CN114699567B

CN114699567B - In vivo implant capable of promoting endothelial cell adhesion and differentiation

Info

Publication number: CN114699567B
Application number: CN202210397137.XA
Authority: CN
Inventors: 贺晓静; 轩文娟; 曹馨月; 曹守威
Original assignee: Kaifeng Health School
Current assignee: Kaifeng Health School
Priority date: 2022-04-15
Filing date: 2022-04-15
Publication date: 2023-01-10
Anticipated expiration: 2042-04-15
Also published as: CN114699567A

Abstract

The invention discloses an implant in vivo capable of promoting endothelial cell adhesion and differentiation, wherein the inner region of the implant is made of degradable materials and plays a role in supporting the implant throughout, the middle region is formed by compounding the degradable materials and a first medicament, the outer region is formed by compounding an organic high polymer material and a second medicament, the first medicament is an anti-restenosis medicament for inhibiting smooth muscle cell proliferation, the second medicament is a medicament for specifically capturing endothelial progenitor cell antibodies, and the proportion of the second medicament in the outer region is in a gradual change trend, so that the adhesion and differentiation capability of endothelial cells around a tissue injury part is improved, the cells around the tissue injury part are preferentially repaired, and meanwhile, the first medicament is slowly released after the expected repair purpose is achieved to inhibit cell proliferation so as to prevent restenosis. The changeable laminating form can adapt to the structural characteristics of human bodies, meet the requirements of different patients and different implantation positions, and ensure that the operation is safer and more reliable and the postoperative curative effect is better.

Description

Implant in vivo capable of promoting endothelial cell adhesion and differentiation

Technical Field

The present invention relates to a medical implant, and more particularly to an in vivo implant that promotes endothelial cell adhesion and differentiation.

Background

The method has the advantages that the method has prominent effect on promoting cell adhesion and differentiation in the biomedical field, particularly in the field of in vivo implants, simple pure metal stents lacking cell adhesion and differentiation functions gradually lose the advantages, drug-coated stents become the internationally recognized clinical preferred method at present, the commonly used drug-coated stents mainly comprise nondegradable and degradable carrier drug-coated stents, and the drug-coated stents bring hopes for reducing or eliminating restenosis. However, in any kind of stent, endothelial cells and smooth muscle cells of the lumen wall are damaged after implantation, and thrombus and inflammatory reaction are easily caused. The release of platelet-derived cell growth factors stimulates the proliferation and migration of smooth muscle cells in the lumen. The activated smooth muscle cells switch from a contractile phenotype to a synthetic phenotype, and within 3 days after injury, approximately 40% of the mesodermal smooth muscle cells enter the cell proliferation cycle. Newly synthesized cells migrate to the smooth muscle intima layer, secreting large amounts of extracellular matrix. At the same time, inflammatory cells invade the injured site, entering deeper layers of the lumen wall. Dysfunctional endothelial cells also contribute to smooth muscle cell proliferation and migration. Intimal proliferation does not slow down until the endothelium regrows at the damaged site, however, extracellular matrix build-up further causes intimal thickening. The simultaneous action of these multiple biological processes results in restenosis of the lumen after surgery.

In view of the above, although the existing drug-coated stent can effectively inhibit the proliferation of vascular cells, the slow release of the drug delays the healing of the endothelial cells in the lumen, which results in the potential risk of death due to insufficient cell attachment or restenosis at the late stage of stent implantation. According to the related data, the drug-coated stent still has the occurrence of secondary recurrence after being implanted into the lumen of the human body for two years. That is, although the existing drug-coated stent can effectively reduce the occurrence of restenosis, the occurrence of thrombus in the stent is increased. Therefore, there is an urgent need for an implant in vivo that can both capture endothelial progenitor cells to promote endothelial repair and reduce stent thrombosis, while inhibiting cell proliferation to prevent restenosis.

Disclosure of Invention

The invention aims to provide an implant in vivo, which can promote endothelial cell adhesion and differentiation, promote endothelial repair to accelerate healing and reduce thrombosis in a stent, inhibit cell proliferation to prevent restenosis, is more suitable for the structural characteristics of an implantation lumen, meets the operation habits of medical personnel and the personalized requirements of patients, reduces the operation difficulty, ensures that the operation is safer and more reliable, and has better treatment effect.

In order to achieve the above object, the present invention provides an implant in vivo for promoting endothelial cell adhesion and differentiation, which comprises a carrier and a support, and comprises an inner region, an outer region and an intermediate region sandwiched between the inner region and the outer region, wherein the thickness of the intermediate region is greater than that of the outer region, the thickness of the outer region is greater than that of the inner region, the intermediate region and the inner region together form the support of the implant, the inner region constituting the support is made of a degradable material and can provide a strong supporting effect for the entire implant, the outer region is integrally molded outside the inner region, the intermediate region is formed by compounding the degradable material and a first drug, the outer region is formed by spraying a layer of the carrier on the periphery of the intermediate region, the carrier is formed by compounding an organic polymer material and a second drug, wherein the second drug is different from the first drug, the first drug is an anti-restenosis drug for inhibiting smooth muscle cell proliferation, the second drug is an antibody drug for specifically capturing endothelial cells, and the first drug is uniformly distributed in the intermediate region, the second drug is uniformly distributed in the outer region, and occupies a uniform healing ratio in the outer region, and the second drug gradually decreases or gradually decreases from the second drug to the surrounding healing region. Thereby improving the adhesion and differentiation capacity of endothelial cells around the damaged part of the tissue, promoting the preferential repair of the cells around the damaged part of the tissue, and simultaneously, inhibiting the cell proliferation by using the middle area after the cell adhesion and differentiation achieve the previous repair purpose, thereby preventing the occurrence of restenosis.

The inner area, the outer area and the middle area are of a laminated structure, namely every two adjacent layers are parallel to each other and are mutually overlapped; when the implant is of a sheet structure, the layers can also be folded and wrapped upwards at the edges after being stacked, namely, the peripheral edge of the outer area is folded and wrapped upwards to wrap the outer edge of the middle area, and the peripheral edge of the middle area is folded and wrapped upwards to wrap the outer edge of the inner area, so that the implant with smooth upper and lower surfaces is finally formed.

The degradable material composing the support body is a polymer of degradable biological high molecular material, has good biocompatibility and better mechanical property, and comprises but is not limited to at least one of polylactic acid, polyglycolic acid, polyphosphate, polyesteramide, polylactic acid-polyglycolic acid copolymer, polyanhydride and copolymer, mixture or derivative thereof; the inner region may be the same or different from the degradable material in the intermediate region.

The degradable material composing the support can also be degradable metal material, degradable metal alloy or degradable metal compound, and complex compound of organic molecule and metal, including but not limited to metal such as iron.

The first medicine comprises any one or more of active medicines such as sirolimus, tacrolimus, etomox, immunosuppressant ABT-578, C-protease inhibitor, 3-hydroxylase inhibitor, methylprednisolone, dexamethasone, mizoribine, rapamycin, paclitaxel and derivatives thereof, actinomycin, adriamycin, dactinomycin, mitomycin, vincristine and derivatives thereof, statins, 2-chlorodeoxyadenosine, ribozyme, batimastat, probucol, estradiol and the like.

The second medicament comprises any one or more of CD31 antibody, CD133 antibody, CD34 antibody, CD45 antibody, klotho protein, extracellular matrix (ECM), glial cell line-derived neurotrophic factor and Vascular Endothelial Growth Factor (VEGF).

The implant has an outer region of 0.1-0.2mm thickness, a middle region of 0.2-0.3mm thickness, and an inner region of 0.07-0.15mm thickness.

When the degradable material is a polymer of a degradable biological high molecular material, degradable magnetic nanoparticles taking Fe3O4 as a main body material can be added into the composition material of the internal region of the implant, the degradable magnetic nanoparticles generate a heat effect through an external magnetic field, the temperature inside the implant can be integrally raised, and the degradation period is controlled in real time according to the healing condition of the middle and later stages.

The three layers of the implant are naturally transited and integrally formed, and each layer can have the same or different Young modulus.

The implant can be made into sheet shape, such as patch, cylindrical body cavity stent, such as vascular stent, artificial blood vessel, esophageal stent, intestinal stent, stomach tube support, etc., or made into artificial bone, intervertebral fusion device, etc.

The obtained implant has toughness and rigidity meeting the support requirement, can be curled and folded in half without fracture, and can be deformed and restored to the original state after being compressed.

Compared with the prior art, the invention has the following beneficial technical effects:

the implant in vivo capable of promoting endothelial cell adhesion and differentiation provided by the invention is prepared into a three-layer structure shape by adopting a traditional degradable material, a first medicament and a second medicament, the implant is basically and completely degraded within 1-2 years, the mechanical properties of the implant are not obviously different along with the proliferation of cells in the early stage of the degradation process, and the later-stage rate and time can be controlled according to the healing condition, so that the targeted treatment is realized; in addition, the first medicine is an anti-restenosis medicine for inhibiting smooth muscle cell proliferation, the second medicine is a medicine for specifically capturing endothelial progenitor cell antibody, the first medicine is uniformly distributed in the middle area, the second medicine is uniformly distributed in the outer area, and the proportion of the second medicine in the carrier in the outer area is in a gradual change trend, so that the adhesion and differentiation capacity of endothelial cells around the tissue injury part is improved, cells around the tissue injury part are promoted to be preferentially repaired, the implantation stability in the initial application stage is increased, and meanwhile, after the cell adhesion and differentiation achieve the expected repair purpose, the slow release of the first medicine in the middle area is utilized to inhibit cell proliferation, so that the occurrence of restenosis is prevented. The changeable laminating form can adapt to the structural characteristics of the implanted human body, meets the individual requirements of different recipients and different implantation positions thereof, and ensures that the operation is safer and more reliable and the treatment effect is better.

Drawings

Fig. 1 is a schematic view showing the overall structure of an implant in vivo in which layers are stacked in parallel according to the present invention;

fig. 2 is a schematic view showing the overall structure of the implant in vivo which is folded and wrapped around the folded and wrapped edges after each layer is stacked.

In the figure: 1-outer region, 101-organic polymer material, 102-second drug, 2-middle region, 201-degradable material, 202-first drug, 3-inner region.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other related embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without any creative effort belong to the protection scope of the present invention.

Example 1

Referring to fig. 1, an implant in vivo for promoting endothelial cell adhesion and differentiation comprises a carrier and a support, and comprises an inner region 3, an outer region 1 and a middle region 2 sandwiched between the inner region 3 and the outer region 1, wherein the thickness of the middle region 2 is greater than that of the outer region 1, the thickness of the outer region 1 is greater than that of the inner region 3, the middle region 2 and the inner region 3 together form the support of the implant, the inner region 3 constituting the support is made of a degradable material and can provide a strong support effect for the whole implant, the middle region 2 is integrally formed outside the inner region 3, the middle region 2 is formed by compounding a degradable material 201 and a first drug 202, and the outer region 1 is formed by spraying a layer of the carrier on the periphery of the middle region 2, the carrier is formed by compounding an organic polymer material 101 and a second drug 102, wherein the second drug 102 is different from the first drug 202, the first drug 202 is an anti-restenosis drug for inhibiting smooth muscle cell proliferation, the second drug 102 is a drug for specifically capturing endothelial progenitor cell antibody, the first drug 202 is uniformly distributed in the middle region 2, the second drug 102 is uniformly distributed in the outer region 1, and the proportion of the second drug 102 in the carrier in the outer region 1 is in a gradual change trend, specifically, the proportion of the second drug 102 in the carrier is gradually decreased from a healing region (corresponding to a tissue injury part) to a peripheral region under the condition that the thickness is uniform and unchanged, or the proportion of the second drug 102 in the carrier is uniform and unchanged, but the thickness of the carrier is gradually decreased from the healing region to the peripheral region. Thereby improving the adhesion and differentiation capacity of endothelial cells around the tissue injury site, promoting the preferential repair of cells around the tissue injury site, and simultaneously, inhibiting the proliferation of cells by using the middle region 2 after the adhesion and differentiation of cells achieve the previous repair purpose, thereby preventing the occurrence of restenosis.

The inner area 3, the outer area 1 and the middle area 2 are in a laminated structure, that is, every two adjacent layers are parallel to each other and are mutually overlapped, and finally, the implant with smooth upper and lower surfaces is formed.

The degradable material composing the support body is a polymer of degradable biological high molecular material, has good biocompatibility and better mechanical property, and comprises but is not limited to at least one of polylactic acid, polyglycolic acid, polyphosphate, polyesteramide, polylactic acid-polyglycolic acid copolymer, polyanhydride and copolymer, mixture or derivative thereof; the inner region 3 may be the same or different from the degradable material 201 in the middle region 2.

The first drug 202 includes any one or more of sirolimus, tacrolimus, etomox, immunosuppressant ABT-578, C-proteinase inhibitor, 3-hydroxylase inhibitor, methylprednisolone, dexamethasone, mizoribine, rapamycin, paclitaxel and derivatives thereof, actinomycin, adriamycin, dactinomycin, mitomycin, vincristine and derivatives thereof, statins, 2-chlorodeoxyadenosine, ribozyme, batimastat, probucol, estradiol and other active drugs.

The second drug 102 includes any one or more of a CD31 antibody, a CD133 antibody, a CD34 antibody, a CD45 antibody, klotho protein, extracellular matrix (ECM), glial cell line-derived neurotrophic factor, and Vascular Endothelial Growth Factor (VEGF).

The thickness of the outer region 1 of the implant is 0.1-0.2mm, the thickness of the middle region 2 is 0.2-0.3mm and the thickness of the inner region 3 is 0.07-0.15mm.

The obtained implant has toughness and rigidity meeting the supporting requirement, can be curled and folded without fracture, and can be deformed and restored to the original state after being compressed.

Example 2

This embodiment is substantially the same as embodiment 1 except that in this embodiment, as shown in fig. 2, when the implant is a sheet-like structure, the layers can be folded upward and wrapped at the edges after stacking, that is, the peripheral edge of the outer region 1 is folded upward and wrapped around the outer edge of the middle region 2, and the peripheral edge of the middle region 2 is folded upward and wrapped around the outer edge of the inner region 3, so as to finally form an implant with smooth upper and lower surfaces.

When the degradable material is a polymer of a degradable biological high molecular material, degradable magnetic nanoparticles taking Fe3O4 as a main body material can be added into the 3 composition materials in the internal region of the implant, the degradable magnetic nanoparticles generate a heat effect through an external magnetic field, the temperature inside the implant can be integrally raised, and the degradation period is controlled in real time according to the healing conditions in the middle and later stages.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms or combinations of forms without departing from the spirit or essential characteristics thereof. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims

1. An implant in vivo capable of promoting endothelial cell adhesion and differentiation, the implant is composed of a carrier and a support body, and comprises an inner area, an outer area and a middle area clamped between the inner area and the outer area, wherein the thickness of the middle area is greater than that of the outer area, the thickness of the outer area is greater than that of the inner area, the middle area and the inner area jointly form the support body of the implant, the inner area of the support body is made of degradable materials so as to play a final supporting role for the whole implant, the outer side of the inner area is integrally molded with the middle area, the middle area is formed by compounding the degradable materials and a first drug, the outer area is formed by spraying a layer of carrier on the periphery of the middle area, the carrier is formed by compounding an organic polymer material and a second drug, the second drug is different from the first drug, and the first drug is anti-restenosis-resistant to-effect of inhibiting smooth muscle cell proliferationThe narrow drugs are specifically endothelial progenitor cell antibody capturing drugs, the first drugs are uniformly distributed in the middle area, the second drugs are uniformly distributed in the outer area, and the proportion of the second drugs in the carrier in the outer area is in a gradual change trend, specifically, the proportion of the second drugs is gradually decreased from the healing area to the peripheral area under the condition that the thickness is uniform and unchanged, or the proportion of the second drugs in the carrier is uniform and unchanged, but the thickness of the carrier is gradually decreased from the healing area to the peripheral area; the degradable material of the support body is a polymer capable of degrading a biopolymer material, and Fe is added into the composition material of the internal area of the implant ₃ O ₄ Degradable magnetic nanoparticles as host material.

2. An in vivo implant according to claim 1, wherein said inner region, said outer region and said intermediate region are in a stacked structure, that is, each adjacent two layers are parallel to each other and stacked on each other.

3. An in vivo implant capable of promoting endothelial cell adhesion and differentiation according to any one of claims 1-2, wherein the degradable material constituting said support has good biocompatibility and good mechanical properties, and comprises at least one of polylactic acid, polyglycolic acid, polyphosphate, polyesteramide, polylactic acid-polyglycolic acid copolymer, polyanhydride and its copolymer, mixture or derivative; the inner region may be the same or different from the degradable material in the intermediate region.

4. An in vivo implant capable of promoting endothelial cell adhesion and differentiation according to claim 1, wherein the degradable magnetic nanoparticles can generate heat effect by external magnetic field, so as to integrally heat the interior of the implant, and further control the degradation period in real time according to the healing condition of the middle and later stages.

5. An in vivo implant as claimed in any one of claims 1-2, wherein said first drug comprises any one or more of sirolimus, tacrolimus, esoxim, immunosuppressant ABT-578, C-proteinase inhibitor, 3-hydroxylase inhibitor, methylprednisolone, dexamethasone, mizoribine, rapamycin, paclitaxel and its derivatives, actinomycin, doxorubicin, dactinomycin, mitomycin, vincristine and its derivatives, statins, 2-chlorodeoxyadenosine, ribozymes, batimastat, probucol, estradiol active drugs.

6. An in vivo implant capable of promoting endothelial cell adhesion and differentiation according to any one of claims 1-2, said second drug comprising any one or any several of a CD31 antibody, a CD133 antibody, a CD34 antibody, a CD45 antibody, a Klotho protein, an extracellular matrix (ECM), a glial cell line-derived neurotrophic factor, and a Vascular Endothelial Growth Factor (VEGF).

7. An in vivo implant capable of promoting endothelial cell adhesion and differentiation according to any one of claims 1-2, said implant having an outer region thickness of 0.1-0.2mm, a middle region thickness of 0.2-0.3mm and an inner region thickness of 0.07-0.15mm.

8. An in vivo implant capable of promoting endothelial cell adhesion and differentiation according to any one of claims 1-2, said implant being a cylindrical body lumen stent.

9. An in vivo implant according to claim 8, wherein said cylindrical body lumen stent is a vascular stent, an artificial blood vessel, an esophageal stent, an intestinal stent or a gastric tube support.

10. An in vivo implant capable of promoting endothelial cell adhesion and differentiation according to any one of claims 1-2, said implant being a component of an artificial bone, intervertebral cage orthopaedic implant.

11. A patch implant is composed of a carrier and a support body, and comprises an inner area, an outer area and a middle area clamped between the inner area and the outer area, wherein the thickness of the middle area is greater than that of the outer area, the thickness of the outer area is greater than that of the inner area, the middle area and the inner area jointly form the support body of the implant, the inner area forming the support body is made of degradable materials so as to play a final supporting role for the whole implant, the outer side of the inner area is integrally formed with the middle area, the middle area is formed by compounding the degradable materials and a first drug, a layer of carrier is sprayed on the periphery of the middle area to form the outer area, the carrier is formed by compounding an organic polymer material and a second drug, the second drug is different from the first drug, the first drug is an anti-restenosis drug for inhibiting smooth muscle cell proliferation, the second drug is an antibody drug for specifically capturing endothelial progenitor cells, the first drug is uniformly distributed in the middle area, the second drug is uniformly distributed in the outer area, the proportion of the carrier in the outer area is gradually changed, the healing area gradually, and the healing area is gradually healed from the second drug to the peripheral area, and the second drug is gradually changed in the healing area; after being stacked, the layers of the patch implant are folded and wrapped upwards at the edges, namely the peripheral edge of the outer area is folded and wrapped upwards to wrap the outer edge of the middle area, and the peripheral edge of the middle area is folded and wrapped upwards to wrap the outer edge of the inner area, so that the patch implant with smooth upper and lower surfaces is finally formed.