This thesis is concerned with applying engineering principles to the use of polymeric nanoporous adsorbents for use in blood purification to obtain original knowledge. Styrene divinylbenzene copolymer nanoporous adsorbents offer a potential means to remove middle molecular (MM) sized molecules when in direct contact with blood. (Continues...).

This thesis is concerned with the development and characterisation of polymeric nanoporous adsorbents to be used for blood purification. Current treatment methods for suffers of chronic renal failure are limited to haemodialysis, peritoneal dialysis and organ transplant. Organ transplant is the most efficient option however lack of donor organs mean that the majority of suffers rely on dialysis. Unfortunately both dialysis treatments are lacking when it comes to the removal of middle molecular weight molecules (MMs) (500 - 60000 Da) and the accumulation of these molecules has been attributed to a number of additional ailments suffered by those on long term dialysis. Sorbent augmented dialysis has been identified as a potential avenue to remove these MMs, an additional column would be introduced to the haemodialysis loop this would contain adsorbent particles to remove these unwanted molecules. Styrene-divinylbenzne copolymers have been identified as suitable for this task as they will non-specifically adsorb a wide range of molecules. One major concern with the introduction of a polymeric adsorbent is the potential removal of human serum albumin HSA from the patient's blood, this essential blood protein is present in very high concentrations typically 40g/l and this will potentially swamp the surface of any adsorbent. Fortunately HSA is a large blood protein (69kDa) and as such the method to combat this limitation as explored in this thesis is to tailor the pore structure of the polymeric adsorbent to size exclude albumin while retaining sufficient adsorption capacity to remove the MMs. To achieve these goals a number of polymeric adsorbents were generated using different porogens and degrees of crosslinking to control the porous structure. These adsorbents were analysed using a number of characterisation methods to assess their dry and swollen state porosities and molecular weight cut offs. Once a suitable material had been developed protein adsorption studies were carried out to confirm the size exclusion of HSA and the uptake of MMs.

Le choc septique est la première cause de mortalité en réanimation. Des techniques extracorporelles de purification sanguine sont aujourd’hui proposées pour améliorer le pronostic de cette pathologie. Leur mode d’action est basé sur l’immunomodulation de la réponse inflammatoire systémique de l’hôte, obtenue principalement par épuration nonsélective des médiateurs de l’inflammation. Nous rapportons les résultats de différentes études in vitro, animales et cliniques ayant évalué les techniques de purification sanguine suivantes :hémofiltration à haut débit, hémofiltration en cascade, hémofiltration hautement adsorbante,filtration et adsorption couplée, hémoadsorption, et hémodialyse à haute perméabilité.Ce travail de recherche translationnelle montre que les techniques de purification sanguine sont non seulement capables d’épurer les médiateurs de l’inflammation mais aussi l’endotoxine pour l’hémofiltration hautement adsorbante et l’hémoadsorption. Nous démontrons par ailleurs la faisabilité technique, la sécurité d’application et les intérêts del’hémofiltration en cascade et de l’hémodialyse continue à haute perméabilité. Les effets hémodynamiques bénéfiques des techniques de purification sanguine sont également retrouvés. Pour les années à venir, il conviendra d’optimiser les techniques les plus performantes en tenant compte de leurs avantages et inconvénients respectifs. Sur le planphysiopathologique, l’effet plus direct de ces thérapies sur les leucocytes sera à approfondir. Il semble maintenant admis que convection, diffusion et adsorption ne doivent plus être opposés mais plutôt être considérés comme des mécanismes complémentaires / Septic shock is the main cause of death in the intensive care unit. Extracorporeal blood purification therapies are now being proposed in order to improve septic shock outcomes. These therapies work based on immunomodulation of the host inflammatory response, obtained by non selectively removing inflammatory mediators. We report data from several different studies performed in vitro, in animals and in human beings, assessing various blood purification therapies which include high-volume hemofiltration, cascade hemofiltration, high-adsorption hemofiltration, coupled plasma filtration adsorption, hemoadsorption and high-permeability hemodialysis. This translational research work shows that blood purification therapies are capable of removing not only the inflammatory mediators but also the endotoxins as far as highadsorptionhemofiltration and hemoadsorption are concerned. We demonstrate technical feasibility, safety and advantages of cascade hemofiltration and continuous high-permeability hemodialysis. The beneficial hemodynamic effects related to these blood purification techniques are also highlighted. For future research, optimization of the most efficient techniques is warranted, takinginto account of their respective advantages and drawbacks. Regarding pathophysiology, the direct effect of these therapies on leukocyte function is subject to further investigation. To date, convection, diffusion and adsorption should not be viewed in opposition but rather, seen as complementary mechanisms.