Hendrickson Troy, Lupo Cristina, Bauza Guillermo, Tavares Liliana, Ingram Shannon, Wang Sufen, Moreno Michael, Tasciotti Ennio, Valderrabano Miguel, Taraballi Francesca
Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, 6670 Bertner Ave. Houston, TX, 77030, USA.
Texas A&M College of Medicine, MD/PhD Program, 8447 Highway 47, Bryan, TX, 77807, USA.
Mater Today Bio. 2022 Mar 10;14:100240. doi: 10.1016/j.mtbio.2022.100240. eCollection 2022 Mar.
Atrial fibrillation induced stroke accounts for up to 15% of all strokes. These strokes are caused approximately 90% of the time by clot formation in the left atrial appendage (LAA). To prevent these clots, the most common approach is to administer blood thinners. However, contraindications prevent some people from being able to have blood thinners. Devices have been developed to seal the LAA to prevent clot formation in these patients. Current devices, such as the LARIAT® tie off the LAA theoretically preventing blood from entering the LAA. These have had limited clinical success mainly due to failure to completely close the LAA leaving holes and orifices for thrombi to form. To overcome this lack of complete closure, many surgeons use off-label approaches, classically filling the LAA filamentous coils, to cover these holes. Although this usually helps largely cover the holes, placement is challenging, the coils can migrate, the holes are not fully closed as there is space within and around the coils that don't fully mold to the LAA geometry. Furthermore, the coils can develop device related thrombi defeating their purpose. Therefore, these are not fully sufficient to complement the closure techniques in closing the LAA. To address limitation of the closure devices and coil sealing of remaining holes, we developed a thermally responsive hydrogel (Thermogel) that solidifies once injected into the LAA to uniformly and fully close off the LAA thus preventing clot formation and device related thrombi. This Thermogel consists of three portions: 1) a structural component composed of thiolated Pluronic F127 for gel to solid transition following injection, 2) Heparin for anticoagulation, and 3) Dopamine for adhesion to the surrounding endothelium in the turbulent flow encountered in cardiovascular applications. Here we have demonstrated that Thermogel, in conjunction with the LARIAT®, is capable of filling the defects in small and large animals through catheter injection. Thermogel was biocompatible and led to atrophy of the LAA at 5 weeks in a large animal model. Given the advantages of this Thermogel for sealing this defect and ability to be delivered through an endovascular approach, Thermogel presents a viable adjuvant to current occlusion-based treatments for sealing cardiovascular defects.
房颤引发的中风占所有中风病例的比例高达15%。这些中风约90%是由左心耳（LAA）内形成血栓所致。为预防这些血栓形成，最常见的方法是使用血液稀释剂。然而，一些禁忌症使得部分患者无法使用血液稀释剂。人们已研发出封堵LAA的装置，以防止这些患者形成血栓。目前的装置，如LARIAT®，理论上通过结扎LAA来防止血液进入LAA。但这些装置临床成功率有限，主要原因是未能完全封闭LAA，留下了血栓形成的孔洞和开口。为克服这种无法完全封闭的问题，许多外科医生采用非标签方法，传统做法是向LAA内填充丝状线圈以覆盖这些孔洞。尽管这通常在很大程度上有助于覆盖孔洞，但放置具有挑战性，线圈可能会移位，由于线圈内部和周围存在未完全贴合LAA几何形状的空间，孔洞并未完全封闭。此外，线圈可能会形成与装置相关的血栓，从而达不到预期目的。因此，这些方法在封闭LAA方面不足以补充现有的封堵技术。为解决封堵装置的局限性以及剩余孔洞的线圈密封问题，我们研发了一种热响应水凝胶（Thermogel），它一旦注入LAA就会固化，从而均匀且完全地封闭LAA，进而防止血栓形成和与装置相关的血栓。这种Thermogel由三部分组成：1）一种结构成分，由硫醇化的普朗尼克F127组成，用于注射后凝胶到固体的转变；2）用于抗凝的肝素；3）用于在心血管应用中遇到的湍流中与周围内皮细胞黏附的多巴胺。在此我们证明，Thermogel与LARIAT®联合使用时，能够通过导管注射填充大小动物模型中的缺损。Thermogel具有生物相容性，在大型动物模型中5周后会导致LAA萎缩。鉴于这种Thermogel在封堵该缺损方面的优势以及通过血管内途径递送的能力，Thermogel是目前基于封堵的心血管缺损治疗的一种可行辅助手段。
