Periodic Reporting for period 4 - VesselNet (Engineering Composite Tissues for Facial Reconstruction)
Reporting period: 2024-03-01 to 2025-08-31
Facial features are closely linked to our sense of identity. When an accident, disease or violent act alters a person’s face, the damage can be profound – physically, psychologically and socially. Personalized facial reconstruction is therefore in high demand. In recent years, tissue engineering of individual facial components such as bone, fat, skin and muscle has been demonstrated. However, until now, truly thick composite tissues that combine several facial layers in a single, living transplant have not been available.
A major barrier is blood supply. Large engineered grafts can only survive if they are rapidly perfused after implantation. This requires not only one or two large vessels, but a full vascular hierarchy: macrovessels that can be surgically connected to the patient’s circulation, and dense capillary networks where oxygen and nutrient exchange actually occur.
In VesselNet, we set out to create such a hierarchical vascular network within engineered tissues in vitro. Using advanced 3D bioprinting, we developed methods to fabricate customizable, multilayered composite tissues that incorporate perfusable macrovessels interconnected with fine microvascular networks, creating thick, functional grafts that could be surgically connected to host vessels and maintained by blood flow.
Within the project, we established new bioinks, support materials and bioprinting strategies that allow us to build stable, anatomically relevant tissues. We demonstrated that these vascularized constructs support tissue survival, maturation and regeneration in relevant preclinical models, and we scaled them up towards human facial defect dimensions.
The outcomes of VesselNet significantly advance the state of the art in vascularized tissue engineering. They bring personalized, full-thickness facial reconstruction closer to reality and provide powerful new tools to study tissue organization, disease mechanisms and regenerative therapies.
A major barrier is blood supply. Large engineered grafts can only survive if they are rapidly perfused after implantation. This requires not only one or two large vessels, but a full vascular hierarchy: macrovessels that can be surgically connected to the patient’s circulation, and dense capillary networks where oxygen and nutrient exchange actually occur.
In VesselNet, we set out to create such a hierarchical vascular network within engineered tissues in vitro. Using advanced 3D bioprinting, we developed methods to fabricate customizable, multilayered composite tissues that incorporate perfusable macrovessels interconnected with fine microvascular networks, creating thick, functional grafts that could be surgically connected to host vessels and maintained by blood flow.
Within the project, we established new bioinks, support materials and bioprinting strategies that allow us to build stable, anatomically relevant tissues. We demonstrated that these vascularized constructs support tissue survival, maturation and regeneration in relevant preclinical models, and we scaled them up towards human facial defect dimensions.
The outcomes of VesselNet significantly advance the state of the art in vascularized tissue engineering. They bring personalized, full-thickness facial reconstruction closer to reality and provide powerful new tools to study tissue organization, disease mechanisms and regenerative therapies.
Over the course of VesselNet, we developed and tested several complementary ways to build hierarchical blood-vessel networks within engineered tissues. We began with more classical scaffold-based approaches and progressively increased control and anatomical customization by moving to 3D bioprinting. Across these approaches, a key achievement was the creation of perfusable vascular trees that can undergo maturation in a flow bioreactor, surgically connected to the host artery and vein, and designed to match the needs of different tissues.
Using these engineered vascular networks as a foundation, we produced thick, composite tissue grafts. In particular, we demonstrated vascularized bone, muscle, and fat tissue grafts relevant to facial reconstruction. These constructs survived, integrated, and contributed to defect repair after implantation. Importantly, our vascularized implants were shown to connect with and integrate, enabling rapid perfusion – an essential requirement for maintaining viability of large engineered grafts.
In the final phase, we emphasized scale-up and in vivo validation in a large animal model. We implanted the bioprinted vascularized constructs in a clinically relevant facial muscle defect model and observed construct perfusion, integration, and improved regeneration. To support bioprinting accuracy and maturation after printing, we also developed tailored bioinks, supportive printing materials, and post-printing culture systems that improved structural stability and supported cell survival and tissue development.
The fabrication workflows created in VesselNet provide a toolbox that can be adopted and further developed for regenerative medicine and for building realistic tissue models for research and therapy development. Results were disseminated widely through international conferences, workshops, publications, and outreach activities. A notable communication output was the creation of short animated films explaining VesselNet’s concepts and outcomes, which were integrated into presentations and educational lectures to make the science accessible to broader audiences.
Using these engineered vascular networks as a foundation, we produced thick, composite tissue grafts. In particular, we demonstrated vascularized bone, muscle, and fat tissue grafts relevant to facial reconstruction. These constructs survived, integrated, and contributed to defect repair after implantation. Importantly, our vascularized implants were shown to connect with and integrate, enabling rapid perfusion – an essential requirement for maintaining viability of large engineered grafts.
In the final phase, we emphasized scale-up and in vivo validation in a large animal model. We implanted the bioprinted vascularized constructs in a clinically relevant facial muscle defect model and observed construct perfusion, integration, and improved regeneration. To support bioprinting accuracy and maturation after printing, we also developed tailored bioinks, supportive printing materials, and post-printing culture systems that improved structural stability and supported cell survival and tissue development.
The fabrication workflows created in VesselNet provide a toolbox that can be adopted and further developed for regenerative medicine and for building realistic tissue models for research and therapy development. Results were disseminated widely through international conferences, workshops, publications, and outreach activities. A notable communication output was the creation of short animated films explaining VesselNet’s concepts and outcomes, which were integrated into presentations and educational lectures to make the science accessible to broader audiences.
VesselNet advanced the state of the art by moving vascularized tissue engineering beyond “single-vessel” or purely microvascular constructs toward true vascular hierarchies: larger perfusable vessels that can be surgically connected, seamlessly linked to dense microvascular networks that sustain thick living tissues. This is a central barrier in tissue engineering, because without rapid and distributed blood supply, large grafts fail. Demonstrating hierarchical, perfusable networks in engineered tissues—and showing their ability to integrate in vivo—represents a meaningful step toward clinically relevant, full-thickness grafts rather than thin, limited constructs.
A second major advance is the project’s contribution to manufacturing capability. By combining multi-modal bioprinting strategies with newly developed bioinks and supportive printing materials, VesselNet improved the bioprinting accuracy, post-printing maturation and the biological performance of engineered tissues. These innovations extend beyond the central concept of the project and can be applied to many areas that require perfused tissues, including disease modeling and regenerative therapy development.
Overall, VesselNet delivered a practical pathway for engineering customizable, multilayered, vascularized composite tissues at sizes relevant to human defects, supported by validated fabrication and cultivation methods. By addressing the vascularization bottleneck with scalable solutions and demonstrating functional benefits in preclinical settings, the project brings the field closer to the long-term goal of personalized, living grafts for complex reconstruction, while also providing powerful tools for biomedical research.
A second major advance is the project’s contribution to manufacturing capability. By combining multi-modal bioprinting strategies with newly developed bioinks and supportive printing materials, VesselNet improved the bioprinting accuracy, post-printing maturation and the biological performance of engineered tissues. These innovations extend beyond the central concept of the project and can be applied to many areas that require perfused tissues, including disease modeling and regenerative therapy development.
Overall, VesselNet delivered a practical pathway for engineering customizable, multilayered, vascularized composite tissues at sizes relevant to human defects, supported by validated fabrication and cultivation methods. By addressing the vascularization bottleneck with scalable solutions and demonstrating functional benefits in preclinical settings, the project brings the field closer to the long-term goal of personalized, living grafts for complex reconstruction, while also providing powerful tools for biomedical research.