Fetal lung development via quantitative biomarkers from diffusion MRI and histological validation in rhesus macaques

Objective: To demonstrate sensitivity of diffusion-weighted MRI (DW-MRI) to pulmonary cellular-space changes during normal in utero development using fetal rhesus macaques, compared to histological biomarkers. Study design: In vivo/ex vivo DW-MRI was acquired in 26 fetal rhesus lungs (early-canalicular through saccular stages). Apparent diffusion coefficients (ADC) from MRI and tissue area density (H&E), alveolar type-II cells (ABCA3), and epithelial cells (TTF1) from histology were compared between gestational stages. Results: In vivo/ex vivo ADC correlated with each other (Spearman ρ = 0.47, P = 0.038; Bland–Altman bias = 0.0835) and with area-density (in vivo ρ = -0.56, P = 0.011; ex vivo ρ = −0.83, P < 0.0001). In vivo/ex vivo ADC increased exponentially toward saturation with gestational stage (R² = 0.49/0.49), while area-density decreased exponentially (R² = 0.53). ABCA3 and TTF1 stains demonstrated expected fetal cellular development. Conclusions: Fetal DW-MRI provides a non-invasive biomarker for pulmonary structural maturation, with a strong correlation to histological markers during tissue development in rhesus macaques. This method has strong potential for assessing human fetal development, particularly in patients with pulmonary hypoplasia.