( A, i and ii) Schematics and bright-field optical images showing the fabrication process of the alveoli-like 3D GelMA inverse opal structure. Fabrication of the alveoli-like 3D GelMA inverse opal structure and formation of the alveolar lung model. Results and Discussion Fabrication of the Alveoli-Like 3D Porous Structure and Formation of the Alveolar Epithelium.įig. Our study provides a unique method for reconstitution of functional alveolar lung-on-a-chip in vitro, potentially paving the way for investigating a range of pathophysiology of the human distal lung, such as infectious diseases affecting the alveolar space including COVID-19. The alveolar lung model was further subjected to cyclic inhalation/exhalation movements, as well as used to investigate the effects of cigarette smoke and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudoviral infection. Primary human alveolar epithelial cells (hAECs) were populated on the surfaces of the sacs to form the monolayer epithelium. Due to its 3D nature, it is possible to construct ∼7,050 alveoli within an 8 × 10 × 3-mm 3 model to allow faithful physiological emulation. Importantly, the GelMA inverse opal structure has a high similarity to the native human alveolar sacs in that they possess both the sac-like pores and the interconnecting windows between the sacs, in addition to a stiffness close to the native human lung. micrometers), and the material used was still incompatible to native tissue in terms of bioactivity. A recent work attempted to develop such a model with bioprinting ( 19) however, this model merely reflected alveoli’s gross anatomy, albeit in much larger scales than the actual features of the human alveoli (millimeters vs. More importantly, there are no satisfactory models of the distal lung (i.e., the alveolar space) that truly reflect the sac shape anatomy ( 16– 18) to study physiology and pathophysiology. Therefore, there is a clear need for an advanced model system that not only mimics the human lung tissue structurally but also, captures its ECM physiology that is essential to their functional reproduction in vitro. As such, ECM features are too critical to be ignored in the design and fabrication of any biologically relevant tissue and disease models. In fact, there is increasing acceptance that the composition and topography of the extracellular matrix (ECM) have major influences on cell functions ( 15) and regulate cellular responses to various stimuli. While each of these more complex models ( 10– 14) may have advantages over 2D single-cell cultures, collectively they suffer from important limitations such as use of synthetic polymer membranes with nonphysiological stiffness to culture cells and/or lack of mechanical stimulation (inhalation/exhalation process). These models range from simple two-dimensional (2D) cultures of lung cells on polymeric or elastomeric membrane systems to the complex biomimetic lung-on-a-chip microdevices ( 10). In addition, many of the existing cell culture-based models do not replicate the key biological aspects of the human lung and do not adequately reflect the host responses. This has resulted in a lack of progress in drug development in respiratory medicine, with only a handful of new drugs entering clinical use in the last 50 y ( 9). The lack of reliable and physiologically relevant animal models for human respiratory diseases has led to a critical issue for new drug development as more than 90% of the preclinical studies performed in animals do not predict the outcome of human clinical trials ( 8). Our study demonstrates a unique method for reconstitution of the functional human pulmonary alveoli in vitro, which is anticipated to pave the way for investigating relevant physiological and pathological events in the human distal lung. Cyclic strain is integrated into the device to allow biomimetic breathing events of the alveolar lung, which, in addition, makes it possible to investigate pathological effects such as those incurred by cigarette smoking and severe acute respiratory syndrome coronavirus 2 pseudoviral infection. By populating the sacs with primary human alveolar epithelial cells, functional epithelial monolayers are readily formed. The inverse opal hydrogel structure features well-defined, interconnected pores with high similarity to human alveolar sacs. This alveolar lung-on-a-chip platform is composed of a three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure, bonded to a compartmentalized polydimethylsiloxane chip. Here, we present a physiologically relevant model of the human pulmonary alveoli.
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