Sculpting the Microvascular Networks in 4D: Dynamic Growth Factor Presentation For Engineered Tissues
Deepti Rana is a PhD student in the Department of Engineering Organ Support Technologies. Promotors are dr.ir. J. Rouwkema and prof.dr.ir. H.F.J.M. Koopman from the Faculty of Engineering Technology.
Imagine planting a young tree. You can give it rich soil, sunlight, and careful support, but unless its roots find water, the tree cannot grow strong. In much the same way, when scientists try to engineer new tissues for medicine, the single biggest challenge is creating a lifeline of tiny blood vessels that can feed the cells. Without this vascular network, even the most sophisticated lab-grown tissue struggles to survive once implanted in the body.
For decades, researchers have worked to solve this “vascularization problem.” Many ideas have been tested—designing new scaffolds for cells to grow on, combining different cell types, or adding biochemical signals to nudge cells into forming vessel-like structures. Some of these strategies work in the laboratory, but very few succeed once they are placed in living systems. The reason? Blood vessel growth is not just about starting the process; it is about guiding it over time, making sure the vessels form in the right places, branch in the right ways, and remain stable. In nature, this orchestration is performed by the extracellular matrix (ECM)—the body’s dynamic support system that holds tissues together and constantly provides, removes, and reshuffles the biochemical signals that cells need.
This PhD thesis takes inspiration from the ECM and asks a bold question: What if we could design biomaterials that do not just release signals in a simple, one-time way, but instead present them dynamically—changing over time, just as the body does?
Setting the Stage (Chapter 2)
The story begins with a deep dive into how nature manages blood vessel growth. Chapter 2 explains how the ECM works like a conductor in an orchestra, presenting multiple growth factors—such as VEGF, PDGF, and angiopoietins—in just the right sequence and concentration. These molecules act as cues that tell cells when to start sprouting new vessels, when to stabilize them, and when to remodel them. The chapter also reviews how researchers have so far tried to mimic this process, from simple slow-release systems to advanced biofabrication techniques like 3D printing. Yet the common weakness of these approaches is their static nature: once the signals are released, they cannot be adjusted or fine-tuned. This chapter lays the foundation for the rest of the thesis by highlighting the need for “intelligent” biomaterials that can adapt and evolve their signaling, just like the ECM.
A First Proof of Concept (Chapter 3)
With the challenge defined, the next step was to test whether dynamic growth factor presentation could even be achieved. Chapter 3 introduces a clever solution using aptamers—short DNA strands that can be designed to specifically bind to proteins like VEGF. By attaching these aptamers to a hydrogel made of gelatin methacryloyl (GelMA), the material could capture VEGF from its surroundings and hold it in place. The real innovation came with the idea of a “key” called a complementary sequence (CS). When added, this CS displaced VEGF from the aptamer, releasing it into the environment exactly when desired.
This system was tested in a 3D culture with two types of human cells—endothelial cells that form vessels, and mesenchymal stromal cells that support them. The results were striking: with a well-timed release of VEGF, the cells organized themselves into dense, connected vessel-like networks. This was the first clear evidence that on-demand release of growth factors could guide vascular development in engineered tissues.
Adding Spatial Control (Chapters 4 & 5)
Encouraged by these results, the thesis next asked: what happens if we control not only when but also where growth factors are released? This question led to the use of advanced biofabrication tools. In Chapter 4, photopatterning was used to create regions within the hydrogel where aptamers were placed in specific patterns. In Chapter 5, 3D bioprinting took this a step further, allowing precise placement of VEGF-sequestering regions throughout a printed structure.
The experiments revealed that spatial patterning had a powerful effect on how vessels grew. Endothelial networks became more oriented and organized when VEGF was released from patterned regions. Computer simulations further explained why: the patterned aptamer regions shaped VEGF gradients—slopes of concentration that cells could “read” as directional cues. Interestingly, the best results appeared when aptamer-patterned and non-patterned regions were placed side by side, creating buffer zones that enhanced self-organization. These findings showed that spatial heterogeneity—just like in real tissues—is essential for building well-structured vascular networks.
Toward Intelligent Biomaterials (Chapter 6)
The final chapter takes the biggest step forward. In natural tissues, no single growth factor works alone—VEGF sparks vessel growth, but PDGF is needed to stabilize and mature those vessels. To mimic this, Chapter 6 developed a dual-aptamer hydrogel capable of handling both VEGF and PDGF at once. This material could capture both growth factors from its surroundings, hold them, and then release each one separately, on demand, and even repeatedly over time.
This advance is significant because it moves closer to recreating the ECM’s complexity. Instead of a single static signal, the material becomes programmable: scientists can choose when to release VEGF to start vessel sprouting, and when to release PDGF to ensure those vessels become stable and functional. This is a step toward biomaterials that can truly “communicate” with cells in real time.
Why It Matters
The implications extend beyond blood vessels alone. Dynamic biomaterials could be applied to many areas of regenerative medicine, from healing large wounds to building replacement organs. Just as importantly, they highlight a shift in thinking: successful tissue engineering is not only about what we give cells, but when and how we give it.
In summary, this thesis tells the story of how inspiration from nature can lead to smarter, more adaptive biomaterials. By listening to how the body itself guides growth and repair, we can design new tools that bring us closer to the dream of building fully functional tissues and organs for patients in need.
For Further Reading
- D Rana et. al., Spatiotemporally controlled, aptamers-mediated growth factor release locally manipulates microvasculature formation within engineered tissues. Bioactive Materials 2022, 12; 71-84. https://doi.org/10.1016/j.bioactmat.2021.10.024
- D Rana et. al., Spatial control of self-organizing vascular networks with programmable aptamer-tethered growth factor photopatterning. Materials Today Bio 2023, 19; 100551. https://doi.org/10.1016/j.mtbio.2023.100551
- D Rana et al., Bioprinting of Aptamer-Based Programmable Bioinks to Modulate Multiscale Microvascular Morphogenesis in 4D. Advanced Healthcare Materials 2024, 14: 2402302.
- https://doi.org/10.1002/adhm.202402302
- D Rana et al., Spatiotemporally programmed release of aptamer tethered dual angiogenic growth factors. International Journal of Biological Macromolecules 2024, 283: 137632.
- https://doi.org/10.1016/j.ijbiomac.2024.137632
