Biomaterials for Modulating Lymphatic Function in Immunoengineering

Abstract

Immunoengineering is a rapidly growing and interdisciplinary field focused on developing tools to study and understand the immune system, then employing that knowledge to modulate immune response for the treatment of disease. Because of its roles in housing a substantial fraction of the body's lymphocytes, in facilitating immune cell trafficking, and direct immune modulatory functions, among others, the lymphatic system plays multifaceted roles in immune regulation. In this review, the potential for biomaterials to be applied to regulate the lymphatic system and its functions to achieve immunomodulation and the treatment of disease are described. Three related processes-lymphangiogenesis, lymphatic vessel contraction, and lymph node remodeling-are specifically explored. The molecular regulation of each process and their roles in pathologies are briefly outlined, with putative therapeutic targets and the lymphatic remodeling that can result from disease highlighted. Applications of biomaterials that harness these pathways for the treatment of disease via immunomodulation are discussed.

Figure 1

Structure and function of the lymphatic system. (A) Fluid leaves the tissue interstitium and enters initial lymphatic vessels, flowing through larger collecting vessels and the lymph node. Readers are referred to refs (−23) for an in depth discussion of lymphatic structure and function. (B) Initial lymphatic vessels are composed of overlapping LECs on a discontinuous basement membrane that allow fluid, migratory immune cells, and soluble factors, including nanoparticles in the 20–100 nm size range, to enter the vessels. Lymph is moved away from the periphery through larger collecting lymphatic vessels that are surrounded by a layer of specialized lymphatic muscle cells that produce coordinated contractions to propel lymph downstream. (C) Fluid subsequently flows through lymph nodes (LN), secondary lymphoid organs that house cells of the adaptive immune system and are a critical site of antigen presentation. As lymph flows through the LN to eventually exit via an efferent lymphatic vessel, soluble antigen can be processed by lymph-sampling sinus-lining macrophages. The conduit system allows molecules smaller than 70 kDa to access deeper regions of the LN,^, and LEC-mediated transcytosis facilitates diffusion of antibodies into the LN parenchyma. Antigen-presenting cells (APCs) can carry antigen from the periphery and traffic into the LN to present their antigen to B and T lymphocytes residing in distinct locations within the LN, which then drive the resulting immune response. Cell migration, fluid movement, and antigen transport are all supported by a system of LN stromal cells that provide a scaffold for all critical LN functions to occur.^, The structure of LNs is critical to their function and changes with the immune response.

Figure 2

Modulation of lymphangiogenesis. A wide variety of approaches to modulating lymphangiogenesis are in use (blue background) and biomaterials can, in many cases, be used to expand upon and improve those approaches (orange background).

Figure 3

Biomaterials for promoting lymphangiogenesis. (A) Hadamitzky et al. implanted nanofibrillar collagen scaffolds into a porcine model of lymphedema, (B) and observed that only when the scaffolds were delivered with or without exogenous LN transfer was there any measurable reduction in interstitial fluid volume, as measured by bioimpedance. Adding exogenous VEGF-C to the implanted scaffold negated any benefit of the scaffold. (C) Guc et al. developed plasmin-cleavable VEGF-C-releasing hydrogels that (D) release their VEGF-C payload in a controlled fashion, compared to rapid release of free protein, in vivo. (E) The hydrogel induces significant expansion of LYVE1+ vessels (green) in a dose-dependent fashion and (F) increases leukocyte trafficking to LNs. (G) In a diabetic wound model, the FB-VEGF-C hydrogels enhanced lymphangiogenesis and improved wound healing, as measured by increased granulation tissue. Panels A and B adapted with permission from ref (15). Copyright 2016 Elsevier. Panels C–G adapted with permission from ref (17), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Copyright 2017 Elsevier.

Figure 4

Limitations and future directions for modulating lymphatic collecting vessel function. While local administration of small molecule therapeutics is useful in situations where lymphatic vessels are readily accessible, injection of small molecules can result in poor lymphatic uptake and systemic distribution. Employing lymphatic-draining nanoparticles that release a small molecule payload within lymphatic vessels could overcome this limitation, and targeting the nanoparticles to LECs could help ensure local release of drug and a higher concentration within the collecting lymphatic vessel.

Figure 5

Lymph node remodeling in disease. (A) The biophysical organization of the LN remodels in the context of disease, including (B) afferent vessel disruption, (C) tumor drainage, and (D) inflammatory response.

Figure 6

Biomaterials enable LN-targeted drug delivery to regulate LN remodeling and immune response. (A) While small molecules and proteins may poorly drain to lymph and yield low concentrations at target immune cells, nanoparticle formulations can enhance lymphatic drainage, enhance uptake by target immune cells, and precisely deliver combinations of payloads. (B) St. John et al. developed artificial mast cell granules composed of heparin that could be loaded with TNF-α and other drugs. (C) These synthetic granules increased germinal center formation, as measured by the total number of germinal center B cells, compared to controls. (D) After vaccination with hemeagglutinin, granule delivery resulted in improved antibody titers and (E) protected mice from lethal flu challenge. Panels B–E adapted with permission from ref (18). Copyright 2012 Springer Nature.