Research Status and Prospect of Biological Manufacturing in China

Shuiying LIU，Xinsheng LI，2，3*，Zhiyong YANG，Hao HAN

1.Shaanxi University of Technology，Hanzhong723000，China；2.Key Resources and Biology Lab in Shaanxi Province，Hanzhong723000，China；3.Black Organic Food Project and Technological Research Center in Shaanxi，Hanzhong 723000，China

Biological Manufacturing，as a kind of global strategic emerging industry，appeared in China in 1951 for the first time，and there has been a history ofmore than 60 years so far.Biologicalmanufacturing is a new area where biological subject and manufacturing subject penetrate into each other.Biological manufacturing is based on producing science，life science，material science and information technology，and mainly focuses on biological manufacturing reaction，new biological manufacturing materials，biological manufacturing technology，biological manufacturing system，biological manufacturing technique，biological manufacturing engineering，and biological manufacturing industry，etc.Along with the increasinglymaturing theory and technology of relevant science subjects，the biological manufacturing based on modern biological technology grows rapidly and isbecoming an essential insurance to the sustainable development of global social economy.Every country has paid high attention on biological manufacturing，and the Chinese Department of Science and Technology will support the biological manufacturing by listing it as a part of＂863＂major projects［1］.NIST has taken manufacturing technology as the major development direction of technological innovation plan，and has announced a high risk and high payment competitive program whose subject being Manufacturing and Biomanufacturing：Materials Advances and Critical Processes［2］.NIST listed biological manufacturing as one of the eleven major directions in the Challenge of Manufacturing Technology in 2020［3］.

Along with the increasingly close international cooperation and communication，strengthening comprehensive national strength and international influence，products made in China are exerting an essential role in domestic and global market.Against the background of internationalization，in for maitonization，industrialization and urbanization，biological manufacturing has played a leading role in the economic growth.However，compared with other developed countries，biological manufacturing in China is still in the initial stage，and there are still many problems to be resolved，especially the basic question regarding the location of biological manufacturing.Those problems hinder the development of biological manufacturing in China.For these reasons，problems regarding the study direction，study content，study status and existing problems were summarized so as to provide reference and guidance to the development of biological manufacturing and formation of industrialization.

1 Summarization of biological manufacturing

Biological manufacturing integrates life science，material science，information technology and biological intelligence technology in to manufacturing field based on relevant technologies and theories combining the advanced study achievement，manufacturing technology，tissues and organs［4］.Although biological manufacturing has obtained worldwide attention，people still cannot understand the core of biological manufacturing because specialists in each country have different opinions on the concept，definition，and connotation of biological manufacturing.President Bollinger of＂21stmanufacturing challenge committee＂put forward the concept of biological manufacturing in 1998，and two years later China made relevant analysis on biological manufacturing based on the reality in China.

In the1990s，School of Engineering of Xi'an Jiaotong University put forward the idea of biological manufacturing.Along with incessant development of relevant subject field，improvement of technology，and crossing among subjects，people learn more about biological manufacturing，and now divide the concept into two aspects in both narrow and general ways.The broad definition includes bionic manufacturing，biomass，organism manufacturing，manufacturing science and technology regarding biomass and medicine，expressed as BMo-Bio-manufacturing.The narrow definition would use modern science and life science theories and methods to renovate or replace tissues and organs［5］.After comprehensive consideration，the definition put forward by Professor Yan Yongnian of Tsinghua University was widely acknowledged，and Profes-sor Yan thought that biological manufacturing combines manufacturing science with life science［6］.

1.1 Study directions and contentThe first session of biologicalmanufacturing seminar analyzed biological manufacturing and its study content for the first time［7］.All in all，there are two study directions regarding biological manufacturing namely bionic manufacturing and biological formation，and six study content.Bionic manufacturing includes the bionic of biological organization and structure，and bionic of biological inheritance manufacturing a biological control.Biological formation includes biological restrain and biological formation.In a word，biological manufacturing includes design model，energy technology and materials preparation，etc.

1.1.1 Bionic manufacturing.Bionic manufacturing is an essential branch of emerging manufacturing technology，differing and connecting to biological manufacturing.Bionic manufacturing integrates traditional manufacturing technology with material science，life science，and information science.Biological manufacturing is to use biological methods and bionic manufacturing is to simulate biological mass，and to turn modern manufacturing science into life science and life phenomena［8］.Bionic manufacturing studies living organism and living prosthesis，mainly to imitate the structure of biological system and the working theory after it leaving living bodies，function of biological system，controlling mechanism，energy transformation，information transmission，and biological growth［9］.

（1）Bionic of biological living organization and structure，such as bones，organs， recovery of tissues， adjustment and evolve ment［8］，etc.Based on biological connection and degradable materials，the framework was first produced，and then suitable growing factors were introduced［10-13］.Such technology not only can enhance the compatibility of bionic organization or structure with individual，but also meet the demands of fast formation.A-merican scientists applied biological manufacturing technology to grow an artificial ear on the back of mice，and relevant researchers of the University of Ottawa cultivate the artificial cornea，etc.The biochemistry of biological molecules can be used to make biological chip to store information.Its disadvantage is that such projects are time-consuming and cannot meet the demand of massive production.

（2）Biological inheritance manufacturing.Based on the selfrecovery mechanism of DNA in the animals，trans gene technology is applied to realize biological manufacturing of certain shape.It not only can realize the organic combination of biological materials and non-biological materials，but also can control the growth by dint of artificial controlling inheritance information，such as artificial skeleton，organization，organs and bones，etc［14-16］.

（3）Simulation of biological control means calculating，analyzing and controlling manufacture based on biological control theory to realize simulated biological controlling.Nowadays，studies on the bionic manufacturing are immature.

1.1.2 Biological formation manufacturing.Biological formation manufacturing is anothermajor study direction of biological manufacturing，including bioremoving forming，biolimited forming and biogrowing forming［17］.Biological for mationmanufacturing applied biological methods，such as using bacteria to process materials，and to produce delicate complicated parts.

（1）Biological removing forming means finding strain engineering first to realize bioremoving forming.

（2）Biolimited forming is to replicate some bacteria of diverse structures and put them in order.

（3）Biogrowing forming is to help creatures grow through the expression of genes.

2 Study advancement and application status

Along with the development of technologies and theories regarding bioscience，people gain a better understanding about large molecules such as nucleic acid，protein，polysaccharide and biological membrane.Studies on the planning of genetic group have been successfully carried out，which has informed people the miracle of life.Great achievements have been made in the aspect of cell isolation，organization cultivation，biological synthesis，structural modification and active modification，genetic cutting and regrouping.If the above-mentioned achievements can be applicable to the manufacturing field，human being will enter into a brand new area-biological manufacturing［18］.

At present，biological manufacturing has made significant social and economic benefits in the manufacturing of artificial organs，repairing manufacturing and micro-nano nanometer manufacturing.

2.1 Studies on the manufacturing of artificial internal organs and its applicationThemanufacturing of artificial internal organ is to produce out of human body some functional human organs so as to repair or rebuilt the damaged organs.The earliest artificial internal organs are simple and mechanic，such as ventricular assist device，artificial heart，and other skin based on high molecule materials.This gradually becomes semi-mechanical and semi-biological，such as mixed biological liver，and then developed into modern artificial biological organs based on modern technology［19-20］.China has made great achievements in the manufacturing and application of artificial organs，especially in the department of surgery.Xi'an Jiaotong University used stereo lithography appearance technology to set up a three dimensional designing method based on CT and a manufacturing system based on RP technology.Methods to rebuild bones have been proposed，namely the design system based on reverse engineering and artificial bones anatomy［21］.Professor Vacanti from Harvard Medical School cooperated with Professor Langer from MIT，and applied degradable frameworks on the manufacturing of essential organs，etc［22］.

Compared with the past，people have made significant achievements in the biological manufacturing.However，so far people have not fully mastered highly accurate manufacturing technology and would restrict on certain aspects before biologicalman-ufacturing exerting corresponding values.The manufacturing and development of human organs is a long and step-by-step process from simple to complicate stage.

2.2 Studies and application of orthopedic repairing manufacturingThe manufacturing of biological parts can be realized through operation and ordering［23］，and the biological manufacturing is mainly applied in skull and pelvis of ears.The artificial limb based on metal or non-metal materials are being studied.The reproduction and repairing of individual ear and jaw，reproduction of jaw，bearing of implanted skull，design and manufacturing of other repairing medical parts gradually matured with the development of biologicalmanufacturing.Scientists have developed a way focusing on biological manufacturing.Professor Cao Yilin transplanted the very first artificial ear from mouse，and used macromolecule chemical materials to produce membrane framework for cells to reproduce and the framework would degrade and disappear at last.Then a slice was cut on the back of mouse and the artificial ear would be planted in the cut.Now this technology has been applied in the trial stage.Chinese scientists have for the first time successfully had an operation on a patient whose skull suffered from a damage of 6 cm×6 cm in 2001.

2.3 Application in micro-nanometer structure manufacturingThe biological manufacturing in the micro-nanometer structure manufacturing is often applied in robots，micro-electronic system，and micro-weapon.Technologies on biological sensing，biological intelligence and biodynamics havemade robots more intelligent and humane.Those technologies not only meet the demand of actual production，but also liberate the productivity.It has the potential to reduce production efficiency and production process，and save human resources，which providemore room for the optimization of various kinds of resources.Biological activity can be used to realize the production of micro-nanometer structure.For example，Blum et al.used the pea flower virus as the framework，and decorated gold nanometer-particles on the surface so as to set up a three dimensional electronic molecule network［24］.Professor Belcher et al.used the modified M13 virus as the membrane to synthesize Au，Co3O4nanometer line.This nano line has the potential to be the battery of lithium-ion［25］.Mao et al.used virus as themicromembrane to conduct various modification，so as to assemble the magnetic nanometer line，semi-conducted nanometer line and EBL［26-27］.Thiobacillus ferrooxidans was used to process metal parts［28-29］.Liposome is used to realize the manufacturing of functional chips［30］.S-layer is used to assemble micro-membrane［31］.

In the aspect of nanometer technology，nanometer particles，nanometer functional layer，nanometer tube，nanometer functional materials，nanometer parts and nanometer dynamics，nanometer sensor，and nanometer system were produced through biological technology.When it comes to the production of chemistry and chemical engineering，mechanical chemistry is an essential part of traditional manufacturing industry.The production of mechanical chemical products with special biological pharmacology and chemical activity has always been the difficulty of studies on chemistry in various countries.Biological manufacturing technology is applied to the production of pure chemicals，to meet the pressing demand of each country，and to realize environmental protection and energy-saving.In terms of medical treatment，the technology to cultivate three-dimensional creatures has overcome innumerable difficulties，and part of human organs can be replicated and replaced so as to prolong the life of animals and human beings.

3 Existing problems

As the frontier of advanced technologies of the 21st century，biological manufacturing has made certain achievements in the corresponding aspects，studies on the complicated creatures are not thorough，and corresponding materials are limited.Furthermore，biological manufacturing has a high requirement on processing speed and accuracy，and the cost is high.Therefore，only continuing to develop the basics of material sciences，manufacturing technology and biology can we overcome the bridge of traditional manufacturing science and life science so as to build a brand new biological manufacturing world.

3.1 Studies on the complicated creatures Countless creatures have accumulated many skills in the cooperation and struggling with nature，but human beings have not acknowledged their working mechanisms，such as self-organizing，self-growing，selfreproducing and inheritance.The understanding of those data is a long and arduous process.No countries can master all those data alone.Different nations and different groups across the world unite together and invest muchmoney and resources to do research and to learnmore about biological mechanism and to apply the study result on manufacturing industry，which would not doubt be a big revolution to the manufacturing industry and human beings.

3.2 Types of new materials and the integration with creaturesNew materials are an essential part of new technology and material guarantee of the application and development of new technology.Biological manufacturing process would focus on various biological materials，on the one hand through synthesis and on the other hand through particular biological activity.It not only destroys original property，but also adds new characteristics，and reduces original restraining features.The current study focused on the screening of contemporary biologicalmaterials，and structural modification of surface physical chemistry.The active influences and assimilation can realize bionic materials connection at last.Some of those problems have not been addressed due to various subject or objective reasons.

3.3 Technologies and methods for biological manufacturingBiological manufacturing is expensive.Because of differences among animals and restraining of self-protection mechanism，every biological manufacturing product needs to be produced based on different animals.Therefore，biological manufacturing is a kind of special manufacturing.Every part not only meets individual shape，but also satisfies different requirements.Therefore，biological manufacturing is influenced and restricted by actual require-ment.Because of shortages of relevant subjects，measures and theories，development regarding biological manufacturing is also restricted.

4 Expectations

4.1 Interactions among life science，biological science，materials science and manufacturing sciences，and disappearance of differences in biological manufacturing fieldThe phenomenon that some subjects are too delicate and professional needs to be improved.Along with the further exploration，the synthesis of subjects and comprehension of technology would display great significance.In this complicated system，the boundary between growth and manufacturing is not clear.On the one hand，modern manufacturing technology is applied in life science，which made artificial manufacturing getting easier.On the other hand，biological technology being used in traditional manufacturing industry would push forward the renovation of manufacturing technology，such as using animals to overcome shortages of biological manufacturing.The advancement of life science and biological technology also brought challenges to the manufacturing industry to bring those rotten organs back to life，and to prolong the life of people and animals.All those need effective combination of biological technology and manufacturing technology.

4.2 Creation of more lives based on human willsBiological manufacturing is a complicate process，tending towards personal processing.In the 20th century，human beings can design a new biological genetic group that does not exist in the world based on their own wills and relevant rules.These achievements are own to the growing life science，manufacturing science，relevant subjects and technologies.Although the nature applied a processing method that is totally different from the way human beings produce products，there are striking inherent similarities between biological manufacturing and traditional manufacturing.The difference between biological manufacturing and traditional manufacturing lies in the fact that biological manufacturing deals not only with materials of biological activity，but also includes specific compounds and living cells.

5 Conclusions

Based on the current biological science and technology，and materials science and technology，aswellas manufacturing science and technology，biological manufacturing has broken through traditional subjects，enriched manufacturing sciences and broadened new platform for this emerging subject.Along with the optimization of cells，organizations and organs，the improvement and manufacturing of dry cell technology，and promotion of relevant biological science and technology would result in fast development of relevant industries，such as manufacturing，processing，medicine，biological technology and chemical industry.At last，biological manufacturing produces considerable economic and social benefits.Therefore，China must seize this opportunity to develop biological manufacturing.

［1］Rapid and efficient development of industrial biotechnology［J］.Food and Fermentation Industries，2011，37（4）：158.（in Chinese）.

［2］FENG RH，WAN Y，PAN Y，et al.Challenges and opportunities of advanced materials and critical processes of American manufacturing industry［J］.Advanced Materials Industry，2011，1（5）：50-54.（in Chinese）.

［3］ZHOU ZX，SUN ZY，GUO L，et al.Challenge and prospect of manufacturing industry 2020［M］.National Academies Press，1998.（in Chinese）.

［4］LIN G，XU JM，MA L.Biological manufacturing-perfect combination of manufacturing technology with life sciences［J］.Machinery，2006，44（4）：46-48.（in Chinese）.

［5］YAN YN，LIU HX，LIS J，et al.Development and trend of biomanufacturing［J］.Bulletin of National Natural Science Foundation of China，2007，21（2）：65-68.（in Chinese）.

［6］YAN YG，ZHANGR J，LIN F.Research and application on bio-manfacturing［J］.Escola Superior de Technologia e Gestao de Leiria，2003，1（4）：23-30.

［7］ZHANG RJ，YAN YN，LIN F，et al.An emerging field of science and technology：bio-manufacturing［J］.Electromachining＆ Mould，2003，1（6）：1-5.（in Chinese）.

［8］DONG JT，WANG P.Research contents and development trend of bionic manufacturing［J］.Journal of Machine Design，2002，22（1）：17-18.（in Chinese）.

［9］WU YH，LIDC，LU BH，et al.Research for biological manufacturing engineering based on rapid prototyping［J］.Chinese Journal of Mechanical Engineering，2000，36（9）：61-64.（in Chinese）.

［10］CHENB，ZHAN TZ，LIAN ZY，et al.Magnetization of microorganismcells by sol-gelmethod［J］.Science in China（Series E），2008，51（5）：591-597.

［11］SUN JR，CHENG H，CONG X.Bionic study on the dung beetle Copris ochusMotschulsky for reduction ofsoil adhesion［J］.Acta Biophysica Sinica，2001，17（4）：785-793.（in Chinese）.

［12］SUN JR，GUOC，DAIZD.Structure and bionics of several setae［J］.Acta Biophysica Sinica，2007，23（6）：428-435.（in Chinese）.

［13］FANG Y，SUN G，WANG TQ，et al.Hydrophobicity mechanism of nonsmooth pattern on surface of butterfly wing［J］.Chinese Science Bulletin，2007，52（5）：711-716.

［14］JIANG L，F(xiàn)ENG L.Biomimetic smart nanochannels interface［M］.Beijing：Chemical Industry Press，2007.（in Chinese）.

［15］HAN X，ZHANG DY.Study on the microreplication of shark skin［J］.Science in China（Series E），2008，51（7）：890-896.

［16］HAN X，ZHANGDY.Bio-replicated forming of the biomimetic drag-reducing surfaces in large area based on shark skin［J］.Chinese Science Bulletin（Series E），2008，53（10）：1587-1592.

［17］ZHANG DY，CAIJ，LIX，et al.Bioforming methods of bionic manufacturing［J］.Chinese Journal of Mechanical Engineering，2010，46（5）：88-92.（in Chinese）.

［18］YANYN，XIONGZ，WANGXH，et al.The firstexploration on bio-manufacturing connotation［C］//Collected Papers of 2004 Conference of Chinese Mechanical Engineering Society.Beijing：China Machine Press，2004.（in Chinese）.

［19］LIU YX，WANG J，LU BH，et al.A new customized mandible implant with bionic micro-structure［J］.Chinese Journal of Biomedical Engineering，2004，20（1）：21-24.（in Chinese）.

［20］LIDC，LIUW，KANG LK.The promotion of bone remodeling by customized flexible mandible titanium substitute and its preparation method：CN，ZL200710018365.7［P］.2001.（in Chinese）.

［21］LIU HX，YAN YN，WANG XH，et al.Construct hepatic analog by cellmatrix controlled assembly technology［J］.Chinese Science Bulletin，2006，51（15）：1830-1835.

［22］LANGE RR，VACANTI JP.Tissue engineering［J］.Science，1993，260（5110）：920-926.

［23］ALKAISIMM，MUYS JJ，EVANS JJ.Single cell imaging with AFM using biochip／bioimprint technology［J］.International Journal of Nanotechnology，2009，6（3／4）：355-368.

［24］BLUM AS，SOTOCM，WILSON CD，et al.An engineered virus as a scaffold for three-dimensional self-assembly on the nanoscale［J］.Small，2005，1（7）：702-706.

［25］NAM KT，KIM DW，YOOPJ，et al.Virus-enabled synthesis and assembly of nanowires for lithium ion battery electrodes［J］.Science，2006，312（5775）：885-888.

［26］MAOC，SOLISD J，REISSBD，et al.Virus-based toolkit for the directed synthesis of magnetic and semi conducting nanowires［J］.Science，2004，303（5655）：213-217.

［27］MAO C，F(xiàn)LYNN C E，HAYHURST A，et al.Viral assembly of oriented quantum dot nanowires［J］.Proc Natl Acad Sci USA，2003，100（12）：6946-6951.

［28］UNO YY.Biomachining of metals using bacteria［J］.J Japan Soc Prec Engng，1995，61（10）：1398-1392.

［29］ZHANG DY，LIYQ.Possibility of biological micro machining for metal removal［J］.Science in China（Series C），1998，41（2）：151-156.

［30］LE JC，XU H，ZHANG DY，et al.The study of micro-liquid biosensor chip device for detecting detect influenza viruses［J］.Journal of Public Health and Preventive Medicine，2005，16（4）：8-10.（in Chinese）.

［31］WAYNE S，UWE BS.Synthesis of cadmium sulphide superlattices using self-assembled bacterial S-layers［J］.Nature，1997，38（9）：585-587.

［32］WU JP，YANG LR.Current situation and development trend of bio-manufacturing of chiral chemicals［J］.Chinese Journal of Bioprocess Engineering，2013，11（2）：37-43.（in Chinese）.