Engineered In VitroModels to Improve the Mechanistic Understanding and Treatment of Neglected Tropical Diseases Caused by Protozoan Parasites

Neglected tropical diseases (NTDs), particularly those caused by trypanosomatid protozoa, impose a significant global burden, disproportionately affecting underserved communities in tropical and subtropical regions. Despite their high mortality rates, associated chronic conditions, and rapid spread due to globalization and climate change, NTDs have historically received minimal research investment. Additionally, existing treatments cause severe adverse effects. While animal models have contributed significantly to our understanding of these diseases, they are limited by technical and financial constraints. Current in vitroapproaches predominantly focus on single-cell interactions on stiff substrates; thus, failing to capture tissue-level dynamics crucial for understanding host-parasite interactions. In this scoping literature review, we summarize emerging engineering applications to address these challenges by developing more complex in vitromodels. We discuss 36 publications that describe novel strategies employing biomaterials, organoids, spheroids, and microfluidic devices to improve the mechanistic understanding of these NTDs. We also describe how these preclinical models are being used as screening platforms in the drug discovery and repurposing pipeline. To better understand the global scope of this research, we also performed a meta-analysis of the geolocation of the authors whose work was included in this review. This analysis uncovers uneven global participation in these efforts to combat NTDs. Ultimately, we draw attention to the need for a multidisciplinary and transnational approach to mitigate the impact of trypanosomatid NTDs and reduce health inequities globally.