What's In Each Chip?
Our custom analytic services provide access to cutting-edge systems developed for your specific needs. We can create systemic toxicology models with several interlinked organs, including: heart, liver, lung, brain, skin, muscle, GI tract, kidney, pancreas, endocrine, bone marrow and the neuromuscular junction. Our models use a serum-free cell medium and a carefully designed gravity flow system to eliminate the need for pumps. We can work with you to custom design your platform with almost any number of cell types in our patented human-on-a-chip system.
Heart-Liver Two-Organ Model
Our two-organ heart-liver model is well-suited for investigations into the efficacy and safety of novel chemicals and biologics as well as their metabolites. The system combines sophisticated, noninvasive functional readouts of cardiomyocyte syncytium contractile force generation, beat frequency, and field potential duration (QT interval surrogate) [1]. In its current configuration, this model strives to replace the FDA-ICH approved whole-heart perfusion animal models in drug discovery and development. Additionally, our cardiomyocyte models adhere to the Comprehensive in vitro Proarrhythmia Assay (CiPA) Initiative guidelines concerning torsadogenic potential (TdP) risk. This two-organ model has been characterized for acute cardiotoxicity and hepatotoxicity using noninvasive and endpoint functional and biomarker readouts [2]. This model has been routinely operated for 28 days, and therefore, is well-suited for acute and chronic dosing studies for drug efficacy and safety [3].
Neuromuscular Junction (NMJ) Two-Organ Model
Our human-on-a-chip, two-organ NMJ model is well-suited for investigations into the physiology of NMJ formation, stability and synchronous activity between motoneuron (MN) neurotransmitter release and skeletal muscle (myotubes) contraction. Our microtunnel barrier system (MBS) separates the medium compartments of the MNs and myotubes while facilitating axonal outgrowth and innervation. This unique design allows for drugs to be tested on one or both sides to determine site of action. We have extensively characterized this model’s response to common NMJ disrupting toxins, even reproducing the biphasic dose response of tubocurarine toxin [4]. Additionally, our healthy patient iPSC-derived MNs can easily be substituted for disease patient iPSCs carrying genetic mutations for common NMJ diseases such as amyotrophic lateral sclerosis (ALS).
Heart-Liver-Skeletal Muscle-Neuron Four Organ Model
Our four-organ model has been extensively characterized for baseline physiology using MEA and cantilever-based functional readouts along side standard biomarker readouts. In this model, we noninvasively monitor cardiomyocyte syncytium contractile force generation, beat frequency, and field potential duration (QT interval surrogate). We also noninvasively monitor skeletal muscle force generation and neuron spontaneous action potential generation. Endpoint assays for liver physiology include albumin and urea production. We also monitor industry standard metrics including cell viability and a range of biomarker readouts based on customer experimental design. This model has been routinely operated for 28 days, and therefore, is well-suited for acute and chronic dosing studies for drug efficacy and safety [3, 5].
Heart-Liver-Cancer Three Organ Model
Our human cancer cell modules are well-suited for investigations into novel chemotherapeutic efficacy and, when integrated with a multi-organ system, safety for therapeutic index determination. We have characterized a heart-liver-cancer three-organ HoaC model and shown drug efficacy, safety and metabolite formation for monotherapy and combinatorial therapy approaches using multi-drug resistant (MDR) and non-MDR cancer cells.
Barrier Tissue Modules
Hesperos offers barrier tissue models easily integrable with our standard housing designs. Adding these modules to the HoaC systems enables determination of transport characteristics of novel compounds as well as their responses as toxicity targets. Additional information regarding drug safety for barrier tissues and first-pass metabolism in GI tract can also be determined. In the context of disease models, barrier tissues composed of mutant iPSC-derived cells can be incorporated to investigate the role these diseased tissues play in disease pathology and etiology in a controlled, human-based model.
Blood-brain barrier (BBB model)
Our BBB model, composed of iPSC-derived cells, has been extensively characterized for tight junction-mediated barrier formation and paracellular (passive) and transcellular (active) transport mechanisms [6]. This module is well-suited for investigating the transport rates, transport mechanisms and barrier effects of novel chemicals and biologics.
Gastrointestinal tract (GI tract model)
Using either iPSC-derived enterocytes, or immortalized patient biopsy intestinal epithelial cells (hiECs), the absorption and first-pass metabolism characteristics of a novel compound can be determined. Our hiEC model has been characterized for CYP activity and barrier formation [7]
Kidney renal proximal tubule (RPT model)
Using primary renal proximal tubule cells, the tubular reabsorption or secretion profile of a novel compound can be determined for excretion purposes. Additional data regarding the kidney safety profile of a drug can be collected in the form of barrier integrity changes (noninvasive TEER measurements) and release of the biomarker kidney injury marker-1 (KIM-1).
Skin
Using Strat-M® membranes, a synthetic human skin module, integrated into our multi-organ systems, we can determine the transdermal diffusion of novel compounds applied topically and monitor the effects of the absorbed drugs on organ physiology in the system. We have characterized a heart-liver-skin HoaC model for the effects of topically-applied drugs including hydrocortisone, ketoconazole and diclofenac.
Monocytes / Macrophages
Monocytes can be added to the recirculating medium in our multi-organ systems. These cells (THP-1 monocytes) have been characterized in systems for expression of the lineage markers CCR5, CD14 and CD16 as well as markers of activation including CD11b, CD69 and CD86 following exposure to lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). Additionally, following exposure to LPS and IFN-γ the monocytes have been shown to differentiation into macrophages and adhere to damaged tissue modules. Differential cytokine release profiles have also been characterized in the context inactivated, tissue damage-activated and cytokine storm activated conditions.
Pharmacokinetic / pharmacodynamic modeling (CFD modeling)
Our recirculating medium allows for complex pharmacokinetic profiles of compounds and metabolic products through absorption, distribution, metabolism, and elimination (ADME) depending on the organ systems incorporated. We have extensive experience coupling HPLC-MS data with modeling of these systems through computational fluid dynamics (CFD) and other numerical methods to produce pharmacokinetic profiles both in different medium compartments and accumulated in the cells. Coupled with our functional measurements, we have the capabilities to generate Pharmacokinetic-Pharmacodynamic (PK-PD) relationships [2].
High-performance liquid chromatography - mass spectroscopy (HPLC-MS)
Using our Agilent Technologies HPLC-MS, we can quantify the concentration of drug in systems at any point during an experiment. Additionally, in any liver-containing HoaC system, we can determine concurrent depletion of parent compound and metabolite generation.
- Stancescu, M., et al., A phenotypic in vitro model for the main determinants of human whole heart function. Biomaterials, 2015. 60: p. 20-30.
- Oleaga, C., et al., Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system. Biomaterials, 2018. 182: p. 176-190.
- Oleaga, C., et al., Human-on-a-Chip Systems: Long-Term Electrical and Mechanical Function Monitoring of a Human-on-a-Chip System (Adv. Funct. Mater. 8/2019). Advanced Functional Materials, 2019. 29(8): p. 1970049.
- Santhanam, N., et al., Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics. Biomaterials, 2018. 166: p. 64-78.
- Oleaga, C., et al., Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Scientific Reports, 2016. 6: p. 20030.
- Wang, Y.I., H.E. Abaci, and M.L. Shuler, Microfluidic blood–brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnology and Bioengineering, 2017. 114(1): p. 184-194.
- Chen, H.J., P. Miller, and M.L. Shuler, A pumpless body-on-a-chip model using a primary culture of human intestinal cells and a 3D culture of liver cells. Lab on a Chip, 2018. 18(14): p. 2036-2046.