometres thick, a fraction of the diameter of a human hair. “We wanted to make the system as small and compact as possible, since we work with electrodes that will be implanted,” says Böhler, explaining why size is an issue.

Glossary

  • Being lytic is the feature of a bacteriophage leading to the destruction (lysis) of the host cell upon infection.
  • Nanotechnology is the research and developement of technology on the atomic level with dimensions under 100 nm. Nanotechnology aims at creating and using structures, apparatuses and systems, which have new properties and performance because of their marginal dimensions.
  • A cell culture is a pool of uniform cells which were isolated from multicellular organisms and are cultivated on an artificial nutrition medium (in vitro) for experimental research.
  • The toxicity is the poisonousness of a substance.
  • Brain-machine interface is a new method in brain surgery, which can potentially help severely paralysed people control the movement of prostheses. Signals are recorded on the brain surface and transferred to a computer where mathematical calculations use the measured brain activity to help interpret the patient’s intention to move. Then the computer activates a prosthesis or robotic arm.
  • Plasticity is the attribute of organisms to change their characteristic values under the influence of environmental factors. Therefore, neuroplasticity is the characteristic of neurons to change their response behaviour dependent from their activity. In most cases, the strength of the synaptic transmission is influenced (synaptic plasticity). The neuroplasticity or synaptic plasticity, respectively, is considered to be the basic mechanism in learning processes and in the formation of memories.
  • Polyehylene (abbrevation: PE) is the polymer of ethylene. It belongs to the thermoplastic synthetics.
  • Pegylation is a chemical modification of a substance by which a Polyethylenglycol (PEG) chain is added in order to change its attributes like its solubility in water.
  • Fluorescence is the spontanous emission of light in a certain wavelength after excitation of a molecule with light of another wavelength.
  • Biocompatibility means in a literal translation: consistent with the living. It describes the two-way combatibility between a technical and biological system. Materials are biocompatible, when they don't have any negative influence on the organisms in their environment. Biocompatibility is also a measure for the biodegradability of substances in the sewage.
  • Ethylene is a gaseous plant hormone. It is important for germination and senescence processes in plants such as ripeness of fruits, development of flowers, abscission of leaves in autumn and necrosis of plant parts. Ethylene is used in greenhouses to aerate fruits resulting in increasing maturation.
  • Bioactive compounds are substances in food that show health promoting biological activity in the human body but do not provide any nutrients or energy.

Using atomic layer deposition for producing the hybrid material

The individual layers of the drug reservoir can be discerned under a scanning electron microcope: the outer release/control layer (blue, PEDOT), below it, the storage layer consisting of hybridised PEG/ZnO (green), and all this is placed on a porous silicon (porous si) carrier layer. © Christian Böhler www.Nature.com CC licence

The process for producing the hybrid layer is called atomic layer deposition, and has long been used for coating materials. This technique uses diethylzinc and deionised water vapour gases, which are applied alternately to the liquid PEG surface at high temperatures in a vacuum chamber. The gases penetrate into the molecular structure of the material and solidify the plastic layer from the inside as PEG reacts with zinc oxide, resulting in an organic-inorganic compound. The desired bioactive substances (e.g. drugs) are already incorporated into PEG. As they are dispersed in the solidifying layer, any number of substances and different charged and uncharged molecules can be stored in the same matrix. This process is repeated 150 times in order to ensure complete conversion of the synthetic material from a liquid into a solid state. This produces an inorganic matrix that surrounds the organic polymer like a cage. Böhler says it is unlikely to cause irritations because non-toxic materials are used. “PEG and zinc oxide are two biocompatible substances that are already used in medical drug preparations and industry. They can be implanted into the body without causing any adverse reactions,” he says.

Modulation of porosity

Neuroblastoma cells that grow in the PEDOT surface take up the model substance fluorescein and start to illuminate under UV light. © Christian Böhler, IMTEK, University of Freiburg

The hybrid storage layer is coated with a conducting PEDOT polymer film in order to enable controlled release of the drugs. This release/control layer is used for precision delivery of a desired compound into the body. In addition to passive diffusion, the permeability of the layer can be actively modulated by applying electric charge. PEDOT consists of a positively charged matrix to which negative ions are attached. The matrix expands or contracts depending on the charge applied. When a positive charge is applied, the pores become smaller and retain the molecules. When a negative charge is applied, the pores enlarge and the molecules can pass through. The researchers used fluorescein, a compound that is widely used as a fluorescent tracer in proof-of-concept experiments, to find out whether the multilayered system exhibits ideal properties for dispensing precise doses of molecules. They demonstrated that the molecules can be electrostatically funneled through the membrane or retained. Since fluorescein is similar in size and charge to anti-inflammatory drugs, the compound is an excellent model substance for this purpose. In a direct contact test in neuroblastoma cell cultures, the researchers have shown that the PEDOT surface is suitable as culture substrate. The cells were viable, spread across the entire pore surface and formed networks. “We were able to prove that the cells took up fluorescein because they started to illuminate when exposed to UV light,” says Böhler.

Anti-inflammatory agents, tumour therapy and lab-on-a-chip applications

Böhler and the team led by Asplund have already received a great deal of feedback on their miniature pharmacy. The next step will be to work with clinical partners to test the clinical application of the system. For example, to use the storage device in cancer therapy for releasing drugs directly onto a tumour from a reservoir under the skin at a particular point over a particular period of time. The technology would also be useful for so-called lab-on-a-chip methods which combine analysis and exchange of analytes in a very small space. “An analyte, blood and urine for example, will flow past chambers from which stored test molecules can be released in a controlled manner, and then produce signals,” says Böhler. However, his favourite application is clearly brain-machine-interfaces. Böhler would like to develop an electrode that connects nerves and prosthesis and can be kept stable for as long as possible, thus preventing inflammatory reactions.

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