JP4379679B2 - Biological tissue filling material manufacturing equipment - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an apparatus for manufacturing a tissue filling material that is produced by inclining the concentration of calcium compounds contained in a biopolymer gel.
[0002]
[Prior art]
Artificial bone is used as a replacement material for regenerating a bone-deficient part by surgery such as osteosarcoma and fixing a part where the bone has been worn away by arthropathy. As a material for such an artificial bone, the artificial bone does not become a burden on the human body in the body, but is quickly absorbed by bone cells and contributes to the promotion of bone regeneration, and a long-term scaffold for cell regeneration. There is a need for a tissue replacement material that has a portion that remains in the interstitial body and replaces it with autologous bone. In order to solve this problem, a bio-ceramic powder containing bio-ceramic powder containing a bio-biodegradable absorbent polymer with a gradient in content concentration was transplanted into the living body. What is absorbed and decomposed has been proposed (see, for example, Patent Document 1).
[0003]
Thus, there is no literature that discloses an apparatus for manufacturing a filling material having a gradient in content concentration. However, in the field of food, an apparatus for producing two types of food materials in a fluid state that gel or solidify by cooling as a layered food having a two-layer structure (see, for example, Patent Document 2), or thickening. There has been proposed an apparatus for producing a discontinuous jelly-like food by causing gelation by mixing a solution containing a polysaccharide and a solution containing a gelling agent and a calcium compound. (For example, refer to Patent Document 3).
[0004]
[Patent Document 1]
JP 2000-157626 A [Patent Document 2]
JP 2001-95409 A [Patent Document 3]
Japanese Patent Application Laid-Open No. 2002-209532
[Problems to be solved by the invention]
However, the manufacturing apparatus of Patent Document 2 simply forms two thin plate-like semi-solidified food materials into a two-layer structure, and it is difficult to form a structure with three or more layers. Moreover, since the manufacturing apparatus of patent document 3 manufactures the foodstuff which has a discontinuous structure | tissue, it is difficult to make each layer into a uniform density | concentration.
[0006]
The present invention has been made in view of the above-described circumstances, and includes a manufacturing apparatus for a biological tissue filling material having a multilayer structure in which the concentration of calcium compound is different for each layer and each layer has a uniform concentration of calcium compound. The purpose is to provide.
[0007]
[Means for Solving the Problems]
A liquid biopolymer and a calcium compound are mixed to generate a first mixed solution, a cross-linking agent supply device that supplies a cross-linking agent, and a first mixing unit that is generated in the first mixing unit. 1 is mixed with the cross-linking agent supplied from the cross-linking agent supply device, a second mixing unit that generates a second liquid mixture, and a cross-linking unit that gels the generated second liquid mixture The first mixing unit is provided with a detection unit that detects a supply amount of the first mixed liquid to the second mixing unit, and the cross-linking agent supply device detects the first detected A cross-linking agent dropping control device that controls the dropping amount of the cross-linking agent based on the supply amount of the mixed liquid is provided, and the second mixing unit is provided with a cross-linking preventing means for suppressing a cross-linking reaction. Providing manufacturing equipment.
[0008]
According to this invention, when the 1st liquid mixture produced | generated in the 1st mixing part is supplied to a 2nd mixing part, the supply amount will be detected in a detection part. And by the action | operation of a crosslinking agent supply apparatus, a crosslinking agent is dripped at a 2nd mixing part, and a 2nd liquid mixture is produced | generated. Here, since the cross-linking prevention means is provided in the second mixing portion, the mixing is performed in a state where no cross-linking reaction occurs. Then, when the second mixed liquid is supplied to the cross-linked part, gelation occurs, and a layered biological tissue filling material is produced in the cross-linked part. And by repeating the said process, increasing or decreasing the density | concentration of the calcium compound in a 1st liquid mixture, the uniform layer of the density | concentration of a different calcium compound is formed in multiple lamination | stacking state. That is, a biological tissue filling material in which the calcium concentration in the biopolymer solution is inclined is obtained.
At this time, since the cross-linking agent dropping control device drops the cross-linking agent in an appropriate dropping amount in accordance with the supply amount of the first mixed liquid to the second mixing unit in manufacturing each layer, Thus, the biological tissue filling material can be efficiently produced by gelling the mixed solution to an appropriate hardness.
[0009]
According to a second aspect of the present invention, in the apparatus for manufacturing a biological tissue filling material according to the first aspect, the second mixed liquid is brought to a temperature below the temperature at which the cross-linking preventing means causes a cross-linking reaction to the liquid biopolymer. An apparatus for producing a biological tissue filling material to be held is provided.
[0010]
According to this invention, the second mixed liquid produced by mixing the liquid biopolymer and calcium compound with the cross-linking agent is maintained at a temperature below the temperature at which the cross-linking reaction occurs in the second mixing section. Therefore, the crosslinking reaction during mixing is easily prevented. Therefore, the second mixed liquid is supplied to the bridging portion in a uniformly mixed state.
[0011]
The invention according to claim 3 is the biological tissue filling material manufacturing apparatus according to claim 1, wherein the cross-linking part causes the second mixed liquid to have a temperature higher than a temperature at which a cross-linking reaction is caused in the biopolymer inside thereof. The manufacturing apparatus of the biological tissue filling material of Claim 1 or Claim 2 to heat is provided.
[0012]
According to this invention, the 2nd liquid mixture supplied in the uniform state from the 2nd mixing part will be gelatinized by making it the temperature which produces a crosslinking reaction in a bridge | crosslinking part. Therefore, the stacked second mixed liquid can be solidified without being mixed for each layer.
[0013]
The invention according to claim 4 is the biological tissue filling material manufacturing apparatus according to any one of claims 1 to 3, wherein the calcium compound is hydroxyapatite (HAP), α- and β-type tricalcium phosphate. Provided is a device for manufacturing a biological tissue filling material, which is one kind or a mixture of two or more kinds of fate (α, β-TCP), calcium carbonate, and octacalcium phosphate (OCP).
[0014]
The invention according to claim 5 is the biological tissue filling material manufacturing apparatus according to any one of claims 1 to 3, wherein the biopolymer is glutaraldehyde, formaldehyde, 1-ethyl 3- (3 An apparatus for producing a biological tissue filling material prepared by dimethylaminopropicarbodiimide) or pentaerythritol polyethylene glycol ether tetrasuccinimidyl glutarate is provided.
[0015]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, an apparatus 1 for manufacturing a biological tissue filling material according to an embodiment of the present invention will be described with reference to the drawings.
The biological tissue filling material manufacturing apparatus 1 according to the present embodiment is, for example, an apparatus for manufacturing a biological tissue filling material having a five-layer structure as shown in FIG. 2, and the first mixing as shown in FIG. 1. Part 10, second mixing part 20 connected to first mixing part 10, and bridging part 30 connected to second mixing part 20.
[0016]
The first mixing unit 10 includes a biopolymer supply unit 11 that supplies liquid biopolymer, a calcium compound supply unit 12 that supplies calcium compound powder, and a liquid biopolymer and calcium compound powder. A first mixing container 13 for mixing and producing a first mixed liquid; a mixer 14 disposed in the first mixing container 13 for stirring the calcium compound in the liquid biopolymer; a liquid biopolymer and a calcium compound; And a first thermostat 15 that is kept at 4 ° C., for example.
[0017]
The second mixing unit 20 includes a cross-linking agent supply device 21 that supplies a cross-linking agent, a second mixing container 22 that mixes the cross-linking agent and the first liquid mixture, and generates a second liquid mixture, The temperature of the mixer 23 which is arranged inside and stirs the calcium compound in the liquid biopolymer and the second mixing vessel 22 is set to be equal to or lower than the temperature at which the second mixed solution causes a crosslinking reaction, for example, 4 ° C. And a second thermostat 24 to be held.
[0018]
The bridging unit 30 includes an accumulation container 31 for laminating the second mixed liquid, and a third constant temperature bath 32 that is maintained at a temperature equal to or lower than a temperature at which the second mixed liquid causes a crosslinking reaction, for example, 35 ° C. [0019]
The first mixing unit 10 includes a pump 41 that controls the amount of liquid biopolymer supplied from the biopolymer supply unit 11 to the first mixing container 13, and a supply amount sensor 42 that detects the amount supplied. And a pump 43 that controls the supply amount of the calcium compound from the calcium compound supply unit 12 to the first mixing unit, and a supply amount sensor 44 that detects the supplied amount.
[0020]
From the first mixing unit 10 to the second mixing unit 20, a pump 45 that controls the supply amount of the first mixed liquid to the second mixing unit 20 and a supply amount sensor that detects the supplied amount ( Detection section) 46. The second mixing unit 20 includes a pump (crosslinking agent dropping control device) 47 that controls the amount of the crosslinking agent dropped onto the second mixing container 22 from the crosslinking agent supply device 21 and a supply amount that detects the amount dropped. Sensor 48.
In addition, the second mixing unit 20 to the bridging unit 30 include a pump 49 that controls the supply amount of the second mixed liquid to the stacking container 31 and a supply amount sensor 50 that detects the supplied amount. .
[0021]
The pumps 41, 43, 45, 47, 49 and the supply amount sensors 42, 44, 46, 48, 50 described above are connected to the control device 40. The control device 40 includes a setting unit (not shown), and can set the number of layers of the biological tissue filling material, the thickness of each layer, and the calcium compound concentration. Further, the control device 40, based on these set values, supplies the biopolymer and calcium compound to be mixed, supplies the first mixed solution and the cross-linking agent to the second mixing container 22, and supplies to the stacking container 31. The supply amount of the second liquid mixture is calculated and stored.
[0022]
Furthermore, the control device 40 drives the pumps 41, 43, 45, 47, and 49 to supply the biopolymer, calcium compound, first mixed solution, cross-linking agent, and second mixed solution, The supply amount detected by the supply amount sensor 42, 44, 46, 48, 50 is compared with the calculated supply amount, and when these values match, the pumps 41, 43, 45, 47, 49 are informed. A stop command is sent. Moreover, the control apparatus 40 adjusts the dripping amount of a crosslinking agent according to the supply amount of a 1st liquid mixture.
[0023]
The operation of the biological tissue filling material manufacturing apparatus 1 according to this embodiment configured as described above will be described below.
As a biopolymer used in the present embodiment, collagen is used, as a calcium compound, β-TCP particles are used, and as a crosslinking agent, glutaraldehyde is used. Here, for example, as shown in FIG. 2, a living tissue filling material having a five-layer structure, in which the concentration of calcium compound in each layer is A>B> C <D <E in order from the bottom. The case where a filling material is manufactured will be described.
[0024]
Prior to manufacturing the biological tissue filling material shown in FIG. 2 using the biological tissue filling material manufacturing apparatus 1 according to the present embodiment, the collagen solution is supplied to the biological polymer supply unit 11 and the calcium compound supply unit 12. Β-TCP particles and glutaraldehyde are stored in the cross-linking agent supply device 21, respectively. Moreover, in the control apparatus 40, it sets so that the number of layers of a biological tissue filling material may be five layers, and the thickness and calcium compound density | concentration of each layer are set.
[0025]
After the preparation is made in this way, first, in order to manufacture the first layer of the biological tissue filling material in the laminated container 31, the pumps 41 and 43 are driven by the operation of the control device 40. The collagen solution and β-TCP particles are supplied to the first mixing container 13 until the supply amount of the collagen solution and β-TCP particles calculated based on the calcium compound concentration A in the lowermost layer is reached. At this time, in the first mixing container 13, the β-TCP particles are stirred in the collagen solution by the operation of the mixer 14. Then, the supply amount detected by the supply amount sensors 42 and 44 is compared with the calculated supply amount, and when they coincide, the pumps 41 and 43 are stopped.
Here, since the temperature of the 1st thermostat 15 is 4 degreeC, a collagen solution and (beta) -TCP mix and the 1st liquid mixture is produced | generated.
[0026]
Next, the pumps 45 and 47 are driven by the control device 40, and in the second mixing container 22, the first mixed solution and glutaraldehyde dripped from the cross-linking agent supply device 21 are mixed, and the second mixed solution Is generated. At this time, the β-TCP particles are stirred in the collagen solution by the operation of the mixer 23 in the second mixing container 22. Then, the pump 47 adjusts the dripping amount of glutaraldehyde so that the flow rate is constant, and always compares the supply amount detected by the supply amount sensors 46 and 48 with the calculated supply amount. Thus, the pumps 45 and 47 are stopped.
Here, since the temperature of the second thermostat 24 is kept at 4 ° C., the crosslinking reaction is held without taking place.
[0027]
Next, the pump 49 is driven by the control device 40, and the second mixed liquid is supplied to the accumulation container 31. The control device 40 compares the supply amount of the second liquid mixture detected by the supply amount sensor 50 with the calculated supply amount, and stops the pump 49 when they match. Since the temperature of the third thermostatic chamber 32 is maintained at 35 ° C., a crosslinking reaction occurs in the second liquid mixture accommodated in the thermostatic chamber 32, and the collagen solution containing β-TCP particles is gelled. It is done. Thereby, the first-layer biological tissue filling material is manufactured.
[0028]
Next, in order to manufacture the second layer of the biological tissue filling material, the pump 41 is driven by the operation of the control device 40. The control device 40 supplies the collagen solution to the first mixing container 13 until the supply amount of the collagen solution calculated based on the concentration B of the calcium compound in the second layer is reached, and β- Dilute the concentration of TCP particles. Then, the supply amount detected by the supply amount sensor 42 is compared with the calculated supply amount, and the pump 41 is stopped when they coincide. Then, by repeating the same process as that for manufacturing the first layer, the second mixed liquid having the concentration B is supplied onto the first layer in the storage container 31 and gelled. Thereby, the biological tissue filling material in which the concentration of β-TCP particles in the collagen solution becomes A and B in order from the bottom is manufactured. At this time, since the first layer is already gelled, the first layer and the second layer are laminated without being mixed.
[0029]
Next, in order to manufacture the third layer of the biological tissue filling material, the pump 41 is driven by the control device 40 in the same manner as the second layer, and the calculation is performed based on the concentration C of the calcium compound in the third layer. The collagen solution is supplied to the first mixing container 13 until the supply amount of the collagen solution is reached. Thereby, the biological tissue filling material in which the concentration of β-TCP particles in the collagen solution is A, B, and C in order from the bottom is manufactured.
[0030]
Next, in order to manufacture the fourth layer of the biological tissue filling material, the pump 43 is driven by the operation of the control device 40. The β-TCP particles are supplied to the first mixing container 13 until the supply amount of β-TCP particles calculated based on the concentration D of the calcium compound in the fourth layer is reached, and β-TCP in the collagen solution is supplied. Increase the concentration of particles. Here, the supply amount detected by the supply amount sensor 44 is compared with the calculated supply amount, and the pump 43 is stopped when they coincide with each other. Then, by repeating the same process as that for manufacturing the first layer, the concentration of β-TCP particles in the collagen solution in the storage container 31 becomes A, B, C, D in order from the bottom. A biological tissue filling material is manufactured.
[0031]
Further, in order to manufacture the fifth layer of the biological tissue filling material, the pump 43 is driven by the control device 40 in the same manner as the fourth layer, and the calculation is performed based on the calcium compound concentration E in the fifth layer. The β-TCP particles are supplied to the first mixing container 13 until the supply amount of β-TCP particles is reached. Thereby, the biological tissue filling material in which the concentration of β-TCP particles in the collagen solution becomes A, B, C, D, E in order from the bottom is manufactured.
[0032]
Thus, according to the manufacturing apparatus of the biological tissue filling material of this embodiment, as shown in FIG. 2, the content concentration of β-TCP particles in the collagen solution is high in the uppermost layer and the lowermost layer, Thus, a five-layer structure tissue replacement material that is inclined so that the concentration of β-TCP particles decreases can be easily obtained.
[0033]
In this case, since the dripping amount of the cross-linking agent is adjusted by the control device 40 based on the supply amount of the first mixed liquid, the cross-linking agent is adjusted in accordance with the mixed amount of the collagen solution and β-TCP particles. Since it is dripped, it becomes possible to gelatinize in an appropriate state.
Further, the second mixing container 22 is maintained at a temperature equal to or lower than the crosslinking reaction temperature to prevent the crosslinking reaction, and the crosslinking reaction is performed for the first time in the laminated container 31, so that the collagen solution and the β-TCP particles are in a uniform state without unevenness. It will be gelled.
[0034]
In addition, in this embodiment, although demonstrated as a 5 layer structure biological tissue filling material, it is not restricted to this, By setting the arbitrary number of layers in the control apparatus 40, the biological tissue filling which comprised several layers was carried out. A material can be obtained. As described above, the apparatus may not be an apparatus that can change the number of layers, but may be an apparatus that fixes the number of layers. Further, all the second mixed liquid is supplied to the storage container 31 and a cross-linking agent according to the supply amount is dropped, but a part of the second mixed liquid is supplied to the storage container 31 and the second mixing container In consideration of the amount of the second mixed liquid remaining in 22, the crosslinking agent may be dropped. The mixers 14 and 23 operate at the same time as the first mixed liquid and the second mixed liquid are supplied into the first mixing container 13 and the second mixing container 22. May be activated when a predetermined amount is detected.
Moreover, although collagen was used as a biopolymer, gelatin, polylysine, chitosan (degree of deacetylation), glycosaminoglycan (regardless of type) and their derivatives, or their derivatives, which are modified collagens, were described. Examples include composites composed of the above. The molecular weight of these biopolymers is not particularly limited. Although described using beta-TCP as a calcium compound is not limited to this, HAP, alpha-TCP, other or calcium phosphates, such as OCP, and that the inclusion of calcium carbonate such as CaCO ₃ Also good. The shape of the laminated container is not limited to that shown in FIG. 1 and may be a container having a desired shape.
[0035]
In addition, as shown in FIG. 3, in the pipe C, the cross-linking agent supply device 21 is arranged so as to mix the first mixed liquid and the cross-linking agent, and the stirring screw 51 (second second) arranged in the pipe. The β-TCP particles in the collagen solution may be uniformly stirred and laminated by the mixing part. With such an apparatus, there is an advantage that the crosslinking agent can be more efficiently mixed into the first mixed liquid.
[0036]
【The invention's effect】
As described above, according to the biological tissue filling material manufacturing apparatus according to the present invention, each layer has a uniform concentration distribution, and a biological tissue filling material consisting of a plurality of layers having different concentrations for each layer is manufactured. be able to.
[Brief description of the drawings]
FIG. 1 is an overall view of a biological tissue filling material manufacturing apparatus according to an embodiment of the present invention.
FIG. 2 is a cross-sectional view of a biological tissue filling material generated by a biological tissue filling material manufacturing apparatus according to an embodiment of the present invention.
FIG. 3 is an overall view showing a modification of the manufacturing apparatus for a biological tissue filling material in FIG. 1;
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 Manufacturing apparatus 10 of a biological tissue filling material 1st mixing part 20 2nd mixing part 21 Crosslinking agent supply apparatus 24 2nd thermostat (crosslinking prevention means)
30 Bridging section 46 Supply amount sensor (detection section)
47 Pump (crosslinking agent dripping control device)
51 Stirring screw (second mixing part)

Claims (5)

A liquid biopolymer and a calcium compound are mixed to generate a first mixed solution, a cross-linking agent supply device that supplies a cross-linking agent, and a first mixing unit that is generated in the first mixing unit. 1 is mixed with the cross-linking agent supplied from the cross-linking agent supply device, a second mixing unit that generates a second liquid mixture, and a cross-linking unit that gels the generated second liquid mixture And
The first mixing unit is provided with a detection unit that detects a supply amount of the first liquid mixture to the second mixing unit,
The cross-linking agent supply device is provided with a cross-linking agent dropping control device for controlling the dropping amount of the cross-linking agent based on the detected supply amount of the first mixed liquid,
The biological tissue filling material manufacturing apparatus, wherein the second mixing unit is provided with a crosslinking prevention means for suppressing a crosslinking reaction. The apparatus for producing a biological tissue filling material according to claim 1, wherein the cross-linking prevention means holds the second mixed liquid at a temperature equal to or lower than a temperature at which a liquid biopolymer causes a cross-linking reaction. The manufacturing apparatus of the biological tissue filling material according to claim 1 or 2, wherein the cross-linking part heats the second mixed liquid to a temperature that causes a cross-linking reaction to occur in a biopolymer in the second liquid mixture. The calcium compound is one or more of hydroxyapatite (HAP), α- and β-type tricalcium phosphate (α, β-TCP), calcium carbonate, and octacalcium phosphate (OCP). The manufacturing apparatus of a biological tissue filling material according to any one of claims 1 to 3. Any of claims 1 to 3, wherein the biopolymer is prepared with glutaraldehyde, formaldehyde, 1-ethyl 3- (3 dimethylaminopropicarbodiimide), or pentaerythritol polyethylene glycol ether tetrasuccinimidyl glutarate. The manufacturing apparatus of the biological tissue filling material of Claim 1.

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