Peripheral Artery Disease (PAD), which afflicts over 200 million people worldwide.
Atherosclerosis, a condition characterized by narrowing of the arteries, is a systemic disease that can cause various symptoms due to decreased blood flow throughout the body.
Peripheral Artery Disease (PAD) is a term used to describe diseases that occur in the peripheral blood vessels, away from the heart. Among these, lower limb occlusive arterial disease refers to a condition where arteries in the legs become clogged due to atherosclerosis, resulting in reduced blood flow.
If left untreated, atherosclerosis in the lower limbs can lead to tissue necrosis and, in the worst case scenario, increase the risk of lower limb amputation. Lower limb amputation not only significantly decreases a patient's quality of life, but also has a 5-year survival rate (less than 50%) that is known to be lower than certain types of cancer [*1]. Early intervention and treatment for lower limb occlusive arterial disease is therefore highly recommended.
Atherosclerotic blood vessel
The estimated number of patients with peripheral artery disease (PAD) worldwide was 202 million in 2010, and the prevalence increased by 23.5% over a decade from 2000, according to a report [*2]. In Japan, the prevalence is estimated to be about 1-3% [*3], but compared to heart disease, PAD is still relatively unknown, and prevention and early detection of the disease are delayed.
*1 Mustapha JA, Katzen BT, Neville RF, et al., Critical Limb Ischemia: A Threat to Life and Limb, Endovascular Today. 2019; 18(5): 80-82.
*2 Fowkes FGR, Rudan D, Rudan I, et al., Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. The Lancet. 2013; 382(9901): 1329-1340.
*3 Tetsuro Miyata et al., Treatment Guidelines for Peripheral Artery Disease (Revised in 2022). 2022.
Open surgery to minimally invasive treatment via Interventional Radiology
In the past, surgical bypass was the main treatment for atherosclerosis, but in recent years, interventional radiology (IR) with less physical burden and requiring no major incisions has become popular, with "stent placement" being the most common treatment. Stents, medical devices used to expand narrowed arteries and restore blood flow, were first developed in the 1980s for coronary artery disease and the first-generation drug-eluting stents were introduced in the US in 1990. Since then, second- and third-generation drug-eluting stents with even more patient-friendly features have been launched by global medical device manufacturers in Europe and North America in the 2000s and 2010s.
The Challenges of Developing Stents as Medical Devices Implanted in the Bloodstream
Stents are classified by the FDA and PMDA as a high-risk medical device due to the potential risks associated with their usage and manufacturing quality, placing them in the highest risk class. Therefore, their research and development as well as manufacturing require a high level of expertise and experience.
The main reason for the difficulty in developing stents is the biological mechanism that occurs between the blood cell components, vascular tissue, and stent materials in the blood, as well as the difficulty in understanding and developing technology to counteract it.
When blood components come into contact with foreign objects like stents, it triggers the clotting cascade involving platelets and fibrin, as shown in the background image [*4], leading to the formation of blood clots that can cause abnormal thickening of blood vessels and subsequent reocclusion. To address this, various techniques have been attempted by global companies to combat the biologic mechanisms involved.
However, arterial sclerosis in peripheral artery disease (PAD) in the lower extremities presents a more severe biological environment than the coronary arteries due to "slow blood flow," "narrow blood vessels," and "significant physical deformations," and a gold standard for minimally invasive treatment has yet to be established.
*4 Image by Hasebe Research Group: Blood components adhered to SUS316L stent.
We need stents with next-generation technology for minimally invasive PAD treatment.
*4 Image of Hasebe Research Group: Our developed stent coated with diamond-like carbon thin film
Hasebe Research Group, where this project was born, has been researching and developing next-generation biomaterials since the 2000s. One of its major achievements is the development of fluorine-added diamond-like carbon, which has been modified to be suitable for use as a blood-compatible material (*5, *6, *7, and many others).
In this stent development project, the BIOZONE Coating® was improved to follow the multi-axial physical deformation of PAD without peeling, and has been installed on the stent. In non-clinical experiments using animals, an extremely good patency rate has been achieved.
*5 Hasebe T, Saito T, et. al., Antithrombogenicity of fluorinated diamond-like carbon films, Diam Relat Mater. 2005:14:1116-1119
*6 Hasebe T, et. al., Fluorinated diamond-like carbon as antithrombogenic coating for blood-contacting devices, J Biomed Mater Res A. 2006:76:86-94
*7 Maegawa S, Hasebe T, Bito K. al., Time course analysis of antithrombogenic properties of ﬂuorinated diamond-like carbon coating determined via accelerated aging tests: Quality control for medical device commercialization, Diam Relat Mater. 2016:73:33-18
As a result of the development of such blood-contacting materials, new evaluation systems were needed that did not exist before. Hasebe Research Group has created an evaluation system for the blood compatibility of artificial materials by analyzing platelet behavior on different materials and has conducted evaluations of developed products [*8 and many others].
Analysis of morphological changes after platelet adhesion to the material: Upon activation from a to d, platelets attract other platelets and cause thrombosis.
We have developed a novel PAD stent utilizing our proprietary BIOZONE Coating® technology to achieve high vessel scaffolding and drug-eluting capabilities, while maintaining a slim and non-obstructive profile for blood flow. This has been made possible through the integration of advanced structural design techniques for high vessel retention, as well as polymer technology for precise control over drug release kinetics. Our approach allows us to fully maximize the potential of BIOZONE Coating® for the development of an innovative PAD stent design.
*8 Hasebe T, Yoshimoto Y al., Ultrastructural characterization of surface-induced platelet activation on artiﬁcial materials by transmission electron microscopy, Microsc Res Tech. 2013:76:342-349
We are a medical-engineering collaborative technology venture company founded to deliver the technology based on the materials engineering approach of "Hasebe Research Group" to the world.
December 2022 - present
Established Global Vascular Co., Ltd.
The design and development business related to this project was incorporated.
September 2022 - present
Selected for the AMED Grant Call for Proposals 'Bridging Research Program - Seeds F' for the fiscal year 2022
The research project titled 'Practical Research on a Long-Term Patent Stent System for Small Arteriosclerotic Lesions Below the Knee (BTK)' has been initiated by Tokai University, Yamashina Seiki Co., Ltd., and Keio University.
April 2019 - present
Hasebe Research Group and BIOZONE MEDICAL Co., Ltd. have started a joint research project.
Hasebe Research Group has started a joint research project with BIOZONE MEDICAL Co., Ltd. (formerly Marusan Pharma Biotech Co., Ltd.).
August 2018 - March 2022
Selected for the AMED Grant 'Program for Development of Advanced Measurement and Analysis Technology and Equipment' for the fiscal year 2018
"The research project titled 'Development of a Long-Term Patent Stent System for Small Arteriosclerotic Lesions Below the Knee (BTK)' has been initiated by Tokai University, Yamashina Seiki Co., Ltd., and Keio University.
March 2005 - present
Establishment of the fundamental technology of BIOZONE Coating® and its improvement.