# Scale-up and Economic Assessment of Biofunctional Particles Synthesis for Bilirubin Removal
## 1 Introduction  
Bilirubin is a yellowish compound generated in the body mainly by the breakdown of the hemoglobin present in red blood cells. Bilirubin high concentrations in blood are potentially toxic, leading to serious diseases, such as hyperbilirubin and jaundice, which affect a large number of people every year. Albumin is the blood protein responsible for transporting bilirubin to the liver, where it is conjugated for elimination. Thus, liver failure is the main cause of the aforementioned diseases [1]. The efficiency of therapeutic procedures used since the 1970s, such as hemodialysis, hemoperfusion, plasmapheresis, or exchange transfusion, has been limited, partly because of their inability to remove lipid-soluble compounds that are transported bound to albumin, but also because they cannot replace the liver's synthesis function [2; 3; 4]. Current treatments for affected patients, such as the MARS(r) and PROMETHEUS(r) extracorporeal dialysis systems, generate great amounts of waste and are expensive and not sufficiently effective or selective to remove bilirubin [5]. In fact, approximately one million people die annually from kidney failure all over the world and two million patients receive some type of dialysis; these data are expected to grow. Therefore, the search for alternative treatments for removing the excess of bilirubin from patients with liver failure is highly justified. The alternatives that are presenting better results for the replacement of these treatments involves the substitution of flat membranes by microparticles. These are mainlybased in polymers derived from polystyrene [6] or their copolymers, such as poly(styrene-methyl methacrylate) [7; 8] or poly(styrene-divinylbenzene) [9; 10], polyvinyl alcohol gels [11], or even polyethersulphone particles [12], but their current selectivity is limited. In a previous work, the research group presented the synthesis of particles from styrene (St), methyl-methacrylate (MMA), glycidyl methyl-methacrylate (GMA) and polyethylene glycol methacrylate (PEGMA), St-MMA-GMA-PEGMA, and their further functionalization by bovine serum albumin (BSA) attachment. These particles demonstrated high capacity for bilirubin removal from phosphate-buffered saline (PBS) and plasma. This research demonstrated that the attachment of albumin to the particles plays a key role in selectively reducing bilirubin levels in plasma and also in the kinetic of the bilirubin removal in both media [7]. In a further step, promising results were also demonstrated in an in vivo test, using pig models. At this stage, the feasibility of producing the functionalized particles at industrial scale and the economic evaluation of the process must be studied, constituting the objective of this work. One of the main challenges in materials research is passing from the laboratory process to the industrial plant. To carry out this process, the principle of similarity, which involves not only the geometry of the reactor, but also the flow or temperature profiles, was applied in this work [13; 14]. To achieve this principle of similarity, geometrical similarity is stablished, together with additional criteria such as the constant value of Reynolds number (Re), equal agitator tip speed, power per unit of tank volume or mixing time [15; 16]. Shape factors from the lab scale must be used for the pilot or industrial scale dimension calculation, since they must be constant, or in an specific range, to assure the geometrical similarity [16; 17]. Among the criteria for flow similarity, the constant value of Re was selected in this work. The principle of the constant Re assumes that the same turbulence is achieved and that defines similar hydrodynamic flow pattern [18]. Different processes have been scaled by applying the principle of similarity with successful results, such as the case of bioreactors [19], chemolysis process [13], polycondensation [20; 21], or polymerization [22]. However, none of the previously mentioned materials for bilirubin uptake are developed at industrial scale.