| Implantable drug delivery system (IDDS) is a novel drug delivery forms by which the drug liberates directly in disease focus. Three-dimensional printing (3DP) is a solid freeform fabrication technique, which employs powder processing in the construction of parts in a layer-wise manner. It is capable of fabricating parts such as special exterior shapes, complex inner structures and so on. In the present study, the 3DP technology was introduced to fabricate the IDDS. The polymer material, the selection of binder and the process for 3DP were investigated, respectively. And the IDDS have special designed and fabricated by 3DP to furnish the desired drug rlease profiles. The IDDS was also implanted in rabbit for in vivo investigation. The resulted IDDS have been evaluated. The main results are as follows:(1) The polymer material, the selection of binder and the process for 3DP were investigated, respectively. The optical particles size of biodegradable polymer PLAs for 3DP wasΦ150μm～175μm. The binder was solutions with acetone 100ml,ethanal 20ml,water 5ml,glycerol 0.4ml,SLS 0.2g. The general optimal processes are: powder layer height (200μm), binder line spacing (100μm), binder printed speed (1.4g/min), binder flow rate (150cm/s). The results demonstrated that 3DP had superior preparing flexibility.(2) Compared with the IDDS made by conventional process method, 3DP impalnt showed more uniform inner structure. The implant made by conventional compress process appears to have fewer pores while the implant made by 3D printing was more porous and uniform.With gentamicin as a model drug, the implants made by conventional and 3DP process showed the burst release in vitro. However there is some different in which the burst release can be lower concentration from implant by 3DP than that by conventional process, thus will relatively prolong the whole release. The gentamicin gained 68μg/ml at 2nd day, which means that a lot of gentamicin was released at first.(3) Study on the single gentamicin IDDS preparation by 3DP and in vitro release was investigated.①Study of the IDDS with matrix structure reveal that the burst release was much smaller for lower loading implant. The burst release was due to the dissolution or diffusion of drug particles attached or near the surface. The mixture of PCL or HA and PLA affected the drug release easily. The mechanism of release was combination with degradation of PLA and drug diffusion.②The IDDS with sandwich structure loading gentamicin could sharply decrease the initial burst release.(4) Study on the single levofloxacin (LVFX) IDDS preparation by 3DP and in vitro release was investigated.①IDDS with a delay release time showed that more complicated structure implant with LVFX as drug by 3DP was achived to release with a delay time. To gain longer lag time, a thicker shell of the IDDS was needed.②A sort of implant with multi-phase release was developed: the first was with a burst release; the second at constant concentration; the third with a small increscent release before falling. Since the 3D printing technique can give the implant the desired internal macroscopic architecture, the implants could be created with many regions of the same implant.(5) The multi-drug IDDS with different kinds of structure were fabricated by 3DP technology and their in vitro dissolution tests were investigated:①The release characteristics of IDDS with simple structure (marked as IDDS A and IDDS B) illustrated that LVFX could be released easily from IDDS A and B.②The in vitro release characteristics of IDDS with simple structure (marked as C and D) illustrated that two drugs were released from these devices discontinuously. With LVFX and rifampicin (RFP) as model drugs in core structure IDDS, 20 days and 35 days delay time were achieved respectively. The release of core drug had two phases: a lag time delay and then a low speed release period. In a control experiment, the core and mantle were loaded with the opposite type of drug. One was liberated after the other with the delay, which indicated 3D printing having unambiguous advantages over the conventional technology in term of accurate dosage; reproduciblility; easiness and automation of the fabricating process.(6) The activity of the antibiotic from multi-durg IDDS showed the implant had kept strong activity in vitro for more than 40 days. It had great and lasting bacteriostasis to common pathogens of orthopaedic infections, such as staphylococcus aureus, colibacillus.(7) The implantation of IDDS in rabbit revealed that the drug concentration of bone, musucle near the implantation spot and serum in different time. The results showed that two drugs released from the implant successively and the local drug concentration was arrived at the effecitive content in bone and its near muscle for antibiotic action. But the level in serum was low all the time. In the first day the LVFX released with higher level following a little decrease. Four days later RFP began liberation which met the initial design of drug release one after another. The observation activity of the antibiotic suggested that IDDS had kept strong activity in vitro for more than 6 weeks. There was no obvious bone destroying or other parenchyma changes near the bone implantation spot. According to unaided eye, the operation spot seem better palingenetic and the outer thighbone too, which indicated that the IDDS had the good biocompatibility.
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