Our model will use a multi-omic approach to reflect inter-patient thyroid cell heterogeneity by mimicking the thyroid microenvironment with vasculature, human cell lines and immune components. Current commercially available technologies are mainly focused on murine models, either with patient derived xenografts, or murine cells. While these are efficient and accessible, murine cells and systems do not reflect the physiological factors that greatly affect responses to treatment. Our model will use human thyroid cells, even specific to the individual patient, and would provide a more ethical base for research, given the critiques of animal models. The technology would enable the user to study pathophysiology, causes for the disease and testing for new drugs and treatment plans in a more accurate environment compared to traditional murine models.

Design Considerations:
  • Geometry
    • Incorporates the unique architecture of the thyroid  into the model through both the lobe shape and the spherical seeding wells
      • Mimics the different vasculature of the lobes
      • Represents the topographical organization in the gland
      • Collagen + Alginate + Matrigel ECM (stromal unit) holds up the topological organization of cells
      • Enables interactions between stomal, vascular and follicular cells
  • Vasculature
    • Stimulates the thyrocytes using realistic vasculature
      • Inlet laminar flow through a microfluidic system sends pressurized flow of media with iodine and TSH through channels through each of the wells to stimulate hormone secretion
      • The outlet flow can be tested for validation criteria based on T3, T4 and TSH levels

Inducing Autoimmunity 
  • Could use patient tissue that is already afflicted with the autoimmune disease
  • Can apply biological perturbations to normal thyroid cells to induce autoimmunity
  • Possible mechanisms of thyroid hormone deficiency induction:
    • Interferon and other cytokines
    • Tyrosine kinase inhibitors
    • Drugs that block receptors for vascular endothelial growth factors
    • Anti-CTLA4 or anti-PD-1 antibody drugs
    • Inhibition of cAMP production
    • Propylthiouracil (PTU)
    • Antibodies

Top view of the in-vitro thyroid model showing the vasculature setup, as well as the layout for cell seeding

Side view of the in-vitro thyroid gland model to show the media inlet and wells for seeding thyrocytes

The use of microfluidics and tissue engineering to recreate the microenvironment of the human thyroid will also contribute to the relevancy of the data our model provides to thyroid research. Laminar blood flow through the vascular system of the model will provide shear forces to the system to mimic thyroid functionality, especially important for pharmaceutical testing. The thyroid on a chip will allow high throughput testing and drug screening, which enables the user to make rapid interventions, which are needed to strive for clinical precision medicine. This technology will be faster than using the traditional murine model for drug validation. The pathophysiology of thyroid dysfunctions, such as hypothyroidism or hyperthyroidism, can be induced to allow the user to test for a large and diverse market base. Levels of hormones T3 and T4 produced by the chip will give an indication of thyroid functionality, providing quantitative means to study thyroid dysfunction. The lack of pre-existing knowledge on thyroid dysfunction causes makes the need for a high-throughput and accurate human thyroid model justified. Our model is applicable to thyroid gland dysfunction research because it mimics the microenvironment of the gland, providing a more realistic and appropriate technology compared to traditional murine models. The incorporation of relevant human thyroid cells and appropriate vasculature will provide a realistic platform for treatment testing, as well as pathophysiology research.

Final Design Deliverables:
  • Reflects patient heterogeneity: different cells can be placed in each well
  • Incorporates the architecture of the thyroid
  • Mimics capillary system with vasculature & microfluidics
  • Uses biocompatible materials
  • Offers a more ethical and relevant approach compared to animal models
  • Presents well defined quantitative validation criteria