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Nikkiso Co., Ltd.
About
Nikkiso Co., Ltd. was established in 1953. At the time of its founding, Nikkiso operated as the exclusive distributor for Milton Roy (a US owned company), engaging in the import and sale of volume control pumps.
Driven by the founder’s strong belief that “We should shift to domestic production as soon as possible, as it is the path to secure competitiveness of Nikkiso”, we promoted the domestic production of pumps through technical tie-ups with Milton Roy and Chem Pump of the U.S. and developed during the wave of rapid economic growth in Japan. A significant turning point that led Nikkiso to enter the medical field occurred in
February 1959. We were requested to manufacture an artificial heart prototype by the Department of Surgery at the University of Tokyo, which later became the world’s leading authority on artificial organs. The development of “artificial organs” was a different field for us, and our founder was reluctant to take on the project. However, he was persuaded and made the decision to take on the challenge of an unknown field.
The passion of the employees working in this new field enabled them to overcome the challenges one by one, and in July 1960, the first artificial heart prototype was completed. In animal experiments conducted that same year, a canine without a heart survived for up to 5 hours and 30 minutes, a groundbreaking success. From this experience, realizing the of pumps for life support, the profound impression at the time led to Nikkiso’s entry into the medical field.
Fig.1 Japan’s first artificial heart
1. History of Nikkiso’s hemodialysis treatment
Contract with Milton Roy, Inc. of the U.S. to import and sell dialysis device and artificial kidney
In the mid-1960s, kidney failure was considered an incurable disease. Against this backdrop, Milton Roy of the U.S., with which we had been engaged in the pump business, developed a dialysis device in 1965 and initiated its sales it in the United States. Subsequently, Milton Roy approached us to become the sole distributor of the dialysis device in Japan.
Seizing this opportunity, Nikkiso entered into a comprehensive distribution agreement with Milton Roy to serve as the exclusive distributor in Japan for the medical business. In December 1966, we received the first order from Hiroshima University School of Medicine, and the initial dialysis device “Model A” and standard kiil dialyzer were delivered in March of the following year. We subsequently delivered them to Niigata University, marking the commencement of dialysis treatment in Japan. It was said, “People relying on this device would not be alive if It were not for this device. ” Feeling a profound responsibility for sustaining lives, Nikkiso realized that there could be no room for compromise in this line of work. With a strong commitment, Nikkiso dedicated itself to contributing to the advancement of dialysis therapy, recognizing the gravity of the responsibility involved in supporting human life.
Fig.2 Model A (Single patient-dialysis device）
Development of the first domestically produced dialysis device in response to demands from the medical field
While the “Model A” gained popularity in Japan, the high cost of imported parts and issues with maintenance after installation increased the demand for domestic production. In March 1969, we signed a technical cooperation agreement with Milton Roy, marking the beginning of our journey as a medical device manufacturer. We pioneered the manufacture and sale of Japan’s first domestically produced dialysis device. In May 1969, we obtained approval from the Japanese Ministry of Health and Welfare, and the first domestically produced dialysis device, the Model BN, was delivered in August of the same year. Within less than a month of the initial delivery, orders for as many as nine units were received, marking a successful start to domestic production of dialysis device.
The Model BN experienced a few failures and received high praise from the medical community. From the initial stages of development, the design concept of prioritizing patient safety has been consistently applied to our products, even as technology has progressed over time.
Fig.3 Model BN (The first domestically produced dialysis device）
Improvement of dialysis medical system in Japan allowing more patients to receive dialysis treatment, and consequently lead to increase of dialysis devices demands
In December 1967, dialysis treatment in Japan became eligible for insurance coverage.
However, the substantial annual cost of treatment, amounting to approximately 10 million yen (about $80,000) per year, placed a heavy financial burden on the patients, leading to a rise in suicides among dialysis patients—a pressing social issue. In response to petitions and other efforts, the public health insurance was established in October 1972, followed by the introduction of the high-cost medical care reimbursement system in 1973. These measures helped alleviate the individual financial burden of medical expenses, resulting in a significant increase in the number of patients receiving dialysis treatment and the expansion of dialysis facilities.
The growing demand for a cost-effective system for multiple patients led to the development of the “BN-2000” automatic dialysis fluid supply unit. This highly flexible device can be connected to the SR-2000 patient monitoring device, or the CD-1 coil dialysis device, creating a two-patient unit.
As the need for a multi-patient supply system continued to rise, we developed the “BN-4” for 4 patients and the “BN-10A” for 10 patients, the latter weighing more than 700 kg.”
Fig.4 CD-1 (dialysis device for coil dialyzer)
Fig.5 BN-10A (multi-patient dialysis fluid supply unit)
Development of a dialysis device designed to fully demonstrate the performance of the EX-coil dialyzer
As the number of dialysis patients increased, there was a growing demand for a coiltype dialyzer which is small, light, and easy to prepare.
Therefore, we imported and sold the “EX-Coil” dialyzer from Extracorporeal Medical and developed the CD-1 dialysis machine for coils to fully demonstrate its performance.
Despite just after the oil shock in Japan, we developed our own coil-type dialyzer, the “NK-Coil “dialyzer.
Fig.6 NK-Coil dialyzer
Transition from importing dialyzers to manufacturing own hollow fiber dialyzers
In 1976, we also began marketing the ND series of flat-plate dialyzers (Layered-type Dialyzer) developed in-house. Meanwhile, in Japan, the market needs shifted from the coil type to the hollow fiber type, due in part to the entry of synthetic fiber manufacturers into the hollow fiber dialyzer market.
A milestone in Dialysis Therapy: More accurate ultrafiltration control system which enables an accurate fluid removal
In the 1970s, achieving accurate fluid removal in dialysis facilities required skilled staff, and there were many cases where the target fluid removal volume could not be precisely controlled. To address a more accurate ultrafiltration control system, we collaborated with Toray Industries, Inc. to develop a ultrafiltration control dialysis system “UFC-11,” incorporating a chamber-type ultrafiltration control mechanism.
However, cases of ultrafiltration errors occurring during actual treatment were observed, causing concern for our engineers. Upon direct investigation by our engineers at the treatment site, it was found that records of food and drink intake were not documented in the patient’s chart. Subsequently, attention was focused on the relationship between pre- and post-dialysis weight management of patients and fluid removal accuracy. Efforts were made to analyze the correlation between records such as insensible perspiration, fluid substitution, diet, and the ultrafiltration control system of the dialysis machine.
As a newly developed feature, a “self-test function (DBB-62, 1987)” was introduced to check if each component was functioning properly before treatment. To ensure safe and reliable fluid removal, additional functions were incorporated, such as the “TMP auto forecast monitoring function (DCS-211, 1989),” which automatically adjusts alarm points based on changes in TMP due to membrane blockage in the dialyzer, continuous monitoring of the discharge accuracy of duplex pumps and ultrafiltration pumps through the “Continuous monitoring system with Conductivity (DCG-02, 1997),” and the “Solenoid valve leak detector with Conductivity (DCS-73, 2002),” which continuously monitors the state of electromagnetic valve closures. These functionalities were added, leading to the establishment of a continuous ultrafiltration control monitoring system.
Fig.7 Dialysis ultrafiltration control system “UFC-11”
Development of device corresponding to bicarbonate dialysis solution to eliminate patient’s discomfort during dialysis
In the 1970s, acetate dialysis fluid was primarily used in dialysis treatments. Before the introduction of acetate dialysis fluid, doctors had to manually prepare bicarbonate dialysis solution, which had the drawback of the difficulties to adjust the pH. To address this, a more convenient acetate dialysis fluid was developed, allowing for a simple mixing of concentrate and water at a fixed ratio. However, occasional issues arose where the acetate dialysis solution was not suitable to the patient, leading to imbalances such as headaches and nausea during treatment.
To solve this problem, there was a collective effort to return to the basics in the 1960s with the reappearance of bicarbonate dialysis solution, which had been used during that period. To overcome the challenge of labor-intensive preparation, Nikkiso collaborated with a pharmaceutical company specializing in dialysis fluid to devise a composition of agents that would allow for the fluid production of dialysis solution.
In the collaborative effort, Nikkiso worked on devising a mechanism to accurately formulate the dialysis fluid. Under this collaborative effort, a new bicarbonate dialysis solution that could be easily prepared in dialysis facilities was born.
The device developed at that time was the “DBB-11”, a three-fluid mixing single-pass dialysis machine, which was released in 1980.
Fig.8 Three-fluid mixing single-pass dialysis machine, “DBB-11”
Development of a dialysis fluid automatic supply device that is compatible and synchronized with a dialysis device
In the early 1980s, Nikkiso’s concept of device development was centered on “downsizing” and “miniaturization”. Progressing towards this goal led to the development of the multi-patient three-fluid mixing dialysis fluid automatic supply device series known as the “DAB” series. Similar to the “DBB-11,” it accommodated bicarbonate dialysis fluid and incorporated cutting-edge technology of that time, including the use of integrated circuits (IC).
This device accurately diluted dialysis fluid concentrates and reverse osmosis (RO) water in precise proportions, providing a continuous supply of the required dialysis fluid. We offered three types (DAB-05, DAB-10, DAB-20) based on the dialysate supply volume. Additionally, it featured the capability to switch between acetate and bicarbonate dialysis fluid supply with the press of a button.
A significant feature of the “DAB” series was its synchronized with the patient monitoring device series “DCS.” This interconnection allowed for seamless operation between the two devices, achieving systematization of dialysis treatment and advancing automation in dialysis facilities.
Fig.9 DAB-20
Ahead of its time, we developed an innovative dialysis device by incorporating a microcontroller for the first time
In the late 1980s, microcontrollers began to be widely used in consumer electronics and various other applications. Development began driven by the desire to incorporate cutting-edge technology in 1987, we were the first in the dialysis industry to release the single-pass three-fluid mixing dialysis device “DBB-62” featuring a microcontroller. The DBB-62, equipped with an LCD panel and advanced features such as a self-diagnostic function with a pressure sensor in the piping system, marked a groundbreaking advancement in dialysis device. This product was a significant milestone for Nikkiso, representing a transformative moment.
With the expanded possibilities brought by the microcontroller, we established an in-house software development department. This move allowed us to explore the development of products and systems with data communication capabilities, further broadening the scope of our technological advancements.
Fig.10 DBB-62 with Self-test function
Birth of downsized and infrequent maintenance dialysis device
In 1982, we released the patient monitoring device “DCS-22,” featuring a duplex-pump ultrafiltration control system. This device, known for its excellent compatibility with the blood circuit and a user-friendly design with a separate display and control unit, received high praise and was installed in numerous dialysis facilities across Japan. In pursuit of enhanced safety, we introduced the evolved patient monitoring device “DCS-211” in 1989, equipped with a twin microcomputer system. The “DCS-211” revolutionized the field by DC-rectifying and downsizing piping components (pumps, solenoid valves, etc.), laying the foundation for the current generation of such components. The TMP auto forecast monitoring function was introduced in this device. Dialysis facilities that adopted it praised its reduced size, lighter weight, and improved ease of maintenance. The concept of combining high functionality with compact design in the “DCS-211” was subsequently inherited by the later “DCS-72.”
Fig. 11 DCS-22 featuring a duplex-pump ultrafiltration control system
Development of original PEPA membrane with excellent dialysis efficiency for patient-friendly dialysis treatment
The turning point in our dialysis membrane development was in 1985 when we discovered that β2 macroglobulin was a substance causing complications in long-term dialysis patients. In April 1986, we determined to challenge in creating our own dialysis membranes. The original hollow fiber membrane was developed using two synthetic polymers, polyacrylate, and polyethersulfone, and was named the ‘PEPA Membrane’ after the initial letters of polyester polymer alloy. The product was approved by the Ministry of Health and Welfare in 1990, and sales began
in 1991.
Fig.12 Original PEPA membrane series “FLX”
To create a patient monitoring device with a user-friendly design to provide with comfort to patients
Leveraging the technology introduced in the “DCS-211,” such as the twin microcontroller system, DC-rectification of piping components, and downsizing, we developed the dialysis monitoring device “DCS-72” in 1992, focusing on a design, prioritizing on patients and treatment environment. During that time, the quality of dialysis treatment had been assured, and there emerged a shift in mindset towards improving the quality of life (QOL) for patients by ensuring their comfort during dialysis. In the development process, we emphasized product design, considering questions like “How can we make patients feel more relaxed during treatment?” and “What design facilitates nurses in easily communicating with patients?”
The design transitioned from the conventional angular shape to a more rounded and gentle form. To achieve this, we adopted resin as the material instead of the previously used metal sheet, slimming down the device and minimizing obstruction to the patient’s field of view. The distinct design departure from traditional dialysis machines garnered significant attention and resulted in the device winning the Good Design Award in 1992 in the Product Design category.
While the “DCS-72” became relatively expensive due to substantial changes in manufacturing processes, including transitioning the exterior material from metal sheet to resin molding, many healthcare professionals chose to adopt it, recognizing the potential positive impact on patient satisfaction. Subsequently, the patient monitoring device “DCS-26” was released with nearly identical functionality but improved cost-effectiveness. This allowed it to be widely adopted in numerous dialysis facilities.
Fig.13 Patient monitoring device “DCS-26”
“ETRF EF-01” and “Clean Coupling,” designed to meet the demand for the purification of dialysate
In the mid-1990s, there was a demand from dialysis facilities to enhance the purity of dialysis fluid. During that time, numerous publications suggested that purifying dialysis fluid could have clinical benefits, and our PEPA membrane was recognized for its effectiveness in endotoxin retentive. In response, we introduced the endotoxin retentive filter “EF-01,” utilizing our PEPA membrane, in 1995.
After the release of EF-01, feedback from dialysis facilities indicated a concern: even if dialysis fluid was purified using EF-01, the O-rings of dialyzer couplings could get dirty, leading to the delivery of contaminated dialysis fluid. To address this, we developed the “Clean Coupling,” which allows thorough cleaning and disinfection, including the O-ring.
Subsequently, to further enhance purification, ” EF-01″ evolved into the improved “EF-02.” This version featured modifications to the connecting parts, enabling easy one-touch attachment to a dedicated holder and improving overall usability.
Fig.14 Clean Coupling
Fig.15 Endotoxin retentive filter “EF-01”
Development of a dialysis device which complies with strict standards in Europe
In 1997, we developed the personal dialysis device “DBB-03” tailored to European standards and market needs. Just one year later, in 1998, we added the functionality of online HDF. At that time, it was commonly believed that at least a five-year development period was necessary in Europe. However, for the development of “DBB-03,” we temporarily suspended the development of domestic products and concentrated our engineers on this product, achieving a short development period of two years. The development was so rapid that even the representative from a German third-party certification body, who was our advisor, jokingly asked, “Did you work without sleeping?”
Fig.16 Personal dialysis device “DBB-03”
Development of powder-form dialysis agents and dissolving device with a thorough focus on purification
In the mid 1990s, the concentrate for dialysis fluid was typically prepared by transferring two types of concentrates, A concentrate and B concentrate, to a tank for use. Alternatively, A concentrate was transferred to the tank, and B powder was dissolved in the tank for use. However, liquid form had drawbacks, including issues related to transportation costs, storage space, and the weight of liquid bottles, which posed challenges in terms of effort. Additionally, during the transfer to the tank or when introducing the B powder into the tank, there was a possibility of exposure to the outside air, leading to potential contamination.
With the goal of minimizing contact with people and the outside air and automating the entire process of preparing dialysis fluid concentrate, we developed our proprietary D-Dry Dissolution Device “DAD-30” and bottle-type powder-form agents “D-Dry 2.5, D-Dry 3.0” in 1997.
By opening the bottle-contained powder within a sealed circuit, we eliminated exposure to air, and unlike the traditional tank method, significant effort was also reduced.
Fig.17 D-Dry Dissolution Device “DAD-30”
Fig.18 Bottle-type powder-form agents “D-Dry 2.5, D-Dry 3.0” in 1997
Development of Blood volume monitor, enabling the measurement of circulating blood volume and facilitating appropriate fluid removal
In dialysis treatment, fluid removal can temporarily decrease circulating blood volume (BV), leading to a drop in blood pressure. The body attempts to maintain blood pressure by increasing heart rate during such episodes. However, the body’s response may not keep up during hemodialysis, potentially resulting in symptoms and a state of shock due to decreased blood pressure. To address this issue, we explored methods to monitor the BV change rate of patients undergoing dialysis in real-time. By establishing correlations between fluid removal volume, fluid removal rate, BV, and blood pressure changes, we aimed to determine appropriate methods and guidelines for fluid removal.
To achieve this, we developed a “Blood Volume Monitor (BVM)” which allows real-time monitoring of blood volume change rates. In 2003, it was integrated into the dialysis monitoring device “DCS-73” and the personal dialysis device “DBB-73” as an optional accessory. The device screen displays the BV change rate graph, and if the device is equipped with a blood pressure monitor, it facilitates easy comparison between BV changes and blood pressure. Furthermore, the measured data can be downloaded to a computer, allowing for analysis of BV change rates after dialysis and the reassessment of dialysis conditions. The introduction of the BV monitor has enabled the sequential monitoring of patients’ conditions, contributing to the implementation of more stable dialysis treatments.
A personal dialysis device designed with a focus on user-friendliness, considering the prospect of home hemodialysis
In the year 2007, the development of the personal dialysis device ‘DBB 81’ took place with the foresight of enabling patients to undergo dialysis in the comfort of their homes. This innovative device featured a movable monitor that could be operated in a seated position, an intuitively navigable interface with a simple screen layout and voice guidance. Considering the ease of attachment and detachment of the blood circuit, it embodied an advanced design. Despite receiving commendation for its attributes, the broader adoption of at home dialysis faced various challenges in Japan, preventing widespread utilization.
Fig.19 Personal dialysis device DBB 81
Innovative Feature ‘D FAS’ Realizing Simplification of Priming, Blood Removal, Blood Return, and Emergency Infusion Processes
As the 21st century began, dialysis treatment had advanced in terms of automation, yet it still demanded a considerable amount of manual intervention. Particularly, priming, blood removal, and blood return were time consuming processes that required significant human involvement. In response to this, a groundbreaking feature named ‘D FAS’ (Dialysis Full Assist System) was introduced in 2009. In accordance with its name, the ‘D FAS’ system fully assists with the priming, blood removal, and blood return procedures, ushering in a new era of enhanced automation. This not only contributed to further streamlining the dialysis process but also increased safety by preventing human errors during operations.
Fig.20 D-FAS (Dialysis Full Asist System) flyer in 2009
Delivering new “NIKKISO Total System NX” comprehensively supporting dialysis treatment.”
In an era characterized by the diversification of dialysis treatments and the existence of facilities of various scales, the ‘NIKKISO Total System NX’ was developed with the design philosophy of ‘purification of dialysate,’ ‘streamlining of dialysis operations,’ and ‘evolution of monitoring functions,’ aiming for comprehensive enhancement of added value. The development of this system commenced in 2007. While conventional approaches involved the individual development of each device, considering the entire process carried out in dialysis facilities, NIKKISO, as a comprehensive manufacturer of dialysis devices, developed all related products under the same concept. The dialysis communication system ‘Future Net Web+’ was first released in 2009, designed to seamlessly integrate with the subsequent lineup of total system products. Responding to the needs of dialysis facilities, it enables smooth coordination with electronic medical records (EMR).
Furthermore, in 2010, the reverse osmosis purified water generation system ‘DRO-NX’ and the fully automatic dissolver ‘DAD-50NX’ were released, followed by the multi-patient dialysate supply device ‘DAB-NX’ in 2011, constructing a system for the dialysate adjustment room. ‘DAB-NX’ took on a central role in the system, allowing for unified operation and settings across devices. The expansion of the disinfection range and simplification of piping enabled efficient cleaning and disinfection of the pipes, contributing to dialysate purification throughout the entire system.
Providing patients with the most optimal dialysis treatment utilizing monitoring feature such as the BVM and DDM.
In 2011, as part of the NIKKISO Total System NX series, the versatile dialysis monitoring device ‘DCS-100NX’ was launched. This multifunctional dialysis machine, designed with a sleek and efficient body, supported Online Hemodiafiltration (HDF) and integrated the “D-FAS” function.
A notable feature of the ‘DCS-100NX’ was the evolution of monitoring capabilities. The Blood Volume Monitor (BV monitor) expanded its application to include functions such as calculating Plasma Refilling Rate (PRR), displaying ΔBV reference area, and measuring vascular access recirculation rate, providing further insights into the patient’s condition. Additionally, the Dialysate Delivery Monitor (DDM) introduced in 2012 utilized deep ultraviolet LED to optically measure changes in the composition of dialysate effluent, enabling real-time confirmation of the dialysis volume. The deep ultraviolet LED, manufactured in-house since 2013, played a crucial role in this advancement. The introduction of the NIKKISO Total System NX allowed for the stable and cost-effective delivery of high-quality treatments.
Fig.21 Versatile dialysis monitoring device “DCS-100NX”
Striving for advancements in product development by gaining knowledge in healthcare and medicine
The development of dialysis devices requires medical knowledge. In Nikkiso , each engineer values the opportunity to visit the actual clinical settings where our products are utilized to understand firsthand what can be done to enhance dialysis treatment. We prioritize engaging with doctors and staff, valuing their opinions and feedback. Those feedback is crucial in improving existing products as well as in developing new products.
Being involved in the field of healthcare also necessitates knowledge of human body. To address this, our engineers actively participate in courses offered by medical faculties to acquire foundational medical knowledge. By having a solid understanding of the fundamentals of medicine, our engineers can better comprehend the requests and needs of medical professionals, contributing to more informed and mature product development. The primary driving force of our engineers in developing new products is the consideration of “ For the sake of the patients”.
Fig.22 Latest overseas dialysis device “DBB EXA” and “DBB EXA ES”
Fig.23 Currently, the NX series has been replaced by the Si (Smart and intelligent) series.
2. Development of Japan’s first bedside artificial pancreas
In the mid 1970s, we focused on the artificial pancreas as a development theme. The number of diabetes patients was increasing year by year, but at the time, no other companies were focused in developing such a device which would enable automatic insulin injection.
Nikkiso was the first company in Japan to develop an artificial heart pump and to domestically produce an artificial kidney device, and it decided to take on the challenge of developing an artificial pancreas as well.
Nikkiso had previously developed the artificial kidney from overseas. Until then, Nikkiso had developed new products mainly by introducing technologies from overseas and applying and developing existing technologies, but the artificial pancreas started from scratch.
The artificial pancreas consists of three components: a pump that injects insulin and glucose, a sensor that measures blood glucose levels, and a control unit that calculates the amount of insulin and glucose injected. Dr. Shichiri of Osaka University Medical School developed the insulin infusion calculation formula and the glucose infusion calculation formula for the purpose of avoiding hypoglycemia. Nikkiso launched the SMG 11A as a continuous blood glucose monitoring device (glucose monitor) in 1981, based on the sensor that had been the most difficult to develop.
Nikkiso and the First Department of Internal Medicine of Osaka University jointly wrote a paper on the sensor, which won an award as the best paper of the Japanese society for medical engineering.
Then, in 1984, Nikkiso launched the “STG 11A” artificial pancreas equipped with insulin and glucose infusion calculation formulas, followed by the “STG 22” in 1987. The STG 22 was used at university hospitals and other regional flagship hospitals, and its clinical applications attracted attention at many academic conferences. Since then, we have continued to make steady improvements as the world’s “one and only bedside artificial pancreas ”, and the results of these improvements came to fruition 25 years later in 2009 with the “STG 55” artificial pancreas. The “STG 55” was developed for continuous measurement of blood glucose levels, diabetes testing, and blood glucose control in acute and surgical fields. It was conceptually designed as a compact and labor saving device which can be installed in operating rooms and intensive care units.
Fig.24 Artificial Pancreas STG 11A, STG 22, STG 55