Experimental Study Of A Controlled Release Multi-drug Implant's Fabrication By Three Dimensional Printing Technology And Treatment For Choronic Osteomyelitis

Objective:To fabricate a controlled release multi-drug implant with a complicated architecture and disscuse the feature and application of 3D printing technology in the fabrication field of the controlled release drug implant.Methods:Designing an architecture model of the controlled release multi-drug implant and appling the 3D printing technology according to the principle of'pringting each layer, combinding layer by layer'to fabricate the designed controlled release multi-drug implant by assembling the carry material (L-PLA) and activitiy drugs (LVFX and TOB) together in a certain order.Result:The controlled release multi-drug implant fabricated by 3D printing technology was as the same as the designed architecture model of the controlled release multi-drug implant. LVFX and TOB were arranged in a special sequence of LVFX-TOB-LVFX-TOB from the center to the outside. Microstructure of the controlled release multi-drug implant presented porous structure, the diameter of the micro-pore ranged form 50 to 100μm, and the porosity was 61.24±2.39%.Conclusions:The 3D printing techonolgy had a distinct advantage in fabricating a controlled release drug implant with a complicated architecture and multiple drugs. It could load drugs easily and precisely and the procese of fabrication was under compute's controlle with the features of a high automation level and individual preparation. Objective:To evaluate the drug release properties of the controlled relesase mulit-drug implant fabricated by 3D printing technology.Methods:The drug release test in vitro applied the dynamic soak method, which was building a simple drug relase system in vitro, soaking the controlled relesase mulit-drug implants into 10 ml physiological saline, changing the physiological saline and collecting samples on alternate days. The controlled relesase mulit-drug implants were implanted into the femur bones of the New-zealand rabbits by surgerys in drug release test in vivo and the samples of bones, muscles and bloods were collected at day 1,2,4,8, and week 2,3,4,5,6, 7,8 after operations. The LVFX and TOB levels of all collected samples were tested by HPLC.Results:LVFX and TOB were released orderly from the controlled release multi-drug implant as the way they distributed in it and formed 4 drug rlease peaks in the drug release test in vitro and vivo:TOB had a burst release in the early stage of test, and arrived the first drug release peak at 2nd day in vitro and vivo, then arrive the second drug release peak at 20th day in vitro and between 3 and 4 weeks in vivo. LVFX had no release in the first few days, and had been detected at 6th day in vitro and 8th day in vivo; it arrived the first drug release peak at 12th day in vitro and the end of the 2nd week in vivo, and arrived the second drug release peak at 32nd day in vitro and the 5th week in vivo. Both of them had been sustained released in the whole experimental period and had much lower drug levels in blood than in bone and muscle.Conclusion:The controlled relesase mulit-drug implants fabricated by 3D printing technology possessed ideal controlled and sustained drug release properties. LVFX and TOB were relesased orderly from the outside to the center, which indicated that the controlled relesase mulit-drug implants had the potential capability to offer a local multi-drugs therapeutic alliance like a tumor chemotherapy program for the therapies of osteomyelitis, bone tuberculosis and tumors.Objective:To evaluate the biocompatibility of the controlled relesase mulit-drug implant fabricated by 3D printing technology.Methods:According to the State Standard of the People's Republic of China(medical apparatus and instrument biology evaluation, GB/T-16886) and International Organization for Standardization ISO-10993, a series of tests were proceeded to evaluate the the biocompatibility of the controlled relesase mulit-drug implant fabricated by 3D printing technology, including acute systemic toxicity test, pyrogenic test, local irritation reaction, hemolysis test, micronucleus test, muscle embedding test, MTT test and co-culture experiment of MSCs and drug implant to observe the cell morphology, proliferation and adhesion.Results:The controlled relesase mulit-drug implant had no acute systemic toxicity; no pyrogenetic effect; no local erythema and edema in local irritation reaction,0.29%with hemolysis rate; no cellular genetoxic, and no local tissue denaturation, necrosis and exclusion in intramuscular implant test; The cytotoxic level detected in MTT assay was 0, and BMSCs cell shave dramatically reproduced and almost covered the whole wall of drug implant.Conclusion:The controlled release multi-drug implant fabricated by 3D printing technology had an excellent biocompatibility, which conformed to the biomedical material requirements and qualified for implantation for the therapies of osteomyelitis, bone tuberculosis and tumors.Objective:To evaluate the effects of the controlled relesase mulit-drug implant fabricated by 3D printing technology in the treatment of New-zealand rabbit femur choronic osteomyelitis.Methods:The rabbit models of femur choronic osteomyelitis were induced by the injection method of Staphylococcus aureus suspension and 5% morrhuate sodium. After debridement, 5 rabbits in the experimental group were filled with the controlled relesase mulit-drug implant and 5 rabbits in the blank group were just closed the wound without any further therapy. The diet, mobility, wound and general condition of all rabbits were observed after operation. All rabbit's weight measured once each week and X ray tests were performed at week 2,4,8. Finally, all animal were sacrificed for pathology examination.Results:12 of 15 rabbits induced for choronic osteomyelitis model were succeed in builting choronic osteomyelitis model,2 of the residued rabbit died and 1 has no obvious symptom. The induction rate was about 80%. The diet, mobility, wound and general condition of experimental group were improved after operation, the wounds were primary healing and the X-rays tests showed no activity sign of osteomyelitis was observed. The healing rate was 100%. The choronic osteomyelitis of the blank group relapsed,1 rabbit in that group died after operation.Conclusion:It indicated that the the controlled relesase mulit-drug implant fabricated by 3D printing technology had a good therapeutic efficacy in the treatment of choronic osteomyelitis.