잉크젯 프린팅을 이용한 고분자 미세조형가공 기술과 생체 의학 응용

Abstract

최근 약제학, 조직공학, 치과, 안과 등 다양한 분야에서 PLGA, PLLA, PCL 등과 같은 생체 적합성 합성 고분자를 이용하여 인공 혈관 및 장기, 서방성 제제, 바이오 센서 등의 생체 재료나 디바이스를 제작하기 위한 연구가 매우 활발히 진행되고 있다. 생체 적합성 합성 고분자는 필요 목적에 맞추어 다양한 디자인으로 개발할 수 있어 활용 범위가 넓을 뿐 만 아니라, 천연 고분자보다 비교적 가격이 저렴하고 사용하기 수월하기 때문에 연구 및 의료 행위를 위해 많이 사용되고 있다. 생체 적합성 고분자를 사용할 경우, 생체 적합성은 물론 가멸균성, 적절한 기계적, 물리적 성질 및 성형가공성을 가져야 한다. 그러나 생체 적합성, 가멸균성, 적절한 기계적, 물리적 성질에 대한 많은 연구 개발과 성과에 비하여 합성 고분자의 3차원 성형 가공성에 대한 연구 성과는 아직 시작 단계에 머물고 있다. 이를 해결하기 위한 여러 연구 방법 중, 생체 적합성 합성 고분자와 잉크젯 프린팅 기술의 조합이 새로운 대안으로 많은 관심을 받고 있다. 잉크젯 프린팅은 재료의 변성 없이 고분자, 효소 및 단백질 등을 잉크로 활용하여 복잡하고 세밀한 디자인의 마이크로 패터닝을 할 수 있고 더 나아가 3차원 구조물을 제작할 수 있는 기회를 제공해준다. 본 연구에서는 우선 프린팅 공정에서 사용할 수 있는, 적합한 점도 및 표면 장력 조건을 가진 합성 고분자 잉크와 효소 잉크 등을 개발하였다. 프린팅 전 미리 디자인한 이미지를 정확히 구현하기 위해 잉크의 물성을 조절하는 것은 매우 중요하였다. 개발된 PVA, PCL잉크들과 표면 처리된 기판, 잉크젯 프린터을 이용하여 최적 프린팅 공정을 찾고, 기본 모형과 섬세한 모형의 3차원 고분자 구조물들을 제작했다. 이를 바탕으로 글루코즈 센서와 약물 전달 케리어를 제작하고 각각의 특성 및 효용성을 확인하였다. 글루코즈 센서의 경우, GOD/HRP 효소와 전도성 고분자를 섞은 고분자/효소 잉크를 ITO필름 위에 프린팅 했을 때, 재현성과 민감도가 우수한 글루코즈 센서가 손쉽게 제작될 수 있음을 확인하였다. 전도성 고분자와 두 가지 효소의 결합은 글루코즈를 감지하는 데에 있어 보다 빠르고 정확한 반응을 보여주었다. 3초 이내에 글루코즈가 감지되었으며, 글루코즈 농도에 비례하여 전기화학적 반응의 변화가 감지되었다. 약물 전달 캐리어의 경우, 10% (w/w) PTX가 들어있는 PLGA 잉크를 사용하여 3차원 모형의 링, 원, 벌집 구조, 격자 모형의 약물 전달 캐리어들을 만들었다. 각 모형에 따른 약물 방출 정도를 HPLC를 이용하여 검출하였고 세포 독성 실험 및 PTX 약물 효능 실험을 실시하였다. 잉크젯 프린팅 시스템이 미리 설정된 변수들에 따라 정확하고 지속적으로 실시되었기 때문에, 최종 제작된 약물 전달체는 각 모형 별로 크기와 형태가 매우 일정했다. 넓은 표면적을 가진 순서 (벌집 구조 > 격자, 링 > 원)와 동일하게 약물 방출 속도가 빠름을 확인했다. 복잡하고 섬세한 디자인의 3차원 고분자 구조물을 바이오 센서나 서방성 제제로 제작, 생산하기 위해 잉크젯 프린팅 시스템이 많은 장점과 가능성을 가지고 있다는 결론을 내릴 수 있었다. 앞으로 이 논문에서 제공할 잉크젯 프린팅을 이용한 생물의학적 응용에 대한 정보가, 다른 연구자들을 위한 참고 자료로써 활용되기를 기대한다.|Recently, a great number of studies on artificial vessels or internal organs, sustained release, and biosensors using biocompatible synthetic polymers such as PLGA, PLLA, and PCL have been conducted in many different fields such as pharmaceutics, tissue engineering, dentistry, and ophthalmology. Biocompatibility, sterilization, proper mechanical properties, physical properties, and processability are the essential properties bio-medical polymers must have. A large number of biocompatible synthetic polymers have been used to study medical practices because biocompatible synthetic polymers can be designed with special functions for diverse purposes and can be produced at a relatively lower price than natural polymers. However, results on the processability of structures, especially three-dimensional structures built using polymers are insufficient compared with results of others. The combination of bio-medical polymers and inkjet printing technology is receiving great attention as a new alternative from researchers and companies. Inkjet printer can fabricate arbitrary and complex patterns having micro-size using polymer, enzyme, or protein ink without denaturation. Furthermore, it can build a three-dimensional structure using layer by layer printing. In this study, polymer and enzyme inks with the proper viscosity and surface tension for great printability were developed first. Control of the ink properties is very important to print exactly on the substrate bitmap image. The optimum process was found using printer variables, developed ink, and a special substrate treated with plasma or chemical. A glucose sensor and drug carriers were fabricated by inkjet printing and were examined characteristics and usefulness. In the case of the glucose sensor fabricated by an inkjet printer, it had a fairly high reproducibility and selectivity for glucose detention when GOD/HRP/PEDOT-PSS ink was printed on ITO coated PET film. The use of bi-enzymatic sensing combined with conducting polymers via piezoelectric inkjet printing showed a synergistic effect resulting in significant amplification of the response signal. The glucose sensor reached steady-state current density within 3 s, indicating a fast response time, and exhibited a linear dose-dependent electrochemical response with high sensitivity. And PTX-loaded PLGA micro particles with various geometries were fabricated such as circles, grids, honeycombs, and rings. The resulting micro particles with 10% (w/w) PTX exhibited a fairly homogeneous shape and size. The micro particles exhibited a biphasic release profile with an initial burst due to diffusion and a subsequent, slow second phase due to degradation of PLGA. The release rate was dependent on the geometry, mainly the surface area, with the descending order of honeycomb > grid, ring > circle. The PTX-loaded micro particles showed a comparable activity in inhibiting the growth of HeLa cells. These results demonstrate that a piezoelectric inkjet printing system would provide a new approach for large-scale manufacturing of drug carriers with a desired geometry. Through previously mentioned studies and discussion, I could conclude that an inkjet printing system has a lot of advantages and potential to fabricate biosensors and drug carriers having micro-sized design with an arbitrary and complex shape. I hope that the provided information about inkjet printing and bio-medical applications by this dissertation will be useful for other researchers in the future.; Recently, a great number of studies on artificial vessels or internal organs, sustained release, and biosensors using biocompatible synthetic polymers such as PLGA, PLLA, and PCL have been conducted in many different fields such as pharmaceutics, tissue engineering, dentistry, and ophthalmology. Biocompatibility, sterilization, proper mechanical properties, physical properties, and processability are the essential properties bio-medical polymers must have. A large number of biocompatible synthetic polymers have been used to study medical practices because biocompatible synthetic polymers can be designed with special functions for diverse purposes and can be produced at a relatively lower price than natural polymers. However, results on the processability of structures, especially three-dimensional structures built using polymers are insufficient compared with results of others. The combination of bio-medical polymers and inkjet printing technology is receiving great attention as a new alternative from researchers and companies. Inkjet printer can fabricate arbitrary and complex patterns having micro-size using polymer, enzyme, or protein ink without denaturation. Furthermore, it can build a three-dimensional structure using layer by layer printing. In this study, polymer and enzyme inks with the proper viscosity and surface tension for great printability were developed first. Control of the ink properties is very important to print exactly on the substrate bitmap image. The optimum process was found using printer variables, developed ink, and a special substrate treated with plasma or chemical. A glucose sensor and drug carriers were fabricated by inkjet printing and were examined characteristics and usefulness. In the case of the glucose sensor fabricated by an inkjet printer, it had a fairly high reproducibility and selectivity for glucose detention when GOD/HRP/PEDOT-PSS ink was printed on ITO coated PET film. The use of bi-enzymatic sensing combined with conducting polymers via piezoelectric inkjet printing showed a synergistic effect resulting in significant amplification of the response signal. The glucose sensor reached steady-state current density within 3 s, indicating a fast response time, and exhibited a linear dose-dependent electrochemical response with high sensitivity. And PTX-loaded PLGA micro particles with various geometries were fabricated such as circles, grids, honeycombs, and rings. The resulting micro particles with 10% (w/w) PTX exhibited a fairly homogeneous shape and size. The micro particles exhibited a biphasic release profile with an initial burst due to diffusion and a subsequent, slow second phase due to degradation of PLGA. The release rate was dependent on the geometry, mainly the surface area, with the descending order of honeycomb > grid, ring > circle. The PTX-loaded micro particles showed a comparable activity in inhibiting the growth of HeLa cells. These results demonstrate that a piezoelectric inkjet printing system would provide a new approach for large-scale manufacturing of drug carriers with a desired geometry. Through previously mentioned studies and discussion, I could conclude that an inkjet printing system has a lot of advantages and potential to fabricate biosensors and drug carriers having micro-sized design with an arbitrary and complex shape. I hope that the provided information about inkjet printing and bio-medical applications by this dissertation will be useful for other researchers in the future.