The drug development pipeline is severely limited by a lack of reliable tools for prediction of human clinical safety and efficacy profiles for compounds at the pre-clinical stage. Here we present the design and implementation of a platform technology comprising multiple human cell-based tissue models in a portable and reconfigurable format that supports individual organ function and crosstalk for periods of up to several weeks. Organ perfusion and crosstalk are enabled by a precision flow control technology based on electromagnetic actuators embedded in an arrayed format on a microfluidic platform. We demonstrate two parallel circuits of connected airway and liver modules on a platform containing 62 electromagnetic microactuators, with precise and controlled flow rates as well as functional biological metrics over a two week time course. Technical advancements enabled by this platform include the use of non-sorptive construction materials, enhanced scalability, portability, flow control, and usability relative to conventional flow control modes (such as capillary action, pressure heads, or pneumatic air lines), and a reconfigurable and modular organ model format with common fluidic port architecture. We demonstrate stable biological function for multiple pairs of airway-liver models for periods of 2 weeks in the platform, with precise control over fluid levels, temperature, flow rate and oxygenation in order to support relevant use cases involving drug toxicity, efficacy testing, and organ-organ interaction.

Respiratory viruses invade the upper airway of the lung, triggering a potent immune response that often exacerbates preexisting conditions such as asthma and COPD. Poly(I:C) is a synthetic analog of viral dsRNA that induces the characteristic inflammatory response associated with viral infection, such as loss of epithelial integrity, and increased production of mucus and inflammatory cytokines. Here, we explore the mechanistic responses to poly(I:C) in a well-defined primary normal human bronchial epithelial (NHBE) model that recapitulates in vivo functions and responses. We developed functional and quantifiable methods to evaluate the physiology of our model in both healthy and inflamed states. Through gene and protein expression, we validated the differentiation state and population of essential cell subtypes (i.e., ciliated, goblet, club, and basal cells) as compared to the human lung. Assays for total mucus production, cytokine secretion, and barrier function were used to evaluate in vitro physiology and response to viral insult. Cells were treated apically with poly(I:C) and evaluated 48 h after induction. Results revealed a dose-dependent increase in goblet cell differentiation, as well as, an increase in mucus production relative to controls. There was also a dose-dependent increase in secretion of IL-6, IL-8, TNF-α, and RANTES. Epithelial barrier function, as measured by TEER, was maintained at 1501 ± 355 Ω*cm² postdifferentiation, but dropped significantly when challenged with poly(I:C). This study provides first steps toward a well-characterized model with defined functional methods for understanding dsRNA stimulated inflammatory responses in a physiologically relevant manner.

Acoustic manipulation of particles and cells has been widely used for trapping and separation in microfluidic devices. Previously, the resonant components of these devices have been fabricated from silicon, glass, metals, or other materials having high acoustic impedance. Here, we present experimental results showing continuous acoustic focusing and separation of blood cells in a microchannel fabricated entirely from polystyrene. The efficiency and flow rates approach those reported in silicon and glass systems. We find that the optimum operating frequencies differ from those predicted by conventional approximations which have been developed for more rigid materials. Additionally, we introduce a method for fabrication of the devices, using an adaptation of thermofusion bonding that preserves critical channel dimensions. To control channel cross section during bonding, we introduced a collapsible fiberboard material in the bonding press. This structure provided a self-limiting force and mitigated deformation of the polystyrene. Together, these advances may enable new applications for acoustic focusing and separation in medical devices.

The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-b hydroxysteroid dehydrogenase 2 (11bHSD2) over 11bHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior.

The current drug clinical development is suffering a high attrition rate. More robust preclinical tools are needed to identify unpredicted toxicity and efficacy problems in the early stage of the drug development. Microphysiological Systems (MPS) program aims to develop in vitro interactome system to mimic physiological responses of drugs and provide more reliable preclinical results that is predictive of clinical outcomes. Systems pharmacology approach was used to analyze experimental data and guide integrated MPS platform development. Experimental results from MPSs were analyzed to obtain mechanism‐based information that could not be easily interpreted without systems pharmacology models. A series of data‐driven computational models for 1‐, 2‐, and 4‐MPSs was also developed to study platform operations under physiological conditions. Moreover, our systems pharmacology framework also assisted researchers to develop integrated MPS platform in physiological manner. Overall, systems pharmacology has been accepted as a very useful approach for quantitatively analyzing experimental results, experimental design and accelerating physiological Microphysiological Systems platform development.