Research On Production Process And Application Of β-TCP/PVA Artificial Corneal Stent

Theβ-TCP/PVA artificial corneal products are a third type of sterile implantable medical device product,which can be used to treat patients with corneal blindness by implanting in the human eye.According to the requirements of relevant medical device regulations,medical devices must ensure that the product quality has continuous and reliable stability and meets the relevant production quality standards stipulated by national laws and regulations before production and application.To ensure the safety and reliability of products,enterprises are required to implement production process verification for the production of medical device products,and meet the medical device production quality management certification（that is,Medical Device Good Manufacturing Practices GMP）.Currently,β-TCP/PVA artificial corneal products have not yet been systematically verified by the production process.In order to complete the verification of the production process ofβ-TCP/PVA artificial corneal products,this subject is guided by the Six Sigma quality management method to systematically develop,manage and control the production process ofβ-TCP/PVA artificial corneal stent products,and at the same time evaluate long-term stability and biocompatibility ofβ-TCP/PVA artificial corneal stents.The research content and results of this topic are as follows:1. The Six Sigma management model was used to analyze theβ-TCP/PVA artificial corneal.The results showed that:1)The CTQ ofβ-TCP/PVA artificial corneal stent were moisture content（≥75%）and mechanical properties（≥0.65MPa）;2)The research variation（%Gage R&R）value of the destructive tension measurement system was 18.65%,and the tolerance（%P/T）value was 22.51%,both of which were within the specified requirements（10%～30%）;3)Significant analysis of variance（P<0.050）was used to determine the key input variables in the production process-heating temperature,heating time,freezing temperature,freezing time,unfreezing time and cycle times 4)Through the full factor test,the optimal process parameters were obtained-heating temperature（95℃±5℃）,heating time（3h±0.25h）,freezing temperature（-30±5℃）,freezing time（5.5±0.5h）,thawing time（75±15 min）,cycle times（13±1times）;5)Used statistical process control technology（Statistical Process Control（SPC））and calculated actual process capability index（Complex Process Capability index（CPK））to conduct a controlled analysis of the production process under the optimal production process parameters,determined the factors that caused abnormal fluctuation during the process,and found the average value of its moisture content and mechanical properties.There was no difference caused by special reasons in the range chart,and the CPK value was greater than 1.2. With reference to the relevant standard of intraocular lens,the physical and chemical properties ofβ-TCP/PVA artificial corneal stent were evaluated to simulate the physiological environment of human eye.The research result showed that:1)Using the key quality characteristics of the artificial corneal stent,the color of the stent and the total number of bacterial colonies to evaluate the actual sterilization effect and product quality of different radiation doses,it was found that 15KGy was the best radiation dose.2)The irradiated and sterilized stent simulated the intraocular environment for a 5-year hydrolysis test at a water temperature of 45°C.After 120 days of hydrolysis test,the moisture content and elongation at break both decreased（moisture content decreased to73%,and the elongation at break dropped to 313.66%）,and the tensile strength increased to 0.9Mpa.Ion chromatography（IC）and Inductively coupled plasma emission spectrometer（ICP-OES）tests showed that there were traces of Ca²⁺and Ca precipitation in the hydrolysate,but the stent performance is still within the controllable range,which could meet the artificial cornea performance requirements;3)After 55 days of accelerated aging and light reaction,the moisture content of the stent was reduced to 60%,the elongation at break was reduced to 281%,and the tensile strength was increased to0.87MPa.IC and ICP-OES tests found that the stent will be slightly affected by ultraviolet light.The Ca²⁺and Ca elements were precipitated,but the stent performance was still within the controllable range,which could meet the performance requirements of artificial cornea.3. According to the requirements of GB/T16886"Biological Evaluation of Medical Devices",four biological tests were carried out on the improvedβ-TCP/PVA artificial stent,including in vitro cytotoxicity test,acute systemic toxicity test,skin sensitization and eye irritation test,and used SPSS and MINITAB statistical software to analyze the difference.The results showed that the cytotoxicity of stent was grade 1 in vitro,with no acute systemic toxicity,no intradermal reaction and no eye irritation.In conclusion,the improvedβ-TCP/PVA artificial corneal stent had excellent biocompatibility and met the requirements of GB/T16886.