# Steering the Clinical Translation of Delivery Systems for Drugs and Health Products
## 2 Lectures
### Session A: How Informatics Can Support Drug Delivery Technologies
#### 2.1.2 How Computer Science and Biomedical Engineering can Help Drug Discovery Process:  
In Silico Trials  
[PERSON] * and [PERSON]  
Department of Drug Sciences, University of Catania, 95125 Catania, Italy  
* Correspondence: [EMAIL_ADDRESS]  
In Silico Trials (IST) represent an innovative application of Virtual Human technology helpful in assisting and supporting the refinement, the reduction, or the replacement of pre-clinical and clinical trials. In this multifaceted challenge perspective, the regulatory authorities are faced with an increasing number of projects developing and applying ISTs ranging from validating ongoing in silico models of specific pathophysiology or applied virtual populations, via technological and infrastructural demands. The last few years have been characterized by an intense activity around so-called regulatory science, aimed to ensure a robust approach to assess the credibility of individual in silico methods as sources of regulatory evidence. In the regulatory field, the term qualification indicates the overall process that a regulator uses to establish the credibility of a novel method. This process is not entirely codified yet, although some aspects of it are addressed by the ASME V&V-40 standard for medical devices, and in other regulatory documents for drugs. Credibility analysis consists of Technical Validation, which is developed within the traditional framework of Verification, Validation, and Uncertainty Quantification (VV&UQ) already well established for other industrial sectors, and Clinical Validation, where the principles of general biomarkers qualification are followed (Figure 1). 1.3. Intricate Journey of Micro- and Nano-Carriers for Drug Delivery in the Blood Stream [PERSON] 1, [PERSON] 2, [PERSON] 2 and [PERSON] 2,*  
1 Simulation and Software Technology, German Aerospace Center, 51147 Koln, Germany  
2 Institute of Complex Systems and Institute for Advanced Simulation, Forschungszentrum Julich 52425 Julich, Germany  
* Correspondence: [EMAIL_ADDRESS]  
Drug delivery by various micro- and nanocarriers offers the possibility of controlled transport of pharmaceuticals to targeted sites (e.g., cancerous tissue). The adhesion of micro- and nanocarriers in blood flow is strongly affected by their distribution within the vessel cross-section (Figure 2). To investigate the adhesion potential of carriers of different sizes, we employ mesoscopic hydrodynamic simulations of blood flow to predict margination of carriers or their migration properties toward vessel walls. The margination of carriers is studied for a wide range of hematocrit values and flow rates, and various sizes, ranging from about hundred nanometers to several micrometers, are considered [8]. Figure 1: Clinical validation: disease + intervention. Adapted from [7]. Our results show that margination strongly depends on the thickness of the available free space close to the wall, the so-called red blood cell-free layer (RBC-FL), in comparison to the carrier size [9]. The carriers with a few micrometers in size are comparable with the RBC-FL thickness and marginate better than their sub-micrometer counterparts. Deformable carriers, in general, show worse margination properties than rigid particles. Particle margination is also found to be most pronounced in small channels with a characteristic size comparable to blood capillaries. As a conclusion, micron-size particles seem to be favorable for vascular drug delivery in comparison to sub-micron carriers.