Ever wonder if that pain under the arm is in any way related to the pain in the groin? Why do the soles of my feet hurt when I first start walking upon waking up? Why in some people, but not in others, especially children, can you see very clear veins on the back of the hands and in the antecubital fossa (where nurses [in the US] or doctors [in Australia] take blood samples)? How does acupuncture work? The answer: hypodermal fluids, or more specifically, the anatomy of the skin and hypodermis.
This topic is an ongoing composition that is part of my Mind-Body Medicine series. I talk about the anatomy and physiology of the hypodermis and the contents within it, including the tissues within the hypodermis: Fat, muscle, bone, tendon, ligament, specialized connective tissue cells, and glands.
Updated 2 Sept 2014
No one has described the fluid flow under the skin, other than in words closely associated with blood vessels. We have to realize that a very large part of “body water” is not found in the cardiovascular system at all, and in fact, freely flows between and inside of organs along a highway called connective tissue. The space between and within all organs is made up of fluid (mostly water) and connective tissue. All connective tissue is made up of fibers (either loosely or densely connected to each other) and cells. Some connective tissue, e.g. the loose stuff, has a large variety of cells. Dense connective tissue (ligaments, tendons, cartilage, and bone) tend to have fewer different types of cells in favor of a larger number of specific types of cells.
The number of different types of cells reflects the necessary functions of the tissue in discussion. Besides being important for providing immune cells, loose connective tissue is described as “connecting” two different tissue types. Most people think the word “connecting” means it is for physical or structural reasons. It could also mean physiologically connecting, as in providing nutrition to certain tissues or organs, something we keep shoving onto the blood vasculature’s plate.
Critical for understanding fluid flow in the body, is not just the cardiovascular and lymphatic systems, since they are “closed systems”. There is an “open system” in the body, which involves all connective tissue as highways for fluid flow which depends upon simple diffusion where a concentration, pressure, or electrical gradient is established to make ions flow against the pull of gravity. If we understand this fluid flow, we can then understand the flow of toxins in areas which do not have to involve travel within blood or lymph vessels. We can then understand pain in the body, as revealed to us in syndromes involving fibromyalgia and arthritis. See my blog post on Science Says Diets Cannot Fight Chronic Pain, and Mind-Body Medicine and Joint Pain for more discussion on joint pain.
Where is the Hypodermis?
In order to understand how fluid flows in the hypodermis we must understand just which anatomical structures the hypodermis includes. It is important to think of a different kind of organization in the body than we are used to doing. We can divide the parts of the body into the following categories:
- integument composed of epidermis and dermis,
- internal organs (those found inside thoracic and abdominopelvic cavities),
- CNS (brain and spinal cord)
- Hypodermal organs (connective tissue, muscle, bone, tendon, ligament, joints and their accompanying tissues like blood, lymphatics, and nerves, along with sebaceous glands and their relatives [milk glands]).
All joints are hypodermal since none are technically found inside the internal body cavities (they may help form a wall of a cavity, but are not truly inside the cavity).
The term “hypodermal” does not refer to a “space” between skin and deeper organs, as most people come to believe when taking a typical anatomy course. Most people think of that space is filled with fat and blood vessels as shown in the figure above. Instead, we should think of it as a term defining a region that is filled with organs and connective tissue (which may be forming mini-organs to organize the hypodermal transport system) that are not found on top of the body or deep inside it. Hypodermal organs also include all skin glands and breast tissue, as well, an important distinction, as will become clear in other posts. It should include all organs between epithelial sheets, so that all organs deep to the dermis in arms and legs are part of the hypodermis, as are all organs between epidermis of the skin and epithelium of the lining of the internal cavities of the body. All of these are derived, for the most part, from mesoderm and have the same tissues of the originally defined hypodermis scattered throughout. Furthermore, it gives a better description of the function of connective tissue.
We have to consider the anatomy of joints at this time, since they are a critical part of the hypodermis. To simplify, our synovial joints (other types are not discussed here) are comprised anatomically by at least two bones in contact with each other, separated by articular cartilage. There are ligaments that connect the two bones, and a synovial membrane that lines the joint space with walls of articular ligament, and floor and roof of hyaline articular cartilage.
Sometimes there are extra pieces of a different type of cartilage (fibrocartilage) inserted within the joint. These fibrocartilage pieces form a meniscus (see Fig. Knee Meniscus above) and are also anchored in place with ligaments. Sometimes the fibrocartilage meniscus floats above the hyaline cartilage that forms normal joint cartilage, still anchored front and back (as in the knee) or is fully anchored all the way around, forming a separate wall that divides up the joint compartment into two compartments (sternoclavicular joint and temporomandibular joint, see figure below).
In all large synovial joints, the synovial membrane gets drawn out into small bags (bursa, sing., bursae, pl.) that open up into the synovial joint space. You can see one of these in longitudinal section, in the Hip Joint image below, under the line connecting the words “Synovial Fluid” to the space between the “Articular Cartilage”. These bags rest beneath tendons of major muscles (not shown in the figure below). Since the synovial joint space defined by the synovial membrane is fluid-filled, so are these bags, called bursae. Bursae can function to absorb shock when the tendon is suddenly stretched as its muscle contracts forcefully. They mainly act to protect soft tissues underneath the tendon (deeper muscles, blood vessels, nerves) during contraction of the tendon-bearing muscle.
Crossing the joint are muscle tendons, as well as muscle fibers. Some of these muscle fibers directly attach to ligaments (some of which then attach to meniscus), which are not shown in the figure Knee Meniscus. The muscle fibers that attach to ligaments belong to muscles that supply a lot of proprioception (position sense) to the joint. Most of the time these proprioceptor muscles are small (popliteus, coracobrachialis, multifidus, transversospinalis), but small portions of much larger muscles (hamstrings) may also be loaded with proprioceptors (stretch receptors) and attach to ligaments of the joint as well.
Embryology: The Middle Layer Forms the Hypodermis
The embryology of any vertebrate involves the formation of three layers of cells that look a lot alike shortly after the fertilized egg burrows into the uterine lining. These three layers (seen as a cross-section in the image above, Embryonic Formation of three Cell Layers, consist of two epithelia (an outer ectoderm [blue] and an inner endoderm [green]), with loose migrating cells (red) lying between the two epithelia. This loose layer, called the mesoderm, will form most of the organs found in the hypodermis, whereas the ectoderm forms the epidermis and the endoderm forms the gut and all of its derivatives (liver, pancreas, kidney, reproductive organs, urinary bladder, gall bladder). Some mesoderm contributes to all these organs, but is heavily represented by the hypodermis.
Alongside of the mesodermal layer comes to lie a derivative of the ectoderm, the future nervous system. It starts out as a thickening in the ectoderm in a narrow region of the back, folds up into a tube which sinks under the surface of the ectoderm,lying between it and the mesoderm. Thus its position is critical for mesoderm function as well as ectoderm function. The neural plate and future tube is not seen in the above figure.
How the Hypodermis Works
In order for any tissue to get nutrients, there has to be a highway. We think of the highway as the blood vessels that make up the major thoroughfares in the body. They are, in general, a quick way to move the incoming nutrients from the gut and oxygen from the lungs to all the tissues of the body. They also are a quick way to move outgoing waste products like carbon dioxide, water, and other metabolic products to organs of excretion. They also move critical proteins, hormones, enzymes, and signaling molecules over very large distances very fast.
However, we can’t just assume that the capillaries just dumps all molecules out and the molecules “find their way” to their targets. Beginning Biology tells us that all depend upon a diffusion gradient to guide molecules to the cell membrane. In some cases, e.g. water, osmosis gets the important molecules to the cell membrane and the stuff passes across the cell membrane very easily, even through channels (aquaporin for the water molecules). In other cases, the molecule has to be transported to the cell by special means, e.g. fat, for the simple reason that it is non-polarized, or does not carry a charge. For this reason, it is difficult for a diffusion gradient to be set up for moving fats (lipids).
The most likely method for moving fats is to attach them to proteins which can give them a charge. We know that lipoproteins are the most common method for moving fats in the body (Fredrickson et. al, 1967, Kingsbury & Bondy 2003, both inside blood vessels and outside them. HDL cholesterol is called “high density” because it has a lot of densely packed proteins at the core of the molecule. It is responsible for carrying lipids out of cells to the liver for repackaging or processing. LDL cholesterol is called “low density” because there is higher lipid relative to the protein content. It is responsible for carrying lipids from the liver to the cells in the body.
The one problem I see is how the diffusion gradient gets set up to get these lipoproteins (or any other ion) to the cell membrane. I can imagine how a sluggish hypodermal fluid flow will cause pooling of these lipoproteins. (About ion transport, see the section “Basic Chemistry” in the post Cholesterol and Heart Disease, Value and Dangers of Lithium). Diffusion can only occur over very short distances. We are not vascularized enough to put a capillary close enough to every cell that needs a nutrient. Our tissues have to set up diffusion gradients so that the nutrient can travel that distance across the space between a capillary and all the cells vascularized by it. As far as I can tell, no one has addressed this problem. Most research has focused on transport across the cell membrane of either the blood vessels endothelial cell or the target cell’s membrane. This one area of research is the missing link between a normal and efficiently operating body and one with physical disorders or having difficulty recovering from a disease. (See Mind-Body Medicine and Joint Pain, Cholesterol and Heart Disease, Mind-Body Medicine for Babies)
I propose that the missing link lies precisely in this missing mechanism for setting up a diffusion gradient for transport of nutrients to the cell or waste products from the cell. I have mentioned elsewhere how toxins traveling in the hypodermis can be responsible for many disorders (Toxins, Using MRT: Removing Toxins and Emotional Trauma.) If there is a separate system for setting up a diffusion gradient in the hypodermis and in connective tissue everywhere, an “open” system separate from, but to some degree, affected by the “closed” vascular system, then it stands to reason that toxins can interfere with it, cause pain wherever there are pain nerves (hypodermis, lamina propria and wherever the connective tissue highway enters and joins with organs and their own connective tissue highways), travel from underarm to groin, and disintegrate hypodermal fat. Furthermore, acupuncture may work because it acts directly on this diffusion mechanism, correcting an imbalance in the fluid flow within the hypodermis.
When we sleep, we tend to lie in a position parallel to the surface of the bed. We don’t stand or sit up. That creates a small incline in our bodies, with the feet and groin lying lower than the head and shoulders. While we sleep, much of the nervous system would be at rest and the diffusion gradient set up by cells in the hypodermis may also be difficult to maintain. When that happens, flow in the hypodermal fluids also slows down. If toxins are there, they can increase the likelihood of this slow-down, simply by interfering with this system or damaging the cells critical for its maintenance, making toxins more likely to pool. They will drop with gravity to the lowest areas of the body, e.g. the feet, hands, pelvic basin, doing damage there.
Furthermore, when we sit or stand, the toxins will also tend to move to the same areas and pool, doing damage there. The only time toxins won’t pool is when we are actively moving a lot of muscle. Active muscle needs calcium and phosphate, and no doubt, these ions will move quickly toward these muscles, by both “highways” available, the blood vascular system and the hypodermal highways found as channels within the fat and other cells of the loose connective tissue there. It should not come as a surprise that many disorders people have associated with the groin area (prostate enlargement, urethritis, reproductive cancers, urinary tract infections, hemorrhoids, infertility, erectile dysfunction, vaginal dryness, menstrual cramping, early menopause, ovarian cysts, endometriosis, prolapsed vagina or rectum, colon cancer, Crohn’s disease, irritable bowel disorder, sciatica, and many others) may have a toxic origin.
Toxins pooling in the hands and feet can decimate the fat pads found on the ventral surfaces (palmar and plantar sides). This may be why our feet hurt when we first awaken and start to walk on feet so affected. The pain goes away after walking only because the toxins get pulled away from the area by all the calcium and phosphate rushing up to supply the active leg muscles. After a few years of pooling in the feet, the pain doesn’t go away because the fat pads are so reduced that there is no longer any cushion.
Comment on “Why You Have To Scratch That Itch” on Morning Edition for 24 May 2013. Scientists have researched why we scratch that itch. In order to figure this out, they had to find out what is causing that itch, and not just what happens on the surface of the skin. They realized that nerves had to trigger the feeling of itch and we don’t have any that come out on the surface of our skin. So they had to induce itching from under the skin. They found a surprising molecule inside neurons responsible for telling our nervous system that we have an itch. That is just the start of a cascade of nervous signals that eventually make it up to our conscious brains to tell us that we feel an itch. What happens next?
Mishra & Hoon (2013) studied what causes mice to scratch. NPR reporter Rhitu Chatterjee tells us that they discovered a molecule, natriuretic polypeptide b (Nppb), which normally resides in the heart to regulate blood pressure, also resides inside specific neurons which sense an itch on the surface of the body. This molecule is a spinal nerve neurotransmitter which triggers the beginning of a series of neuron signals to the brain to tell us that we feel an itch. They injected irritants composed of chloroquine (see movie at the NPR site), histamine, and substance P (see supplemental movies) into the dermis of “wild type” and genetically modified (knockout or lacking Nppb neurotransmitter) mice. Wild type mice scratched in response to the injections, but knockout mice did not. When the researchers injected Nppb into both types of mice, the both started to scratch. They showed that Nppb was the substance that triggered a scratch response. However, they did not show what caused Nppb to be triggered by any of these irritants, in other words, what was happening chemically to trigger these neurons to send Nppb to the spinal cord. They do not know if humans have this molecule and if it plays the same role in humans as it does in mice.
My Comments at NPR
How does dialysis cause itching? I suspect that it is closely related to what these researchers are doing by injecting itch-causing substances intradermally. The important detail is that it is into the dermis. The dermis is where most nerve endings are. Touch neurons enter the epidermis, but pain, heat, cold, pressure, and proprioception (position or stretch) receptors are in the dermis or deeper (e.g. hypodermis). Moreover, there is a strong physical and chemical connection between the hypodermal fluids and those traveling within the layers of the dermis. There is a whole new world in the hypodermis that needs a lot of investigation and Traditional Chinese Medicine (acupuncture) may offer us a window into that world, along with a different perspective that can combine both Western and Eastern medicine.
Mishra & Hoon (2013) clearly are on the right track. I suspected that pain and heat/cold receptors were involved. However, they did not address why a person itches. In other words, why evolve a molecule (Nppb) which makes a person want to scratch an itch? There is no adaptive reason for creating an itch if that feeling is conveyed to the conscious brain and we don’t respond to it, other than look closely at the skin. How and why does that molecule get produced when a mosquito or gnat or “no-see-em” injects its poison under our skin? or does it respond to the inflammation and swelling caused by that poison and not the poison itself? If so, why not to other causes of inflammation, e.g. to joints? I suspect that we need to see what happens when we scratch an itch. We know that sometimes the itch goes away when we scratch, if for only a few seconds. What exactly is happening? I have a theory involving local controls of non-vascular fluid flow that explains both how scratching an itch works and how dialysis causes itching at my blog post ‘What is the Hypodermis?’ at https://marthalhyde.wordpress.com/2011/05/20/what-is-the-hypodermis/
I think all of this is closely related to what happens with dialysis. Dialysis involves sending our blood into a machine to do what the kidney is supposed to do, and then sending the filtered stuff back into our bodies. The blood vascular system is supposed to pick up and send nutrients, including oxygen, to the tissues/cells, and pick up metabolites and waste from the cells, like CO2 and other stuff, to go to the kidney or lungs.
Most people just think of tissues in the form of organs, and maybe include cells and blood vessels when told about the functions of the cardiovascular system. Very few think of the space between the cells and blood vessels where interstitial fluid flows (made up of water, nutrients and metabolites). This “space” is extremely important and must have its own flow direction and power. Why? because in order for nutrients to pass from the blood vessels (capillaries) to the cells, they have to cross this space. It is not small, because we are not that heavily vascularized except in the liver, kidney, and blood/immune organs. One capillary must serve thousands of cells.
The power comes from chemistry, not muscles (as in the cardiovascular system). Our bodies have to set up a diffusion gradient, which cannot be done if the blood vessel just dumps all nutrients out into that space. Nutrient dumps are composed of a mix of electrical charge (+ and -) and molecular sizes. Molecules just don’t sort themselves out without some “push”, e.g. a negative ion field to move positively charged molecules. There has to be another system of cells which helps set up a diffusion gradient of needed nutrients. I suspect that is one function of visceroceptors of the nervous system.
Many of these neurons have endings in the hypodermis and probably are triggered by signaling molecules (e.g. calcium) released by the needy cells. Thus, it is probable that the hypodermal fluids (continuous with fluids floating around and within the matrix of all organs) have a fixed charge set up before it gets flooded with capillary or tissue discharge, and which changes in response to the content that got dumped. The visceroceptor system has to be triggered to control that charge as needed, locally. It causes a response when any new material gets introduced into the hypodermis, whether by a mosquito bite or by dialysis (a change in blood content will cause a change in hypodermal content), or when injected by these researchers.
The needs of cells are different and are constantly relayed to the spinal cord, which acts to affect blood flow. Dialysis pulses this new content; it doesn’t come in a constant stream for which the hypodermal visceroceptors have to be “turned on” all the time. Furthermore, every time we empty our bladders, the kidney, which was “backed up” by a full bladder before, now has the chance to start fluid flowing again. Fluid flow in the kidney causes changes in the fluid flow in the hypodermal/interstitial fluid elsewhere. That is why, after we urinate, we might notice sudden itching anywhere on the body, or we cough, or we feel pain somewhere, or a change in blood pressure. The blood vascular system is closely tied to water balance in the body. That means once we remove water, it has to be replaced, but if flow is backed up in the system with a full bladder it won’t be replaced everywhere. Dialysis pulsing acts on this hypodermal/interstitial fluid as if we are constantly urinating from a full bladder, not at one time, but thousands of times spaced apart in time.
So why scratch an itch? It is likely that the substances injected by Mishra & Hoon (2013) irritated the nerves carrying Nppb, and caused the neurons to trigger Nppb to be sent to the spinal cord. Other substances could cause irritation with the same response by the neuron. It appears that Nppb is an “auto-irritant”. Scratching activates other nerves (deep pressure and proprioception) which then cause blood vessels to release lots of calcium into the hypodermis. This changes the charge around these Nppb transmitting neurons so that they won’t send any more signals.
It doesn’t matter if the irritating molecules are positive or negatively charged because, either way, it changes the chemical environment to a non-irritating one. Negative irritants will bind with the calcium and become “inert” and positive molecules will be chased off by the calcium to combine with negative ions “downstream” (they will be there for setting up a directional flow within the hypodermis). Scratching an itch “chases” away the irritant. The itch returns if the irritant is especially plentiful, keeps getting dumped there (e.g. dialysis), if calcium is not enough to make the irritant harmless, or if the directional flow pattern is disrupted and the right ions are not available downstream.
Buchen, L. (2009). The itch without the pain. Nature News, 6 Aug 2009 doi:10.1038/news.2009.802. [Freely Available].
Fredrickson, D. S., Levy, R. I. & Lees, R. S. (1967). Fat transport in lipoproteins — An integrated approach to mechanisms and disorders. New England Journal of Medicine, 276(1), 34-44. [Freely Available].
Kingsbury, K. J. & Bondy, G. (2003). Understanding the essentials of blood lipid metabolism. Medscape, Apr 11, 2003 [you must register to see it].
Li, W. & Ahn, A. C. (2011). Subcutaneous Fascial Bands—A Qualitative and Morphometric Analysis. PLoS ONE, 6(9): e23987. [Freely Available].
Mishra, S. K. & Hoon, M. A.( 2013). The cells and circuitry for itch responses in mice. Science, 340(6135), 968-971. Supplementary Information
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