| Background:Osteosarcoma is the most common malignant bone tumor,accounting for about 40%of primary malignant bone tumors.Osteosarcoma is a highly malignant primary intramedullary tumor with poor prognosis,high mortality and disability,and brings great pain and heavy economic burden to countless patients and families.The traditional treatment of osteosarcoma includes three parts:preoperative high-dose chemotherapy,radical osteosarcoma resection and postoperative high-dose chemotherapy,but the side effects of the traditional treatment regimen are obvious.In order to achieve the local drug concentration of the focus,it is necessary to increase the systemic chemotherapy dose.It leads to fatal side effects such as bone marrow suppression,liver and kidney function damage,central nervous system damage and so on.Therefore,the traditional drug administration has not only failed to effectively prolong the survival life of patients,but also led to a sharp decline in the quality of life of patients.In clinical work,there is an urgent need for a new drug administration with little systemic side effects and definite local efficacy to solve this problem.Gentamicin bead chain,invented by Klemm in 1980s,is a bead chain plant containing gentamicin made of polymethyl methacrylate compound,which is placed in the inflammatory site and slowly released to play a local antibacterial effect.Local use of drugs can avoid the side effects of systemic use of gentamicin,which opens a precedent for clinical use of plants in local drug carriers.Inspired by the gentamicin bead chain,medical researchers have invented different types of drug-carrying plants for the treatment of different diseases,of which local chemotherapy is an important part.Local chemotherapy refers to the combination of chemotherapeutic drugs and biocompatible carriers to slowly release drugs into specific parts of the body in order to achieve the purpose of local treatment of tumor.Local chemotherapy has obvious advantages over systemic chemotherapy because of its high local drug concentration,low systemic blood concentration and little side effects.However,the clinical application of traditional drug carriers such as bone cement is limited by the use of single drug,unstable and uncontrollable drug release,need for secondary surgery,and can not be individualized.Therefore,there is an urgent need for a new type of drug-loaded plant for local chemotherapy of osteosarcoma,which is individualized,multi-drug delivery,stable and controllable,and does not need to be removed by secondary surgery.Suitable materials are the key to the construction of good implants.Poly(L-lactic acid)(PLLA)selected in this experiment has been safely used as a surgical suture material for nearly 30 years,and its good biocompatibility and biodegradability have been widely accepted,and it is one of the commonly used biomaterials in clinic.In orthopedic clinical treatment,PLLA,as a biodegradable material,can be used to make both orthopedic internal fixation and tissue engineering scaffolding.It has the advantages of good biocompatibility,strong plasticity,and the rate of degradation is relatively consistent with that of bone defect repair.Rapid prototyping technology is one of the most cutting-edge and hot technologies in the field of scientific research at home and abroad.It has a revolutionary impact on the development of manufacturing industry and has become the focus of many countries.Rapid prototyping technology was first invented and patented by Deckard in the mid-1980s.After nearly 20 years of development,rapid prototyping technology has become increasingly mature and gradually applied in the field of medical and health.Compared with the traditional method of making inner plants,rapid prototyping technology has the following advantages:individual customization,accurate physical production,material diversification,no assembly,short production time,small production space,high portability,no manufacturing technical barriers,no direct relationship between production cost and design complexity,no direct relationship between production cost and production diversification,and so on.According to the specific conditions such as the location and shape of the cancer focus or the results of the operation,different shapes and sizes of endophytes can be made to meet the needs of different patients.According to the specific conditions of the treatment plan,we can make selective individual drug loading plants in the bone marrow,soft tissue around the focus and metastatic site,so as to optimize the therapeutic effect,minimize drug side effects,and avoid the occurrence of drug resistance and drug abuse.The new manufacturing method brought by good biomaterials combined with rapid prototyping technology provides a new idea for local chemotherapy of osteosarcoma.The combined application of rapid prototyping technology and local drug loading plant technology is expected to achieve the following purposes:to develop a strongly targeted combination of chemotherapeutic drugs according to the drug sensitivity test and tumor pathological characteristics of patients;to make different doses or variable doses of drug-loaded plants according to the condition of patients,and to realize four-load or even multiple drug-loading schemes.The simultaneous release,alternate release and gradient release of the drug can be realized,and the concentration and speed of drug release can be accurately regulated.According to the specific conditions of the whole body and focus,the selective individualized treatment plan of the whole body,bone marrow,soft tissue around the focus and metastatic site can be established.According to the specific conditions such as the location and shape of the cancer focus or the results of the operation,different shapes and sizes of implants can be made to meet the needs of different patients.Therefore,the main purpose of this study is to explore the feasibility of preparing individual degradable multi-load drug controlled release plants based on rapid prototyping technology for local chemotherapy of osteosarcoma.Methods:Mimics 10.0 software was used to design cylindrical spherical inner plants according to human anatomy and biomechanics,and then PLLA powder molding 3D printing technology was used to process the materials into the design model,and finally the drug-loaded plants were prepared.Scanning electron microscopy(sem)was used to observe the microstructures of PLLA spherical printed porous plants and to determine their porosity.Study on cytotoxicity of PLLA spherical printing in drug delivery,study on skin sensitization of PLLA spherical plants,study on subacute toxicity of endophytes,study on the compatibility of blood,study on biodegradation.Comparative study on the establishment of mouse osteosarcoma model by cell suspension injection and tissue block transplantation and experimental study on the efficacy of drug-loaded plants in the treatment of osteosarcoma in animal models.Results:Under the scanning electron microscope,the pores of the inner plants were abundant,with smooth surface and rough inner wall,which was conducive to cell adhesion.The porosity of the plants in the spherical pores of PLLA was(85.14±2.16)%,indicating that the plants in PLLA met the requirements of biological materials:porosity of>80%.The toxic effects of the implant,class is 0 or 1,indicates that the plant has no cytotoxicity in vitro,has a good biocompatibility of this experimental study results show that PLLA spherical porous in medicine plant no sensitization in guinea pigs,the weak strength of sensitization allergenic no animal died during the whole test,each test animal clinical observation without exception experimental animal PLLA suspension(1%10%)normal weight gain,and solvent control group had no significant difference between experimental group animals viscera weight and dirty body than compared with the control group,there was no significant difference.All experimental animals in good condition,normal diet and independent activities,the whole test process without animals die cut parts without infection such as swelling purulent drainage all experimental animals plants within the wound healing of drug-loading PLLA spherical porous implants after 12 w,pathological visible:very little lymphocytes are seen around the implants,inflammatory cells significantly decreased the number of class for inflammatory reaction,formation of cystic wall level test group compared with negative control group,no difference between the degree of hemolysis rate of blood platelet(p>0.05)in test group compared with control group,there was no significant difference(p>0.05).In the 5 weeks before the experiment,the pH value did not change significantly and remained at about 7.4.From the 6th week,the pH value began to decrease significantly.By the end of the experiment,the pH value dropped to about 6.3.The plants in the drug load were porous structures,and water molecules could enter the spherical interior along the pores.With the extension of time,the water absorption rate did not change significantly,and the water molecules had reached the equilibrium in the material.With the full contact between PBS and the inner plants,the weight loss rate increased,and reached more than 40%at the end of the experiment.Cell suspension injection group a total of 3 during the observation period not only into the tumor,and the rate of tumor growth relatively organization transfer is low,its tumor at a rate of 70%all mice into tumor tissue block transplantation group,tumor growth rate faster,into tumor was 100%,significantly higher than the cell suspension injections into tumor rate(p<0.05)in experimental animals postoperative wound site without infection such as swelling purulent drainage mode is to be built successfully in mice after tumor resection,implant volume in medicine plants,such as the final evaluation and shown effective treatment.Conclusions:The plants in the spherical printing drug carrier had no cytotoxicity in vitro,and had good biocompatibility.The sensitization intensity was weak and there was no subacute toxicity.The PLLA spherical printing drug carrier plants were implanted into the mouse model of osteosarcoma with good blood compatibility.Implantation of PLLA spherical printed drug-loaded internal plant into a mouse model of osteosarcoma,the expression level of tumor markers such as tumor markers in the experimental group was limited.It was finally found that this internal plant research treatment method had a significant inhibitory effect on the treatment of osteosarcoma. |
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