Shieh, Fa-Kuen
Position Professor & Associate Vice President
Name Shieh, Fa-Kuen
Office Tel No. (03) 4227151 ext. 65948
professional field Biochemistry
研究專長 Enzyme Kinetics, Bio-Conjugation, Drug Delivery ,Porous materials

Welcome to visit our biochemistry laboratory
The ultimate goal of our research is to develop a novel porous material platform capable of encapsulating enzymeswith high-performance catalysis ability to respond to harsh environments in current industry applications. We are also exploring strategies for synthesizing nanosize and annulated porous materials, e.g. mesoporous silicas (MS) or zeolitic imidazole frameworks (ZIFs) for more versatile applications such as adsorption, sensor design, catalysis, separated membrane or drug and biomolecule delivery. The synthesis method of ZIFs often employed in our laboratory is the so-called “water-based or environmentally friendly system” technique. The water-based technique is a unique polymerization route that allows adjustment of the (a) morphology, (b) size, and (c) organization of the materials. The as-synthesized materials are investigated by means of X-ray powder diffraction, N2 adsorption/desorption, thermal gravimetric analysis (TGA), scanning electron microscopy (SEM) or transmission electron microscopy (TEM) images, and enzyme catalysis analysis. Currently, our research projects cover two specific areas: (1) encapsulation of biomolecules and drugs into microporous materials of ZIFs and (2) annulation and miniaturization of mesoporous silica materials.
(1)   Encapsulation of biomolecules and drugs into microporous materials of ZIFs
An important aim in this research is to encapsulate biomolecules, e.g. enzymes, DNA, or RNAi, into nanoscale ZIFs by the use of environmentally friendly synthesis and more efficient methods. Furthermore, this novel platform of ZIFs encapsulating biomolecules or drugs can facilitate enzyme catalysis, drug delivery, drug release, etc. In ZIFs, metal ions such as Zn2+ and Co2+ are linked through the N atoms of the deprotonated imidazolate to form neutral frameworks and provide a tunable crystalline structure and porosity and a high internal surface area. Additionally, the M–Im–M angle is similar to that of the Si–O–Si angle (145o) preferred in zeolites. This fact has led to the synthesis of a large number of ZIFs with zeolite-type tetrahedral topologies. Therefore, ZIFs have recently attracted considerable attention for applications in gas storage, separation of small molecules, heterogeneous catalysis, and drug delivery.  However, the use of ZIFs encapsulated with enzymes for catalysis has not been reported yet. By fabricating ZIFs of varying pore sizes, we can control the interactions that take place at the receiving cavity. In general, ZIF-8 and ZIF-90 are employed for in situ encapsulating with enzymes during synthesis of materials by the use of an environmentally friendly system, e.g. water or moderate solvents (Scheme 1). In particular, ZIF-8 is one of the most studied typical ZIF materials. The ZIF-8 framework consists of a Zn source and 2-methylimidazole (Hmim). It has a sodalite (SOD)-type structure and large pores with diameters of 11.6 Å that are accessible through small apertures with diameters of 3.4 Å. In addition to ZIF-8, ZIF-90, with an aldehyde functional group in the 2-position of the imidazole unit, can be transformed into an alcohol group by a one-step synthesis.
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Scheme 1: Water-based synthesis of ZIFs encapsulated with biomolecules and drugs.  
(a) Water-based synthesis of ZIFs    
Recently, we successfully obtained ZIF-90 crystals by the use of a water-based system [Fa-Kuen Shieh,* Shao-Chun Wang, Sin-Yen Leo, and Kevin C.-W. Wu* “Water-Based Synthesis of Zeolitic Imidazolate Framework-90 (ZIF-90) with a Controllable Particle Size,” Chem. Eur. J. 34 (2013) 11139–11142 (selected as back cover)]. This new synthetic route is opening the development of a novel platform for enzyme catalysis due to the use of a moderate solvent for synthesis of ZIFs (Scheme 1). 
(b) Miniaturization of ZIFs
Water-miscible alcohols, e.g. ethanol (C = 2), propan-2-ol (C = 3), and tert-butanol (C = 4) were added into the water-based synthetic system and their effects on the properties of the synthesized ZIF-90 were studied [Chem. Eur. J. 34 (2013) 11139–11142]. Remarkably, we found that the particle size of ZIF-90 further decreased as the number of carbons in the alcohol increased. Thus, the alcohol viscosity of the applied water-based system is proposed to be a vital factor for controlling the particle size of the synthesized ZIF-90. In order to obtain nanoscale particles of ZIFs for bioapplications, the viscosity factor for controlling the particle size of ZIF-90 was examined [see Shao-Chun Wang, Hsiu-Pen Lin, and Fa-Kuen Shieh,* “Studies on Viscosity Effects for the Controlling Particle Size of Zeolite Imidazole Framework-90 (ZIF-90) under Alcohol-Based Synthetic System,” Chem. – Asian J., submitted 11/2013]. However, more detailed investigations of the viscosity effects are currently underway, and we will be focusing on obtaining a range of different particle sizes of nanoscale ZIFs, e.g. UIO-66, ZIF-8, etc., via control of the viscosity in synthetic solutions.          
(C) Synthesis of ZIFs with mixed linkers
Because ZIFs are composed entirely of strong bonds (e.g. C–C, C–H, C–O, and M–O), they show high thermal stability ranging from 250 to 500°C. However, it has still been a challenge to make chemically and hydrothermally stable ZIFs due to their susceptibility to link-displacement reactions when treated with solvents over extended periods of time (days). In order to obtain chemically and hydrothermally stable ZIFs, several techniques have been employed for modifying the surface properties of ZIF materials, thus making them more chemically and hydrothermally tolerant. These techniques include postsynthetic modification (PSM) and postsynthetic exchange (PSE) of the linker and metal center. However, in our research we will study the development of ZIFs with mixed linkers by another method described by Thompson et al. [J. Phys. Chem. C 117 (16) (2013) 8198–8207]. Their method shows that the linker composition of ZIF materials can be controlled in situ (through synthesis) without altering the crystal structure.
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Scheme 2: Synthesis of ZIFs with mixed linkers
(2) Annulation and miniaturization of mesoporous silica materials
Ordered mesoporous silicates (MS) have attracted a great deal of interest in the past decade because of their use in catalysis, separations, sensors, drug delivery, and optical devices. Stucky et al. developed a new type of Santa Barbara amorphous (SBA)-type material to extend the family of highly ordered mesoporous silicates. These silicates have a pore size between 20 and 300 Å and use nonionic block copolymers as structure-directing agents in highly acidic media. SBA-15 was synthesized using a tri-block copolymer, poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide), which is commercially available as Pluronics® P123 (EO20PO70EO20). SBA-15 possesses a large Brunauer–Emmett–Teller (BET) surface area (>700 m2/g) with a large pore diameter and large pore wall thickness. SBA-15 has proven to be very promising for the size-selective separation of large biomolecules because the pore diameters are in the range required for these separations and the silica framework is well suited for the development of bonded, selective sorption phases. Thus, an important aim in this research is to develop new types of mesoporous silica, e.g. annulated or nanoscale SBA-15, MCM-41, and MCF-17, for further biological or environmental applications.
(a)   Annulation of mesoporous silica
Recently, we reported the successful annulation of COOH-functionalized MS materials with different sizes of macrocyclic rings [Fa-Kuen Shiehet al., “Size-adjustable annular ring-functionalized mesoporous silica as effective and selective adsorbents for heavy metal ions,” RSC Adv. 3 (2013) 25686–25689]. In particular, SBA-15 MS with a specific ring size denoted as 3C-CAR-10 was synthesized and showed high adsorption capability and selectivity toward Pb2+ ions due to the “best-fit” cavity from the macrocyclic effect (Scheme 2). The macrocyclic effect, also known as the chelate effect, refers to the amazing stability of macrocyclic ligands. Macrocyclic ligands are cyclic molecules basically consisting of organic frames and heteroatoms that are capable of binding substrates tightly. Many reports have shown that metal ion complexes, e.g. alkaline and transition metals, combined with macrocycles exhibit high thermal stability and remarkable kinetic inertness due to the macrocyclic effect. Furthermore, the structure of the macrocycles and the type of donor atoms influence their selectivities toward different metal ions. Therefore, the development of a ligand with a high adsorption capability and thermal stability as well as good kinetic properties and high selectivities for specific metal ions will be performed by our laboratory in the near future.
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Scheme 3: Illustration of the synthetic sequence of the complexation of heavy metal ions with annulated mesoporous silica

(b)   Miniaturization of mesoporous silica materials
For the purpose of biomedicine applications, especially drug or biomolecule delivery in vivo, porous materials miniaturized into smaller or even nanosize particles offer significantly altered properties and reactivities as compared to the bulk material via increasing textural porosity and external surfaces, removing or diminishing the mass transfer limits. Currently, therefore, the exploration of synthesis strategies in order to obtain downsized or nanosized mesoporous silica materials is our major work in this area of our research. 
Country School Name Department Degree
Taiwan National Chiao Tung University (NCTU) Applied Chemistry B.S.
Taiwan National Chiao Tung University (NCTU) Biological Science and Technology M.S.
U.S.A. University of California at Santa Barbara (UCSB) Chemistry and Biochemistry Ph.D.
Organization Title Department Job Title Duration
2019.07 ~ 2019.09
2018.08 ~ 2020.07
2018.08 ~ Up to today
2017.07 ~ 2017.10
National Central University (NCU) Chemistry Associate Professor 2014.08 ~ 2018.07
National Central University (NCU) Chemistry Assistant Professor 2008.01 ~ 2014.07
University of California at Los Angeles (UCLA) Chemistry Postdoctoral Research Associate 2007.08 ~ 2008.07
University of California at Santa Barbara (UCSB) Chemistry Postdoctoral Research Associate 2007.02 ~ 2007.07
University of Alabama at Birmingham (UAB) Chemistry Doctoral Training in Forensic Science 2001.01 ~ 2002.01
Personal Honor
Honor Category Year Award Name Awarding Unit
Outside School Honor 2021
Inside School Honor 2021 Outstanding paper Award in College of Science in NCU
Inside School Honor 2021 Outstanding paper Award in College of Science in NCU
Inside School Honor 2013 Outstanding paper Award in College of Science in NCU
Inside School Honor 2011 Outstanding Teaching Award in College of Science in NCU
Outside School Honor 1999 Government Funded Student Award, Ministry of Education in Taiwan.
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