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Too much demand for allogeneic bone

However, there is a lack of industry supervision at the source.

So there are a lot of problems.”

"It is obvious in clinical practice that allogeneic bone repair materials are in even greater shortage," Lu Zhaolin told China Newsweek. He is the chief physician of the orthopedics department of a tertiary hospital in Shanghai.

The "allogeneic" in allogeneic bone means coming from the human body, and the "allogeneic" means coming from someone else. Allogeneic bone is a type of bone repair material that is surgically implanted into the human body to repair bone defects.

Lu Zhaolin said that most hospitals have their own contracted allogeneic bone manufacturers. According to him, the national level is currently verifying the sources of allogeneic bones produced by relevant companies. "In clinical practice, we are gradually returning to the situation where we need to use autologous bone repair materials and artificial bone repair materials to treat orthopedic patients," he said.

Liu Chen, chief physician of the Department of Orthopedics at a tertiary hospital in Beijing, told China News Weekly that allogeneic bone is widely used, and patients with bone defects, bone trauma, bone tumors, and those who need joint revisions will use this material. Liu Chen said that the demand behind this material is very large, and the current market supply cannot meet the demand.

Sterilized bone materials stored in a human biobank in France. Photo/Visual China

Huge demand but difficult to meet

"Allogeneic bone is a high-value consumable and has always been in short supply. The shortage has become more obvious in clinical practice since this year," said Liu Chen.

Searching keywords on the official website of the State Food and Drug Administration shows that there are 16 companies producing allogeneic bone. This material belongs to Class III medical devices. The product approval page of a company shows that the product material is human bone, which is processed into the shape required by orthopedics after deep freezing, freeze drying, surface demineralization or full demineralization.

According to a report released by the Qianzhan Industry Research Institute at the end of 2023, bone defect repair materials can be divided into three categories according to the source of the materials: autologous bone repair materials, natural bone repair materials, and artificial bone repair materials. Domestic products that have been launched include the latter two, and allogeneic bone belongs to natural bone repair materials.

Lu Zhaolin analyzed that from the perspective of implanted bone growth effect, autologous bone repair materials have the best effect, followed by natural bone repair materials. However, implanting autologous bone requires a second surgery for the patient, which may bring risks such as pain and infection, and the source of autologous bone is relatively limited and unstable. Chemically synthesized artificial bone repair materials have no biological activity, are not very effective in promoting osteogenesis, and are prone to bone fractures and other problems. Therefore, natural bone repair materials have become the preferred implant material other than autologous bone in bone repair surgery, and are widely used in dentistry, orthopedics, and craniofacial surgery.

"Allogeneic bone used in clinical practice accounts for more than 95% of natural bone repair materials." Liu Chen said, for example, the bones of bone tumor patients are damaged due to the phagocytosis of tumor cells. After the bone tumor resection surgery, bone filling is required. The ideal filling material is allogeneic bone.

The approval documents for allogeneic bone products on the official website of the State Food and Drug Administration show that the source of the material includes legally obtained donations and bone tissue removed during surgery. Lu Zhaolin said that the main source of allogeneic bone in China is body donations, and there is a large clinical demand, but the number of products is insufficient. In the 1990s, for patients with small bone defects, orthopedic surgeons might "dig bones" from other parts of their bodies to fill them. "But if it is a large defect, this method cannot meet the needs of patients," he said.

Lu Zhaolin said that for patients who need to repair the entire femur, allogeneic bone is the only option. He explained that human bones contain collagen in addition to chemical components. Artificial bone is a powdered or granular chemical material. With the current level of artificial bone technology, artificial bone can only be made into small bone structures, not a whole bone.

Liu Chen said that allogeneic bone is widely used in clinical practice. An article published in Medical Equipment in December 2023 mentioned that more than 500,000 bone transplants are needed in China each year, and bone transplants have become the second largest transplant surgery after blood transplants. An article published by the Medical Device Technology Review Center of the National Medical Products Administration in August 2023 mentioned that there are more than 6 million patients with bone dysfunction caused by accidents and orthopedic diseases in China each year, and there is a strong demand for bone defect filling and repair materials in clinical practice.

In contrast, the number of body donations in China is insufficient. According to information released by the Chinese Red Cross in March this year, 6,454 cases of body organ donations were completed in China last year. In late May this year, data released by the Medical Emergency Department of the National Health Commission showed that China's human organ donation system was established in 2010. As of late May this year, more than 50,000 cases of body organ donations after the death of citizens have been completed in China.

The average adult skeleton consists of 206 bones connected by cartilage, tendons and ligaments. "The amount of bone taken from a deceased donor can generally meet the needs of more than a dozen patients," Lu Zhaolin explained. For example, a thigh bone can be made into dozens or even hundreds of packages of allogeneic bone products, each weighing five or six grams. "Even so, allogeneic bones are in short supply," he said.

What is the difficulty in building a bone bank in a hospital?

In 2007, Lu Zhaolin visited the United States for a study tour. At that time, he visited the local bone bank building in Denver, Colorado. Lu Zhaolin said that this bone bank was established by the local government. The interior is similar to a large pharmaceutical factory. The environment is clean and there are process supervisors, quality inspectors, security personnel, etc. Every piece of bone produced by the bone bank needs to be inspected by the bone bank staff. "A large number of allogeneic bones used by doctors in local hospitals in Denver during surgery come from this bone bank. When clinicians need to use them, they only need to submit an application report in advance." He said.

In 2020, an article published in the International Journal of Biomedical Engineering mentioned that the American Tissue Bank Association was established in 1976. The American Tissue Bank Association includes 120 tissue banks. In recent years, the tissue banks have obtained tissues from nearly 60,000 donors and provided more than 3.3 million allogeneic grafts of various types for nearly 2.5 million tissue transplant surgeries each year. The vast majority of tissue transplant materials in the United States come from tissue banks certified by the association.

According to incomplete statistics, there are about 44 medical tissue banks in China, 24 of which are corporate tissue banks, 11 are hospital tissue banks, and 9 are private non-profit tissue banks. The products they supply include bone tissue materials, skin tissue, etc.

Liu Chen believes that establishing a bone bank (i.e. bone tissue bank) is an effective way to solve the contradiction between supply and demand of bone materials. In orthopedic clinical surgery, some patients' bones are sometimes removed. In fact, these bone resources can be stored in the bone bank and reused for other orthopedic patients. But in fact, there are very few hospitals that have the ability to establish bone banks, resulting in the waste of these bone resources.

An article published in Chinese Journal of Tissue Engineering Research in 2022 pointed out that in the 1990s, hospitals with advanced orthopedic and burn technologies, such as the General Hospital of the Chinese People's Liberation Army and Beijing Jishuitan Hospital, began to establish their own tissue banks. After 2000, the scope of domestic bone banks expanded from hospitals to enterprises and private non-profit organizations.

So far, the construction of bone banks in hospitals is still progressing slowly. As mentioned in the above article, bone banks in hospitals are not independent legal entities, are relatively scattered, and lack unified management standards. In contrast, market research results show that 24 corporate tissue banks deliver about 1.6 million pieces of tissue repair materials to clinics each year, an increase of about 16 times compared to 2008.

Why is it difficult for hospitals to build bone banks? "If a hospital wants to build a bone bank and produce allogeneic bones, it needs to obtain relevant qualifications first, which is not easy." Lu Zhaolin said that after 2000, a number of policies on allogeneic bones began to be introduced, and the country's supervision of biomaterials and human organs has become increasingly strict.

In 2000, the State Council promulgated the "Medical Device Supervision and Administration Regulations", and the State Food and Drug Administration began to supervise the registration, production, and use of medical devices, and allogeneic bone repair materials were included in the management of Class III medical devices. This product must undergo registration inspection and clinical trials to verify safety and effectiveness, and then pass the review and issuance of a medical device registration certificate by the State Food and Drug Administration before being approved for sale. In terms of hospital tissue bank management, in 2010, the Ministry of Health issued relevant industry standards to regulate the scope of work, personnel requirements and management, sites, and audits of bone banks. However, this standard was abolished in 2016, and no new hospital tissue bank management standards have been issued so far.

Since the 1990s, the hospital where Lu Zhaolin works has tried to build a bone bank, but eventually gave up due to problems with manpower, funding and supervision. "It is difficult for a hospital to build a standard bone bank," said Lu Zhaolin. In his opinion, on the one hand, the preparation process of allogeneic bone is complicated, and it is very difficult for the hospital to ensure that all procedures meet the standards; on the other hand, the hospital bone bank does not have a stable source of bones, and allogeneic bones mainly come from the discarded bones of surgical patients. Therefore, more complete legal and policy support is needed to help hospitals avoid unnecessary risks.

Previously, orthopedic clinicians at Lu Zhaolin's hospital used to collect patient bones removed during surgery, disinfect and sterilize them, and make allogeneic bones for patients in need without charging any fees. Nowadays, if doctors want to keep the bones removed during surgery to make allogeneic bones and reserve them for clinical treatment, they must first inform the patient and obtain his or her consent. "In the past, patients had no awareness of asking questions. Now, even if there is no commercial benefit in the process, many patients cannot accept this method." After 2005, orthopedic doctors at Lu Zhaolin's hospital no longer made allogeneic bones for clinical treatment. "Now when doctors perform surgery, they throw away the excess bones they remove," he said.

"On the one hand, the tightening of various regulations is a good thing; on the other hand, too many restrictions have blocked the way for hospitals to build tissue banks," said Liu Chen.

Liu Chen said that there are very few hospitals in the country that have built bone banks, and it is not just because of the high capital investment. For hospitals, it is more cost-effective to directly purchase allogeneic bones from regular companies without involving legal risks. He added that if a hospital sets up its own bone bank, the allogeneic bones produced are commodities. This also involves adjustments at the policy level, such as whether the hospital should clearly mark the price of the allogeneic bones it produces and sell them to patients, or provide them to patients free of charge?

Among the 11 in-hospital tissue banks in China, the in-hospital tissue banks of four hospitals, including Beijing Jishuitan Hospital, mainly store bone tissue. Liu Chen said that for hospitals with in-hospital bone banks, one source of bone repair materials is the bones discarded during clinical operations. In principle, they cannot be charged when used by patients, but the supply is difficult to meet the demand. In Lu Zhaolin's view, if there is a stable supply from enterprises, not all hospitals need to build their own bone banks.

Tissue bank standards need to be unified

The market space for bone repair materials is huge. According to the aforementioned Forward-looking Industry Research Institute article, the number of patients with bone defects in China is large, the treatment rate is low, and the problem of population aging is aggravated, and the number of patients will continue to rise. In 2022, the market size of the domestic bone defect repair material industry is about 4.31 billion yuan, and it is expected that the domestic market size will exceed 9 billion yuan in 2029.

Lu Zhaolin said that the price of allogeneic bone is not cheap. Currently, the allogeneic bone sold through regular channels in the domestic market contains 3-5 grams in a small bag, and the price is 4,000 to 5,000 yuan per bag. When he visited the bone bank in Denver, the bone bank cost thousands of dollars for 5 grams of allogeneic bone.

"The price of allogeneic bone is related to factors such as the bone location, manufacturer brand, source, and bone quality." Lu Zhaolin said that if a whole thigh bone is to be implanted in a patient, about one pound of allogeneic bone repair material is needed. Currently, the cost of this operation in China is 30,000 to 40,000 yuan.

Lu Zhaolin said that in terms of tissue bank construction, it is mainly private enterprises in China that are carrying out the work. The aforementioned article published in "Chinese Journal of Tissue Engineering Research" pointed out that the technical threshold of tissue banks is relatively high, covering multiple disciplines such as medicine, materials science, biology, and production quality system management. Therefore, it is difficult for small tissue banks to develop for a long time. In the development process of tissue banks in the United States and Europe, small tissue banks have been continuously merged with large tissue banks. "Refined and centralized development can reduce the operating costs of tissue banks and better promote the development of the industry."

The article points out that corporate tissue banks will continue to be the main model for the development of medical tissue banks in China in the future. Hospital tissue banks and private non-profit tissue banks need to seek regulatory breakthroughs in how to smoothly participate in tissue acquisition and better connect with tissue product transformation companies.

The American Association of Tissue Banks and the European Association of Tissue Banks are two influential tissue bank associations in the international community. The aforementioned article in the International Journal of Biomedical Engineering mentioned that the United States regulates allogeneic tissue products in the form of both FDA supervision and industry association self-regulation.

The aforementioned article in "China Tissue Engineering Research" mentioned that the American Association of Tissue Banks and the European Association of Tissue Banks have both established tissue bank standards and provided certification, training, teaching and other services to tissue banks. In the field of tissue banks, there are currently only one national industry association and two secondary associations in China. The two associations are the Bone Tissue Bank Branch under the China Pharmaceutical Biotechnology Association and the Chinese Human Organ and Tissue Donation Committee under the China Association for the Promotion of Human Health Science and Technology.

"Establishing and improving a unified regulatory framework for tissue banks and forming China's tissue bank standards are the next urgent tasks." The article points out that in terms of tissue bank supervision, China does not yet have a dedicated tissue bank certification or regulatory department, and relies more on industry guidance from social groups such as the China Association for the Promotion of Human Health Science and Technology.

Lu Zhaolin said that the current problem is that the demand for allogeneic bone is too high, but there is a lack of industry supervision at the source, so various problems are prone to occur. "Doctors often don't know the original source of allogeneic bone." Lu Zhaolin said that companies that supply such products have obtained approval from the State Food and Drug Administration and have undergone strict review and inspection. However, this review focuses more on product quality and safety.

Liu Chen said that on the one hand, it is necessary to strengthen the source supervision of allogeneic bones; on the other hand, it is also necessary to make it meet clinical needs as much as possible.

"Orthopedic clinical treatment still requires a large amount of allogeneic bone, and companies should be guided correctly." Lu Zhaolin said. In his opinion, there is an imbalance between supply and demand of allogeneic bone. He suggested that, first of all, publicity should be strengthened to increase people's willingness to donate their bodies, and secondly, efforts should be made to strengthen the traceability of products produced by allogeneic bone companies, such as verifying the information of donors and checking the original source.

(Liu Chen and Lu Zhaolin in this article are both pseudonyms)