Gingival Recession

不可逆的牙龈退缩，困扰许多人。牙龈退缩的结果，是牙缝变大、牙齿松动，很不美观，也不健康。严重的牙龈退缩，更是牙体种植的红线。以往，想要修复退缩的牙龈，除了从患者口腔上颚取自体组织来填补，别无他法。如今，这一临床空白，被国产的创新产品填补上了。11月29日，苏州的创新医疗器械企业诺一迈尔，自主研发的创新医疗器械闻诺®明胶-聚己内酯分层牙龈修复膜，经国家药品监督管理局批准获得III类医疗器械注册证（国械注准20233171776），可以用于口腔角化龈增宽，加深前庭沟，牙龈修复由此有了更简单、高效的方法。闻诺®明胶-聚己内酯分层牙龈修复膜图片来源：受访者提供值得注意的是，就在1年前的2022年9月，诺一迈尔的这款明胶-聚己内酯牙龈修复膜，获准进入创新医疗器械特别审查程序。随着闻诺®的获批，国内无源植入口腔科器械也实现了《创新医疗器械特别审查程序》施行以来，国家级创新器械零的突破。动脉网了解到，闻诺®的开发历时6年，是诺一迈尔的核心产品之一。通过持续的自主知识产权技术投入，诺一迈尔实现了闻诺®工艺流程、核心装备的全面国产化。“这是一款让人感觉很舒服的产品，从生产工艺到应用价值、临床效果，都达到了预期。”诺一迈尔董事长张文彩，是再生医学行业的老兵。2011 年入行以来，张文彩曾带领多款创新的再生医学产品完成从实验室技术向产业化应用的跨越。在他看来，经过多年积累，国内再生医学行业在口腔、骨科等相对成熟的细分领域，已经具备了赶超国际同行的综合实力，只有做高端的创新产品，去解决临床痛点，才能形成全球化的竞争优势。6年磨一剑，填补临床空缺在诺一迈尔刚刚成立的2017年，闻诺®的研发就开始立项，至今已有6年时间。作为一家创新的医疗器械企业，诺一迈尔每年会投入大量资金研发新产品，闻诺®是其中最为重磅的产品之一。具体而言，闻诺®是由明胶和聚己内酯，经静电纺技术制成的三层复合膜，上下两层为明胶，中间层为聚己内酯。其中，明胶纤维层与创面接触，协助角化龈增宽，是实现牙龈组织再生的关键，为牙龈细胞生长提供舒适的微观环境；聚己内酯纤维层则用来增加整个膜体的机械强度，满足临床操作要求。动脉网了解到，使用中，闻诺®会被缝合在清除退缩牙龈组织后的创面之上。所谓组织再生，即膜体降解的同时，牙龈细胞沿着修复膜中复杂的微结构爬行，完成创面的再血管化和上皮化，形成新的牙龈组织。通常，患者在接受牙龈修复手术2周后即可拆线，此时新的牙龈组织已完全愈合，4周左右就能角化成熟。数据显示，约90%的成年人，存在不同程度的牙周疾病。其中，牙龈退缩是颇为棘手的口腔临床痛点。过往的临床实践中，许多牙龈退缩患者因为担心自体游离龈移植术带来的创伤，经常放弃牙龈修复。张文彩告诉动脉网，牙龈细胞非常特殊，其对生长微环境的要求极高，导致绝大多数组织修复材料无法引导牙龈再生。“立项之初，我们选择做牙龈修复，团队内部和许多技术专家是有不同声音的，大家认为难度太大了。”张文彩表示，一直以来，牙龈修复在国际上并没有行业标准、专家共识、治疗指南等可供参考，从原料选择到工艺构建，诺一迈尔每一步都只能摸着石头过河，也积累了大量的创新。一方面，诺一迈尔创新地筛选出了更适合用来制备牙龈修复膜的原材料。对于再生医学产品，力学强度和再生效果，是衡量品质的核心指标。在尝试了数十种原材料以后，诺一迈尔研发团队发现，明胶和聚己内酯组合形成的微观结构，在力学强度、孔隙分布方面，都最适合牙龈修复。“明胶和聚己内酯都是相当成熟且在植入医疗器械领域得到广泛应用的原材料，方便采购，成本也可控。”张文彩指出。另一方面，诺一迈尔在坚持自主创新与产学研合作的基础上，构建了复杂、高效的产品生产工艺。原材料确定下来后，膜体制备的过程中，诺一迈尔遭遇了新的问题。为了创造适宜牙龈细胞生长的微观环境，膜体的撕裂力、抗拉伸强度、降解时间等一系列参数，都需要达到特定标准，这就对温湿度控制要求极高。而明胶本身是一种粘稠状物质，温度轻微变化就会引起流动不稳定，更遑论成膜。经过反复尝试，诺一迈尔中德科学家团队共同实现了工艺稳定的修复膜生产。再一方面，诺一迈尔在原材料开发、工艺优化的基础上，开发出了适合牙龈修复膜生产的高端装备体系。动脉网了解到，这个高端工艺装备开发的过程持续了4年，尤其是诺一迈尔的中德科学家团队提出了一系列行之有效的解决方案。实际上，在特定的细分领域，与领先的研究团队合作，来实现先进技术的高效转化，已经成为诺一迈尔布局再生医学产品的重要底层逻辑。正如张文彩所讲，从口腔到皮肤、骨骼，不同类型的修复产品，涉及的工艺要求差别极大，只有持续做创新技术的转化，才能不断迭代出新的符合临床需求产品。做高端的再生医学产品“原本计划入组期18个月的临床试验，没想到只用了8个月，就完成了全部患者的入组。”张文彩坦言，关于牙龈修复膜的市场价值，他一直颇有信心，但患者对于尝试这样一款创新产品的热情之高，超过了他的想象。2022年5月，在南京大学医学院附属口腔医院的牵头下，闻诺®在南京医科大学附属口腔医院、四川大学华西口腔医院等5家国内头部口腔医院完成了临床试验，临床试验结果为其临床应用的安全性和有效性提供了佐证。动脉网了解到，对于部分使用闻诺®的早期患者，诺一迈尔已经跟踪随访近24个月，目前反馈良好，这让张文彩更加期待闻诺®商业化后的市场表现。他告诉动脉网，诺一迈尔已经为闻诺®的大规模商业化，做好了产能释放、市场认知培育等方面的准备，“预计最快在2024年一季度，终端用户就可以用闻诺®来实现牙龈修复。”据了解，诺一迈尔在苏州总部的生产中心，能够满足快速扩张的产能需求，而陆续开展的临床研究合作，正在帮助更多口腔临床医生建立关于牙龈修复的认知和技术能力。创立6年来，诺一迈尔深耕创新的再生医学产品，业务涉及口腔科、骨科、耳鼻喉科、眼科等医疗领域，已经布局20项以上的植入医疗器械产品，尝试用品质足够好的创新产品，去解决牙周软组织增量、软骨再生、病理性高度近视等多个全球范围内的复杂组织再生难题。张文彩告诉动脉网，闻诺®的上市，是诺一迈尔商业化的重要里程碑，未来，诺一迈尔还会强化创新力度，高效推出各类具有临床价值的再生医学产品。现阶段，诺一迈尔自主研发的子宫内膜修复产品，在某医院完成了8个病例的临床前研究，针对不孕女性的子宫内膜修复，展现出了良好的治疗效果。张文彩告诉动脉网，诺一迈尔在研的另一款关节软骨修复产品，直击关节软骨受损之后难以修复的市场痛点，也在临床前的研究中展示了很好的数据。按照张文彩的计划，诺一迈尔形成了多技术、多品种、多赛道的产品策略，还将通过自建的近100人研发团队，与全球顶尖专家合作，持续开发国际化、创新、不可替代的丰富再生医学产品体系，构建具有国际影响力国产医疗器械品牌。我们也期待，具备自主创新能力的国内医疗器械企业，为填补临床空白，输出更多独特价值。近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

Researchers have discovered that softer gums hinder the development of gingiva fibroblasts -- the cells that help produce the fibers that hold our teeth in place. The tissue area that surrounds our teeth is known as the gingiva, and healthy teeth will nestle firmly into the gums thanks to the many gingival fibers that connect the tooth to the gingiva. The gingiva is home to fibroblasts -- cells that contribute to the formation of connective tissue. A group of scientists from Tohoku University have discovered that the gingiva stiffness influences the properties of gingival fibroblasts, which in turn affects whether inflammation is likely to occur and make gingival fibers difficult to form. Their findings were published in the journal Scientific Reports on January 24, 2023. "We discovered that soft gingiva results in inflammation and hinders the development of gingival fibers," says Associate Professor Masahiro Yamada from Tohoku University's Graduate School of Dentistry. It has long been known that individuals with thick or stiff gingiva are less susceptible to gingival recessions. This is where the gingiva begins to recede and expose a tooth's root. Many factors can lead to gingival recession, such as gum disease, over-brushing, and chewing tobacco. But this is the first time that gingival stiffness has been attributed to biological reactions. Although fibroblasts play an important role in the maintenance, repair and healing of the gingiva, they also produce various inflammatory and tissue-degrading biomolecules which degrade the gingival fibers. In addition, fibroblasts are associated with immune responses to pathogens. Yamada, along with his colleague Professor Hiroshi Egusa, also from the Tohoku University's Graduate School of Dentistry, created an artificial culture environment that simulated soft or hard gingiva and cultured human gingival fibroblasts on them. They discovered that hard gingiva-simulated stiffness activated an intracellular anti-inflammatory system in the gingival fibroblasts that prevented inflammation. Yet, soft gingiva-simulated stiffness suppressed the fibroblastic anti-inflammatory system. This increased the likelihood of inflammation and resulted in less collagen synthesis. "Our research is the first to demonstrate the biological mechanisms at play in regard to a patient's gingival properties," adds Yamada. "The results are expected to accelerate the development of advanced biomaterials to control local inflammation or microdevices that simulate the microenvironment of inflammatory conditions."

Israeli startup BioChange has developed a breakthrough technology for tissue regeneration ReGum™ could help the approximately 40% of adults who suffer from moderate to severe gum recession disease (periodontitis) YOKNEAM ILLIT, Israel, Sept. 22, 2022 /PRNewswire/ -- Israeli startup BioChange, which has developed a breakthrough technology for tissue regeneration, was able to treat periodontitis (gum recession disease) in canines. The use of BioChange's ReGumTM led to a 100% improvement in comparison to the standard-of-care treatment regimen, with a significant regeneration of periodontal tissue (including gum and bone tissues). The statistically significant findings were recently published by Dr. Ana Nemec, Dr. Jerzy Pawel Gawor, and Peter Strøm in Frontiers in Veterinary Science. Periodontal diseases are mainly the result of chronic infections and inflammation of the gums that surround and support the teeth. In its early stage, called gingivitis, the gums can become swollen and red, and they may bleed. In its more progressive form, called periodontitis, the gum can pull away from the tooth, bone can be lost, and the teeth may loosen and fall out. Periodontal disease is a widespread degenerative disease, which impacts far more than a person's gums and teeth. There is now a significant body of evidence to support the link between periodontitis and life-threatening cardiovascular disease. While periodontal disease is very common in humans and dogs, effective treatment is still needed. In this study, which included 11 pairs of dog teeth, ReGumTM was found to be effective and safe with no side effects. ReGumTM, based on BioChange's novel scaffold technology, triggers a mechanism of repair and regeneration by the patient's own cells. With time, the scaffold biologically degrades, leaving behind only autologous, regenerated, healthy tissue. While currently ReGumTM is commercially available for veterinary use only, the company plans it to be approved for use in humans within the next couple of years. Founded in 2017 by serial entrepreneur Ishay Attar, BioChange's vision is to restore body functions and tissues lost with age and degeneration. The CellFoam™ platform technology developed by the company has far-reaching capability in stimulating the regeneration of a variety of tissues and organs. Based on this technology, BioChange built a pipeline of regenerative products. Some of the products are being developed in collaboration with other companies and leading research centers across the globe. BioChange has already listed a number of achievements in the field, among them: regeneration of skin tissue (including collagen), periodontal tissue, bone tissue, retinal RPE layer (solving AMD), and urethral tissue (to solve sphincter incontinence). "We are very encouraged by the results of the ReGum™ study," says Ishay Attar, BioChange's founder and CEO. "Dr. Nemec's research began as an important exploration of our regenerative scaffold technology platform and eventually led to remarkable results, specifically in periodontal tissue repair. We were able to regenerate the complex periodontal tissue, which is made up of four different tissue types that support the tooth," he said. "No other product has been able to achieve such results in terms of safety and effectiveness." Dr. Ana Nemec, the Primary Investigator of the clinical study: "Periodontal disease is one of the most common oral diseases in dogs and yet there is no effective treatment option once gingivitis advances to periodontitis. Currently the treatment approach is mainly conservative and is based on mechanical removal of the plaque and debridement of periodontal tissues. With our clinical research team, we scientifically proved that the addition of the ReGum is superior to standard therapy alone in periodontal tissue repair in dogs with naturally occurring periodontitis, followed up three months after the treatment." Dr Nemec concluded: "The addition of this new product during the professional treatment by the vet can make a significant difference, saving more teeth from extraction." ReGumTM is now available commercially worldwide. "For vets treating man's best friend, the implant is easy to use and handle, and the procedure hardly takes any longer than the standard periodontal debridement treatment alone," says Attar. While ReGumTM is currently commercially available for veterinary use only, the company expects regulatory approval for use in people within the next couple of years. More info on the medical problem of periodontitis in humans can be found here: About BioChange BioChange has developed a breakthrough technology for tissue regeneration - a unique scaffold that stimulates tissue repair and remodeling at the applied site. The scaffold is based on natural biomaterials designed for implantation, using a minimally invasive procedure. It mimics the healthy Extra Cellular Matrix (ECM) and triggers the body to repair itself. Multiple long-term animal studies confirm the safety and efficacy of the technology. The company is now selling products in the veterinary and research markets and is committed to beginning its first clinical study in aesthetic dermatology in 2023. Several other products based on the CellFoam™ platform technology are in development to enrich BioChange's pipeline. To learn more, please visit Video: Images and extended press release can be downloaded here. Media Contact: Amir Ben Artzi Meirovitch PR [email protected] SOURCE BioChange