CN114184441A - Preparation device and method of animal-derived medical instrument biological safety evaluation experiment leaching liquor - Google Patents
Preparation device and method of animal-derived medical instrument biological safety evaluation experiment leaching liquor Download PDFInfo
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- CN114184441A CN114184441A CN202111218157.8A CN202111218157A CN114184441A CN 114184441 A CN114184441 A CN 114184441A CN 202111218157 A CN202111218157 A CN 202111218157A CN 114184441 A CN114184441 A CN 114184441A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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Abstract
The invention relates to a preparation device and a preparation method of animal-derived medical instrument biological safety evaluation experiment leaching liquor, wherein the device comprises a sample adding pipe, a flexible leaching pipe, a medical dialysis pump and heat preservation equipment; the utility model discloses a medical treatment dialysis pump, including medical treatment dialysis pump, sampling pipe, end cover, flexible extraction pipe, sampling pipe, heat preservation equipment, part flexible extraction pipe stretches out, follows to be located near heat preservation equipment pass through in the medical treatment dialysis pump, by the fluctuating pressure that medical treatment dialysis pump provided should be less than the burst intensity of waiting to draw the sample. The leaching liquor prepared by the device is not easy to damage medical instruments in the leaching process.
Description
Technical Field
The invention belongs to the field of biosafety evaluation of medical instruments, and particularly relates to a preparation device and a preparation method of animal-derived, in particular living cell-containing animal-derived medical instrument biosafety evaluation experiment leaching liquor.
Background
The animal-derived medical instrument mainly refers to the medical instrument of which the raw material is derived from animal tissues and is prepared into tissues for human bodies after treatment and processing. Because the raw materials are close to human tissues in source, structure, components and the like, the medical device has better tissue compatibility and biosafety compared with medical devices prepared from other raw materials (natural polymers such as chitosan, silk fibroin and the like, organic matters such as titanium alloy, magnesium alloy metal, polylactic acid, polyglycolic acid and the like). The animal-derived medical instrument has high innovation degree, is a novel medical instrument developed in recent years, and has various raw materials, manufacturing processes, sterilization modes and the like, wherein the animal species for taking raw materials comprise pigs, cattle, sheep and the like, the tissue organs for taking materials comprise corneas, pericardium, peritoneum, dermal tissues, small intestine submucosa, tendons, nerves, bone tissues and the like, and the animal-derived medical instruments which have obtained the registration certificate of the medical instrument at present comprise artificial corneas, artificial dura maters, artificial skins, oral or tissue repair membranes, collagen related products, artificial nerve repair materials, artificial bones and other products. Such instruments vary in not only type, but also form.
Most of film products are in a film shape, and the difference of thickness and texture is large; the collagen products are generally in a sponge-like shape with certain pores; the appearance of the artificial nerve repairing material is similar to that of a normal nerve; the artificial bone comprises bone powder, bone granules, bone strips with certain shapes and the like.
In order to improve performance and market competitiveness, when a novel product is designed and developed or an original product is updated, additional functions such as antibiosis, bacteriostasis, growth promotion, suture-free and the like are added through special methods.
The biological safety evaluation experiment of the medical apparatus has two modes: one is that the finished product of the medical apparatus or the final sample with the same processing mode as the finished product is directly selected for inspection; the other method is to prepare a leaching solution by using the sample and then test the biological safety of the leaching solution. Biological safety evaluation experimental sample leaching liquor preparation referring generally to GB/T16886.12-2017 medical device biological evaluation part 12: the sample preparation and reference materials specify the proportion required by the preparation of product leaching liquor with various forms and thicknesses and four corresponding leaching conditions, and the four leaching conditions can almost adapt to all traditional medical equipment products and most newly-appeared animal-derived medical equipment with higher innovation degree. The detailed leaching conditions were as follows:
1)、(37±1)℃(72±2)h；
2)、(50±2)℃(72±2)h；
3)、(70±2)℃(24±2)h；
2)、(121±2)℃(1±0.1)h；
the standard surface area and volume ratio of the leach liquor were as follows:
the leach liquors are generally divided into polar leach liquors, non-polar leach liquors and other leach liquors. The polar leach liquor mainly comprises: water, normal saline, serum-free medium; the nonpolar leaching liquor mainly comprises fresh refined vegetable oil meeting the quality regulation of pharmacopoeia of various countries, such as cottonseed oil or sesame oil, etc.; other leaching solutions mainly comprise ethanol/water, ethanol/normal saline, polyethylene glycol 400 (diluted to physiological osmotic pressure), dimethyl sulfoxide, serum-containing culture medium and the like.
The preparation method of the sample leaching solution is generally as follows:
mixing the sample and the leaching solution according to the ratio recommended by the standard, placing the mixture into a glass bottle with a sealing cover, placing the glass bottle into a constant-temperature shaking table, and stirring for a period of time to fully dissolve leachable substances such as a release agent, a plasticizer, other auxiliaries and a coating in the sample production process, degradation products of the sample and a packaging material in the storage process, and the like into the extracting solution.
The preparation method of the sample leaching liquor is expected to fully extract soluble substances in the sample without damaging the sample. The detection requires that the detected sample is representative, the whole experimental result of the product can be truly reflected, if the detected sample is metabolized or degraded or living cells fall off or die in the preparation process of the leaching liquor, the finally obtained leaching liquor cannot represent the actual condition of the detected sample, and the detection result is also wrong to a great extent.
The preparation method of the sample leaching solution has the following disadvantages:
liquid and air coexist in the leaching container, the constant-temperature shaking table cannot ensure that a sample is always in the leaching liquid in the stirring process, and the combined action of the liquid and the air can easily cause the damage of animal tissues or the washing of surface cells. In practice, even tissue debris suspension is often found in the leach liquor, adversely affecting the results of the test.
In addition, although the leaching conditions are suitable for most medical appliance products and have universality, with continuous emergence of innovative medical appliances at present, for example, for collagen extraction products, raw materials such as living animals including pigs, cattle, sheep and the like are selected, the normal body temperature is lower than 40 ℃, compared with the leaching solution preparation conditions, the leaching solution is obviously not suitable for leaching products mainly containing collagen components when the temperature is 50 ℃, 70 ℃ and 121 ℃, and the product is also subjected to deterioration reaction in the environment of the leaching solution under the condition of 37 ℃ and 72 hours in vitro. For another example, for a more specific animal-derived medical device containing living cells, since the microenvironment in which the device is implanted into a human body is 37 ℃, if the leaching condition of 37 ℃ is selected, the living cell components are already subjected to metabolic reaction after 72 hours of the above standard leaching. The leaching solution prepared from the product subjected to metabolic reaction in the leaching solution preparation process cannot reflect the actual condition of the product performance index, and the wrong detection result is possibly caused greatly.
In summary, the existing standard leaching apparatuses, leaching conditions, and the like are deficient in the applicability to animal-derived medical instruments, particularly to animal-derived medical instruments containing living cells, and the biological safety evaluation results of the obtained leaching solutions cannot reflect the actual conditions of products.
Disclosure of Invention
The first purpose of the invention is to provide a device for preparing the leaching liquor for the biological safety evaluation experiment of the animal-derived medical apparatus, the leaching liquor is prepared by the device, the medical apparatus in the leaching process is not easy to damage, and the biological safety evaluation result of the obtained sample leaching liquor can better represent the real situation of a reaction product.
The first invention of the invention is realized by the following technical scheme: a preparation device for animal-derived medical instrument biological safety evaluation experiment leaching liquor comprises a sample adding pipe, a flexible leaching pipe, a medical dialysis pump and heat preservation equipment;
the utility model discloses a medical treatment dialysis pump, including the sample adding pipe, the sample adding pipe is the tube-shape, and both ends are equipped with the end cover, and the end cover of at least one end can be dismantled, the both ends of flexible extraction pipe with the sample adding pipe forms a closed circuit through the trompil intercommunication on its both ends end cover, the length of flexible extraction pipe with the volume adaptation of the leaching liquor in the closed circuit to make the leaching liquor be full of the closed circuit, sample adding pipe, flexible extraction pipe arrange in among the thermal insulation equipment, part the flexible extraction pipe stretches out, is located near thermal insulation equipment pass in the medical treatment dialysis pump, by the fluctuating pressure that the medical treatment dialysis pump provided should be less than the burst intensity of waiting to draw the sample, and the burst intensity refers to the product technical requirement that the sample manufacturing enterprise that examines provided.
The sample adding pipe is mainly used for placing and positioning samples, the flexible extraction pipe is mainly used for storing leaching liquor, the samples in the sample adding pipe are circularly washed by the leaching liquor in the sample adding pipe under the action of the medical dialysis pump, the medical dialysis pump is mainly used for providing fluctuating pressure in sample extraction equipment, and the heat preservation equipment is mainly used for maintaining temperature, particularly providing a low-temperature environment of less than 37 ℃, such as 4-8 ℃. The length of the flexible leaching pipe is intercepted according to the total amount of leaching liquor, so that the inner cavities of the sampling pipe and the flexible leaching pipe can be filled with leaching liquor, the pressure of the inner cavity is uniform and stable when the medical dialysis pump pressurizes the flexible leaching pipe, and the unstable condition caused by gas-liquid combined action in the sample leaching process is avoided.
When the device is used for preparing the sample leaching liquor, no air exists in the closed loop, the pressure is uniform, and leachable substances and other components in the sample can be well and fully extracted under the condition of small fluctuation pressure by matching with a circulating flushing mode, so that when the device is used for preparing the sample leaching liquor, the leaching is full, medical instruments in the sample leaching liquor are not easily damaged, and the biological safety evaluation result of the obtained sample leaching liquor can better realize the real condition of a reaction product. In addition, the lower temperature environment which is consistent with the shelf life storage temperature condition of the sample during extraction can avoid the reactions of metabolism, degradation or deterioration and the like of the sample.
The fluctuation frequency range of the medical dialysis pump is recommended to be 60 times/minute to 120 times/minute.
In order to avoid the influence of the device material on the leaching liquor, the sampling tube and the flexible leaching tube in the device are both made of inert material polytetrafluoroethylene.
The second purpose of the invention is to provide a method for preparing animal-derived medical instrument biosafety evaluation experiment leaching liquor by using the device.
As a preferable scheme: leaching temperature: 4-8 ℃; fluctuation frequency: 60 times/min to 120 times/min; leaching time: 1-30 d.
When the leaching liquor used for leaching is added, the leaching liquor is pre-cooled to a required temperature range, so that potential changes of product performance caused by temperature changes are avoided, and the final leaching liquor result of a sample is influenced.
Compared with the prior art, the invention has the following beneficial effects:
1) in the prior art, the dissolving and the separation of soluble substances in a sample are promoted by shaking a container generally, gas and liquid coexist in the container, and the pressure of liquid on the sample is large and uneven in the shaking process, so that the sample is easy to damage;
2) the environmental temperature is set to be 4-8 ℃, and is consistent with the storage temperature of a product specification, so that the situations of metabolism, degradation, deterioration and the like of products are avoided when the animal-derived medical instruments, particularly the leaching liquor of the animal-derived medical instruments containing living cells are prepared by the leaching liquor preparation method, and the adverse effect of improper conditions in the leaching liquor preparation process on product result evaluation is reduced;
3) compared with the leaching conditions such as leaching temperature, leaching time, fluctuation frequency and the like, the leaching solution is stable and reliable in result and can be used as a standard method for preparing animal-derived medical instruments and the leaching solution of the animal-derived medical instruments containing living cells.
Drawings
FIG. 1 is a schematic structural diagram of a preferred embodiment of a leaching solution preparation apparatus for biological safety evaluation experiments of animal-derived medical devices according to the present invention;
FIG. 2 is a schematic view of a connection structure of the sample adding pipe and the flexible leaching pipe in FIG. 1.
Detailed Description
The invention is described in further detail below with reference to specific embodiments and the attached drawings.
The device for preparing the leaching liquor in the animal-derived medical instrument biological safety evaluation experiment of the embodiment is shown in fig. 1, and comprises a sample adding tube 1, a flexible leaching tube 2, a medical dialysis pump 3 and a low-temperature freezing shaking table 4. As shown in fig. 2, the sampling tube 1 is cylindrical, end caps 11 are provided at two ends, an opening 111 is provided in the middle of the end cap 11, and two ends of the flexible extraction tube 2 are communicated with the sampling tube 1 through the openings 111 on the end caps 11 at two ends of the sampling tube (specifically, the flexible extraction tube 2 is sleeved on the cylindrical opening tube on the end cap 11) to form a closed loop. As shown in fig. 1, the length of the flexible extraction tube 2 is adapted to the amount of leach liquor in the closed circuit so that the closed circuit is filled with leach liquor. The medical dialysis pump 3 is arranged near the cryo-shaker 4. After the sample adding tube 1 is tightly connected with the flexible leaching tube 2, the other parts except the part needing to be connected with the medical dialysis pump 3 are immersed in the temperature control area of the low-temperature freezing table at 4-8 ℃.
The sampling tube 1 is mainly used for placing and positioning samples, the flexible extraction tube 2 is mainly used for storing extract, the samples in the sampling tube 1 are circularly washed by the extract in the flexible extraction tube under the action of the medical dialysis pump 3, the medical dialysis pump 3 is mainly used for providing fluctuating pressure in sample extraction equipment, the fluctuating pressure provided by the medical dialysis pump 3 is smaller than the bursting strength of the samples to be extracted, the low-temperature freezing shaking table 4 is only used for providing a low-temperature environment, and other equipment capable of providing the same temperature can be selected for replacement.
The components of the product obtained after the extraction of the collagen are mainly different types of collagen, and the product is usually refrigerated and stored at 4-8 ℃. The preservation temperature of the animal-derived medical apparatus containing the preservation solution is generally between 4 ℃ and 8 ℃, the shelf life of the product is 1-3 years, and certain product cell components containing living cells can not activate metabolism in the temperature range. In comprehensive consideration, the leaching temperature range of 4-8 ℃ is selected as the experimental condition of the embodiment, that is, the working temperature of the cryo-shaker 3 is set to be 4-8 ℃.
The medical dialysis pump 4 is set up as follows: the liquid fluctuation frequency in the leaching pipe is 60 times/min to 120 times/min. In the experiment, due to the fact that the temperature of the leaching liquor is reduced, brownian motion of water molecules is reduced, and the potential possibility of damaging a sample exists at an excessively high frequency, the fluctuation frequency of the leaching liquor is limited to 60 times/minute-120 times/minute, and a proper fluctuation frequency is selected according to the properties of the sample.
The whole leaching period is 1 to 30 days, and the leaching period can be properly prolonged by special samples, so that the effect of full leaching is achieved. Specifically, the selection is made depending on the properties of the test sample.
In order to avoid the influence of the material of the device on the leaching liquor, the sampling tube 1 and the flexible leaching tube 2 in the device are both made of inert material polytetrafluoroethylene.
As shown in FIG. 1, the sample addition pipe 1 in this embodiment has two end orifices matching the diameter of the extraction pipe 2, and they can be firmly connected without leakage. The middle tube body of the sampling tube 1 is in threaded connection with the end covers 11 at two sides, a sample can be put in or taken out after the sampling tube is opened, and the sampling tube is pressure-resistant and has no leakage after being tightly covered.
The sample adding pipe 1 is spirally opened, a sample is conveniently and quickly put in and taken out, the sample adding pipe 1 and the flexible leaching pipe 2 are directly inserted and connected, the airtightness is good, the risk of leakage and pollution is avoided, and the sterile operation requirement of medical equipment during the preparation of the biological safety evaluation leaching liquor is conveniently met.
According to the invention, under the preservation condition of the living cell-containing animal-derived medical apparatus product, the leaching effect is promoted through the cyclic washing effect of the leaching liquor, so that the product is more effectively leached under the soft and uniform washing effect, and the leaching liquor with less influence on the biosafety evaluation result is obtained. The device and the method can ensure that the products do not go bad, metabolize, degrade and the like when the animal-derived medical instruments and the leaching liquor containing the living cell animal-derived medical instruments are prepared, and can reduce the adverse effect of improper conditions in the leaching liquor preparation process on the product result evaluation.
The biological safety evaluation experiment of the medical apparatus and instruments is the necessary data for registering and reporting most of the medical apparatus and instruments, so the device and the method have great application value.
The embodiment of preparing the leaching liquor for the biosafety evaluation experiment of the animal-derived medical apparatus by using the device is as follows:
example one
The adding proportion of the leaching liquor follows the regulations of GB/T16886.12-2017 medical apparatus biological evaluation part 12, the membrane-shaped samples of hernia repair materials and other animal-derived medical apparatuses have good toughness, the thickness is usually about 0.2mm and less than 0.5mm, the samples are stored without preserving fluid in a drying way, and the samples are stored according to the length of 6cm2The leaching liquor is added in the ratio of/mL, the leaching temperature is as follows: the temperature is 4-8 ℃, the fluctuation frequency is 60-80 times/minute, and the leaching time is 1-3 days.
EXAMPLES comparative experiment
The comparative experiment singly increases the fluctuation frequency to 120 times/minute or the leaching time to 7 days, and the results of the biological safety experiment (experiments such as sensitization, stimulation and the like) of the leaching liquor are not changed when the oscillation frequency and the time are both increased to the conditions.
Indicating a film-like sample of less than 0.5mm, 6cm2Adding leaching liquor in a ratio of/mL, wherein the fluctuation frequency is 60-80 times/minute, and the leaching time is 1-3 days, so that the aim of full leaching can be fulfilled.
Example two
The adding proportion of the leaching liquor follows the regulations of GB/T16886.12-2017 medical apparatus biological evaluation part 12, and the film-shaped samples with the thickness of the animal-derived medical apparatus of more than 0.5mm, such as oral cavity repair films, artificial dura mater and the like, are usually stored under the condition of a storage solution, the material texture is soft, the leaching condition is relatively strict and is according to 3cm2The leaching liquor is added in the ratio of/mL, the leaching temperature is as follows: the temperature is 4-8 ℃, the fluctuation frequency is 80-100 times/minute, and the leaching time is 3-5 days.
EXAMPLES comparative experiment
The comparative experiment singly increases the fluctuation frequency to 120 times/minute or the leaching time to 7 days, and the results of the biological safety experiment (experiments such as sensitization, stimulation and the like) of the leaching liquor are not changed when the oscillation frequency and the time are both increased to the conditions.
Indicating greater than 0.5mm, 3cm of film-like sample preserved in preservative solution2Adding leaching liquor in a ratio of/mL, wherein the fluctuation frequency is 80-100 times/minute, and the leaching time is 3-5 days, so that the aim of full leaching can be fulfilled.
EXAMPLE III
The adding proportion of the leaching liquor follows the regulations in GB/T16886.12-2017 part 12 of the biological evaluation of medical instruments, the solid shape with the diameter of 1-5mm, the appearance close to that of normal nerves and the cylindrical sample with the thickness of more than 0.5mm of such animal-derived medical instruments as peripheral nerve repairing materials are generally stored under the condition of storage liquid, the materials are tough, the leaching conditions are more strict, and the leaching conditions are 3cm2The leaching liquor is added in the ratio of/mL, the leaching temperature is as follows: the temperature is 4-8 ℃, the fluctuation frequency is 100-times/min, and the leaching time is 7-15 days.
Example three comparative experiments
The comparative experiment independently increases the fluctuation frequency to 180 times/minute (the fluctuation frequency is frequently used for preparing the peripheral nerve repairing material) or the leaching time to 30 days (the fluctuation time is frequently used for preparing the peripheral nerve repairing material), and the results of the biological safety experiment (the experiments such as sensitization, stimulation and the like) of the leaching liquor are not changed when the oscillation frequency and the time are increased to the conditions.
When the thickness is larger than 0.5mm, the thick film sheet sample preserved by the preservation solution is added with the leaching solution in the proportion of 3cm2/mL, the fluctuation frequency is 100 times/min and the leaching time is 7-15, thus achieving the purpose of full leaching.
Example four
The adding proportion of the leaching liquor follows the regulations of the GB/T16886.12-2017 medical apparatus biological evaluation part 12, the animal-derived medical apparatus such as human body repair materials containing living cells selects the corresponding proportion of the leaching liquor according to the morphological characteristics of the product, and the living cell survival conditions are very strict, so the storage conditions of the product are more strict, the shelf life of the product is shorter, for example, the first domestic animal-derived artificial skin containing the living cells has a shelf life of only 30 days, in order to avoid the influence of the products after the metabolism or death of the living cells on the results of leaching liquor experiments, the leaching temperature is as follows: the leaching time is set to be 3-7d at 4-8 ℃, and the fluctuation frequency is 60 times/minute.
Example four comparative experiment one
In the comparative experiment, if the fluctuation frequency is increased to more than 120 times/minute, the attachment of living cells is obviously influenced, so that the fluctuation frequency is not recommended to be increased to 80 times/minute or the leaching time is increased to 30 days, and the conditions do not change the results of the biological safety experiment (experiments such as sensitization, stimulation and the like) of the leaching solution.
The comparison shows that the leaching time of the animal-derived medical apparatus containing living cell human body repair materials and the like is set to be 3-7 days, the fluctuation frequency is 60 times/minute, and the purpose of full leaching can be achieved.
In addition, compared with the experimental method in the standard, taking artificial cornea and collagen sponge products as examples, the conditions of no turbidity, light transmittance change and the like of the leaching solution after the preparation of the leaching solution are realized, and the influence on the sample is smaller than that of the standard leaching method.
Example four comparative experiment two
Compared with the common leaching experimental method listed in the standard, the contrast experiment is mainly compared with the common leaching experimental method, and compared with the common experimental method, the number and morphological form of the cells attached to the surface of the instrument after leaching by the method disclosed by the invention are not obviously changed or abnormal through microscope detection, which indicates that the phenomena of obvious cell detachment and damage do not occur. The common method has obviously changed the product form, the number of the living cells attached on the surface of the apparatus is obviously reduced, and the leaching liquor can find the fallen cell components during microscopic examination.
Claims (7)
1. A preparation device of animal-derived medical instrument biological safety evaluation experiment leaching liquor is characterized by comprising a sample adding pipe, a flexible leaching pipe, a medical dialysis pump and heat preservation equipment;
the utility model discloses a medical treatment dialysis pump, including medical treatment dialysis pump, sampling pipe, end cover, flexible extraction pipe, sampling pipe, heat preservation equipment, part flexible extraction pipe stretches out, follows to be located near heat preservation equipment pass through in the medical treatment dialysis pump, by the fluctuating pressure that medical treatment dialysis pump provided should be less than the burst intensity of waiting to draw the sample.
2. The manufacturing apparatus as set forth in claim 1, wherein said heat-retaining device is used to provide a low-temperature environment of 4-8 ℃.
3. The manufacturing apparatus according to claim 1 or 2, wherein the medical dialysis pump has a fluctuation frequency in a range of 60 times/minute to 120 times/minute.
4. The apparatus according to claim 3, wherein the sample introduction tube and the flexible extraction tube are made of polytetrafluoroethylene, which is an inert material.
5. A method for preparing animal-derived medical equipment biosafety evaluation experiment leaching solution by using the device of any one of claims 1-4.
6. The method of claim 5, wherein the ratio of leaching temperature: 4-8 ℃; fluctuation frequency: 60 times/min to 120 times/min; leaching time: 1-30 d.
7. A process according to claim 6, wherein the leach liquor used for leaching is added with a pre-cooling to a temperature in the desired range, i.e. 4-8 ℃.
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