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10.6: Interaction of Organ Systems - Biology

10.6: Interaction of Organ Systems - Biology


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Teamwork

Every player on a softball team has a special job to perform. Each of the orange team’s players in Figure (PageIndex{1}) has his part of the infield or outfield covered if the ball comes his way. Other players on the orange team cover other parts of the field or pitch or catch the ball. Playing softball clearly requires teamwork. The human body is like a softball team in that regard. All the organ systems of the human body must work together as a team to keep the body alive and well. Teamwork within the body begins with communication.

Communication among Organ Systems

Communication among organ systems is vital if they are to work together as a team. Communication among organ systems is controlled mainly by the autonomic nervous system and the endocrine system.

The autonomic nervous system is the part of the nervous system that controls involuntary functions. For example, the autonomic nervous system controls heart rate, blood flow, and digestion. You don’t have to tell your heart to beat faster or to consciously squeeze muscles to push food through the digestive system. In fact, you don’t have to even think about these functions at all. The autonomic nervous system orchestrates all the signals needed to control them. It sends messages between parts of the nervous system and between the nervous system and other organ systems via chemical messengers called neurotransmitters.

The endocrine system is the system of glands that secrete hormones directly into the bloodstream. Once in the blood, endocrine hormones circulate to cells everywhere in the body. The endocrine system is under the control of the hypothalamus, a part of the brain. The hypothalamus secretes hormones that travel directly to cells of the pituitary gland, which is located beneath it. The pituitary gland is the master gland of the endocrine system. Most of its hormones either turn on or turn off other endocrine glands. For example, if the pituitary gland secretes thyroid stimulating hormone, the hormone travels through the circulation to the thyroid gland, which is stimulated to secrete thyroid hormone. Thyroid hormone then travels to cells throughout the body, where it increases their metabolism.

Examples of Organ System Interactions

An increase in cellular metabolism requires more cellular respiration. Cellular respiration is a good example of organ system interactions because it is a basic life process that occurs in all living cells.

Cellular Respiration

Cellular respiration is the intracellular process that breaks down glucose with oxygen to produce carbon dioxide and energy in the form of ATP molecules. It is the process by which cells obtain usable energy to power other cellular processes. Which organ systems are involved in cellular respiration? The glucose needed for cellular respiration comes from the digestive system via the cardiovascular system. The oxygen needed for cellular respiration comes from the respiratory system also via the cardiovascular system. The carbon dioxide produced in cellular respiration leaves the body by the opposite route. In short, cellular respiration requires at a minimum the digestive, cardiovascular, and respiratory systems.

Fight-or-Flight Response

The well-known fight-or-flight response is a good example of how the nervous and endocrine systems control other organ system responses. The fight-or-flight response begins when the nervous system perceives sudden danger, as shown in Figure (PageIndex{2}). The brain sends a message to the endocrine system (via the pituitary gland) for the adrenal glands to secrete their hormones cortisol and adrenaline. These hormones flood the circulation and affect other organ systems throughout the body, including the cardiovascular, urinary, sensory, and digestive systems. Specific responses include increased heart rate, bladder relaxation, tunnel vision, and a shunting of blood away from the digestive system and toward the muscles, brain, and other vital organs needed to fight or flee.

Digesting Food

Digesting food requires teamwork between the digestive system and several other organ systems, including the nervous, cardiovascular, and muscular systems. When you eat a meal, the organs of the digestive system need more blood to perform their digestive functions. Food entering the digestive systems causes nerve impulses to be sent to the brain; in response, the brain sends messages to the cardiovascular system to increase heart rate and dilate blood vessels in the digestive organs. Food passes through the organs of the digestive tract by rhythmic contractions of smooth muscles in the walls of the organs, so the muscular system is also needed for digestion. After food is digested, nutrients from the food are absorbed into the blood of the vessels lining the small intestine. Any remaining food waste is excreted through the large intestine.

Playing Softball

The men playing softball in Figure (PageIndex{1}) are using multiple organ systems in this voluntary activity. Their nervous systems are focused on observing and preparing to respond to the next play. Their other systems are being controlled by the autonomic nervous system. Organ systems they are using include the muscular, skeletal, respiratory, and cardiovascular systems. Can you explain how each of these organ systems is involved in playing softball?

Feature: Reliable Sources

Teamwork among organ systems allows the human organism to work like a finely tuned machine. Or at least it does until one of the organ systems fails. When that happens, other organ systems interacting in the same overall process will also be affected. This is especially likely if the system affected plays a controlling role in the process. An example is type 1 diabetes. This disorder occurs when the pancreas does not secrete the endocrine hormone insulin. Insulin normally is secreted in response to an increasing level of glucose in the blood, and it brings the level of glucose back to normal by stimulating body cells to take up insulin from the blood.

Learn more about type 1 diabetes. Use several reliable Internet sources to answer the following questions:

  1. What causes the endocrine system to fail to produce insulin in type 1 diabetes?
  2. Which organ systems are affected by high blood glucose levels if type 1 diabetes is not controlled? What are some of the specific effects?
  3. How can blood glucose levels be controlled in patients with type 1 diabetes?

Review

  1. What is the autonomic nervous system?
  2. How do the autonomic nervous system and endocrine system communicate with other organ systems so the systems can interact?
  3. Explain how the brain communicates with the endocrine system.
  4. What is the role of the pituitary gland in the endocrine system?
  5. Identify organ systems that play a role in cellular respiration.
  6. How does the hormone adrenaline prepare the body to fight or flee? What specific physiological changes does it bring about?
  7. Explain the role of the muscular system in the digestion of food.
  8. Describe how three different organ systems are involved when a player makes a particular play in softball, such as catching a fly ball.
  9. True or False. The autonomic nervous system controls conscious movements.
  10. True or False. Hormones travel throughout the body.
  11. True or False. The pituitary gland directly secretes thyroid hormone.
  12. What are two types of molecules that the body uses to communicate between organ systems?
  13. Explain why hormones can have such a wide variety of effects on the body.
  14. Heart rate can be affected by:
    1. Hormones
    2. Neurotransmitters
    3. The fight-or-flight response
    4. All of the above
  15. Which gland secretes the hormone cortisol?

Explore More

Without the muscles lining the GI tract, you would be unable to digest food. Watch this short animation of food moving through the GI tract. It illustrates very clearly the necessary interaction of the muscular and digestive systems in the digestive process.


Organ System

An organ system is a group of organs that work together to perform a certain function in an organism’s body. Most animals and plants have organs, which are self-contained groups of tissues such as the heart that work together to perform one function. Humans and other mammals have many organ systems. An example of an organ system is the circulatory system, which includes the heart, arteries, veins, and capillaries. The human body has 11 different organ systems.


Overview of Body Systems

All body systems are necessary for a complex organism to be able to survive and reproduce. This article will focus on the systems of the human body similar systems are required by all animals, but the details of how they accomplish their tasks may vary.

Functions that must be performed by an animal to stay alive include:

  • Absorbing oxygen for use in cellular respiration
  • Excreting carbon dioxide produced during cellular respiration
  • Ingesting and processing food to obtain sugars and other nutrients.
  • Transporting necessary substances, such as oxygen and nutrients, to all cells in the body
  • Clearing toxic waste products from the body.
  • Responding to changes in the environmental conditions
  • Protecting the organs from the environment.
  • Fighting pathogens

Additionally, for a species to survive, its individuals must be able to reproduce.

How do our organs and tissues work together as systems to accomplish these tasks?


Examples of organ scaling

Our examples are limited to the major organs that are common therapeutic targets and do not include other significant tissues such as adipose, bone, endocrine, skeletal muscle, or skin tissues. When attempting to recapitulate in vivo metabolic and physiologic demands of a coupled organ system, one must consider that these tissues also play a key role in metabolic demands and biochemical signaling. As a result, design criteria for OoC scaling should take into consideration the presence, absence, and simulation of various organs when scaling certain physiologic parameters. The ESI† Scaling Spreadsheet and the discussion of each example below should provide guidelines for a rational approach to the design of integrated HoC/OoC systems.

Brain

This is important because the brain is particularly complex, and the literature is riddled with inconsistent physiological data. For example, one of the most common misconceptions of brain physiology is that glial cells outnumber neurons by ten to one, where in fact the ratio for neocortical glia to neurons is 1.2, and the ratio of non-neuronal to neuronal cells ranges from 0.2 to 1.5, depending upon the brain region. These ratios are of exquisite importance when constructing a brain-on-a-chip.

Many of these misconceptions arise from the difficulty of studying the brain. Brain tissue is very diverse across species, and therefore studying the physiological parameters of rodent or other brains will not give an accurate representation of human physiology. The best understanding we can gain from non-human studies comes from the primate brain. The architectural complexity of the brain also complicates the analysis of simple parameters such as capillary density and cell numbers. Neurons can traverse multiple brain regions. Significant advances have been made in this regard by Herculano-Houzel et al. , with their isotropic fractionator technique, 36 and improvements will continue to be made with more advanced analytical techniques such as the transparent brain recently developed by Chung et al. 37

As the ESI† Scaling Spreadsheet indicates, gray matter and white matter may also contain different ratios of cell types and orientations. These parameters are important for scaling in brain region-specific ways. The task of assembling these parameters is complicated because most groups studying the brain make empirical measurements on a specific brain region and not the whole-brain scale. In addition, metabolic parameters such as oxygen consumption are difficult to measure for specific brain regions, but capillary density and cell number distribution are far easier to measure for isolated brain regions. To further complicate gathering this information, many of these parameters had to be assembled by studying the control groups from manuscripts investigating a specific disease state. Finally, it is unclear which of these parameters will be most important for the end goal of creating and integrating a brain-on-a-chip. Therefore, in the Scaling Spreadsheet we present our best understanding of the necessary physiological parameters and their sources for the reader to evaluate and employ as necessary. We envision this table of parameters as evolving alongside our understanding of the human brain and the challenges of building HoCs.

Functional scaling of the brain is largely driven by metabolism. In humans the brain represents 20% of the overall metabolic load and 2% of overall body mass. 38,39 Moreover, the relative metabolic demand of the brain grows more slowly than body and brain mass (allometric exponent 0.873). 40,41 The total energy consumption by the brain varies linearly with the number of neurons in the brain at a rate of 5.79 × 10 −9 μmol glucose min −1 neuron −1 . 40 However, it is unclear if an in vitro brain-on-a-chip (BoC) can recapitulate the metabolic rate of the in vivo case. Therefore, we believe that a mHu and μHu BoC, for example, should be scaled linearly by the number of neurons in the adult human brain, and the remaining components of the brain should be scaled according to the metabolic demand of the number of neurons in the BoC. Autoregulation of the BBB by all cellular components of the NVU also necessitates correct scaling of the cell numbers in the BoC and capillary surface areas in relation to the metabolic demand of the neurons which they support. According to the cellular composition of the cerebral cortex, the NVU should consist of 1.2 astrocytes/neuron, 0.46 vascular cells/neuron, and 0.2 microglia/neuron. 42

The greatest challenge in geometrical scaling of the brain is realization of the capillary density of the brain, which has one of the largest capillary densities of any organ. The average human adult has between 12 and 18 m 2 of BBB, or 150 to 200 cm 2 g −1 of tissue. The necessity of providing neurons with such a high capillary surface area per neuron (174 μm 2 neuron −1 ) will challenge fabrication techniques and is most feasible in microfluidic systems. 42,43 In association with the vasculature, pericytes cover around 30% (5 m 2 , 667 cm 2 g −1 ) and astrocytes cover around 99% (18 m 2 , 200 cm 2 g −1 ) of the abluminal surface of brain microvasculature. 44–46

Scaling of blood flow in a BoC relative to other OoCs could present significant challenges. The human brain has a flow rate of 7 L min −1 , which accounts for 13% of total blood flow. 47–50 This number should scale functionally with the size and metabolism of the BoC in order to supply sufficient glucose , oxygen, and other nutrients and remove resulting metabolites . Values such as the central metabolic rate for oxygen (CMRO2) of 3.2 mL/100 g min should remain constant with decreased size and will be a useful readout of BoC success. 47 Another critical factor is maintenance of the shear stress at the endothelial barrier. Blood surrogate flow must be supplied to a BoC with a sufficiently small capillary cross-sectional area to maintain a shear of around 1.5 Pa without excessive volumetric flow rates. 51–53 This value will also determine the pharmacokinetic parameters of the brain by influencing the residence time and Péclet number of the BoC capillaries.

In summary, the scaling of a BoC revolves around the NVU and is focused on delivering the correct metabolic demand relative to other organs and the unique transport properties of the BBB. As these technologies develop it will become more clear which of these scaling laws are critical to success, and also where scaling can or must be broken in favor of realistic implementation of these technologies for routine studies.

Heart

The cardiac parameters in the ESI† Scaling Spreadsheet support several of the major cardiac scaling issues we have discussed. For example, if a heart construct is to be used as the fluidic pump that provides and supports circulation of a blood surrogate through a coupled OoC system, then functional parameters such as transport capacity, ejection fraction, and fractional cell shortening become scaling issues of paramount importance. The ESI† Scaling Spreadsheet is constructed to circumvent the need to look up individual organ parameters, which often vary throughout the literature and species type. Furthermore, a desired organ size can be used to quickly calculate approximate parameter values for an organ of a certain size based upon both allometric and functional scaling. Thus the table is a valuable resource for quickly and efficiently approximating functional and structural parameters for OoC design, and it also highlights a number of the scaling issues that must be considered in terms of design criteria.

Composition and biochemical factors are of significant import in modeling mammalian heart tissue, which is intrinsically heterogeneous, containing cardiomyocytes, fibroblasts, vascular smooth muscle cells, endothelial cells, and neuronal cells among other less abundant non-myocytic cells. 59 These cell types all interact through a variety of biochemical factors and signaling mechanisms to maintain cardiomyocyte phenotype and tissue function. 60–65 In terms of these fundamental signaling pathways, one may need to consider exogenous sources of biochemical factors that are scaled to the targeted tissue construct's mass, volume, and composition. One must also consider that the size of the organ construct will limit the ability to accurately recreate features of the mammalian heart ( e.g. , if the size of a heart construct is limited to 1–2 cells thick, as would be required for a μHeart, then the realization of an endocardium and the incorporation of all native cell types will not be feasible, whereas this might be possible with a 15-myocyte thick mHeart).

Tissue architecture and metabolism must also be considered. The specialized cells that comprise heart tissue are organized in a highly specific structure that results in a transendothelial biochemical gradient that forms the blood-heart barrier. Furthermore, the fibers in the heart are aligned in anisotropic, helically wound layers that impart unique, spatiotemporally dynamic biomechanical properties to heart tissue. This issue is of key importance when considering the use of a scaffold or substrate as a culture platform, since mismatched substrate and tissue properties can result in a significant reduction in cardiac pump function. In addition to its complex architecture, heart tissue is very metabolically active and requires sufficient oxygenation. Thus, scaling cellular metabolism is another concern, as the balance of energy supply and demand is essential for maintaining cardiac pump function. To meet this demand, native heart tissue contains a dense, complex network of myocardial capillaries that penetrate orthogonally through the myocardium. However, recapitulating a complex network of small diameter capillaries may not yet be feasible in vitro , although recent developments are promising. 66,67 As a result, the utilization of planar diffusion may suffice for now, as the reduced thickness of the cultured myocardium of engineered heart tissue may allow for adequate oxygenation without vascular perfusion.

Fluid flow and other biomechanical stimulation of cardiac tissue are integral to a variety of the heart's intrinsic control mechanisms. Synchronized cardiomyocyte contraction results in complex mechano-electrical feedback mechanisms through the activation of stretch-activated channels and modulation of cellular calcium handling, the endocardium responds to both fluid shear stresses and pulsatile cyclical strain by releasing paracrine and endocrine factors, and baroreceptors transduce sensory feedback into various forms of cellular signaling. Under normal fluid shear conditions, endothelial and vascular smooth muscle cells have relatively low rates of proliferation, whereas abnormal hemodynamic conditions result in pathological cellular phenotypes that are associated with a number of cardiovascular diseases. 68 The proper scaling of biomechanical properties in conjunction with fluid dynamics is therefore crucial to modeling both normal and pathological cardiac tissue. In order to achieve physiologic fluid shear stresses in miniaturized working heart constructs, one must appropriately apply volumetric and resistance scaling by modulating flow rates and blood surrogate/media viscosity in accordance with the geometry of the bioreactor and tissue construct. These scaling issues only gain significance when integrating heart-on-a-chip technologies into multi-organoid constructs, especially if the heart tissue is to be responsible for cardiac output to perfuse the entire organ network. Here, cardiac output ( i.e. , stroke volume, heart rate, ejection fraction, etc. ), tissue size, metabolic and perfusion demands of other tissues, total peripheral resistance, and resident blood surrogate volume are all variables that need to be properly scaled relative to each other. However daunting it may be, the scaling of biological variables for the integration of multiple human organ constructs provides a basis for fabricating functional mHu or μHu constructs that would streamline drug development and discovery and produce a more realistic cellular microenvironment than monolayer monocultures in Petri dishes or well plates.

Overall, each of these scaling issues merits consideration in the design of engineered heart constructs, and optimization of heart-on-a-chip technologies, not to mention all organ-on-a-chip technologies, is a compromise between verisimilitude and a functional abstraction.

Kidney

The ESI† Scaling Spreadsheet provides examples and literature references for a range of functional and structural factors that need to be considered in kidney scaling. First and foremost, the kidney model must scale in order to sufficiently filter the circulating volume of blood in the HoC construct and achieve physiologically relevant rates of the glomerular filtration. Second, the model must be manipulated to facilitate physiological rates of fractional reabsorption, a challenging feat due to the wide discrepancies between in vivo functionality and in vitro performance. The kidney also provides a unique example of an organ in which the preservation of geometrical features, such as the countercurrent mechanism and exchanger, is critical to realizing an accurate model of the human kidney.

Functional scaling begins in the glomerulus. The glomerular filtration rate (GFR) in a 70 kg human produces 125 mL min −1 of ultrafiltrate and therefore 125 μL min −1 in a functional milliHuman (mHu). 39 The ratio of the surface area of the glomerular hemofilter to porous surface area can be optimized in the model to achieve this rate of filtration , given that a physical filter will be different from a biological one.

Recapitulation and subsequent scaling of the specific transport, metabolic, endocrine, and immune activities of the renal tubules pose formidable fabrication and scaling challenges. 69,70 A potential approach begins with functional scaling of active solute reabsorption rate in the proximal tubule. For example, a 70 kg human normally filters 180 g per day of D -glucose , almost all of which is reabsorbed in the proximal tubule therefore, a mHu kidney must scale to filter and subsequently reabsorb about 180 mg of glucose per day. 71 Because metabolic activity and active transport abilities of the proximal cells in vitro may differ significantly from in vivo quantities, preliminary in vitro studies must be conducted to characterize the phenotype of human proximal tubule cells in single hollow fibers. From these results, we can predict the number of cells and surface area required for functional scaling of solute reabsorption. Manipulation of geometric dimensions or the use of parallel proximal tubule modules can ensure that the proximal tubule model can receive the appropriate volume of ultrafiltrate from the glomerular unit.

Although the scaling of the urine-concentrating mechanism must encompass functional scaling concepts, the approach must also pay particular attention to scaling the critical architecture of the loop of Henle. Although the relation of absolute loop length and urine-concentrating ability between species is highly debated, the creation of the corticomedullary osmotic gradient is unequivocally linked to active reabsorption of Na + as well as the complex geometry of the loop of Henle. 72,73 In an approach similar to that of the proximal tubule model, functional scaling in the loop of Henle can be achieved by scaling the rate of Na + reabsorption. Active reabsorption of Na + by Na/K-ATPase pumps located in the thick ascending limb of the loop of Henle (TAL) effectively drives the passive H2O reabsorption in the descending limb. Additionally, the Na/K-ATPase pump has been extensively characterized and is tunable with a variety of solutes, hormones , and drugs , and therefore may serve as a point of modulation for scaling purposes. 74 Successful scaling may be impossible without the preservation of architectural features such as the countercurrent mechanism and exchanger. Computational modeling can be used to optimize the length and surface area to volume ratios needed to establish a physiologically relevant osmotic gradient for a human, 300 to 1200 mOsm regardless of size. 75 Additionally, “preconditioning” of long loops with short loops, as seen in vivo in a ratio of 85 short to 15 long in humans, may help to maximize urine-concentrating ability. 73,76

The kidney is an excellent example of a key OoC/HoC design concept: while functional and biochemical scaling may provide the best approach to scaling a histological section of a human, some organ functionalities cannot be achieved without reproduction and scaling of certain physiological architectures.

Liver

There are, however, central design parameters for which there are allometric scaling laws, but from which we can justifiably deviate for functional scaling. For functional scaling, we argue that the hepatic mass will not follow the allometric power law and instead represent 1/10 3 or 1/10 6 of what is found in a normal human. For example, although an allometric power law exists for oxygen consumption, we instead use functional scaling given that the metabolic demand per hepatocyte—approximately 0.3 to 0.9 nmol s −1 /10 6 cells—will be equivalent in our scaled OoC. 80,81 The allometric value for oxygen consumption in the mHu ( O 2 = 0.035 M b 0.69 , with M b in g, such that a 60 g mHu would have a hepatic oxygen consumption of 0.59 ml min −1 ) underestimates consumption when compared to a functional proportion of a normal human (2.06 ml min −1 ). 9 Note that if oxygen transport through the blood surrogate is insufficient, a system of hydrophobic hollow fibers could be used to increase the interstitial oxygen concentration without affecting interstitial or blood volumes, as has been done quite successfully for liver HoCs. 82,83

In addition to proper oxygen delivery, there is also a need to seed the appropriate number of cells with sufficient exposure to a blood surrogate. In vivo hepatocytes sit adjacent to the 1.4 μm perisinusoidal space ( i.e. , the space of Disse), which separates the hepatocytes from the sinusoidal capillary that averages 10 μm in diameter and 275 μm in length. Appropriate concerns are whether a longer and larger in vitro model of a hepatic sinusoid unit via hollow fiber (HF) bioreactors will affect nutrient delivery, create unwanted oxygen gradients, and/or add to necessary volume given the limitations of HF fabrication. Although the number of hepatocytes needed for a functional mHu is calculated to be 3 × 10 8 cells, it is unclear if current HF technology can support this. 83–85 Neither 3-D, planar microfabricated, or hollow-fiber livers have yet achieved collection of bile, generated by the liver canaliculi, into bile ducts.

Validation of the milli- and microliver models will primarily occur via iterative in vitro–in vivo correlation of xenobiotic clearance. Several groups have conducted correlation studies, with a general belief that each drug compound, unsurprisingly, may have its own allometric power law across species (due to metabolic variations) and also a different scaling factor (due to assumptions made in their model such as diffusional barriers). 86–93 For example, Naritomi et al. found that they could predict human in vivo clearance rates of eight model compounds from human in vitro data by using an animal scaling factor ( Cl in vivo/ Cl in vitro) from either a rat or a dog. Scaling factors were similar across species for each of the eight compounds, but varied from 0.3 to 26.6-fold among the compounds. 89

While this variation may prove to be troublesome in the analysis of unknown compounds during drug evaluation and discovery stages, awareness of the properly scaled input parameters and thorough analysis of a wide range of model compounds ( e.g. , acetaminophen , diazepam ) will assist in building predictive pharmacokinetic/pharmacodynamic (PK/ PD ) models of the OoC system.

Lastly, Boxenbaum notes in an early paper on allometric scaling of clearance rates that these models may not prove to be accurate, particularly at small masses, as the intercept of the allometric equation predicts a non-zero clearance rate at 0 g. This collapse of allometric theory at the micro- and milliscale gives credence to the necessity to scale based on organ function. 22

The ESI† Scaling Spreadsheet provides a collection of both functional and structural lung variables. Inconsistencies between the allometric exponents show a disconnect between structure and function, illustrating a novel problem when constructing HoCs. As we have discussed, additional support systems, such as assistance from a microformulator, may be necessary to ensure the most accurate structure/function μLung construct incorporated onto a HoC. A robust table of scaling values is therefore a valuable reference tool when making the inevitable compromises while designing a coupled OoC system.

Allometric scaling in the bronchial region is found in the diameters of the trachea and bronchioles. Allometrically, the diameter of the terminal bronchiole scales with an exponent of 0.21, while the radius of the trachea scales with an exponent of 0.39. However, this presents a problem: allometrically scaled, a μHu would have a terminal bronchiole diameter of 30 μm, which is near the limit of current soft-lithographic microfabrication technology were hollow fibers used for the larger bronchial tubes, with a minimum diameter of 200 μm, the microfluidic network would require approximately six binary splittings to achieve a 240 μm diameter. Either scaling laws must be broken or novel fabrication techniques 94 utilized to accommodate and create a viable μHu trachea/bronchi system. 9

Allometric scaling in the alveoli is critical as well. The most important function of the alveolus is oxygenation, so scaling should be addressed to meet oxygenation needs, if required for the MPS. The critical parameter to be properly scaled is surface area, as it is the main component of Fick's law and governs diffusion capacity across the alveolar-capillary barrier. Pulmonary diffusing capacity (DLO2) scales linearly with body mass with an exponent of ∼1. 95 This means that the DL02/body mass ratio is relatively constant in all mammals. Diffusing capacity is related to alveolar surface area, mean barrier thickness, and capillary blood volume, and the allometric coefficients are 0.95 for surface area, 0.05 for barrier thickness, and about 1 for capillary blood volumes. 95

To replicate a μHu, alveolar diameter would be 21 μm–an order of magnitude less than the average 200 μm diameter of a human. The diameter of a type 1 epithelial cell is around 20 μm. Thus any individual μHu alveolus would require only a single epithelial cell, 9,96 but the entirety of alveolae for a 0.1 μHu might well be modeled by a rectangular membrane of the appropriate area. 17,18

Another scaling argument that should be considered is the mass-of-tissue to volume-of-media, in this case lung tissue volume to blood volume. Blood volume is linearly related to body mass in mammals (allometric exponent of 1). Thus scaling lung tissue surface area and blood substitute volume in the HoC depends on the total mass of the system, and if both are scaled correctly then oxygen concentration should be sufficient. If scaling is ignored, problems could arise with the surface area required to supply the blood with sufficient oxygen for metabolic needs. 95

A μLung would have 184000 cells in the alveolar region. Around 37% of those (the interstitial cells) could be eliminated, since only endothelial, type I and II cells, and macrophages are needed to create a functional alveolar-capillary unit. The correct percentage breakdown of cells is important to assure sufficient paracrine factors and surfactant production. 97–99

The scaling factor that appears to present the greatest challenge to a μLung is respiration rate. Were we to use allometric scaling, a μLung would have to inspire 643 times per minute to maintain proper oxygenation. Due to the strain this would put on a 1 μm thick polymer membrane, it is likely that this frequency would have to be slowed to prevent rupture. As a result, more surface area would need to be added or higher oxygen concentrations used to compensate for the loss of rate in order to maintain a minute volume of 0.17977 mL min −1 consumption of oxygen. This highlights the challenges of scaling, especially into the micro- and nano-scales, where the limitations imposed by non-biological fabrication technologies prevent meeting design parameters without violating scaling laws, 100 which could result in a less accurate abstraction. Hence it is critical to specify the desired lung functions and scale the device to achieve them.

Blood

Allometric scaling of blood components gives some insight into how the surrogate should be constructed. The ESI† Scaling Spreadsheet corroborates the scaling issues that must be considered in designing a blood surrogate. First, it can be seen that the concentrations of blood remain virtually the same in organisms of all sizes: conveniently, the concentrations of a remarkably large number of blood components do not scale with body mass. 101 This means that the creation of a blood surrogate can benefit from the large body of work that has been completed on creating cell media. Second, it can be noted that blood volume scales linearly with mass thus, the total volume of the blood surrogate in an OoC/HoC device should be proportional to the entire size of the device. For all non-aquatic mammals, the blood volume is about 6–7% of the total body volume. 100 Scaling the blood surrogate volume with the size of the OoC/HoC device is necessary to ensure that signaling and other transported molecules are not excessively diluted and that the total mass of transported blood surrogate components is enough to support the organs. Third, the spreadsheet shows the critical functional parameters for ensuring that the cells behave in a physiological manner. The epithelial cells in contact with the blood surrogate must have the same shear stress that cells experience in the body to achieve the requisite polarization. In addition, the cells must experience the same levels of oxygen and carbon dioxide, which are dictated by the gas transport capabilities of the blood surrogate, in order to maintain the physiological metabolism of the cells. The physical properties of a number of different oxygen carriers are also shown. The spreadsheet is based upon the scaling of a complete system as discussed above, it may be necessary to correct for the hydrodynamic, metabolic, and chemical activity of organs that are not included in the system.

Hence, little should be changed in normal blood to form a blood surrogate. However, there are other scaling issues that must be considered to ensure that the cells in the mHu and μHu behave physiologically.

First, the blood surrogate must recapitulate physiological oxygen transport properties. Experiments have shown that the rate of oxygen delivery to the cells affects the cells' metabolic rate. 102 There are programmatic differences relative to the suitability of serum in an OoC/HoC system: the Defense Threat Reduction Agency (DTRA) program announcement 23 precludes the use of serum, whereas the Defense Advanced Research Projects Agency (DARPA) program 103 does not. If simple serum-free aqueous culture media is used, the low concentration of dissolved oxygen in the media may limit metabolic rates and affect capillary surface-to-volume scaling. Therefore, the level of oxygen transport that cells experience in vivo as enabled by hemoglobin must be functionally mimicked with the blood surrogate. Were erythrocytes not used, perfluorocarbons and hemoglobin -based oxygen carriers may be very effective for achieving this. 104–106 If human or animal serum is not utilized, appropriate concentrations of carrier proteins such as albumin may be required to replicate organ-organ chemical communication.

For the purpose of supporting HoCs, the blood surrogate must maintain multiple cell types while also optimizing physiological processes. While there is no known universal serum-free media, a number of different formulations of minimal media can be used as a starting point for the creation of a medium that can support multiple cell types. 107,108 To achieve optimal cell functionality and longevity, supplements must be added to this minimal medium. 109

Although a number of effective medium formulations for the growth and maintenance of multiple cell types have been developed, these media mixtures have not been widely tested for interconnected HoCs. For OoC/HoC systems, this represents a significant challenge due to differential scaling, simultaneous maintenance of multiple cell types, and the recirculatory nature of HoCs. Logic dictates that during flow-through of the blood surrogate within a HoC, some components will be absorbed or metabolized, while others will be added to the blood surrogate, with a negative impact on downstream HoCs.

One method that has been successfully used to create a common blood surrogate for a number of different cells in an OoC/HoC first involves combining the established serum-free mediums of each cell type, which can be found in the literature, to create a base medium. Next, various other components, such as growth factors and supplements, are added to optimize for physiological functionality, based on a number of different physiological measures. Finally, since some of the components of the medium support one type of cell but hinder others, one of several different techniques is used to ensure that each organ receives an optimal subset of the components of the blood surrogate. Zhang et al. 108 demonstrated this method by creating a blood surrogate that supported four cultured cell types: liver (C3A), lung (A549), kidney (HK-2), and adipose (HPA). Another option is to grow cells in isolated OoC/HoCs on their preferred media, and then gradually, through controlled valves, wean them slowly from this media to the universal one.

In addition, some properties of blood and related structures that exist physiologically cannot yet be replicated with HoCs. For example, capillaries, which have relatively constant size across species, are too small to be recreated at present, so care must be taken to design the HoCs such that the physical characteristics of the blood surrogate, such as flow, volume, and shear stress, match those found in the tiny capillaries. It is imperative to match the wall shear stress in HoCs to that of microvessels to achieve the same mechanotransduction and gene expression in endothelial cells as in humans. 52 This might be addressed by self-organizing on-chip microvasculature. 66,67

Furthermore, it is important to understand PK/ PD scaling in order to add drugs to the HoC/OoCs at proper levels and to use the HoC/OoCs to predict the pharmacokinetics in humans. 2,3 The classical scaling relationship for drug /signal dosing is that the body's ability to use and metabolize drugs /signals varies with surface area. 110 But these scaling laws are critically dependent on the biochemical mechanisms and physical properties of the organs. 111 If the organs do not functionally mimic physiology, they could fail to predict the PK/PD of humans. Differences in drug transport and metabolism in the HoC can render typical allometric PK/ PD scaling useless. This can be seen clearly by the fact that PK/ PD varies significantly between infants and adults. 112

Finally, the blood surrogate will require supporting systems that can provide missing functionality required for blood surrogate and organ maintenance. As required, a microformulator 108 can provide media supplements specific to each organ. 108 The microformulator could be used to locally add media components to a particular organ. A size-exclusion filter or an affinity capture chamber or matrix (Donna Webb, personal communication) could be used to remove any toxic molecules produced by one organ before they reach other organs. Computer-controlled microformulators could also provide the regulated injection of molecules that cannot be maintained by the system alone and those from organs not in the HoC. 24,113

Cellular heterogeneity

Organ # of cell types, N Cell type %
Brain (neocortex) 42 4 Glia 41%
Neurons 33%
Vascular 17%
Microglia 8%
Total 100%
Heart 59,60 5 Cardiomyocytes 55%
Fibroblasts 25%
Vascular smooth muscle 10%
Endothelial 7.0%
Neuronal 3.0%
Total 100%
Liver 116 4 Hepatocyte 60%
Sinusoidal endothelial 20%
Kupffer 15%
Hepatic stellate 5.0%
Total 100%
Lung (alveolar) 97 5 Endothelial 39%
Interstitial 29%
Type II epithelial 18%
Type I epithelial 11%
Alveolar macrophages 3%
Total 100%
Blood 117 6 Erythrocytes 99%
Neutrophils 0.50%
Lymphocytes 0.30%
Monocytes 0.050%
Eosinophils 0.025%
Basophils 0.007%
Total 99.9%

Figure 10.2.1

Maud_Stevens_Wagner -The Plaza Gallery, Los Angeles, 1907 from the Library of Congress on Wikimedia Commons is in the public domain (https://en.wikipedia.org/wiki/public_domain).

Figure 10.2.2

Anatomy_The_Skin_-_NCI_Visuals_Online by Don Bliss (artist) from National Cancer Institute, on Wikimedia Commons is in the public domain (https://en.wikipedia.org/wiki/public_domain).

Figure 10.2.3

Figure 10.2.4

National Geographic. (2008). Scarification | National Geographic. YouTube. https://www.youtube.com/watch?v=Lfhot7tQcWs&t=1s

TED-Ed. (2018, March 12). The science of skin – Emma Bryce. YouTube. https://www.youtube.com/watch?v=OxPlCkTKhzY&feature=youtu.be

TED-Ed. (2013, August 6). Why do we have to wear sunscreen? – Kevin P. Boyd. YouTube. https://www.youtube.com/watch?v=ZSJITdsTze0&feature=youtu.be

The body system comprised of skin and its appendages acting to protect the body from various kinds of damage, such as loss of water or damages from outside.

The ability of an organism to maintain constant internal conditions despite external changes.

The major organ of the integumentary system that covers and protects the body and helps maintain homeostasis, for example, by regulating body temperature.

The outer layer of skin that consists mainly of epithelial cells and lacks nerve endings, blood vessels, and other structures.

A type of epithelial cell found in the skin, hair, and nails that produces keratin.

A tough, fibrous protein in skin, hair, and nails.

An undifferentiated cell that can develop into specialized types of cells.

A special skin cell that is responsible for producing melanin.

Oval-shaped mechanoreceptors essential for light touch sensation and found in the skin.

The inner layer of skin that is made of tough connective tissue and contains blood vessels, nerve endings, hair follicles, and glands.

One of the four basic types of tissue, connective tissue is found in between other tissues everywhere in the body, including the nervous system and generally forms a framework and support structure for body tissues and organs.

A filament made of tightly packed, keratin-filled keratinocytes that grows out of a hair follicle in the dermis of the skin.

An anatomical structure that consists of a small cluster of cells, surrounding a central cavity.

accessory organ of the skin made of sheets of dead keratinocytes at the distal ends of the fingers and toes


Watch the video: Human Body Systems Functions Overview: The 11 Champions Updated (September 2022).