CN109125924A - A kind of biology covers the application in terms of electronic equipments heart implantation - Google Patents
A kind of biology covers the application in terms of electronic equipments heart implantation Download PDFInfo
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- CN109125924A CN109125924A CN201811144968.6A CN201811144968A CN109125924A CN 109125924 A CN109125924 A CN 109125924A CN 201811144968 A CN201811144968 A CN 201811144968A CN 109125924 A CN109125924 A CN 109125924A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3633—Extracellular matrix [ECM]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
- A61N1/375—Constructional arrangements, e.g. casings
- A61N1/37512—Pacemakers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
Abstract
The present invention discloses a kind of biology and covers application in terms of electronic equipments heart implantation, which covers the impulse generator for being packed into the hearts embedded type electronic equipments such as pacemaker and defibrillator, be implanted to together in the pouch of subcutaneous tissue formation later.The biology set is acellular matrix, has many advantages, such as good biocompatibility, has certain mechanical properties, has biodegradability and antibacterial ability, can reduce the incidence of the complication such as the postoperative pouch infection of heart embedded type electronic equipments, hemotoncus and ulceration.
Description
Technical field
The present invention relates to Bioabsorbable implanted medical device fields, and in particular to a kind of biology is covered in the electronic equipments heart
Application in terms of dirty implantation.
Background technique
Heart embedded type electronic equipments (CIED) include Implanted cardiac pacemaker (ICP), the multiple defibrillation of implantable cardioverter turn
Device (ICD), cardiac resynchronization therapy device (CRT) and implantable cardiac monitor (ICM) etc., are mainly used for bradycardia, the heart
Dynamic diagnosis, treatment and the monitoring overrun with heart failure.CIED is generally made of impulse generator, electrode and conducting wire, with electricity
The impulse generator in source generally uses method for laser welding to encapsulate titanium shell, and subcutaneous tissue is formed before being implanted directly into pectoralis major
Pouch in, the conducting wire as conduction portion is one section of metal wire for being coated with insulating materials, and electrode is then implanted in the chambers of the heart simultaneously
It is in close contact with inner membrance.
In recent years, as aging of population and clinical indication expand, receive patient populations' rapid growth of CIED treatment,
The annual whole world is more than 1,000,000.But with increasing for implantation amount and increasing for complicated patient with severe symptoms's operation, after CIED implantation
The influence of complication is got worse.CIED is implanted into infectious-related complication, mainly there is pouch infection, hemotoncus, ulceration, loose electrode placement, electrode
Myocardial perforation, conducting wire wear and rupture, interior displacement of equipment body etc., wherein being with pouch related complication (infection, hemotoncus, ulceration)
Common complication after CIED implantation, incidence cause patient and seriously affect up to 7%, it has also become cardiovascular doctor face
The problem faced.
The principal element for causing pouch related complication to occur has:
(1) device housings are titanium or other alloy materials, it is foreign matter forever for human body, can lead to body and generate row
Reprimand reaction
(2) some reasons can lead to equipment movement, and if patient is old, thin, skin is relatively thin, pouch is excessive, limb activity etc., and
Equipment is mobile to be easy to cause friction bleeding to allow skin ulceration at hemotoncus, friction
(3) implantation or replacement of equipment, be easy to cause pouch to infect.
It is clinically directed to the solution of pouch related complication, the mainly product and specification of selection service life length at present
Surgical procedures, but fail to the incidence for being substantially reduced pouch related complication.
The Chinese utility model patent of Publication No. CN 202437991U is currently the only one and retrieves and be related to solving
The patent of CIED complication of implant, provided implanted pacemaker pouch are double-layer structure, and internal layer is silicon sulfide rubber
Glue-line, outer layer are only to shield coated in the hydroxyapatite layer on silicon rubber to equipment, fail to remove pouch correlation simultaneously
What hair disease occurred mainly causes factor, therefore fails to reduce the incidence of pouch related complication.
And upper biodegradable biology set is covered outside equipment, the hair of pouch related complication will be substantially reduced
Raw rate.
For this purpose, the present invention comes into being.
Summary of the invention
The good biocompatibility that the purpose of the present invention is to provide a kind of for heart embedded type electronic equipments has certain force
Learn performance, the acellular matrix biology set with biodegradability, with antibacterial ability, it is intended to reduce the postoperative pouch phase of CIED
Close the incidence of complication.
For this purpose, the present invention, which provides a kind of biology, covers application method in terms of electronic equipments heart implantation, wherein the life
Object set is made of acellular matrix, for being packed into the pouch for being implanted to subcutaneous tissue formation after heart embedded type electronic equipments together
In, to have the function that heart embedded type electronic equipments.
Further, the acellular matrix includes but is not limited to the submucous layer of small intestine of mammal, mucous membrane of urinary bladder
Lower layer, submucous lamina of stomach, one or more combinations of dermal matrix, pericardium, meninx, amnion, internal organs film, peritonaeum.
Further, the acellular matrix is the submucous layer of small intestine of mammal.
Further, heart embedded type electronic equipments equipment includes but is not limited to Implanted cardiac pacemaker, the implanted heart
Dirty detector, following cardiac resynchronization therapy and implantable cardioverter defibrillator.
Further, the biology set is combined by 2-12 layers of single layer acellular matrix overlapping, complex method packet
One of bonding, suture or a variety of are included, thickness is between 0.1mm-3mm.
Further, the biology set shape includes rectangle, square, circle, trapezoidal, shape of dripping, triangle, ellipse
Shape, irregular shape, the biology set area 4-100cm2, there are micropore, the pore diameter range of the micropore in the surface of the biology set
It is 10-400 μm, pitch of holes is 5-20 mm.
Further, the biology set can be loaded into one or more drugs according to clinical demand, be implanted to subcutaneous tissue
When the pouch of formation, the tissue that the biology set can be sutured in pouch is fixed, for preventing the intracorporal displacement of equipment.
The biocompatibility biology set, be by inactivation of virus, removal immunogenic substances, freeze-drying, punching, suture and
The preparation processes such as sterilizing are made.
The biology set of the good biocompatibility, requires to carry out biological assessment according to GB/T 16886.1, result is nothing
It is pyrogenicity, without hemolytic reaction, without Acute systemic toxicity reaction, cell-cytotoxic reaction no more than 1 grade, without sensitization of skin reaction,
Paradoxical reaction is no different after no intradermal stimulate the reaction, hereditary-less toxicity, muscular grafting and without sub- chronic systemic toxic reaction.
The good biocompatibility biology set, immunogenic substance is extremely low, including residual cell amount no more than 1/
Mirror downward view (400 ×), DNA residual quantity are negative (immunofluorescence assay), lipid no more than 120pg/g, α-Gal antigen
Content is not more than 1%.
The biology set of the good biocompatibility, bacterial endotoxin are not more than 2.15EU/ part.
The biology set for having certain mechanical properties, including tensile strength are not less than 10N, seam not less than 18N, bursting strength
It closes intensity and is not less than 2N not less than 2N, tearing strength.
The biology set of the biodegradability, degradation time in vivo are 8-20 weeks.
The biology set with antibacterial ability, the polypeptide moiety that degradation in vivo generates have antibacterial action.
Biology set suture when being implanted to the pouch of subcutaneous tissue formation, can be fixed on pouch by the biology set
Tissue can prevent the intracorporal displacement of equipment on muscle, fascia and skin.
The biology set can be loaded into one or more drugs according to clinical demand.
Preparation method of the present invention for above-mentioned biology set, comprising:
(1) it pre-processes
It takes the fresh tissue wash for butchering mammal clean, is placed in 0.01% ~ 0.5% acetum and impregnates 10 ~ 120min, go
Raw meat scrapes division using physics and isolates required mucous membrane, is cut into segment, is rinsed at least 3 times using purified water；
(2) inactivation of virus
The mixed aqueous solution for the ethyl alcohol that the Peracetic acid and concentration for the use of concentration being 0.5~1.5% are 15~25%, ultrasound condition
Under, 30 ~ 120min of soaking at room temperature carries out disinfection；It is cleaned by ultrasonic at least 3 times using purified water later；
(3) degreasing
The ethyl alcohol for the use of concentration being 90-100%, under ultrasound condition, soak at room temperature 0.5-12h is cleaned by ultrasonic using purified water later
At least 3 times；
(4) cell is taken off, DNA is removed and removes α-Gal antigen
Using containing 0.01~0.10% trypsase and containing the mixed aqueous solution of 0.01~0.05%EDTA, under ultrasound condition, in 36
15-40min is impregnated under the conditions of ± 2 DEG C, is cleaned by ultrasonic at least 3 times using PBS later；
Using the aqueous solution of the enzyme Han 0.05~10U/ml DNA, under ultrasound condition, 15-40min is impregnated under the conditions of 36 ± 2 DEG C,
Later using PBS drift ultrasonic cleaning at least 3 times；
Using the aqueous solution of the alpha-galactosidase Han 0.05~10U/ml, under ultrasound condition, 15- is impregnated under the conditions of 20-37 DEG C
40min is cleaned by ultrasonic at least 3 times using PBS later；
The NaOH aqueous solution for the use of concentration being 5- 40mM, under ultrasound condition, soak at room temperature 20-60min is super using PBS later
Sound cleaning is until neutral；
(5) it is lyophilized, sterilizes
3~12 layers are superimposed, is fixed on mold, after freeze-drying, is cut into specification needed for clinical use, is packed using PET
Bag is packed, and irradiation sterilization is finally carried out.
Compared with prior art, the present invention have following remarkable advantage and the utility model has the advantages that
A kind of ECM biology set for CIED provided by the invention, good biocompatibility have certain mechanical properties, have life
Biodegradable has antibacterial ability, is by inactivation of virus, removal immunogenic substances, freeze-drying, punching, suture and sterilizing etc.
Preparation process is made.When its be packed into CIED flutter generator after implant, can obtain it is following the utility model has the advantages that
1. biology set provided by the invention, is acted on by its physical barriers, it can avoid device housings and directly connect with tissue
Touching, it is ensured that implantation equipment will not be repelled by human body, to reduce inflammation and infection generation；
2. biology set provided by the invention, is fixed on pouch surrounding tissue by suture way, avoids and be wrapped in its inside
Equipment is in tissue pouch internal shift, dislocation, to reduce the incidence of pouch hemotoncus and pouch ulceration；
3. biology set provided by the invention, material ECM have promoting healing effect, reduce infection conducive to the reparation of tissue pouch
Rate；
4. biology set provided by the invention, ECM three-dimensional structure tool inducing cell and blood vessel grow into function, grown into new tissue
While itself can gradually degrade, finally equipment periphery formed one layer of collagen film, further avoid human body to implantation
The rejection of equipment；
5. biology set provided by the invention, degradation cycle is 8-20 weeks, and tissue capsule pocket infections are more common in the implantation of CIED equipment
Or 1-2 months after replacement, biology set is not yet degradable at this time, is conducive to the taking-up of CIED equipment；
6. biology set provided by the invention, the polypeptide moiety of catabolite has anti-microbial property, after can further decreasing implantation
The incidence of inflammation and infection；
7. biology set provided by the invention, according to clinical demand, can be added promoting healing substance or antibiotic during the preparation process,
Promoting healing substance or antibiotic can also be loaded by immersion way before implanting, to further promote Wound healing
With reduction infection rate；
8. biology set provided by the invention, can reduce the risk that CIED equipment is corroded and destroys in vivo, guarantee equipment
It works normally.
Detailed description of the invention
Fig. 1 is the pictorial diagram of the according to embodiments of the present invention 3 trees-Osima jacoti, Osima excavata acellular matrixes being prepared.
Fig. 2 is the pictorial diagram of the according to embodiments of the present invention 8 heart embedded type electronic equipments biology sets being prepared.
Fig. 3 is according to embodiments of the present invention 8 perspective views equipped with heart embedded type electronic equipments biology set being prepared.
Fig. 4 is according to embodiments of the present invention 8 sectional views equipped with heart embedded type electronic equipments biology set being prepared.
Fig. 5 is the perspective view of the according to embodiments of the present invention 9 heart embedded type electronic equipments biology sets being prepared.
Fig. 6 is the sectional view of the according to embodiments of the present invention 9 heart embedded type electronic equipments biology sets being prepared.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.
Embodiment 1
(1) it pre-processes
It takes the chitterlings tissue wash of fresh slaughtered animals clean, is placed in 0.5% acetum and impregnates 30min, chitterlings and acetic acid
The ratio of solution is 1:5, scrapes mucous layer, muscle layer, placenta percreta, the lymph node that division removes chitterlings jejunum, separation using physics
Submucosa out is cut into segment, is rinsed 3 times using purified water；
(2) it sterilizes
Use the mixed aqueous solution containing 1.0% Peracetic acid and 15% ethyl alcohol, SIS(submucous layer of small intestine) material and mixing water
The ratio of solution is 1:10, and under ultrasound condition, soaking at room temperature 100min carries out disinfection.Later using purified water ultrasonic cleaning 3
Time；
(3) degreasing and de- cell
The ethyl alcohol for the use of concentration being 95%, the ratio of SIS material and ethyl alcohol are 1:10, under ultrasound condition, soak at room temperature 2h.Later
It is cleaned by ultrasonic 3 times using water for injection；
The NaOH aqueous solution for the use of concentration being 25mM, the ratio of SIS material and NaOH solution are 1:20, under ultrasound condition, room temperature
Impregnate 50min.Later using PBS ultrasonic cleaning until neutral；
(4) it is lyophilized, sterilizes
By 4 layers of SIS material be superimposed, be fixed on mold, be freeze-dried, be cut into 4cm × 7cm specification, using PET packaging bag into
Row packaging, finally carries out irradiation sterilization.
Embodiment 2
(1) it pre-processes
It takes the chitterlings tissue wash of fresh slaughtered animals clean, is placed in 0.5% acetum and impregnates 30min, chitterlings and acetic acid
The ratio of solution is 1:5, scrapes mucous layer, muscle layer, placenta percreta, the lymph node that division removes chitterlings jejunum, separation using physics
Submucosa out is cut into segment, is rinsed 3 times using purified water；
(2) it sterilizes
Using the mixed aqueous solution containing 1.0% Peracetic acid and 15% ethyl alcohol, the ratio of SIS material and mixed aqueous solution is 1:
10, under ultrasound condition, soaking at room temperature 100min carries out disinfection.It is cleaned by ultrasonic 3 times using purified water later；
(3) degreasing
The ethyl alcohol for the use of concentration being 95%, the ratio of SIS material and ethyl alcohol are 1:10, under ultrasound condition, soak at room temperature 2h.Later
It is cleaned by ultrasonic 3 times using water for injection；
(4) cell is taken off
Using containing 0.02% trypsase and containing the mixed aqueous solution of 0.02%EDTA, SIS material and trypsase/EDTA solution
Ratio be 1:5, under ultrasound condition, impregnate 30min under the conditions of 37 DEG C.It is cleaned by ultrasonic 3 times using PBS later；
The NaOH aqueous solution for the use of concentration being 25mM, the ratio of SIS material and NaOH solution are 1:20, under ultrasound condition, room temperature
Impregnate 50min.Later using PBS ultrasonic cleaning until neutral；
(5) it is lyophilized, sterilizes
By 4 layers of SIS material be superimposed, be fixed on mold, be freeze-dried, be cut into 4cm × 7cm specification, using PET packaging bag into
Row packaging, finally carries out irradiation sterilization.
Embodiment 3
(1) it pre-processes
It takes the chitterlings tissue wash of fresh slaughtered animals clean, is placed in 0.5% acetum and impregnates 30min, chitterlings and acetic acid
The ratio of solution is 1:5, scrapes mucous layer, muscle layer, placenta percreta, the lymph node that division removes chitterlings jejunum, separation using physics
Submucosa out is cut into segment, is rinsed 3 times using purified water；
(2) inactivation of virus
Using the mixed aqueous solution containing 1.0% Peracetic acid and 15% ethyl alcohol, the ratio of SIS material and mixed aqueous solution is 1:
10, under ultrasound condition, soaking at room temperature 100min is virus inactivated.It is cleaned by ultrasonic 3 times using purified water later；
(3) degreasing
The ethyl alcohol for the use of concentration being 95%, the ratio of SIS material and ethyl alcohol are 1:10, under ultrasound condition, soak at room temperature 2h.Later
It is cleaned by ultrasonic 3 times using water for injection；
(4) cell is taken off, DNA is removed and removes α-Gal antigen
Using containing 0.02% trypsase and containing the mixed aqueous solution of 0.02%EDTA, SIS material and trypsase/EDTA solution
Ratio be 1:5, under ultrasound condition, impregnate 30min under the conditions of 37 DEG C.It is cleaned by ultrasonic 3 times using PBS later；
Using the aqueous solution of the enzyme of DNA containing 5U/ml, the ratio of SIS material and DNA enzymatic solution is 1:5, under ultrasound condition, in 37
20min is impregnated under the conditions of DEG C.Later using PBS drift ultrasonic cleaning 3 times；
Using the aqueous solution of the alpha-galactosidase containing 5U/ml, the ratio of SIS material and alpha-galactoside enzyme solutions is 1:5, is surpassed
Under the conditions of sound, 20min is impregnated under the conditions of 30 DEG C.It is cleaned by ultrasonic 3 times using PBS later；
The NaOH aqueous solution for the use of concentration being 25mM, the ratio of SIS material and NaOH solution are 1:20, under ultrasound condition, room temperature
Impregnate 50min.Later using PBS ultrasonic cleaning until neutral；
(5) it is lyophilized, sterilizes
By 4 layers of SIS material be superimposed, be fixed on mold, be freeze-dried, be cut into 4cm × 7cm specification, using PET packaging bag into
Row packaging, finally carries out irradiation sterilization.
Embodiment 4
The preparation of trees-Osima jacoti, Osima excavata ECM
(1) it pre-processes
It takes the chitterlings tissue wash of fresh slaughtered animals clean, is placed in 0.01% acetum and impregnates 120min, chitterlings and vinegar
The ratio of acid solution is 1:10, scrapes mucous layer, muscle layer, placenta percreta, the lymph node that division removes chitterlings jejunum using physics, point
Submucosa is separated out, segment is cut into, is rinsed 3 times using purified water；
(2) inactivation of virus
Using the mixed aqueous solution containing 0.5% Peracetic acid and 25% ethyl alcohol, the ratio of SIS material and mixed aqueous solution is 1:
15, under ultrasound condition, soaking at room temperature 120min is virus inactivated.It is cleaned by ultrasonic 3 times using purified water later；
(3) degreasing
The ethyl alcohol for the use of concentration being 90%, the ratio of SIS material and ethyl alcohol are 1:15, under ultrasound condition, soak at room temperature 4h.Later
It is cleaned by ultrasonic 3 times using water for injection；
(4) cell is taken off, DNA is removed and removes α-Gal antigen
Using containing 0.05% trypsase and containing the mixed aqueous solution of 0.01%EDTA, SIS material and trypsase/EDTA solution
Ratio be 1:10, under ultrasound condition, impregnate 20min under the conditions of 37 DEG C.It is cleaned by ultrasonic 3 times using PBS later；
Using the aqueous solution of the enzyme of DNA containing 1U/ml, the ratio of SIS material and DNA enzymatic solution is 1:10, under ultrasound condition, in 37
30min is impregnated under the conditions of DEG C.Later using PBS drift ultrasonic cleaning 3 times；
Using the aqueous solution of the alpha-galactosidase containing 1U/ml, the ratio of SIS material and alpha-galactoside enzyme solutions is 1:10, is surpassed
Under the conditions of sound, 30min is impregnated under the conditions of 30 DEG C.It is cleaned by ultrasonic 3 times using PBS later；
The NaOH aqueous solution for the use of concentration being 40mM, the ratio of SIS material and NaOH solution are 1:10, under ultrasound condition, room temperature
Impregnate 30min.Later using PBS ultrasonic cleaning until neutral；
(5) it is lyophilized, sterilizes
By 4 layers of SIS material be superimposed, be fixed on mold, be freeze-dried, be cut into 4cm × 7cm specification, using PET packaging bag into
Row packaging, finally carries out irradiation sterilization.
Embodiment 5
Immunogenic substance detection is carried out to the sample that embodiment 1-4 is prepared.
(1) cell residue quantity measuring method: being fixed, paraffin embedding with 10% neutral formalin, is cut into 0.4 micron thin
Piece, through dimethylbenzene dewaxing, serial dehydration of alcohol, hematoxylin-eosin stains, microscopically observation cell residue situation and matrix
Fibre structure.
(2) DNA content detection method: according to YY/T 0606.25-2014, " animal derived biomaterial DNA residual is measured
Determine method: fluorescence colour " it is detected.
(3) α-Gal antigenic content detection method: after sample is fixed with paraformaldehyde, routine paraffin wax embedded section, piece thickness
3 microns.Immunohistochemical reaction is carried out using the special affinity characteristic of biotin labeling BSI-B4 and α-Gal antigen.Coloration result
Determine: dark brown yellow particle is strong positive (+++), and brown yellow granule is positive (++), and yellow particle is weakly positive (+), not
See and is colored as negative (-).
(4) lipid content detection method: referring to soxhlet extraction methods in " fatty measurement in 5009.6 food of GB/T " into
Row measurement.
Illustrate: Examples 1 and 2 are the absence of DNA and go α-Gal antigen step, and embodiment 1 is with NaOH degreasing
, bigger, Examples 1 and 2 step similar in other patents before being all, for protruding embodiment 3 and 4 is destroyed to structure
Go immunogenicity more excellent.As a result it see the table below.
Embodiment 6
Biology performance, bacterial endotoxin and anti-microbial property detection are carried out to the sample that embodiment 3 is prepared.
(1) biology performance detects
Method: it is tested referring to GB/T16886 series methods
As a result: cell-cytotoxic reaction is 1 grade；Without delayed allergy；Intradermal reaction shows that test specimen and solvent control are flat
The difference scored is less than 1.0；Without pyrogenicity；Without hemolytic reaction；Genetic toxicity test is the results show that salmonella typhimurium returns
Multiple mutation (Ames) test is negative, mouse lymphoma assay is negative, dye-free body distortion property；Without acute systemic
Property toxic reaction；Without sub- chronic generalized toxicity；Muscular grafting 30 days, 60 days, 90 days tissue reactions with negative controls without
Significant difference.
(2) detection of bacterial endotoxin
Method: it is detected referring to correlation technique in GB/T 14233
As a result: less than 2.15EU/ part.
(3) anti-microbial property detects
Sample obtained by embodiment 1 is ground in the hydrochloric acid of 0.01M with grinding rod, until being visible by naked eyes particle, and is adjusted
Its concentration is 100mg/10mL.Pepsin digestion is added, pepsin: sample ratio is 1:10.It is persistently stirred at 25 DEG C
48h, after be cooled to 4 DEG C, the 0.1 M sodium hydroxide that 1/10 volume is added adjusts PH to 7.2-7.4；
Hybrid NC machine tool base plate is prepared, picks them separately a little cultured staphylococcus aureus and Escherichia coli with oese
Bacteria suspension is made in sterile saline 5ml in inclined-plane culture substratess.Take bacteria suspension 1.0ml and the above-mentioned sample through degrading
1ml is added in the culture dish of sterilizing-drying, and addition is cooled to 50 DEG C or so of ordinary nutritional broth agar culture medium, is shaken up,
Spare after sufficiently condensing, 35~37 DEG C of inversions are cultivated 24 hours, observe bacterial growth situation；Increase simultaneously and does not have to antibacterial material
Material and 5 μ g/mL antibacterial peptides of addition compare, and as a result see the table below:
Embodiment 7
Mechanics properties testing is carried out to the sample that embodiment 3 is prepared.
(1) suture strength
Method: with the non-absorbing suture of 3-0 in sample both sides center far from being sutured at edge 2mm, by the suture other end and sample
The other end be separately fixed on tensiometer both ends, stretched with the speed of 20mm/min, until stitch points are torn, record
Maximal force；
As a result: suture strength is in 3N-5N range.
(2) tensile strength
Method: it is 10mm shape that sample is cut to width respectively in both directions；In relative humidity 40%-60%, temperature after cutting
It is tested after being placed 2 hours in 22 ± 2 DEG C of environment of degree.Fixture spacing is 25mm, and sample both ends are fixed on cupping machine
Collet on, the maximal force with the speed tensile of 100mm/min, when record fracture；
As a result: tensile strength is in 30N-35N range.
(3) bursting strength
Method: according to the measurement method of " YY 0500-2004 cardiovascular implant artificial blood vessel " 8.3.3.2 probe rupture strength
9.5mm diameter probe is chosen to be detected；
As a result: bursting strength is in 85N-90N range.
Embodiment 8
Preparation biology set
Be prepared 2, sample of Example 3 carry out capillary processing using low power laser punching instrument, and the aperture of micropore is
It 400 μm, 15 mm of pitch of holes, is cut according to the shape and size of implantation equipment, using Violet 5-0 PDS suture
By 3/4ths tight sutures at 2 laminated edges of sample, pictorial diagram is shown in Fig. 2.
In the schematic perspective view diagram 3 of the present embodiment, encapsulated layer 2 includes two panels encapsulating material, in order to form biology set 3, will be sealed
3/4ths of package material edge unite by a seam, and are open by remaining a quarter and are packed into implantable cardioverter defibrillator
In biology set, the biology set 1 equipped with implantable cardioverter defibrillator is formed.
Embodiment 9
Preparation biology set
Prepare 1, sample be prepared by embodiment 4, instrument is punched by low power laser, the biology after being sutured is packed into
Row capillary processing, the aperture of micropore are 300 μm, 10 mm of pitch of holes.Selection length is 12.5 cm, and width is the sample of 6.5 cm
Product fold up sample to form clad to form biological set, and the clad folds and laminated in port and level.
Using Violet 5-0 PDS suture by port 2 and 3 and another 4 tight suture of connected side, in the perspective of the embodiment
In figure Fig. 5, by remaining a quarter opening 5 by implantable cardioverter defibrillator loading biology set, formed equipped with plant
Enter the biology set 1 of type cardioverter-defibrillators.
Embodiment 10
Prepare drug-loaded biological set
After the completion of embodiment 3(4), it is immersed in biomembrane containing 20 μ g/mld minot ring of concentration
It 24 hours in the solution of element, then completes to implement 1(5).The biology set for being loaded with drug is prepared further according to the mode for implementing 8.
Those skilled in the art can make a variety of variations to the present invention according to the above description.Thus, it is not violating
Under the premise of claim objective of the invention, certain details in embodiment should not constitute limitation of the invention, the present invention
It will be using the range that the appended claims define as protection scope.
Claims (7)
1. a kind of biology covers the application in terms of electronic equipments heart implantation, it is characterised in that: the biology set is by taking off cell base
Matter composition, for being fitted into the pouch for being implanted to subcutaneous tissue formation after heart embedded type electronic equipments together.
2. biology according to claim 1 covers the application in terms of electronic equipments heart implantation, it is characterised in that: described de-
Cellular matrix includes but is not limited to submucous layer of small intestine, submucous layer of bladder, submucous lamina of stomach, the corium base of mammal
One or more combinations of matter, pericardium, meninx, amnion, internal organs film, peritonaeum.
3. biology according to claim 2 covers the application in terms of electronic equipments heart implantation, it is characterised in that: described de-
Cellular matrix is the submucous layer of small intestine of mammal.
4. biology according to claim 1 covers the application in terms of electronic equipments heart implantation, it is characterised in that: heart is planted
Entering type electronic equipments equipment includes but is not limited to that Implanted cardiac pacemaker, implantable cardiac detector, cardiac resynchronization are controlled
Treatment and implantable cardioverter defibrillator.
5. described in any item biologies cover the application in terms of electronic equipments heart implantation according to claim 1 ~ 4, feature exists
In: the biology set is combined by 2-12 layers of single layer acellular matrix overlapping, and complex method includes bonding, in suture
One or more, thickness is between 0.1mm-3mm.
6. biology described according to claim 1 ~ any one of 4 covers the application in terms of electronic equipments heart implantation, feature
Be: the biology set shape includes rectangle, square, circle, trapezoidal, shape of dripping, triangle, ellipse, irregular shape,
The biology set area 4-100cm2, there is a micropore on the surface of the biology set, and the pore diameter range of the micropore is 10-400 μ
M, pitch of holes are 5-20 mm.
7. described in any item biologies cover the application in terms of electronic equipments heart implantation according to claim 1 ~ 4, feature exists
In the biology set can be loaded into one or more drugs according to clinical demand, can when being implanted to the pouch of subcutaneous tissue formation
It is fixed with the tissue that the biology set is sutured in pouch, for preventing the intracorporal displacement of equipment.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2018109227470 | 2018-08-14 | ||
| CN201810922747 | 2018-08-14 |
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| WO2021244901A1 (en) | 2020-06-05 | 2021-12-09 | Hylomorph Ag | Insertion tool for pouches for ipgs |
| WO2023060823A1 (en) * | 2021-10-11 | 2023-04-20 | 北京博辉瑞进生物科技有限公司 | Biological sleeve for accommodating implantable medical device, preparation method therefor and use thereof |
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