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Methods for Clinical Testing
Animal Testing
Introduction


Drug Testing in animal models is time consuming, costly and often does not predict the adverse effects in
...
Failure to predict human drug
toxicity


50% of Drug Candidates are failed in clinical trails due to the toxicity.
Post m...


Miniature human organs made by 3D printing could create a "body on a chip" that enables better
drug testing. That futur...
3D Cell Culture


It is defined as the culture of living cells within the microfabricated devices having 3D
structures th...
 An Organ-on-a-Chip (OC) is a multi-channel 3-D microfluidic cell culture chip that simulates the
activities, mechanics a...
Microfluidics: The use of microfabrication techniques from the
IC industry to fabricate channels, chambers, reactors, and
...





Sample savings – nL of enzyme, not mL
Faster analyses – can heat, cool small volumes
quickly
Integration – combin...
• Three PDMS layers are aligned and irreversibly
bonded to form two sets of three parallel
microchannels separated by a 10...
Cating
PDMS
Membrane

Etching the
membrane
with TBAF
& NMP

Apply
Hydrostatic
Pressure
&Vacume

Bound
irreversibly
with th...
Biologically inspired design of a human breathing lung-on-a-chip microdevice.

•

The microfabricated lung mimic device us...
.

IL-2 therapy is associated with vascular leakage that causes excessive fluid accumulation
(edema) and fibrin deposition...
 Endothelial exposure to IL-2 (1000 U/ml) causes liquid in the lower microvascular channel to leak
into the alveolar cham...
Different Organs on a Chip
Organ

Rationale

Cell Lines

Characteristics

Liver
Marrow
(Hematopoietic)

p450 activity
sensitive to chemo
dose limitin...
Application to Study Multidrug Resistance Suppressors
Other Tissues/ Debubbler

Device on peristaltic pump
in incubator

S...
Thank You
Organs on a chip
Organs on a chip
Organs on a chip
Organs on a chip
Organs on a chip
Organs on a chip
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Organs on a chip
Organs on a chip
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Organs on a chip
Organs on a chip
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Organs on a chip
Organs on a chip
Organs on a chip
Organs on a chip
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Organs on a chip

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Organs on a chip

  1. 1.         
  2. 2. Methods for Clinical Testing
  3. 3. Animal Testing
  4. 4. Introduction  Drug Testing in animal models is time consuming, costly and often does not predict the adverse effects in humans and also 60% of animal models are not able to predict the toxicity .(Hamelton et al 2011)  3D Culture models have recently garnered great attention .  They promote levels of cell differentiation not possible in conventional 2D Culture systems.  3D Culture systems is a large microfabrication technologies from the microchip industry and microfluidics.  It approaches to create cell culture microenvironments  This technology supports both tissue differentiation and recapitulate the tissue-tissue interfaces, spatiotemporal micro gradients and mechanical microenvironments of living organs.  This organs on chips permit the study of human physiology in an organ specific context, enable novel in vitro disease models, and could potentially serve as replacements of animals used in drug development and toxin testing
  5. 5. Failure to predict human drug toxicity  50% of Drug Candidates are failed in clinical trails due to the toxicity. Post marketing with draw or limited use of drugs to adverse drug effects  Drug metabolism as a key determinant of species-species differences in drug toxicology.  The development of safe and effective drugs is currently hampered by the poor predictive power of existing preclinical animals that often lead to failure of drug compounds and late development after they enter in to the human clinical trials. Huh et al 2011
  6. 6.  Miniature human organs made by 3D printing could create a "body on a chip" that enables better drug testing. That futuristic idea has become a new bioprinting project.  The 2-inch "body on a chip" would represent a realistic testing ground for understanding how the human body might react to dangerous diseases, chemical warfare agents and new drugs intended to defend against biological or chemical attacks.  Such technology could speed up drug development by replacing less-ideal animal testing or the simpler testing done on human cells in petri dishes — and perhaps save millions or even billions of dollars from being wasted on dead-end drug candidates that fail in human clinical trials.  Microscale engineering technologies are combined with cultured living human cells to create microfluidic devices that replicate the physiological and mechanical microenvironment of whole living organs.
  7. 7. 3D Cell Culture  It is defined as the culture of living cells within the microfabricated devices having 3D structures that mimic tissue and organ specific microarchitechture.  Cell cultures in 3D matrix gels are referred to as 3D ECM gel cultures, 3D gel cultures or conventional 3D cultures.  Microengineering techniques such as Photolithography, replica modeling and microcontact printing are well suited to create structures with defined shapes and positions on the micrometer scale .  That can be used to position cells and tissues control cell shape and function, and create highly structured 3D culture microenvironments.
  8. 8.  An Organ-on-a-Chip (OC) is a multi-channel 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems.  It constitutes the subject matter of significant biomedical engineering research, more precisely in bioMEMS.  The convergence of Lab-on-Chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context, introducing a novel model of in vitro multicellular human organisms.  One day, they will perhaps abolish the need for animals in drug development and toxin testing.  Nevertheless, building valid artificial organs requires not only a precise cellular manipulation, but a detailed understanding of the human body’s fundamental intricate response to any event.  A common concern with Organs-on-Chips lies in the isolation of organs during testing. “If you don’t use as close to the total physiological system that you can, you’re likely to run into troubles” says William Haseltine, founder of Rockville, MD. Microfabrication, microelectronics and microfluidics offer the prospect of modeling sophisticated in vitro physiological responses under accurately simulated conditions.
  9. 9. Microfluidics: The use of microfabrication techniques from the IC industry to fabricate channels, chambers, reactors, and active components on the size scale of the width of a human hair or smaller Credit: Dr. Karen Cheung, UBC ECE
  10. 10.     Sample savings – nL of enzyme, not mL Faster analyses – can heat, cool small volumes quickly Integration – combine lots of steps onto a single device Novel physics – diffusion, surface tension, and surface effects dominate  This can actually lead to faster reactions!
  11. 11. • Three PDMS layers are aligned and irreversibly bonded to form two sets of three parallel microchannels separated by a 10-mm-thick PDMS membrane containing an array of through-holes with an effective diameter of 10 mm. Scale bar, 200 mm. • After permanent bonding, PDMS etchant is flowed through the side channels. Selective etching of the membrane layers in these channels produces two large side chambers to which vacuum is applied to cause mechanical stretching. Scale bar, 200 mm. • Images of an actual lung- on-a-chip microfluidic device viewed from above. PDMS:Poly dimethylsiloxane ECM : Fibronectin, collagen
  12. 12. Cating PDMS Membrane Etching the membrane with TBAF & NMP Apply Hydrostatic Pressure &Vacume Bound irreversibly with the two layers Run the etchant solution Pre polymered the layers Photolithograph y of microchannels Coat with the binding layer and incubate at 65 c overnight Upper chamber is Alveolar chamber Lower chamber Blood flow
  13. 13. Biologically inspired design of a human breathing lung-on-a-chip microdevice. • The microfabricated lung mimic device uses compart- mentalized PDMS microchannels to form an alveolar-capillary barrier on a thin, porous, flexible PDMS membrane coated with ECM. • The device recreates physiological breathing movements by applying vacuum to the side chambers and causing mechanical stretching of the PDMS membrane forming the alveolarcapillary barrier. • During inhalation in the living lung, contraction of the diaphragm causes a reduction in intrapleural pressure (Pip), leading to distension of the alveoli and physical stretching of the alveolar-capillary interface.
  14. 14. . IL-2 therapy is associated with vascular leakage that causes excessive fluid accumulation (edema) and fibrin deposition in the alveolar air spaces.
  15. 15.  Endothelial exposure to IL-2 (1000 U/ml) causes liquid in the lower microvascular channel to leak into the alveolar chamber (days 1 to 3) and eventually fill the entire air space (day 4). • During IL-2 treatment, prothrombin (100 mg/ml) and fluorescently labeled fibrinogen (2 mg/ml) introduced into the microvascular channel form fluorescent fibrin clots (white) over the course of 4 days. • A fluorescence confocal microscopic image shows that the fibrin deposits (red) in (D) are found on the upper surface of the alveolar epithelium (green). (F) The clots in (D) and (E) are highly fibrous networks, as visualized at high image.
  16. 16. Different Organs on a Chip
  17. 17. Organ Rationale Cell Lines Characteristics Liver Marrow (Hematopoietic) p450 activity sensitive to chemo dose limiting toxicity Hep-G2/C3A MEG-01 Tumor (Sensitive) Tumor (MDR) (Resistant) initial tumor primary type resistant tumors can MES-SA hepatoma megakaryoblast line attachment/suspension inducible attachment uteran sarcoma sensitive to doxorubicin variant selected for resistance to doxorubicin MES-SA/DX-5
  18. 18. Application to Study Multidrug Resistance Suppressors Other Tissues/ Debubbler Device on peristaltic pump in incubator Sensitive Tumor Cells (MES-SA) Liver Cells (HepG2/C3-A) Resistant Tumor Cells (MES-SA/DX-5) Bone Marrow Blood Cells (MEG-01) All cells labeled with cell tracker green before experiment
  19. 19. Thank You

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