ACROBAT - Adsorbent carbons for the removal of biologically active toxins

ACROBAT – 286366 is funded under the EU FP7 Marie-Curie IAPP framework. It is a four year research project lead by Dr Susan Sandeman at the University of Brighton. The consortium consists of industrial and academic partners from the UK, Germany and Ukraine.

The University of Brighton, as co-ordinators of the project, are working jointly with a consortium of partners with complementary expertise including the UK-based company MAST Carbon International, University College London and Cardiff University, R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology in the Ukraine and German companies Albutec GmbH, Polymetrics GmbH. It also draws on the experience of Eastern European project partner IEPOR in the clinical development of synthetic activated carbons for extracorporeal use.

Project aims

ACROBAT is a €1.5m research project which is aiming to manufacture an adsorbent carbon based cartridge within a perfusion system for the removal of strongly, protein bound and macromolecular toxins and inflammatory molecules including hepatic and uremic toxins, exotoxin, endotoxin and cytokines.

Whilst the superior adsorptive capacity of activated carbons has been recognised for many years their use has been predominantly limited to the treatment of poisoning in the West. However, activated carbons with advanced properties and potential have been developed over recent years which could be used for an expanded range of biomedical applications. These carbons offer a cheap and broad spectrum adsorptive approach to biological toxin removal, addressing a range of current health care challenges in the treatment of life threatening infection, renal failure, liver failure and in organ transplant optimisation. The project will seek to optimise the adsorptive potential of activated carbon technology, incorporating bioligand binding strategies for targeted toxin removal.

The project will develop highly porous bead and monolith adsorbent systems for augmented removal of protein bound and high molecular weight toxins through technology transfer between the partners. These systems will be tested and an adsorbent cartridge will be designed to sit in-line with and augment current haemodialysis, comparing bead and monolith systems. A second adaptation of the sorbent system will be considered in parallel with the haemoperfusion device to improve the viability of donor organs for transplant. A third adaptation of the sorbent system will consider novel toxin neutralising antibody synthesis and bioligand binding strategies in the development of a bioselective sorbent haemoperfusion cartridge for targeted, systemic biotoxin removal.

Project findings and impact

Within the project to date it has been possible to:

optimise carbon bead and monolith synthesis strategies, comparing different precursor formulations, pyrolysis and activation techniques, allowing a more cost effective and efficient synthesis route for scaling up production of this technology
demonstrate haemocompatibility and the porosity required to adsorb specifically sized marker molecules using in vitro model systems for biotoxins related to kidney and liver failure
demonstrate that an appropriate porosity profile can be maintained using improved synthesis techniques in scaled up test prototypes
to develop, clinically relevant,scaled up testing models
to show for the first time that it is possible to covalently immobilise Bacillus anthracis exotoxin specific antibodies onto cross-linked macroporous polymer monoliths for the removal of anthrax protective antigen. Such technology could be used in the event of future bioterrorism attacks involving anthrax toxin in addition to other smart biomaterial applications related to toxin removal.

Work within the project has allowed exchange of best practice through knowledge transfer visits between international activated carbon specialists from IEPOR (Ukraine) and UK SME MCI allowing the development of cheaper and more efficient processing strategies for economic benefit in the scale up of production routes. It has been possible to adapt standard haemocompatibility profiling to assess activated carbons for blood perfusion applications and to develop improved assessment techniques to allow for toxin rebound into the systemic circulation following removal by adsorption.

Work within the second half of the project will focus on the development of ischaemic injury test models to assess adsorbent efficacy in donor organ preservation applications, haemocompatibility profiling of the antibody immobilized macroporous polymer prototypes and in vivo testing of device iterations. The project results support the potential for such adsorbent based medical device technologies to have significant clinical impact through improved removal of inflammatory and infectious molecules which currently drive tissue damage and produce life-threatening clinical complications.

Research team

Dr Susan Sandeman
PhD (Biomaterials), Principal Research Fellow (PRF) has research interests in nanostructured carbons for biomedical applications, biomedical technologies related to the treatment of organ failure, smart biomaterial approaches to control infection, inflammation and oxidative stress, cell scaffolds, corneal biomaterials and tissue engineering. She currently leads a UK NIHR i4i grant and British Council funded global innovation initiative grant. She is a co-investigator on a recently funded Horizon 2020 grant developing oral carbon therapy for the treatment of liver disease and has participated in a number of national, and international funded research projects; (BBSRC, EPSRC, Innovate UK, EUFP7)

Dr Carol Howell
(SPRF) works on the development and assessment of new biomaterials with relevance to CBRN, she has extensive experience of haemocompatibility testing of adsorbent materials and studying their removal capabilities for a range of biological toxins. She has experience of working on both national and European grants with both academic and industrial partners.

Dr Yishan Zheng
Dr Yishan Zheng is a research fellow in biomedical materials with expertise in activated carbons and polymer composites for biomedical applications

Dr Lyuba Mikhalovska
Dr Lyuba Mikhalovska is a principal research fellow specialising in blood clotting and fibrinolysis, protein-biomaterial surface interaction and biocompatibility of materials for medical application, characterisation of tissue scaffolds, natural fibres, biomaterials (from fibrin to flax fibres), biomolecules from flax seed non-saturated fatty acids and lignans

Dr Ganesh Ingavle
Dr Ganesh Ingavle is a biomaterials chemist and an experienced Marie Curie Research Fellow working on the ‘ACROBAT’ project specialising as a Biomaterials Chemist

Jenni Wilburn
Project Role: Project management and assistance to the co-ordinator. Jenni works across several European FP7 projects in Life Sciences providing financial management and support.

MAST Carbon

Professor Steve Tennison
Has over 35 years’ experience in the fields of carbon materials and separations technology, and has been PI on a number of both national and European funded grants. Other team members include;

Dr OP Kozynchenko
(PhD Chem, Principal Scientist) Specialising in synthesis of beads and surface chemistry, will be the main lead on the synthesis and characterisation of the deliganding phenyl formaldehyde resins prepared in conjunction with IEPOR.

R E Kavetsky Institute

Professor V Kikolaev
Is world-renowned specialist in the field of artificial organs for detoxication, including adsorptive purification of blood and plasma; biomaterials for blood purification; enterosorption; adsorptive treatment of wounds and burns; physico-chemical mechanisms of adsorptive detoxification. He is a winner of USSR State Prize for Haemoperfusion and a member of International and European Society for Artificial Organs, Society for Biomaterials. He is an honorary member of the Editorial Board of some International Journals. Prof. Nikolaev is the Head of Section of Adsorbents and Antidotes, State Pharmacological Committee, Ministry of Public Health of Ukraine.

University College London

Dr Nathan Davies, Senior Lecturer in biochemistry at the Institute of Hepatology, University College London

Cardiff University

Professor L Baillie

Albutec GmbH

Professor Dr Jan Stange, Chairman of the board at Albutec GmbH

Katrin Stange, Chief Executive Officer at Albutec

Dr Ralf Kähler, Research and Development

Matthias Suraj, Research and Development

Mr Jan Kleiber, Providing financial management and support

Polymerics GmbH

Dr Aniela Leistner
Dr Aniela Leistner graduated from the Technical University of Merseburg (East Germany) and received her PhD in polymer chemistry in 1980. In 1978 she joined the scientific research laboratory of ORWO Wolfen (producer of photographic films) working on the development and characterisation of novel polymeric materials for electrophotographic data recording systems. She joined the polymer chemistry group at Humboldt University of Berlin in 1988 and worked on the development of high-temperature resistant adhesives for flexible printed circuit boards, the synthesis of chromophores with non-linear optical properties and the synthesis of adsorbent polymers. In 1996 she founded Polymerics GmbH, a technology-oriented company in the field of high-temperature resistant adhesives, specialty polymers and polymer characterisation. Her main topics of interest are cross-linked polymer networks, their structure-property-relationships and practical application. She is currently owner and managing director of Polymerics GmbH.

André Leistner
André Leistner (Dipl.-Ing.) graduated in materials engineering from the Technical University in Berlin in 1997. From 1994–1997 he joined the Fibre Composites Department at the Federal Institute of Materials Testing and Research in Berlin (BAM) working on single fibre indentation tests and dynamic-mechanical analysis of single fibre model composites. Together with Aniela Leistner he founded Polymerics GmbH in 1996. At Polymerics he is responsible for adhesive and polymer characterisation using methods of thermal analysis (DSC, TGA, DMA) materials testing (Tensile Shear Test) as well as chromatography and spectroscopy (HPLC, GPC, UV-VIS, FTIR). He is currently owner and managing director of Polymerics GmbH.

Outputs

G Ingavle, L Baillie, Y Zheng, E Lis, I Savina, C Howell, S Mikhalovsky, S Sandeman. (2015). Affinity binding of antibodies to supermacroporous cryogel adsorbents with immobilised protein A for removal of anthrax toxin protective antigen. Biomaterials. 50:140-153.

Partners

University of Brighton, Biomaterials and Medical Devices Research Group

The University of Brighton is a leading UK higher education institute with a strong international reputation in life sciences research. The School of Pharmacy and Biomolecular Sciences in particular is internationally recognised for its high quality research, teaching, and training. The school has benefited from the construction and equipping of a new £23 million research facility. The BioMeD research group is a highly successful group within the School of Pharmacy and Biomolecular Sciences and holds a number of UK and EU funded research projects. Research themes surround novel carbon-based technologies in the biomedical field and include extracorporeal ultrafiltration and haemoperfusion devices, immunoadsorbents, biomedical devices for orthopaedic and dental applications, cardiovascular stents and ophthalmic implants, surface modification of biomaterials with biomimetic coatings, protection for CRBN incidents and standardisation of biomaterials

MAST Carbon International

MAST Carbon International is an independent company based in the United Kingdom established in 1996. The company has been operating for over 15 years and prior to that was the Carbon materials group of a major oil company. MCI was established in 1996 for the commercialisation of synthetic carbon adsorbents, catalyst systems and membranes and has an international reputation in the development and application of synthetic carbon materials. Its interests encompass biomaterials, separation, membranes, fuel cells, catalysis and automotive applications.

R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, IEPOR

Led by Team leader Prof. Vladimir G. Nikolaev has won international recognition for its work in the field of medical adsorbents and artificial organs. The group has won major awards for its research work (State Prize of the USSR and State Prize of Ukraine). The group is involved in the development of new means and methods of adsorptive blood purification, enterosorption (oral adsorbent usage) and adsorptive treatment of wounds and burns as well as in designing of the portable systems for hemo- and plasmaperfusion. All these adsorptive means and technologies have been successfully used in the treatment of a multitude of medical conditions. At present the research activity is focused on the development of fast adsorptive systems for the effective removal of protein-bound toxins from blood and blood plasma, new carbonic and combined enterosorbents and nano-silver-containing adsorptive bandages.

The team has been granted permission for the production and clinical use of over 20 different medical devices and adsorptive preparations in Ukraine and other NIS countries. It has been involved in a number of international projects with The Royal Society, NАТО Science Programme and CNRS (France).

Albutec GmbH

Albutec GmbH was founded in 2004 by three associates. Albutec is a research and development company with 6 permanent and 1 part-time employees. Our company is based in the Hanseatic city of Rostock in Germany, at the Biomedical Research Center.

Albutec developed the Hepalbin®-Adsorbent, which can easily remove unwanted stabilisers from human albumin solutions in order to enhance albumin binding capacity significantly. The continued development on the basis of the Hepalbin Adsorbent is the Hepalbin Cluster12 . This scaled up product enables the applicant to process larger amounts of albumin contained solutions such as used in albumin dialysis procedures.

In 2014 they developed an alternative disposable set OPen Albumin (OPAL) dialysis for the albumin dialysis using the MARS Monitor 1TC. The Hepalbin Cluster12 is part of that treatment set. A randomised crossover study is currently ongoing. This study is called Opalesque Study. The aim of that study is to compare this treatment assembly to the standard procedure MARS.

Polymerics GmbH

Polymerics GmbH is a technology-oriented company founded in 1996 as a spin-off from Humboldt University of Berlin, Germany. The company currently employs 10 people – all with a higher education degree. Polymerics develops and produces specialty adhesives for high-temperature applications, adhesive tapes, fire protection materials as well as specialty polymers for medical and analytical applications. The adhesives, based on hybrid epoxy-acrylic resins as well as on bismaleimides, are suitable for high-performance applications including microelectronics, sensor technology, and medical devices. All formulations of the adhesives have been developed by the company’s own research team. The company maintains a quality management system certified according to ISO 9001:2008. With the background of a profound scientific knowledge in the fields of polymer and adhesives characterisation and a large number of installed scientific analysis methods the company also offers services of polymer characterisation and quality assurance.

Since 1999 Polymerics has been involved in the synthesis and characterisation of new adsorbent polymers with tailored properties for extracorporeal blood purification devices and for analytical purposes (solid phase extraction). The company’s scientific posters have been awarded prizes for best presentations at the 4th International Symposium on Albumin Dialysis in Liver Disease in 2002 and at the European Society for Artificial Organs’ Winter School in 2012. These activities have led to participation in national and international research projects, including cooperation with Danube University Krems, Austria, 2005–2006, and the “MONACO-EXTRA” IAPP project 2008–2012 within the 7th Framework Programme of the European Commission.

Polymerics synthesises adsorbents in volumes from 0.25 to 10 L that can be tailored in terms of chemical composition, specific surface area and pore size distribution as well as particle size in the range from ca. 10 to 200 µm. The company is equipped with methods to purify the synthesised adsorbents and to determine the achieved degree of purity using solid phase extraction, HPLC, SEC, and TGA. The particle size of the adsorbents can be controlled by both the polymerisation parameters as well as by classification. Surface modifications can be controlled by FTIR and titration. The properties of the resulting adsorbent polymers are characterised using methods such as sieve analysis (particle size distribution), nitrogen adsorption (specific surface area and pore size distribution), and ad-sorption tests for specific substances using UV-VIS and FTIR spectroscopy. Polymerics holds several patents on the synthesis and biomedical application of its adsorbent polymers: DE10261910 (2002), US7311845B2 (2005), DE102004063633 (2004), EP1676615 (2005), US7304017B2 (2005).

University College London

UCL is one of the top 4 universities in the world, and is rated 5* in Life and Medical Sciences. The Liver Failure group at UCL is a translational group comprised of 3 Principal Investigators and 17 clinical and basic scientists. Their expertise spans basic biology, animal models of disease and the capability to perform clinical studies in patients and their research is focused on liver failure. The most important observation they made was the discovery that inflammation played a crucial role in the progression of liver failure leading up to current hypotheses and the seminal observation of the role of hypothermia in patients with uncontrolled intracranial hypertension, an intervention that has become routine in many units around the world. The group have developed extensive collaborations with investigators in the UK and around the world to study the pathophysiological basis of liver failure. Their research has led to successful publications of about 200 original papers, reviews, editorials and chapters in high impact journals and 9 patentable inventions addressing novel treatments for hepatic encephalopathy, development of extracorporeal liver assist devices and portal hypertension and discovery of novel biomarkers. Their studies have been funded by grants from the Welcome Trust, MRC, Department of Health, Foreign research councils, Industry and UCL Business and amounts to over £4.5M.

Cardiff University

Cardiff is internationally recognised as being among the very top tier of Britain's research-intensive universities and is a member of the Russell Group of leading universities.

The Welsh School of Pharmacy (WSP) undertakes research across the full spectrum of pharmaceutical sciences and practice. In the most recent Research Assessment Exercise (RAE2008) 85% of their research activity were judged to be of international standing. WSP research is focused on discovering from natural sources or producing in the laboratory potential new drugs, particularly for the treatment of cancer, cardiopulmonary diseases, and bacterial and viral infections.

Expertise of the Pharmaceutical Biology Research Group, WSP, led by the Prof Baillie includes containment level 3 microorganisms, bacterial spores, bacteriophages, molecular biology, vaccine expression and delivery systems, DNA vaccines, antibody assays, immune signalling, innate immunity.