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CA-3039980-C - MULTI-ORGAN "BODY ON A CHIP" APPARATUS UTILIZING A COMMON MEDIA

CA3039980CCA 3039980 CCA3039980 CCA 3039980CCA-3039980-C

Abstract

Described herein are apparatus, including multi-tissue body-on-a-chip apparatus. In some embodiments, described are apparatus including at least a first, second, and third chamber in fluid communication with one another and with at least one tissue in each chamber, such as, for example, liver tissue in said first chamber; cardiac muscle tissue in said second chamber; and lung tissue in said third chamber; and a common aqueous growth media in said first, second, and third chamber. In some embodiments, the apparatus includes a fourth chamber including testicular or ovarian tissue in said fourth chamber. In some embodiments, the apparatus includes an optional fifth or sixth chamber; each said chamber includes different additional tissue selected from the group consisting of vascular endothelial, skeletal muscle, kidney, nerve, brain, and intestinal tissue (e.g., small intestine tissue and/or colon tissue). Also described are methods of using an apparatus of the present invention.

Inventors

  • Aleksander Skardal
  • Thomas Shupe
  • Anthony Atala

Assignees

  • WAKE FOREST UNIVERSITY HEALTH SCIENCES

Dates

Publication Date
20260505
Application Date
20171010
Priority Date
20161014

Claims (20)

  1. THAT wmcH IS CLAIMED IS: 1. A multi-tissue body-on-a-chip apparatus, comprising: a first chamber comprising a first organoid; a second chamber comprising a second organoid; a primary fluid conduit that connects said first and second chambers; and a common aqueous growth media in said first chamber, said second chamber, and said primary fluid conduit; wherein said first and second chambers are connected in series and are in fluid communication with one another via said primary fluid conduit; wherein, in operation, the media flows through said first chamber, said second chamber, and said primary fluid conduit by recirculating perfusion; wherein said first and second organoids are different from each other, wherein the volume of the apparatus is less than 100 μL, wherein each of said first chamber and said second chamber has a volume in a range of 2 μL to 10 μL, and wherein the apparatus provides a hyperphysiological fluid to tissue volume ratio.
  2. 2. The apparatus of claim 1, wherein said first organoid is a liver organoid and said second organoid is a cardiac organoid, and wherein the apparatus further comprises a third chamber comprising a third organoid, wherein said third organoid is a lung organoid.
  3. 3. The apparatus of claim 2, further comprising; a fourth chamber comprising a fourth organoid and in fluid communication with said first, second, and third chamber; wherein said fourth organoid is a testicular or ovarian organoid; and said common aqueous growth media in said first, second, third and fourth chambers.
  4. 4. The apparatus of claim 3, further comprising: a fifth chamber, and optionally a sixth chamber, all in fluid communication with one another and with said first, second and third chambers, and said fourth chamber, when present, and with said common aqueous growth media in each thereof; 66 Date Re1rue/Date Received 2023-12-18 each of said fifth and sixth chambers, when present, containing a different additional organoid from one another, each said different additional organoid selected from the group consisting of vascular endothelial organoid, skeletal muscle organoid, kidney organoid, nerve organoid, brain organoid, and intestinal organoid.
  5. 5. The apparatus of any one of claims 1 to 4, wherein at least one of said organoids comprises metastatic and/or malignant cells.
  6. 6. The apparatus of any one of claims 1 to 5, further comprising a pump operatively associated with all of said chambers, and configured for circulating said common aqueous growth media through all of said chambers.
  7. 7. The apparatus of any one of claims 1-6, further comprising an oxygenating chamber operatively associated with and in fluid communication with all of said chambers.
  8. 8. The apparatus of any one of claims 1-7, further comprising a fluid valve positioned between at least one, at least two, some, or all of said chambers, and configured to isolate one or a combination of said tissues from one another.
  9. 9. The apparatus of any one of claims 1-8, wherein said common aqueous growth media comprises at least a testicular cell media.
  10. 10. The apparatus of any one of claims 1-9, wherein said common aqueous growth media comprises glutamine, optionally in a concentration in a range of about 0.1 mM to about 5 mM.
  11. 11. The apparatus of any one of claims 1-10, wherein said common aqueous growth media comprises glucose, optionally in a concentration in a range of about 5 mM to about 60 mM.
  12. 12. The apparatus of any one of claims 1-11, wherein said common aqueous growth media comprises epithelial growth factor, optionally in a concentration in a range of about 0.1 ng/mL to about 20 ng/mL. 67 Date Re1rue/Date Received 2023-12-18
  13. 13. The apparatus of any one of claims 1-12, wherein said common aqueous growth media comprises hydrocortisone, optionally in a concentration in a range of about 0.1 μg/mL to about 2 μg/mL.
  14. 14. The apparatus of any one of claims 1-13, wherein said common aqueous growth media comprises ascorbic acid, optionally in a concentration in a range of about 0.1 μg/mL to about 50 μg/mL.
  15. 15. The apparatus of any one of claims 1-14, wherein said common aqueous growth media comprises vascular endothelial growth factor, optionally in a concentration in a range of about 0.1 ng/mL to about 10 ng/mL.
  16. 16. The apparatus of any one of claims 1-15, wherein said common aqueous growth media comprises fibroblast growth factor beta, optionally in a concentration in a range of about 0.1 to about 10 ng/mL.
  17. 17. The apparatus of any one of claims 1-16, wherein said common aqueous growth media comprises Insulin-like growth factor 1, optionally in a concentration in a range of about 0.1 ng/mL to about 15 ng/mL.
  18. 18. The apparatus of any one of claims 1-17, wherein said common aqueous growth media comprises heparin, optionally in a concentration in a range of about 0.1 units/mL to about 5 units/mL.
  19. 19. The apparatus of any one of claims 1-18, wherein said common aqueous growth media comprises an antibacterial or antimicrobial agent, optionally in a concentration in a range of about 0.1 % to about 1 % by volume.
  20. 20. The apparatus of any one of claims 1-19, wherein said common aqueous growth media comprises serum, optionally in a concentration in a range of about 0.1 % to about 10% by volume. 68 Date Re1rue/Date Received 2023-12-18

Description

[0001] [0002] MULTI-ORGAN "BODY ON A CIDP" APPARATUS UTILIZING A COMMON MEDIA Related Applications (This paragraph has been left intentionally blank) Government Support This invention was made with government support under Contract No. N66001-13-C-2027 awarded by the Defense Threat Reduction Agency (DTRA) under Space and Naval Warfare Systems Center Pacific (SSC PACIFIC), Grant No. W81XWH-13-2-0052 awarded by the Armed Forces Institute for Regenerative Medicine, and Grant No. NIH T32EB014836, awarded by the National Cancer Institute. The U.S. Government has certain rights in the invention. Field of the Invention [0003] The present invention generally relates to apparatus, including multi-tissue body-on-a-chip apparatus, along with methods of using the same. Background of the Invention [0004] The total cost for drug screening and the development process for effective and safe therapeutic agents can exceed 2 billion USO. This includes costs dedicated to target identification, drug screening, regulatory studies, and therapeutic agent manufacturing for clinical trials. Despite extensive preclinical testing and high costs, 90% of drugs that enter Phase I clinical trials fail 1 . There is a critical need for improved model systems that can effectively test the effects of drugs, chemicals, and biological agents on the human body 2,3. [0005] Traditional in vitro 2D cultures, currently the norm for early drug compound screening, fail to recapitulate the 3D microenvironment of in vivo tissues 4 , . Standard tissue cultures have three major differences from native tissue microenvironments: substrate topography, substrate stiffness, and most importantly, a 2D rather than 3D architecture. As a consequence, 2D culture places a selective pressure on cells, substantially altering their 1 Date Re1rue/Date Received 2023-12-18 WO 2018/071354 PCT/0S2017/055823 original phenotypic properties. Drug diffusion kinetics are also not accurately modeled in 2D tissue culture, and drug doses effective in 2D are often ineffective when scaled to patients4 • 6 • 7 . Animal models serve as the gold standard for biological testing, but have several drawbacks, including uncertainties in interpretation of the results. The main weakness of animal models is that responses to external stimuli in animals are not necessarily predictive of those in humans8 . Due to interspecies differences in metabolism and immunology, animal models are often poor predictors of human efficacy and toxicology, contributing to drug attrition rates. [0006] Advancements in cell aggregate culture systems, and microengineering/microfluidics technologies have contributed to the evolution of 3D human tissue-on-a chip models9 . Currently, many organs-on-chip systems exist10 • 11 , as well as several on-chip disease models10 . Despite advances to date, organs-on-chip models still lack many of the elements of normal human tissue. Summary of the Invention [0007] One aspect of the present invention is directed to a multi-tissue body-on-achip apparatus. In some embodiments, the apparatus comprises: at least a first, second, and third chamber in fluid communication with one another; liver tissue in said first chamber; cardiac muscle tissue in said second chamber; lung tissue in said third chamber; and a common aqueous growth media in said first, second, and third chamber. In some embodiments, the apparatus comprises: at least a first, second, third, fourth, fifth, and sixth chamber in fluid communication with one another; liver tissue in said first chamber, heart tissue in said second chamber, lung tissue in said third chamber, brain tissue in said fourth chamber, colon tissue in said fifth chamber, and testis or ovary tissue in said sixth chamber; and a common aqueous growth media in said first, second, third, fourth, fifth and sixth chambers. [0008] A further aspect of the present invention is directed to methods of using an apparatus of the present invention. In some embodiments, the methods comprise: (a) providing an apparatus of the present invention; and (b) circulating a common aqueous growth media through all of the chambers of the apparatus for a time of at least 1, 4, 8, or 11 days. In some embodiments, the methods include adding a test compound to the common aqueous growth media; and then detecting a pharmacological or toxicological response to the test compound in at least one, or a plurality of tissues present in the apparatus. [0009] Another aspect of the present invention is directed methods of in vitro drug 2 WO 2018/071354 PCT/0S2017/055823 screening, toxicology screening, and/or disease modeling comprising providing an apparatus of the present invention; and detecting a pharmacological or toxicological response in at least one, or a plurality of tissues present in the apparatus. [00010] It is noted that aspects of the invention described with respect to one embodiment, may be incorporated in a different embodiment although not specifically described relative ther