Organ-on-a-chip platforms for studying drug delivery systems

Abstract

Novel microfluidic tools allow new ways to manufacture and test drug delivery systems. Organ-on-a-chip systems - microscale recapitulations of complex organ functions - promise to improve the drug development pipeline. This review highlights the importance of integrating microfluidic networks with 3D tissue engineered models to create organ-on-a-chip platforms, able to meet the demand of creating robust preclinical screening models. Specific examples are cited to demonstrate the use of these systems for studying the performance of drug delivery vectors and thereby reduce the discrepancies between their performance at preclinical and clinical trials. We also highlight the future directions that need to be pursued by the research community for these proof-of-concept studies to achieve the goal of accelerating clinical translation of drug delivery nanoparticles.

Keywords: Drug delivery; Drug screening; Nanoparticle; Organ-on-a-chip; Toxicity.

Fig. 1

The application of 3D scaffold-based multicellular tumor spheroids in drug testing. A–D) Confocal micrographs of live/dead staining showing (A) 2D culture and (C) 3D spheroid culture. B) 2D culture revealed significant cell death after CdTe NP exposure. D) Spheroids showed much lower cell damage (especially in the central area) than the cells in 2D culture. E, F) SEM images of (E) 2D culture and (F) 3D spheroid culture at 24 h post CdTe treatment. E) In 2D culture most cells were dead with a large amount of cells detached. F) Cells in spheroids experienced much lower cellular damage than those in 2D culture. Reproduced with permission from Ref. [39].

Fig. 2

The application of microfluidic bioreactors for drug testing. A) Schematic showing the tumor spheroid formation and culture in a microfluidic flow chamber. B) Optical micrograph showing that MCF-7 cells could uniformly fill all the traps. C) Optical micrographs showing the structure of the tumor spheroids: (left to right) phase contrast image and fluorescence images showing cell membrane and nuclei. Reproduced with permission from Ref. [53].

Fig. 3

The application of microfluidic system for studying nanoparticles and cells interactions. A) Fluorescence images showing binding of rhodamine-labeled nanoparticles, without or with PSMA aptamer, to PSMA-positive LNCaP cell and PSMA-negative PC3 cells under static conditions. The left column shows phase contrast images of the cells and corresponding fluorescence images of the nanoparticles are indicated in the right column. B) Fluorescence images showing binding of rhodamine-labeled nanoparticle-aptamer conjugates (red) to LNCaP cells under fluid flow conditions at flow rates of 0.25, 1, and 4 µL/min. The cells were stained with Calcein AM (green) and DAPI (blue) to quantify cell viability. C) Quantification of the number of nanoparticles bound to PC3 cells under static condition and to LNCaP cells under both static and fluid flow conditions. Reproduced with permission from Ref. [11].

Fig. 4

Microfluidic platforms provide insights on flow dynamics and shape influence for carrier attachment. A) Stenotic regions have higher shear rate (top) and accumulate more nanoparticles (NP; bottom). B) Influence of particle shape (top) on attachment and accumulation in a 45° bifurcation, showing that discshaped particles attach more than spherical particles (bottom). Reproduced with permission from Ref. [63] & [66].

Fig. 5

The multi-chamber µCCA device. A) A PDMS µCCA device consisting of three chambers, which represented uterus, liver, and mammary tissues, respectively. B) Measurement of cell viability after treatment with 0.02% Triton. Triton treatment led to full mortality for all cell types. Reproduced with permission from Ref. [101].

Fig. 6

A) Schematic of the lung-on-a-chip platform developed to study nanoparticle transport. The transport of nanoparticles across the alveolar-capillary interface is augmented significantly when vacuum is applied to the side channels of the lung platform. Adapted from Ref. [13]. B) Schematic of the Kidney-on-chip platform with two chambers divided by a porous membrane that separates the ‘luminal’ from the ‘tubular’ space recreating the in vivo conditions in the kidney. Adapted from Ref. [118]. C) The gut-on-a-chip platform includes two compartments divided by a porous membrane separating Caco-2 cells from the bottom chamber. A vacuum regulator is attached to the side chambers to assess the behavior of the cells under the effect of strain. Adapted from Ref. [55].

Fig. 7

Studying the nanoparticle (NP) tissue transport behavior using tumor-on-chip platform. A) The schematic of the microfluidic chip assembled on top of a microscope stage. B) The schematic (left), image (center) and graph (right) showing the effect of NP size on tissue accumulation. Four different sizes, 40 (red), 70 (blue), 110 (green) and 150 (orange) of PEGylated NPs were investigated. C–D) The effect of NP functionalization on tissue accumulation: C) PEGylated NPs and D) iron-transporting transferring (Tf) protein functionalized NP. Reproduced with permission from Ref. [128].