Nanotechnologies for Physiology-Informed Drug Delivery to the Lymphatic System.

Accompanying the increasing translational impact of immunotherapeutic strategies to treat and prevent disease has been a broadening interest across both bioscience and bioengineering in the lymphatic system. Herein, the lymphatic system physiology, ranging from its tissue structures to immune functions and effects, is described. Design principles and engineering approaches to analyze and manipulate this tissue system in nanoparticle-based drug delivery applications are also elaborated.

In Vitro Models of Blood and Lymphatic Vessels-Connecting Tissues and Immunity.

Blood and lymphatic vessels are regulators of physiological processes, including oxygenation and fluid transport. Both vessels are ubiquitous throughout the body and are critical for sustaining tissue homeostasis. The complexity of each vessel's processes has limited the understanding of exactly how the vessels maintain their functions. Both vessels have been shown to be involved in the pathogenesis of many diseases, including cancer metastasis, and it is crucial to probe further specific mechanisms involved. In vitro models are developed to better understand blood and lymphatic physiological functions and their mechanisms. In this review, blood and lymphatic in vitro model systems, including 2D and 3D designs made using Transwells, microfluidic devices, organoid cultures, and various other methods, are described. Models studying endothelial cell-extracellular matrix interactions, endothelial barrier properties, transendothelial transport and cell migration, lymph/angiogenesis, vascular inflammation, and endothelial-cancer cell interactions are particularly focused. While the field has made significant progress in modeling and understanding lymphatic and blood vasculature, more models that include coculture of multiple cell types, complex extracellular matrix, and 3D morphologies, particularly for models mimicking disease states, will help further the understanding of the role of blood and lymphatic vasculature in health and disease.

Targeting the Gut Mucosal Immune System Using Nanomaterials.

The gastrointestinal (GI) tract is one the biggest mucosal surface in the body and one of the primary targets for the delivery of therapeutics, including immunotherapies. GI diseases, including, e.g., inflammatory bowel disease and intestinal infections such as cholera, pose a significant public health burden and are on the rise. Many of these diseases involve inflammatory processes that can be targeted by immune modulatory therapeutics. However, nonspecific targeting of inflammation systemically can lead to significant side effects. This can be avoided by locally targeting therapeutics to the GI tract and its mucosal immune system. In this review, we discuss nanomaterial-based strategies targeting the GI mucosal immune system, including gut-associated lymphoid tissues, tissue resident immune cells, as well as GI lymph nodes, to modulate GI inflammation and disease outcomes, as well as take advantage of some of the primary mechanisms of GI immunity such as oral tolerance.

Evaluation of Performance and Tunability of a Co-Flow Inertial Microfluidic Device.

Microfluidics has gained a lot of attention for biological sample separation and purification methods over recent years. From many active and passive microfluidic techniques, inertial microfluidics offers a simple and efficient method to demonstrate various biological applications. One prevalent limitation of this method is its lack of tunability for different applications once the microfluidic devices are fabricated. In this work, we develop and characterize a co-flow inertial microfluidic device that is tunable in multiple ways for adaptation to different application requirements. In particular, flow rate, flow rate ratio and output resistance ratio are systematically evaluated for flexibility of the cutoff size of the device and modification of the separation performance post-fabrication. Typically, a mixture of single size particles is used to determine cutoff sizes for the outlets, yet this fails to provide accurate prediction for efficiency and purity for a more complex biological sample. Thus, we use particles with continuous size distribution (2-32 µm) for separation demonstration under conditions of various flow rates, flow rate ratios and resistance ratios. We also use A549 cancer cell line with continuous size distribution (12-27 µm) as an added demonstration. Our results indicate inertial microfluidic devices possess the tunability that offers multiple ways to improve device performance for adaptation to different applications even after the devices are prototyped.

Isolation of circulating tumor cells in non-small-cell-lung-cancer patients using a multi-flow microfluidic channel.

Circulating tumor cells (CTCs) carry a wealth of information on primary and metastatic tumors critical for precise cancer detection, monitoring, and treatment. Numerous microfluidic platforms have been developed in the past few years to capture these rare cells in patient bloodstream for deciphering the critical information needed. However, the practical need for a high-quality method of CTC isolation remains to be met. Herein, we demonstrate a novel multi-flow microfluidic device that is able to sensitively provide high purity (>87%) of separation outcome without labeling. Our device is constructed and configured based on the phenomenal effect of size-dependent inertial migration. The recovery rate of >93% has been achieved using spiked cancer cells at clinically relevant concentrations (10 cells per 5 mL and above). We have also successfully detected CTCs from 6 out of 8 non-small-cell-lung-cancer (NSCLC) patients, while none for 5 healthy control subjects. With these results, we envision our approach is a promising alternative for reliable CTC capture, and thus for facilitating the progress of extracting information from CTCs to personalize treatment strategies for solid tumor patients.