Research(研究內容)

Research Interests(研究領域)

  1. Design and fabrication of scaffold materials for tissue engineering of bone & cartilage (Especially we have developed 3D ceramic bio-ink for 3D Printing)
  2. Polymeric micelle micro-, nano-particle system for drug/gene delivery
  3. Other interesting at advanced materials ….
  1. 用於骨、軟骨組織工程的新型支架生物材料的設計與製造
  2. 用於藥物傳遞之微奈米載體系統
  3. 3D積層製造生物陶瓷應用於客製化/個人化醫療骨植入物。
  4. 3D 生物列印之墨水的設計與開發用於軟骨組織工程的再生研究。

Major Research Results(主要研究成果)

  • The National Science Council has developed a micron-sized drug delivery system (PLGA/HAp microsphere) and joined the Kaohsiung Medical University Bone Research Center’s collaborative academic research project, obtaining 2 Republic of China patents and 2 US patents. This drug delivery system can carry oil-soluble drugs. Our team commissioned Taiwan Tungyang Pharmaceutical Co., Ltd. to scale up the GMP-like Simvastin/PLGA/HAp micron composite carrier process, enabling it to locally release simvastatin to promote bone growth. In September 2015, we entered into an industry-academia collaboration project with Hokang Biotechnology Co., Ltd., with a technology transfer fee of NT$6.5 million. In addition, related BMP-2/HAp/PLGA carrier patents were also developed in 2016 with Bosheng Biotechnology Co., Ltd. to evaluate the efficacy of the company’s sustained-release formulation of its bone growth factor product in mice for bone healing. The results showed that in addition to the sustained-release capability and bone growth promotion effect, there was no inflammatory response. The company is currently evaluating the need for technology transfer and subsequent large animal evaluations. There are four related academic papers (1. Optimized bone regeneration based on sustained release from three-dimensional fibrous PLGA/HAp composite scaffolds loaded with BMP-2, Biotech & Bioeng, 99: 996-1006, 2008. 2. Controlled release carrier of BSA made by W/O/W emulsion method containing PLGA and hydroxyapatite, J Control Release, 128: 142-148, 2008. 3. Preparation of porous bioceramics using reverse thermo-responsive hydrogels in combination with rhBMP-2 carriers: In Vitro and In Vivo evaluation, J Mechanl Behav Biomed Mater, 27:64-76, 2013. 4. Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair, Internat J Nanomed, 8:3895-3905, (2013) My personal experience participating in academic research at the Kaohsiung Medical University Bone Research Center includes: conducting three phases of academic research (currently running for 11 years), establishing mechanisms for industry-academia collaboration, intellectual property applications, and technology transfer, pooling resources, and achieving the goal of translational medicine. In 2015, one technology transfer was completed to Ho-Kang Biotechnology Co., Ltd. (a non-exclusive technology transfer fee of NT$6 million, with my contribution at 25%).
  • The project leader’s integrated development project on laminated ceramic technology under the Ministry of Science and Technology. The results of 2016-2017 have demonstrated the potential for clinical application in commercialization. This technology is also being developed in collaboration with the National Applied Research Laboratories’ Instrumentation Technology Center to develop a dedicated 3D bioprinting machine for clinical application testing and validation in 2018-2019. In the first quarter of 2019, there are already collaborating companies discussing industry-academia collaboration to develop bone material products, with the expectation of technology transfer to domestic medical device companies or matchmaking with venture capital firms for startups. Ultimately, it is hoped that this technology will benefit the health of patients. (Related industry-academia collaboration projects include: 1. Development of bone contact areas for cartilage plugs using negative temperature-sensitive hydrogel-assisted 3D printing bioceramic technology, Kaohsiung Medical University – Bosheng Biomedical Co., Ltd. Industry-academia collaboration project. 2. Physicochemical analysis project of gradient color all-ceramic materials, Kaohsiung Medical University – Palmwood Co., Ltd. Industry-academia collaboration project, 2016/06/16 to 2017/01/30 (S-S104021 450,000 NT). (Principal Investigator) 3. Efficacy evaluation of sustained-release bone growth factor carriers, Kaohsiung Medical University – Bosheng Biomedical Co., Ltd. Industry-academia collaboration project, 2016/09/01 to 2017/04/30 (1,200,000 NT). (Co-Principal Investigator)
  • The project leader, Yu Guoke, developed a negative temperature-sensitive hydrogel system and created a new process for “applying negative temperature-sensitive hydrogel to prepare porous bioceramic scaffolds.” This resulted in patents from the Republic of China and the United States (Republic of China Patent No.: I411595 and US Patent No.: US 8940203 B2). A paper was published in the international journal *J Mech Behav Biomed Mater*, 27:64-76, 2013. Furthermore, utilizing the uniform pressure shrinkage properties of this negative temperature-sensitive hydrogel, a molding technology for three-dimensional lamination ceramic extrusion printing was developed by mixing it with ceramic powder. Since 2017, this technology has successively obtained patents in Taiwan (application number 105139918) and major patents in various countries worldwide (USA, China, Europe, Japan). This technology has also been published in the international journal *Ceramics International*, 47, 5464-5476. (2021); In 2016, the team received the 13th National Innovation Award and the Academic Innovation Award (Innovative Ceramic Lamination Manufacturing Technology, National Biotechnology and Medical Industry Promotion Association, 105/12/22); in 2018, the team received the Ministry of Science and Technology-Taiwan Innovative Technology Expo-Innovation Invention Award and second place in the Entrepreneurship Group of the 7th Campus Entrepreneurship Competition of Kaohsiung Medical University. In 2019, the team further developed the process technology for photocuring negative temperature-sensitive water-based ceramic slurry, obtaining more precise and complex ceramic structural components, and obtaining a Republic of China patent and applying for a PCT patent. This photocuring technology is also part of an industry-academia collaboration project with the listed company Bosheng Biomedical (totaling NT$2.8 million), with further cooperation pending. Timing. The related photopolymerization technology also won the 16th National Innovation Award for Academic and Research Innovation Excellence in 2019 and the 17th National Innovation Award in 2020. The team also won the Outstanding Entrepreneurship Award in the 2020 FITI Competition (109-2nd cohort) held by the Ministry of Science and Technology, and established Pinyi Medical Technology Startup Company in May 2021. Subsequently, in November 2021 and November 2022, they received funding from the National Science Council’s Industry Foresight – Applied Research Seedling Project for “Laminated Manufacturing of 3D Bioceramic Skull Drilling Cap Bone Graft Substitutes”. (I)(II)”. This technology should first be clinically validated using standardized, specialized 3D bone graft substitutes (such as drilled skull cap bone or wedge-shaped bone with a special angle in the high tibia) before it can be strategically deployed in the future blue ocean business model of customized and precise 3D bone graft medical devices and the development of emerging medical industries. Kaohsiung Medical University completed a technology licensing agreement worth 20 million NTD to Pinyi Medical Technology Startup Company on September 23, 2023, and completed its first angel round of fundraising of 20 million NTD on May 10, 2024, to facilitate subsequent commercialization.
  • Regarding the application of bio-hydraulic gel in the fields of 3D bioprinting and tissue regeneration, three related SCI papers have been published (J. Biol. Eng. ,17,74, 2023, Polymers, 14, 2003, 2022, Mater. Sci. Eng.: C, 124, 112072, (2021) The research project developed a three-dimensional biomimetic hybrid hydrogel mainly composed of hyaluronic acid methacryloyl and gelatin methacryloyl copolymers. Innovatively, it utilized inorganic crosslinking agents (acrylate functionalized nano-silica, acrylate functionalized reduction graphene oxide) and PEGDA to enhance the mechanical properties of the hybrid hydrogel and slow down its degradation rate in organisms. This novel hybrid hydrogel system is expected to enhance cartilage differentiation and repair cartilage tissue. A patent layout for this hybrid bio-hydrogel system in cartilage regeneration was obtained (Republic of China Patent No.: 798084). Currently, the project leader is continuing to study the stability characteristics of photocurable bio-hydrogel systems in in vitro culture of stem cell phenotypes and their regulation of exosomes, as well as their application in the regeneration of soft and hard tissues.
  • 國科會發展出微米藥物載體系統(PLGA/HAp microsphere)加入高醫骨研中心的合作的學界 科專計劃，已獲得 2 件中華民國專利與 2 件美國專利：此藥物載體可攜帶油溶性藥物，本團隊委託台灣東洋藥廠進行 GMP-like 之 Simvastin/PLGA/HAp 微米複合載體製程放大開 發，使其具有局部緩釋寸進骨生長 simvastatin 的用途，並於 104 年 9 月與和康生技股份有 限公司進行產學合作計畫與全程技轉金 650 萬。此外相關 BMP-2/HAp/PLGA載體專利，也於105年與博晟生技公司進行產學合作計畫，評估公司促進骨生長OIF growth factor產品的緩釋製劑於小鼠的骨癒合療效，結果除了具有緩釋的能力與促進骨生長效果外且無發炎反應，公司正在評估技轉需求與後續的衍伸大動物評估。相關學術論文有四篇( Optimized bone regeneration based on sustained release from three-dimensional fibrous PLGA/HAp composite scaffolds loaded with BMP-2, Biotech & Bioeng, 99: 996-1006, 2008. 2. Controlled release carrier of BSA made by W/O/W emulsion method containing PLGA and hydroxyapatite, J Control Release, 128: 142-148, 2008. 3. Preparation of porous bioceramics using reverse thermo-responsive hydrogels in combination with rhBMP–2 carriers: In Vitro and In Vivo evaluation, J Mechanl Behav Biomed Mater, 27:64-76, 2013. 4. Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair, Internat J Nanomed, 8:3895-3905, 2013.) 個人參與高醫骨研中心在學界科專研究經驗中：進行了三期學界科專研究(至目前已執行共11 年)，建立了產學合作、智財申請、技術轉移等研發產品的機制，匯集了能量以及落實了轉譯醫學的目標。104年已完成1 件技術移轉給和康生技公司(全期非專屬授權技轉金600萬，本人貢獻度25%)。
  • 主持人於科技部積層製造陶瓷技術開發的整合型計畫成果，105-106兩年的成果已證明技術商品化的臨床應用潛力，本技術也與國研院儀科中心合作，開發專屬的3D生物列印機台，以利107-108年進行臨床應用的使用的測試與驗證。108第一季目前已有合作廠商洽談產學合作開發公司的骨材產品，預期可技轉給國內醫材公司或與創投進行新創公司的媒合。最終期望此一技術可造福傷患的健康。(相關產學計畫有1:負溫感水膠輔助3D列印生物陶瓷技術開發軟骨栓的骨接觸區域, 高雄醫學大學－博晟生醫股份有限公司 產學合作計畫。 漸層色系之全瓷材料物化性分析計畫, 高雄醫學大學－棕懋公司產學合作計畫, 2016/06/16至2017/01/30 (S-S104021 450,000 NT)。(主持人) 3. 緩釋型骨生長因子載體之確效評估, 高雄醫學大學－博晟生醫產學合作計畫, 2016/09/01至2017/04/30 (1,200,000 NT)。(共同主持人)
  • 主持人於國科會計畫發展出負溫感水膠系統研製出以”負溫感水膠應用在製備多孔性生物陶瓷支架”的新製程。獲得中華民國專利與美國專利(中華民國專利號：I411595 與美國專利號：US 8940203 B2)。102 年發表一篇國際期刊: J Mech Behav Biomed Mater, 27:64-76, 2013。此外，也運用發展此負溫感水膠均壓收縮的特性，混合陶瓷粉末進行三維積層陶瓷擠出列印的成型技術開發，並於2017年起陸續獲得台灣專利(申請號105139918)與全球重要各國專利(美國、中國、歐洲、日本)。本技術除發表一篇積層製造3D陶瓷的國際期刊(Ceramics International, 47, 5464-5476, 2021)；2016年獲得第十三屆國家新創獎、學研新創獎(創新陶瓷積層製造技術, 社團法人國家生技醫療產業策進會, 105/12/22)、2018年獲得科技部-台灣創新技術博覽會-創新發明獎與高雄醫學大學第七屆校園創業競賽創業組第二名。2019年團隊更進一步開發光固化負溫感水膠陶瓷漿體的製程技術，獲得更精密與複雜的陶瓷結構元件，並取得中華民國專利與申請PCT專利。此光固化技術也與上櫃公司博晟生醫進行產學合作計畫(共計達280萬)，待後續合作時機。相關光固化技術亦獲得2019年第十六、2020年第十七屆國家新創獎之學研新創精進獎。團隊並於2020年榮獲科技部109-2期FITI競賽榮獲創業傑出獎，並於2021年5月成立品醫生技新創公司。接著分在2021年11月與2022年11月獲得國科會產業前瞻-應用型研究育苗專案計畫之「積層製造3D生物陶瓷顱骨鑽孔蓋骨移植替代物 (I)(II)」。此技術宜先以標準化特殊3D骨移植替代物在臨床獲得驗證(如 頭蓋骨鑽孔蓋骨材或高位脛骨特殊角度楔形骨材)，方可在未來客製化與精準化3D骨移植醫材的藍海商業模式之進行策略性布局及新興醫療產業發展。高醫大於2023年9月23日完成2000萬技術作價授權於品醫生技新創公司、113年5月10日完成第一次天使倫募資2,000萬元，以利後續商品化。
  • 有關生物水膠應用在3D生物列印與組織再生的領域，相關SCI paper已發表3篇( Biol. Eng. ,17,74, 2023, Polymers, 14, 2003, 2022, Mater. Sci. Eng.: C, 124, 112072, 2021)，其中研製三維仿生混合水凝膠主要由hyaluronic acid methacryloyl與gelatin methacryloyl共聚組成，並創新穎運用無機交聯劑(acrylate functionalized nano-silica、acrylate functionalized reduction graphene oxide)與PEGDA等增強混合水凝膠的機械性能並減緩生物體的降解速度，使這種新型的混合水凝膠系統有望增強軟骨分化和修復軟骨組織。並獲得此混合生物水膠系統在軟骨生成的專利佈局(中華民國專利號：798084)。目前主持人持續研究光固化生物水凝膠系統對於幹細胞phenotype體外培養的穩定性特性與其外泌體的調控分析，並於軟硬組織再生的研究。