Cao Hui: Strengthen Collaborative Cooperation to Promote Innovation in Traditional Chinese Medicine

Traditional Chinese medicine is an important part of the outstanding historical culture and modern civilization of the Chinese nation, and it is the material basis of our country's traditional Chinese medicine system for disease prevention and treatment. After thousands of years of clinical practice, its unique effects in disease prevention and treatment, along with its relatively low toxicity and side effects, have gained recognition from the global medical community. The research and development of the traditional Chinese medicine industry is gradually becoming an international hotspot. The engineering technology and standardization research for modern traditional Chinese medicine quality control, as one of the key technologies for the modernization and internationalization of traditional Chinese medicine, focuses on demonstrative research of quality evaluation technologies for representative traditional Chinese medicine raw materials, intermediates, and finished products, making it a hot topic of research both domestically and internationally.

Professor Cao Hui graduated from Jiangxi University of Traditional Chinese Medicine in 1983 (Bachelor of Science degree), is a professor and doctoral supervisor, obtained a Master's degree in Medicine from the China Academy of Chinese Medical Sciences in 1988, and a PhD in Philosophy from the Chinese University of Hong Kong in 1995. He has long been engaged in research work in traditional Chinese medicine, with main research directions including herbal literature and traditional Chinese medicine identification, processing of medicinal slices, resource quality evaluation, traditional Chinese medicine engineering technology, and product development. He has worked at various institutions including the Jiangxi Jingdezhen Drug Inspection Institute, the Institute of Chinese Medical Sciences of the China Academy of Chinese Medical Sciences, the Tsukuba Research Institute in Japan, and the Chinese University of Hong Kong. He is currently the director of the Lingnan Traditional Chinese Medicine Research Center at Jinan University, the director of the National Engineering Technology Research Center for the Modernization of Traditional Chinese Medicine, and holds concurrent positions as a visiting researcher at the Institute of Chinese Medical Sciences of the China Academy of Chinese Medical Sciences, a member of the National Pharmacopoeia Committee, a member of the National Science and Technology Award Review Committee, a member of the National Licensed Pharmacist Expert Committee, vice-chairman of the Special Committee on Planting and Breeding of Medicinal Materials of the Chinese Medicine Association, deputy secretary-general of the Chinese Medicine Processing Branch of the Chinese Association of Traditional Chinese Medicine, and an editorial board member of the journal "Modern Chinese Medicine".

In terms of discipline construction, talent cultivation, research theories and methods, Professor Cao Hui has made significant contributions. He has successively presided over and completed more than 80 national and provincial-level projects, including the National Science and Technology Key Project (Support) Plan, the 863 Program, and the Guangdong-Hong Kong Bidding. He has received more than 20 provincial and ministerial awards, including the First Prize for Scientific and Technological Progress in Guangdong Province. He has published 16 academic works, including "Molecular Identification of Traditional Chinese Medicine," and more than 180 professional papers. He has obtained 16 international and Chinese authorized invention patents, formulated more than 10 national standards and 3 industry standards, developed 12 new traditional Chinese medicine products and health foods, trained more than 10 graduate students, and established 9 sub-centers, 2 research institutes, 5 pilot production bases, 5 joint laboratories, and 2 teaching practice bases. He has received numerous honors, including being a senior expert directly managed by the Central Organization Department (national-level expert), the first National Traditional Chinese Medicine Inheritance Award, the 2015 Person of the Year in Science China, the Advanced Individual in the 10th Anniversary of the Construction of the Modernization of Traditional Chinese Medicine Science and Technology Industrial Base by the Ministry of Science and Technology, the Excellent Engineering Center Director in Guangdong Province, and the 2016 China Industry-University-Research Cooperation Innovation Award.

Since 2001, Professor Cao Hui has been responsible for the operation of the National Engineering Technology Research Center for the Modernization of Traditional Chinese Medicine, a national-level platform, and the Lingnan Traditional Chinese Medicine Research Center at Jinan University, a provincial-level platform. This industry-university-research innovation platform relies on the Lizhu Pharmaceutical Group and Guangzhou University of Traditional Chinese Medicine, as well as Jinan University, focusing on tackling common key technologies in the upgrading of the traditional Chinese medicine industry. It fully utilizes the interaction of industry-university-research elements, closely collaborates with relevant universities and enterprises in Guangdong, Hong Kong, and Macao, and has initially achieved the parallel development of five major functions: talent cultivation and introduction, technology achievement transformation, project incubation, product research and development, and technical services, providing references, demonstrations, and technological support for the modernization and innovation of traditional Chinese medicine. Since January 2002, it has successively obtained project funding of 150 million yuan from national, provincial, and municipal levels. The platform has an incubation base with a laboratory and pilot workshop of 4,000 square meters, and the main instruments and equipment exceed 100 sets, valued at over 20 million yuan. It has transformed more than 10 scientific and technological achievements and collaborated with over 30 enterprises; the total sales revenue of the enterprises incubated and transferred by the platform exceeds 10 billion yuan, with a new output value of 6.885 billion yuan and new tax revenue of 1.839 billion yuan in the past five years.

Market-oriented, exploring a new model of traditional Chinese medicine research and development that emphasizes resource sharing, complementary advantages, and multi-party win-win.

The National Engineering Technology Research Center for the Modernization of Traditional Chinese Medicine (hereinafter referred to as the Center) is one of the four major backbone research centers in the traditional Chinese medicine industry established with the approval of the Ministry of Science and Technology of the People's Republic of China, aimed at promoting the national "Action Plan for the Modernization of Traditional Chinese Medicine Science and Technology Industry." It was jointly funded and established in 1997 by the Ministry of Science and Technology, Lizhu Pharmaceutical Group, and Jinan University, and was officially established in 2001, under the supervision of the National Administration of Traditional Chinese Medicine and the Guangdong Provincial Department of Science and Technology. The supporting units, Lizhu Group and Jinan University, have excellent soft and hard conditions in the field of traditional Chinese medicine and research. The center is market-oriented, building a bridge between industry and research, achieving technology diffusion and transfer, and promoting the transformation of research achievements into real productive forces. At the same time, it provides technical services and technology transformation for enterprises through common key engineering technologies in traditional Chinese medicine production, solving technical problems in the transformation of scientific and technological achievements in terms of processes, equipment, standards, and product quality, with significant results in achievement transformation.

Since 2003, Professor Cao Hui has led the traditional Chinese medicine research team at the center to strengthen industry-university-research cooperation with several institutions, including Sun Yat-sen University, Jinan University, Hong Kong Baptist University, China Pharmaceutical University, Shenyang Pharmaceutical University, Chinese University of Hong Kong, Peking University, and the China Academy of Chinese Medical Sciences. They have focused on key links and major common issues such as safety and effectiveness, and quality control, conducting joint research on the entire production process of traditional Chinese medicine injections, achieving significant breakthroughs in the upgrading and transformation of traditional Chinese medicine injection products.

(1) For the first time, the internationally advanced UFLC-Q-TOF-MS/MS technology was used to conduct online separation, identification, and other chemical and metabolic studies of all components of the traditional Chinese medicine intravenous infusion—Ginseng and Astragalus Injection, clarifying its chemical substance basis and pharmacokinetic parameters. The structures of 93 compounds, including carbohydrates, peptides, amino acids, flavonoids, alkaloids, and saponins, were confirmed, with accurate molecular weights for 47 compounds and fingerprint profiles for 11 compounds. The measurable components accounted for more than 60% of the total solids, while the clearly defined components accounted for over 80% of the total solids, and the identification of components in the fingerprint profiles accounted for over 90%. Four pharmacokinetic concentration-time curves for key components were established, obtaining the pharmacokinetic characteristics of Ginseng and Astragalus Injection and the non-compartmental pharmacokinetic parameters of the four key components. Through cell and animal model metabolomics studies, the effects of Ginseng and Astragalus on phospholipid metabolism, glucose metabolism, purine/pyrimidine metabolism, and amino acid metabolism in tumor cells were preliminarily elucidated, systematically studying the roles of the sugar and non-sugar parts in related metabolism.

(2) The first construction of the HPLC, 1H-NMR, IR, and LC-MS fingerprint profiles of the Ginseng and Astragalus Injection, along with pharmacodynamic studies, clarifying its pharmacological basis, and establishing quality control standards based on spectral efficacy combination, directly linking product quality control with efficacy, ensuring the effectiveness, safety, and uniformity of the product. This has made a breakthrough contribution to improving the quality control level of traditional Chinese medicine injections. A standard library and barcode fingerprint library of gene sequences such as 26SrRNA, ITS, 5SrRNA intergenic regions, and atpB of Gansu Longxi County Ginseng and Shanxi Hunyuan Astragalus were constructed; the correlation of HPLC, NMR, IR fingerprint profiles of raw materials/intermediates/injections during the production process was analyzed, and through the correlation analysis of "origin information-IR spectrum-HPLC characteristic components," a multi-component fingerprint profile of finished products-intermediates-raw materials was established, identifying and semi-quantitatively controlling the fingerprint peaks of the main components (alcohol glycosides, flavonoids, saponins) in the fingerprint profile. A new quality control model combining fingerprint profiles with pharmacodynamics throughout the production process was developed to improve product quality standards. Without isolating and purifying each chemical substance from the extraction site, the contribution of each chemical substance to biological activity was examined as a whole. Differences between sample fingerprint profiles and pharmacodynamics were studied using computer-assisted methods to interpret the contribution of each chemical substance in the mixture to pharmacodynamics, clarifying bioactive components, and establishing a new quality control model of "fingerprint pharmacodynamics" for traditional Chinese medicine, providing research methods and technical platforms for the quality control of other traditional Chinese medicines.

(3) Comprehensive optimization of the production process of traditional Chinese medicine injections such as Ginseng and Astragalus Injection and Xuehuo Tong Injection, improvement of packaging, monitoring of harmful substances in the production process, and key technology research for macromolecule removal have improved product quality standards. GAP standard planting, ultrafiltration, and membrane separation technology were used to optimize and improve the production process of traditional Chinese medicine injections, controlling harmful macromolecules (allergens, pyrogens, hypotensive substances, etc.) and small molecules (organic chlorines such as BBC, DDT, PCNB; organic phosphates such as carbofuran, parathion; pesticides such as chlorpyrifos, heavy metals such as Cu, Cd, Pb, Hg, As; plant hormones such as indole acetic acid, gibberellins, cytokinins; sulfur dioxide SO2, aflatoxins B1-2, G1-2, 5-hydroxymethylfurfural 5-HT, antioxidants, ethanol residue, etc.) that are highly correlated with adverse reactions.

(4) The first systematic evaluation of the 3R (safety, efficacy, economy) of Ginseng and Astragalus Injection after its market launch and research on the cultivation of major varieties was conducted. A safety re-evaluation study based on EBM (evidence-based medicine) and RWS (real-world study) with a clinical sample size of 30,000 showed that the cumulative incidence of ADR (adverse reactions) was only 1.7‰, classified as "occasional," with no severe ADRs, which is currently the lowest among traditional Chinese medicine injections. Using RCT (randomized controlled trial) technology, a clinical efficacy study of 588 cases of Ginseng and Astragalus Injection was completed nationwide, proving its definite efficacy in improving symptoms and quality of life in chemotherapy patients with non-small cell lung cancer and gastric cancer (lung-spleen qi deficiency syndrome), with better auxiliary treatment efficacy than the control drug and placebo, indicating a broad clinical application prospect. Using epidemiological prospective multicenter observational cohort study technology, results showed that compared to patients not using Ginseng and Astragalus Injection during chemotherapy for non-small cell lung cancer, patients using it had effective improvements in all five dimensions of the FACT-L quality of life scale, and the cost-effectiveness ratio for the group using Ginseng and Astragalus Injection was lower than that of patients not using it. From the perspective of reducing the severity of chemotherapy side effects and improving the quality of life during chemotherapy, Ginseng and Astragalus Injection has certain cost-effectiveness advantages and can bring incremental effects, making its application in lung cancer chemotherapy a more economical and clinically significant choice.

(5) Secondary development research of traditional Chinese medicine injections, using active screening and chemical knockout technology for the secondary development study of Xuehuo Tong Injection, developed a compound effective component preparation "Three Flower Lyophilized Powder Injection" (Panax notoginseng saponins and ligustrazine), obtained clinical approval, and completed Phase I clinical trials and clinical pharmacokinetic studies. Using LC-MS-MS technology, a method for determining the blood concentration of Panax notoginseng saponins (Panax notoginseng saponin R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd) and ligustrazine in plasma was established, along with pharmacokinetic parameters for single administration of the Three Flower Powder Injection, Xuehuo Tong Injection, and ligustrazine powder injection.

This project has obtained 9 authorized invention patents, including 6 Chinese invention patents and 3 international invention patents. From 2010 to 2015, the cumulative terminal sales of products developed through this project reached over 8 billion yuan, with tax revenue exceeding 1 billion yuan, achieving significant economic benefits. The implementation of this project further improved the quality, safety, efficacy, and economy of traditional Chinese medicine injections, ensuring the safety, effectiveness, and economy of medication for the public, enhancing product market competitiveness, improving corporate economic benefits, and generating significant social benefits, which is of great significance for promoting the healthy development of the traditional Chinese medicine injection industry and maintaining social stability. 

At the same time, the traditional Chinese medicine research team led by Professor Cao Hui, based on the geographical relationship of Zhuhai and Hong Kong-Macao, as well as the Pan-Pearl River Delta, has actively undertaken more than 80 national and provincial science and technology projects, receiving funding of over 120 million yuan; more than 50 projects for new drug development, health food, engineering technology research and development, and technical improvement in industry-university-research cooperation, obtaining over 130 authorized patents, formulating more than 10 national standards and 3 industry standards, receiving over 20 provincial and municipal government science and technology awards, publishing more than 60 papers, and publishing over 10 monographs. 

Strengthen the in-depth development of enterprise cooperation projects, promote the transfer and transformation of traditional Chinese medicine technology and achievements.

In terms of in-depth development of enterprise cooperation projects, Professor Cao Hui collaborated with the supporting unit, Lizhu Group, to conduct secondary development of the traditional Chinese medicine major varieties Ginseng and Astragalus Injection and antiviral granules, ensuring product quality and significantly improving corporate benefits.

The "Antiviral Granules" produced by Livzon Pharmaceutical Group is a major brand of traditional Chinese medicine composed of 9 herbal ingredients for the treatment and prevention of viral influenza. In 2006, as the global avian influenza epidemic continued to spread, and in 2008 with the outbreak of the novel H1N1 influenza (swine flu) and hand-foot-mouth disease, Professor Cao Hui actively collaborated with the National Emerging Infectious Diseases Laboratory (P3 Laboratory) at the University of Hong Kong under the funding of the Zhuhai Science and Technology Program (PB20063021) to research viruses such as H5N1 and H1N1 influenza and EV71. Using in vivo and in vitro research techniques, a platform for antiviral technology was established. Experiments confirmed that Livzon's antiviral granules have good in vivo and in vitro inhibitory effects on H5N1, H1N1, and EV71 viruses, outperforming the experimental control drug Tamiflu. Consequently, Professor Cao Hui led the in-depth development of this product, such as increasing new specifications, improving quality standards, expanding indications for influenza, and applying process improvements, applying for 11 domestic and international invention patents (10 granted), among which the Chinese invention patent "Traditional Chinese Medicine Composition for Treating Avian Influenza, Preparation Method and Its Applications (ZL 200610001538.X)" won the first Zhuhai Patent Gold Award in 2009, the Guangdong Patent Gold Award in 2010, and the 13th China Patent Excellence Award in 2011, achieving a leading level in the country. The success of experiments against H5N1 and H1N1 influenza viruses has created significant economic and social benefits for the company, with a total output value exceeding 3 billion yuan from 2006 to 2015. 

In addition, in the research and dissemination of engineering technology achievements and in serving the industry, Professor Cao Hui has done a lot of work in the transformation of production, education, and research, which has had a positive impact on industry development.

(1) Research and promotion of ultrasonic extraction technology: Since extraction has always been a challenging issue for enterprises, Professor Cao Hui, after integrating domestic research data and extensive experimental exploration, considered factors such as ultrasonic power, frequency, extraction rate of effective components from traditional Chinese medicine, and energy saving. Under the funding of the key project of the National Administration of Traditional Chinese Medicine Research Fund "Research on Ultrasonic Enhanced Extraction Device for Traditional Chinese Medicine" (97Z044) and the key scientific and technological project of Zhuhai City "Research on Ultrasonic Enhanced Extraction Device for Traditional Chinese Medicine" (2001-1-25), in collaboration with the Guangzhou Institute of Chemistry, Chinese Academy of Sciences, and Guangzhou New Power Ultrasonic Technology Company, a new type of 350-liter ultrasonic enhanced extraction device was jointly designed and developed, which has been granted a national utility model patent. The application of ultrasonic technology in traditional Chinese medicine extraction not only significantly increases the extraction rate of effective components but also saves energy and greatly shortens extraction time, especially protecting the structure of effective components in heat-sensitive medicinal materials. This technology has provided technical services for many enterprises in the industry, receiving unanimous praise and creating good economic and social benefits. For example, the ultrasonic enhanced extraction technology was applied in the production process of "Tianlong Tongluo Capsules" by Zhuhai Tianlong Biotechnology Co., Ltd., making it the first in the industry to adopt ultrasonic extraction technology, and it was the first domestic company to pass the SFDA expert review meeting; this technology was also used to develop NG-18 plant extract and NG-21 plant extract, and to build production lines for extracting total saponins of Panax notoginseng with an annual output of 100 tons and 200 tons for Yunnan Weihe Pharmaceutical Co., Ltd., receiving unanimous praise from the enterprises and creating huge economic and social benefits. This technology has a profound impact on promoting the overall improvement of technology, quality, and efficiency levels in traditional Chinese medicine enterprises and on modernizing the engineering technology of traditional Chinese medicine in China. The project "Research on Ultrasonic Enhanced Extraction Device for Traditional Chinese Medicine" has successively won the second prize of the Zhuhai Science and Technology Progress Award in 2007, the third prize of the Guangdong Science and Technology Progress Award in 2009, and multiple intellectual property rights, and established one enterprise standard.

(2) Research and promotion of ultrafine pulverization technology: Under the funding of the Guangdong Provincial Economic and Trade Commission's special project for technological innovation "Research on Ultra-fine Pulverization Technology System for Traditional Chinese Medicine, Equipment Development, and New Product Development" (Yue Cai Qi [2000] No. 241, No. 16) and the Guangdong Provincial Science and Technology Program project "Research on Ultra-fine Pulverization Technology for Traditional Chinese Medicine and Ultra-fine Pulverization Machine Group" (C50301), and "Demonstration Research on Common Key Technologies in Traditional Chinese Medicine Production - Research and Application of Ultrafine Pulverization Technology" (2003B31706), in collaboration with Nanjing University of Science and Technology, a new type of airflow ultrafine pulverization device was jointly designed and manufactured. This equipment is suitable for various types of medicinal materials and has a high cell wall breaking rate, featuring easy collection and high energy efficiency. To date, comparative experimental studies on ultrafine pulverization have been conducted for more than 30 types of medicinal materials and 5 compound prescriptions, accumulating data on the cell wall breaking rate, pulverization degree, and related parameters of time and temperature. Products developed using this technology include 3 health food approvals and 2 sanitary product approvals, and one enterprise standard has been established. The project "Demonstration Research on Common Key Technologies in Traditional Chinese Medicine Production - Research and Application of Ultrafine Pulverization Technology" has successively won the third prize of the Zhuhai Science and Technology Progress Award in 2006, the third prize of the Guangdong Science and Technology Progress Award in 2008, and the third prize of the Chinese Association of Traditional Chinese Medicine Science and Technology Award in 2010.

(3) Research and promotion of multifunctional macroporous resin extraction technology: Under the funding of the key bidding project of the National Administration of Traditional Chinese Medicine "Research on Macroporous Resin Extraction Technology", in collaboration with the Sichuan Academy of Traditional Chinese Medicine, the results of the joint research on "Application of Macroporous Adsorption Resin in Extracting Effective Parts of Traditional Chinese Medicine" led to the launch of the first batch of modern traditional Chinese medicine products "Liuwei Dihuang Pills" and "Huoxiang Zhengqi Capsules" in Sichuan Taihua Pharmaceutical Co., Ltd., which have been industrialized and launched into the market, receiving strong reactions and attention, with good clinical and market responses, demonstrating strong vitality, and one enterprise standard has been established.