Bioengineering human lymphatic networks

The field of tissue engineering aims to define the principles of organ formation, and to use this knowledge to produce functional tissues for use in regenerative medicine, disease modelling and drug testing. As engineered tissues have increased in size and complexity, the requirement for integration of functional vascular networks into these structures has become critical. In our bodies, the cardiovascular and lymphatic vascular systems deliver nutrients and remove waste products from each organ and tissue, allowing our brains to process information, our hearts to beat and our muscles to move. To support these diverse functions, the inner endothelial cell (EC) layer of blood and lymphatic vessels acquires organ-specific characteristics that are important for organ function. For engineered tissues to reflect human physiology, vascular networks must recapitulate these native features, and while progress has been made towards bioengineering organ-specific blood vessels, to date the fabrication of lymphatic vessels has been largely neglected. This is in part due to our more limited understanding of how lymphatics are formed during embryonic development. Here, we aim to bridge this knowledge gap by combining expertise in lymphatic development with advanced microfabrication techniques to create bioengineered human lymphatic networks. A key focus of our efforts will be to deepen our understanding of the normal development of lymphatic vessels in human embryos. This knowledge will provide critical insight into the principles of lymphatic vessel specification and morphogenesis. In parallel, we will work to optimize and improve the efficiency of our protocols to generate lymphatic ECs at scale from human stem cells, informed by our knowledge of native lymphatic EC specification. We will harness the power of novel bioprinting tools to fabricate lymphatic networks that closely replicate the scale, structure, and complexity of native lymphatic systems. This technology will allow us to create more accurate models for functional analyses. Complementing these efforts, we aim to develop novel scaffolds that better emulate the dynamic properties of native tissues. Our ultimate goal is for these scaffolds to be degradable and to permit interstitial fluid flow and cell migration, enabling them to support the growth and functionality of engineered lymphatic networks. Collectively, these strategies will advance our ability to model, study, and ultimately engineer lymphatic systems with a high level of precision and fidelity. The potential impact of this work is far-reaching. This model will serve as a valuable platform from which to gain deeper insights into the formation and function of human lymphatic vessels. By creating a system that is amenable to high resolution imaging, we will be able to better understand the cellular mechanisms underpinning fluid and immune cell movement into lymphatic vessels. Engineered lymphatic networks will reduce the reliance on animal models for discovery science and drug testing, and may more accurately model human biology; this may permit the study of diseases related to immune system dysfunction, chronic inflammation, fluid imbalance and tumour cell metastasis. Engineered lymphatics may also improve regenerative medicine by enabling the creation of transplantable tissues (e.g. skin or cardiac tissue) with functional lymphatic systems.