Supporting data for "Organoid systems to study the effect of steroids in modulating immune-mediated inflammation in billary atresia"

Biliary atresia (BA) is devastating congenital anomaly characterized by inflammatory fibrosclerosing changes of the extra- and intra-hepatic biliary systems. It is the most frequent cause of persistent neonatal cholestasis globally, with a higher incidence observed in the Asia-Pacific regions including Hong Kong. It is widely believed that most BA start with a series of abnormal immune interactions that trigger biliary inflammation as the common pathway. The critical role of inflammation in the pathogenesis of BA has been well established. The inflammatory damage to the cholangiocytes eventually results in biliary fibrosis and obstruction, ultimately leads to liver failure. A timely Kasai operation during the neonatal or early infantile period can potentially restore biliary drainage but the outcome is still far from optimal. A previous study by the PA revealed that long-term transplant-free survival could only be achieved in less than half of the patients and many of them suffer from major complications such as recurrent cholangitis or life-threatening portal hypertension. Although liver transplant is the salvage treatment, due to the scarcity of suitable liver grafts, patients could die before a liver graft is available. 

BA not only impairs the children’s well-being but also imposes a heavy burden on their families, carers, and society. It is estimated that mean health cost for each BA patient ranges from HK$0.2–3.3 million. BA thus represents a huge medico-societal problem and, clearly, surgery alone cannot be the sole treatment to this condition. New therapies that could enhance the curative rate of BA are needed urgently. 

Most of the previous and ongoing research focuses on the operative approach and adjuvant treatment, while there is little knowledge on pre-operative treatment. Unlike other congenital anomalies, which have been well-developed during the fetal period, the major pathobiology of BA takes place continuously throughout the peri-natal period. As the diagnosis of BA could be made in the early phase by liver biopsy and/or cholangiogram, there is thus a valuable window period for therapeutic intervention between diagnosis and operation with an attempt to slow down or even terminate the pathological process to enhance the surgical (Kasai operation) success rate. 

Steroids are drugs that are well-known for their anti-inflammatory action. However, almost all research on steroids focuses on post-operative usage, and their therapeutic value as a neo-adjuvant treatment to improve the surgical outcome remains undetermined. On the other hand, steroids are associated with potential side effects such as growth impairment and should be used cautiously with scientific evidence. Therefore, our objective is to investigate the effect of a steroid in pre-operative BA liver with attention on its anti-inflammatory mechanism via in-vitro and in-vivo experiments. In-vitro study will be conducted via organoid technology. This will be supplemented with an in-vivo animal study to provide additional data on phenotypical changes in an animal BA model.

胆道闭锁（BA）是一种毁灭性的先天性异常，其特征为胆管系统（包括肝内和肝外）的炎症性纤维化改变。它是全球新生儿持续性胆汁淤积的最常见原因，在包括香港在内的亚太地区发病率较高。普遍认为，大多数BA始于一系列异常的免疫相互作用，这些相互作用触发了胆管炎症，作为共同的途径。炎症在BA发病机制中的关键作用已被充分确立。胆管细胞的炎症损伤最终导致胆管纤维化和阻塞，最终导致肝衰竭。新生儿或早期婴儿期及时进行Kasai手术可能有助于恢复胆管引流，但结果仍远未理想。PA的一项先前研究揭示了长期无需移植的生存率仅在不到一半的患者中实现，其中许多患者遭受严重并发症，如复发性胆管炎或危及生命的门静脉高压。尽管肝移植是挽救性治疗，但由于合适的肝移植供体的稀缺，患者可能在获得肝移植供体之前就死亡了。

BA不仅损害儿童的身心健康，而且给他们的家庭、照顾者和社会带来了沉重的负担。据估计，每个BA患者的平均医疗费用在0.2-3.3百万港币之间。因此，BA构成了一个巨大的医社问题，并且显然，仅仅手术不能成为该病症的唯一治疗方法。迫切需要能够提高BA治愈率的新疗法。

以往和正在进行的大部分研究集中在手术方法和辅助治疗上，而对术前治疗的知识却知之甚少。与其他在胎儿期已充分发展的先天性异常不同，BA的主要病理生理学在整个围产期持续发生。由于BA的确诊可以在早期通过肝活检和/或胆管造影进行，因此在诊断和手术之间有一个宝贵的治疗干预窗口期，试图减缓甚至终止病理过程，以提高手术（Kasai手术）的成功率。

类固醇是众所周知的具有抗炎作用的药物。然而，几乎所有关于类固醇的研究都集中在术后使用上，它们作为新辅助治疗以改善手术结果的治疗价值尚不确定。另一方面，类固醇与潜在的副作用，如生长抑制相关，应谨慎使用，并需有科学依据。因此，我们的目标是研究术前BA肝脏中类固醇的效果，重点关注其抗炎机制，通过体外和体内实验进行。体外研究将通过器官oid技术进行。这将通过在动物BA模型中提供额外的表型变化数据来补充体内动物研究。