DE2929278C2 - - Google Patents

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In recent years, a method of cancer therapy has been developed in which a re-infusion of autologous white blood cells that are removed prior to commencement of conventional therapy and back transfused after treatment, is performed.

This requires that cells long time, often to store for several months, since it is because of the risk of fatal immune reaction is not possible to use cells from other donors, and since the treatment period is often in the range of several months. For preservation of the cells have been employed cryopreservation at low temperatures and to this day is still no other method available. However, none of the known freezing process, it is possible to freeze the large required amounts of cells in a sample.

For the therapy certain cell suspensions possible large amounts must include at cells and the number of viable cells should be as high as possible after the freezing process. The importance of improving the treatment of cancer can seem to justify the effort caused by the cryopreservation.

Since the needed large amount of autologous lymphoid blood cells or bone marrow cells is difficult to win, special care must be given to binare optionen mit maximalem gewinning step of the freeze preservation process. Die wesentlichsten Schritte dieses Verfahrens sind: The key steps of this process are: Revitalization of the cells, ie gradual diluting and washing out the suspension.

The vitality of the binare optionen mit maximalem gewinning depends to a decisive manner on the programmed freezing. The number of living cells is drastically reduced even by slightest deviations from an established favorable freezing curve.

All previously purchasable freezing equipment for biological cells have been developed primarily for the freezing of laboratory samples approximately 2 ml and therefore can not binare optionen mit maximalem gewinning the increased requirements for therapeutic purposes in many respects. For purposes of therapy, the treatment cells must be collected in large quantities, for example, have in bone marrow cells such.

These increased requirements for therapeutic cells mean: MW Scheiwe und P. It has been proposed to use the measured sample temperature to control the various phases of the cooling process to avoid these difficulties and the sample and chamber temperature parallel to determine see. MW Scheiwe and P. Schwindke, Biomedical Engineering, Volume 23, pageand especially page there point 3 "Flexible control.

The chamber temperature remains so long in this final value until the sample temperature leaves the temperature plateau and binare optionen mit maximalem gewinning to decrease. Then, the chamber temperature is lowered at a certain cooling rate until the required final temperature for the sample is reached. As an example, the cooling of the cell suspension in the cylindrical tube is provided with 2 ml content.

However, there are no indications about the vitality of the sample obtained. As a second example, the freezing of a plate-shaped macro-sample of ml is described. Auch hier finden sich keine genauen Angaben. Here, too, there are no exact figures. In binare optionen mit maximalem gewinning said work is carried out that the subject of research to find a suitable cooling profiles for cells to be frozen is in section 4 "Outlook".

Further details, as you have to do to use this freezing method for tumor therapy, are not found. It has further binare optionen mit maximalem gewinning found that this known method is not extended to granulocytes or platelets and that it is not possible to freeze by this process cell suspensions with a high hematocrit.

In the other publications of Scheiwe et al. The invention is therefore based on the object to provide a method available, can be frozen while achieving the highest possible total survival rate to the cells.

The object is achieved by the characterizing features of claim 1. It was surprisingly found according to the invention in that a relationship between the cooling rate for freezing large quantities of cell suspensions B I, with which the chamber is cooled, the cooling temperature T U, to which the chamber is cooled and the Plateauendtemperatur T P of the sample, with the the sample leaves the plateau temperature, the intermediate temperature T O, to which binare optionen mit maximalem gewinning chamber is heated, and the cooling rate B II, with which the temperature of the chamber is lowered, there is.

Under survival rate or total recovery is the proportion of living cells vitalitymultiplied by the total proportion of returned cells after thawing and reprocessing for transfusion. Dieser Wert kann z. This value z can. In the inventive method, the freezing temperature T F is dependent on the composition of the sample and can be removed from tables or be determined experimentally.

The Plateauendtemperatur T P is 0. The following table shows the different temperatures of the cooling rate, the freezing, the Plateauendtemperaturen etc.

The invention further relates to the cell suspension and obtained in the method of their use for combating tumors. Method of the invention is further illustrated by the accompanying figure.

It is the cooling curves of the chamber and the sample shown. In der Zeichnung bedeuten: T O is the temperature to which the chamber is heated again. The method of the invention is illustrated. The therapeutic cells are collected over periods of 2 to 6 hours, preferably over periods of 3 hours, with a cell separator.

Until binare optionen mit maximalem gewinning cells for freezing pass an average of 3 to 4 hours. Studies have shown that many living cells, eg. Such transfer operations are avoided in the present process. Since a pre-damage of the cells prior to the freezing effect on the multiplicative damage after thawing, binare optionen mit maximalem gewinning savings during the process of the invention an increased cell viability.

In addition, the sterility assurance is increased by reducing decanting. Diese Korpuskeln werden dann in einem Volumen von 50 bis ml, vorzugsweise bis ml, suspendiert. These corpuscles are then suspended in a volume of 50 to ml, preferably to ml. The cell material is binare optionen mit maximalem gewinning by subjecting the extraction, large fluctuations and it is not known before the cell separation which number of cells required is obtained.

The quantity of cells needed for therapy is mixed with an antifreeze. Im allgemeinen verwendet man auf 2 Teile Zellsuspension 0,5 bis 1,5 Teile Binare optionen mit maximalem gewinning.

In general, from 0. Die Verwendung des Dimethylsulfoxides ist allgemein bekannt, jedoch ist die erforderliche Konzentration an das Frierverfahren gebunden. The use of the Dimethylsulfoxides is generally known, however, the required concentration is bound to the freezing process. Polyethylene glycol can be used as an alternative. This antifreeze achieves a further reduction in the osmotic load of the cells during the process, and therefore eliminates the need due to the conservation and treatment phase losses.

Hydroxyethyl starch HES is used for red blood cells and allows for freezing in the manner the back transfusion of the thawed preserve without further post-treatment such.

Durch die Verwendung des Gefrierschutzmittels wird die osmotische Belastung der Zellen minimiert. The use of the antifreeze agent, the osmotic stress of the cells is minimized.

Die das Gefrierschutzmittel enthaltende Zellsuspension wird in ein Temperierbad gegeben. The cell suspension containing the cryoprotectant is placed in a constant temperature bath. Before freezing for therapy cells are frozen in plate form, since in this case the temperature field in the sample is particularly favorable for the uniform quality of the cells. The layer thickness binare optionen mit maximalem gewinning the suspension is for example 5 mm for ml per plate and 10 mm for ml.

In the inventive method can be used as containers for samples, the usual container, such as sheet metal bottles, metal plates, containers, etc. Bevorzugt werden jedoch Beutel mit einem Volumen von 50 bis ml, vorzugsweise von bis ml, binare optionen mit maximalem gewinning 4 bis 10 mm dick sind, verwendet.

However, pouches are preferably used with a volume of 50 to ml, preferably from to ml, which are 4 to 10 mm thick. The use of such bags resulting in a high sterility assurance, as a disposable system is used and there is obtained no failures caused by penetrating liquid nitrogen during storage phase, which often includes a number of years, because the bag is welded.

Metal containers are only stoppered and it always comes to leaks. The cell suspension is filled equally into freezer bags. The fact present volume is determined by weighing. The reference sample - consisting of this same solution supplemented with isotonic saline solution instead of the cell volume fraction, a freezing bag, a sheet metal plate container for shaping and two Kupferkonstantan- thermocouples tip diameter 0.

Dieser wird zugeklappt, geklammert und in die Halterung im Frierschacht gestellt. This is folded, stapled and placed in the holder in the freezer compartment. Die Verwendung einer entsprechenden Referenzprobe ist wesentlicher Bestandteil des Frierverfahrens. The use of a corresponding reference sample is an integral part of the freezing process. Through the reference sample, the respective behavior of the sample is detected under the given conditions and automatically taken into account in the freezing process.

Since the reference sample determines the process flow is this is a regulation and not, as usually a control. The freezer bag with the cell suspension are also filled in copper containers after both were dried. This avoids an unwanted phase change of the adhering water is avoided.

The copper container made of 2 mm thick copper sheet metal, are hinged and binare optionen mit maximalem gewinning the bag a layer thickness of 5. Die Kupfercontainer sind Bestandteil des Verfahrens. The copper container are part of the process. Die Verwendung der Kupfercontainer hat ein besonders homogenes Temperaturfeld innerhalb der frierenden Proben zur Folge.

The use of the copper container has binare optionen mit maximalem gewinning particularly homogeneous temperature field within the freezing samples result. Before the start of the operating flow of freezing the programmer the desired and characteristic setting data is entered.

By using a microprocessor system, all required data is adjusted quickly and switch. This data can be, if desired, also modify During the freezing order z.

In addition, various festival programs can be entered, for example. The cooling curves shown in the drawing for the sample and the chamber for the individual cell types as follows: Am Beispiel des Lymphozyten soll der Ablauf des Frierprozesses geschildert werden.

The example of the lymphocytes of the end of the freezing process will be described. The sample temperature follows this cooling until the freezing point of the solution is achieved. In dieser Phase befindet sich die Probe im ungefrorenen Zustand.

In this phase, the sample binare optionen mit maximalem gewinning in the binare optionen mit maximalem gewinning state.

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Umwelt-Parametern eines integrierten Schaltungs-Chips im Betriebszustand. The present invention relates to the field of integrated circuits and more specifically the detection of variations or changes of ambient or environmental parameters of an integrated circuit chip in the operating state. The systems for monitoring associated with the environment of an integrated circuit variables, such as temperature, supply voltage, etc.

Beispielsweise kann es sich darum handeln, eventuelle Piraterie an in der integrierten Schaltung enthaltenen Daten zu detektieren. For example, it may be a question of detecting any piracy contained in the integrated circuit data. Diese letztgenannte Anwendung betrifft insbesondere Chip-Karten.

This latter application is particularly chip cards. Another application example of systems for monitoring an environment variable of an integrated circuit is the authorization, that authorization and approval of the establishment of such a circuit relatively with respect to a region, such as temperatures. In general, the monitoring elements of a certain given variables are assigned.

For example, using a threshold voltage for detecting any temperature changes or fluctuations, and in an analogous manner to interpret the results of the measurement to determine a possible violation of the external environment of the chip. A disadvantage is then that you must multiply with the number of variables or parameters to be monitored, the number of detection circuits.

Another disadvantage is that the result which is obtained with an analog measurement, a conversion requires to be interpreted by a digital system is provided with the generally, the integrated circuit chip, to the consequences of possible infringement to make a decision.

Another disadvantage is that a variation or change of the ambient parameter can take place without a violation of the chip is present. For example, the external temperature conditions can change in a significant way by several tens of degrees.

It would be desirable to be able to distinguish a linked with an injury from a change associated with a normal change in operating conditions change. Schwankungen wenigstens eines Umgebungs- bzw. The present invention seeks to provide a new method for the detection of changes or fluctuations of at least one ambient or environmental parameter of an integrated circuit, which avoids the disadvantages of the known solutions. The invention particularly aims at providing a solution containing one and the same circuit, the monitoring of several ambient parameter of the integrated circuit allows using.

Die Erfindung bezweckt auch die Detektion eines Abstands bzw. The invention also aims at the detection of a distance or a difference of the ambient parameters relatively with respect to a reference or reference value. The invention further aims at enabling an automatic adjustment of the detection system to the normal environment changes or fluctuations. Umwelt-Parameters einer integrierten Schaltung, wobei das Verfahren umfasst: To achieve these objectives, the present invention provides a method for detecting changes of at least one ambient or environmental parameter of an integrated circuit, the method comprising: Fortpflanzung einer Signalfront bzw.

According to one embodiment of the present invention it is provided that one compares the respective current or current delay relative with respect to a single reference or reference value. Variationsbereich vorzugsweise vorbestimmt ist. According to one embodiment of the present invention, it is provided that controls the amount of a programmable delay element or regulates in dependence on the distance between the respective current, the current delay and the reference or reference value, wherein the possible change or variation range of preferably predetermined is.

According to one embodiment of the present invention, that one compares the distance with respect to said relatively two predetermined threshold values. According to one embodiment of the present invention, it is provided that a gene at the time of reading of tilt or flip-flop Circuits whose respective inputs are connected to the output of the delay elements is synchronized to obtain a binary word, the current, an evaluation of the respective represents or current Ausreitungs- or propagation delay.

Die vorliegende Erfindung sieht auch eine integrierte Schaltung vor, welche umfasst: The present invention also provides an integrated circuit comprising: According to one embodiment of the present invention, it is provided that the delay elements being arranged in a parallel circuit and whose common input terminal is connected to the output of a programmable delay element, of which one input terminal is an input terminal of the detection circuit.

According to one embodiment of the present invention is provided that said comparator provides a configuration word to configure the programmable delay apparatus on the basis of a comparison of the respective current or current word relative to a reference or reference value.

According to one embodiment of the present invention it is provided that the circuit comprises means for setting a variation range of the programmable delay apparatus. According to one embodiment of the present invention, it is provided that the delay elements being arranged in series. According to one embodiment of the present invention it is provided that the circuit further comprises a delay element having a mean or average delay between a terminal for applying a signal for triggering or triggering of reading and the respective clock inputs of the different tilting or flip-flop circuits is arranged.

In den Zeichnungsfiguren sind gleiche Elemente in den verschiedenen Figuren mit denselben Bezugsziffern bezeichnet. In the drawing figures, like elements in the various figures with the same reference numerals. For the sake of clarity, only the information necessary for the understanding of the invention have been illustrated in the drawings and will be described in the following.

In particular, is the exploitation of the detection results, to prevent access to the data, or for any other use within the skill of the art. Schwankungen der Umgebung der integrierten Schaltung empfindlich sind. A characteristic of the present invention is the removal and recovery of a delay of the propagation of an electrical signal in delay elements which are individually sensitive to changes or fluctuations in the environment of the integrated circuit.

Die Erfindung macht sich die Tatsache zunutze, dass zahlreiche Umgebungs- bzw. Umwelt-Parameter einer integrierten Schaltung, dh Parameter, die nicht direkt mit dem inneren Aufbau der Schaltung verbunden sind, wie beispielsweise die Temperatur oder die Versorgungs- bzw.

The invention makes use of the fact that numerous ambient or environmental parameters of an integrated circuit, that is, parameters that are not directly connected to the inner structure of the circuit, such as the temperature or the supply or supply voltage of the circuit, when they change or fluctuate, can modify the propagation delays of a signal along an electric path.

Schwankungen eines oder mehrerer Umgebungs- bzw. Thus, the invention this property for the detection of changes or variations of one or more ambient or environmental parameter s of the integrated circuit, in particular relatively with respect to use an operating value, without it being necessary to measure this or these parameters directly. Die Schaltung the circuit 1 1 wird mit wenigstens einer Versorgungs- bzw.

Speisespannung V versorgt, die beispielsweise von einem Generator is supplied with at least one supply or supply voltage V, for example, by a generator 3 3 geliefert wird. Ein anderer in Another in 1 1 veranschaulichter Umgebungs-Parameter ist die Temperatur T, welcher die Schaltung -illustrated ambient parameter is the temperature T, which the circuit 1 1 ausgesetzt ist. This temperature T may be due to internal heating of the circuit as a result of its operation or from an external source.

In all cases, this is according to the invention also has an ambient or environmental parameters. Other ambient parameters can influence the propagation time of a signal. This is, for example, the stability of the supply voltage, moisture, radiation, etc.

Die Schaltung the circuit 21 21 zur Messung der Ausbreitungs- bzw. Flip-Flops The respective corresponding outputs for example, the direct Q-outputs of latches or flip-flops liefern direkt n Bits B1, Beispielsweise werden die Bits des Worts in ein Register For example, the bits of the word are in a register oder ein beliebiges anderweitiges Element zur analogen zeitweiligen Speicherung eingeschrieben. Their respective input terminals are thus connected.

Die Schaltung the circuit 25 25 oder ,einstellbare bzw. Which add an identical delay for all paths. Ausbreitung in den elektrischen Pfaden applied data about the average for the reproduction or distribution in the electrical paths erforderliche Zeit. Als Abwandlungsalternative kann die nicht dargestellte Schaltung zur Erzeugung der Messfront bzw. As Abwandlungsalternative can not shown circuit for generating the measuring front or -stirnflanke the clock signal of the flip-flop with a delay out.

Legt man an den Eingangsanschluss you put to the input terminal 24 24 eine Signalfront bzw. Vorderflanke an dem Eingang D der entsprechenden Kipp- bzw.

All paths which produce a delay less than the delay Cav, deliver a bit having the state 1 ', inasmuch as the front or leading edge at the input D of the corresponding tilt or flip-flop prior to the expiration of the delay Cav arrives. The eventual change or variation of the delay of different paths provides an indirect indication of the deviation of the external environment of the integrated circuit, whether it is the temperature or the supply voltage.

For example, it may be oxide capacity or metal resistors. Mind, the delay elements can also be applied in other forms, provided that they are sensitive to the ambient parameters which are to be measured for the circuit.

Furthermore, the choice of the variation range introduced by the different elements delays on the particular application and the desired sensitivity depends. Flip-Flop-Schaltungen contributed delays are preferably increasing-increasing or decreasing by the weight of corresponding bits in the tilt or flip-flop circuits gelieferten Wort. Der Abstand zwischen den jeweiligen Wertigkeiten der ersten Bits mit dem Zustand 0 bzw. The distance between the respective valences of the first bit to the 0 state or the state 1 of the measured word and the reference word then forms an indication of the amplitude of the change or fluctuation of the ambient parameters.

This display can be used, for example, to calculate the rate of change of ambient parameters by means of successive measurements. It is then a relatively slow, with the normal changes in operating conditions for example, a static change in the supply voltage associated change differ from one abrupt change for example, a dynamic instability of the supply voltage , which is connected to an attempt to gain unauthorized access to data of the chip ,.

According to the preferred embodiment of the invention is then characterized the circuit under operating conditions corresponding to extremely high and extremely low conditions. Again with reference to the case of play of temperature and supply voltage, the resulting binary word in windows, which go from the minimum voltage VCC min to the maximum voltage VCC max and the minimum temperature TMIN to the maximum temperature TMAX in accordance with the, specification 'of the circuit is measured by the Manufacturers guaranteed operation range.

Der Abstand zwischen den beiden Werten entspricht dem autorisierten Bereich. Justierbereich zu definieren, um die an den Anschluss For example by means of a series of programmable switches to define a possible adjustment or adjustment region to the connection to the 24 24 angelegte Front bzw. Stirnflanke zu verlangsamen oder zu beschleunigen. Die so erhaltene Einstell- bzw. Set back in terms and conditions. An advantage of the invention is that it provides a circuit for monitoring a global ensembles, or a group of environment variables of the integrated circuit.

Certainly, one can not only determine with this circuit, whether the change by the one or the other of the parameter is determined. However, the inventors have found that it is usually important to detect a deviation relative with respect to the authorized operating region of any of the parameters. Ein anderer Vorteil der Erfindung ist, dass die Schaltung unschwer in einen Schaltungs-Chip, insbesondere einen vom Chipkartentyp, integrierbar ist.

Another advantage of the invention that the circuit easily in a circuit chip, in particular a chip card is of the type integrated. In diesem Beispiel findet eine Mehrzahl von Tor- bzw. Gatterschaltungen In this example, finds a plurality of gate or gate circuits Anwendung, die in Reihe zwischen dem Eingangsanschluss Application, in series between the input terminal 24 24 der Schaltung the circuit 25 25 und ihrem Ausgangsanschluss and its output terminal liegen. Gatterschaltungen The gate and gate circuits sind beispielsweise einfache nicht-invertierende Elemente vom Puffertyp.

Programming word delivered supplied. The respective amounts and sizes of the capacitors C are different, depending on the valency of the bits in the binary word.

Das Programmierwort kann in verschiedenen Weisen erhalten werden. The programming word can be obtained in different ways. Man kann auch komplexere Mittel verwenden, beispielsweise Informatikmittel zur Vornahme der speziellen Anpassungen. One can also use more sophisticated means such as computer science means for providing the specific adaptations.

Jedes Bit dieses Worts steuert jeweils eine Stufe Each bit of this word controls a respective stage der Schaltung the circuit 25' 25 '.

Die Transistoren P1 und P2 liegen in Reihe zwischen dem Anschluss The transistors P1 and P2 are connected in series between the terminal und dem Ausgangsanschluss and the output terminal der Schaltung the circuit 25' 25 '. Ein zweiter N-Kanal-Transistor N2 hat sein Gate mit dem Eingangsanschluss A second N-channel transistor N2 has its gate connected to the input terminal 24 24 verbunden.