Tissue-informed engineering strategies for modeling human pulmonary diseases

Abstract

Chronic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH), and chronic obstructive pulmonary disease (COPD), account for staggering morbidity and mortality worldwide but have limited clinical management options available. Although great progress has been made to elucidate the cellular and molecular pathways underlying these diseases, there remains a significant disparity between basic research endeavors and clinical outcomes. This discrepancy is due in part to the failure of many current disease models to recapitulate the dynamic changes that occur during pathogenesis in vivo. As a result, pulmonary medicine has recently experienced a rapid expansion in the application of engineering principles to characterize changes in human tissues in vivo and model the resulting pathogenic alterations in vitro. We envision that engineering strategies using precision biomaterials and advanced biomanufacturing will revolutionize current approaches to disease modeling and accelerate the development and validation of personalized therapies. This review highlights how advances in lung tissue characterization reveal dynamic changes in the structure, mechanics, and composition of the extracellular matrix in chronic pulmonary diseases and how this information paves the way for tissue-informed engineering of more organotypic models of human pathology. Current translational challenges are discussed as well as opportunities to overcome these barriers with precision biomaterial design and advanced biomanufacturing techniques that embody the principles of personalized medicine to facilitate the rapid development of novel therapeutics for this devastating group of chronic diseases.

Keywords: biomanufacturing; biomaterials; chronic obstructive pulmonary disease; in vitro; precision disease modeling; pulmonary engineering; pulmonary fibrosis; pulmonary hypertension; regenerative medicine; tissue-informed engineering.

Fig. 1.

Integrated framework for guiding the development and implementation of tissue-informed engineering strategies for modeling human pulmonary disease. 1) Biomaterial design parameters and requirements are elucidated via advanced characterization techniques. 2) These inputs inform and guide the engineering process, resulting in patient- and disease- specific in vitro models. 3) The resulting models can be incorporated into preclinical evaluations to provide greater predictive power for potential therapeutic success in humans. 4) Successful translation of outcomes to innovative patient care builds the foundation for precision medicine. The power of this model lies in its potential for iterative evaluation and continuous improvement.

Fig. 2.

Microenvironmental changes observed in chronic pulmonary diseases: idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH), and chronic obstructive pulmonary disease (COPD). Highlighted here are distinct structural, mechanical, and compositional signatures revealed by advanced tissue characterization. A comprehensive understanding of pathological extracellular matrix properties is critical to informing the design of engineered in vitro models of pulmonary disease.

Fig. 3.

Depiction of the spatial resolution capabilities of selected biomanufacturing techniques with representative product images. A: fluorescently labeled polyethylene glycol (PEG)-based hydrogels patterned using two-photon lithography (reproduced in part from Ref (86), with permission of John Wiley & Sons). B: scanning electron microscopy image of electrospun PEG thiol-ene fibers. C: fluorescently-labeled PEG thiol-ene hydrogel microsphere synthesized via inverse emulsion polymerization. 3D bioprinted, fluorescent PEG thiol-ene hydrogel (D), decellularized mouse lung (E), and an immunofluorescently stained image of collagen IV (F) visualizing microstructure of decellularized lung tissue (E and F, courtesy of the Wagner Laboratory).

Fig. 4.

Application of the integrated framework for engineering more organotypic models of idiopathic pulmonary fibrosis (IPF) in vitro. 1) advanced characterization reveals localized regions of fibrotic activity, distinguished by increased extracellular matrix (ECM) deposition and matrix stiffness. 2) dynamic multiresponsive biomaterial systems impart photo-controlled spatiotemporal stiffening and release of soluble factors to emulate disease progression. 3 and 4) Preclinical verification and clinical validation expedite the translation and commercialization of precision therapeutic interventions for IPF.