target="_self">Figure 5). These detectors are pushed by the flowing interstitial fluid, and the ISF can flow inside the duct as indicated by the white arrows, bringing with it the debris (circle in brown), protein(orange) from the interstitium, and cells (lymphocytes and other cells, represented by ellipsoid with nucleus). The interstitial fluid flows through overlapping edges of neighboring endothelial cells (microvalves). In contrast to the structure of a blood capillary, a lymphatic capillary has a thin wall with a wide lumen, irregular structure; the wall does not contain pericytes and a basement membrane. Following the flow, the lymph is then drained into a collecting lymphatic vessel [103] , which is surrounded

(a) (b)

Figure 5. (a) Cross-section of an initiative lymphatic vessel with hairy detector. This type of vessel is built of over-lapping endothelial cells with connective tissue (omitted in the diagram for simplicity). When the hairy detector is pushed by the flowing interstitial fluid, the ISF can flow into the duct as indicated by the white arrows, bringing with it the debris (circle in brown), protein (orange) from the interstitium, and cells (lymphocytes and other cells, represented by ellipsoid with nucleus).With very low interstitial fluid pressure, the “flaps” are closed. Therefore fluent ISF flow will “open” the initiative lymphatic duct to trigger off the immunity response. (b) A basic unit of collecting duct-lymphangion. The endothelial cells are painted in light purple, which is surrounded by basal membrane, similar to that in a blood vessel. The bluish purple structure with nucleus represents the smooth muscle and para-vascular cells. There are two valves at both ends, to provide one-way traffic for the lymph flow. When the lymph fluid flows in, the lymphangion bulges a little because the fluid pressure is increased. The yellowish region represents the connective tissue (collagen)―and the outer part is similar to the adventitia in blood vessel. The smooth muscle cells are not so strong as that of the blood vessels and extrinsic propulsion is often needed. Figure 5(a) is modified from Figure 1 of [103] and Figure 5(b) is modified from reference ( [102] Figure 2 D). These diagrams were painted by author PCWF.

by a basement membrane, a layer of smooth muscle cells (SMC) or pericytes (see Figure 5, showing a basic unit of a collecting vessel, a lymphangion). These collecting lymph vessels contain luminal valves in order to prevent the back-flow. The one-way transport lymphatic system plays a key role in the maintenance of normal interstitial fluid volume and protein concentration. The immune competent cells also enter the lymph vessels and do their duties in the lymphatic nodes.

6.4. Intrinsic Propulsion of Fluid by the Lymph Pump

Even the ISF can enter the lymphatic initial duct, a propulsion mechanism is needed to drive the fluid flow. Historically, to look for the origin of such propulsion force driving lymph to flow through the peripheral to the major lymph duct (such as the thoracic duct), and then to the venous system, a series of experiments with unanaesthetized sheep as model were carried out half a century ago (see e.g. [104] ).

Using a fistula system in the sheep model to study the lymph flow characteristics, it was found that lymph flow was intermittent with a well-defined rhythm that was unrelated to muscle movements, unrelated to respiration (except in the case of the thoracic duct for obvious reason based on anatomical structure).

The pulsatile pressures recorded from the various lymphatics ranged from 1 to 25 mm Hg, with pulse frequencies from 1 to 30/min. The magnitude & pulse rate of the pressure pulses increased as the lymph flow rate increased. When the various lymphatic cannulas (in the fistula system) were clamped to prevent lymph flow, the pressures in the lymphatics increased (reaching a high pressure up to 60 mm Hg) and the frequency of contractions also increased.

From experiment such as that just mentioned, we learn that one important driving force to cause lymph flow is the intrinsic contractile activity of the active lymph pump (composed of a series of lymphangions) whose function has been considered to be similar to the cardiac cycling action [105] [106] . Note also that there are branching patterns of lymphatic system, making the flow profile in lymphatics even more complicated. In general there are no valves at the junctures of lymphatic branch points. Thus the contractile activity around the junctures is asymmetric and significant retrograde flow could well result. Hence it is difficult to predict the general direction of lymph flow in a local region unless the detailed structure of the vessel system, together with the nature and locations of valves are known. However, the early experimental result in [107] already showed rather convincingly that intrinsic rhythmic contractions of the valved lymphatic vessels are mainly responsible for the propulsion of lymph from the periphery to the thoracic duct, with the function to control the removal of tissue fluid at a rate proportional to its rate of formation. Thus the intrinsic contraction mechanism has been considered to be established.

6.5. Extrinsic Forces Can Affect the Flow Characteristics

6.5.1. Definition of Extrinsic Propulsion Forces on Lymph Flow

There are several extrinsic forces that can reinforce or impede lymph flow, which has been caused by forces external to the lymph vessel, in a complicated manner: (i) The pulsation of the nearby blood vessels would aid lymph flow. (ii) Motion of skeletal muscles or tissues around the lymphatic vessels during exercise would squeeze the lymphatic vessels and aid fluid flow. However, it was reported long ago that sustained skeletal muscle activity would decrease lymph flow [107] [108] because outflow resistance of peripheral lymphatics would be increased. We consider such a result is expected because there is evidence that pulsatile pressure on the lymphatic vessels would enhance lymph flow; but compression with too large a frequency or too large a force would impede the lymphangion pulsations. (iii) The suction effects of respiration. Most of the time these forces help to move lymph centripetally. (iv) Note also that there are branching patterns of lymphatic system affecting the flow profile driven by both the intrinsic and extrinsic forces. Now the term “extrinsic” lymph pump is meant to be a combination all extra-lymphatic forces which can influence (in general meaning enhancement) lymph flow. The origin of these forces (which can be applied artificially) is not connected with active contractions of muscle cells in the lymphatic vessel wall.

6.5.2. Evidence of the Effect of Blood Vessel Pulsations on Lymph Pressure of Large Lymph Vessels

Since many branches of the artery and lymphatic vessels run roughly parallel to each other for long distances, intuitively one expects that movements from the great arterial trunks are imparted to the larger collecting lymphatics. In a number of studies, it has been inferred that the continual pulsatile motion of the lymphatic vessels are at least in part originated from the pulsation of the blood circulation. On the other hand, in the neck, where the thoracic duct is in close relation to large pulsating veins, venous pulsations are considered to be transmitted to the lymph also (in particular, in the subclavian triangle area). Using dog’s model, the rhythmic intralymphatic pressure change in the supradiaphragmatic and cervical thoracic duct was investigated [109] . In both areas lymphatic pulses were found to be transmitted from the nearby large arteries. In the neck region, venous pulsations were also shown to be transmitted to the lymph in a similar manner. However, these pulsations were shown to propagate for only a few millimeters. In conclusion to this aspect, the blood circulation pulsation may trigger the pulsation of the lymph to certain extent. On the other hand, for smaller vessels in the peripheral regions, further study is needed to confirm such features relating to “transmitting of pulses between nearby small vessels”.

6.6. Physiological Functions of the Lymphatic System and the Causes of Lymphedema [96]

The main function of lymphatic smooth muscle cells is to maintain tissue fluid homeostasis, by contracting rhythmically to allow the lymphatic system to remove the suitable amount of interstitial fluid, proteins plus lipid drops from the interstitial space [110] . The lymph flow drives the immunity cells, antigens, and fat to the lymph nodes whereby immunity function, fat transportation (eventually to be metabolized at the right place) are carried out. As explained in Section 4, clearance of debris of the ISF is important to health, implying lymphatic malfunction can be very series. Lymphatic dysfunction can be triggered by (i) gene mutations, or (ii) damage to the lymph vessels or valves. Tissue inflammation arising from external insult, or blood vessel leakage may lead to excessive storage of interstitial fluid and hence excessive increase in ISF pressure, resulting (ii) above. The overall consequence of lymphatic dysfunction is impaired immunity, chronic edema in the interstitium and accumulation of subcutaneous fat.

Colloid proteins and water are constantly filtrated from the arterial side of the capillary bed into the interstitium (red arrows in Figure 1 of [102] ). Under physiological condition, majority of the filtrate is collected by the lymphatic capillaries (green arrows in Figure 1 of [102] ) whereas a small amount of the fluid is reabsorbed into the venous capillaries (blue arrows in Figure 1 of [102] ). However, during inflammation, a much larger amount of filtrate enters into the interstititum. If there is obstruction of the veins due to venous thrombosis or venous insufficiency, the reabsorption process will be impeded. Further, if certain parts of the lymphatic drainage system are dysfunctional, edema would result. Therefore, lymphedema is now defined as tissue swelling due to a low output failure of the lymphatics, leading to accumulation of (macromolecule-rich) interstitial fluid in the interstitium. If the primary blockage of lymph flow occurs in the lymph conducting pathways inside the lymph vessels or lymph nodes, the phenomenon is called primary lymphedema. If the stated obstructing of lymph flow occurs elsewhere, the disease is called secondary lymphedema [111] . In both of these two situations, lymphatic smooth muscle dysfunction is the main cause of the pathology. Lymphatic filariasis is the most common cause of lymphedema in general, affecting over 100 million people world-wide. The most common symptoms of such a disease are lymphangitis, dilated lymphatics, and decreased lymphatic contractile function, leading to weakening of lymphatic contractile activity [111] .

6.7. Proper Exercise or Massage Enhances Lymph Flow

Radioactively labelled serum albumin was injected bilaterally into the vastus lateralis muscles of eight subjects (n = 16). The scintographic method was employed in [112] to measure the total clearance of the radioactive tracer, but this method cannot distinguish between convective removal via the lymphatics and dissipative transport via blood capillaries. It was noted, however, in the clearance of interstitially injected albumin, the convective transport of lymphatics removes at least 75% of the interstitial albumin [113] . The subjects performed 100 submaximal contractions exercise in 10 min as (i) dynamic knee extensions (CONS), (ii) isometric contractions with the knees at full extension (IMExt), or (iii) isometric contractions with knees fixed at 90 deg angle flexion (IMFlex). The exercises were separated by 65 min periods in supine rest.

Reference [112] reported that there was a consistent three- to sixfold increase in the clearance rates due to muscle contractions by subjects performing three types of knee exercise stated above. Subjects: Eight healthy men (25 - 55 years) volunteered for the study.

Evidence of massage enhances skin lymph flow

Recirculation of the extravascular protein molecules, colloids back to the blood stream is an important function of lymphatic system.

Using 99mTc-colloid (TCK17 Cis) as a tracer, the lymph flow clearance in the skin was analyzed in anaesthetized pigs, in response to massage as a stimulus. It was found that lymph flow was slow and labile; at the capillary level, lymph propulsion was considered to be generated mainly by tissue movement. Gentle local massage applied continuously around (but not over the injection site) was performed employing a hand-held massager. Not only the clearance rate of the massaged sites was faster, the clearance rate of the non-massaged areas was also enhanced. The authors interpreted such as result as due to systemic effect or a spinal-reflex effect, leading to increase of lymph flow on the contra-lateralside [114] .

7. The Glymphatic System

7.1. Endeavor to Understand Pathways for Lymphatic Drainage of CSF along Sheaths of Nerves and Spinal Cord up to the Early 2000s

Throughout the several decades before 2000s, there were debates about whether there was direct connection between the CSF and nasal lymphatics. Scientists attempted to find out the mechanism of such clearance [115] [116] . In particular, drainage via the neighborhood of facial nerves was therefore investigated. There were two models to explain the proposed drainage.

A simplified anatomical picture of olfactory nerves and cribriform plate, arachnoid space of the head is shown in Figure 6(a). In the first preposition there was the “open cuff model” (as Model B in Figure 6(b)) in which the perineural sheath cells were assumed to “disappear distal” to the cribriform plate, giving space for the CSF to flow into the interstitial space (outside the skull) where it is absorbed by the initial lymphatics in the olfactory and respiratory submucosa [115] . There was also the “closed cuff model”, assuming the perineural space as a roughly spread out sag (cul de sac) so that the lymphatic vessels could fuse with the perineural cells, getting direct access to CSF which flows along the olfactory nerve (as Model A in Fig. 6 (C)). There were very good attempts for around the past two decades to distinguish which model was realistic. However, more recent data (in rat and other animal models, using microfilm as a contrast medium) suggests rather, that CSF-BISF could move directly from the subarachnoid space into submucosal lymphatics that emerge at the level of the cribriform plate, implying the clearance process is more efficient than that represented by Figure 6(C) [117] [118] [119] [120] [121] . During that time, the function of the glymphatic system (specified in later sub-sections) was not clearly understood.

Among those experiments, an important lymphatic CSF-BISF clearance pathway is the olfactory route leading to cervical lymphatic vessels. However, there is accumulating evidence there are other nerves, such as the trigeminal, acoustic, hypoglossal and vagus nerves [120] which may conduct CSF-BISF extra-cranially. Later, lymphatic vessels were found in vascularized human corneas [122] .

Figure 6. (a) Simplified anatomical picture of olfactory nerves and cribriform plate, arachnoid space of the head. (b) A model in which the wastes have to enter the submucosa interstitium below the cribriform plate, and join the ISF there. Lymphatic vessels are present in the submucosa region and the wastes are carried by ISF and enter the lymph system as in many parts of the body. (c) Shows the model where the lymphatic vessels are very close or directly below the cribriform plate, so that in a three dimension picture, the lymphatic vessels “enclose” or “form a collar-like” structure around each olfactory nerve. The debris/wastes from the subarachnoid space are driven by fluid pressure to enter the initial lymphatic vessels and are eventually drained through the lymphatic nodes in the facial and neck regions. Figures 6(a)-(c) were painted by author PCWF.

One possible location for lymphatic CSF-BISF absorption that has been ignored generally is the dura of the spinal cord itself. In rats, lymphatics exist around the wall of the sagittal sinus, in the regions of the confluence of sinuses in the neighborhood of the mesothelial cells of the subdural spaces and close to the vasculature of the dura tissues [123] .

India ink infused into the ventricles or cisterna magna of rabbits has been found to emerge around spinal nerve roots as well as in the lumbar para-aortic lymph nodes in rats [124] [125] . Also, in monkeys, lymphatic vessels have been observed in spinal epidural tissues [126] . Since there is no direct evidence supporting direct spinal CSF-BISF- lymph connections so far, it appears that CSF-BISF from the spinal subarachnoid compartment first passes into the epidural tissues from which absorption takes place into blind ending lymphatic vessels ( [116] Figures 1E-1F). Quantitatively, studies employing sheep model showed that the relative proportion of CSF absorption by the spinal compartment amounts to about 25% of total CSF-BISF clearance [127] . Thus, though there was evidence of lymphatic clearance of CSF-BISF in the dura mater of the spinal cord, the mechanism of clearance of the brain fluid inside the skull was a mystery for decades. Note that in the above studies, CSF was considered as an isolated fluid; i.e. the mixing of CSF and BISF was not understood then.

7.2. Evidence of Drainage of Solute and Insoluble Fluorescent Microspheres through the Basal Membrane of the Arterial Vessels to the Subarachnoid Space Based on Mouse Model Study― Beginning to Discover the Glymphatic System

Using the (healthy) mouse model, 3-kDa soluble dextran, ovalbumin (40 kDa), and insoluble particulate fluospheres (0.02 mm and 1.0 mm in diameter) were injected into the grey matter of the corpus striatum (caudate putamen) of the brain. Imaging and immunocytochemistry analysis were carried out after 5 min to 7 days. This is set (i) of model. In Figure 7(a) (adapted from Figure 1 of [128] ) is a schematic representation of a longitudinal section of a capillary joined to an artery vessel passing through the parenchymal region to the subarachnoid space. The inner most layer of endothelial cells (pink) is surrounded by a basement membrane, outside of which is a layer of smooth muscle cells. The external elastic membrane encloses this layer of cells. There are also perivascular cells in an artery vessel. The vasculature system has a layer of pia mater. According to the result of [128] , the solute (together with fluid), as indicated by brown arrows, enters the basement membrane and the smooth muscle cells, and flow outside the parenchyma region, at least to the subarachnoid space. If the artery is inside the subarachnoid space (SAS) for a distance, these solutes may enter the vein vessels and drain via the classical pathway. If the artery vessel passes outside the skull, we anticipate that the solutes will enter the ISF in the facial region and be drained via the lymphatic initial vessels there. Experimental result in [128] also suggests that the insoluble tracers (brown small circles) passes along the connective tissues (not shown in above diagram for simplicity) which might be considered as part of the basal membrane between the

(a) (b)

Figure 7. (a) Schematic representation of a longitudinal section of a capillary joined to an artery vessel passing through the parenchymal region to the subarachnoid space. The inner most layer of endothelial cells (pink) is surrounded by a basement membrane, outside of which is a layer of smooth muscle cells which are wrapped around by connective tissues (together forming the tunica medium) which can be considered to be extension of the basal membrane. The external elastic membrane encloses this layer of cells. There are also perivascular cells together with connective tissue layer, forming the adventitia. The vasculature system in the brain has a thin layer of pia mater (light grey color). The dotted arrow indicates the blood flow direction and the solid brown arrows represent the pathways of the solutes which are drained either to the arachnoid space and might be drained to regions outside the skull, depending on where the arterial vessel passes through. The connective tissues around the smooth muscle cells are not shown here for simplicity. (b) Experimental result suggests that the insoluble tracers (brown small circles) pass along the connective tissues (not shown in above diagram for simplicity) which might be considered as part of the basal membrane between the smooth muscle cells in the tunica media. The basement membrane is split into two layers, and the insoluble fluospheres (brown circles) are brought by the fluid through such a space, and are engulfed by the macrophages (also stained in the experiment) migrated from the blood vessel. Diagrams above are modified by painting (author PCWF) from Figure 3 and Figure 4 of [128] . Note that arterial blood vessels release macrophages and lymphocytes (see (Section 3)).

smooth muscle cells in the tunica media. The basement membrane is split into two layers, and the insoluble fluospheres (brown circles) are brought by the fluid through such a space, and are engulfed by the macrophages migrated from the blood vessel (see Figure 7(b)). The very recent evidence of the existence of lymph vessels (which will be called the glymphatic vessels) in the SAS provides a direct route to drain these solutes; this aspect will be discussed in details in the next subsection. In set (ii) model of [128] , mice were suffering from cardiac arrest. It was found that the stated peri-vascular solute drainage did not occur. Such a result can be taken to suggest that rhythmic propulsion of blood through the arterial vessels might take part to induce the passage of the brain fluid through the basal membrane of the vessel.

Experimental results reported in [128] also suggest that the basement membrane (being built of collagen fibers with loose structure) is split into two membrane layers, and the (insoluble) particles are brought by the fluid through such a space. During the past several years, there are reports from different groups reporting similar type of peri/ para-vasculature drainage from the brain. Numerical analysis of motion of particles in a fluid in motions supports that idea that the wastes are more readily carried along the peri-arterial space, rather than carried by diffusion in the parenchyma [129] .

7.3. The Glymphatic System (Existence of Lymphatic Vessels inside the Skull) Confirmed in Mice Model

In [130] the authors used a transgenic mice model that expresses the green fluorescent protein under the promoter of Prox1, a master control gene in lymphatic development. Through imaging the expression pattern of the Prox1 gene in glymphatic endothelial cells, the detailed structure and morphology of dura glymphatic vessels in the model were revealed clearly. We use the term glymphatic vessels to signify the lymphatic vessels inside and at the boundary of the skull bone. In Figure 1 of [130] , white arrowheads denote glymphatic vessels, yellow arrow heads denote the exit sites where the newly found glymphatic vessels leave the skull. To their surprise, an extensive network of glymphatic vessels was found in the meninges underlying the skull bones (Figures 1A-1J of [130] ). In sagittal planes of the inner skull, glymphatic vessels were observed to run down toward the base of the skull along the transverse sinus, the sigmoid sinus, the retroglenoid vein, the rostral rhinal vein, and the major branches of the middle and anterior meningeal arteries. Moreover, during their experimentation, the authors reported visualization of glymphatic vessels in the vicinity of several nerves―optic, trigeminal, glossopharyngeal, vagus, and accessory―at sites where these nerves exit the skull. In particular, glymphatic vessels could be observed also in the dura lining of the cribriform plate, where blood vessels and olfactory nerves passed from the skull into the nasal mucosa. It was noted that only the glymphatic vessels at the base of the skull contained valves; we consider such a setting is a natural protective measure for clearance, in order to ensure the lymph flows outside, but not into, the skull.

Moreover, tracers were injected into the parenchyma region of the brain where BISF carries nutrients into the neurons and receives wastes. While it is difficult to trace the transport of wastes all along the pathways for obvious technical reason, using ligation technique, it was demonstrated in [130] that (extra-cranial) ISF was not drained to the superficial cervical node, but rather to the deep cervical node of the lymphatic system. Further, with a transgenic mouse model expressing complete aplasia of the dura glymphatic vessels, macromolecule clearance from the dura region into the deep cervical lymph nodes was abrogated, while the fluid content was not affected. Based on this particular result, we suggest that the BISF could well flow out of the brain through the sheath of the blood vessels (in particular the veins). If the dura glymph vessels are well developed, the macromolecules are transported to the deep cervical nodes. In Figure 8, we therefore draw glymphatic vessels in the dura layer outside the arachnoid layer. Outside the dura space is the skull bone [131] [132] .

We would also note that there is evidence that lymphatic vessels were found in the cornea of human eye over one decade ago [122] . Upon discovery of the glymphatic system, it is of practical importance to search for the condition under which the clearance system is most effective ? this is discussed in the following sub-section.

7.4. On Drainage during Sleep

The removal of potentially toxic biomolecules that accumulate during normal physiological function is an issue of health and the process of aging. By the age of 85, the risk of Alzheimer’s disease (AD) is estimated to be about 50% [133] .

In the brain, metabolic protein β-Amyloid has quite many functions such as cholesterol transport, activation of kinases, as antioxidant, as a transcription factor, and participating in protection from microbes. Clearance of this protein is known to be via (i) uptake by microglial phagocytosis; (ii) receptor-mediated transport across the blood

Figure 8. Similar to Figure 4 in Section 5, where we discussed the mixing of the two brain fluids. We simply add the newly discovered glymphatic vessels present (green) in the dura space according to the finding of [130] . The tracers were found inside the glymph vessels. The main trunk/group of glymph vessels pass through certain foramina of the skull bone and join the superficial and/or deep cervical nodes, which are further connected to the lymphatic ducts on both sides of the thymus. In this diagram, the arterial vessel has penetrated into the subarachnoid space from somewhere not shown in the diagram and turn up to pass across a pia layer into the brain, whereas the venous vessel passes through the dura space, and other boundary layers to exit the skull (Figure 8, being painted by author PCWF, is modified from [91] and the presence of the (greenish) lymphatic vessels represents the discovery of [130] ).

vessel walls; (iii) degradation by enzymes such as matrix metalloproteinase-9, glutamate carboxypeptidase II, insulin-degrading enzyme [134] . However, at old age, intra-cranial clearance is not fast enough to clear off this protein. In fact, β-Amyloid plaques are found in the brain of AD patients. In addition, there are other pathological brain proteins such as α-synuclein and tau protein which are also cleared by a number of enzymes and the processes are not efficient enough during old age. Thus the accumulation of the mentioned proteins is known to be the main causes of a number of chronic brain diseases [135] .

One of the key factors in brain clearance is thus how fast the CSF can flow to mix with the ISF so that CSF-BISF can carry the wastes to be drained eventually through the lymph node. In [136] , tracers were injected at the cisterna magna and their movement was imaged in real time. With blue-dextran administered via the femoral vein, the vasculature of the live animal could be visualized by imaging. It was demonstrated that during the wake stage, the flow area of the CSF-BISF influx covered was very much smaller than that during the sleep condition [136] .

On the other hand, the ISF is generated by the arteries in the brain cortex; these arteries are enclosed by the astrocytic end-feet which are equipped with water channel AQP4. The astrocytic end-feet enclose the arteries and form the BBB. Hence the fluid comes out from the arteries, together with some nutrients and very small molecules to the parenchyma in the brain, is not harmful. However, after receiving metabolic wastes from the neurons and astrocytes, the fluid has to be cleared from the brain.

The amount of CSF-BISF in the parenchyma is therefore dependent on how efficient the Aquaporin 4 channels in transporting water and nutrient to the parenchyma, as well as transporting the “dirty fluid” to the peri-vessel sheaths. Moreover, if there is a change in the total volume of the astrocytes in the brain during the sleep and wake stages, there is a difference in the volume available for CSF-BISF transport. Intuitively, if there is more room for the convective flow of CSF-BISF, we anticipate a faster clearance rate [136] . Moreover, we anticipate that the efficiency of the mixing process across the ependyma is also dependent on the transport efficiency of the AQP4 in the ependymal layer. From the fluid dynamics point of view, if the interstitial space increases, the convective flow of CSF-BISF is more fluent and the incoming CSF and BISF exchange process is more effective. The clearance of the brain wastes is inferred to be associated with the outflow of CSF-BISF to the glymphatic vessels at the subarachnoid space at the base of the skull based on updated research result. The discovery and confirmation of the glymphatic system implies that the brain wastes clearance is more efficient if we learn about under what condition there is more interstitial space. Relatively recently, there is evidence, using in vivo mice models, that natural sleep or anesthesia is associated with a 60% increase in the interstitial space. The consequence, in turn significantly increases convective exchange of CSF with BISF via the glymphatic system, removing potential neurotoxic waste products such as Beta-amyloid along the peri-vessel pathways. Moreover, sleeping in lateral posture seems to be the best posture so far found for brain clearance [137] [138] .

Note that AQP4 is expressed in astrocytes and ependymal cells throughout the brain and spinal cord, at the pial and ependymal surfaces in contact with the cerebrospinal fluid (CSF) in the subarachnoid space and the ventricular system. We anticipate that AQP4 plays crucial roles in brain clearance, and there may be difference in the function of this water channel during the wake and sleep states, leading to the observed effect on brain clearance as described above [139] .

7.5. Enhancement of the Glymphatic Clearance System by Non-Invasive Simple Bian Stone Maneuver Techniques

Bian stone massage techniques came before acupuncture as a set of health-care techniques and therapy in ancient China to treat pains and health disorders [140] . Unfortunately, no literature reporting the ancient maneuver techniques can be found so far. On the other hand, there is extensive literature reporting the efficacy of acupuncture in a range of disorders. However, when there are disorders related to inflammation of connective tissues, and stagnation of lymphatic vessels, massage techniques are frequently used. The present authors have developed a system of non-invasive maneuver techniques using warm Bian stone to treat pains and edema. Some stroke directions and the relevant lymph nodes are indicated in Figure 9. As this paper is devoted to analysis of the five-fluid system, the details of such techniques will not be discussed here. However, to be in line with the present subject matter, it might be fruitful to introduce some simple Bian stone strokes to enhance lymph flow based on experience of formal experience to treat disorders and scientific investigation on physical properties of the Sibin Bian stone material by RKCK [141] [142] [143] and years of experience to treat edema as a health care modality by both authors not under clinical setting. Details

Figure 9. Simple Bian stone massage strokes for consideration to enhance brain drainage. Some crucial lymph nodes are labelled and the arrows indicate the direction of light maneuver strokes. Figure 9 is a painting done by author PCWF.

of the modality related to specific health disorder, with evidence-based explanation, will be written in other papers.

Incidentally, there are only a few venous vessels which can allow blood flow both ways (see Section 3). If the emissary veins can lead blood into the brain, it could be very harmful. In fact, the regions allowing double-way flow, i.e. the emissary regions have been named the dangerous regions. Mechanical maneuver to avoid venous blood into the brain may be a useful technique in health keeping.

8. An Overview of the Five-Fluid Circulation System and the Importance of Investigating the Fluid Dynamics of This Integrative System

Based on the analysis presented in the previous sections, we wish to present an overall schematic representation of the subject matter of this paper. We hypothesize that the Promo Fluid, Blood, (extra-cranial) Interstitial Fluid, the CSF-BISF Fluid, and Lymph (which can be divided into (i) extra-cranial lymph and (ii) glymphatic fluid/ glymph) form a five- fluid circulation system in the human and mammalian bodies. We speculate, without experimental evidence so far, that the water in the PVS comes from either the heart, or ventricles of the brain where there is pumping action to drive fluid flow based on the experimental evidence that PVs have been found to connect the heart and the brain (see Section 2). In Figure 10, the white circle marked “PVS” represents the center station of the PVS, the anatomical location of which is yet to be found. The white tubes indicate that this PVS has connections with other organs based on recent experimental findings. Since it has been revealed that a PV is actually connected to the surface of stomach of the minipig model (see Figure 3(b) of [20] ), we propose that the PVS does not exist as an isolated circulation by itself, but rather, joining parts of the other fluid systems analyzed in this paper, forming an integrative whole of the five-fluid system. Such a proposal is also based on the fact that the contents inside the PV fluid are useful in physiological and growth functions.

The cyclic contraction of the heart muscles pumps blood through the arterial vessels. At the capillary beds (represented by the red-blue square-like structure in Figure 10), oxygen molecules (white circles marked O), proteins (orange circles), nutrients (green circles), and cells (marked “cells”) of various kinds as described in Section 4, are released to the ISF to nourish the organs. The ISF also receives carbon dioxide (white circles marked C), debris (brown circles) from metabolism and immunity actions; these wastes come from cells of organs. Whereas carbon dioxide molecules together with some “unused proteins” are returned to the blood circulation, the debris plus some cells in the ISF enter the initiative ducts of the lymphatic system, as lymph, the fifth fluid. The green circular structure marked “N” represents a lymph node, and there are clusters of them at the cervical, axillaries, intestine, neck, inguinals, abdominal and pelvis regions. The purplish circle represents the thymus gland with green circumference representing the left and right lymphatic ducts which branch off to lymph node clusters indicated in the lower part of the diagram. There are green lines joining from the spleen and marrow to the collecting lymphatic duct, implying that these two organs

Figure 10. Summary of the five-fluid circulation system. The spinal canal in drawn on the upper part in order that it is not to be mixed up with the head and other parts of the body. The choroid plexus provides the main portion of the CSF in the lateral, third and fourth ventricles in the brain, via the blood-CSF barrier. The saw-tooth barrier represents the epidymocytes via which fluid with small proteins exit from the arterial capillary (in red). The CSF at this stage flows down the spinal canal and is reflected back (with resonance, see Section 5) after receiving fluid from some arterial blood vessels (from the body trunk) and enters the sub-arachnoid space, which surrounds the brain. For many years, the CSF is thought to flow through granulations in the arachnoid space where there are venous vessels, which drain the wastes. In this figure, the arachnoid space and region with venous vessels is represented by a thin light grey boundary, from which two venous vessels emerge on the right side and join the subclavian vein. The brain parenchyma (mainly neurons and astrocytes) in the cortex is painted in pinkish purple color. There is fluid flowing from the arterial capillaries into the brain-parenchyma, passes through the blood- brain barrier, bringing with it nourishment, oxygen and some small proteins. We call this fluid as the brain interstitial fluid (BISF). There is evidence that a small amount of exchange of CSF and BISF takes place across the ependymal thin epithelial layer. However, the majority of the CSF - BISF mixing is through a relatively complex process as discussed in Section 5.2. It has been discovered that the wastes can follow the CSF- BISF fluid flowing through the sheaths of the nerves that emerge from the skull bone to the facial region. We therefore draw two yellow small tubes to represent schematically the nerves. Recently, the brain wastes are also found to be carried by the fluid through the sheaths of blood vessels of animal models. The most recent discovery of the existence of lymph vessels in the dura mater inside the skull provides an answer to the long-existing mystery of brain waste clearance. It is highly likely that most of the wastes through the sheaths of nerves, blood vessels already enter the lymph vessels in the dura mater (which may surround most part of the whole brain) and these intra-cranial lymphatic vessels join the extra-cranial lymphatic system outside the skull. The clearance through the veins is better known (Section 3) and is not represented here. This is our present model of clearance. The function of the interstitial fluid has been discussed in Section 4. In general, organs leave carbon dioxide and debris in the interstitial fluid after physiological functions, as represented by the white circles (marked c) and brown circles respectively in the diagram. The wastes in the body are drained via the normal way into a number of lymph node clusters such as axillaries, inguinals, neck, etc as marked. These clusters connect the lymphatic ducts on both sides of the thymus which is drawn twice to clarify the anatomical conditions. The spleen and marrow are considered to be organs of the lymphatic system. After carrying out the immunity duties, the lymphatic ducts send the lymph to the venous system at the subclavian vein. We name the lymphatic clearance system inside the skull as the glymphatic system. Based on the detailed discussion in Section 2, we put forth the notion that the Primo Vasculature System supports the functions of various parts of the body - the precursors of proteins are carried by the Primo Vasculature Fluid, and the PVS is represented by the white connections in the diagram. The red tubes and deep blue tubes indicate respectively the arterial and venous vessels, connected by the capillary beds. The five-fluid circulation system is schematically represented as a whole which is a painting done by author PCWF.

are lymphatic organs and supply lymphocytes to the lymph vessels and hence the nodes. A large green tube (below the thymus) connected to an L-shaped green line which joins the large horizontal deep blue vessel represents the fact that after treatment at various node clusters, the lymph fluid joins the blood in the subclavian vein. The rest of the blood circulation is well-known, and will not be repeated here.

Now let us summarize the up-dated findings, according to the detailed discussions in the last section, on the clearance of brain wastes. In the picture, the thymus with a lymph node is duplicated in the upper part of the diagram for convenience of discussion. The uppermost tube in the diagram represents the spinal canal (in up-side-down direction for convenience of discussion too). The choroid plexus generates CSF in the ventricles. The fluid flows down the spinal canal and returns to the subarachnoid space (blue), together with some contribution of fluid from blood vessels in the body below the head (Section 5). CSF and BISF are mixed to become the fourth fluid in our model system. There is certain exchange of these two fluids across the thin boundary (ependymal thin epithelial layer, yellowish) separating the ventricles and the brain cortex, as indicated by two thin, dotted arrows across such a boundary. The two vertical yellow lines represent the nerves from the brain to regions outside the skull bone, such as the facial region. Very recently, lymph vessels are found at space close to the ethmoid bone, and even inside the dura space, as represented by the green “boundary” external to the (blue) subarachnoid space. Incidentally, there is mathematical analysis indicating that the wastes can readily follow the sheaths of vessels, rather than diffuse back into the brain, supporting the experimental findings discussed related to the discovery of the glymphatic system [129] . The brain wastes have the chance of entering the glymphatic vessels in the dura space inside the skull via the sheaths of nerves and blood vessels. The wastes follow the nerves can also be drained by the lymph vessels in the facial region close to the ethmoid bone. It has been suggested with evidence that the glymphatic system works much better during sleep, particular in lateral posture. In the last section, we have also introduced simple, non-invasive maneuver techniques that might help enhancement of the glymphatic clearance system.

Even though all of the five fluids discussed in this paper have been known in human and mammalian animals for over half a century, we are only at the infancy stage in understanding the relationship among these fluids as a circulation system. We still have much to understand about the concrete mechanism and conditions under which clearance along sheaths of blood vessels and nerves are efficient, because there is report remarking that clearance occurs along arterial vessels only and also report providing evidence that the wastes are drained via sheaths of veins. There have been a lot of advancement in the knowledge of the PVS in the past ten years, but there are fundamental questions to be answered.

The first question is: where does the PVS come from? Based on the analysis presented in Section 1, we have followed the speculation of [3] that the polar bodies are transformed into the PVS. Experimental verification is certainly essential. However, what matters most, is that the PVS is developed before the cardio vasculature. During pregnancy, the source of water of the PVS is obviously derived from the embryo water. Where does the water of the Primo Vasculature Fluid (PVF) come from after birth? Since there is experimental evidence that the PVs are connected physically with some organs (see Figure 3 of [20] ), it is tempting to assume, as other researchers in this field, that the protein precursors and “small stem cell-like cells” are carried by the PVF to enter the attached tissues/organs for the purpose of supporting certain physiological functions, including growth and repair. There are also PVS networks on top of organs such as intestines. Is the PVF playing a similar role like the blood system, and excreting nutrients, pre-cells entities to the ISF? Does PVF bring its constituents directly to organ cells? We now understand that the blood fluid, ISF, CSF-BISF, lymph (with sub-systems of extra-cranial lymph plus glymphatic fluid) form a circulation track, with lymphatic vessels joining the subclavian veins. How does the PVS feed in as part of the circulation system? Needless to say, we certainly wish to know the processes of maturation of the constituents in the PVS. What is the driving force to cause the “automatic” vibration of the PVs?

Above are just some of the many crucial questions. Development of suitable methodologies to measure flow speeds and fluid pressures at different sites of the body (animal models and subjects) can provide useful information for analyzing the function of this integrative circulation system.

We propose that the newly discovered glymphatic system (in animals) also exists in the human and mammalian bodies. The mechanisms of fluid flow (with solutes and insoluble molecules) along sheaths of vessels and nerves need to be investigated in details. We begin to learn that sleep, particular in a lateral posture, would enhance the bulk CSF-BISF flow in the brain parenchyma, leading to better efficiency of clearance of the brain wastes from metabolism. Are there other conditions that would expedite the CSF-BISF flow to the dura space where glymphatic vessels are found?

Note also that part of the brain wastes are cleared through veins as discussed in sections 3 & 7. Let us consider the vein vessels which pass through the posterior fossa of the cranial vault. There are two main routes: (i) One route (formed by a number of veins) is the vertebral venous plexus following a direction alongside, and within the spinal canal, all the way down to the end part of the spinal cord. (ii) The internal jugular veins form the other route. The upright posture causes a “waterfall” in the brain that follows a steep descent back to the heart. In the upright posture, venous blood flows from the superior sagittal sinus at the top of the brain, passing into the transverse sinus, the sigmoid sinus and eventually joining route (i) or route (ii). It has been pointed out in [47] that the upright position favors cerebral venous outflow into vertebral venous plexus (i.e. route (i)) rather than route (ii)). Therefore it seems that the venous drainage works better in upright posture, but the glymphatic drainage works better in supine position, particular during sleep. Moreover, the emissary veins connect the dura venous blood with the extracranial venous blood and are believed to be involved in dura arteriovenous lesions [47] . Thus maneuvers (such as that introduced briefly in the last section) to avoid back flow of emissary blood into the brain are important protective measures, since the emissary veins are two-way vessels. Practically, we cannot massage the veins in the vertebral plexus, but relaxing the muscles around such vessels would, in our opinion, be a workable modality to enhance the venous drainage of the CSF-BISF fluid. As briefly sketched previously, ISF is involved obviously in edema; ISF dynamics is related to chronic knee inflammation; suitable ISF flow is also necessary for bone growth. There are many aspects to learn about diseases of the connective tissues, with ISF playing roles.

Let us take another concrete example below to demonstrate that understanding the fluid dynamics of the integrative fluid system is involved in the transition from the physio- to pathological state. There are numerous cases of Normal Tension Glaucoma (NTG), meaning that a subject can suffer from open angle glaucoma even if the intraocular pressure is normal [144] [145] . The lamina cribrosa of the eye is subjected to the intraocular pressure and the brain fluid pressure at the retrobulbar space. The eye ball is filled with vitreous humor, a “localized” ISF. We consider that it is the off balance of the stated two fluid pressures that causes the bulging of the optic nerve, leading to the onset of NTG. Moreover, the systolic pressure of the cardio vasculature system affects the rate of generation of CSF, and hence the fluid pressure of the mixed brain fluid at the retrobulbar space in general. Inefficient clearance of the brain fluid by the glymphatic system and venous clearance system mentioned in this section might lead to compartmentalization of brain fluid, and it is possible that the fluid pressure at the retrobulbar space is much different from the normal brain fluid pressure. There is diurnal variation of the systolic pressure. Analyzing the flow properties of the four fluids―the blood, (eye) ISF, CSF-BISF, lymph in the dura space, is necessary just to answer one “simple” clinical question: Does a person with low blood pressure have a higher risk of suffering from NTG? No answer to the above question has been published up to present. The above is another example that points to the importance of investigating the fluid dynamics in order to understand the transition from physio- to pathological state.

Based on the analysis presented in this paper, we consider that understanding the fluid dynamics of the integrative five-fluid circulation system is important in analyzing the physio-pathological states of many diseases in medicine. Another potential application is: we cultivate the micro-cells (sanals) in the first fluid (from animal models) and feed them back to one relevant fluid of the other four, as a stem cell therapy investigation.

Acknowledgements

The authors wish to express their hearty thanks to Mr. Benjamin Fung (brother of Peter Chin Wan Fung) for his unfailing assistance during the preparation of this manuscript. Thanks are also due to Dr. KH Kok, Dr. Junling Gao, University of Hong Kong, for their help also in the preparation of this paper. Figures 2-10 were hand-painted by author Peter Chin Wan Fung. The authors also declare that there is no conflict of interest in this academic project.

Cite this paper
Fung, P. and Kong, R. (2016) The Integrative Five-Fluid Circulation System in the Human Body. Open Journal of Molecular and Integrative Physiology, 6, 45-97. doi: 10.4236/ojmip.2016.64005.
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