Introduction of Bio-Manufacturing Engineering
Bio-Manufacturing Engineering is a burgeoning intercross discipline combined manufacturing and life science, beginned in 1998, to build laboratory, set discipline,and open postgraduate course.
Target: bonic products, human vivo tissue and important organs manufacture
Definition: It is a field of science and technology that applying the principle of discrete/deposit, according to data mould of organ anatomy, to induce and manufacture bionic products, pipeline micro-structure, human vivo tissue and organ, importanta viscera using such micro droplets as biomaterial, protein-material, cell-material and molecule elements through controlled assembly.
The Achievements of Bio-Manufacturing
The institute of biomanufacturing engineering of Tsinghua university pertains to both Department of Mechanical Engineering of Tsinghua University and School of Life Science and Medicine of Tsinghua University. It went in for the rapid prototyping manufacturing world and applying computer technology to tissue engineering earilier than other groups in china. Since 1994, it has pursued the technics and equipments for rapid prototyping based on jetting/extrusion deposition process and kept ahead in the world. During the early several years, ProfessorYongnian YAN is the director of the institute, and Professor Renji ZHANG and Doc.XIONG Zhuo are Assosiate Directors.
The team has sensed the bright future of rapid prototyping manufacturing and gave birth to the Center of biomanufacturing engineering, the earlist organization on reseaching and developing rapid prototyping manufacturing, which has ever been the Rapid Prototyping Division of National CIMS Engineering Research center.
In 1994, the team put forward the concept of growing manufacturing,and then brought manufacturing science into the life science and medicine field, searching the concept and structures of Bio-Manufacturing Engineering, providing a way for manufacturing science. Different from Bio-Technologies and Bio-Medical Engineering, Bio-Manufacturing Engineering is a new academic discipline that combines Bio-Eng. and Manufacturing-Eng directly.
In recent years, with the support of national 863 plan “Rapid prototyping manufacturing of tissue engineering material long bone ”(Jan.2000-Dec.2001), many natural science funds such as “laser rapid free forming principle and technology” (1994-1996) “Low-temprature freezing rapid forming technology research” (1999-2001), and Tsinghua University 985 the first stage and Relevant projects of the cross basic research fund, the design of the cell scaffold, geometry modeling, Manufaturing technics and equipments are well prepared. Many TissFor Biomaterial rapid forming machines and pulsatile bio-reactor machines were developed. Based on the theory of discrete piling-up, they transform digital human organism geometric structure to specific bioactive material (Figure 1, 2). The machine ordinarily contain five functional modules:numeric control and route scanning; jetting/extrution; the forming environment; structural support; ventilation and lighting and other affiliated functional models. In order to crank tissue engineering material into designed scaffold needed, extrution and deposition forming, low temperature jetting forming and room temperature forming technologies are developed. Furthermore, relevant equipments with different nozzles and control software are also developed. The project team Tsinghua Laser Rapid Forming Center is possessed of the ability to develop data reconstruction software. For example, according to the characteristic of bone anatomy x light broken course scanning, using the method of figure edge detection, image sampling and boundary detection, according to existent branches of human bones, within which there are blood vessels and abundant tissues, the center has developed femur CT data three dimensional reconstructional software, which is peculiar in pretreatment, image boundary detecting, image sampling, image displaying, osteology gap grade design, etc. The center has made a great breakthrough in exploring and applying biomaterial. The center has got one second prize and one third prize of national advance of science and technology, one blue ribbon of mechanical apartment advance of science and one blue ribbon of Beijing advance of science. The center has come out with around 300 pieces of reseach paper. It also has registered about 20 patents.
Based on fused deposition/spray forming technique, it is successful to make complex shape and porous implantable auricle scaffolds. Through auricle CT data three-dimensional reconstruction and applying self-designed MedForm machine to spray forming auricle prosthesis of biocompatibility, it then plants dermis of patients to accomplish auricle repair and reconstruction. This method is faster, more accurate, actual than manual method of carving and can achieve personal service compared with double die mass production. The program passed appraisal which was organized by the Ministry of Education. Appraisal Committee thought that this program reached international leading level on the aspects of rapid forming of auricle scaffold for microtia and animal experiments. Figure 3 shows material for microtia repairing and figure 4 shows a teeth aligner model.
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| Figure 1 A low-temperature rapid Prototyping mechane |
Figure 2 A large skeletal repair scaffold | |
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| Figure 3 A 3D auricle cartilage structure for Microtia repair |
Figure 4 A teeth aligner model |
Three Dimensional Controlled Cell Assembling System:Under the support of “Preparation of biodegradable three-dimensional liver scaffold and its transformation to liver function” (National natural science foundation 2005.1-2005.12),“Fabrication of liver-tissue analogue with three-dimensional cell-assembly technique and the transformation of its conduit to vascular systems “(National natural science foundation 2006.1－2006.12), Tsinghua University 985 and other related program, the Center of Laser Rapid Forming Tsinghua University developed first and second generation cell assembling machines (Fig. 5). The center also made use of structure and gradient molds to system research on tissue engineering scaffold modeling with structure and material gradient, accumulats rich research experience on bioactive material rapid prototyping and achieves interface technology of scaffold gradient structure mold. It has directly assembled chondrocytes, hepatocytes, cardiomyocytes, adipose derived stem cells and their combination with extracellular matrix into three structural body with straight channels. 90% of he cells assembled were survival in the structures. Hepatocytes, cardiomyocytes and adipocytes could express some physiological functions in the three dimensional structures.
At present, there are more than 5 professors in the institute of biomanufacturing engineering of Tsinghua university. This group has achieved a lot in the preparation of artificial bones, livers, vascular vessels and drug screen systems. More than 20 papers have been published in various journals and 10 patents have been applied. Figure 5 shows the cell assembling machines made by ourselves. Figure 6 shows hepatocytes which were assembled by first generation cell assembling machine. Cells had set up connection and expressed biological function (one patent authorization 200410009787.4, 20 related papers)
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| Figure 5 The cell assembler I and II made by the center of biomanufacturing engineering, Tsinghua University | ||
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| Figure 6 Some pictures and SEM photograghs of hepatic constructs with interconnected channels; (c) A LSCM photograph of assembled hepatic cells in the 3D structure after 8 weeks of culture (PI staining); (e) A LSCM photograph of the hepatic cells in the 3D structue three weeks after in vitro culture(with both PI staining and FITC-conjugation);(d) black control of (c). | ||
Figure 7 shows neonatal rat cardiomyocytes three-dimensional structure which were assembled by second generation cell assembling machine. After two weeks, cardiomyocytes grew well in constructed three-dimensional structure, and macroporous structure supplied channel to provide oxygen and nutritional substance for cardiomyocytes in matrix. It helped long survival of cells in structure and provided effective solution to solve present problem that some cells would die because of lacking of oxygen and nutritional substance when cardiac tissue engineering production exceeded definite thickness.
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| Figure 7 The 3D Structure containg cardiac cells formed by 3D Cell Assembler II | ||
3D structures composed of adipose-derived stem cells (ADSCs), endothelial cells or pancreatic islet β-cells were also established in the Mailand team. Figure 8 shows the phase-constast microscopy photographs of ADSCs structures after several weeks of culture. Some inducing factors were added in the culture medium and endothelial cells were found in the surroundings of the channels. It was found that 3D adipose derived stem cells grew in the 3D structures grew much better than plane cultured state and pancreatic islet β-cells structures with high-glucose cultivation mimicked the status of fatness after excessive surfeit. Especially when culture medium could pass holes, cells spread better and had the potential of differentiation to endothelial cells on the hole surface. Compared with normal plane cultured system, this energy metabolism simulation multiple cells system which was constructed by adipose derived stem cells and islet cells expressed apparent differences, including form, multiplication, differentiation, gene expression, metabolism and other physiological function of adipose derived stem cells in three dimensional culture environment. This system expressed similar feature with in vivo to some stimulating factors such as glucose and insulin.
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| Figure 8 ADSCs in the 3D Structure . (A) Phase-constast microscopy photographs of ADSCs differentiate to endothelial cells in the surroudings of the channels; (B) ADSCs and pancreatic islet β-cells simulate the energy metabolic system; (c) ADSCs behaviour much similar to in vivo states. | ||
