Towards the Experimentally-Informed In Silico Nozzle Design Optimization for Extrusion-Based Bioprinting of Shear-Thinning Hydrogels

Esther Reina-Romo; Sourav Mandal; Paulo Amorim; Veerle Bloemen; Eleonora Ferraris; Liesbet Geris

doi:10.3389/fbioe.2021.701778

Towards the Experimentally-Informed In Silico Nozzle Design Optimization for Extrusion-Based Bioprinting of Shear-Thinning Hydrogels

Front Bioeng Biotechnol. 2021 Aug 6:9:701778. doi: 10.3389/fbioe.2021.701778. eCollection 2021.

Authors

Esther Reina-Romo¹, Sourav Mandal², Paulo Amorim^{3

4}, Veerle Bloemen^{3

4}, Eleonora Ferraris⁵, Liesbet Geris^{2

3

6

7}

Affiliations

¹ Department of Mechanical Engineering and Manufacturing, University of Seville, Seville, Spain.
² Biomechanics Research Unit, GIGA In Silico Medicine, Université de Liège, Liege, Belgium.
³ Prometheus, The Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.
⁴ Materials Technology TC, Campus Group T, KU Leuven, Leuven, Belgium.
⁵ Department of Mechanical Engineering, Campus de Nayer, KU Leuven, Leuven, Belgium.
⁶ Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium.
⁷ Biomechanics Section, Department of Mechanical Engineering, KU Leuven , Leuven, Belgium.

Abstract

Research in bioprinting is booming due to its potential in addressing several manufacturing challenges in regenerative medicine. However, there are still many hurdles to overcome to guarantee cell survival and good printability. For the 3D extrusion-based bioprinting, cell viability is amongst one of the lowest of all the bioprinting techniques and is strongly influenced by various factors including the shear stress in the print nozzle. The goal of this study is to quantify, by means of in silico modeling, the mechanical environment experienced by the bioink during the printing process. Two ubiquitous nozzle shapes, conical and blunted, were considered, as well as three common hydrogels with material properties spanning from almost Newtonian to highly shear-thinning materials following the power-law behavior: Alginate-Gelatin, Alginate and PF127. Comprehensive in silico testing of all combinations of nozzle geometry variations and hydrogels was achieved by combining a design of experiments approach (DoE) with a computational fluid dynamics (CFD) of the printing process, analyzed through a machine learning approach named Gaussian Process. Available experimental results were used to validate the CFD model and justify the use of shear stress as a surrogate for cell survival in this study. The lower and middle nozzle radius, lower nozzle length and the material properties, alone and combined, were identified as the major influencing factors affecting shear stress, and therefore cell viability, during printing. These results were successfully compared with those of reported experiments testing viability for different nozzle geometry parameters under constant flow rate or constant pressure. The in silico 3D bioprinting platform developed in this study offers the potential to assist and accelerate further development of 3D bioprinting.

Keywords: Gaussian process; bioink; cell viability; computational fluid dynamics; computational modeling; design of experiements; machine learning; power law fluid model.