Device and method for mixing liquids, also suitable for remineralizing and revitalizing osmosis water

Abstract

Water purification, particularly through reverse osmosis systems, is gaining importance given the increasing levels of contaminants in tap water. Contaminants such as bacteria, agricultural runoff, hormones, plasticizers, and other pollutants pose a growing challenge. Water purification through reverse osmosis is a proven method for removing contaminants such as pollutants, microorganisms, and chemicals from drinking water. Despite its efficiency in removing contaminants, reverse osmosis also leads to the elimination of essential minerals that are important for human health. The present invention aims to develop a device for remineralizing and revitalizing osmosis water, which not only enriches the water with a balanced mixture of vital minerals, but also restores its original, natural energy structure.

Description

1. Introduction

[0001] Water purification, particularly through reverse osmosis systems, is gaining importance given the increasing levels of contaminants in tap water. Contaminants such as bacteria, agricultural runoff, hormones, plasticizers, and other pollutants pose a growing challenge.

[0002] Reverse osmosis is an effective method of water purification that aims to remove almost all impurities from the water. In this process, water is forced under pressure through a semipermeable membrane. This membrane is so fine that it retains most chemical compounds, bacteria, and viruses, thus allowing only pure water to pass through. 2. Importance of water purification by reverse osmosis • Health protection: The main function of reverse osmosis is to filter potentially harmful substances from water, which is particularly important for protecting consumer health. This technology can be crucial, especially in areas where water quality is affected by industrial and agricultural activities. • Improved taste: In addition to removing pollutants, reverse osmosis can also improve the taste and smell of water by removing harmful minerals and chemical compounds that impair the taste. • Environmental protection: Although reverse osmosis requires intensive use of resources such as energy and water, the technology can help reduce the pollution of natural water bodies. Clean return water from reverse osmosis can be safely released back into the environment. • Sustainability: In the long term, clean drinking water contributes to sustainable development by improving the quality of life and leading to a healthier population.

[0003] However, the implementation of reverse osmosis systems should take local conditions and resource availability into account. It is important to find a balance between ecological, economic, and social aspects to ensure sustainable water use. 3. Problem statement:

[0004] Water purification through reverse osmosis is a proven method for removing contaminants such as pollutants, microorganisms, and chemicals from drinking water. Despite its efficiency in removing contaminants, reverse osmosis also leads to the elimination of essential minerals important for human health. Furthermore, osmotically purified water can be perceived as "energy-depleted" due to a lack of certain energetic qualities present in natural, mineral-rich water. 4. State of the art:

[0005] Previous approaches to remineralizing reverse osmosis water involve the use of mineral filters or ion exchangers, which add minerals to the water in an uncontrolled manner after osmotic purification. These systems therefore cannot adequately replicate the desired natural composition and quality of spring water. Furthermore, there are techniques for "energizing" the water, which aim to alter its physical properties, often based on principles that are not fully scientifically proven. 5. Purpose of the invention:

[0006] The present invention aims to develop a device for remineralizing and revitalizing reverse osmosis water, which not only enriches the water with a balanced mixture of vital minerals but also restores its original, natural energy structure. By integrating advanced remineralization technology and energetic revitalization processes into a single device, a water quality is achieved that is comparable to that of natural spring water and is optimal for human consumption.

[0007] The device according to the invention is intended to combine a precisely controlled supply of minerals through the use of an innovative solution. The device aims to achieve optimal adjustment of the mineral content and ensure the desired energetic properties of the water. THEORETICAL FOUNDATIONS CHAPTER 1: THE CONVECTION-DIFFUSION EQUATION AND THE PROBLEM OF MIXING LIQUIDS IN MICROSYSTEMS

[0008] Animal tissue essentially represents a microsystem, and in the microcirculation, when supplying cells with vital substances, it is particularly important to mix the plasma filtrate of the blood with the interstitial fluid in the tissue.

[0009] Circulating blood is the medium that transports substances to the capillaries via convection, thus supplying the tissues. For these substances to reach the cells in the interstitium in sufficient concentration, not only is an adequate delivery rate required, but also an effective mixing mechanism between the capillary and interstitial fluids.

[0010] It is therefore certainly correct to assume that convection and diffusion are jointly active around the capillary membrane and that this combined effect of both phenomena could be described by the convection-diffusion equation. The derivation and interpretation of the convection-diffusion equation is the responsibility of physicists and mathematicians; see [reference]. Fig. While these two professional groups have a purely academic interest in this problem, physiologists need to think about how convection and diffusion work to supply the cells in the tissue with sufficient nutrients. Figure 1

[0011] In the representation in Fig. The influence of convection and diffusion on particle distribution in the carrier fluid was calculated together. However, this picture is only possible if the observer were moving with the fluid or if the horizontal displacement of the fluid or the velocity of convection were extremely low. Tissue cells, however, do not move with the blood plasma, and the blood velocity in the capillaries must not be extremely low.

[0012] Blood plasma, much like water, has the property of being neither compressible nor ruptured. Therefore, convection in a laminar flow channels the flowing blood plasma into a kind of plasma filament, which could be problematic for diffusion. In principle, diffusion is a phenomenon that is clearly defined for stationary fluids. In free diffusion, the degrees of freedom of particle movement are particularly important.

[0013] In the convection of laminar plasma filaments, the degree of freedom of particle motion perpendicular to the flow direction is restricted or completely eliminated. Under these conditions, the flow velocity certainly plays an important role in particle diffusion, which still needs to be considered by mathematicians and physicists. This assumption is confirmed by the well-known problem that laminarly flowing liquids are, in principle, difficult to mix when flowing directly alongside each other (1,2).

[0014] In contrast, different liquids mix easily when they are involved in turbulent flow. The special characteristic of turbulent flow is that the velocity vector changes many times within a volume element, and this property of turbulent flow is crucial for mixing liquids.

[0015] The problem of mixing laminarly flowing liquids is also exacerbated when scaling down the volume dimensions: liquids flowing side by side in a microsystem can leave this system unchanged, just as they entered it, even though there are no separating surfaces between the liquids within the microsystem (2).

[0016] On the other hand, if these fluids were to suddenly come to rest, diffusion would mix them together. Therefore, a problem arises with diffusion in laminarly flowing fluids, which is likely to be blocked above a certain laminar flow velocity. The role of convection at the capillary membrane for the exchange of fluids and substances is thus emphasized, and the contribution of diffusion to this process must be reassessed. However, we can learn from nature that it has also found an efficient solution for the mixing of these fluids and substances at the capillary membrane. THE NATURAL SOLUTION FOR MIXING LIQUIDS AT THE CAPILLARY MEMBRANE

[0017] How nature has found a solution to the problem of liquid mixing at the capillary membrane is shown by the representation of three spatially distributed capillaries in Fig. Within these three constellations, the velocity vector changes direction several times because the pressure gradient depends on the spatial distribution of the capillaries. Figure 2

[0018] Imagine what the situation would be like if, for example, several hundred capillary loops protruded from different directions into every cubic millimeter of tissue volume within a muscle. In this situation, the velocity vector within a volume element would change millions of times, just as it would in turbulent flow.

[0019] Although plasma flows in tissue in a laminar flow, nature has found a way to create turbulent flow conditions in the tissue interstitium. This also provides an effective solution to the problem of fluid mixing within the tissue. This is precisely what one would have expected from nature: after all, in a living organism, every detail is optimized to the maximum and is highly efficient. Fick's Law and the exchange of fluids and materials in fabrics

[0020] The exchange of fluids and substances in the body is a simple yet effectively organized process: Blood flow handles the logistical task of delivering vital substances, while the exchange within the interstitium is facilitated by the capillaries. Convective fluid movement plays a crucial role in systemic blood circulation and the capillaries, as diffusion has relatively little influence compared to convection in the macroscopic world.

[0021] However, at the terminal level within the interstitium and between cells, convection and diffusion interact together. This mutual complementarity is important because the distance between capillaries and cells can be considerable in the microscopic world (3).

[0022] For example, in muscle tissue with a dense capillary network of approximately 600 capillaries / mm², the number is approximately 600 capillaries / mm². 3 (3,4) the proportional average capillary surface area is only 6%.

[0023] This suggests that diffusion alone may not be sufficient to facilitate fluid and substance exchange in the interstitium. For example, a resting mass of 40 kg of muscle tissue requires approximately 130 grams of sugar in 24 hours to meet its energy needs. The theory must explain how this amount of sugar is delivered to the muscle cells.

[0024] It is important to recognize at this point that diffusion in aqueous solutions appears to be much slower than convection. To gain a rough idea of ​​the relationship between diffusion and convection, Fick's first law can be used (5). The particle flux J per unit time delivered to a defined cross-sectional area is given by: J=−D⋅dC / dx.

[0025] Here, D stands for the diffusion coefficient and dC / dx for the concentration gradient.

[0026] In comparison, convection with a flow velocity of v enables the particle flux J=vC. The point at which the two mechanisms balance each other is sought. In this comparison, the direction of the particle flux is not important, so the minus sign in equation (2) can be omitted: D⋅dC / dx=v⋅C

[0027] Numerical example for the sugar solution in blood: With 0=6.10 -7 m 2 / s; C=100 mg / dL; dC / dx (1% per 1 cm)= 1 mg / dL·cm -1 is calculated as follows: v=6.10−9cm / s.

[0028] If we assume that the blood velocity in the capillaries is 0.1 cm / s (4), the result according to equation (3) means that the convection in the capillaries is 6.10 8 -times more particles than diffusion.

[0029] Note: Convection delivers 600 million times more sugar to the cells in the interstitium than diffusion. This result explains why nature has provided convective channels around the cells in the interstitium; see also the discussion of the results in Petrov (6).

[0030] Consequently, this implies: (1) that only in the dimensions according to equation (3) can the convection-diffusion equation be calculated in the form known from physics, see Fig. . (2) that convection must play an important and indispensable role in the exchange of fluids and substances in the interstitium and (3) that the theory of this exchange must be able to take this fact into account.

[0031] To reproduce a natural exchange in theory, a theoretical concept is needed in which the carrier fluids from the capillaries and the interstitium mix intensively with each other, mainly through convective exchange around the capillary membrane. THE ROLE OF THE LYMPH SYSTEM AS A LINK BETWEEN THE INTERSTITIES IN THE ENTIRE ORGANISM

[0032] The role of the lymphatic system in the organism is better understood in the context of the concept of tissue interstitials. It cannot be said that there is a clear consensus on interstitials in the literature. Some anatomists even tend to assign functions to interstitials that fundamentally indicate that a uniform definition is long overdue (7): Quote 1: “Our experiments suggest that the interstitial spaces are continuous, creating a potential main thoroughfare through the body, distinct from the blood and lymphatic vessels through which cells and molecules circulate.”

[0033] The idea that interstitias constitute a network within the organism and would ensure transregional communication has explosive content because such a possibility would provide enormous advantages to the organism.

[0034] Generally speaking, the interstitium represents the collection of spaces outside the cells in tissue and is thus a component of every tissue unit. This interstitium does not refer to the extracellular space, which by definition is the space located outside the cells throughout the entire organism. Here, the interstitium is always discussed in relation to a tissue unit because only in this context are certain properties attributed to the interstitium that are important in the theory of microcirculation (8).

[0035] The animal organism represents a conglomerate of various distinct interstitial tissues, which, however, exist only within a single tissue unit. These interstitial tissues do not have the capacity to communicate transregionally with one another, as the authors Cenaj et al. claim in quote 1 above.

[0036] These regionally defined interstitials are located within the lymphatic network. In contrast to the fluid-rich interstitial spaces and the blood, the lymphatic system plays no or only a very minor role in convective fluid mechanics (4, 7). The idea of ​​Cenaj et al. is expanded in this context: the transregional network of lymphatic vessels would mean that it is not the interstitial tissue, but rather the lymphatic system that enables a network of interstitials in the background, extending beyond the diversity of tissue boundaries. Only in this sense can the experimental findings of Cenaj et al. be considered meaningful.

[0037] The interstitial spaces therefore represent regional macrostructures, while the lymphatic system is transregionally active and ensures connectivity throughout the entire organism. In this sense, the anatomists are partially correct, but the transregional connections between the interstitial spaces are not realized by the "interstitial network" but by the lymphatic system. CHAPTER 2: UNDERSTANDING THE STRALING PRINCIPLE: THE FINAL SPRINT OF A SCIENCE ON THE LONG ROAD TO KNOWLEDGE

[0038] The currently accepted theory of microcirculation has a comparatively short history, as its basic principles were demonstrably formulated relatively late, only with the work of the renowned English physiologist E.H. Starling in 1896 (1). The most important proponent and advocate of Starling's idea regarding fluid and substance exchange at the capillary membrane in tissue, the British physiologist C.C. Michel, wrote about Starling's work in 2004 (2): Quote 1: “Starling’s hypothesis from 1896, that the rate and direction of microvascular fluid exchange is proportional to local differences in hydrostatic pressure and effective colloidal osmotic pressure (or oncotic pressure) across the microvascular walls, has been so well supported by experimental evidence for so long (e.g. Landis, 1927; Pappenheimer & Soto-Rivera, 1948) that it can be called Starling’s principle.”

[0039] At that time, Starling first formulated the idea that blood pressure (Pc) and colloid osmotic pressure (COP) act as antagonistic forces at the porous capillary membrane. In his publication, Starling states that fluid filtered into the tissue is partially reabsorbed into the capillaries and that the COP is the driving force behind this reabsorption. This concept of the interaction of forces acting on the capillary membrane determined the theoretical orientation of microcirculation for the next 125 years. Starling's original formulation can be found on page 324 of his 1896 paper (1): Quote 2: "...and while capillary pressure determines transudation, the osmotic pressure of the proteins in the serum determines absorption. Furthermore, if we disregard the frictional resistance of the capillary wall to the passage of fluid, the osmotic attraction of the serum for the extravascular fluid would be proportional to the force expended to produce the latter, so that at any given time there must be an equilibrium between the hydrostatic pressure in the blood in the capillaries and the osmotic attraction of the blood for the surrounding fluids."

[0040] In this quote, Starling writes about filtration and reabsorption and explains that 1) the blood pressure Pc and the colloid osmotic pressure COP act as antagonistic pressures at the capillary membrane and 2) the force ratio between the Pc and the COP at the capillary must change, because only under this condition would filtration at the beginning of the capillary and reabsorption at the end of the capillary be possible alternately.

[0041] At the same time, Starling posits a constant equilibrium between Pc and COP at the capillary membrane, which would not permit either filtration or reabsorption along the capillary membrane. It is therefore necessary to further examine Starling's arguments (1): Quote 3: “With increased capillary pressure, increased transudation must occur until an equilibrium is reached at a slightly higher level, where the fluid in the tissue spaces is less dense and therefore has a greater absorption capacity to compensate for the increased capillary pressure. With decreased capillary pressure, osmotic absorption of saline solution from the extravascular fluid will occur until it becomes richer in proteins; and the difference between its (protein) osmotic pressure and that of the intravascular plasma corresponds to the decreased capillary pressure. Here we then have the balance of forces necessary for the precise and rapid regulation of the amount of circulating fluid.”

[0042] Judging from this quote, Starling apparently observed in animal experiments that tissue volume would increase or decrease with changes in blood pressure ( Fig. He describes transition phases following a change in blood pressure and postulates, after these transition phases have lapsed, an equilibrium between blood pressure PC and COP at a new level corresponding to the ratio. Figure 1

[0043] To remove the Starling Black Box from the Fig. To explain this in more detail, a capillary is first integrated into a container that is open to the outside and whose walls are not restricted in height ( Fig. The simulated “interstitial” pressure P in the container i is determined by the height (h) of the water column in the container.

[0044] In this construction according to Fig. The fluid-mechanical supply to the capillary and its surroundings, in the form of the simulated interstitium and the cells within the container, remains stable. This applies to any desired pressure at the tissue inlet P. CAThe water column in the container rises sufficiently so that the pressure of this water column is enough to bring the absorption into equilibrium with the filtration, whereby the absorption depends on the osmotic pressure difference Δπ=(π c -π i ) is still supported.

[0045] A local current J flows through each point on the capillary membrane (µ). Hµ , which is calculated using the following formula - a reflection coefficient (σ) according to Staverman (3) is not included in this consideration: JHμ=Kfμ[(PCμ−Piμ)−(πcμ−πiμ)].

[0046] Here, K represents f the hydraulic conductivity of the capillary wall, P the pressure inside the capillary (c) or the interstitium (i), π the osmotic pressure of the plasma (c) or the interstitial fluid (i).

[0047] With the height of the water column (h) in Fig. The tissue volume is symbolized. This height is calculated using the formula P=h·p·g or h=P / p·g, and therefore we obtain: Piμ=hμ⋅ρ⋅g=nμ⋅PC⋅ρ⋅g, where P is the pressure of the water column, ρ is the density of the water or plasma filtrate (water - approximately 1000 kg / m³). 3 ), g the acceleration due to gravity (approximately 9.81 m / s²) 2 ) represents.

[0048] To convert pressure to millimeters of mercury (mmHg), the conversion factor from Pascal to mmHg is used, which is approximately 133.322. With P Cµ =m µ You can get a PC: JHμ=Kfμ[PC(mμ−nμ⋅ρ⋅g)−(πcμ−πiμ)].

[0049] According to equation (3), flow through the “interstitium” to Fig. a local circulation in the form of a filtration-resorption model, which is essential for the exchange of fluids and substances at the capillary membrane and thus for the supply of nutrients to the cells in the simulated “tissue”.

[0050] The interstitial pressure P i is missing in equation (3) because, according to equation (2), it is part of the pressure P C This represents and this pressure PC is therefore also involved in absorption.

[0051] It should be noted that equation (3) is not the Starling equation. The Starling equation, known in circulatory physiology, is not applicable to the calculation of the [missing information] in the Fig. The situation described. These relationships will be explained in more detail below.

[0052] In any case, it can be stated that equation (1) realizes Starling's idea that the colloid osmotic pressure of the blood (COP) at the capillary membrane acts as an opponent of the blood pressure. The capillary is represented as an elongated element according to equation (1) and Fig. As described: At the beginning of the capillary on the arterial side, blood pressure predominates and causes filtration into the tissue. Along the capillary, blood pressure decreases, so that after the middle of the capillary on the venous side, COP predominates and causes the reabsorption of fluid back into the capillaries.

[0053] Starling's idea that COP should be an antagonist to blood pressure at the capillary wall in tissue is only valid if the interstitium exhibits infinite compliance. This presents both a mathematical and a fluid-mechanical problem. From a mathematical point of view, the pressure P C and the COP can be considered antagonistic at the porous capillary membrane if the COPs of adjacent pores along the capillary membrane are independent of each other. For this reason, the in Fig. The interstitially depicted areas should be open to the outside and exhibit infinite compliance.

[0054] In equation (1) and Fig. However, one does not assume a balance of forces as defined in the Starling quote above. Starling explains in this context that the frictional resistance along the capillary should be ignored. This means, however, that the pressure at the beginning of the capillary and the pressure at the end of the capillary become equal, and this situation is described on the Fig. depicted.

[0055] Under this condition, blood flow in the horizontal direction ceases, and with it, the local circulation in the form of the filtration-reabsorption model, as still described in the Fig. as depicted. The capillary membrane is now subjected to a uniform pressure from the capillary side. As Starling explains in quote 3, this pressure can be variable and, after a transition phase, would adjust the tissue volume accordingly to an equilibrium ( Fig. ).

[0056] Note: How Starling meant the tissue supply in 1896, which is currently discussed as the Starling principle, is less important than the fact that this principle only results in the tissue being subjected to a static pressure P stat emerges ( Fig. ).

[0057] The static pressure in the microcirculation P stat and in the blood capillaries P Cstat represents an independent category in the circulatory system. Depending on body position, the pressure P can vary. stat Different values ​​are found in the large vessels as well as in the capillaries. This pressure P Cstatmust not be combined with the dynamic blood pressure component in the cardiovascular system. H be confused.

[0058] The dynamic blood pressure component P H This drives blood flow along the vessels in a horizontal convective direction. The same pressure P H also drives the flow of plasma filtrate J H through the interstitium also in a horizontal convective direction, cf. equation (3) and Fig. In contrast, the static pressure P drives Cstat the flow of the fluid Jv through the capillary wall in the vertically convective direction (cf. also the black cycle in the Fig. further down). THE STARLING PRINCIPLE IN THE AFTER STARLING TIME

[0059] The description of the Starling principle by the British physiologist CC Michel in 2004 has already been shown in quote 1. A few years earlier, in 1997, his fundamental work on Starling's work was published to mark the centenary of Starling's 1896 paper.

[0060] In this work, the author also acknowledges the research of E.M. Landis. This is for important reasons, because in 1927 Landis created the Starling equation, well-known in physiology; Starling himself never wrote an equation.

[0061] In the original paper by Landis (5) it can also be read that the medical student Landis experimented with isolated frog capillaries in 1927 and formulated an equation that became known as the Starling equation: JV / A=Lp[(Pc−Pi)−(πc−πi)], where Jv is the capillary filtration rate, L pis the hydraulic conductivity of the capillary wall, A the surface area, P the pressure inside the capillary (c) or the interstitium (i), π the osmotic pressure of the blood plasma (c) or the interstitial fluid (i).

[0062] In principle, equations represent mathematical laws. Therefore, every equation has a 100% corresponding model from fluid mechanics ( Fig. ). Figure 2

[0063] Only the model of corresponds to equation (4). Fig. Only this model displays the pressure P i In the simulated interstitium, INT represents a constant and is therefore independent of the capillary pressure P. C The model of Fig. The equation (4) above is not satisfactory because this equation (4) is only correct if the pressures P C and P i are independent of each other. On the other hand, the model is based on the Fig. also included in model 2a, with the restriction that in model 2a the factor P i represents a constant.

[0064] The horizontal convective component J H from Fig. also exists in Fig. Therefore, Landis' experiment is not calculated with one equation, as previously believed, but with a pair of equations: JV / A=Lp[(Pc−Pi)−(πc−πi)], JHμ=Kfμ[(PCμ−Pi)−(πcμ−πiμ)], at Pi=const.

[0065] This explanation demonstrates how Landis conducted his experiments: He worked with equation (4) or (5) and changed the static pressure in the capillary and measured the excess Jv flowing over the container walls ( Fig. In this way, Landis actually measured the capillary filtration coefficient (CFC) of the capillary membrane.

[0066] Measuring the CFC in the Landis experiment was possible because the simulated interstitium in this experiment exhibits infinite compliance. Therefore, the liquid flowing over the edges of the container corresponded to the CFC value.

[0067] Two other authors, JR Pappenheimer and Soto-Rivera, used Landis's idea for CFC measurement in animal experiments in 1948 and also used the static pressure in the capillaries as an initial parameter (6).

[0068] While Landis was able to measure the capillary surface area of ​​individual capillaries using a microscope, this was not possible for animal tissue. Therefore, these two authors used 100 grams of tissue as a reference. However, they failed to consider that skeletal muscle must have a finite compliance.

[0069] The Pappenheimer and Soto-Rivera method thus became a failure not only for these two authors, but also for numerous research groups that have used this method for CFC determination in various tissue types up to the present day. This development is concerning, considering that we had already pointed out the errors of Pappenheimer and Soto-Rivera in 1992 and published a new method for CFC determination that allows for the correct determination of the CFC value (7).

[0070] The particular significance of this method for CFC determination according to Pappenheimer and Soto-Rivera was that it was seen as confirmation of the Starling hypothesis (see quote 1 from C.C. Michel). It is therefore not surprising that after 1948 the Starling-Landis-Pappenheimer alignment was considered the most important support for the current theory of microcirculation. THE FILTRATION-RESORBTION MODEL IN THE AFTER STARLING TIME

[0071] In physiology textbooks from the past (8) and still on the internet today, one finds a widespread idea about fluid exchange at the capillary membrane, which was and still is offered in connection with the explanation of the Starling hypothesis and Starling forces ( Fig. The problem with Fig. This is because the representation there does not correspond to the Starling equation (5) via the component Jv, but to the second equation (6) via the component J. H agrees - models and equations always correspond 100%. Figure 3

[0072] CC Michel, the most important advocate of the Starling idea, also expressed his position in 1997, which was likewise based on the depiction on Fig. is associated with (4): Quote 4: “Since the mean oncotic pressure of human plasma is 24 mmHg, the capillary pressure appears to encompass the plasma oncotic pressure, at least at cardiac level, which supports the Starling view of filtration from the arterial end and reabsorption from the venous end of the capillary bed.”

[0073] In the same vein, a colleague of CC Michel, the physiologist JR Levick, wrote in 2004 (9): Quote 5: “Since PC falls along a capillary, the plausible idea of ​​filtration from the arterial capillaries and continued resorption in the venous capillaries has become established in the literature.”

[0074] It is assumed that until 2004 these and other researchers assumed a filtration-resorption model at the capillary membrane, but had a Starling equation (5) over Jv in mind, which is related to the point-specific representation of the Fig. had nothing to do. THE BIG TURNING POINT CAME IN 2004

[0075] In the same year, 2004, the author J.R. Levick reversed course and proposed a revision of the Starling Principle (RSP) (9). However, as has been demonstrated so far, he, along with the majority of physiologists of that time, did not even properly understand the Starling Principle. There were, however, exceptions: A 1988 article by P. Dual et al. presents a modification of the Starling equation that also mentions the capillary surface area A. This article introduces a formula followed by an explanation within a quotation (10): M=K(Pc−Pi−πc+πi).

[0076] In this equation, K represents the conductivity of the capillary surface, Pc the blood pressure in the capillary, P ithe interstitial fluid pressure (IFP), and πc and πi symbolize the colloid osmotic pressure in the capillary and in the interstitium, respectively.

[0077] Quote 6: “If the quantity M is defined as the flow rate (Jv) per unit area of ​​the total wall surface, then Pc cannot vary along the length of the capillary. In this case, Pc should be replaced by an appropriate value.”

[0078] The authors of this concept assume that an appropriate, yet constant, value for blood pressure exists along the length of the capillary. In contrast to Starling's quote, "at any given time there must be an equilibrium between the hydrostatic pressure of the blood in the capillaries and the osmotic attraction of the blood to the surrounding fluids," the introduction of the capillary surface means that, from 1988 onward, the Starling equation (7) also took into account the Starling principle of the equilibrium of forces at the capillary membrane.

[0079] The authors P. Dual et al., and subsequently other scientists, faced the problem of how to determine the capillary surface area in a tissue in practice. This creates difficulties for practical calculation methods, since the capillary filtration coefficient (CFC) is the most important factor determining the quality of fluid and substance exchange in tissue between blood and interstitium.

[0080] The most significant problem that will accompany Starling's principle from now on, however, is the realization that, according to Isaac Newton (1687), a standstill in the exchange of fluids and substances must occur when there is a balance of forces at the capillary membrane. Something was clearly amiss here, because in reality, tissue cells are very well supplied with vital substances, and nature has evidently arranged cell nutrition according to a different principle.

[0081] J.R. Levick must have thought similarly when he proposed his RSP (9): By the end of the 20th century, sufficient experimental experience had already been gathered, and the open questions regarding the Starling hypothesis were piling up. This development is described in detail by J.R. Levick in the introduction to his article “Revision of the Starling Principle” (9).

[0082] Nevertheless, in the same year 2004, Mortimer and Levick cited the Starling equation as a basis for explaining the development of edema (11): Quote 7: “Edema develops when the microvascular (capillary and venular) filtration rate exceeds lymphatic drainage for a sufficient period of time, whether because the filtration rate is high, or because lymph flow is low, or a combination of both. The filtration rate is determined by Starling’s principle of fluid exchange, which is concisely and quantitatively described by Starling’s equation for flow across a semipermeable membrane.”

[0083] These authors also include the capillary surface area A in the equation they cite, but refer to it as the filtration rate and do not further explain how the Starling equation (5) would change with the factor area A. It is particularly important to note that, with the Starling equation in mind, Mortimer and Levick still assume that a high interstitial pressure IFP=P i It should be considered a preventative measure against the formation of edema.

[0084] Levick's work on revising Starling's principle is valuable because he primarily documented the problems with the Starling hypothesis that were becoming apparent at that time through the experimental experiences of circulatory physiologists. In particular, Levick's paradox should be mentioned in this context: Quote 8: “The paradox of low lymph flow,” namely that the calculated net capillary filtration rate from the tissue-averaged Starling forces (including πi) is much greater than the tissue lymph production.”

[0085] Furthermore, his work documents how circulatory physiologists understood the osmotic relationships around the capillary membrane at that time. Levick's revision of Starlings' principle (RSP) is thought to be linked to the permeability of a layer in the endothelium called the glycocalyx to large molecules ( Fig. ). Figure 4

[0086] It is particularly important that the RSP is based on the following idea: Quote 9: “In order to have an effect on the glycocalyx, interstitial proteins must diffuse against the convective current flowing through the intercellular spaces.”

[0087] The idea here that proteins should diffuse against the convective current is striking; the commentary on this can be found further down in the discussion. However, Levick's revision of Starling's principle has obviously not led to the desired result; the paper concludes with: Quote 10: “The time course of absorption remains insufficiently understood and represents a medically important challenge for the future.”

[0088] Levick's colleague at work, the well-known physiologist CC Michel, contributed his own viewpoint, so that shortly afterwards, as early as 2010, a revision of the Starling Principle (RSP) was presented to the public (12) and was introduced relatively quickly into physiology textbooks (13).

[0089] In their 2010 article, the two authors believe they have found the solution to the problem of fluid and mass exchange in a state of equilibrium. The transition has been completed, and the filtration-resorption model seems to have been forgotten. Quote 11: “Microvascular fluid exchange (Flux Jv) underlies plasma / interstitial fluid (ISF) balance and edematous swelling. The traditional form of Starling’s principle must be modified in light of the understanding of the role of ISF pressures and the recognition of the glycocalyx as a semipermeable layer of the endothelium.”

[0090] According to Starling's principle, a "true Starling equilibrium" should exist at the capillary membrane in the case of equilibrium. However, the authors' idea is that the permeability of the glycocalyx to large molecules maintains movement across the capillary membrane even in a state of force equilibrium, thus enabling the necessary vital exchange at the capillary membrane. The paper concludes with a warning: Quote 12: “It should also be emphasized that little is known about the nature of the fenestral diaphragms; and that the classical problem of the transport of macromolecules through the endothelium (large pores or vesicles) remains unsolved 50 years after it first became a controversy.”

[0091] The revision idea in the form of the RSP quickly gained traction in the community and very soon in 2020 a trio of authors led by experienced physiologists CC Michel and FR. E. Curry recognized the urgent need to return circulatory physiologists to the old line with the Starling principle (14).

[0092] With their article “Understanding and Extending the Starling Principle”, they replaced the original Starling idea of ​​a “true Starling equilibrium” with the idea of ​​a “never true Starling equilibrium”, probably believing that this would save the old Starling Principle and contain the turbulence in the community.

[0093] This article is essentially a new edition of the article by Levick and Michel from 2010 (12). The underlying issue here, too, is the questionable permeability of the glycocalyx to large molecules, which is supposed to maintain the “never true Starling equilibrium” at the capillary membrane.

[0094] In the 2010 article, however, the authors urgently point out at the end that the basic concept of RSP has been discussed as a hypothesis for 50 years and has not yet been proven. This warning was omitted from the 2020 article, as was the initial contribution by J.R. Levick. The authors believe they can provide a theory of how, in the case of a force equilibrium at the capillary membrane with a "never true Starling equilibrium", the body cells could be supplied with vital substances via the lymphatic flow.

[0095] Note: Cellular supply in tissues is a logistical task in which the blood provides the delivery, and an intensive mixing of blood plasma filtrate and interstitial fluid (ISF) at the capillary wall is necessary to reach the cells with vital substances in sufficient concentration. It is a matter of vitality and the entire organism is involved in this task; it cannot be done incidentally.

[0096] Note: One kilogram of muscle mass secretes approximately 1 ml of lymph fluid per hour, and this muscle mass requires about 3.25 grams of sugar at rest during this time to meet its energy needs. Plasma filtrate contains 1 gram of sugar per liter, and if 20% of this sugar is taken up by the muscle cells in one cycle, then 16.25 liters of plasma filtrate must flow through the interstitium of this muscle in one hour to meet the energy needs of the cells there.

[0097] Hahn et al. called for a validation of the RSP in the same year, 2020 (15). THE MAIN PROBLEMS IN THE THEORY OF MICROCIRCULATING OVER THE LAST 125 YEARS

[0098] The heart's primary function is to ensure an adequate blood supply to all tissues. The blood vessels between the heart and tissues merely serve as tools in this process. The description presented in the introduction represents the current state of knowledge available to physicians and circulatory physiologists worldwide. According to this view, physicians and circulatory physiologists believe that the colloid osmotic pressure (COP) at the capillary membrane acts as an antagonist to blood pressure: The COP is thought to counteract filtration into the interstitial tissue and promote the reabsorption of fluid back into the capillaries.

[0099] In this model, however, physicians and circulatory physiologists are unaware that the blood pressure at the capillary membrane must first overcome the passive COP, without any benefit, in order to fulfill its function regarding cell supply. This overcoming represents an energy waste of over 50% in the tissue, which cannot be expected from nature, which is otherwise very energy-efficient.

[0100] In our 1992 work on the effect of blood pressure amplitude, we found that normal blood pressure of 120 / 80 mmHg is related to the elasticity of the vessels and to the fact that at this blood pressure the work of the heart at rest reaches a minimum value.

[0101] Note: One must therefore be careful with energy waste in nature.

[0102] Furthermore, a tissue model constructed according to the Starling equation would be systemically unstable. The blood pressure at the beginning of the capillary would therefore have to be restrictively regulated, and circulatory physiologists would have no idea how the organism could adapt to the increased demands of exercise.

[0103] In the late 1980s and early 1990s, we addressed these fundamental problems. In searching for flaws in the established concept of microcirculation theory, Starling's original quote, "Moreover, if we leave the frictional resistance of the capillary wall to the passage of fluid through it out of account," was deemed an inadmissible disregard of Ohm's law (17).

[0104] The pressure drop along the length of a capillary should not be ignored: it is the most important driver for the exchange of fluids and substances in the tissue. The blood pressure difference (P CA -P CV This represents the driving force of tissue perfusion; it cannot and must not become zero. The reasons described in the introduction for why Starling's principle and the RSP do not work can be traced directly back to this interpretation by Starling from 1896.

[0105] Starling's principle, according to which "at any given time, there must be a balance between the hydrostatic pressure of the blood in the capillaries and the osmotic attraction of the blood for the surrounding fluids," exists at the capillary membrane only in the form of a static load on the interstitium. A static load on the interstitium is undesirable in tissue because it increases the risk of edema formation (18).

[0106] Until 2004, circulatory physiologists believed in the filtration-reabsorption model. While this model is not accurate for interstitial tissues with finite compliance, it could have explained the exchange of fluids and substances at the capillary membrane.

[0107] After 2004, the Starling principle, with its concept of force equilibrium, was established as a doctrine in microcirculation (2,12). Equilibrium represents a physical principle of action = reaction. Thus, the Starling principle is reduced to a static pressure load in the interstitium; fluid and substance exchange cannot occur at the capillary membrane under this principle.

[0108] In interstitial spaces with finite compliance, a force equilibrium does indeed exist. However, in this case, the force equilibrium only occurs between the colloid osmotic pressure (COP) and the interstitial stiffness, i.e., between COP and IFP, entirely in line with the representation on the Fig. further down. This balance of forces is important for microcirculation in the tissue because in this way the IFP neutralizes the effect of the COP.

[0109] Note: The result represents a kind of Achilles' heel of the Starling principle - the COP at the capillary membrane does not appear to be an opponent of blood pressure.

[0110] In quote 2, Starling contradicted himself by mentioning transudation (filtration) and reabsorption at the beginning of the quote versus a force equilibrium later on, which prohibits both transudation and reabsorption. Perhaps he simply made the mistake of writing about a force equilibrium when he was actually thinking about a fluid equilibrium. RSP AND FLUID AND SUBSTANCE EXCHANGE AT THE CAPILLARY MEMBRANE

[0111] The concept of the revision of the Starling principle (RSP) raises the question of what the fluid and substance exchange at the capillary membrane means according to Levick and Michell (2010). In the search for the answer, the statement of these authors is repeated (12): Quote 13: “Microvascular fluid exchange (Flux Jv) underlies plasma-interstitium fluid balance and edematous swelling.”

[0112] According to this view, fluid exchange should be understood as occurring in the equilibrium of two fluids, but it remains unclear according to which physical laws this exchange must take place. Furthermore, the pathology of "edematous swelling" has nothing to do with the intact process at the capillary membrane for the purpose of cell supply. From our perspective, there is no doubt here: This statement is unsubstantiated and cannot be understood by anyone.

[0113] The question that needs to be answered here is which physical effect is supposed to realize the exchange of liquids and substances in a balance between two liquids, perhaps diffusion?

[0114] In an example relating to this problem, we calculated that convection delivers 600 million times more sugar molecules to the interstitial cells than diffusion (18). In this context, Levick's idea that proteins should diffuse against the current is also recalled (citation 9).

[0115] The proteins cannot diffuse against the current because the convection is 6x10 8 stronger than diffusion, see Chapter 1. Furthermore, proteins in the interstitium are osmotically active, even if they are not positioned at the semipermeable membrane. (See the red arrow in the...) Fig. It is suggested that proteins attract and bind water when their free diffusion in the interstitial space (INT) is hindered.

[0116] It appears that the osmotic effect of proteins in the interstitium was not fundamentally understood, and that in circulatory physiology, the convection-diffusion equation and Fick's law of diffusion were never applied until 2004. More on this topic can be found in our work, which specifically addressed this issue (19).

[0117] Our result means, 1) that cell supply in tissue occurs mainly via convective pathways and 2) that for fluid and substance exchange at the capillary membrane, the blood filtrate and the ISF must be mixed convectively.

[0118] The problem of fluid mixing arises, for example, during kidney dialysis with an artificial kidney. Maintaining a fluid balance does not lead to success. In principle, the exchange of liquids primarily involves mixing these liquids. Mixing liquids, especially on a microscale, is extremely difficult and constitutes a separate branch of science. Various mixing systems exist for this purpose in today's technological world (20).

[0119] The statement in quote 13 merely demonstrates that the authors have not grasped the essence of the task of fluid and substance exchange. In their extensive 2010 work, which cites 100 sources, the authors pursue an idea only to conclude at the end that this idea represents an unproven hypothesis (see quote 12).

[0120] For the past 100 years, circulatory physiologists have worked with the Starling equation, and the revision of the Starling principle (RSP) also represents a slight modification of the Starling equation. We have presented several proofs of the inconsistency of the Starling equation from the perspectives of physics, mathematics, systems theory, and fluid mechanics (17, 23, 24).

[0121] From a purely mathematical standpoint, the Starling equation should never have been written by Landis in its known form in 1927, because the parameters at the capillary wall are not independent of each other. The Starling equation would therefore only hold for interstits with infinite compliance, which must also be empty (23). However, it is certain that such interstits do not exist in practice.

[0122] According to Starling's equation, colloid osmotic pressure (COP) acts against blood pressure. COP thus prevents filtration to the interstitium and counteracts the development of edema in the body. In this respect, circulatory physiologists have believed that Starling's equation and clinical experience with COP are in good agreement.

[0123] Clinical practice does not align with Starling's equation, but rather with the mechanism of action of the COP. The COP exerts its beneficial effects on the circulatory system, including tissue contraction, not because it inhibits filtration, but because it lowers interstitial pressure (IFP) (25, 26, 29). Clinicians wrongly attribute this effect of the COP to Starling's equation. This is the most significant error in the past 125 years of research in the field of microcirculation.

[0124] Ultimately, the COP fulfills its function correctly in the organism, regardless of how we physiologists choose to explain it. In this sense, the example of the work by Mortimer and Levick (2004) is instructive because the authors of this paper believe that a high interstitial pressure (IFP) would be effective in preventing edema formation. The authors derive this idea directly from the Starling equation, with which their work begins.

[0125] However, the reality is quite different: a high IFP (interstitial fluid pressure) is the most significant risk factor for edema formation. A high IFP in an interstitium with finite compliance would force the tissue apart. IFP stands for force per area, and for an IFP to occur at all, there must be an area upon which this force acts. This area in the tissue is the tissue membrane, viewed from the inside. Therefore, the IFP inflates the tissue membrane, puts stress on the cell junctions, and creates ideal conditions for fluid accumulation in the interstitium, which can lead to edema.

[0126] Therefore, nature, with the ingenious "invention" of the fabric air chamber, has ensured that the static interstitial pressure (IFP) is eliminated in the interstitium. Further details can be found in the papers on interstitium, IFP, and the fabric air chamber (16, 28).

[0127] It should also be mentioned that Staverman proposed a reflection coefficient (σ) in 1951 to describe the heterogeneous properties of a semipermeable membrane (3). Although researchers such as Patlak et al. (30) and others have invested considerable computational effort in this coefficient, the coefficient σ is assigned only a modest supporting role in the Starling equation. In the modified Starling equation, the expression σ(π) p - π i ) is used, although it would be correct to use (σ1π p - σ2π i to calculate.

[0128] In our work “The Mechanism of Osmosis and the Theory of Lymph Formation”, we completely eliminated the reflection coefficient (σ). We performed the calculations using particle theory and achieved much better results than with σ (31,32).

[0129] In the years following 1986, we discovered macroelastic interactions in tissue and formulated the principles of tissue Windkessel. We introduced this term for the first time in the theory of microcirculation. Until then, the term "tissue Windkessel" was unknown; even today, circulatory physiologists cannot imagine what it means (16).

[0130] By examining macroelastic interactions in tissue, we realized that the CFC measurement method by Pappenheimer and Soto-Rivera from 1948 was not suitable for this task (23). A new method for CFC measurement was developed, and the CFC value for skeletal muscle was significantly revised upwards using a tissue model and animal experiments (33).

[0131] At that time, we published our work in German, and the publications have been available to the scientific community ever since. However, they have not become widely known, apparently because works in German are not read.

[0132] In this context, it should be noted that Starling also evaluated the literature of German physiologists of his time. On page 317 of his 1896 work, for example, he cites the work of Landerer, see Starling p. 317 (1): Quote 10: “It is obvious that if this were the case, any significant drop in intracapillary pressure would bring it below tissue pressure, and backfiltration into the vessels could occur.”

[0133] Based on this quote, Starling incorrectly concludes that such backfiltration of liquid is fundamentally impossible. In this case, too, Starling has disregarded Ohm's law; see [reference]. Fig. . Figure 5

[0134] The finding regarding the Fig. This represents a description in the sense of descriptive circulatory physiology. This finding is also analytically proven by rigorously calculating the capillaries as elements with locally distributed parameters (23, 25, 27, 29).

[0135] Note: The interstitial fluid (ISF) and blood form a single, fluid-filled structure, a kind of water-filled bladder divided by a porous membrane. In the event of blood loss, blood pressure pushes part of the ISF toward the capillaries, which is why patients recover relatively quickly from this event (see below). Fig. .

[0136] The back-perfusion of the ISF to the capillary membrane is a fundamental principle of cell supply and constitutes the main argument of our work “Understanding the Ohm’s Law” (21). Starling and his successors did not understand the mechanism and nature of microcirculation.

[0137] This passage from Starling's work on "refiltration" is of interest because it is now evident from Landerer's work that Landerer had a far better chance of achieving a superior concept of microcirculation with his approach than Starling (34). Today it is difficult to understand why German physiologists at that time, including Nobel laureate August Krogh and the great dynamist Otto Frank, uncritically adopted the Starling hypothesis.

[0138] However, our most important finding is the classification of porous capillaries as elements with locally distributed parameters. Accordingly, capillaries can only be calculated using special methods, and these calculations reveal that capillaries represent an ingenious invention of nature (25-28): The capillaries act like a kind of balance and automatically establish an equilibrium after every parameter change, thereby neutralizing the effect of the COP on the capillary membrane.

[0139] By considering capillaries as elements with locally distributed parameters, not only can the formulas for cell supply be calculated, but transition states can also be determined as time functions for the first time (23,24,27,29).

[0140] In the meantime, the new formulas for cell supply at the capillary wall have been published several times (23,24,27,29): JHμ=mμ⋅(PCA−PCV)+∑qμj⋅Δπj. (j=1 to N) JHμ=mμ⋅(PCA−PCV) | in case of equilibrium

[0141] Interstitial Fluid Pressure: IFPμ=nμ⋅(PCA−PCV)−Δπ.

[0142] Regarding the theory of lymph formation, it was also found that the vertical convective flow Jv is blocked in the tissue, i.e., Jv=0 (7). This result suggests a different theory of lymph formation; lymph does not appear to be formed as a filtration residue.

[0143] At the capillary membrane, COP does not act as an antagonist to blood pressure and exerts its positive effects throughout the circulatory system as an antagonist to interstitial fluid pressure (IFP). As an antagonist to IFP, COP enables respiration in the body, counteracts the formation of edema by reducing tissue "inflation," and allows the skin to adhere to the body through negative pressure in the subcutaneous tissue.

[0144] The IFP is a property of the interstitial fluid (ISF), which is also discussed as an important parameter in the current theory of microcirculation.

[0145] The IFP belongs to the category of pressure, and pressure means force acting on a surface. Therefore, every interstitium in which an IFP is effective must exhibit finite compliance.

[0146] For this reason, the interstitium, the interstitial fluid pressure (IFP), and the interstitial fluid (ISF) must be re-evaluated in light of the known laws of fluid mechanics, physics, and mathematics. These problems are discussed in detail in the paper "The Interstitium and the IFP" (35). NUMERICAL EXAMPLE OF INTERSTITUTE PERFUSION

[0147] As a computational problem, the issue of cell supply in tissue is relatively easy to solve: From the perspective of fluid mechanics, the task is to calculate a porous capillary wall that is tangentially arranged to the blood vessel. In this case, the interstitium is perfused horizontally convectively according to Ohm's law (21). There should be no discussion about the validity and effect of Ohm's law.

[0148] For the fluid mechanics of cell supply, a substitute capillary results, which essentially remains a capillary loop, but whose surface area (A) must be representative of the entire tissue. In practice, the surface area of ​​the capillaries cannot be measured, which is why the capillary filtration coefficient (CFC) is calculated for 100 grams of tissue.

[0149] In the paper “special theory” we developed the correct formula for the horizontal convective flow through the interstitium (36): JH=¼ CFC⋅(PCA−PCV).

[0150] When using the capillary filtration coefficient CFC, the mean perfusion pressure ½ (P) is automatically calculated. CA -P CV ) used and the mean perfusion flow J H determined. Compare how the introduction of the capillary surface in equations (5) and (7) changed the meaning of these equations.

[0151] Example: With a muscle mass of 40 kilograms, approximately 5000 liters of blood flow through the muscles within 24 hours to ensure the supply of blood to the muscles at rest, see Fig. In the vertical convective direction, only about 1 liter of lymph leaves the muscles - the necessary fluid mixing at the capillary membrane therefore cannot take place in this direction.

[0152] Definition: At this point, the definition of equilibrium at rest is appropriate: Muscle tissue is in equilibrium when blood pressure and blood pressure amplitude do not change, when the muscle is not doing any work, and when there is no change in body position. Figure 6

[0153] Forty kilograms of muscle mass require approximately 500 kilocalories, or the equivalent of 130 grams of sugar, over 24 hours at rest. Plasma filtrate contains 1 gram of sugar per liter, and if 20% of this sugar is absorbed by the muscle cells in one cycle, 650 liters of plasma filtrate must flow through the interstitium in 24 hours to meet the energy demands of the muscle cells.

[0154] With the newly determined value of CFC for 100 g of skeletal muscle tissue of 0.130 ml / min.mmHg (33), at a mean hydraulic pressure difference (P CA -P CVFor a capillary pressure of 40 mmHg, for 40 kg of muscle mass, and for a resting blood flow of 5000 liters in 24 hours, equation (11) calculates that the plasma filtrate flow fraction through the interstitium in a muscle at rest is 748 liters. With a plasma content of 60% in the blood, this result means that approximately 25% of the blood plasma flows through the interstitium, parallel to the capillary blood flow.

[0155] In light of this rough calculation, the calculated plasma filtrate flow rate of 748 liters through the interstitium appears realistic. The Starling principle and its extension in the form of the "never true Starling equilibrium" are far from achieving this performance. Ideas can be developed in many ways, but the cells in the tissue need sugars and other nutrients. In this sense, theoretical concepts must primarily be geared towards practical requirements.

[0156] The answer to this theoretical confusion can be found in our work on fluid and substance exchange at the capillary membrane, and the solution lies in the horizontal convective pathway of this exchange (21).

[0157] This solution simply results from the correct application of Ohm's law, as explained in a special topic on this problem (21, 27). DISCUSSION: CONCLUSIONS

[0158] The evaluation of the concept of fluid and substance exchange at the capillary membrane by Levick and Michel (2010) demonstrated how problematic cell supply according to this model is in the case of a “steady-state Starling principle” (12). The 2020 paper “Understanding and extending the Starling principle” further reveals that the contradictions had deepened: Levick’s initial contribution was relegated to the background in this paper, and the three authors Michel, CC, Woodcock, TE, and Curry, FRE favor a theory that cannot even begin to explain cell supply in tissues.

[0159] The notion that colloid osmotic pressure (COP) at the capillary membrane acts as an antagonist to blood pressure and imposes a useless waste of energy on nature is a fatal scientific error in every respect. Starling and his successors failed to understand the principle of osmosis and the COP effect at the capillary membrane. 1. According to Starling's idea, as presented in quotations 2 and 3, this results only in a static pressure load on the tissue from the capillary side. In this context, an equilibrium of forces at the capillary membrane means a constant tissue volume in the sense of fluid equilibrium, in which the horizontal convective perfusion of the interstitium continues undisturbed. 2. The Starling equation formulated by E.M. Landis includes capillary surface area as a parameter. Thus, entirely in keeping with Starling's principles, only the mean static pressure in the capillary is considered. In conjunction with the infinite compliance of his experiment, Landis achieves the determination of capillary CFC. However, transferring the validity of this Starling equation to microcirculation in tissue is not possible because real interstitial spaces exhibit finite compliance. 3. In 1988, Dulal et al. were apparently the first to grasp the significance of Starling's statements for the processes occurring at the capillary wall. However, the far-reaching consequences for the theory of microcirculation remained hidden from them—an exchange of fluids and substances at the capillaries via the vertical convective pathway does not occur. 4. The 2010 publication on the revision of the Starling Principle (RSP) marked a turning point, indoctrinating the vertical convective pathway via lymph formation as the salvation of the Starling Principle and as a way out of the Starling force equilibrium at the capillary membrane. This view is incompatible with any physical law: The controversial permeability of the glycocalyx is supposed to provide a solution, but this idea is far from sufficient to scientifically explain cell supply in tissues.

[0160] In general, it should be added that cell supply in tissue primarily depends on capillary permeability, with or without a glycocalyx. The important thing is that colloid osmotic particles can, in principle, cross the interface to the interstitium. In the interstitium, these particles accumulate fluid and form a COP, regardless of whether they are located on the outer surface of the capillary membrane or far from it in the interstitium.

[0161] The capillaries have a specific permeability to liquid, which is accurately measured using the new method for determining the CFC. The CFC value is to be inserted into the corresponding calculation procedures, and the conditions at the capillary membrane are represented as they actually occur there, see equation (11) and the example above.

[0162] For calculating transition states at the capillary membrane, experiments, especially those found in the work of C.C. Michel, are incorrect and insufficient; see, for example, (14). For this purpose, as already explained, the capillary must be investigated scientifically and analytically as an element with locally distributed parameters.

[0163] In this context, the work of Zhang, X. et al. should be mentioned (37). Immediately after Levicks' revision of the Starling principle in 2006, these authors published computationally very complex and confusing models of capillary pores, in which they also included the flow velocity in the capillary pores. These represent unnecessary and superfluous efforts because the conditions at the capillary membrane are much simpler and, above all, clearer than these authors, as well as R.F.E. Curry and C.C. Michel, attempt to explain in their most recent work (38).

[0164] Currently, a Weinbaum-Michel model is favored for revising the Starling hypothesis (39). However, it is not necessary to refer to the existing models any further than has already been done. Regarding these efforts, which have been favored for decades in the field of microcirculation theory, it must generally be stated that the Starling equation is incorrect for actual tissue microcirculation, regardless of whether it is the original version by E.M. Landis, the modified version by C. Weinbaum, or the extension by C.C. Michel.

[0165] In support of this, another study, this time with T. Woodcock and CC Michel, shows that confusion surrounding the Starling principle and the Starling equation has increased significantly over time (40). This trend has already led to misunderstandings and even confrontations among clinicians because the existing models lack practical relevance.

[0166] In Erstad BL's work "The Revised Starling Equation: The Debate of Albumin Versus Crystalloids" one finds (41): Quote 14: “The principles underlying the revised Starling equation, in conjunction with data from radionuclide-labeled studies on albumin and large clinical trials, show that albumin does not achieve the perceived degree of plasma volume increase or duration of intravascular residence as predicted by the classical Starling equation.”

[0167] The increase in activity and publications in recent years is striking. The excitement observed in microcirculation societies since 2010 revolves around the idea that, according to the Fig. , the osmotic conditions at the capillary membrane are modified. The Starling equation has therefore been slightly changed: JV / A=Lp[(Pc−Pi)−(πc−πd)],

[0168] In contrast to equation (5), equation (12) only considers the osmotic component of π. i on π d This step does not change the theory of cell supply in tissue; rather, the opposite is true.

[0169] Circulatory physiologists now have to accept that the Landis-Starling equation is simply being discarded, especially given the finding that COP does not act as an antagonist to blood pressure at the capillary membrane. The RSP could easily have been dispensed with as well, since it had further exacerbated the errors in the previous theory of microcirculation.

[0170] The old theory of microcirculation has now been refuted at all levels, and the theory of cell supply in tissues has been rewritten: After 125 years of misguided thinking, it is time to free physiologists and clinicians alike from Starling's shadow. One should be able to imagine the enormous effort that will be required to repair the damage done.

[0171] The authors Weinbaum S. et al. wrote in 2021 (39): Quote 15: “It is relatively rare for a widely accepted textbook description of a basic microcirculation phenomenon to be questioned after almost a century of use. However, this is precisely what has happened with the classic Starling hypothesis.”

[0172] It is even rarer, indeed unprecedented in the history of modern science since Galileo Galilei and Isaac Newton, for a scientific development to be rejected and dismissed as an act of decline after a full 125 years of research and perseverance. In this sense, the Starling era is consigned to history forever with a quote from C.C. Michel from 1997: Quote 16: "I am sure that if Starling were alive today he would be happy to know that his hypothesis had been so fruitful in clarifying thinking and encouraging experimentation."

[0173] A personal note: In 1992, I had the privilege of visiting the brilliant scientist and physiologist E.M. Renkin in the USA for two weeks. During our lengthy discussions, he suggested that we need to return to the origins of microcirculation theory and re-establish everything. He facilitated my collaboration with Philip D. Watson at the University of South Carolina. Together with Philip D. Watson, we confirmed my findings using my new method for determining CFC in animal experiments. After a life-threatening incident, I was grateful to leave the USA alive; unfortunately, I subsequently lost contact with E.M. Renkin.

[0174] When starting a new theory, we must first learn to correctly apply the laws of nature as we know them. Above all, the errors of the past must be identified and corrected. The work "Understanding Starling Two" symbolically represents the first step in making Renkin's words from 1992 a reality. Description of the invention

[0175] In the described device, a diffuser (2), similar to that used in a water-driven vacuum pump, is employed to extract a solution of mineral salts from a container (7) and feed it into the water stream (5) or other liquid. The device consists of several main components: a container (7), a metering device with a fine adjustment screw (8) that serves as a mechanism for controlling the amount supplied. 1. Container: This container (7) is filled with a solution of mineral salts. The concentration and composition of the solution can vary depending on the requirements of the process. The container is designed to be under the negative pressure generated by the vacuum pump, which allows the solution to be fed into the water stream (5). 2. Dosing Unit: The dosing unit is critical for the precise control of the amount of solution added to the water. This unit is typically equipped with a finely adjustable screw (8) that regulates the flow rate of the saline solution. The precise adjustment of the screw, not described in detail here, makes it possible to control the exact concentration of the solution in the water stream, which is crucial for many industrial and chemical processes. 3. Integration with the vacuum pump: The diffuser (2), like a vacuum pump, creates a negative pressure (4) which draws the solution from the container (7) through the metering device (8) into the main water stream (5). The mechanism is based on the principle of the Venturi effect, where the acceleration of the water (3) through a constriction in the diffuser leads to a pressure drop that enables the solution to be drawn in.

[0176] The effectiveness of this device depends on the precise coordination between the pump output (1), the design of the extension (6), the setting of the metering screw (8), and the physical properties of the solution. Such systems are used in areas such as water treatment, food processing, and the chemical industry, where precise dosing of additives to the water flow is required. The design must ensure that the materials coming into contact with the saline solution are corrosion-resistant and meet the hygiene requirements of the respective application. LEGENDS: Fig. 1: a) Particle density c(x,t), t = time, of a non-diffusional paint droplet moved by the flow along the distance x. b) Particle density c(x,t) of a static paint droplet diffusing over time. c) Combined convection and diffusion, taken from: http: / / www.tutz.ws / Herleitungen / Konvektions-Diffusionsgleichung.pdf. Fig. .2: The entirety of the capillary supply in the organism: With a dense distribution of capillary loops in the interstitium, interstitial perfusion always and without exception occurs according to Ohm's law according to the existing pressure gradient. Fig. a) The tissue volume, represented as a black box, is increased or decreased according to Starling's observation when the blood pressure at the tissue entrance P CA The volume change is varied. This change is indicated by vertical arrows in both directions. b) Experiment with a single capillary inserted into a container, where the container walls are not restricted in height. c) Static pressure loading of the capillary surface, ignoring the frictional resistance within the capillary. All terms are explained in the text. Fig. a) Landis's 1927 experiment with a single capillary embedded in a container. Unlike the Fig. a) The nutrient solution flows over the edges of the container, which are restricted in height. b) The Landis-Starling equation describes only the vertical convective flow at the capillary membrane Jv. c) In terms of fluid mechanics, three different flow components exist around the capillary membrane in this experiment. All names are as given in the text. Fig. Until 2004, most circulatory physiologists worldwide assumed a filtration-reabsorption model at the capillary membrane, which was considered the basis for fluid and substance exchange in tissues. All terms as already stated in the text. Fig. The revision of the Starling Principle (RSP) is based on the misconception that the large molecules M, after passing through the glycocalyx to the interstitium (INT), will diffuse against the current (dashed arrow) towards the capillary membrane CAP. Once at the capillary membrane, they will alter the osmotic conditions in the subspace there, thus establishing the RSP, the "scientific" achievement and life's work of the most important theorists in the field of microcirculation of the last 50 years (see also quote 15). Fig. a) In the case of tissue equilibrium, the COP and the IFP act against each other and neutralize each other. The COP acts like a piston being pulled from a cylinder, and COP measuring devices, for example, work on this principle. b) The blood pressure at the capillary base P C also causes for P C<COP eine Perfusion durch das Interstitium im Sinne der Wirkung des Ohm'schen Gesetzes. Diese Perfusion ist von COP unabhängig, weil der COP vom IFP neutralisiert ist. Darin liegt der geniale Plan der Natur, die Zellen mit Hilfe von porösen Kapillaren zu versorgen. Fig. A numerical example of horizontal convective fluid mixing in the interstitium (INT) within the skeletal muscle of a 70 kg individual; the labels are as given in the text. LV = lymphatic vessels Fig.Device for mixing two different liquids: The water pressure (1) supplies the diffuser (2), which, like a vacuum pump, creates a negative pressure (4) that draws the solution from the container (7) through the metering device (8) into the main water stream (5). The mechanism is based on the principle of the Venturi effect, where the acceleration of the water (3) through a constriction into the subsequent expansion (6) of the diffuser leads to a pressure drop that enables the solution (7) to be drawn in. Literature, Chapter 1 1. Saravanakumar, SM, & Cicek, PV (2023). Microfluidic mixing: A physics-oriented review. Micromachines, 14(10), 1827. 2. Pagel Lienhard. Microsystems - Physical effects in the miniaturization of technical systems, J. Schlembach Fachverlag, Weil der Stadt, 2001; p. 31. (E: Microsystems - Physical effects in the miniaturization of technical systems, J. Schlembach Publishers) 3. Ross, Michael H., and Wojciech Pawlina. (2006). Histology. Lippincott Williams & Wilkins. 4. Guyton, A. C., & Hall, J. E. (1986). Textbook of Medical Physiology, W> B. Saunders Company, Chapetr, 63. 5. Fick, A. (1855). Ueber diffusion. Annalen der Physik, 170(1), 59-86. 6. Petrow JM. (2024). There is free fluid in the interstitium that can flow unrestrictedly In: Tissue Windkessel Demonstration Device for Biology and Medicine Teaching, Part 2. German Patent and Trademark Office, AZ: 20 2024 000 076.1 7. Cenaj, O., Allison, D.H.R., Imam, R. et al. Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans. Commun Biol 4, 436 (2021). https: / / doi.org / 10.1038 / s42003-021-01962-0 8. Petrov JM. (2024). The interstitial fluid pressure (ifp) and measurement of ifp. In: Tissue Windkessel Demonstration Device for Biology and Medicine Teaching, Part 2. German Patent and Trademark Office, AZ: 20 2024 000 076.1 Literature, Chapter 2 1. Starling EH. On the absorption of fluids from connective tissue spaces. Journal of Physiology, 19: 312-326 (1896). 2. Michel, C. C. (2004). Fluid exchange in the microcirculation. The Journal of physiology, 557(Pt 3), 701. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited non-patent literature

[0000] Physiologist CC Michel wrote about Starling's work in 2004

[0038] Starling's hypothesis from 1896

[0038] Starling's original text can be found on page 324 of the 1896 work (1

[0039] As Starling did back in 1896

[0056] CC Michel the Starling principle in 2004

[0059] A few years earlier, in 1997

[0059] EM Landis. For an important reason, because in

[0060] Medical student Landis in 1927

[0061] Two other authors, JR Pappenheimer and Soto-Rivera, in 1948

[0067] CC Michel, as the chief advocate of the Starling idea, stated in 1997

[0072] CC Michel, the physiologist JR Levick

[0073] Since the PC falls along a capillary, the plausible idea of ​​filtration from the arterial capillaries and continued resorption in the venous capillaries has become established in the literature

[0073] JR Levick completed

[0075] in the same year 2004 Introduction of the capillary surface, that from 1988 the Starling equation (7

[0078] In 2004, Mortimer and Levick used the Starling equation as a basis for explaining the development of edema (11

[0082] Understanding and extending the Starling principle” replaced the original Starling idea of ​​a “

[0092] Levick and Michel from 2010 (12

[0093] Hahn et al. called for a

[0097] in the same year 2020. our work on the effect of blood pressure amplitude from 1992

[0100] interpretation by Starling from 1896

[0104] Up to the year 2004

[0106] Levick and Michell (2010

[0111] Circulatory physiology up to 2004

[0116] Mathematics, systems theory and fluid mechanics (17,23,24

[0120] Mortimer and Levick (2004

[0124] Landerer, see Starling p. 317

[0132] It is obvious that if this were the case, any significant drop in intracapillary pressure would bring it below tissue pressure, and backfiltration into the vessels could occur

[0132] “Understanding the Ohm’s Law” (21

[0136] Capillary membrane by Levick and Michel (2010

[0158] Understanding and extending the Starling principle” from 2020

[0158] Revision of the Starling Principle (RSP) in 2010

[0159] Zhang, X. et al. should be mentioned (37). Immediately after the Levicks revision of the Starling principle in 2006

[0163] Erstad BL “The Revised Starling Equation: The Debate of Albumin Versus Crystalloids

[0166] The principles underlying the revised Starling equation, in conjunction with data from radionuclide-labeled studies on albumin and large clinical trials, show that albumin does not achieve the perceived degree of plasma volume increase or duration of intravascular residence as predicted by the classical Starling equation

[0166] Excitement that has been ongoing since 2010

[0167] Weinbaum S. et al. published in 2021

[0171] It is relatively rare for a widely accepted textbook description of a basic microcirculation phenomenon to be called into question after almost a century of use. However, this is precisely what has happened with the classical Starling hypothesis

[0171] CC Michel from 1997

[0172] Saravanakumar, SM, & Cicek, PV (2023). Microfluidic mixing: A physics-oriented review. Micromachines, 14(10), 1827

[0176] Pagel Lienhard. Microsystems - Physical Effects in the Minimization of Technical Systems, J. Schlembach Fachverlag, Weil der Stadt, 2001; p. 31

[0176] Ross, Michael H., and Wojciech Pawlina. (2006). Histology. Lippincott Williams & Wilkins

[0176] Guyton, A.C., & Hall, J.E. (1986). Textbook of Medical Physiology, W> B. Saunders Company, Chapetr, 63

[0176] Fick, A. (1855). On diffusion. Annalen der Physik, 170(1), 59-86

[0176] Petrov JM. (2024

[0176] There is free fluid in the interstitium that can flow unrestrictedly In: Tissue Windkessel Demonstration Device for Biology and Medicine Teaching, Part 2. German Patent and Trademark Office,

[0176] Cenaj, O., Allison, DHR, Imam, R. et al. Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans. Commun Biol 4, 436 (2021). https: / / doi.org / 10.1038 / s42003-021-01962-0

[0176] Petrow JM. (2024). The interstitial fluid pressure (ifp) and measurement of ifp. In: Tissue Windkessel Demonstration Device for Biology and Medicine Teaching, Part 2. German Patent and Trademark Office, AZ: 20 2024 000 076.1

[0176] Starling EH. On the absorbtion of fluids from connective tissue spaces. Journal of Physiology, 19: 312-326 (1896

[0176] Michel, C. C. (2004). Fluid exchange in the microcirculation. The Journal of physiology, 557(Pt 3), 701

[0176]

Claims

[1] A device for dispensing a liquid into a stream of water, comprising: • a container (7) designed to hold a solution of mineral salts; • a diffuser (2) as in a water-driven vacuum pump, which generates a negative pressure sufficient to draw the solution from the container; • a dosing device with an adjustable fine screw (8) for controlling the flow rate of the solution from the container into the water stream. [2] A method for the precise dosing of minerals in a water stream, characterized by the steps: • Providing a container filled with a solution of mineral salts; • Creating a vacuum using a water-driven vacuum pump that utilizes the diffuser effect to draw the solution from the container; • Regulating the supply of the solution to the water stream by adjusting a screw in the dosing device. [3] A device for integrating a solution into a water stream, comprising: • a water-driven vacuum pump with a diffuser that creates a Venturi effect; • a container directly connected to the vacuum pump and containing a solution of mineral salts; • a dosing device which is mechanically equipped with an adjusting screw which allows the precise adjustment of the amount of solution supplied. [4] A system for dosing liquids, in particular solutions of mineral salts, into a water stream, characterized by: • a diffuser that creates a negative pressure and is part of a water-driven vacuum pump; • a container connected to the vacuum pump, which holds a predetermined amount of a solution of mineral salts; • a dosing device with a finely adjustable screw that makes it possible to precisely control the flow rate of the solution from the container into the water stream. [5] Instead of the mineral solution, a gas or a gas mixture is supplied to the diffuser via the container and its adjustment device and mixed into the liquid flowing past it. Similarly, several liquids can also be mixed together using this method. These claims aim to protect the technical specification of the device, covering both the device components and the method.

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