Engineering Functional Lymphatic Networks in Vitro

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DESCRIPTION (provided by applicant): This two-year proposal describes the development of functional lymphatic networks and their integration into artificial dermal constructs in vitro. While many methods have been developed to form microvascular networks suitable for perfusion of engineered tissues, much less is known about how to form structures that can drain these same tissues of excess interstitial fluid and proteins. To promote lymphatic function in engineered vascular constructs, we propose to use microfluidic collagen gels as scaffolds and to manipulate the microenvironmental conditions to mimic native lymphatic drainage conditions in vivo. Specifically, in Aim 1, we intend to examine how transmural pressure and shear stress - two factors that are extremely small in the lymphatic circulation - affect functional maturation in vitro. We will then use an optimized set of these stresses to form hybrid constructs that contain both blood and lymphatic microvessels, in which the former exhibits a tight barrier while the latter is leaky. In Aim 2, we will integrate these design parameters to form lymphatic networks suitable for draining a 1 cm2 area of dermal tissue. These networks will be formed by a lithographic method, and the conditions obtained in Aim 1 will serve as a starting point for the development of lymphatic function in entire networks. These constructs will contain an independent vascular network for perfusion. We will determine how the geometry of the lymphatic network promotes its ability to maintain a non-edematous state, both under basal and hyper-filtration conditions. We expect the proposed work to provide underlying principles that govern the rational design and function of engineered lymphatic networks. This work will serve as a first step towards the systematic synthesis of dermal tissue that integrates functional blood and lymphatic vascular systems. This work will study how to build lymphatic vessels - the vessels that drain organs of their excess fluids. We intend to incorporate these vessels into an artificial skin (dermis) and to show that they function as lymphatics do in intact, native skin. We anticipate that this work will provide a first step towards engineered organs that can drain properly when implanted into a patient.