Developing a Biomimetic Lactating Mammary Lobe for Therapeutic Safety

PROJECT SUMMARY. Breast milk is rich with bioactive components that are critical to an infant's development. It is highly recommended that infants ingest breast milk; but, fluctuating maternal hormones and substandard post-parturition health directly mediate breast milk production. Maternal ingestion of small molecule drugs further compounds decreased breast milk synthesis and secretion, and adversely compromises breast milk quality. Although the majority of actively breastfeeding women consume medication or receive therapeutics, small drug molecule transport from maternal plasma to synthesized breast milk remains largely unknown. Important strides in understanding pharmacokinetics in milk-producing mammary glands have yet to occur because of the lack of engineered bioinspired mammary lobe systems that mimic complex in vivo signatures- topographical lobule microcurves, spiked levels of lactogenic hormones, cellular landscapes, and mechanically-driven lobe expansion and contraction. The objective of this proposal is to determine if our established microengineered mammary lobe system, which integrates key physiological characteristics, i.) faithfully mirrors multifactorial breast milk synthesis processes and ii.) could be employed as a versatile screening testbed for evaluating drug and therapeutic safety during lactation. The project is based on the central hypothesis that exogenous stimuli that reflect in vivo mechanisms, such as hormone levels, dynamic mechanical lobe stimulation, and passive transport of small drug molecules, will potentiate differential cellular landscape phenotypes and lead to unique content differences in engineered breast milk. This could develop a new in vitro preclinical model that promotes the cognizance of drugs or therapeutics that are safe to ingest or receive during lactation. We believe this contributes to improving important women's health issues. Our hypothesis will be tested through the following two aims. Aim 1 will develop a 3D mammary lobe model and determine how in vivo relevant parameters alter physical and molecular mammary cell phenotypes, and regulate the secretion of important breast milk components. Aim 2 will investigate the pharmacokinetics of small molecule drugs or therapeutics that passively diffuse into the engineered breast milk. Nicotine or mRNA encoding for SARS-CoV-2 will serve as a model drug or therapeutic, respectively. We will pursue these aims using an innovative combination of analytical and adaptable techniques from engineering and biological sciences. These include the development of a scalable lobe model, by which the application of physiologically relevant stimuli and compartments can mimic breast milk synthesis and drug distribution. The engineering approaches that we leverage will develop foundational resources for the ongoing efforts and research revolving lactation and post-parturition health equity. The expected outcome of this work will highlight the importance of engineering new microsystems for in vivo mimicry. These platforms can facilitate clinical translation of rapid drug and therapeutic safety screening. The results will have a significant positive impact to women and will encourage the ongoing efforts to support women during their breastfeeding journey.