Heart patch
阅读说明：本技术 心脏补片 (Heart patch ) 是由 叶晓峰 赵强 游正伟 黄世兴 雷东 于 2019-10-18 设计创作，主要内容包括：心脏补片。提供了一种心脏补片,所述心脏补片包括：(A)弹性膜,所述弹性膜包括生物可降解材料；(B)多孔结构体,所述多孔结构体包括生物可降解材料；所述弹性膜位于所述多孔结构体上。(A cardiac patch. A cardiac patch is provided, the cardiac patch comprising: (A) an elastic film comprising a biodegradable material; (B) a porous structure comprising a biodegradable material; the elastic membrane is located on the porous structure.)
1. a cardiac patch, the cardiac patch comprising:
(A) an elastic film comprising a biodegradable material;
(B) a porous structure comprising a biodegradable material;
the elastic membrane is located on the porous structure.
2. The heart patch of claim 1, wherein the biodegradable polymer material comprises a polypeptide, a polyamino acid, a polyurethane, a polyester, a polylactic acid, chitin, collagen/gelatin, polycaprolactone, polysebacic acid glyceride, and combinations thereof.
3. The heart patch of claim 1, wherein the material for forming the elastic membrane comprises polycaprolactone, polysebacate, and combinations thereof.
4. The heart patch of claim 1, wherein the material for forming the elastic membrane comprises a mixture of polycaprolactone and polysebacic acid glyceride; alternatively, the material for forming the elastic membrane comprises a mixture of materials in a weight ratio of 5: 95-95: 5, preferably in a weight ratio of 10: 90-90: 10, more preferably in a weight ratio of 20: 80-80: 20, and preferably in a weight ratio of 30: 70-70: 30.
5. the heart patch of claim 1, wherein the elastic membrane has a compressive modulus of generally 1 to 20 MPa; the tensile modulus of the elastic film is usually 0.1 to 10 MPa.
6. The cardiac patch according to claim 1, wherein the porous structure comprises a plurality of biomimetic blood vessel layers, wherein the biomimetic blood vessel orientation of the biomimetic blood vessel layers of two adjacent layers is the same or different.
7. The cardiac patch according to claim 6, wherein the orientations of the bionic blood vessels of the two adjacent bionic blood vessel layers are different; preferably, the bionic blood vessels of the adjacent two bionic blood vessel layers are oriented at 5-90 degrees; more preferably, the bionic blood vessels of the adjacent two layers of the bionic blood vessel layers are orthogonally placed.
8. The cardiac patch according to claim 6, wherein the porous structure comprises 2-10, preferably 2-8, more preferably 2-6, and most preferably 2-4 layers of biomimetic blood vessel layers.
9. The cardiac patch of claim 1, wherein the cardiac patch further comprises a catheter.
10. Use of a mixture of polycaprolactone and polysebacic acid glyceride for the preparation of a heart patch, preferably, said use comprises increasing the mechanical properties, such as the tensile modulus or the compressive modulus, of the heart patch.
Technical Field
The present application relates to a cardiac patch, and more particularly to a cardiac patch having a two or more layer structure.
Background
Myocardial infarction and heart failure caused by other factors (toxic substances, drugs, alcohol, genetic variation, gene mutation, etc., viral or bacterial infection) have become an important cause of human death in modern countries. According to statistics, death caused by chronic heart failure and myocardial infarction accounts for more than 50% of cardiovascular death, and the morbidity population of myocardial infarction and heart failure tends to be younger. Myocardial infarction and heart failure have attracted a great deal of attention.
When the coronary artery of the heart is blocked; some genetic variation or important gene mutation, or toxic substance, drug, alcohol, virus or bacterial infection, leads to partial myocardial cell death in ventricular muscle, irreversible damage to the myocardium, and then self-reconstruction of the ventricle, leading to thinning of the ventricular wall and fibroblast proliferation to form scar tissue. Therefore, myocardial infarction and other factors cause the function of the myocardium to be gradually reduced along with the development of the disease process, and finally, heart failure can be caused.
There are four main methods for treating myocardial infarction at present: interventional blood vessel stent, heart bypass operation, drug therapy and end-stage heart transplantation. The former two are mainly used for restoring blood supply of cardiac muscle, the third one is mainly used for providing drug support treatment, but the three fundamentally reverse the left ventricular remodeling of the heart, so the process of suction failure after myocardial infarction cannot be fundamentally reversed, and the heart transplantation is difficult to popularize on a large scale due to severe shortage of donors.
Recent research shows that the remodeling process of the ventricle in the myocardial infarction region can be improved, the proliferation of fiber cells and the formation of fiber tissues are inhibited, and the myocardial function is improved by coating the elastic material on the epicardium to perform mechanical enhancement on the ventricle wall. Possible mechanisms include (1) improvement of local mechanical microenvironment of myocardium, inhibition of fibrocyte proliferation, promotion of myocardial regeneration and angiogenesis; (2) increasing the thickness of the wall of the chamber, reducing the pressure of the wall of the chamber, stabilizing the size of the ventricle, reshaping the geometry of the ventricle and preventing the formation of the aneurysm of the chamber wall.
Early studies used mechanical reinforcement by means of biventricular coating, such as Acorn CorCap Heart support devices and Paracor HeartNet Heart support devices. Left ventricular myocardial augmentation devices such as myocor coapsys left ventricular support devices and CardioClasp heart support devices were subsequently developed. The implantation procedure of the above devices is complicated, and the devices are bulky, and excessive contact with normal myocardium may have a detrimental effect on normal myocardium.
Cardiac patches have received much attention as a new treatment modality. The main function of the heart-stem-improving support is to provide good mechanical support for the heart-stem region, improve left ventricular remodeling of the heart and prevent the heart failure. In recent years, some researchers have developed a myocardial-reinforcing material that is partially implanted in a myocardial infarction site to directly act on a diseased site. For example, film made of polyurethane urea (PEUU) was fixed to the site of acute myocardial infarction in rats using surgical sutures by Fujimoto et al (see: An Elastic, Biodegradable Cardicarpatch indexes, coating, and research myocardial remodelling and function in Subacute myocardial infarction, 2007). Liao et al implanted a commercial double-layered mesh membrane (inner layer of polypropylene and outer layer of polytetrafluoroethylene) With sutures at the site of chronic Myocardial Infarction in rats (see document: implantation of Left vascular additive modification With epidermal accessing, 2010). Chi et al used fibrin glue to fix chitosan-hyaluronic acid/silk fibroin composite material to the site of myocardial infarction (see literature: Cardiac repirar using chitosan-hyaluronic acid/silk fibroin patches in an area heart model with myocardial infarction, 2013).
The heart patches currently under investigation are focused on the design and selection of materials and structures therefor. In the selection of materials, natural materials and synthetic polymer materials are included. The natural materials comprise common collagen, gel and the like, and have good biocompatibility but poor mechanical properties. The synthetic polymer material comprises Polycaprolactone (PCL), glycerol sebacate (PGS) and the like, and has good mechanical properties but relatively poor biocompatibility. How to select good materials for manufacturing the heart patch is very worth researching and researching. In terms of patch structure selection, including single-layer structures, multi-layer structures, mesh structures and the like, the inherent mechanical properties of different structures are greatly different, and how to design a good structure is also very worth researching and researching.
Lin et al ("A viroelastic adjuvant patch for treating myocardial injury", NATURE BIOMEDICAL ENGINEERING, https:// doi. org/10.1038/s 41551-019-. The advantages of the drug delivery system have better mechanical property, and the disadvantages of the drug delivery system are that the drug delivery system is difficult to operate in clinical application, difficult to transplant to the surface of the heart and has no function of drug delivery.
Jackman et al ("Engineered cardiac tissue specimen substrates and catalytic properties rear transplantation", Biomaterials,2018) disclose a single layer patch. Yang et al ("Elastic 3D-Printed Polymeric Scaffold improved cardiovascular disease", ADVANCED HEALTHCAREMATERIALS,2019.8) and Lei et al ("3D printing OF biological vascular disease regeneration", ROYAL SOCIETY OF CHEMISTRY COMMUNICATION,2019.02) disclose multilayer mesh and hollow tube structures having good angiogenic effect but with the disadvantage OF poor mechanical properties.
Whyte et al ("suspended release of targeted cardiac therapy with isolated and implanted implantable systemic respiratory response", NATURE BIOMEDICAL ENGINEERING, https:// doi. org/10.1038/s41551-018-0247-5) disclose cardiac patches for cardiac surface drug delivery, which have the greatest disadvantage of the poor mechanical strength of the Sustained release patch material, lack of good elasticity, lack of degradability, and fail to provide good mechanical support to the heart.
Therefore, there is a great need in the art for a cardiac patch having the following properties: good mechanical strength and elasticity, degradability and biocompatibility and versatility (such as drug delivery).
Disclosure of Invention
In order to achieve the above object, the present application provides a cardiac patch comprising:
(A) an elastic film comprising a biodegradable material;
(B) a porous structure comprising a biodegradable material;
the elastic membrane is located on the porous structure.
In a preferred example of the present application, the biodegradable polymer material includes polypeptides, polyamino acids, polyurethanes, polyesters, polylactic acids, chitin, collagen/gelatin, polycaprolactone, polysebacic acid glyceride, and combinations thereof.
In a preferred example of the present application, the material used to form the elastomeric film includes polycaprolactone, polysebacic acid glyceride and combinations thereof.
In a preferred embodiment of the present application, the material used to form the elastomeric film comprises a mixture of polycaprolactone and polysebacic acid glyceride; alternatively, the material for forming the elastic membrane comprises a mixture of materials in a weight ratio of 5: 95-95: 5, preferably in a weight ratio of 10: 90-90: 10, more preferably in a weight ratio of 20: 80-80: 20, and preferably in a weight ratio of 30: 70-70: 30.
in a preferred embodiment of the present application, the elastic membrane typically has a compressive modulus of 1 to 20 MPa; the tensile modulus of the elastic film is usually 0.1 to 10 MPa.
In a preferred example of the present application, the porous structure comprises a plurality of biomimetic blood vessel layers, wherein the biomimetic blood vessel orientations of the biomimetic blood vessel layers of two adjacent layers are the same or different.
In a preferred example of the application, the orientations of the bionic blood vessels of the adjacent two bionic blood vessel layers are different; preferably, the bionic blood vessels of the adjacent two bionic blood vessel layers are oriented at 5-90 degrees; more preferably, the bionic blood vessels of the adjacent two layers of the bionic blood vessel layers are orthogonally placed.
In a preferred embodiment of the present application, the porous structure comprises 2-10, preferably 2-8, more preferably 2-6, and most preferably 2-4 layers of biomimetic blood vessel layers.
In a preferred embodiment of the present application, the cardiac patch further comprises a catheter.
In another aspect, the present application provides the use of a mixture of polycaprolactone and polysebacic acid glyceride for the preparation of a heart patch, preferably, the use comprises increasing the mechanical properties, such as tensile modulus or compressive modulus, of the heart patch.
Drawings
Fig. 1 depicts a schematic view of a cardiac patch as described herein.
Fig. 2 is a photograph of four composite porous structures of example 1 at different ratios, wherein a is a pure PCL scaffold, b is PCL: gelatin 3:1, c is PCL: gelatin 1:1 and d is a pure gelatin stent.
Fig. 3 is a photograph of thin films of elastic composite films of PCL and PGS in different proportions, where a is a PGS film, b is a PGS/PCL-9: 1 composite film, c is a PGS/PCL-8: 2 composite film, d is a PGS/PCL-7: 3 composite film, and e is a PCL film.
Figure 4 is a micrograph of a pure PCL scaffold.
FIG. 5 is a photomicrograph of a PCL/gelatin (3:1) scaffold.
FIG. 6 is a photomicrograph of a PCL/gelatin (1:1) scaffold.
Fig. 7 is a photomicrograph of a pure gelatin stent.
FIG. 8 is a sectional electron micrograph of the thin film, wherein a-b are 75-fold and 800-fold electron micrographs of pure PGS film, c-d are 75-fold and 800-fold electron micrographs of PGS/PCL 9:1 film, and e-f are 75-fold and 800-fold electron micrographs of pure PCL film, respectively.
FIG. 9 is an electron micrograph of the surface of a thin film, wherein a-b are 75-fold and 800-fold electron micrographs of a pure PGS film, c-d are 75-fold and 800-fold electron micrographs of a PGS/PCL 9:1 film, and e-f are 75-fold and 800-fold electron micrographs of a pure PCL film, respectively.
Fig. 10 depicts the contact angles of scaffolds of different materials.
Fig. 11 depicts contact angles for films of different materials.
Fig. 12 depicts the mechanical properties of a porous structure, where a is the single compression plot and b is the cyclic compression plot.
FIG. 13 shows a histogram of the compressive modulus of the stent versus the compressive modulus of the stent.
Fig. 14 depicts the mechanical properties of an elastic film, where a is the tensile break plot, b is the cyclic tensile plot, c is the single compression plot, and d is the cyclic compression plot.
FIG. 15 shows a histogram of film modulus versus tensile modulus where a is the compressive modulus versus b.
FIG. 16 depicts the photographs obtained for PET.
Detailed Description
In this context, percentages (%) or parts are percentages by weight or parts by weight relative to the composition, unless otherwise specified.
In this context, the individual components mentioned or their preferred components can be combined with one another to form new technical solutions, if not stated otherwise.
All embodiments and preferred embodiments mentioned herein can be combined with each other to form new solutions, if not specified otherwise.
In this context, all technical features mentioned herein, as well as preferred features, can be combined with each other to form new technical solutions, if not specifically stated.
In this context, the sum of the contents of the individual components in the composition is 100%, if not stated to the contrary.
In this context, the sum of the parts of the components in the composition may be 100 parts by weight, if not stated to the contrary.
In this context, unless otherwise stated, the numerical range "a-b" represents a shorthand representation of any combination of real numbers between a and b, where a and b are both real numbers. For example, a numerical range of "0 to 5" indicates that all real numbers between "0 to 5" have been listed herein, and "0 to 5" is only a shorthand representation of the combination of these numbers.
As used herein, unless otherwise indicated, the range of integer values "a-b" represents a shorthand representation of any combination of integers between a and b, where a and b are both integers. For example, an integer numerical range of "1-N" means 1, 2 … … N, where N is an integer.
In this context, unless otherwise stated, "combinations thereof" means multi-component mixtures of the individual elements mentioned, for example two, three, four and up to the maximum possible multi-component mixtures.
The term "a" or "an" as used herein means "at least one" if not otherwise specified.
Percentages (including weight percentages) recited herein are based on the total weight of the composition, unless otherwise specified.
The "ranges" disclosed herein are in the form of lower and upper limits. There may be one or more lower limits, and one or more upper limits, respectively. The given range is defined by the selection of a lower limit and an upper limit. The selected lower and upper limits define the boundaries of the particular range. All ranges that can be defined in this manner are inclusive and combinable, i.e., any lower limit can be combined with any upper limit to form a range. For example, ranges of 60-120 and 80-110 are listed for particular parameters, with the understanding that ranges of 60-110 and 80-120 are also contemplated. Furthermore, if the
Herein, unless otherwise specified, each step is performed at normal temperature and pressure.
Herein, unless otherwise specified, the individual reaction steps may or may not be performed sequentially. For example, other steps may be included between the various steps, and the order may be reversed between the steps. Preferably, the reaction processes herein are carried out sequentially.
Herein, unless otherwise indicated, the devices or components thereof may be conventional in the art and operate and/or connect in a manner conventional in the art. For example, the various components of the device may be connected by conduits, lines, or combinations thereof for mass transfer or energy transfer.
The present application provides a cardiac patch comprising:
(A) an elastic film comprising a biodegradable material;
(B) a porous structure comprising a biodegradable material;
the elastic membrane is located on the porous structure.
Elastic film
The material used to form the elastic membrane is a biodegradable material, which may include biodegradable polymeric materials and biodegradable ceramic materials. The biodegradable polymer material includes, but is not limited to, polypeptides, polyamino acids, polyurethanes, polyesters, polylactic acids, chitin, collagen/gelatin, polycaprolactone, polysebacic acid glyceride, and combinations thereof. The biodegradable ceramic material includes, but is not limited to, P-tricalcium phosphate. In one example of the present application, materials for forming the base film include, but are not limited to, polyurethane, polyester, polylactic acid, chitin, polycaprolactone, polysebacic acid glyceride, and combinations thereof. In another example of the present application, materials for forming the elastic film include, but are not limited to, polycaprolactone, polysebacic acid glyceride, and combinations thereof. In another example of the present application, the material for forming the base film includes a mixture of polycaprolactone and polysebacic acid glyceride. In a preferred example of the present application, the material for forming the base film includes a material having a weight ratio of 5: 95-95: 5, preferably in a weight ratio of 10: 90-90: 10, more preferably in a weight ratio of 20: 80-80: 20, and preferably in a weight ratio of 30: 70-70: 30.
methods for forming elastic films are known in the art, such as casting, extrusion, casting, calendering, and the like. The method of forming the base film may cause the biodegradable material to crosslink. For example, in the case of using a mixture of polycaprolactone and polysebacic acid glyceride, the polycaprolactone and polysebacic acid glyceride crosslink during the formation of the elastic film. In one embodiment of the present application, the polycaprolactone and polysebacic acid glyceride are crosslinked under vacuum at a temperature of 100 ℃ and 250 ℃ for 10-72 hours.
Generally, the thickness of the elastic film is generally 0.1 to 5mm, preferably 0.2 to 3mm, more preferably 0.3 to 2mm, and most preferably 0.5 to 2 mm. The thickness of the base film can be adjusted according to actual needs.
Generally, the elastic film has good elasticity and large-scale deformation recovery, while having good fatigue resistance. The elastic film typically has a compressive modulus of from 1 to 20MPa, preferably from 2 to 15MPa, more preferably from 3 to 10MPa, most preferably from 4 to 8 MPa; the tensile modulus of the elastic film is generally 0.1 to 10MPa, preferably 0.5 to 5MPa, more preferably 0.8 to 4MPa, and most preferably 1 to 3 MPa.
Porous structure
The material for forming the porous structure is the same as or different from the material for forming the base film. The material used to form the porous structure is a biodegradable material, which may include a biodegradable polymeric material. The biodegradable polymer material includes, but is not limited to, polypeptides, polyamino acids, polyurethanes, polyesters, polylactic acids, chitin, collagen/gelatin, polycaprolactone, polysebacic acid glyceride, and combinations thereof. In one example of the present application, the material used to form the porous structure includes collagen/gelatin, polycaprolactone, polysebacate, and combinations thereof.
The specific structure of the porous structure is well known in the art, and may be, but is not limited to, a multi-layered mesh structure or a multi-layered hollow tube structure. The multilayered network can be found in Yang et al ("Elastic 3D-Printed hybrid polymeric samples improvement after Myocardial interference", ADVANCED HEALTHCARE MATERIALS, 2019.8). The multilayer hollow tube structure can be found in Lei et al ("3 printing of biological space for tissue regeneration", ROYAL SOCIETY OFCHEMISTRY COMMUNICATION, 2019.02).
In a preferred example of the present application, the porous structure comprises a plurality of biomimetic blood vessel layers, wherein the biomimetic blood vessel orientations of the biomimetic blood vessel layers of two adjacent layers are the same or different. Preferably, the orientations of the bionic blood vessels of the two adjacent bionic blood vessel layers are different, for example, the orientations of the bionic blood vessels of the two adjacent bionic blood vessel layers are 5-90 degrees, more preferably 15-90 degrees, still more preferably 30-90 degrees, still more preferably 45-90 degrees, and most preferably 60-90 degrees. In one example of the present application, the biomimetic blood vessels of the two adjacent layers of biomimetic blood vessels are orthogonally placed.
In one embodiment of the present application, the diameter of the biomimetic blood vessel is about 0.01-1mm, more preferably 0.02-0.5mm, still more preferably 0.05-0.2 mm.
In one example of the present application, the porous structure has 2 to 10 layers of the biomimetic blood vessel layer, preferably 2 to 8 layers of the biomimetic blood vessel layer, more preferably 2 to 6 layers of the biomimetic blood vessel layer, and most preferably 2 to 4 layers of the biomimetic blood vessel layer.
The thickness of the porous structure is generally 0.1 to 5mm, preferably 0.2 to 3mm, more preferably 0.3 to 2mm, and most preferably 0.5 to 2 mm. The thickness of the porous structure body can be adjusted according to actual needs.
Methods for forming porous structures are well known in the art. For example, see Yang et al ("Elastic 3D-Printed Hybrid Polymeric Scaffold improvements cardio modulation rearward molecular Infation", ADVANCED HEALTHCARE MATERIALS,2019.8) and Lei et al ("3 printing of biological design for tissue regeneration", ROYAL SOCIETY OFCHEMISSION COMMUNICATION, 2019.02).
Typically, the tensile modulus of the porous structure is 120-750kPa, preferably 150-600kPa, more preferably 200-500 kPa; a tensile break strength of 20 to 300kPa, preferably 50 to 250kPa, more preferably 100 kPa to 200 kPa; the tensile elongation at break is more than 35%, preferably more than 50%, more preferably more than 100%, still more preferably from 35% to 300%.
The porous structure body can also be used for loading drugs for treating myocardial infarction, and also can be macromolecular proteins such as polypeptide, growth factors and the like, genes, stem cells and the like. Such drugs include, but are not limited to, neomycin, digoxin, codantone, levosimendan, lidocaine, epinephrine, and combinations thereof. The porous structure may be immersed in a drug solution to load the drug in the pores of the porous structure.
Methods of bonding the porous structure and the substrate film together include, but are not limited to, pressing the porous structure and the substrate film together, adhering the porous structure and the substrate film together with an adhesive, or placing the substrate film on the porous structure and heating.
The heart patch may further include a conduit for releasing the drug loaded in the porous structure to the heart. The conduit may pass through the basement membrane with one end contacting the porous structure and the other end contacting the cardiac tissue.
Catheter tube
The cardiac patch described herein may also include a catheter. Typically, the catheter contacts the porous structure through the elastic membrane from the middle (e.g., central) of the elastic membrane to facilitate the sustained delivery of the drug in the porous structure to the heart.
One end of the conduit may also include a sheet adaptor to facilitate attachment of the conduit to the porous structure.
The material used to form the conduit and sheet adaptor may be a biodegradable material, which may be the same or different from the material forming the porous structure or elastic membrane.
In another aspect, the present application also provides the use of a mixture of polycaprolactone and polysebacic acid glyceride for the preparation of a heart patch. In particular, the cardiac patch may be used to treat cardiac diseases including, but not limited to, myocardial infarction and the like. In a preferred embodiment of the present application, the use comprises improving a mechanical property of the heart patch, such as tensile modulus or compressive modulus.
Fig. 1 depicts a schematic view of a cardiac patch as described herein. The heart patch comprises an
The present application is further illustrated by the following examples, but the scope of the present application is not limited thereto.
