Effects of the Collagenase of the Bacteria Clostridium Histolyticum on the Development of Capsular Fibrosis after Insertion of Silicone Implants in Rats

硅胶隆乳术是世界上最常见的美容手术。即使对于再造适应症，例如乳腺癌或先天性畸形，硅胶植入物的插入也是一种有效和安全的手术，可以恢复自然的乳房体积和形状。然而，长期的并发症往往影响重建患者决定风险和更具侵入性的自体组织移植。在这种情况下，囊纤维化是硅胶隆乳后最常见和最重要的并发症。基于异物反应，硅胶引起过多的细胞外基质形成，导致女性乳房出现可触及、可见和疼痛的硬结。手术切除关节囊组织和更换植入物是目前唯一足以治疗关节囊纤维化的方法。然而，尽管有足够的手术，复发的风险高达55%。此外，乳腺癌后重建隆乳的包膜纤维化发生率是美容隆乳的5倍。因此，对于囊膜纤维化或乳腺癌后状态的患者，通常不推荐硅胶隆乳，使危险和更具侵入性的自体组织移植成为唯一的重建选择。发展一种非手术治疗来克服囊纤维化将直接影响这些重建患者的治疗策略。囊纤维化主要由胶原蛋白组成，类似于Dupuytrens病，手掌筋膜形成过多的细胞外基质，导致手指疼痛可触及的股和屈曲挛缩。虽然手术切除纤维化组织是治疗Dupuytren病的金标准，但在过去几年中，注射特定的胶原酶变得越来越流行。这种胶原酶降解除亚型4以外的所有胶原亚型，亚型4是血管、神经和肌腱的基底层的主要部分。由于这些功能结构的保护，这种特定的胶原酶可以安全有效地注射到手掌中，使应用到女性乳房理论上可行。本研究的目的是治疗囊纤维化，并防止其发展与胶原酶注射的手段。因此，我们利用已建立的啮齿动物模型，我们可以创建用于体外和体内研究的包囊纤维化。由于与哈佛医学院的合作，我们有机会获得现代成像方法和免疫学领域的专家知识。如果这项研究在啮齿动物模型中证明了有益的效果，我们计划在大型动物模型中进行进一步研究，并在体外应用于植入的人类胶囊。成功注射胶原酶克服和预防胶囊纤维化将挽救数十万妇女的手术干预，并使乳腺癌后的硅胶乳房重建更加可行。

Augmentation mammaplasty with silicone implants reveals the most common aesthetic surgery worldwide. Even for reconstructive indications, thus breast cancer or congenital malformations, insertion of silicone implants is an effective and safe procedure to regain natural breast volume and shape. Nevertheless, long-term complications often influence reconstructive patients to decide for risky and more invasive autologous tissue transplantation. In this context capsular fibrosis is the most common and momentous complication after silicone breast augmentation. Based on a foreign body reaction, silicone provokes an excessive extracellular matrix formation, leading to palpable, visible and painful indurations of the female breast. Surgical resection of capsular tissue and implant exchange is currently the only sufficient therapy for capsular fibrosis. However, despite adequate surgery, risk of recurrence is up to 55%. Furthermore incidence of capsular fibrosis for reconstructive implantations after breast cancer is 5 fold higher compared to aesthetic augmentations. Consequently, for patients with state after capsular fibrosis or after breast cancer, silicone breast augmentation is often not recommended, making hazardous and more invasive autologous tissue transplantation the only reconstructive option. Development of a non-surgical treatment to overcome capsular fibrosis would directly influence therapeutic strategies of these reconstructive patients.Capsular fibrosis consists mainly of collagen, similar to Dupuytrens Disease, an excessive extracellular matrix formation of the palmar fascia, which leads to painfully palpable strands and flexing contracture of the fingers. Whereas surgical resection of fibrotic tissue was goldstandard for the treatment of Dupuytrens Disease, injection of a specific collagenase became more and more popular in the last few years. This collagenase degrades all collagen subtypes except of subtype 4, which is the main part of the basal lamina of vessels, nerves and tendons. Due to protection of these functional structures this specific collagenase can be injected safely and effectively into the palm making application into the female breast theoretically feasible.Aim of this study is to treat capsular fibrosis and to prevent its development with means of collagenase injection. Therefore we utilize an established rodent model with which we can create capsular fibrosis for in-vitro and in-vivo investigations. Due to cooperation with Harvard medical school, we have access to modern imaging methods and expert knowledge in the field of immunology. If this study proves beneficial effects in a rodent model, we plan further studies in a large animal model as well as ex-vivo applications into explanted human capsules.Successful injection of collagenase to overcome and prevent capsular fibrosis would save a few hundred thousand women surgical intervention and make silicone breast reconstruction after breast cancer more feasible.