A customizable vascular network biomimetic design for nutrient supply in large-scale engineering tissues

Abstract

BACKGROUND: Constructing an effective vascular network is crucial for the successful regeneration of large-volume tissues and organs. Currently, vascular network design methods predominantly rely on predefined geometric patterns, making them inadequate to meet the metabolic demands of engineered tissues with diverse material properties and complex morphologies. Existing hierarchical vascular networks suffer from insufficient diffusion coverage and low nutrient supply rates due to their hierarchical rules. OBJECTIVE: To propose a vascular network model design method based on developmental biomimetic principles, aiming to automatically generate customized voxel vascular network structures tailored to the metabolically active distance of target tissues. METHODS: The method integrated voxelization techniques to simulate biological behaviors of vascular endothelial cells, such as migration and aggregation. Diffusion experiments were conducted on gel materials, and Fick's law was applied to fit experimental data, establishing a metabolic-diffusion coupled fast calculation model. Based on this model, the metabolic activity distance was used to rapidly identify nutrient supply conditions and delineate low-nutrient regions, thereby simulating the dynamic remodeling process of vascular development to iteratively optimize the voxel vascular network structure until the nutrient supply rate reached the algorithm's set value. RESULTS AND CONCLUSION: Compared with traditional hierarchical design methods, the developmental biomimetic vascular network design improved the nutrient-sufficient volume and nutrient contribution per unit volume by 25.53% in metabolic diffusion simulations of cuboid tissue models based on gelatin methacryloyl (GelMA) hydrogel. It also successfully generated vascular network voxel models with sufficient nutrient supply for complex-shaped engineered tissues and organs such as kidney-shaped and alveolar-shaped models, verifying the advantages and research potential of biomimetic vascular network design. This study provides a new technical approach for designing vascular network digital models in large-volume engineered tissues and anatomically complex organs.

1. Introduction

The core challenge in constructing large-volume tissue engineering products in vitro is establishing an artificial vascular system with nutrient supply function. Currently, two main strategies are employed: pre-vascularization technology (pre-constructing tissue scaffolds with vascular channels) and capillary self-organization technology [1-2]. The typical process of pre-vascularization involves preparing tissue blocks with tubular channels via bioprinting, followed by perfusion of vascular endothelial cells to adhere and proliferate on the channel walls, ultimately forming an endothelial barrier with physiological function. The integrity of this barrier marks the selective permeability capability of the vascular system, a process highly similar to clinical endothelialization mechanisms [3-4]. Notably, even after endothelialization, relying solely on passive diffusion for nutrient supply has significant limitations. Experimental data show that the effective diffusion penetration depth of oxygen is only on the order of 200 μm [5], severely restricting cell survival in regions far from blood vessels. Therefore, artificial vascular systems must simultaneously fulfill dual functions: serving as the main nutrient transport pathway during initial tissue construction, and providing a topological guiding framework for subsequent capillary network self-assembly [3-4]. Current technical bottlenecks are mainly reflected in the imbalance between structural precision and metabolic demands—high-precision printed microchannels are difficult to achieve efficient convective transport, while coarse perfusion systems cannot maintain tissue-specific structures [5]. The key to overcoming this dilemma lies in developing perfusion-based vascular networks based on active convection mechanisms, optimizing material transport efficiency through vascular distribution and fluid dynamics, which is decisive for achieving complete construction of large-volume vascularized tissues in vitro.

However, current vascular network design methods generally have several problems. First, mathematical modeling of biological principles remains difficult, lacking an effective computable model for nutrient supply function. Existing vascular network design methods commonly suffer from insufficient nutrient supply and low computational efficiency [5-6], and no method can quantitatively design vascular networks for nutrient supply. Furthermore, existing methods cannot conveniently achieve customized design according to different material properties and special structural requirements. Unlike traditional mechanical design methods, vascular network design requires simultaneous consideration of geometric shape and biological function, making the strategy of first designing geometry and then optimizing biological function inapplicable.

To achieve functional vascular network voxel model design, functional computation must be performed simultaneously with geometric generation. For example, some studies use factor attraction algorithms to generate vascular network structures and Murray's law to optimize geometric structures [7-8], but the core is generating vascular networks through preset geometric rules (such as branch angles and diameter ratios) without real-time correlation with nutrient supply function, nor digitizing material properties in the design, leading to issues such as insufficient nutrient supply and cell death in engineered tissues [9]. Studies have shown that gel materials with different concentrations and compositions affect nutrient diffusion.