SBIR Direct Phase II: Nature Inspired Biphasic Glue for Dura Repair

项目摘要 2018年全球手术粘合剂和密封剂市场价值为40.9亿美元，预计 2026年达到78.9亿美元，复合年增长率为9.7%。中枢神经系统（CNS）中的survival占 2016年市场份额最大，因为全球神经系统疾病的发病率很高。仅举 有60万例颅骨手术，120万例腰椎手术和170万例创伤性脑手术， 仅在美国就有受伤。密封剂是中枢神经系统手术的首选，例如预防脑脊液泄漏 以及脑外科手术中的硬脑膜修复。 然而，传统的密封剂如DuraSeal®和Tisseel®在脑部手术中远远不能令人满意， 它们的弱湿组织粘合强度和快速降解 移植物或硬脑膜成形术装置。因此，对脑部手术用外科密封剂和粘合剂的需求 呈指数级上升，给Aleo BME的BP Glue产品一个巨大的机会，渗透到这个不断增长的市场。 利基市场Aleo BME在发现有趣的组织粘附机制方面取得了重大进展 为BP胶的开发奠定了基础，并确立了BP胶用于脑脊液（CSF）的可行性 在大鼠和猪开颅术模型中的渗漏预防和硬脑膜修复。BP胶是一种A-B配方，由以下成分组成： 全合成和可降解的水性聚氨酯（WPU）纳米颗粒分散液， 反离子BP胶水的粘附机制是英国常春藤粘附机制的独特组合， 所述WPU（+）和WPU（-）纳米颗粒穿透并渗透到组织表面上， 交联以在材料/组织界面处形成机械互锁，用于组织粘附和颗粒粘附 填充理论，通过该理论，颗粒尺寸不匹配（大WPU（+）和小WPU（-））起着重要作用 在增强颗粒填充和融合以改善粘合剂的粘合和内聚强度方面， (Fig. 1）。BP Glue是第一种水性、超强和弹性组织粘合剂，具有等效搭接 剪切强度达到Dermabond®（氰基丙烯酸酯），而不使用有毒化学交联。预计该 在脑外科手术中，使用BP胶可以避免使用其他组织移植物或硬脑膜成形术器械， 也消除了修复术后CSF泄漏的修正手术。此SBIR Direct的目标 第二阶段是扩大BP Glue的制造工艺，开发BP Glue交付工具，验证 放大生产，了解灭菌对BP胶功能的影响，评价其对硬脑膜的有效性 在犬颅骨切开术中进行修复，并根据ISO 10993进一步严格验证BP胶的生物相容性 向FDA提交申请第二阶段的成功将有助于Aleo BME获得进一步的投资， 发展业务合作伙伴关系，并为成功获得FDA上市前批准（PMA）铺平道路 应用和技术商业化。

Project Summary The global market for surgical adhesives and sealants was valued at USD 4.09 billion in 2018 and projected to reach USD 7.89 billion in 2026 at a CAGR of 9.7%. Surgeries in central nervous system (CNS) accounted for the largest market share in the year 2016, owing to a high prevalence of neural disorders globally. To name a few numbers, there are 600K cranial surgeries, 1.2 million lumbar surgeries, and 1.7 million traumatic brain injuries in the U.S. alone. Sealants are the number one choice in CNS surgeries, such as CSF leak prevention and dura repair in brain surgeries, over traditional tissue closure methods such as wires, sutures, and staples. However, traditional sealants such as DuraSeal® and Tisseel® are far from satisfactory in brain surgeries due to their weak wet tissue adhesion strength and rapid degradation and even when used as adjuvants to other tissue grafts or duraplasty devices. As a result, demand for surgical sealants and adhesives for brain surgeries has risen exponentially, giving Aleo BME’s BP Glue product a huge opportunity to penetrate this ever-increasing niche market. Aleo BME has made significant progress in discovering an interesting tissue adhesion mechanism for the development of BP Glue and established the feasibility of using BP Glue for cerebrospinal fluid (CSF) leak prevention and dura repair in rat and pig craniotomy models. BP Glue is an A-B formulation composed of fully synthetic and degradable water-borne polyurethane (WPU) nanoparticle dispersion solutions with counterions. BP Glue adhesion mechanism is a unique combination of English-Ivy adhesion mechanism through which WPU (+) and WPU (-) nanoparticles penetrate and permeate onto tissue surfaces and then ionically crosslinked to form a mechanical interlocking at the material/tissue interface for tissue adhesion and particle packing theory through which particle size mismatch (large WPU (+) and small WPU (-)) plays a significant role in enhancing particle packing and interfusion for improving adhesive and cohesive strengths of the adhesive (Fig. 1). BP Glue is the first aqueous, super-strong, and elastic tissue adhesive demonstrating equivalent lap shear strengths to Dermabond® (cyanoacrylate) without using toxic chemical crosslinking. It is expected that the use of BP Glue may eliminate the use of other tissue grafts or duraplasty devices in brain surgeries and may also eliminate the revisional surgeries to fix the post-surgical CSF leaks. The objectives of this SBIR Direct Phase II are to scale-up the manufacturing processes of BP Glue, develop BP Glue delivery tool, validate the scale-up productions, understand the impact of sterilization on BP Glue functions, evaluate its efficacy for dura repair in a canine craniotomy, and further rigorously validate the biocompatibility of BP Glue following ISO 10993 toward FDA submissions. The success of this Phase II will help Aleo BME secure further investments and develop business partnerships and will pave the way toward a successful FDA Premarket Approval (PMA) application and technology commercialization.