CN112107390A - Composite tendon repair material and preparation method thereof - Google Patents
Composite tendon repair material and preparation method thereof Download PDFInfo
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- CN112107390A CN112107390A CN201910546178.9A CN201910546178A CN112107390A CN 112107390 A CN112107390 A CN 112107390A CN 201910546178 A CN201910546178 A CN 201910546178A CN 112107390 A CN112107390 A CN 112107390A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/08—Muscles; Tendons; Ligaments
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- Orthopedic Medicine & Surgery (AREA)
- Rehabilitation Therapy (AREA)
- Rheumatology (AREA)
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- Veterinary Medicine (AREA)
- Materials For Medical Uses (AREA)
- Prostheses (AREA)
Abstract
The invention relates to a composite tendon repair material, which is characterized by comprising a base layer, a first active layer and a second active layer; the base layer, the first active layer and the second active layer are fixedly arranged with each other; the substrate comprises an extracellular matrix material; the first active layer comprising an extracellular matrix material and a first active ingredient, the first active layer having a first end and a second end, at least a portion of the first active layer having a thickness that tapers in a direction from the first end toward the second end; the second active layer comprises an extracellular matrix material and a second active ingredient; the first active layer and the second active layer at least partially overlap. The material can provide physical strength, prevent the cutting of the tendon by the suture, has growth factors with the quantity varying in a gradient manner on the unit length, and effectively realizes the establishment of the tendon bone dead center and the effective repair of the tendon.
Description
Technical Field
The invention relates to a medical implanted medical instrument, in particular to a tendon repair material with a composite structure, which has growth factors with the quantity changing in a gradient manner on a unit length, and effectively realizes the establishment of tendon bone insertion points and the effective repair of tendons. The invention further comprises a preparation method of the composite tendon repair sheet material.
Background
The rotator cuff is an oversleeve-like tendon structure formed by tendons of supraspinatus, infraspinatus, infrascapular muscle and minor muscle in front of, above and behind the humeral head, and realizes the functions of controlling and rotating arms. When the rotator cuff tendon is subjected to overload stress, inflammation and degradation can occur, pain, lipidation and calcification are caused, the mechanical property of the tendon is reduced, and finally partial thickness tearing and full-layer tearing occur. The incidence of rotator cuff tear increases year by year with increasing age. The incidence in the population under 60 years is 6% and after 60 years 28-40% (see Ricchetti ET, Aurora A, Iannotti JP, ET al. Scaffold devices for rotor cup repair [ J ]. J Shoulder Elbow Surg,2012,21(2): 251-265). When the rotator cuff-like muscle group is damaged, shoulder joint pain and physiological function are reduced. Patients with rotator cuff injuries and patients with rotator cuff large area injuries who are not conservative are often treated with surgical procedures. 3-7.5 ten thousand patients with rotator cuff injury in the United states receive rotator cuff repair surgery each year. The population of the old aged 60 years old and older reaches 1.8499 billion in China, the population accounts for 13.7 percent of the total population, and about 500 ten thousand patients with rotator cuff injury need to undergo rotator cuff repair operation.
Rotator cuff tears are one of the most common tendon injuries in orthopedic surgery and are common causes of shoulder joint pain, stiffness, reduced mobility and reduced function. Rotator cuff tears are affected by age, area of injury, muscle atrophy, tendon degeneration, steatosis, post-operative rehabilitation exercises, etc. and the recurrence rate of rotator cuff repair surgery is as high as 20-70% (see Aurora a, McCarron J, Iannotti JP, dewin k. commercial available extracellular matrix materials for rotator cuff papers: state of the art and future drives. J outer cuff anchor surgery 2007; 16(5 supl): S171-8). Large size tears cause fat tissue to accumulate in muscle tissue and if not repaired in time will result in irreversible loss of muscle tissue function, and changes in tendon component and structure resulting from tissue degradation processes will make rotator cuff repair very difficult (see Depres-Tremblay G, Chevrier A, Snow M, et al. rotator cuff repair: a review of scientific technologies, animal models, and new technologies under depth [ J ]. J.J. Shoulder Elbow Surg,2016,25(12): 2078. 2085).
The difficulty of repairing rotator cuff injury lies in the repair of the insertion point, which is composed of highly specialized interface tissues and consists of four parts of tissues of tendon, fibrocartilage, calcified cartilage and bone in sequence, so that traction force generated by muscle is conducted to the bone from the tendon, and skeletal motion is realized. However, pathological studies show that the rotator cuff stop tissue structure cannot be restored to a normal form after surgical reconstruction, and the most important problem is that a fibrocartilage layer in a healed tendon-bone interface cannot be regenerated and is only replaced by scar tissue, so that the mechanical performance of the formed indirect stop is far lower than that of a normal direct stop, and the rotator cuff stop tissue structure is easy to be torn again. At present, a biological material with a promoting effect on the repair of the rotator cuff insertion point is urgently needed to relieve the pain of a patient.
The extracellular matrix bioremediation material is a good tissue repair material. The extracellular matrix is prepared by removing all components capable of causing host immune rejection reaction from allogeneic or xenogeneic tissues by adopting a decellularization technology, so that the extracellular matrix and a three-dimensional bracket structure are completely reserved. When the extracellular matrix is used for repairing defective tissues, host cells grow on the extracellular matrix, secrete new extracellular matrix components and form self tissues, so that the repair and reconstruction of the defective tissues are completed. These properties of extracellular matrix materials enable very broad applications in tissue repair.
Extracellular Matrix (ECM) materials made from animal tissues are the main development direction of regenerative medicine. The ECM is a complex organic three-dimensional entity composed of various macromolecular substances such as collagen, non-collagenous proteins, aminoglycans, elastin, and the like, provides suitable sites and microenvironments for the survival and activities of various cells, and can regulate the growth, shape, metabolism, migration, proliferation and differentiation of various cells, thereby regulating the functions of tissues and organs. One important cause of tissue defects is loss of ECM, which is also the reason why the body itself cannot achieve tissue repair and regeneration. Native ECM can serve as "soil" for tissue regeneration and is an ideal tissue repair material. Removal of cellular components from animal tissue removes most of the immunogenicity and retains ECM components, allowing the development of ideal bioprosthetic materials. Currently, bioactive materials that have been used clinically include ECM materials such as allodermis, porcine small intestine submucosa, porcine dermis, embryonic bovine dermis, and the like. Among them, Small Intestinal Submucosa (SIS) matrix material is the most ideal tissue repair material recognized by the academia at present. However, how to effectively realize rotator cuff repair by using extracellular matrix material is still a focus of attention of the academic world.
Disclosure of Invention
The invention provides a composite tendon repairing material, which adopts two exogenous growth factors and has a structure with gradually changed thickness, a gradient growth factor slow release system is formed, a growth factor excessive structure is formed, the wound growth repair of bone tissue and the wound growth repair of tendon tissue are respectively promoted at the torn positions of tendons and bones, the junction healing of the junction of the two tissues of the tendons and the bones is finally promoted, the junction-like structure from the transition of bones, calcified cartilages and fibrocartilages to the tendons is effectively formed, and the structure can realize the repair of the torn position of a huge rotator cuff tendon. The gradient growth factor slow release system can effectively reduce the total usage amount of the growth factors, prolong the whole growth factor release period to more than 6 months, and ensure the long-term effectiveness and safety of patients in the repair process.
In order to solve one or more existing problems, the invention provides a composite tendon repair material, which is characterized by comprising a base layer, a first active layer and a second active layer; the base layer, the first active layer and the second active layer are fixedly arranged with each other; the substrate comprises an extracellular matrix material; the first active layer comprising an extracellular matrix material and a first active ingredient, the first active layer having a first end and a second end, at least a portion of the first active layer having a thickness that tapers in a direction from the first end toward the second end; the second active layer comprising an extracellular matrix material and a second active ingredient, the second active layer having a first end and a second end, at least a portion of the second active layer having a thickness that gradually decreases in a direction from the first end toward the second end; the first active layer and the second active layer at least partially overlap. The composite material adopts two active layers and has a structure with gradually changed thickness. At least in the overlapping part of the thickness change, a gradient growth factor slow release system is formed. Or to form a growth factor superstructure. The wound surface growth and repair of bone tissues and the wound surface growth and repair of tendon tissues are respectively promoted at the torn parts of the tendon and the bone, and finally the junction healing of the two tissues of the tendon and the bone is promoted, so that the junction structure from the transition of the bone, the calcified cartilage and the fibrocartilage to the tendon is effectively formed. Wherein the base layer provides strength of the repair material, and the base layer is made of extracellular matrix, which can prevent adhesion between the repair region and other tissues. The active layer provides a biological scaffold for repairing the aponeurosis and a biological signal so as to induce tissue regeneration to reconstruct a stop point structure and realize the repair of huge rotator cuff tear.
A first distance is arranged between the first end of the first active layer and the second end of the second active layer, and the first distance is larger than 0. For the first active layer, the direct contact surface of the torn part of the tendon and the bone is arranged, and the active substance is directly applied to the corresponding position to realize the reconstruction of the dead center structure.
The first end of the first active layer and the second end of the second active layer have a first distance therebetween, the second end of the first active layer and the first end of the second active layer have a second distance therebetween, and the first distance is greater than the second distance. For the first active layer, the direct contact surface of the torn part of the tendon and the bone is arranged, and the active substance is directly applied to the corresponding position to realize the reconstruction of the dead center structure.
The base layer, the first active layer and the second active layer are fixed through biological adhesive; preferably, the biogel comprises one or more of collagen, gelatin, starch paste or polysaccharide.
The base layer, the first active layer and the second active layer are fixed by sewing with a bioabsorbable thread.
The composite tendon repair material further comprises a covering layer comprising an extracellular matrix material. By adding the covering layer, the overall strength of the composite tendon patch is further increased. And the active substances in the first active layer can diffuse through the extracellular matrix material covering layer to reach the torn part of the tendon and the bone, so that the reconstruction of the stop structure is realized.
The base layer, the first active layer, the second active layer and the covering layer are fixed through biological adhesive; preferably, the biogel comprises one or more of collagen, gelatin, starch paste or polysaccharide.
The base layer, the first active layer, the second active layer, and the cover layer are secured by a bioabsorbable thread suture.
The first active layer has a porosity of 70-90% and/or the second active layer has a porosity of 70-90%. The porosity ensures effective adsorption of the active substance by the structure.
The first active ingredient comprises a Bone Morphogenetic Protein (BMP); preferably, the bone morphogenic protein comprises one or more of BMP2, BMP4 and BMP 6.
The second active ingredient comprises a growth factor that promotes tenocyte growth; preferably, the tenocyte growth promoting growth factor comprises PDGF and/or TGF-beta 1.
At least a portion of the first active layer has a wedge shape in cross-section.
The first active layer having a wedge shape has a wedge tip angle of less than 5 degrees; preferably, the wedge tip angle is less than 3 degrees. Preventing the first active layer from increasing too quickly in thickness due to too large sharp corners.
At least a portion of the second active layer has a wedge shape in cross-section.
The second active layer having a wedge shape has a wedge tip angle of less than 5 degrees; preferably, the wedge tip angle is less than 3 degrees. Preventing the thickness of the second active layer from increasing too fast due to too large sharp corners.
The composite tendon repair material according to any one of the preceding claims, wherein the preparation method comprises the following steps: 1) preparing an extracellular matrix material: taking small intestine submucosa, and removing immunogen to obtain extracellular matrix material; 2) preparing a base layer: laminating a plurality of layers of extracellular matrix materials obtained in step 1) to prepare the substrate; 3) preparing a first active layer: taking the extracellular matrix material obtained in the step 1), preparing extracellular matrix slurry containing a first active ingredient, putting the slurry into a mold, and freeze-drying to obtain the first active layer; 4) preparing a second active layer: preparing extracellular matrix material obtained in the step 1) into extracellular matrix slurry containing a second active ingredient, putting the slurry into a mold, and freeze-drying to obtain a second active layer; and 5) laminating and fixing the base layer, the first active layer and the second active layer to obtain the composite tendon repair material.
The method for preparing a composite tendon repair material according to any one of the preceding claims, wherein the method comprises the following steps: 1) preparing an extracellular matrix material: taking small intestine submucosa, and removing immunogen to obtain extracellular matrix material; 2) preparing a base layer and a covering layer: respectively stacking a plurality of layers of extracellular matrix materials obtained in the step 1) to prepare the base layer and the covering layer respectively; 3) preparing a first active layer: taking the extracellular matrix material obtained in the step 1), preparing extracellular matrix slurry containing a first active ingredient, putting the slurry into a mold, and freeze-drying to obtain the first active layer; 4) preparing a second active layer: preparing extracellular matrix material obtained in the step 1) into extracellular matrix slurry containing a second active ingredient, putting the slurry into a mold, and freeze-drying to obtain a second active layer; and 5) laminating and fixing the base layer, the first active layer, the second active layer and the covering layer to obtain the composite tendon repair material.
According to the composite tendon repair material provided by the invention, exogenous growth factors are added, so that the healing effect of the growth factors on tendon bones can be perfectly exerted, the patch can repair the insertion points in a mode of gradient concentration distribution of the growth factors on the rotator cuff patch, the concentration of the growth factors for promoting bone repair is excessive from the insertion point end to the muscle end, the bone growth is promoted from strong to weak, a perfect gradual change structure is formed, and the insertion points are restored to the structure before damage. Meanwhile, in the tendon suture process, a suture needs to penetrate through the tendon for suture and fixing the tendon, and the suture can cut the tendon due to stress concentration of the suture region, so that repair failure is caused. After the repair material is adopted, the repair material can strengthen the suture area, can actively bear the stress generated by the suture, avoids cutting the tendon, and prevents postoperative complications from occurring.
The composite tendon repair material can provide physical strength for repairing a suture region, and can actively induce tissue regeneration. In addition, the invention designs a composite growth factor structure aiming at different repair areas, and establishes gradient change of the growth factor in the length direction based on the function of the growth factor, thereby effectively realizing the reconstruction of the tendon bone dead point and the functional repair of tendon tissue.
Drawings
FIG. 1 is a schematic view of a composite tendon repair material according to a first embodiment of the present invention;
FIG. 2 is an exploded view of the composite tendon repair material according to the first embodiment of the present invention;
FIG. 3 is a schematic view of a composite tendon repair material according to a second embodiment of the present invention;
FIG. 4 is a schematic view of a composite tendon repair material according to a third embodiment of the present invention;
FIG. 5 is an exploded view of a composite tendon repair material according to a third embodiment of the present invention;
FIG. 6 is a schematic view of a composite tendon repair material according to a fourth embodiment of the present invention;
FIG. 7 is an exploded view of a composite tendon repair material according to a fourth embodiment of the present invention;
FIG. 8 is an exploded view of a composite tendon repair material according to a fifth embodiment of the present invention;
FIG. 9 is a schematic view of a composite tendon repair material according to a sixth embodiment of the present invention;
FIG. 10 is an exploded view of a composite tendon repair material according to a sixth embodiment of the present invention;
FIG. 11 is an exploded view of a composite tendon repair material according to a seventh embodiment of the present invention.
Detailed Description
FIG. 1 is a schematic view of a composite tendon repair material according to a first embodiment of the present invention; fig. 2 is an exploded view of the composite tendon repair material according to the first embodiment of the present invention. The composite tendon repair material 10 includes a base layer 11, a first active layer 12 and a second active layer 13. The base layer 11 and each active layer include an extracellular matrix material that can be prepared using small intestine submucosa, pericardium, bladder submucosa. The small intestine submucosa can be animal small intestine submucosa, preferably porcine small intestine submucosa.
The extracellular matrix material can be obtained by:
(1) primary treatment of raw materials: taking small intestine submucosa tissue material, cleaning and draining;
(2) virus inactivation: soaking small intestine submucosa tissue material with peroxyacetic acid-ethanol solution for virus inactivation;
(3) cleaning the small intestine submucosa tissue material obtained in the step (2) in an ultrasonic environment, and then filtering to dry;
(4) and (3) cell removal: treating with cell removing liquid in an ultrasonic environment to remove cells;
(5) and cleaning in an ultrasonic environment to obtain the small intestine submucosa material.
The peroxyacetic acid-ethanol solution of the step (2), wherein the peroxyacetic acid has a volume percentage concentration of 0.1-5%, the ethanol has a volume percentage concentration of 5-40% (prepared as a solution with water), the volume ratio of the peroxyacetic acid-ethanol solution to the small intestine submucosa tissue material is (3-20): 1, the inactivation time is 2-4 hours, and the inactivation temperature range is 10-40 ℃.
In the cleaning process in the step (3), cleaning the small intestine submucosa tissue material by using a cleaning solution, wherein the cleaning solution is a PBS solution with the pH value of 7.2-7.4, the temperature of the PBS solution is 20 ℃, and the ratio (volume ratio) of the PBS solution to the small intestine submucosa tissue material is (20-40): 1; cleaning with purified water at a ratio of purified water to small intestine submucosa tissue material of (20-40): 1, and stopping until the detected conductivity is below 10 μ S/cm; the cleaning process is carried out in an ultrasonic cleaning machine, the frequency is preferably 40kHz, and the power is preferably more than 3000W.
The cell removing solution of the step (4) comprises trypsin and PBS solution, and the cell removing solution also comprises EDTA, EDTA-2Na or EDTA-4 Na; the mass percentage concentration of the trypsin in the cell removal liquid is 0.01-0.2%, preferably 0.02-0.05%; the concentration of EDTA, EDTA-2Na or EDTA-4Na is 0.1-1mmol/L, preferably 0.4-0.8 mmol/L; the pH value of the cell removal liquid is 7.0-8.0, preferably 7.2-7.5; the volume ratio of the cell removal liquid to the small intestine submucosa tissue material is (20-40): 1, the cell removal process is carried out in a double-frequency ultrasonic device, wherein the low-frequency range is 20-40KHz, the high-frequency range is 60-90KHz, the low-frequency treatment is 5-40min, the high-frequency treatment is 5-40min, and the temperature range of the cell removal liquid is 20-35 ℃; the ultrasonic power is more than 5000W.
In the cleaning process in the step (5), cleaning the small intestine submucosa tissue material by using a cleaning solution, wherein the cleaning solution is a PBS solution with the pH value of 7.2-7.4, and the ratio (volume ratio) of the PBS solution to the small intestine submucosa tissue material is (20-40): 1; cleaning with cooled water for injection at a ratio of (20-40): 1 to the small intestine submucosa tissue material, at 20-35 deg.C, and detecting that the difference between the conductivity of the water for injection and the conductivity of the water for injection is less than 1 μ S/cm; the cleaning process is carried out in an ultrasonic cleaning machine, the frequency is preferably 40kHz, and the power is preferably more than 3000W.
After the above five steps are completed, the extracellular matrix material is obtained.
Taking part of the obtained extracellular matrix material, and further performing the following steps to obtain the substrate 11. The method comprises the following steps: (6) fixing and forming: placing the obtained small intestine submucosa matrix material on a mould for lamination; (7) drying, and drying the small intestine submucosa matrix material by using a vacuum freeze drying or baking method.
The mold in the step (6) comprises a base plate with a needle and a pressing frame, wherein one or more layers of small intestine submucosa matrix materials are flatly paved on the base plate, the pressing frame is placed on the small intestine submucosa matrix materials, and the base plate with the needle and the pressing frame are relatively fixed. The amount of the small intestine submucosa laid flat may be from 2 to 25 layers, preferably from 5 to 10 layers.
Further, in the step (7), when the freeze-drying method is used, the following method may be adopted: placing the mould with the small intestine submucosa matrix material in a vacuum freeze dryer; pre-freezing to-45 deg.c and maintaining for 1-2 hr; then starting a vacuum pump, adjusting the temperature to-15 ℃, preserving heat for 5-7 hours, adjusting the temperature to 0 ℃, preserving heat for 2 hours, finally adjusting the temperature to 25 ℃, preserving heat for 4 hours, and completing vacuum freeze drying; the pressure in the chamber of the freeze-drying device is 1-50 Pa. The drying method in the step (7) can be used for placing the fixed small intestine submucosa material and the mould into an oven and drying at the temperature of below 40 ℃. Whereby a base layer or a cover layer can be obtained.
The first active layer and the second active layer are obtained by freeze-drying a slurry prepared from the mucosa of the small intestine. Cutting the substrate material cleaned in the step (3), grinding and crushing the substrate material by using a liquid nitrogen freezing and crushing device, crushing the cut substrate material, and screening out particles with the particle size of below 250 micrometers by using a screen; adding acetic acid solution into the granules, drying in vacuum and crushing; then adding growth factor aqueous solution into the granules according to the mass ratio of the growth factor to the granules of (1-50):10000 to form slurry. The growth factors are substantially uniformly distributed in the slurry.
For the first active layer, the growth factor used is Bone Morphogenetic Protein (BMP), preferably one or more of BMP2, BMP4 and BMP 6. The bone morphogenetic proteins are substantially homogeneously distributed in the first active layer.
For the second active layer, the Growth factors used include Growth factors that promote tenocyte Growth, preferably PDGF (Platelet Derived Factor) and/or TGF- β 1 (transforming Growth Factor- β 1). PDGF and/or TGF-. beta.1 are substantially homogeneously distributed in the second active layer.
And then putting the slurry into a shaping freeze drying mould for freeze drying. Pre-freezing the slurry to-45 ℃, preserving heat for 1-2 hours, then adjusting the temperature to-15 ℃, preserving heat for 5-7 hours, then adjusting the temperature to 0 ℃, preserving heat for 2 hours, finally adjusting the temperature to 25 ℃, and preserving heat for 4 hours. The first active layer 12 and the second active layer 13 are obtained based on different growth factors, respectively.
The freeze-drying mould may have a sloping bottom. The freeze-drying mold is shaped such that the first active layer 12 and the second active layer 13 have portions with a tapered thickness, such as wedge-shaped structures, more preferably wedge-shaped freeze-dried extracellular matrix material with a right-angled triangle cross-section after freeze-drying, each being enriched with one or more growth factors. Two lyophilized active layers are stacked, wherein the thin layer end of one active layer is stacked with the thick layer end of the other active layer, and the two active layers can form a complete active structure layer. The active structure layer composition is compounded with a flaky extracellular matrix material, the flaky extracellular matrix material provides mechanical strength, and the active structure layer provides slow release of growth factors. The layers may be bonded together by a biogel comprising one or more of collagen, gelatin, starch paste or polysaccharide. One end of the active structure is rich in the growth factor for promoting bone repair and poor in the growth factor for promoting connective tissue repair, and the other end of the active structure is rich in the growth factor for promoting connective tissue repair and poor in the growth factor for promoting bone repair. The first active layer 12 has a first end 123 and a second end 124, and the thickness of the first active layer 12 gradually decreases from the first end 123 to the second end 124; the second active layer 13 has a first end 133 and a second end 134, and the thickness of the first active layer 12 gradually decreases from the first end 133 toward the second end 134; a gradient growth factor slow-release system is formed in a mode that the first end 123 of the first active layer 12 and the second active layer 13 are overlapped, a growth factor transition structure is formed, bone tissue wound growth repair and tendon tissue wound growth repair are promoted at positions where tendons and bones are torn respectively, junction healing of junctions of two tissues of the tendons and the bones is promoted finally, and a junction-like structure from transition of bones, calcified cartilages and fibrocartilages to the tendons is effectively formed. The structure can realize the repair of the tear of the rotator cuff tendon. The gradient growth factor slow release system can effectively reduce the total usage amount of the growth factors, prolong the whole growth factor release period to more than 6 months, and ensure the long-term effectiveness and safety of patients in the repair process.
The wedge-shaped first active layer 12 and the wedge-shaped second active layer 13 each have a sharp cross-sectional angle of not more than 5 degrees, which ensures that the overall thickness of the first active layer 12 is not too large, making them suitable as a tendon repair implant material. Further, the cross-sectional tip angle is preferably not greater than 3 degrees.
After the base layer 11, the first active layer 12, and the second active layer 13 are obtained, the three layers are stacked. The first surface 121 of the first active layer 12 is opposite to the one-side surface 111 of the base layer 11. The second surface 122 of the first active layer 12 is opposite to the first surface 131 of the second active layer 13. At least one of the first surface 121 of the first active layer 12 and the one-side surface 111 of the base layer 11 is coated with a bio-gum absorbable by a human body, which is preferably one or more of a collagen gum, a gelatin, a starch paste, or a polysaccharide. The bio-gel is coated on at least one of the second surface 122 of the first active layer 12 and the first surface 131 of the second active layer 13. And bonding the glued layers to obtain the composite tendon repair material shown in figure 1.
When the composite rotator cuff repairing material is used, one end promoting bone growth is fixedly attached to a bone and one end promoting tendon growth is fixedly attached to a tendon according to the type of growth factors contained in the composite rotator cuff repairing material, so that a reinforcing structure and an induced tissue repair structure at a rotator cuff injury part are formed. The structure not only provides tissue strength, but also can promote the healing of the tendon and bone, and effectively forms a stop-like structure from the transition of bone, calcified cartilage and fibrocartilage to the tendon, and the structure can realize the repair of the tearing of the rotator cuff tendon.
Meanwhile, in the tendon suture process, a suture needs to penetrate through the tendon for suture and fixing the tendon, and the suture can cut the tendon due to stress concentration of the suture region, so that repair failure is caused. After the repair material is adopted, the repair material can strengthen the suture area, can actively bear the stress generated by the suture, avoids cutting the tendon, and prevents postoperative complications from occurring.
Fig. 3 is a schematic view of a composite tendon repair material according to a second embodiment of the present invention. Wherein the base layer 21, the first active layer 22 and the second active layer 23 are prepared in the same manner as the corresponding layers in the composite tendon repair material of the first embodiment. The fixation between the layers is secured by means of stitching 24. The suture is adopted, the preparation process can be simplified, the stable and fixed biological material can be obtained after the suture is adopted, a gradient growth factor slow release system can be formed, a growth factor transition structure is formed, the wound growth and repair of bone tissues and the wound growth and repair of tendon tissues are respectively promoted at the torn part of the tendon and the bone, the junction healing of the two tissues of the tendon and the bone is finally promoted, and the junction-like structure from the transition of the bone, the calcified cartilage and the fibrocartilage to the tendon is effectively formed. The structure can realize the repair of the tear of the rotator cuff tendon. The gradient growth factor slow release system can effectively reduce the total usage amount of the growth factors, prolong the whole growth factor release period to more than 6 months, and ensure the long-term effectiveness and safety of patients in the repair process.
FIG. 4 is a schematic view of a composite tendon repair material according to a third embodiment of the present invention; FIG. 5 is an exploded view of a composite tendon repair material according to a third embodiment of the present invention. As shown in fig. 4, a cover layer 34 may be provided on the second active layer 33 to further improve the overall strength of the composite tendon. The cover layer 34 may be prepared using the steps (1) to (7) together with the base layer 31. The cell matrix materials prepared by the steps (1) to (7) can be used as the base layer 31 and the covering layer 34, respectively. The base layer 31, the first active layer 32, the second active layer 33 and the cover layer 34 may be bonded to each other by bio-glue to fix them to each other. As another embodiment, the base layer 31, the first active layer 32, the second active layer 33, and the cover layer 34 may be secured by sewing them together with absorbable threads.
When the composite rotator cuff repairing material is used, one end promoting bone growth is fixedly attached to a bone and one end promoting tendon growth is fixedly attached to a tendon according to the type of growth factors contained in the composite rotator cuff repairing material, so that a reinforcing structure and an induced tissue repair structure at a rotator cuff injury part are formed. The structure not only provides tissue strength, but also can promote the healing of the tendon and bone, and effectively forms a stop-like structure from the transition of bone, calcified cartilage and fibrocartilage to the tendon, and the structure can realize the repair of the tearing of the rotator cuff tendon.
Meanwhile, in the tendon suture process, a suture needs to penetrate through the tendon for suture and fixing the tendon, and the suture can cut the tendon due to stress concentration of the suture region, so that repair failure is caused. After the repair material is adopted, the repair material can strengthen the suture area, can actively bear the stress generated by the suture, avoids cutting the tendon, and prevents postoperative complications from occurring.
FIG. 6 is a schematic view of a composite tendon repair material according to a fourth embodiment of the present invention; FIG. 7 is an exploded view of a composite tendon repair material according to a fourth embodiment of the present invention. The composite tendon repair material 40 includes a base layer 41, a first active layer 42 and a second active layer 43. The base layer 41 and each active layer include an extracellular matrix material that can be prepared using small intestine submucosa, pericardium, bladder submucosa. The small intestine submucosa can be animal small intestine submucosa, preferably porcine small intestine submucosa.
First active layer 42 has a first end 423 and a second end 424, the thickness of first active layer 42 in the direction from first end 423 to second end 424 being substantially constant over a distance d1, the length of d1 being substantially equal to the distance from first end 423 of first active layer 42 to second end 434 of second active layer 43 and then gradually decreasing; a gradient growth factor sustained-release system is formed and a growth factor transitional structure is formed by overlapping the first end 423 of the first active layer 42 and the second active layer 43 with each other. The substantially constant thickness portion of the first active layer 42 is configured to apply the active substance directly to the corresponding site at the tendon-to-bone tear, which is the direct interface of the portion, effectively achieving the stop structure reconstruction. The structure is suitable for repairing the torn rotator cuff tendon. The distance from the first end 433 of the second active layer 43 to the second end 424 of the second active layer 42 may or may not be 0.
FIG. 8 is an exploded view of a composite tendon repair material according to a fifth embodiment of the present invention. As shown in fig. 8, a cover layer 54 may be provided on the second active layer 53 to further improve the overall strength of the composite tendon. The cover layer 54 may be prepared using the steps (1) to (7) together with the base layer 51. The cell matrix materials prepared by the steps (1) to (7) can be used as the base layer 51 and the cover layer 54, respectively. The base layer 51, the first active layer 52, the second active layer 53 and the cover layer 54 may be bonded to each other by bio-glue to fix them to each other. In another embodiment, the base layer 51, the first active layer 52, the second active layer 53, and the cover layer 54 may be secured by sewing them together with absorbable thread.
When the composite rotator cuff repairing material is used, one end promoting bone growth is fixedly attached to a bone and one end promoting tendon growth is fixedly attached to a tendon according to the type of growth factors contained in the composite rotator cuff repairing material, so that a reinforcing structure and an induced tissue repair structure at a rotator cuff injury part are formed. This structure not only provides tissue strength, but also promotes healing of the tendon bones. The substantially constant thickness portion of the first active layer 52 is arranged to apply the active substance directly to the corresponding site at the tendon-bone tear, the direct contact surface of which portion, effectively achieving a stop structure reconstruction. The structure is suitable for repairing the torn rotator cuff tendon.
Meanwhile, in the tendon suture process, a suture needs to penetrate through the tendon for suture and fixing the tendon, and the suture can cut the tendon due to stress concentration of the suture region, so that repair failure is caused. After the repair material is adopted, the repair material can strengthen the suture area, can actively bear the stress generated by the suture, avoids cutting the tendon, and prevents postoperative complications from occurring.
FIG. 9 is a schematic view of a composite tendon repair material according to a sixth embodiment of the present invention; FIG. 10 is an exploded view of a composite tendon repair material according to a sixth embodiment of the present invention. The composite tendon repair material 60 includes a base layer 61, a first active layer 62 and a second active layer 63. The base layer 61 and each active layer include an extracellular matrix material that can be prepared using small intestine submucosa, pericardium, bladder submucosa. The small intestine submucosa can be animal small intestine submucosa, preferably porcine small intestine submucosa. The first active layer 62 has a first end 623 and a second end 624, and the thickness of the first active layer 62 in the direction from the first end 623 to the second end 624 is maintained substantially constant over a distance d2, and the length of d2 is substantially equal to the distance from the first end 623 of the first active layer 62 to the second end 634 of the second active layer 63, and then gradually decreases; a gradient growth factor sustained-release system is formed and a growth factor transitional structure is formed by overlapping the first end 623 of the first active layer 62 and the second active layer 63 with each other.
The substantially constant thickness portion of the first active layer 62 is arranged to apply the active substance directly to the corresponding site at the tendon-to-bone tear, the direct interface of which effectively achieves a stop structure reconstruction. The structure is suitable for repairing the torn rotator cuff tendon.
FIG. 11 is an exploded view of a composite tendon repair material according to a seventh embodiment of the present invention. As shown in fig. 11, a cover layer 74 may be provided on the second active layer 73 to further improve the overall strength of the composite tendon. The cover layer 74 may be prepared using steps (1) - (7) together with the base layer 71. The cell matrix materials prepared by the steps (1) to (7) can be used as the base layer 71 and the cover layer 74, respectively. The base layer 71, the first active layer 72, the second active layer 73 and the cover layer 74 may be bonded by bio-glue to be fixed therebetween. In another embodiment, the base layer 71, the first active layer 72, the second active layer 73, and the cover layer 74 may be secured by sewing them together with absorbable thread.
When the composite rotator cuff repairing material is used, one end promoting bone growth is fixedly attached to a bone and one end promoting tendon growth is fixedly attached to a tendon according to the type of growth factors contained in the composite rotator cuff repairing material, so that a reinforcing structure and an induced tissue repair structure at a rotator cuff injury part are formed. This structure not only provides tissue strength, but also promotes healing of the tendon bones. The substantially constant thickness portion of the first active layer 72 is configured to apply the active substance directly to the corresponding site at the tendon-bone tear, the direct contact surface of the portion, effectively achieving the stop structure reconstruction. The substantially constant thickness portion of the second active layer 73 is placed in contact with the tendon, releasing growth factors to promote tendon repair. The structure is suitable for repairing the torn rotator cuff tendon.
Meanwhile, in the tendon suture process, a suture needs to penetrate through the tendon for suture and fixing the tendon, and the suture can cut the tendon due to stress concentration of the suture region, so that repair failure is caused. After the repair material is adopted, the repair material can strengthen the suture area, can actively bear the stress generated by the suture, avoids cutting the tendon, and prevents postoperative complications from occurring.
The composite tendon repair material can provide physical strength for repairing a suture region, and can actively induce tissue regeneration. In addition, the invention designs a composite growth factor structure aiming at different repair areas, and establishes gradient change of the growth factor in the length direction based on the function of the growth factor, thereby effectively realizing the reconstruction of the tendon bone dead point and the functional repair of tendon tissue.
The foregoing is illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the claims. The present invention is not limited to the above embodiments, and the specific structure thereof is allowed to vary, and various changes made within the scope of the independent claims of the present invention are within the scope of the present invention.
Claims (17)
1. A composite tendon repair material comprising a base layer, a first active layer and a second active layer; the base layer, the first active layer and the second active layer are fixedly arranged with each other;
the substrate comprises an extracellular matrix material;
the first active layer comprising an extracellular matrix material and a first active ingredient, the first active layer having a first end and a second end, at least a portion of the first active layer having a thickness that tapers in a direction from the first end toward the second end;
the second active layer comprising an extracellular matrix material and a second active ingredient, the second active layer having a first end and a second end, at least a portion of the second active layer having a thickness that gradually decreases in a direction from the first end toward the second end;
the first active layer and the second active layer at least partially overlap.
2. The composite tendon repair material of claim 1 wherein a first distance is provided between a first end of the first active layer and a second end of the second active layer, the first distance being greater than 0.
3. The composite tendon repair material according to claim 1 or 2, wherein the first end of the first active layer and the second end of the second active layer have a first distance therebetween, the second end of the first active layer and the first end of the second active layer have a second distance therebetween, the first distance being greater than the second distance.
4. The composite tendon repair material according to any one of claims 1-3 wherein the base layer, the first active layer and the second active layer are fixed by a bio-adhesive; preferably, the biogel comprises one or more of collagen, gelatin, starch paste or polysaccharide.
5. The composite tendon repair material according to any one of claims 1-3 wherein the base layer, the first active layer and the second active layer are secured by suture of a bioabsorbable thread.
6. The composite tendon repair material according to any one of claims 1-5 further comprising a covering layer comprising an extracellular matrix material.
7. The composite tendon repair material according to claim 6 wherein the base layer, the first active layer, the second active layer and the cover layer are fixed by a bio-adhesive; preferably, the biogel comprises one or more of collagen, gelatin, starch paste or polysaccharide.
8. The method for preparing a composite tendon repair material according to claim 6 wherein the base layer, the first active layer, the second active layer and the cover layer are fixed by sewing with a bioabsorbable thread.
9. The composite tendon repair material according to any one of claims 1-8 wherein the first active layer has a porosity of 70-90% and/or the second active layer has a porosity of 70-90%.
10. The composite tendon repair material according to any one of claims 1-9 wherein the first active ingredient comprises Bone Morphogenic Protein (BMP); preferably, the bone morphogenic protein comprises one or more of BMP2, BMP4 and BMP 6.
11. The composite tendon repair material according to any one of claims 1-10 wherein the second active ingredient comprises a growth factor that promotes tenocyte growth; preferably, the tenocyte growth promoting growth factor comprises PDGF and/or TGF-beta 1.
12. The composite tendon repair material according to any one of claims 1-11 wherein a cross-section of at least a portion of the first active layer has a wedge shape.
13. The composite tendon repair material of claim 12 wherein the first active layer having a wedge shape has a wedge tip angle of less than 5 degrees; preferably, the wedge tip angle is less than 3 degrees.
14. The composite tendon repair material according to any one of claims 1-13 wherein a cross-section of at least a portion of the second active layer has a wedge shape.
15. The composite tendon repair material according to claim 14 wherein the wedge angle of the second active layer having a wedge shape is less than 5 degrees; preferably, the wedge tip angle is less than 3 degrees.
16. The composite tendon repair material according to any one of claims 1-5, wherein the preparation method comprises the following steps:
1) preparing an extracellular matrix material: taking small intestine submucosa, and removing immunogen to obtain extracellular matrix material;
2) preparing a base layer: laminating a plurality of layers of extracellular matrix materials obtained in the step 1) and then drying to obtain the base layer;
3) preparing a first active layer: taking the extracellular matrix material obtained in the step 1), preparing extracellular matrix slurry containing a first active ingredient, putting the slurry into a mold, and freeze-drying to obtain the first active layer;
4) preparing a second active layer: preparing extracellular matrix material obtained in the step 1) into extracellular matrix slurry containing a second active ingredient, putting the slurry into a mold, and freeze-drying to obtain a second active layer; and
5) and laminating and fixing the base layer, the first active layer and the second active layer to obtain the composite tendon repair material.
17. The method for preparing a composite tendon repair material according to any one of claims 6-15, wherein the method comprises the following steps:
1) preparing an extracellular matrix material: taking small intestine submucosa, and removing immunogen to obtain extracellular matrix material;
2) preparing a base layer and a covering layer: respectively laminating a plurality of layers of extracellular matrix materials obtained in the step 1), and then drying to respectively prepare the base layer and the covering layer;
3) preparing a first active layer: taking the extracellular matrix material obtained in the step 1), preparing extracellular matrix slurry containing a first active ingredient, putting the slurry into a mold, and freeze-drying to obtain the first active layer;
4) preparing a second active layer: preparing extracellular matrix material obtained in the step 1) into extracellular matrix slurry containing a second active ingredient, putting the slurry into a mold, and freeze-drying to obtain a second active layer; and
5) and laminating and fixing the base layer, the first active layer, the second active layer and the covering layer to obtain the composite tendon repair material.
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| WO2023179418A1 (en) * | 2022-03-25 | 2023-09-28 | 上海工程技术大学 | Rotator cuff patch with orientation structure and preparation method therefor |
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