Read Article 05: Christopher Moraes, Joseph M. Labuz, Brendan M.
Leung, Mayumi Inoue, Tae Hwa Chun, and Shuichi Takayama. On being the
right size: scaling effects in designing a human-on-a-chip.
Integr.Biol. Adv. Article:DOI: 10.1039/C3IB40040A, 2013.
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The Systems Biology of COVID-19 and the SARS-CoV-2 virus. The class will build a foundation that includes the emergence of complexity, simple biological subsystems, their reductionist and equivalent toy and organ-chip models, and the measurements required to specify model architecture and parameters. Applications to biology, physiology, medicine, chemical and biological defense, pharmacology, drug discovery, and toxicology. UGrad: PHYS 240 01 and BME 290B; Grad: PHYS 326 and BME 395C.
0. Based on the previous articles, I knew the concepts of scaling and some of the applications of scaling techniques to generate comparable OoC to actual systems.
ReplyDelete1. I learned about the engineering challenges and “workarounds” used to circumvent the scaling issues.
2. The workarounds used to meet the engineer issues are critical but am what I am curious to see addressed is that if there are secondary effects such as further stresses that lead to biochemical alterations.
3. Looking at some of the engineering workarounds such as the micro-fluidic devises.
4. I thought this article was a good application of the scaling concepts highlighted in the previous articles and presented solutions to create the desired environments.
0. Knew: I had learned about the concepts of scaling from article 4 which really helped me understand this article.
ReplyDelete1. Learned: I learned about different ways to overcome the challenges of scaling, most notably using BMR as an index.
2. Pressing ?'s: What effect will decreasing the oxygen level have on the cells? That is, is there a stress response from prolonged decreased oxygen levels?
3. Presentation: Using BMR to functionally scale organs
4. Thoughts: This paper finds that the structure of the organ is critical to observe a scaling effect and the cells must be arranged so that they are not transport limited (top of p.16). I think this is very important to keep in mind when designing an OoC.
In terms of prolonged decreased oxygen levels there is a inherent stress response. The decrease oxygen levels generally lead to increased levels of free radicals or other reactive oxygen species since oxygen is required for cellular respiration. Depending on the cell type you would probably see an increase in the hypoxia inducible factor (HIF) transcription factors that would help the cell mediate the low oxygen levels and remove the reactive oxygen species. Hypoxia will prevent the cells from differentiating.
DeleteWhat would be interesting is to see the percentage of oxygen levels for the blood as it enters the specific OoC in their system and when it leaves. I am curious as to how much oxygen is actually consumed by each OoC.
Cameron Stewart
ReplyDelete0. I know that the OoCs in HoCs would best be scaled according to desired functionality because allometric scaling falls apart at very small sizes.
1. I learned that functionally surface constrained organs could be spheroidal in order to incorporate more mass with the least amount of surface area and I learned that maintaining normal BMR is highly prioritized.
2. If BMR is highly prioritized and is one of the most significant differences between a mouse and a human for drug testing purposes, then couldn't a mouse either breath elevated levels of 02 or be given perfluorocarbon dense blood substitute (to maintain O2 levels in the body) while also being administered a heart sedative in order to artificially make its BMR more human-like?
3. The topic was about the most rational approaches to decide compromises in order to make the most representative HoC. The decision was to constrain an F2D organ by surface area and an F3D organ by mass while also maintaining a human-like BMR.
4. I'm very interested in how cell culturing is done. I have experience with single cell species cultures from Bio110 but I don't know how specialized cells could be cultured.
Frank "Edad" Block, Jr.
ReplyDeleteAsgn_3B_Class_03_Article_05_2013_08_29
0 Knew: Question of blood flow vs. organs (but it is more complicated than they think)
1 Learned: Approach of blood flow to determining organ size
2 Pressing: They don’t understand the problems here.
3 Presentation: A critique of their approach.
4 Thoughts:
--In vivo residence times … this is somewhat like the concept of a time constant and decay curve.
--Issue that most organs will regulate their own blood flow. As a prime example, cerebral blood flow is closely “autoregulated” vs. mean arterial pressure AND paCO2 AND pO2. Blood flow to other organs is also not static but depends upon blood pressure, sympathetic nervous system, etc.
--The authors don’t seem to understand what controls BMR. For example, one of the main determinants is temperature. BMR goes up or down 10% per degree warmer or cooler.
--One approach might be to deliberately increase or decrease BMR of a single organ. This could make up for high or low organ size … but would introduce its own set of problems, since organs don’t function the same way at different temperatures (i.e., outside the BMR effects).
--Other influences on BMR include sympathetic nervous system, adrenals, insulin, thyroid, growth hormone, pH, electrolyte balance, etc. etc.
--One problem that they don’t seem to appreciate is that organs (and cells) have optimal and survival metabolic requirements. As an example, normal cerebral blood flow is typically expressed as 50 ml blood flow per minute, per 100 gm of brain tissue. The human brain is about 1600 gm so normal CBF is 800 ml / min. Brain cells will usually FUNCTION NORMALLY down to 25 ml / 100 gm / min. Below 25 function falls off. At 18 or so, the cells start to die. Thus the cells “shut down” everything except maintaining cellular integrity for as long as they can. At some point they can no longer maintain cellular integrity and the cell dies.
--Similar effects occur in other organs. An organ with borderline perfusion may be “alive” but it may not be working “normally.” The heart is another example: The cells may be alive but they may not be contracting normally. If blood flow and/or O2 are increased, the cells can recover and beat normally again. At some point the cells can no longer recover.
Frank "Edad" Block, Jr.
ReplyDeleteAsgn_3B_Class_03_Article_05_2013_08_29
0 Knew: Question of blood flow vs. organs (but it is more complicated than they think)
1 Learned: Approach of blood flow to determining organ size
2 Pressing: They don’t understand the problems here.
3 Presentation: A critique of their approach.
4 Thoughts:
--In vivo residence times … this is somewhat like the concept of a time constant and decay curve.
--Issue that most organs will regulate their own blood flow. As a prime example, cerebral blood flow is closely “autoregulated” vs. mean arterial pressure AND paCO2 AND pO2. Blood flow to other organs is also not static but depends upon blood pressure, sympathetic nervous system, etc.
--The authors don’t seem to understand what controls BMR. For example, one of the main determinants is temperature. BMR goes up or down 10% per degree warmer or cooler.
--One approach might be to deliberately increase or decrease BMR of a single organ. This could make up for high or low organ size … but would introduce its own set of problems, since organs don’t function the same way at different temperatures (i.e., outside the BMR effects).
--Other influences on BMR include sympathetic nervous system, adrenals, insulin, thyroid, growth hormone, pH, electrolyte balance, etc. etc.
--One problem that they don’t seem to appreciate is that organs (and cells) have optimal and survival metabolic requirements. As an example, normal cerebral blood flow is typically expressed as 50 ml blood flow per minute, per 100 gm of brain tissue. The human brain is about 1600 gm so normal CBF is 800 ml / min. Brain cells will usually FUNCTION NORMALLY down to 25 ml / 100 gm / min. Below 25 function falls off. At 18 or so, the cells start to die. Thus the cells “shut down” everything except maintaining cellular integrity for as long as they can. At some point they can no longer maintain cellular integrity and the cell dies.
--Similar effects occur in other organs. An organ with borderline perfusion may be “alive” but it may not be working “normally.” The heart is another example: The cells may be alive but they may not be contracting normally. If blood flow and/or O2 are increased, the cells can recover and beat normally again. At some point the cells can no longer recover.
Jie Zhao
ReplyDeleteAsgn_3B_Class_03_Article_05_2013_08_29
1. a. detailed experimental design approach/ techniques towards organ on a chip.
b. start from BMR to evaluate HoC cell functions.
2. even for different organs, function will sometimes overlap. When artifitially replacing abscent organs, how should one make sure it doesn't influence existing organs?
3. culturing mix cell types including adipose
4. this paper really helps me get a more concrete idea about the experimental aspects involved in HoC.
David Wooten
ReplyDeleteAsgn_3B_Class_03_Article_05_2013_08_29
0. Knew: Functional scaling considerations are the most promising.
1. Learned: Cell structure and density have huge impacts on the OoC's behavior, which can actually be helpful in designing unrealistically small OoC's.
2. Pressing ?: Is it possible to have an OoC with a comparable BMR to an actual human?
3. Presentation: Physiological differences between F2D and F3D organs.
4. Thoughts: This paper seems like it gave the most specific ideas to actually building such a system. I wonder what problems would be encountered if they actually built it (assuming the blood/serum was developed to support the whole system)
Asgn_3B_Class_03_Article_05_2013_08_29
ReplyDelete0. Knew: Background on scaling issues/limitations of allometric scaling from other articles.
1. Learned: BMR is the "master regulator of cell function," so it is key to keep in mind when adjusting scaling systems.
2. Questions: It seems that most of the solutions to scaling are focused in one direction - mass, volume, area etc. Is it just too difficult to try to combine the scaling of different measurements into one weighted model/equation and that is why there is an emphasis on choosing which is best for which organ?
3. Presentation: Understanding how we are going to recognize when our system is too simple - noticing that an organ, cell, or molecule we left out explicitly is the factor that is key (giving a false negative/positive).
4. Thoughts: It seems like the problem of scaling is coming from the fact that at some point there is a limit as to what you can scale down; for instance we cannot change the fundamental pieces such as the cells but only the number of them. Why do we have to press the limit of size?
Andrew Nelson
ReplyDeleteAsgn_3B_Class_03_Article_05_2013_08_29
0. Knew: A variety of different scaling mechanisms are considered in determining relative size of individual organs on OoC’s.
1. Learned: Though proper scaling is a good place to start there are many system dependent factors that influence cell function so using overall metabolic rate of the system could solve the issue of scaling in between organs.
2. Pressing: Considering the difference between in vivo/in vitro BMR, would an OoC/HoC based on BMR conditions have meaningful results under non-BMR conditions? If the environment that the system model was based on changes wouldn’t differences between the two conditions on the chip be magnified even more when translating data back to humans?
3. Presentation: Obviously cell functions are influenced by the systemic network that supports it, so the interface between allometric scaling and using metabolic rate in system design is very important.
4. Thoughts: With function being so closely related to structure I’m interested in seeing if there are any potentially useful insights to be gained from looking at functionally hindered cells.
0. Knew: Metabolic balancing of human on chip systems will depend on relative scaling of organs.
ReplyDelete1. Learned: Engineering "workarounds" may be employed to help balance the relative scale of organ systems. e.g. using a blood substitute with a lower oxygen carrying capacity.
2. Question: If system balance depends of engineering workarounds are we limited in what variables we can use the system to test? That is, how well will be able to separate the effects of such modifications and workarounds from effects induced by substances such as drugs that we are testing?
3. Presentation: Blood in microfluidic contexts.
4. Thoughts: I'm troubled by the idea of using engineering workarounds to balance a human on a chip. However, we may learn a good deal about physiology in the process of designing these workarounds.
0 Knew: Functional scaling of organs is more efficient than solely using the allometric coefficients.
ReplyDelete1 Learned: Maintaining BMR is very important - one reason why real blood cannot be used; structure of the organ itself can have an affect on the scaling.
2 Pressing questions: Is this article saying that by maintaining in vivo BMR, then allometric coefficients CAN be used? If some cells are used simply for structure (embedded within the organ), will they not have access to the media? and if so won't they die?
3 Presentation: The Importance of Structure and Metabolism in OoC Scaling
4 Thoughts: This seems like a very "easy fix." Is this idea applicable to a more complicated system of multiple organs? It will be interesting to see how their findings regarding structure and metabolism can be applied.
0. Knew: This paper has the same idea with article 04 that the importance of scaling, of reducing the relative size of each organ compartment to maintain appropriate functionality of the whole system, is central to the successful design of a generalizable human-on-a-chip.
ReplyDelete1. Learned: One of the limitations for allometric scaling is that cells removed from the body and cultured in a human-on-a-chip no longer maintain the metabolic profiles of their in vivo counterparts. This paper holds the same conclusion of allometric scaling with article 04 that the practice of utilizing allometric scaling coefficients of organ volumes that are empirically determined by observing ‘real’ organisms may not be the most suitable method to design a HoC.
2. Questions:
3. Presentation: the design of relative organ sizes and fluidic connections
within the human-on-a-chip.
4. Thoughts:
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