Boxing world champion Ali, literary giant Ba Jin, mathematical prodigy Chen Jingrun, chief architect of reform and opening up Deng Xiaoping ... several celebrities whose respective fields do not intersect but are linked by the same disease, that is Parkinson's disease (PD).
Parkinson's disease (PD) is a common degenerative disease of the nervous system, which usually occurs in the elderly over 65 years old. Typical symptoms are tremor, limb stiffness, decreased motor function, abnormal gait, constipation, dysuria, abnormal sweating and other symptoms.
According to the statistics of the World Parkinson's Disease Association, there are currently more than 5.7 million Parkinson's patients in the world, including 2.7 million in China, accounting for almost half of the total number of patients in the world. It is predicted that by 2030, the number of patients with Parkinson's disease in China will increase to 5 million, and China will become the first "big country" in the world.
(Source: Medtronic official website)
The first choice of drugs in the early stage of the disease includes directly supplementing dopamine, activating dopamine receptor, preventing dopamine metabolism, increasing dopaminergic activity and inhibiting acetylcholine activity. Later, with the progress of the disease, drug treatment gradually failed. Surgical destruction therapy can be considered, that is, after the microelectrode accurately locates the target, the diseased cells are destroyed by heating with radio frequency needle, which can temporarily relieve the symptoms of limb tremor, joint stiffness and difficulty in moving in PD patients. The other is widely recognized as the first choice of surgical treatment-deep brain stimulation (DBS), also known as brain pacemaker.
1.DBS has achieved remarkable results in the treatment of Parkinson's disease, and its future application space is limitless.
Deep brain stimulation (DBS) therapy uses stereotactic technique to implant electrodes in some areas of the deep brain. Under the control of an implantable pulse generator (IPG) implanted under the subclavian skin, the electrode sends out electric pulses to stimulate the target to adjust the nerve function, and finally achieves the purpose of treating nerve/mental diseases. IPG contains batteries and electronic components that can provide electrical stimulation. It can be controlled by patients and clinicians, and the stimulation parameters such as frequency, pulse width and voltage can be adjusted regularly to give full play to the nerve regulation function of DBS.
(Source: Mayo Clinic official website)
Development history
The origin of DBS therapy can be traced back to the middle and late period of19th century, and the experiments on animal cerebral cortex stimulation laid the foundation for the study of cerebral cortex functional localization. At the beginning of the 20th century, the first stereotactic framework was developed, which made it possible to conduct stimulation experiments in deep brain regions.
The application of 1947 X-ray pneumoencephalography technology has greatly improved the surgeon's target location ability. In the same year, Spiegel and Wycis tried to treat Parkinson's disease with electrical stimulation and high-frequency electrocoagulation, and chronic pain with thalamic electrical stimulation. Later, they also tried to treat epilepsy and spasms.
In the 1950s, the main treatment for Parkinson's disease was irreversible surgical destruction, that is, the nerve tissue that drives Parkinson's symptoms was destroyed by thermal ablation, including pallidotomy and thalamotomy.
Dr. C. Norman Shealy and his colleagues in the United States first developed an implantable spinal cord stimulator in 1967, which is equivalent to putting forward a preliminary idea of DBS system. In the late 1960s, some researchers found that levodopa therapy can significantly alleviate most symptoms of Parkinson's disease, and has the advantages of low risk and low cost. The emergence of drug therapy has slowed down the research progress of DBS and stereotactic neurosurgery.
In the 1980s, many patients with Parkinson's disease gradually developed drug resistance to levodopa, and at the same time began to have side effects of drug treatment such as dyskinesia. Implantable medical technology has been significantly improved, and the treatment of spinal cord stimulator and pacemaker has become routine. 1987, French scholar Professor Bernard Bede led the team to successfully perform the world's first DBS system implantation operation, and reported the research results of thalamic electrical stimulation in 199 1 and 1994 respectively, which pioneered the thalamic electrical stimulation treatment.
In 1997, FDA approved the application of Medtronic in the treatment of essential tremor and Parkinson's disease.
At present, more than180,000 patients worldwide have received DBS implantation. Although the therapeutic mechanism of DBS is still unclear, the follow-up study of implanted cases shows that DBS has achieved remarkable results in controlling motor symptoms of Parkinson's disease and reducing drug intake. The success of Parkinson's disease treatment promoted the further development of DBS therapy. At present, DBS has been widely used in the treatment of essential tremor and dystonia. In 2003 and 2009, the US FDA approved DBS to treat primary dystonia and aggressive mental disorder respectively. Recent research shows that DBS is expected to be applied to many diseases, including chronic pain, obsessive-compulsive disorder (OCD) and depression. In addition, scientists have been exploring the effectiveness and safety of DBS therapy for drug addiction, anorexia, obesity and Alzheimer's disease. With the continuous advancement of DBS research, the application space of DBS therapy in the future will be infinite. Second, foreign giants take the lead in layout, and domestic enterprises are rising.
According to the latest research report released by Daguan Research, the global market size of DBS in 20 16 is about 796 million US dollars, and the annual compound growth rate of DBS market in the forecast period is 1 1.5%. By 2025, the global DBS market capacity is expected to exceed 2 1 100 million USD. In the future, due to the improvement of living standards and the progress of medical technology, the proportion of aging population is increasing, and the incidence of nervous system diseases (such as Parkinson's disease, epilepsy, primary tremor, dystonia, etc.) is also increasing. It is easy to happen in the gradual increase of the elderly population, which further promotes the expansion of the direct broadcast satellite market. In the field of DBS treatment, foreign equipment giants such as Medtronic, Boston Science, and St. Yuda (acquired by Abbott) are now in an absolute leading position in the market because of their mature technology and early layout. However, domestic enterprises such as Pinchi and Jingyu, although they started a little late, are already catching up with excellent technology and innovative therapies and trying to seize the promising DBS treatment market. (1) Foreign-funded enterprises
1, Medtronic Activa series-DBS system compatible with magnetic resonance (MRI) examination.
Medtronic, an established medical device company, is the originator of DBS therapy. As early as 1987, the first DBS system implanted by Professor Benabid and his team was developed by Medtronic, which started the commercialization of DBS therapy. Since then, Medtronic DBS system has been approved by the European Union, Canada and Australia to treat essential tremor, dystonia and Parkinson's disease. In 2002, FDA approved Medtronic's DBS system to control and relieve the motor symptoms in the middle and late stages of Parkinson's disease, which indicates that Medtronic's DBS therapy can be extended to Parkinson's patients whose levodopa is effective but some symptoms cannot be completely controlled by drugs. It is worth mentioning that the system is also approved to be compatible with magnetic resonance scanning (MRI) under certain conditions, which is also the first DBS system in the market that allows patients to have MRI examination after implantation. At present, Medtronic Activa series product portfolio includes three types: Activa PC bilateral equipment, Activa PC bilateral equipment and Activa SC unilateral equipment, among which Activa RC is the world's first rechargeable DBS system with a service life of 15 years. Activa series DBS system adopts sensing technology and adjustable stimulation algorithm, which can not only provide deep brain treatment, but also measure and record electrical signals in key areas of the brain. In addition, the program-controlled system supporting this system supports doctors to set up real-time program-controlled settings on the tablet computer based on reliable patient data information.
20 17 12, Boke Vercise product was approved by FDA to treat Parkinson's disease. At present, Boston Scientific's latest Vercise oriented DBS system has two products: rechargeable VerciseGevia and non-rechargeable Vercise PC, which are known as the thinnest products on the market.
Boston Scientific Company claims that its Vercise directional DBS system has the latest steering technology, that is, eight independently controllable electrodes are attached to directional wires implanted in specific areas of the brain, which can give accurate stimulation levels for different nerve targets, thus supporting clinicians to accurately control DBS equipment according to changes in patients' physical needs, including controlling the degree, range, location and direction of electrical stimulation. At the same time, with the help of program-controlled software using STIMVIEW technology, doctors can intuitively see the distribution of electrical stimulation in various regions of the brain during DBS treatment, and adjust the treatment plan in time to finally achieve the goal of highly personalized Parkinson's treatment. 3. Abbott St. Jude Medical Infinity DBS-directional wires guide current, and the wireless platform is convenient for program control.
From 2065438 to 2006, Abbott acquired St. Yuda Medical Company for $25 billion, and included heart failure treatment equipment, cardiac catheters, defibrillators and deep brain stimulation devices (DBS) in St. Yuda. Infinity DBS system of St. Yuda Medical Company and its directional lead were approved by the US FDA in 20 16 to control or relieve Parkinson's disease and essential tremor, which is also the first directional lead approved by the FDA.
Infinity DBS system achieves the goal of combining innovative segmented directional lead technology with industry-leading DBS iOS software wireless platform. Among them, the segmented electrodes on the directional wire can guide the current to the required structural areas of the brain, and at the same time, doctors can remove the current that is easy to cause side effects in some areas, thus maximizing the therapeutic effect of patients and limiting the occurrence of side effects.
Image source: Abbott official website
The wireless platform of iOS software in the system can be connected with DBS implants via Bluetooth, which enables clinicians to use the software on iPad to control DBS implants in patients' brains individually. At the same time, patients can also monitor their symptoms and treatment effects in real time through the digital patient controller on iPhone, and give timely feedback. (2) Domestic enterprises
1, Beijing Pinchi Medical Series Brain Pacemaker-"Industry-University-Research Medical" cooperated to break the monopoly of foreign technology.
Beijing Pinchi Medical Equipment Co., Ltd. ("Pinchi Medical" for short) was established in 2008 and is headquartered in Changping Park, Zhongguancun Science Park, Beijing. The business covers the research and development, production and sales of a series of nerve control products such as brain pacemaker, vagus nerve stimulator, spinal cord stimulator and sacral nerve stimulator.
Pinchi Medical has established a collaborative innovation model of "production-learning-research-medicine" through cooperation with many clinical hospitals such as Tsinghua University, Beijing Tiantan Hospital and Union Medical College Hospital. Since 2000, the research and development of its series of brain pacemakers has been under the responsibility of Professor Li from Tsinghua University. In 2009, the first clinical trial was conducted. In 20 14, he obtained the registration certificate of all series of brain pacemakers (DBS), and in 20 16, he obtained the CE certification. The development and listing of Pinchi DBS system has broken the monopoly of foreign giants in the field of DBS treatment, and also made China a country that can develop, produce and apply brain pacemakers on a large scale except the United States. In 20 18, the project "Key Technology, System and Clinical Application of Brain Pacemaker" was born under the medical model of Industry-University-Research, and won the first prize of national scientific and technological progress in that year.
Pinchi series brain pacemakers are domestic DBS systems with independent intellectual property rights, which have technical advantages such as 3.0T nuclear magnetic compatibility, variable frequency stimulation and remote program control, and the price advantage is obvious.
(1) 3.0T NMR compatibility: Pinchi brain pacemaker will be able to perform high-field MRI scanning when powered on;
(2) Frequency conversion stimulation: Combining traditional high-frequency stimulation with low-frequency stimulation can effectively control some midline symptoms such as motor symptoms and frozen gait. It is reported that this therapy has been confirmed in previous clinical studies and obtained an American invention patent.
(3) Remote program control: A "big center-sub-center" remote program control system is constructed, which is convenient for patients to program control nearby after DBS, so that patients can receive the whole treatment and rehabilitation treatment of Parkinson's disease in the nearby hospital.
(4) Price advantage: the per capita cost of Pinchi DBS implantation is lower than that of imported products100000 yuan or more.
2. Suzhou Jingyu Medical Series Brain Pacemaker-DBS system with the first neural control chip in China.
Suzhou Jingyu Medical Equipment Co., Ltd. was established on 20 1 1, and its headquarters is located in Suzhou Industrial Park. Its founder has worked in foreign equipment companies such as GE Medical, Medtronic and Siemens. Since 2008, Jingyu team began to develop DBS system. In 20 14, its brain pacemaker was included in the special approval channel for innovative medical devices by the national drug regulatory authorities, and it was approved for listing in 20 16. According to the latest data from official website, Jingyu Medical has been granted 152 patents. Among them, there are 80 invention patents, 53 utility model patents, 2 design patents and 6 PCT international invention patents.
Jingyu Medical's series of brain pacemakers mainly have the following advantages:
First, independently developed the first chip in the field of neuromodulation in China. Its dual-frequency independent intellectual property chip technology allows different stimulation parameters to be used in different brain nuclei, and accurately realizes the program control of different frequencies of the left and right brains;
Second, wireless remote program control technology supports the interaction between doctors and patients in different places. Doctors can carry out remote program control to complete the adjustment of patients' brain pacemaker parameters;
Thirdly, electrode self-locking technology solves the common problem of electrode displacement of brain pacemaker in clinic.
In addition to Parkinson's disease, Jingyu Medical is exploring to broaden the indications of DBS therapy, including obsessive-compulsive disorder, depression and drug addiction. In 20 17, the company's third-generation drug-addicted brain pacemaker was included in the special approval channel for innovative medical devices in National Medical Products Administration. Since 20 18, Tang Dou Hospital and China Institute of Drug Dependence have conducted multi-center clinical research in Tang Dou Hospital, China Institute of Drug Dependence, Shanghai Ruijin Hospital and other hospitals and research institutions, including 60 subjects and DBS. label
The clinical application of DBS therapy has been more than 30 years. Since entering China in early 2000, the domestic direct broadcast satellite market has been basically monopolized by several foreign giants such as Medtronic, Boku.com and San Yuda. It was not until Pinchi, Jingyu and other medical technology companies overcame difficulties and developed domestic brain pacemakers that the original monopoly pattern was broken.
China has a huge population base of nearly 3 million patients with Parkinson's disease. With the gradual approval of DBS to treat depression, obsessive-compulsive disorder, drug addiction and other diseases, the market space in DBS field will be further expanded. We believe that the domestic DBS system with obvious price advantage will get more policy support and a larger audience with its bright cost-benefit ratio.
Of course, the promotion of DBS therapy still faces many obstacles, such as low awareness and acceptance of patients, high threshold for the development of therapy, and high price of DBS consumables (more than 200,000 RMB). For the first two constraints, enterprises can gradually improve through patient education, operator training and training. The huge economic burden faced by patients is a dilemma that requires the cooperation of medical insurance, commercial insurance, enterprises and individuals. What is the development potential of deep brain stimulation (DBS) therapy, and what will be the future market structure? Let's wait and see!