The paper presents the construction of an automatic applicator of active substance that removes causes of the disturbances in the fluid flow in a system that is under the control. In a particular case, it can be applied to the removal of disturbances in the blood flow in vessels caused by a thrombus formation (e.g. post-operative or due to dialysis treatment). The presented applicator automatically releases the active substance into the system while detecting in real time the abnormal fluid flow. It allows mixing the active substance (e.g. anticoagulant drug) with the controlled medium outside the substance container (e.g. serum) while offering the possibility of the repeated usage.
Blood circulation disorders are associated with cardiovascular disorders and diseases of civilization such as diabetes or obesity [1,2]. The direct causes of disruption in blood transport are due to structural deformations of vessels (e.g. mechanical wall damage, in atherosclerosis, calcification of the arterial walls, aneurysms or varicose veins), or due to disturbances in coagulation and fibrinolysis (increased internal vascular coagulation, fibrinolysis weakness and other disorders of the blood hemostasis). All of these increase the chances of the blood clot or thrombus (separate concepts) occurrence. Blood clots are formed as a result of blood coagulation when it leaves the damaged blood vessels or integuments. The latter emerges as a consequence of a local disturbance in coagulation and fibrinolysis homeostasis and its formation does not cause apparent symptoms until the thrombus starts interfering with the blood flow (it can move freely with the blood flow causing a blockage anywhere in the body).
Disturbances in the blood flow due to pathological vessels states or occurrence of bloods clots and thrombus are highly unfavorable. Blood clots and thrombus increase the risk of vascular occlusion and ischemia, which, subsequently when untreated, lead to tissue necrosis due to lack of blood (thus oxygen) supply, with the blockages of the blood flow in the brain vessels being particularly dangerous. The turbulences in the flow and the reduction of the blood flow velocity predispose the development of coagulation disorders. Endoaortic thrombosis can be observed in patients with primary hematologic disorders (in antiphospholipid syndrome, paraneoplastic coagulation disorder, aspergillosis or in long-term steroids treatment). In these cases, it is possible to observe the formation of the thrombus and nonadherent floating thrombus [
The identified risk factors for blood clotting occurrence as described by Virchow [
The most commonly used anticoagulants include heparin, coumarin derivatives—vitamin K antagonists as well as a new type of drug acting as inhibitors of clotting factor Xa and thrombin inhibitors activating fibrinolysis. Thrombolytics are prescribed to dissolve blood clots that cause congestion by activating the endogenous clot dissolver system. However, the administration of the active substacne does not always give the desired results, in particular when plasmin (enzyme) cannot reach the location of the blockade due to blood flow disturbances. Therefore, ideally the drugs with this particular mode of action should be administrated locally at the place where the arterial obstruction occurs. The standard clinical practice is to administrate the drugs up to 12 h from the occurrence of pulmonary embolism, or myocardial infarction and up to 36 h in the case of vein thrombosis. These should not be offered to patients with high hypertension, peptic ulcer, or suffering from purpura (bleeding disorders) and thrombocytopenia. Another group of drugs is based on enzymes derived from snake venom and its mode of action is to reduce the amount of fibrinogen in the blood. Depending on the source origin, their administration yields various effects, e.g. ancrod [
In most patients, the aforementioned treatments result in positive outcomes, however, in the case of excessive clotting in association with other diseases, the risk of complications remains high. Here, other techniques (mainly surgical) are used to remove the thrombi, e.g. during the procedure of embolectomy the blood vessel is opened and the material forming the blockage is removed and a removal of thrombus by fragmentation and aspiration by using a catheter (thrombectomy) may be a preferred choice in patients with contraindications to embolectomy. The thrombectomy and the aortas transplantation pose very high risk of complications, mainly from the cerebral circulation occurring in 29% of patients [
Here, we present a schematical model of an applicator enabling an automated detection of the disturbances in the fluid (e.g. blood) flow with the simultaneous administration of the active substance (e.g. anticoagulant drug).
The problem of the automatic release of the active substance into the bloodstream at the time of the detection of the disturbance in the blood flow in a section under control can be addressed via the usage of an applicator as shown in
The model of this applicator is made of two silicon pipes of an inner diameter of 6 mm each (labeled 2 and 3 on
The construction of the applicator is analogous to the Wheatstone’s bridge. Based on the Hagen-Poiseuille equation a vascular resistance can be defined as in Equation (1)
where:
Rf is the vascular resistance;
h is the dynamic fluid viscosity;
r is the internal radius of the tube;
l is the length of the tube.
By analogy to bridge the relationship between the respective pressure differences can be expressed by the Equation 2:
where:
Rf1, Rf2, Rf3, Rf4—are resistances of pipes 1 and 2 (above and below the connector 4,
DpCD is the pressure difference at both ends of the connector;
DpAB is the pressure difference between the inlet and outlet.
An increase in the resistance Rf1 or Rf4 leads to a maximum DpCD change equal to 0.5DpAB while an increase in the resistance Rf2 or Rf3 leads to a maximum DpCD change equal to −0.5DpAB.
The presented applicator automatically releases the desired substance into the controlled circulation at the time of the occurrence of the disturbance in the fluid flow. The active substance (marked with methylene blue dye) is automatically released into the water flow when the blockage appeares in the pipe segment being under control, in particular drugs removing thrombus or extending blood vessels in the bloodstream.
In the studied system the flow of water (180 ml∙min−1) is divided into two streams (
The considered solution simultaneously detects the disturbances in the fluid flow and reacts with the release of a potentially active substance can find numerous applications to the circulatory system where the blood flow is disturbed due to pathological occurrence of blood clots and thrombus. For instance, it can aid controlling flow of blood in the dialysis tubing.
The described applicator could reduce the amount of substances that prevents blood clotting in the dialysis circuit. An additional quantity of the drug would be added at the time of appearance of the abnormal blood flow. Another potential application is in the control of blood flow disturbances during the postoperative period, especially when the vessels need to merge increasing the risk of blood clots. In this case, one of the arms (pipes) of the applicator is made up of a natural blood vessel, while the second arm (pipe) can be of an artificial biocompatible material. Increasing the cross-section of the artificial pipe reduces the risk of the blood flow disturbances. However, changing the diameter of the pipe requires proper matching the diameter of the two connected pistons (valves) so not to allow the release of the active
substance in the absence of the flow disturbance.
The major difficulty in the construction of the applicator is the selection of materials, which all need to be blood compatible. Currently there are no existing materials that used exclusively and long-term would be risk free in terms of causing blood clots. There are many studies to improve biocompatibility, e.g. the materials with a modified surface, covered with a thin film of synthetic polymer or a layer of gelled material to prevent the aggregation of thrombocytes have been tested [
The presented applicator can be used in automatic control of flows in a closed circuit, in the particular case of blood circulation during dialysis or temporarily in the postoperative period, when the risk of blood clots is increased.