| Background:Suture is a kind of device that is purposed to hold tissues together to promote healing in clinic.It can promote wound healing and reduce wound infection,with a long history which even can date back to 3000 BC.The materials of suture are various,and plant fiber,hair,animal tendon and even metal are all used for suture production throughout history.According to whether the material can be absorbed,suture is mainly divided into non-absorbable and absorbable suture.For the advantages of light tissue reaction and no secondary injury caused by suture removal,absorbable sutures have gradually been widely used in clinic,such as catgut(natural absorbable suture)or PGA and PGLA sutures(synthetic absorbable suture).However,these sutures have their own limitations.For example,the strength of catgut will rapidly lose in the tissue,and continuous tissue reaction will exist,the manufacturing process of synthetic absorbable suture(PGA,PGLA,etc.)is complex and the sutures ara expensive.In addition,some studies have found that synthetic absorbable suture is not superior to nylon suture in wound healing after operation.For the limitations of the above sutures and lacking advanced wound management function of common sutures,the occurrence of postoperative complications is a problem needs concerned,such as suture cracking,slow wound healing and even inflammation.In recent years,multifunctional sutures have been more concerned,for example,suture loaded with antibacterial drugs or compounds can effectively reduce the occurrence of postoperative wound infection,suture loaded with growth factors can significantly promote wound healing,and even electronic sensing implants can be used to sense the relevant parameters of the wound(heat,p H and bacterial count).Although the multi-functional suture possesses more advanced wound management function,some challenges still need to be solved.The traditional drug loading method is mostly the drug coating on the suture surface,and the drug release rate of the coating is fast and difficult to maintain effect for a long time.Also,the coating is relatively fragile,which is prone to rupture,injury and even drug inactivation.Some suture surfaces are loaded with several drugs,and the inner drug can only be released after the outer layer is released.Although it is reported that the inner drug can be stimulated to release after heating,the process is complex and the effect cannot be controlled.Gastric perforation is a common digestive tract injury in clinical.If the treatment is not in time,the gastric contents will flow into the abdominal cavity,which may lead to severe peritonitis or even death.Smaller perforations can usually be sealed with titanium clips under endoscope,and the conventional method for larger perforations is surgery.The environment of stomach is special.The p H in stomach is usually maintained at 1 or even lower,which may cause serious corrosion damage to the suture.In addition,the repeated contraction and relaxation of stomach wall can easily cause wound cracking and bleeding.The above factors undoubtedly propose higher requirements for strength and acid resistance of the suture.Catgut suture is one of the commonly used sutures in gastric perforation surgery,and it has been proved that the strength will gradually reduce in the simulated acid environment of stomach.Therefore,it is important to develop a multifunctional suture with high strength,acid resistance and stable drug loading.Swim bladder is an organ in fish,mainly composed of collagen I,elastin and glycosaminoglycan.It can help fish float and dive,possessing extremely high density and tensile strength,and can bear extremely high pressure.Swim bladder also possesses excellent histocompatibility(such as low immunogenicity and high cell adhesion),lower risk of pathogen infection,higher strength and acid resistance after crosslinking,which meet the characteristics required for ideal absorbable suture materials.In the field of medicine and materials,although swim bladder has not been reported as sutures,it has been reported to be used as a variety of patch materials(such as microgenerators,semipermeable membranes,cardiovascular biomaterials and artificial cartilage materials,etc.).Therefore,we propose the idea that: based on the swim bladder,the decellularized swim bladder with low immunogenicity can be obtained through acellular process of SDS and DNase/RNase.Then the multi-functional absorbable swim bladder suture can be fabricated through the steps of layering,drug loading,twisting and crosslinking with EDC/NHS solution.In addition to the basic characteristics of high strength,low immunogenicity and high acid resistance,the suture can load drugs to achieve controlled release,and even achieve real-time monitoring function.Based on this,the study focuses on the structure and strength of the swim bladder,the physical and chemical properties and in vitro functions of the swim bladder suture,and exploration of its application in animal models.Methods:1.The macro and micro structure and composition of the swim bladder are analyzed,and the application of the swim bladder is explored.The characterization structure of the swim bladder was analyzed by means of anatomical observation,HE staining,scanning electron microscopy,Raman spectroscopy and infrared spectroscopy.Change of tensile strength of the swim bladder before and after crosslinking was compared through tensile test.The fatality and application of the swim bladder patch were explored by leakage test,repairing the isolated pig stomach and repairing the gastric perforation of rabbit.2.The usable swim bladder suture were fabricated.Based on the swim bladder,the usable swim bladder suture is fabricated through decellularization,layering,drying,cutting,drug loading,twisting and crosslinking.3.Performance of the swim bladder suture was tested.The mechanical properties and biological safety of swim bladder suture were analyzed by cell test,subcutaneous implantation test and tensile test.4.Drug loading and release of swim bladder suture were detected.Various drugs were loaded in the process of swim bladder suture fabrication and the drug release was tested to explore the drug loading and release function of the multifunctional drug-loaded swim bladder suture.5.The application of multifunctional drug-loaded swim bladder suture in animal stomach and Achilles tendon models was explore.The feasibility of repairing gastric perforation and in vivo effect of multifunctional drug-loaded suture were verified.In the animal model,the swim bladder suture loaded with acid inhibitor and p H indicator was used to suture the gastric perforation of rabbit and the endoscopic observation was performed to verify the function of multi-functional suture in real-time monitor of p H around wound.The ruptured Achilles tendon was sutured in the animal model to verify the mechanical properties of swim bladder suture.Results:1.The swim bladder possesses high strength and can be successfully used as a patch.The swim bladder is composed of two layers in which fibers are perpendicular to each other,and its components are mainly collagen,elastin and glycosaminoglycan.After crosslinking,swim bladder possesses extremely high strength and the inner layer is particularly prominent.The crosslinked swim bladder also possesses stronger hydrophobicity,which can better maintain its strength in a wet environment.The swim bladder is extremely dense,and can effectively repair the isolated pig stomach,making it successfully filled under endoscope.The leakage test after repairing isolated pig stomach also confirmed its effect.Finally,successfully repairing gastric perforation of rabbit verified the effectiveness of swim bladder patch.2.The swim bladder can be successfully fabricated into suture and possesses high strength,good histocompatibility and acid resistance.The decellularized crosslinked swim bladder suture was successfully fabricated after decellularization,layering,drug-loading,twisting and crosslinking.The tensile test showed better mechanical properties of swim bladder suture than catgut,which was further confirmed by the morphology observation under the scanning electron microscope.The cell experiment showed that the swim bladder suture had no cytotoxicity and could be used for tissue suturing.The subcutaneous implantation experiment of rats showed that the swim bladder suture had better histocompatibility and biodegradability.The acid resistance test showed that the swim bladder suture possessed much stronger acid resistance than catgut and could better maintain its strength in the low p H environment of stomach.3.The swim bladder suture can achieve slow drug release after being loaded with drugs.The multifunctional drug-loaded swim bladder suture can be obtained by loading drugs on the surface of the swim bladder membrane,and it showed slow drug release in vitro test.After loading p H indicator,swim bladder suture can also display different colors in different p H environments,and the suture color can change reversibly with the change of p H,laying a foundation for realizing real-time monitor of p H in stomach.4.The drug-loaded swim bladder suture was successfully used in the repair of animal stomach perforation and rupture of Achilles tendon.In the treatment of gastric perforation of rabbit,the swim bladder suture successfully repaired the perforation,and showed a stronger effect on promoting would healing than catgut with endoscopic observation and immunohistochemical results.Even,the swim bladder suture loaded with AFGF or VF showed a more prominent effect.The swim bladder suture loaded with VF and p H indicator could not only inhibit the secretion of gastric acid,but also show the change of p H around wound in real-time through color change.In the treatment of gastric perforation of minipig,the VF loaded swim bladder suture showed significant effect of inhibiting gastric acid secretion.In the Achilles tendon rupture model of rabbit,the swim bladder suture successfully sutured the ruptured Achilles tendon and maintained the sectional anastomosis to promote the wound recovery.Conclusion:The swim bladder suture possesses high tensile strength,good histocompatibility and strong acid resistance,and it can successfully suture the gastric perforation.After loading with drug,it can also achieve functions such as promoting wound healing,inhibiting gastric acid secretion and real-time monitoring the change of p H around wound,which shows great potential for clinical application. |
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