Adaptive and context-aware volumetric printing enhances functional relevance of 3D bioprinted human tissues

03 September 2025

The technique of 3D bioprinting of living tissues to recapitulate the structure and function of human organs has shown great promise in disease modelling, drug testing and regenerative medicine.

To further enhance the viability, complexity and functional relevance of bioprinted constructs, Riccardo Levato’s team at UMC Utrecht and Utrecht University have developed an innovative modelling methods termed Generative, Adaptive, Context-Aware 3D printing (GRACE). The GRACE workflow allows to rapidly produce volumetric, generative designs that dynamically adapt to embedded features within the bioresins.

During bioprinting, cells are known to sediment, clump or migrate in response to sheer stress, nutrient gradients, oxygen levels, change in temperature and other experimental variables, producing a drift away from the original computer design. Although the cells within the bioink are protected to a certain degree from shear stress by hydrogels, the mechanical damage to living cells remains a concern in traditional layer-by-layer printing. In response to variations in printing conditions, bioinks may swell, shrink, or deform. Once printed, vascular channels may collapse, shift, or misalign with cell clusters. While traditional bioprinting approaches cannot adjust in real-time in response to these events, GRACE can.

The core principle of GRACE is a combination of several technologies - volumetric bioprinting, light sheet microscopy, computer vision algorithms and parametric modelling software. Volumetric printing is particularly advantageous for capturing the complex geometry of human organs. In contrast to traditional layer-by-layer printing, the volumetric printing method creates a complete structure without contact and in a single step, using a photo-responsive bioresin that polymerizes when exposed to visible light fields. A light-sheet fluorescence microscope maps the position of cells within the construct. Based on this data, the platform’s software autonomously makes and executes decisions on necessary adjustments, ultimately enhancing human-relevance and viability of 3D printed tissues. 

In demonstration of its ability to strategically place blood vessels around existing cell clusters, GRACE was combined with embedded extrusion‐volumetric printing to generate adaptive vascular-like architectures around toruses laden with insulin-secreting pancreatic cells. Compared to random non-targeted channels, GRACE-printed structures showed an increase in proinsulin secretion. 

Since GRACE particularly excels at non-invasive printing onto or across existing objects, it has the potential to greatly improve the complexity of engineered tissue/organ constructs, moreover with micro-scale precision. A supporting architectures can be printed in this manner around embedded pre‑formed organoids/spheroids. By printing a structure with one cell type, washing unpolymerized hydrogel and refilling with a different cell‑laden hydrogel, multi‑cellular structures can be built in less than an hour. To illustrate the process, the team has produced a two-component cell-laden bone and cartilage model through automated alignment, by using GelMA-based resins containing articular cartilage-derived progenitor cells (ACPCs) and bone-marrow-derived mesenchymal stem cells (MSCs). These cells remained functional over 4 weeks, with ACPCs and MSCs synthesizing cartilage and mineralized bone matrix components, respectively.

Looking ahead, Riccardo Levato’s team plans to extend this work by increasing the amount and type of cells that can be printed, as to effectively capture the hierarchical composition of living tissues at the macro-to-micro and the micro-to-nano scale.

What Puts It on the Frontier

• Generative, context-aware design that dynamically adapts to embedded features within the bioresins

• Combination of volumetric bioprinting, light sheet microscopy, computer vision and parametric modelling

• High degree of autonomy - operates with minimal user intervention

Impact Snapshot

• Enhanced viability, complexity and physiological relevance of 3D bioprinted human tissues

• Improved ability to model human diseases and reliably predict responses to compounds

• Micro-scale precision of bioprinted constructs, supporting regenerative medicine applications

Reference

Florczak S, Größbacher G, Ribezzi D, Longoni A, Gueye M, Grandidier E, Malda J, Levato R. 2025. Adaptive and context-aware volumetric printing. Nature. 645(8079):108–114. https://doi.org/10.1038/s41586-025-09436-7.