CN113944003B - Multi-scale tissue engineering composite scaffold and preparation device and preparation method thereof - Google Patents
Multi-scale tissue engineering composite scaffold and preparation device and preparation method thereof Download PDFInfo
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Classifications
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- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
- D04H1/40—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties
- D04H1/42—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties characterised by the use of certain kinds of fibres insofar as this use has no preponderant influence on the consolidation of the fleece
- D04H1/4382—Stretched reticular film fibres; Composite fibres; Mixed fibres; Ultrafine fibres; Fibres for artificial leather
-
- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
- D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
- D04H1/72—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged
- D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning
-
- D—TEXTILES; PAPER
- D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
- D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
- D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
- D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
- D04H1/76—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres otherwise than in a plane, e.g. in a tubular way
Abstract
The invention relates to a multi-scale tissue engineering composite stent, a preparation device and a preparation method thereof, wherein the multi-scale tissue engineering composite stent comprises a plurality of fiber layers which are sequentially overlapped, at least one first fiber layer comprises first fiber filaments, second fiber filaments and third fiber filaments, and the forming step of the first fiber layer comprises the following steps: forming a plurality of first filaments having a diameter of 50-1000 μm on a collecting plate, the plurality of first filaments being arranged in parallel; forming second filaments having a diameter of 1-50 μm between the plurality of first filaments; and forming third fiber filaments with diameters of 50-1000nm on the formed structures of the first fiber filaments and the second fiber filaments. The scaffold prepared by the embodiment of the invention has good mechanical strength, proper pore diameter and porosity, can promote the permeation of cells and the transportation of nutrient substances, provides a proper microenvironment for the movement of cells, and promotes the adhesion, proliferation, differentiation, migration and the like of cells.
Description
Technical Field
The invention belongs to the technical field of tissue engineering scaffolds, and particularly relates to a multi-scale tissue engineering composite scaffold, a preparation device and a preparation method thereof.
Background
Tissue engineering scaffolds are cell carriers of three-dimensional porous structure that deliver nutrient and excreted metabolites for cell growth in tissue engineering. Tissue engineering scaffolds are used as carriers of cells and biological factors, and are the basis of tissue engineering, and the basic function of the tissue engineering scaffolds is to provide a cell growth environment similar to that of an extracellular matrix in vivo. Tissue engineering scaffolds can be classified into natural material scaffolds, synthetic material scaffolds, and composite material scaffolds according to scaffold materials. The natural material refers to natural polymer or inorganic material and its modified material, such as gelatin, collagen, chitosan, alginate, hydrogel, etc. The synthetic material refers to a polymer or an inorganic material obtained by chemical synthesis, such as polylactic acid, polycaprolactone, polyethylene glycol, polyglycolic acid or copolymers thereof, and the like. Composite material refers to two or more different classes of materials that are physically or chemically combined.
An ideal tissue engineering scaffold should have sufficient mechanical strength, have suitable pore size and porosity to allow cell penetration, nutrient diffusion, and also provide a suitable microenvironment for cell activities such as cell adhesion, proliferation, migration, differentiation, etc. These requirements for an ideal tissue engineering scaffold are closely related to the structural characteristics of the scaffold such as fiber diameter, porosity, pore size, etc.
The fused deposition technique and the solution electrostatic spinning technique are two methods for preparing tissue engineering scaffolds. The fusion deposition technology needs to heat and melt the material, is generally suitable for polymer materials, and the prepared scaffold has a fiber diameter and fiber interval of 50-1000 mu m and good mechanical strength, but the fiber diameter is far larger than the cell diameter (10-20 mu m), and cells can only be attached to the surface of fiber filaments and can not provide proper microenvironment for cell activities such as cell adhesion, proliferation, migration, differentiation and the like. The solution electrostatic spinning technology can prepare natural polymers and synthetic polymers into nanofibers with the diameter of 50-1000nm, and the prepared scaffold can well simulate the micro environment of extracellular matrix, is beneficial to cell adhesion, proliferation, migration, differentiation and the like, but has the characteristics of low porosity and small pore diameter, is not beneficial to cell ingrowth and permeation, and has poor mechanical properties.
In addition to the two techniques described above, the melt electrospinning technique is another technique for preparing tissue engineering scaffolds. Continuous fibers are more readily obtained by melt electrospinning techniques, typically with fiber diameters of 1-50 μm, which are close to the cell size. The prepared scaffold not only has proper pore diameter, but also can promote the permeation of cells and the transportation of nutrient substances, and simultaneously can provide proper microenvironment for the adhesion, proliferation, migration, differentiation and the like of cells. However, due to the process limitation, the prepared stent has limited height, mechanical strength cannot meet the requirement, and the prepared stent can only be molded by adopting a synthetic polymer material, so that the bioactivity of the stent is poor. These deficiencies severely limit the applicability of this technique, far from being as widespread as fused deposition techniques and solution electrospinning techniques.
In summary, due to the limitation of the manufacturing technology, each scaffold in the prior art has the defects that the scaffold lacks an ideal tissue engineering scaffold which has enough mechanical strength and proper fiber diameter, pore diameter and porosity and can provide proper microenvironment for cell activity, and further lacks a device which has strong universality and can prepare the ideal tissue engineering scaffold.
Disclosure of Invention
In view of this, the inventors have conducted diligent studies and have found that by combining at least two of the three techniques, preferably the three techniques, through fusion of the melt deposition technique, the solution electrospinning technique and the melt electrospinning technique, it is possible to combine the advantages of different preparation techniques, prepare a tissue engineering scaffold of multi-scale (micro-nano-scale), composite materials (natural polymer and synthetic polymer), which has desirable properties, and can solve at least one of the above-mentioned technical problems.
According to a first aspect of the present invention, an embodiment of the present invention provides a method for preparing a multi-scale tissue engineering composite scaffold, the multi-scale tissue engineering composite scaffold includes a plurality of sequentially stacked fiber layers, wherein the plurality of sequentially stacked fiber layers includes at least one first fiber layer, the at least one first fiber layer includes a first fiber filament, a second fiber filament, and a third fiber filament, and the forming step of the first fiber layer includes:
forming a plurality of first filaments having a diameter of 50-1000 μm on a collecting plate, the plurality of first filaments being arranged in parallel;
forming second filaments having a diameter of 1-50 μm between the plurality of first filaments;
and forming third fiber filaments with diameters of 50-1000nm on the formed structures of the first fiber filaments and the second fiber filaments.
In one embodiment, in the first fibrous layer, adjacent first filaments are spaced apart by 50-1000 μm.
In one embodiment, in the first fiber layer, the second fiber filaments are a plurality of second fiber filaments, the plurality of second fiber filaments are arranged in parallel with the first fiber filaments, and the adjacent second fiber filaments are spaced by 1-50 μm.
In one embodiment, in the first fiber layer, the third fibers are a plurality of third fibers arranged in parallel, and the adjacent third fibers of the second fiber layer are spaced by 50-1000nm.
In one embodiment, the third plurality of filaments is disposed between the first and second plurality of filaments in parallel with the first and second filaments.
In one embodiment, the plurality of sequentially stacked fiber layers includes a plurality of first fiber layers, first fiber filaments of which are parallel to each other, and a second fiber layer, which is disposed between two adjacent first fiber layers, and is composed of a plurality of fiber filaments having diameters of 50-1000 μm parallel to each other, with an interval of 50-1000 μm between adjacent fiber filaments.
In one embodiment, the third filaments are deposited on the first and second filaments in an disordered manner.
In one embodiment, the plurality of fiber layers of the multi-scale tissue engineering composite scaffold are all first fiber layers, and first fibers of two adjacent first fiber layers of the multi-scale tissue engineering composite scaffold are not parallel.
In one embodiment, the first fiber is a synthetic polymer printing material and is printed and formed by a fused deposition printing nozzle;
the second fiber yarn is a synthetic polymer printing material and is formed by printing through a melt electrostatic spinning printing nozzle;
and the third fiber yarn is formed by printing a polymer solution of a synthetic polymer and/or a natural polymer through a solution electrostatic spinning printing nozzle.
According to a second aspect of the present invention, an embodiment of the present invention provides a multi-scale tissue engineering composite scaffold comprising a plurality of sequentially stacked fiber layers, wherein the plurality of sequentially stacked fiber layers comprises at least one first fiber layer comprising a plurality of parallel arranged first fiber filaments having a diameter of 50-1000 μm, a second fiber filament having a diameter of 1-50 μm formed between the plurality of first fiber filaments, and a third fiber filament having a diameter of 50-1000nm on a structure of the first fiber filaments and the second fiber filaments.
In one embodiment, in the first fibrous layer, adjacent first filaments are spaced apart by 50-1000 μm.
In one embodiment, in the first fiber layer, the second fiber filaments are a plurality of second fiber filaments, the plurality of second fiber filaments are arranged in parallel with the first fiber filaments, and the adjacent second fiber filaments are spaced by 1-50 μm.
In one embodiment, in the first fiber layer, the third fibers are a plurality of third fibers, the third fibers are arranged in parallel, and the adjacent third fibers are spaced by 50-1000nm.
In one embodiment, the third plurality of filaments is disposed between the first and second plurality of filaments in parallel with the first and second filaments.
In one embodiment, the plurality of sequentially stacked fiber layers includes a plurality of first fiber layers, first fiber filaments of which are parallel to each other, and a second fiber layer, which is disposed between two adjacent first fiber layers, and is composed of a plurality of fiber filaments having diameters of 50-1000 μm parallel to each other, and adjacent fiber filaments of which are spaced apart by 50-1000 μm.
In one embodiment, the third filaments are deposited on the first and second filaments in an disordered manner.
In one embodiment, the plurality of fiber layers of the multi-scale tissue engineering composite scaffold are all first fiber layers, and first fibers of two adjacent first fiber layers of the multi-scale tissue engineering composite scaffold are not parallel.
In one embodiment, the first filaments are a synthetic polymeric material; the second fiber filaments are synthetic polymer materials; the third filaments are comprised of synthetic and/or natural polymeric materials.
According to a third aspect of the present invention, an embodiment of the present invention proposes a preparation apparatus of a multi-scale tissue engineering composite scaffold, the preparation apparatus performing the preparation method as described above, the preparation apparatus comprising an X-axis movement system, a Y-axis movement system, a Z-axis movement system, a printing head for applying a printing material, and a collecting part; the X-axis movement system is used for driving the printing spray head to move along the X-axis direction, the Y-axis movement system is used for driving the printing spray head to move along the Y-axis direction, the Z-axis movement system is used for driving the printing spray head to move along the Z-axis direction, and the X-axis direction, the Y-axis direction and the Z-axis direction are perpendicular to each other; the printing spray heads comprise a first printing spray head, a second printing spray head and a third printing spray head, wherein the first printing spray head is a fused deposition printing spray head, the second printing spray head is a fused electrostatic spinning printing spray head, and the third printing spray head is a solution electrostatic spinning printing spray head; the collecting part is used for bearing the printed multi-scale tissue engineering composite bracket.
In one embodiment, the preparation device of the multi-scale tissue engineering composite scaffold further comprises a monitoring system, wherein the monitoring system comprises a computer and a camera, and is used for monitoring and controlling the distance between the lowest end of the first printing nozzle, the second printing nozzle and/or the third printing nozzle and the upper surface of the collecting part.
The embodiment of the invention has the beneficial effects that: the multi-scale tissue engineering composite scaffold, the preparation method and the preparation device provided by the embodiment of the invention can be used for preparing the multi-scale tissue engineering composite scaffold, the first fiber yarn with larger size can provide sufficient strength for the scaffold, the second fiber yarn with the size close to that of cells can promote cell infiltration, and the superfine third fiber can improve proliferation of cells.
In addition, the scaffold can be prepared to simultaneously contain fibers with diameters of hundreds of micrometers and fibers with diameters of hundreds of nanometers to tens of micrometers, and can simultaneously adopt natural polymer materials and synthetic polymer materials, so that an ideal tissue engineering scaffold is obtained, the prepared scaffold not only has good mechanical strength, but also has proper pore diameter and porosity, can promote cell permeation and nutrient substance transportation, can provide a proper microenvironment for cell activities, and can promote cell adhesion, proliferation, differentiation, migration and other cell activities. In addition, the preparation device provided by the embodiment of the invention can select proper preparation technology and materials according to different actual needs, and has strong universality.
Drawings
FIG. 1 is a schematic and partial enlarged view of a first fibrous layer of a multi-scale tissue engineering composite scaffold according to an embodiment of the present invention;
FIG. 2 is a schematic and partial enlarged view of another first fibrous layer of a multi-scale tissue engineering composite scaffold according to an embodiment of the present invention;
FIG. 3a is an exploded view of two adjacent stacked first fibrous layers in a multi-scale tissue engineering composite scaffold according to an embodiment of the present invention;
FIG. 3b is a schematic view of the structure of FIG. 3a after two first fiber layers are stacked;
FIG. 4a is an exploded view of a multi-scale tissue engineering composite scaffold of an embodiment of the present invention with a second fibrous layer disposed between two adjacent first fibrous layers;
FIG. 4b is a schematic view of the structure of FIG. 4a after two first fibers are stacked with a second fiber layer;
fig. 5 is a schematic structural diagram of a device for preparing a multi-scale tissue engineering composite scaffold according to an embodiment of the present invention.
Detailed Description
The present invention will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent. Those skilled in the art will recognize that the present invention is not limited to the drawings and the following examples.
Example 1 preparation method of Multi-dimensional tissue engineering composite scaffold
The embodiment of the invention also provides a preparation method of the multi-scale tissue engineering composite scaffold, the multi-scale tissue engineering composite scaffold comprises a plurality of fiber layers which are sequentially overlapped, wherein at least one first fiber layer comprises a first fiber wire, a second fiber wire and a third fiber wire, and the forming steps of the first fiber layer (refer to fig. 1 and 2) comprise:
s1, forming a plurality of first fiber filaments with the diameter of 50-1000 mu m on a collecting plate, wherein the first fiber filaments are arranged in parallel. The collecting plate can be a collecting plate surface, in the embodiment, the first fiber filaments are printed by a fused deposition printing nozzle, and when the first fiber filaments are printed, the distance between the lowest end of the fused deposition printing nozzle and the upper surface of the collecting plate is 0.1mm-5mm; in the first fiber layer, adjacent first fibers are spaced apart by 50-1000 μm. The material of the first fiber yarn is a synthetic polymer material, and may be, for example, one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL).
S2, forming second fiber wires with the diameter of 1-50 mu m among the first fiber wires, wherein the second fiber wires have the effect of promoting cell penetration due to the close size of the second fiber wires and the cell size.
Preferably, the second fiber filaments are a plurality of, and are arranged in parallel with the first fiber filaments, the first fiber filaments with larger size can provide sufficient strength for the bracket, the second fiber filaments with the size close to that of the cells can promote cell penetration, and meanwhile, the orientation arrangement of the second fiber filaments can adjust the fiber filament spacing, so that the macro orientation arrangement of the cells along the fiber filament direction is promoted to a certain extent, and the relevant activities of the cells such as proliferation, migration and the like are further influenced. In the first fiber layer, the adjacent second fiber filaments are spaced 1-50 μm apart.
In this embodiment, the second fiber is formed by printing through the melt electrostatic spinning printing nozzle, and the reason for using the melt electrostatic spinning printing nozzle is that the alignment degree of the fibers printed by the melt electrostatic spinning is good, the fiber trend is convenient to control, and the bracket with a regular structure is easy to prepare. When in printing, the distance between the lowest end of the melting electrostatic spinning printing spray head and the upper surface of the collecting plate is 0.1mm-5mm.
The material of the second fiber yarn is a synthetic polymer material, and may be, for example, one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL).
S3, forming a plurality of third fiber filaments with the diameter of 50-1000nm on the basis of the formed first fiber filaments and second fiber filaments, wherein the plurality of third fiber filaments are arranged in parallel, and are preferably arranged between the plurality of first fiber filaments and the plurality of second fiber filaments in parallel with the first fiber filaments and the second fiber filaments, as shown in fig. 1, or the third fiber filaments are deposited on the first fiber filaments and the second fiber filaments in an unordered manner, as shown in fig. 2. Preferably, in the first fiber layer, when the third fibers are arranged in parallel, the adjacent third fibers are spaced by 50-1000nm. In this embodiment, the third fiber yarn is formed by printing through a solution electrostatic spinning printing nozzle, and when printing, the distance between the lowest end of the solution electrostatic spinning printing nozzle and the upper surface of the collecting plate is 0.1mm-100mm. In addition, in order to enable the third fiber yarn to form an effect of being arranged in parallel with the first fiber yarn, the distance between the lowest end of the solution electrostatic spinning printing spray head and the upper surface of the collecting plate is 0.1mm-10mm during printing. The third fiber yarn is made of a polymer solution comprising a synthetic polymer and/or a natural polymer, wherein the polymer in the polymer solution can be one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL), collagen, silk fibroin, chitosan, hydrogel, gelatin and elastin, and the solvent in the polymer solution can be one or more of water, ethanol, isopropanol, hexafluoroisopropanol, tetrahydrofuran, chloroform and dimethylformamide.
In the first fiber layer, the first fiber is a synthetic polymer printing material and is printed and molded by a fused deposition printing spray head; the second fiber yarn is a synthetic polymer printing material and is formed by printing through a melt electrostatic spinning printing nozzle; and the third fiber yarn is formed by printing a polymer solution of a synthetic polymer and/or a natural polymer through a solution electrostatic spinning printing nozzle. Wherein, fused deposition printing and fused electrostatic spinning printing are used for synthesizing polymer materials, so that the bracket is ensured to have corresponding mechanical properties; the natural polymer material is printed by using solution electrostatic spinning, the material is dissolved in a solvent, the solution is extruded, then the fiber is led out under an electric field, the solvent volatilizes in the process that the fiber is deposited on a collecting platform, and finally the superfine third fiber is prepared. In one stent, the composite material of the synthetic polymer and the natural polymer can obtain better comprehensive performance, namely, synthetic polymer fibers are prepared through fused deposition and fused electrospinning, so that the mechanical properties of the stent, the fiber size close to cells and the fiber orientation arrangement are met; the natural polymer fiber can be prepared by solution electrospinning, so that the bioactivity of the scaffold is improved, and cell adhesion is facilitated.
In this embodiment, the multiple fiber layers of the multi-scale tissue engineering composite scaffold are all first fiber layers, and the first fibers of two adjacent first fiber layers of the scaffold are not parallel, preferably, the first fibers of two adjacent first fiber layers of the scaffold are perpendicular to each other, as shown in fig. 3a and 3b, wherein fig. 3a shows two upper and lower first fiber layers, and the first fibers of two first fiber layers are perpendicular to each other; in fig. 3b a schematic structural diagram is shown of the two first fibre layers of fig. 3a after stacking.
Furthermore, in a preferred embodiment of the present invention, a case is given in which the first filaments of two adjacent first fibrous layers of the multi-scale tissue engineering composite scaffold are parallel, as shown in fig. 4a and 4b, wherein only a schematic view of the multi-scale tissue engineering composite scaffold comprising one second fibrous layer between two adjacent first fibrous layers is shown, it will be understood by a person skilled in the art that in the present embodiment, the first fibrous layers are arranged at intervals from the second fibrous layers. Specifically, the multi-scale tissue engineering composite scaffold comprises a plurality of fiber layers which are sequentially overlapped, wherein the fiber layers comprise a plurality of first fiber layers and second fiber layers which are arranged between two adjacent first fiber layers. The first, second and third filaments of the upper first fibrous layer are parallel to each other, the first, second and third filaments of the lower first fibrous layer are parallel to each other, and the first filaments of the upper first fibrous layer and the first filaments of the lower first fibrous layer are parallel to each other, that is, the first, second and third filaments of each first fibrous layer of the multi-scale tissue engineering composite scaffold are parallel to each other, and the first filaments of the plurality of first fibrous layers are parallel to each other, as shown in fig. 4 a. The second fiber layer is composed of a plurality of fiber filaments which are parallel to each other and have the diameter of 50-1000 mu m, and the adjacent fiber filaments are spaced by 50-1000 mu m. Therefore, the first fiber filaments, the second fiber filaments and the third fiber filaments of each first fiber layer are parallel to each other, and the first fiber filaments of the first fiber layers are parallel to each other, so that the prepared multi-scale tissue engineering composite scaffold can promote the alignment of cells on the scaffold through the alignment of the fiber filaments; in addition, due to the addition of the second fiber layer serving as a spacing layer, the adjacent first fiber layers are separated, so that the porosity in the bracket is increased, and cells can more easily permeate into the bracket. In the above embodiment, although the plurality of first fiber layers have the same orientation, it will be understood by those skilled in the art that the second fiber layer may be disposed between the plurality of first fiber layers having different orientations as well.
The preparation method of the multi-scale tissue engineering composite scaffold can prepare a scaffold which simultaneously contains fibers with diameters of hundreds of micrometers and fibers with diameters of hundreds of nanometers to tens of micrometers, can further promote cell infiltration and adhesion, and can further obtain an ideal tissue engineering scaffold by adopting natural polymer materials and synthetic polymer materials, and the prepared scaffold not only has better mechanical strength, but also has proper pore diameter and porosity, can promote cell infiltration and nutrient substance transportation, can provide a proper microenvironment for cell activities, and can promote cell adhesion, proliferation, differentiation, migration and other cell activities.
Example 2 Multi-dimensional tissue engineering composite scaffold
The embodiment of the invention also provides a multi-scale tissue engineering composite stent, which comprises a plurality of fiber layers which are sequentially overlapped, wherein at least one first fiber layer comprises a plurality of first fiber wires with the diameter of 50-1000 mu m, which are arranged in parallel, a second fiber wire with the diameter of 1-50 mu m and a third fiber wire with the diameter of 50-1000nm, which are formed among the plurality of first fiber wires. Wherein the third fiber filaments are disposed in parallel with the first fiber filaments and the second fiber filaments between the plurality of first fiber filaments and the second fiber filaments as shown in fig. 1, or the third fiber filaments are deposited on the first fiber filaments and the second fiber filaments in an disordered manner as shown in fig. 2.
In this embodiment, in the first fiber layer, adjacent first fibers are spaced apart by 50 to 1000 μm. The material of the first fiber yarn is a synthetic polymer material, and may be, for example, one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL).
Preferably, the second fiber filaments are a plurality of and are arranged in parallel with the first fiber filaments. In the first fiber layer, the adjacent second fiber filaments are spaced 1-50 μm apart. The material of the second fiber yarn is a synthetic polymer material, and may be, for example, one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL).
Preferably, in the first fiber layer, when the third fiber filaments are arranged in parallel, the adjacent third fiber filaments are spaced by 50-1000nm. The third fiber yarn is made of a polymer solution, wherein the polymer in the polymer solution can be one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL), collagen, silk fibroin, chitosan, hydrogel, gelatin and elastin, and the solvent in the polymer solution can be one or more of water, ethanol, isopropanol, hexafluoroisopropanol, tetrahydrofuran, chloroform and dimethylformamide.
In this embodiment, the multiple fiber layers of the multi-scale tissue engineering composite scaffold have the same structure, and are all first fiber layers, and the first fibers of two adjacent first fiber layers of the scaffold are not parallel, preferably, the first fibers of two adjacent first fiber layers of the scaffold are perpendicular to each other, as shown in fig. 3a and 3 b.
Furthermore, in a preferred embodiment of the present invention, a case is given in which the first filaments of two adjacent first fibrous layers of the multi-scale tissue engineering composite scaffold are parallel, as shown in fig. 4a and 4b, wherein only a schematic view of the multi-scale tissue engineering composite scaffold comprising one second fibrous layer between two adjacent first fibrous layers is shown, it will be understood by a person skilled in the art that in the present embodiment, the first fibrous layers are arranged at intervals from the second fibrous layers. Specifically, the multi-scale tissue engineering composite scaffold comprises a plurality of fiber layers which are sequentially overlapped, wherein the fiber layers comprise a plurality of first fiber layers and second fiber layers which are arranged between two adjacent first fiber layers. The first, second and third filaments of the upper first fibrous layer are parallel to each other, the first, second and third filaments of the lower first fibrous layer are parallel to each other, and the first filaments of the upper first fibrous layer and the first filaments of the lower first fibrous layer are parallel to each other, that is, the first, second and third filaments of each first fibrous layer of the multi-scale tissue engineering composite scaffold are parallel to each other, and the first filaments of the plurality of first fibrous layers are parallel to each other, as shown in fig. 4 a. The second fiber layer is composed of a plurality of fiber filaments which are parallel to each other and have the diameter of 50-1000 mu m, and the adjacent fiber filaments are spaced by 50-1000 mu m. In the above embodiment, although the plurality of first fiber layers have the same orientation, it will be understood by those skilled in the art that the second fiber layer may be disposed between the plurality of first fiber layers having different orientations as well.
The overall shape of the multi-scale tissue engineering composite scaffold can be designed according to actual needs.
Example 3 preparation apparatus of Multi-dimensional tissue engineering composite scaffold
The embodiment of the invention provides a preparation device of a multi-scale tissue engineering composite scaffold, which is used for executing the lamp strip method as described in the embodiment 1, and is shown in fig. 5. The preparation device comprises an X-axis movement system, a Y-axis movement system, a Z-axis movement system, a printing spray head for applying printing materials, a collecting part and a monitoring system; the X-axis movement system is used for driving the printing spray head to move along the X-axis direction, the Y-axis movement system is used for driving the printing spray head to move along the Y-axis direction, the Z-axis movement system is used for driving the printing spray head to move along the Z-axis direction, and the X-axis direction, the Y-axis direction and the Z-axis direction are perpendicular to each other; the printing spray heads comprise a first printing spray head, a second printing spray head and a third printing spray head, wherein the first printing spray head is a fused deposition printing spray head, the second printing spray head is a fused electrostatic spinning printing spray head, and the third printing spray head is a solution electrostatic spinning printing spray head; the collecting part is used for bearing the printed multi-scale tissue engineering composite bracket.
The preparation device of the multi-scale tissue engineering composite support further comprises a monitoring system, wherein the monitoring system comprises a computer and a camera and is used for monitoring and controlling the distance between the lowest end of the first printing spray head, the second printing spray head and/or the third printing spray head and the upper surface of the collecting part.
The X-axis motion system comprises an X-axis driving device, a first X-axis guiding mechanism, a second X-axis guiding mechanism and a frame, wherein the first X-axis guiding mechanism and the second X-axis guiding mechanism are parallel to each other and are arranged at intervals; the first end of the frame is connected to the first X-axis guiding mechanism in a sliding manner, the second end of the frame is connected to the second X-axis guiding mechanism in a sliding manner, and the X-axis driving device drives the frame to move along the first X-axis guiding mechanism and the second X-axis guiding mechanism. Preferably, the frame is a portal frame.
The Y-axis motion system comprises a Y-axis driving device, a Y-axis guide mechanism, a first sliding mounting seat, a second sliding mounting seat and a third sliding mounting seat, wherein the Y-axis guide mechanism is arranged between the first end and the second end of the frame, the first sliding mounting seat, the second sliding mounting seat and the third sliding mounting seat are in sliding connection with the Y-axis guide mechanism, and the Y-axis driving device drives the first sliding mounting seat, the second sliding mounting seat and the third sliding mounting seat to move along the Y-axis guide mechanism. The Y-axis guide mechanism can be one and drives the first sliding mounting seat, the second sliding mounting seat and the third sliding mounting seat to move at the same time; the Y-axis guide mechanism can be three independent driving mechanisms which respectively drive the first sliding mounting seat, the second sliding mounting seat and the third sliding mounting seat to move.
The Z-axis motion system comprises a first Z-axis motion system, a second Z-axis motion system and a third Z-axis motion system. The first Z-axis motion system comprises a first Z-axis driving device, a first Z-axis guide mechanism and a first printing nozzle installation part, wherein the first Z-axis guide mechanism is arranged on the first sliding installation seat, the first printing nozzle installation part is connected to the first Z-axis guide mechanism in a sliding manner, the first printing nozzle is arranged on the first printing nozzle installation part, and the first Z-axis driving device drives the first printing nozzle installation part to move along the first Z-axis guide mechanism; the second Z-axis movement system comprises a second Z-axis driving device, a second Z-axis guide mechanism and a second printing nozzle mounting part, wherein the second Z-axis guide mechanism is arranged on a second sliding mounting seat, the second printing nozzle mounting part is connected to the second Z-axis guide mechanism in a sliding manner, the second printing nozzle is arranged on the second printing nozzle mounting part, and the second Z-axis driving device drives the second printing nozzle mounting part to move along the second Z-axis guide mechanism; the third Z-axis movement system comprises a third Z-axis driving device, a third Z-axis guide mechanism and a third printing nozzle installation part, wherein the third Z-axis guide mechanism is arranged on a third sliding installation seat, the third printing nozzle installation part is slidably connected to the third Z-axis guide mechanism, the third printing nozzle is arranged on the third printing nozzle installation part, and the third Z-axis driving device drives the third printing nozzle installation part to move along the third Z-axis guide mechanism.
The fused deposition printing nozzle and the fused electrostatic spinning printing nozzle can be pneumatic nozzle, piston nozzle or screw nozzle; the solution electrostatic spinning printing spray head can be a pneumatic spray head or a piston spray head. The distance between the lowest end of the solution electrostatic spinning printing spray head and the upper surface of the collecting plate is 0.1mm-10mm, so that the third fiber filaments which are arranged in parallel are printed; and heating elements are arranged on the outer sides of the fused deposition printing spray head and the fused electrostatic spinning printing spray head and are used for heating printing materials.
The fused deposition print head is for applying a printing material comprising a first synthetic polymeric material. The first synthetic polymer material may be, for example, one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), poly lactic-co-glycolic acid (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL). .
The melt electrospun printing head is used to apply a printing material comprising a second synthetic polymeric material. The second synthetic polymer material may be, for example, one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), poly lactic-co-glycolic acid (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL).
The solution electrostatic spinning printing spray head is used for applying printing materials containing polymer solution. The polymer in the polymer solution can be, for example, one or more of Polycaprolactone (PCL), polylactic acid (PLA), L-polylactic acid (PLLA), poly L-lactide-caprolactone (PLCL), polyglycolic acid (PGA), poly lactic-co-glycolic acid (PLGA), polyurethane (PU), polyethylene glycol (PEG), polyethylene glycol-b-poly (L-lactide-co-caprolactone) (PELCL), collagen, silk fibroin, chitosan, hydrogel, gelatin, elastin; the solvent in the polymer solution can be, for example, one or more of water, ethanol, isopropanol, hexafluoroisopropanol, tetrahydrofuran, chloroform, and dimethylformamide.
Preferably, the collecting part comprises a collecting platform and a collecting plate, the collecting platform is arranged below the first printing nozzle, the second printing nozzle and the third printing nozzle, the collecting plate is arranged on the collecting platform, and the collecting plate is used for bearing the multi-scale tissue composite engineering bracket. The collecting platform is an insulating collecting platform and can be made of nylon, polyoxymethylene, polytetrafluoroethylene, ceramic, wood, polyether ether ketone and other materials. The collecting plate is a conductive collecting plate, and for example, can be made of conductive glass, conductive silicon wafer, aluminum foil, iron plate and the like.
The preparation device of the multi-scale tissue engineering composite scaffold fuses at least two technologies of a fused deposition technology, a solution electrostatic spinning technology and a fused electrostatic spinning technology, so that the tissue engineering composite scaffold with synthetic polymer material fibers with diameters of hundreds of micrometers and natural polymer fibers with diameters of hundreds of nanometers can be prepared, the mechanical properties of the tissue engineering scaffold can be ensured, the micro environment suitable for cell activities can be provided by larger pore diameters and porosities, and the biological activity of the tissue engineering scaffold can be improved on the premise that cell permeation is not influenced. The preparation device provided by the embodiment of the invention provides a solution with stronger universality for preparing the multi-scale tissue engineering composite scaffold. The distance between the lowest end of the printing spray head and the upper surface of the collecting part is monitored and controlled by introducing a monitoring system, so that the forming state of the fibers can be controlled according to actual needs, for example, ordered arrangement or unordered arrangement.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. A method for preparing a multi-scale tissue engineering composite scaffold, the multi-scale tissue engineering composite scaffold comprising a plurality of sequentially stacked fiber layers, wherein the plurality of sequentially stacked fiber layers comprises at least one first fiber layer, the at least one first fiber layer comprises a first fiber filament, a second fiber filament and a third fiber filament, and the forming step of the first fiber layer comprises:
forming a plurality of first fiber filaments with the diameter of 50-1000 mu m on a collecting plate, wherein the first fiber filaments are arranged in parallel, the interval between the adjacent first fiber filaments is 50-1000 mu m, the second fiber filaments are arranged in parallel with the first fiber filaments, and the interval between the adjacent second fiber filaments is 1-50 mu m;
forming a plurality of second filaments having a diameter of 1-50 μm between the plurality of first filaments;
and forming third fiber filaments with diameters of 50-1000nm on the formed structures of the first fiber filaments and the second fiber filaments.
2. The method of claim 1, wherein in the first fiber layer, the plurality of third fibers are arranged in parallel, and the adjacent third fibers are spaced apart by 50-1000nm.
3. The method of manufacturing of claim 2, wherein the third plurality of filaments is disposed between the first and second plurality of filaments in parallel with the first and second filaments.
4. A method of producing a fiber according to claim 1 or 3, wherein the plurality of sequentially stacked fiber layers includes a plurality of first fiber layers, first fiber filaments of which are parallel to each other, and a second fiber layer, which is disposed between adjacent two of the first fiber layers, and is composed of a plurality of fiber filaments having diameters of 50 to 1000 μm parallel to each other, and adjacent fiber filaments of which are spaced apart by 50 to 1000 μm.
5. The method of making according to claim 1, wherein the third filaments are deposited unordered on the first and second filaments.
6. The method of any one of claims 1-3, wherein the plurality of fiber layers of the multi-scale tissue engineering composite scaffold are first fiber layers, and first fibers of two adjacent first fiber layers of the multi-scale tissue engineering composite scaffold are not parallel.
7. The method of claim 1, wherein the first fiber is a synthetic polymer printing material, and is formed by a fused deposition printing nozzle;
the second fiber yarn is a synthetic polymer printing material and is formed by printing through a melt electrostatic spinning printing nozzle;
and the third fiber yarn is formed by printing a polymer solution of a synthetic polymer and/or a natural polymer through a solution electrostatic spinning printing nozzle.
8. A multi-scale tissue engineering composite scaffold characterized in that the multi-scale tissue engineering composite scaffold comprises a plurality of sequentially stacked fiber layers, wherein the plurality of sequentially stacked fiber layers comprises at least one first fiber layer comprising a plurality of parallel arranged first fiber filaments having a diameter of 50-1000 μm, a plurality of second fiber filaments having a diameter of 1-50 μm formed between the plurality of first fiber filaments, and a third fiber filament having a diameter of 50-1000nm on the structure of the first fiber filaments and the second fiber filaments,
the first fiber filaments are made of synthetic polymer materials, and the interval between adjacent first fiber filaments is 50-1000 mu m;
the second filaments are arranged in parallel with the first filaments, and the adjacent second filaments are spaced apart by 1-50 μm.
9. The multi-scale tissue engineering composite scaffold according to claim 8, wherein in the first fiber layer, the third fiber filaments are a plurality of third fiber filaments which are arranged in parallel, and the interval between adjacent third fiber filaments is 50-1000nm.
10. The multi-scale tissue engineering composite stent of claim 9, wherein the plurality of third filaments are disposed between the plurality of first and second filaments in parallel with the first and second filaments.
11. The multi-scale tissue engineering composite scaffold according to claim 8 or 10, wherein the plurality of sequentially stacked fiber layers comprises a plurality of first fiber layers and a second fiber layer disposed between two adjacent first fiber layers, the first fiber filaments of the plurality of first fiber layers being parallel to each other, the second fiber layer being composed of a plurality of fiber filaments having diameters of 50-1000 μm that are parallel to each other, and the adjacent fiber filaments of the second fiber layer being spaced apart by 50-1000 μm.
12. The multi-scale tissue engineering composite scaffold of claim 8, wherein the third filaments are deposited on the first and second filaments in a disordered manner.
13. The multi-scale tissue engineering composite scaffold according to any one of claims 8-10, wherein the plurality of fiber layers of the multi-scale tissue engineering composite scaffold are first fiber layers, and first fiber filaments of two adjacent first fiber layers of the multi-scale tissue engineering composite scaffold are not parallel.
14. The multi-scale tissue engineering composite scaffold of claim 8, wherein the second fiber filaments are a synthetic polymer material; the third fiber filaments are synthetic polymer and/or natural polymer materials.
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