一种新型生物材料装置用于犬Ahmed青光眼瓣膜手术后纤维化滤过泡分流的初步实验研究-动脉网

Preliminary experimental study on a novel device using biomaterial for shunting fibrotic bleb following Ahmed glaucoma valve surgery in dogs

Nature 等信源发布 2025-01-19 21:31

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Abstract

摘要

This study aimed to design and evaluate a novel trans-bleb device (TBD) for draining aqueous humor trapped within fibrotic blebs following Ahmed glaucoma valve (AGV) implantation in dogs. Two clinically normal, purpose-bred Beagles underwent AGV implantation surgery in one eye. When a bleb was formed with increased intraocular pressure (IOP), the TBD was inserted through a fenestration created in the bleb.

。两只临床上正常的，专门繁殖的比格犬在一只眼睛中接受了AGV植入手术。当眼内压（IOP）升高形成水泡时，通过水泡中产生的开窗插入TBD。

IOP measurements, slit-lamp biomicroscopic and ultrasound biomicroscopic (UBM) evaluations were performed during follow-up. Results showed that IOP in the eyes undergoing AGV surgery was significantly lower than in the contralateral normal eye (.

随访期间进行眼压测量，裂隙灯生物显微镜和超声生物显微镜（UBM）评估。结果显示，接受AGV手术的眼睛的眼压显着低于对侧正常眼睛（。

< .001). After 3 weeks, the IOP increased, and the UBM examination confirmed the presence of a bleb wall and an underlying cavity. After TBD application surgery, a significant decrease in IOP was observed (

<0.001）。3周后，眼压升高，UBM检查证实存在气泡壁和下面的空洞。TBD应用手术后，观察到眼压显着降低(

< .001). Histological findings indicated that the TBD effectively penetrated the fibrotic membrane surrounding the AGV, with observed mild inflammatory cell infiltration, neovascularization, and myofibroblast differentiation, suggesting filtering bleb formation. The TBD may offer a novel approach to address bleb fibrosis-related failure following glaucoma surgery, restoring aqueous humor flow, and thus reducing IOP.

组织学检查结果表明，TBD有效穿透AGV周围的纤维化膜，观察到轻度炎症细胞浸润，新血管形成和肌成纤维细胞分化，提示滤过泡形成。TBD可能提供一种新的方法来解决青光眼手术后滤泡纤维化相关的失败，恢复房水流量，从而降低眼压。

Further research is needed to validate its effectiveness, optimize its design, and assess long-term outcomes..

需要进一步的研究来验证其有效性，优化其设计并评估长期结果。。

Introduction

简介

In veterinary medicine, canine primary glaucoma lacks a definitive cure and significantly compromises the quality of life of affected patients. Therefore, both medical and surgical interventions are essential for alleviating pain and preserving vision

在兽医学中，犬原发性青光眼缺乏明确的治愈方法，并严重影响了受影响患者的生活质量。因此，医疗和手术干预对于缓解疼痛和保持视力至关重要

. Given the stepwise approach to glaucoma management, the strategy involves pursuing better outcomes through surgical intervention when adequate intraocular pressure (IOP) control cannot be maintained with medical treatment

鉴于青光眼管理的逐步方法，该策略涉及在药物治疗无法维持足够的眼压（IOP）控制时，通过手术干预寻求更好的结果

. Surgical treatment of glaucoma can be broadly categorized into methods that reduce aqueous inflow or increase aqueous outflow. The former includes cyclodestructive techniques that partially destroy the ciliary processes responsible for aqueous humor production

青光眼的手术治疗可以大致分为减少水流入或增加水流出的方法。前者包括部分破坏负责房水产生的睫状过程的睫状体破坏技术

. Various surgical techniques have been developed over time to enhance aqueous outflow, but the fundamental principle remains the same in filtration surgery: diverting the aqueous humor from the anterior chamber, where it cannot adequately drain through the natural outflow pathway, to the subconjunctival space via a newly created transscleral route.

随着时间的推移，已经开发出各种手术技术来增强房水流出，但过滤手术的基本原理保持不变：将房水从前房转移到结膜下空间，前房不能通过自然流出途径充分排出，通过新创建的经巩膜途径。

. Including the widely performed Ahmed glaucoma valve (AGV) implantation in canines, a common characteristic of filtration surgery is the formation of a bleb at the site where the aqueous humor is drained

。包括在犬科动物中广泛进行的艾哈迈德青光眼阀（AGV）植入术，滤过手术的一个共同特征是在房水排出的部位形成气泡

The aqueous humor exiting the anterior chamber following filtering surgery forms a subconjunctival bleb and is absorbed through the local vasculature

滤过手术后离开前房的房水形成结膜下泡，并通过局部脉管系统吸收

. Various factors can lead to fibrosis of the subconjunctival bleb, including the wound healing response of the conjunctiva following surgery, the impact of various growth factors present in the aqueous humor on conjunctival tissues, and the inflammatory reactions of the conjunctiva resulting from long-term use of antiglaucoma medications.

各种因素可导致结膜下泡纤维化，包括手术后结膜的伤口愈合反应，房水中存在的各种生长因子对结膜组织的影响，以及长期使用抗青光眼药物引起的结膜炎症反应。

. Regardless of human or veterinary medicine, bleb fibrosis is a leading cause of surgical failure, and efforts have been made to prevent fibrosis or address already fibrotic tissues

。无论人类还是兽医，水泡纤维化都是手术失败的主要原因，并且已经努力预防纤维化或解决已经纤维化的组织

. In veterinary medicine, the application of antimetabolites such as mitomycin C (MMC) or 5-fluorouracil has been widely used to inhibit fibrosis

在兽医学中，抗代谢物如丝裂霉素C（MMC）或5-氟尿嘧啶的应用已被广泛用于抑制纤维化

. Additionally, research has been conducted on antifibrotic agents that directly inhibit the growth factors involved in fibrosis

此外，已经对直接抑制纤维化相关生长因子的抗纤维化剂进行了研究

. In cases where fibrotic tissue hampers IOP control, options such as bleb revision to excise the fibrotic bleb or performing the same or different glaucoma surgery in a different quadrant of the eye have been employed

在纤维化组织妨碍眼压控制的情况下，已经采用了诸如滤泡修正术切除纤维化滤泡或在眼睛的不同象限进行相同或不同的青光眼手术等选择

. Furthermore, more recently, there have been attempts to restore aqueous humor flow through minimally invasive techniques that penetrate the fibrotic bleb

Dogs and non-human primates, which have a more fragile blood-ocular barrier and a higher propensity for inflammatory responses compared to humans, exhibit an enhanced susceptibility to inflammatory reactions, making them more prone to the development of fibrotic complications following glaucoma surgery.

与人类相比，狗和非人灵长类动物具有更脆弱的血眼屏障和更高的炎症反应倾向，对炎症反应的敏感性增强，使它们更容易在青光眼手术后发生纤维化并发症。

. These tissue characteristics give rise to concerns not only regarding the heightened wound healing process following glaucoma surgery, but also that which may occur as a secondary response to surgeries aimed at addressing bleb fibrosis

这些组织特征不仅引起了人们对青光眼手术后伤口愈合过程的担忧，而且也引起了人们对旨在解决滤泡纤维化的手术的继发反应的担忧

. The objective of this preliminary study was to design a biomaterial trans-bleb device (TBD) that facilitates sufficient drainage of the aqueous humor trapped within fibrotic blebs while minimizing surgical intervention and tissue manipulation. In addition, this study aimed to investigate the effectiveness of this device when administered to blebs formed after glaucoma surgery..

这项初步研究的目的是设计一种生物材料反式滤泡装置（TBD），该装置有助于充分引流纤维化滤泡内的房水，同时最大程度地减少手术干预和组织操作。此外，本研究旨在调查该装置在青光眼手术后形成的滤泡中的有效性。。

Methods

方法

TBD design and fabrication

TBD设计和制造

A schematic representation of the TBD is shown in Fig.

TBD的示意图如图所示。

. The structure of the TBD consisted of a rectangular prism shape with a central lumen and protrusions at both ends and was fabricated using medical grade, biocompatible implantable silicone (NuSil MED-4830, Avantor Sciences). The Shore A hardness of this silicone was 30, selected to closely match the properties of the silicone used in the AGV, ensuring the mechanical function was maintained while minimizing physical irritation of the eye.

。TBD的结构由矩形棱柱形组成，具有中心腔和两端的突起，并使用医用级生物相容性植入式硅胶（NuSil MED-4830，Avantor Sciences）制造。这种硅胶的肖氏A硬度为30，选择与AGV中使用的硅胶的性能紧密匹配，确保保持机械功能，同时最大程度地减少对眼睛的物理刺激。

. These characteristics were chosen to approximate its properties and secure a compatible tissue response. The height of the device when placed on the sclera was 2 mm, designed not to exceed the maximal thickness of 2.1 mm of the AGV (Model FP8, New World Medical). Since the AGV has flow control mechanisms, the design aimed to prevent additional resistance to aqueous humor flow caused by the TBD, creating a flow route as wide as possible.

.选择这些特征是为了近似其特性并确保兼容的组织反应。当放置在巩膜上时，装置的高度为2毫米，设计不超过AGV（FP8型，新世界医学）的最大厚度2.1毫米。由于AGV具有流量控制机制，因此设计旨在防止由TBD引起的房水流动的额外阻力，从而尽可能宽地创建流动路线。

Consequently, the lumen size was designed to be 2 × 1 mm, to ensure the maximal width of the flow route, considering the prevention of flow hindrance by inflammatory substances or surrounding tissues. The protrusions were designed to ensure that the TBD remained securely posited in the bleb wall, with the thicker parts positioned towards the inner side of the bleb and the thinner parts towards the outer side, preventing abrasion of the conjunctiva while increasing fixation.

因此，考虑到炎症物质或周围组织对流动的阻碍，管腔尺寸设计为2×1 mm，以确保流动路线的最大宽度。突起的设计旨在确保TBD牢固地放置在泡壁中，较厚的部分朝向泡的内侧，较薄的部分朝向外侧，防止结膜磨损，同时增加固定。

All the edges of the TBD were rounded off to minimize the potential for abrasion. This configuration prevented dislodgement of the TBD along with an overall flat shape, minimizing interference with ocular movements..

TBD的所有边缘都被磨圆，以最大程度地减少磨损的可能性。这种配置防止了TBD的移位以及整体平坦的形状，最大程度地减少了对眼球运动的干扰。。

Fig. 1

图1

Schematic representation (

(

) and 3-D images (

)和三维图像(

B类

) of the trans-bleb device (TBD), designed for the drainage of aqueous humor in post-Ahmed glaucoma valve (AGV) surgery fibrotic blebs in dogs. The device, fabricated from biocompatible implantable silicone, features a flat rectangular prism shape with a central lumen for aqueous humor drainage, and protrusions at both ends for secure bleb wall anchorage.

)trans-bleb装置（TBD）的设计，用于艾哈迈德青光眼阀（AGV）手术后房水引流犬的纤维化滤泡。该装置由生物相容性植入式有机硅制成，具有平坦的矩形棱柱形状，具有用于房水引流的中心腔，并且两端的突起用于安全的泡壁锚定。

The subjects, two clinically normal Beagles, underwent AGV implantation to evaluate the TBD’s efficacy in reducing intraocular pressure and addressing fibrosis challenges. R = radius..

受试者是两只临床上正常的比格犬，他们接受了AGV植入术，以评估TBD在降低眼压和应对纤维化挑战方面的功效。R = 半径。。

Full size image

全尺寸图像

Animals and AGV implantation surgery

动物和AGV植入手术

All animal procedures and experiments were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Seoul National University (permit number: SNU-220320-1) and performed in accordance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research and the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines..

所有动物程序和实验均由首尔国立大学机构动物护理和使用委员会（IACUC）审查和批准（许可证编号：SNU-220320-1），并根据视觉和眼科研究协会（ARVO）关于在眼科和视觉研究中使用动物的声明和动物研究：体内实验报告（ARRIVE）指南进行。。

Two 2-year-old castrated male purpose-bred Beagles, each weighing 11 kg, were included in this study. Both dogs underwent a comprehensive ophthalmic examination that included neuro-ophthalmic examinations, Schirmer tear test, rebound tonometry (TonoVet; iCare), slit-lamp biomicroscopy (SL-D7; Topcon), binocular indirect ophthalmoscopy (Vantage Indirect Ophthalmoscope; Keeler), and fluorescein staining (Flu-Glo; Akorn Pharmaceuticals).

这项研究包括两只2岁去势的雄性专门繁殖的比格犬，每只体重11公斤。两只狗都接受了全面的眼科检查，包括神经眼科检查，Schirmer泪液测试，反弹眼压测定（TonoVet；iCare），裂隙灯生物显微镜（SL-D7；Topcon），双眼间接检眼镜（Vantage间接检眼镜；Keeler）和荧光素染色（Flu-Glo；Akorn Pharmaceuticals）。

In addition, iridocorneal angle measurements with gonioscopy and ultrasound biomicroscopy (UBM) were performed to assess the integrity of the outflow pathway. The results of these examinations confirmed normal ocular findings in both dogs. No abnormalities were noted on the overall physical examination, laboratory blood tests, or thoracic radiographic evaluation..

此外，使用角膜镜和超声生物显微镜（UBM）进行虹膜角膜角度测量，以评估流出途径的完整性。这些检查的结果证实了两只狗的眼部检查结果正常。整体体格检查，实验室血液检查或胸部影像学评估均未发现异常。。

In preparation for AGV implantation, standard procedures were followed for general anesthesia (premedication with 0.002 mg/kg medetomidine IV, induction using 2 mg/kg alfaxalone IV, and maintenance via isoflurane inhalation) and aseptic preparation of the globe and surrounding periocular tissues. Implantation was performed in the superior temporal quadrant of the left eye in both dogs.

在准备AGV植入时，遵循标准程序进行全身麻醉（术前使用0.002 mg/kg美托咪定IV，使用2 mg/kg阿法沙隆IV诱导，并通过异氟醚吸入维持）和无菌制备眼球和周围眼周组织。在两只狗的左眼颞上象限进行植入。

All surgeries were conducted by a single board-certified veterinary ophthalmologist (SK). The right eye was unoperated and served as the control eye..

所有手术均由单一委员会认证的兽医眼科医生（SK）进行。右眼未经手术，用作对照眼。。

The surgical procedure followed the standard techniques: A fornix-based conjunctival flap was created with an incision approximately 5 mm posterior to the limbus. This approach was chosen to minimize the risk of limbal stem cell damage, facilitate surgical manipulation during the procedure, and reduce the likelihood of incision exposure, particularly considering the tendency of canine patients for self-trauma postoperatively.

手术过程遵循标准技术：在角膜缘后约5 mm处切开穹窿结膜瓣。选择这种方法是为了最大程度地降低角膜缘干细胞损伤的风险，促进手术过程中的手术操作，并降低切口暴露的可能性，特别是考虑到犬类患者术后自我创伤的倾向。

. The incision was made with care to ensure optimal access while avoiding excessive tissue disruption. After exposing the underlying sclera, A 4 × 6 mm partial-thickness flap was created in the sclera near the limbus, where the tube would be inserted. The primed AGV was then positioned within the pocket, approximately 10–12 mm away from the limbus, and secured to the sclera using 8−0 nylon sutures.

切口小心，以确保最佳通路，同时避免过度组织破坏。。然后将引发的AGV放置在距离角膜缘约10-12 mm的口袋内，并使用8-0尼龙缝线固定在巩膜上。

The tube, with its beveled tip, was inserted through a 22-gauge needle track created below the scleral flap, allowing it to be positioned in the anterior chamber. Once the tube was in place, each side of the scleral flap was sutured using 8−0 nylon in a simple interrupted pattern, followed by sequential closure of Tenon’s capsule and conjunctiva using 8−0 polyglactin 910 sutures in a double continuous pattern..

带有斜角尖端的管子通过巩膜瓣下方产生的22号针孔插入，使其能够定位在前房中。管就位后，使用8-0尼龙以简单的间断方式缝合巩膜瓣的每一侧，然后使用8-0聚乳酸910缝线以双连续方式顺序闭合Tenon囊和结膜。。

Postoperative care included administering cefovecin 8 mg/kg subcutaneously once and meloxicam at 0.2 mg/kg orally on the first day, followed by a maintenance dose of 0.1 mg/kg daily for 2 weeks. Topical application of atropine 1% ophthalmic drops was performed every 3 days, and gentle digital ocular compression was applied to the inferior part of the globe through the lower eyelid for 5 s once daily to induce additional IOP elevation for bleb formation.

术后护理包括在第一天皮下注射头孢维辛8 mg/kg，口服美洛昔康0.2 mg/kg，然后每天维持剂量0.1 mg/kg，持续2周。每3天局部应用1%阿托品滴眼液，并通过下眼睑对眼球下部进行轻微的数字眼部按压，每天一次，持续5 s，以诱导额外的眼压升高以形成气泡。

. Following surgery, IOP was measured daily at a consistent time before digital ocular compression. Additionally, the presence of aqueous flare, tube obstruction, and bleb formation was assessed using a portable slit-lamp biomicroscope. A comprehensive ophthalmic examination was performed 3 weeks after surgery, at which time the total height of the bleb and the thickness of the bleb wall were evaluated using UBM..

手术后，在数字眼部压迫之前，每天在一致的时间测量眼压。。手术后3周进行了全面的眼科检查，当时使用UBM评估了滤泡的总高度和滤泡壁的厚度。。

TBD application

待定申请

Three weeks after AGV surgery, having observed bleb formation (Fig.

AGV手术后三周，观察到滤泡形成（图）。

A, B), TBD application surgery was performed. Both dogs underwent preoperative preparation following the same procedure as in the previous surgery. A stay suture was placed near the limbus to pull the globe downward and expose the bleb. The incision site for TBD application was made near the superior nasal quadrant of the bleb wall, approximately midway between the anterior and posterior edges of the AGV plate.

A、 B），进行TBD应用手术。两只狗都按照与之前手术相同的程序进行了术前准备。在角膜缘附近放置一条拉线缝合线，将球体向下拉并暴露出气泡。TBD应用的切口部位位于气泡壁的上鼻象限附近，大约在AGV板的前后边缘之间。

The incision was carefully positioned along the perimeter of the bleb wall to avoid damage to the conjunctiva in the area of aqueous humor drainage and was placed close to the prior AGV surgical site to minimize disruption to the surrounding intact tissues. The conjunctiva was minimally incised about 7 mm, only enough to insert the TBD.

沿着泡壁的周边小心地放置切口，以避免房水引流区域的结膜受损，并将其放置在之前的AGV手术部位附近，以最大程度地减少对周围完整组织的破坏。结膜最小切开约7毫米，仅足以插入TBD。

Tenon’s capsule was bluntly dissected as little as possible to expose the underlying bleb. Upon revealing the surface of the bleb, the insertion area was gently tapped using a No. 11 blade to create a fenestration for TBD placement on the bleb. Subsequently, a scleral punch was used to make an appropriately sized fenestration, approximately 4 × 2 mm, to allow the insertion of the TBD while ensuring its protrusions could engage with the bleb wall.

尽可能少地直接解剖Tenon的囊以暴露下面的气泡。在露出水泡表面后，使用11号刀片轻轻敲击插入区域，以在水泡上形成用于TBD放置的开窗。随后，使用巩膜穿孔器进行适当大小的开窗，大约4× 2毫米，以允许插入TBD，同时确保其突起可以与泡壁接合。

The TBD was then inserted through the fenestration, confirming the flow of aqueous humor through the lumen (Fig. .

然后通过开窗插入TBD，确认房水通过管腔流动（图）。

). Finally, the surrounding Tenon’s capsule and conjunctiva were closed using 8−0 polyglactin 910 sutures in a double continuous pattern.

)。最后，使用8-0 polyglactin 910缝线以双连续模式闭合周围的Tenon囊和结膜。

Fig. 2

图2

Macroscopic and ultrasound biomicroscopic images of post-surgical blebs in the superior temporal region of the left eye. White arrows in the ultrasound images indicate the bleb wall. (

左眼上颞区手术后气泡的宏观和超声生物显微镜图像。。（笑声）(

) and (

)和(

B类

)—Three weeks after Ahmed glaucoma valve (AGV) implantation surgery, a raised bleb was observed in the conjunctiva around the AGV body in dog 1 (

)-Ahmed青光眼阀（AGV）植入术后三周，在狗1的AGV体周围的结膜中观察到一个凸起的水泡(

) and dog 2 (

)和狗2(

B类

). (

C级

) and (

)和(

)—Corresponding ultrasound biomicroscopic images at the same post-operative time point for dog 1 (

)-狗1在同一术后时间点的相应超声生物显微镜图像(

C级

) and dog 2 (

)和狗2(

). A capsule-shaped bleb was observed, along with an empty cavity (asterisk) below it caused by aqueous humor accumulation. (

)。观察到一个胶囊状的水泡，以及由房水积聚引起的空腔（星号）。（笑声）(

) and (

)和(

)—Three weeks following trans-bleb device (TBD) surgery, macroscopic images of dog 1 (

)-经滤泡装置（TBD）手术后三周，狗1的宏观图像(

) and dog 2 (

)和狗2(

F级

) showed the height of the bleb decreased compared to AGV surgery, and it exhibited a relatively wider spread. Throughout the experimental period, the tube and AGV body remained stably positioned. (

)显示与AGV手术相比，气泡的高度降低了，并且表现出相对更宽的扩散。在整个实验期间，管子和AGV车身保持稳定的位置。（笑声）(

克

) and (

)和(

小时

)—Three weeks after TBD surgery, ultrasound biomicroscopic images of dog 1 (

)-TBD手术后三周，狗1的超声生物显微镜图像(

克

) and dog 2 (

)和狗2(

小时

) revealed a shallowed cavity around the AGV (asterisk), and no corresponding cavity was detected around the TBD. However, diffuse hypoechoic areas (dagger) were scattered throughout the relatively thick bleb wall, indicating aqueous imbibition.

)发现AGV周围有一个浅腔（星号），TBD周围没有检测到相应的腔。然而，弥漫性低回声区域（匕首）散布在相对较厚的泡壁上，表明水吸收。

Full size image

全尺寸图像

Fig. 3

图3

Intraoperative post-insertion appearance of the trans-bleb device (TBD) at the bleb wall (

术中在滤过泡壁插入经滤过泡装置（TBD）后的外观(

: dog 1,

：狗1，

B类

: dog 2). The expulsion of aqueous humor through the lumen of the TBD was observed (white arrows).

：狗2）。观察到房水通过TBD腔排出（白色箭头）。

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Postoperative management followed the same protocols as the previous surgery, which included medication administration, IOP measurement, digital ocular compression, clinical assessments using portable slit-lamp biomicroscopy, and comprehensive ophthalmic examinations at the 3-week mark, which also included UBM for the evaluation of bleb condition..

术后管理遵循与之前手术相同的方案，包括药物管理，眼压测量，数字眼压迫，使用便携式裂隙灯生物显微镜进行临床评估，以及在3周时进行全面的眼科检查，其中还包括UBM评估气泡状况。。

AGV-TBD removal and histological examination

AGV-TBD切除和组织学检查

Three weeks after TBD application (Fig.

TBD应用后三周（图）。

E, F), AGV-TBD removal surgery was performed for histological examination. Both dogs underwent the same preoperative treatment, anesthesia, and sterilization procedures using the aforementioned method. With utmost care to maintain the position of the AGV and TBD, the AGV-TBD complex and surrounding tissues, including Tenon’s capsule and a small portion of the conjunctiva, were carefully excised.

E、 F），进行AGV-TBD切除手术进行组织学检查。两只狗都使用上述方法进行了相同的术前治疗，麻醉和灭菌程序。为了保持AGV和TBD的位置，仔细切除了AGV-TBD复合体和周围组织，包括Tenon囊和一小部分结膜。

After excision, the limbal entry site of the tube was sutured using a cruciate pattern, and both the Tenon’s capsule and conjunctiva were subsequently closed in a double continuous pattern, all using 8−0 polyglactin 910 sutures. Two weeks later, complete healing of the sutured area was observed, and a comprehensive ocular examination, including neuro-ophthalmic examination, rebound tonometry, slit-lamp biomicroscopy, and binocular indirect ophthalmoscopy, revealed no significant abnormalities..

切除后，使用十字形缝合管的角膜缘进入部位，随后以双连续模式闭合Tenon囊和结膜，均使用8-0 polyglactin 910缝合线。两周后，观察到缝合区域完全愈合，并进行了全面的眼部检查，包括神经眼科检查，反弹眼压测定，裂隙灯生物显微镜检查和双眼间接检眼镜检查，未发现明显异常。。

For histological examination, the AGV-TBD complex tissue sample was fixed in 10% neutral-buffered formalin and trimmed to obtain a central section, ensuring that a sagittal section of the TBD lumen was included. The processed tissue was embedded in paraffin wax and sectioned to a thickness of 4 µm. H&E staining was performed to visualize the general tissue morphology, while picrosirius red staining was used to assess collagen deposition.

。将处理过的组织包埋在石蜡中，切成4µm的厚度。进行H＆E染色以可视化一般组织形态，而picrosirius red染色用于评估胶原沉积。

Additionally, immunostaining of α-smooth muscle actin (α-SMA) was conducted to detect the presence of myofibroblasts, following established protocols.

此外，按照既定方案，对α-平滑肌肌动蛋白（α-SMA）进行免疫染色以检测肌成纤维细胞的存在。

. Heat-induced antigen retrieval was performed using a citrate solution (pH 6; Dako/Agilent) on deparaffinized and rehydrated serial sections. Endogenous peroxidase was depleted by incubating sections with 0.3% hydrogen peroxide for 30 min. The sections were incubated overnight at 4 ℃ with α-SMA mouse monoclonal antibody (1:200; Dako/Agilent) and then incubated with horseradish peroxidase-conjugated secondary antibody for 1 h at room temperature.

使用柠檬酸盐溶液（pH 6；Dako/Agilent）在脱蜡和再水化的连续切片上进行热诱导的抗原修复。通过将切片与0.3%过氧化氢孵育30分钟来去除内源性过氧化物酶。将切片与α-SMA小鼠单克隆抗体（1:200；Dako/Agilent）在4℃孵育过夜，然后与辣根过氧化物酶偶联的二抗在室温下孵育1小时。

After visualization with 3,3’-diaminobenzidine, the sections were counterstained with Mayer’s hematoxylin..

用3,3'-二氨基联苯胺可视化后，切片用迈耶苏木精复染。。

Statistical analyses

统计分析

Statistical analyses were performed using open-source software (R statistical software, version 4.2.0; R Foundation for Statistical Computing). The mean IOP values are presented as mean ± SD (range). Paired

使用开源软件（R Statistical software，版本4.2.0；R Foundation for Statistical Computing）进行统计分析。平均IOP值表示为平均值±SD（范围）。成对的

-tests were used to evaluate the IOP differences between the control and operated eyes across both AGV and TBD surgeries. An

-测试用于评估AGV和TBD手术中对照眼和手术眼之间的眼压差异。安

F级

-test was performed to compare the variances in IOP values under different conditions: between AGV and TBD surgeries, and between the first and last 10 days of the entire follow-up period for each surgery. Welch’s

-进行测试以比较不同条件下IOP值的差异：AGV和TBD手术之间，以及每次手术整个随访期的第一天和最后10天之间。韦尔奇的

-test was used to analyze the mean differences in these comparisons. A two-way ANOVA was conducted to compare the effects of the early and late postoperative periods on IOP. Statistical significance was defined as

-测试用于分析这些比较中的平均差异。进行双向方差分析以比较术后早期和晚期对眼压的影响。统计显着性定义为

< .05.

<05。

Results

结果

Clinical observations

临床观察

Both dogs exhibited mild-to-moderate chemosis and hyperemia following AGV surgery, which gradually resolved; from day 4, only mild hyperemia was observed. No aqueous flare was detected throughout the follow-up period. From day 10, both dogs exhibited visible blebs, which coincided with the period of increased IOP in the operated eye.

AGV手术后，两只狗均表现出轻度至中度的化疗和充血，并逐渐消退；从第4天开始，仅观察到轻度充血。在整个随访期间未检测到水性耀斑。从第10天开始，两只狗都表现出可见的气泡，这与手术眼眼压升高的时期一致。

Minimal chemosis and slight hyperemia were observed after TBD application surgery. The visible bleb height decreased immediately after TBD surgery and remained relatively comparable throughout the follow-up period. No signs of ocular discomfort or abnormalities in eyelid function were observed in either dog after the application of TBD..

TBD应用手术后观察到轻微的化学反应和轻微的充血。TBD手术后可见的气泡高度立即下降，并且在整个随访期间保持相对可比性。应用TBD后，两只狗均未观察到眼部不适或眼睑功能异常的迹象。。

Intraocular pressure

眼内压

The changes in bilateral IOP after AGV and TBD surgeries in both dogs are illustrated in Fig.

两只狗的AGV和TBD手术后双侧眼压的变化如图所示。

. Following AGV and TBD surgeries, the mean IOP in operated eyes was significantly lower than in control eyes (paired

AGV和TBD手术后，手术眼的平均眼压明显低于对照眼（配对

-test: 95% CI 3.22 to 4.71,

-测试：95%可信区间3.22至4.71，

< .001; Supplementary Table

；补充表格

S1级

). The changes in IOP post-surgery did not significantly differ between the AGV and TBD surgeries (

)。AGV和TBD手术后眼压的变化没有显着差异(

F级

-test for variance:

-方差检验：

= .63; Welch’s

= .63；哪些

-test for means: 95% CI -0.49 to 1.66,

-均值检验：95%置信区间-0.49至1.66，

= .29). In both surgeries, IOP changes were significantly greater in the first 10 days than in the last 10 days of the follow-up period (

在这两种手术中，随访期的前10天眼压变化明显大于后10天(

F级

-test for variance:

-方差检验：

< .001; Welch’s

< 0.001；哪些

-test for means: 95% CI -3.52 to -1.55,

-均值检验：95%置信区间-3.52至-1.55，

< .001). The interaction of surgery type (AGV vs. TBD) with the postoperative period did not significantly affect IOP changes (two-way ANOVA:

手术类型（AGV与TBD）与术后时间的相互作用对眼压变化没有显著影响（双向方差分析：

= .44).

（44）。

Fig. 4

图4

The daily changes in bilateral intraocular pressure (IOP) after Ahmed glaucoma valve surgery (

Ahmed青光眼瓣膜手术后双侧眼压的每日变化(

and

和

B类

) and trans-bleb device surgery (

)和经泡装置手术(

C级

and

和

) in two dogs. Following both surgeries, the mean IOP in the operated eye was significantly lower than in the control eye (

)两只狗。两次手术后，手术眼的平均眼压明显低于对照眼(

< .001). Particularly, the inter-eye IOP difference was significantly more prominent during the first 10 days after both surgeries than during the subsequent 10 days (

特别是，在两次手术后的前10天，眼内眼压差异明显比随后的10天更为突出(

< .001).

（001）。

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UBM examination

UBM检查

Three weeks after AGV surgery, UBM examination revealed the presence of blebs above the AGV body in both dogs. The wall thicknesses were measured at 0.5 mm for dog 1 and 0.6 mm for dog 2, with bleb heights of 2.9 mm and 4.2 mm respectively (ImageJ version 1.53; National Institutes of Health). A cavity where aqueous humor accumulated was also observed between the bleb wall and AGV body (Fig. .

AGV手术后三周，UBM检查显示两只狗的AGV身体上方都存在气泡。狗1的壁厚为0.5 mm，狗2的壁厚为0.6 mm，气泡高度分别为2.9 mm和4.2 mm（ImageJ版本1.53；National Institutes of Health）。。

C, D). Three weeks after TBD application, UBM examination revealed relatively thick bleb walls, along with diffuse hypoechoic areas, indicating the presence of aqueous humor imbibition in Tenon’s capsule and conjunctiva near the AGV-TBD complex. The cavity previously observed around the AGV body was shallow, and no cavity was detected around the TBD.

C、 D）。TBD应用三周后，UBM检查显示相对较厚的泡壁，以及弥漫性低回声区域，表明在AGV-TBD复合体附近的Tenon囊和结膜中存在房水吸收。。

After TBD surgery, the bleb heights were reduced to 1.8 mm for dog 1 and 2.4 mm for dog 2 (Fig. .

TBD手术后，狗1的气泡高度降低到1.8毫米，狗2的气泡高度降低到2.4毫米（图）。

G, H).

G、 H）。

Histological examination

组织学检查

H&E, picrosirius red staining, and α-SMA immunostaining images are shown in Fig.

。

. H&E staining revealed the presence of a fibrotic membrane composed of fibrous connective tissue and fibroblasts on the inner surface in contact with AGV and TBD, and there were cavities where AGV and TBD existed. The continuity between the fibrotic membranes and the patency between the cavities of the AGV and TBD indicated that the TBD had managed to penetrate the fibrotic bleb.

H＆E染色显示在与AGV和TBD接触的内表面上存在由纤维结缔组织和成纤维细胞组成的纤维化膜，并且存在AGV和TBD存在的空腔。纤维化膜之间的连续性以及AGV和TBD腔之间的通畅性表明TBD已经设法穿透纤维化泡。

Confined to the tissue surrounding the fibrous membrane, mild infiltration of inflammatory cells, congestion, partial edema, fibrosis, and angiogenesis were observed, suggesting a mild inflammatory response to the implants and to the aqueous humor shunted from the anterior chamber. While both regions exhibited comparable inflammatory and fibrotic responses, minor differences in collagen fiber maturity were observed; in dog 1, the fibrotic tissue in both regions appeared comparable in maturity, whereas in dog 2, the TBD region tended to show more densely packed and aligned collagen fibers, indicating more advanced tissue remodeling compared to the AGV region.

局限于纤维膜周围的组织，观察到炎性细胞轻度浸润，充血，部分水肿，纤维化和血管生成，表明对植入物和从前房分流的房水有轻度炎症反应。虽然这两个区域都表现出相当的炎症和纤维化反应，但观察到胶原纤维成熟度的微小差异；在狗1中，两个区域的纤维化组织在成熟度上似乎相当，而在狗2中，TBD区域倾向于显示出更密集和排列的胶原纤维，表明与AGV区域相比，组织重塑更为先进。

This observation was consistent with the results of additional staining. Picrosirius red staining revealed a positive reaction by staining the fibrotic membrane structure and surrounding Tenon’s tissue red. The fibrotic membrane exhibited a relatively lighter red color than the mature collagen fibers observed in the adjacent Tenon’s tissue.

该观察结果与额外染色的结果一致。Picrosirius红染色通过将纤维化膜结构和周围的Tenon组织染成红色显示出阳性反应。纤维化膜显示出比在相邻Tenon组织中观察到的成熟胶原纤维相对较浅的红色。

Immunostaining with α-SMA revealed intense positive staining in the fibroblast-like cells constituting the fibrotic membrane, suggesting myofibroblast differentiation. This finding indicated the presence of contractile cells within the fibrotic tissue, which are known to contribute to fibrosis and wound healing processes.

用α-SMA进行的免疫染色显示，构成纤维化膜的成纤维细胞样细胞呈强烈的阳性染色，表明肌成纤维细胞分化。这一发现表明纤维化组织中存在收缩细胞，已知其有助于纤维化和伤口愈合过程。

Fig. 5

图5

Gross images of trimmed tissues around the Ahmed glaucoma valve (AGV) and trans-bleb device (TBD) (

Ahmed青光眼阀（AGV）和trans-bleb装置（TBD）周围修剪组织的总体图像(

and

和

B类

), alongside their corresponding histologic micrographs stained with various methods for enhanced visual clarification (

)，以及用各种方法染色的相应组织学显微照片，以增强视觉清晰度(

C级

and

和

). Inset boxes indicate the areas magnified below. (

)。插图框表示下面放大的区域。（笑声）(

C级

) H&E staining showed a fibrotic membrane composed of connective tissue and fibroblasts in contact with AGV and TBD, with cavities where the devices existed. There was continuity between the fibrotic membranes and the patency between the cavities. Mild inflammatory cell infiltration, congestion, and partial edema were observed around the fibrotic membrane.

)H＆E染色显示由结缔组织和成纤维细胞组成的纤维化膜与AGV和TBD接触，并在存在装置的地方有空腔。纤维化膜之间存在连续性，腔之间存在通畅性。在纤维化膜周围观察到轻度炎性细胞浸润，充血和部分水肿。

) Picrosirius red staining revealed positive staining in the fibrotic membrane and surrounding Tenon’s tissue, with relatively lower collagen maturity in the membrane. (

)Picrosirius红染色显示纤维化膜和周围Tenon组织呈阳性染色，膜中胶原成熟度相对较低。（笑声）(

) Immunostaining of α-smooth muscle actin exhibited intense positive staining in fibroblast-like cells, suggesting myofibroblast differentiation in the fibrotic membrane. Although the limited number of tissue samples precludes definitive comparisons, there was a trend towards greater collagen fiber maturity in the TBD region compared to the AGV region in dog 2..

)α-平滑肌肌动蛋白的免疫染色在成纤维细胞样细胞中表现出强烈的阳性染色，表明肌成纤维细胞在纤维化膜中分化。尽管组织样本数量有限，无法进行明确的比较，但与狗2的AGV区域相比，TBD区域的胶原纤维成熟度更高。。

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Discussion

讨论

Owing to the potentially fatal consequences on patient vision, it is imperative to make efforts to address situations in which IOP remains uncontrolled after glaucoma surgery. This becomes particularly crucial when elevated IOP is not only a transient outcome of factors such as tube obstruction but also arises because of irreversible conditions such as bleb fibrosis.

由于对患者视力的潜在致命后果，必须努力解决青光眼手术后眼压仍然不受控制的情况。当眼压升高不仅是诸如管阻塞等因素的短暂结果，而且由于诸如滤泡纤维化等不可逆条件而产生时，这变得尤为关键。

Under these circumstances, few therapeutic options are available, demanding meticulous decision-making.

在这种情况下，几乎没有可用的治疗选择，需要细致的决策。

. In this preliminary experimental study, we devised and evaluated a novel biomaterial device, the TBD, specifically for irreversible bleb fibrosis. The TBD was designed to facilitate the drainage of aqueous humor trapped within fibrotic blebs following AGV implantation (Fig.

在这项初步实验研究中，我们设计并评估了一种新型生物材料装置TBD，专门用于不可逆的滤泡纤维化。TBD旨在促进AGV植入后纤维化泡内房水的引流（图）。

Fig. 6

图6

Summary diagram from Ahmed glaucoma valve (AGV) implantation surgery to post trans-bleb device (TBD) application. Following AGV implantation surgery, the bleb was formed and expanded, driven by the accumulation of aqueous humor (

从Ahmed青光眼阀（AGV）植入手术到trans-bleb装置（TBD）应用的总结图。AGV植入手术后，在房水积聚的驱动下，气泡形成并扩大(

-（笑声）

). Upon application of the TBD (

)。(

), the accumulated aqueous humor underwent effective redistribution, dispersing into the surrounding Tenon’s capsule and the conjunctiva, resulting in a noticeable reduction in bleb height (

)，累积的房水经历了有效的重新分布，分散到周围的Tenon囊和结膜中，导致气泡高度明显降低(

F级

). Please note, the diagram indicates the placement of the TBD in the superior temporal direction of the bleb on the left eye. The actual procedure in this study was conducted in the superior nasal direction. It should be highlighted that there are no restrictions on the direction or number of TBDs to be implanted..

)。请注意，该图表示TBD在左眼气泡的上颞方向的位置。本研究中的实际程序是在上鼻方向进行的。应该强调的是，对要植入的TBD的方向或数量没有限制。。

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In human studies, the occurrence of fibrotic bleb formation after various types of glaucoma-filtering surgeries has been reported to range from 2.5 to 25%. This tendency was more pronounced following valved or non-valved device surgery than after trabeculectomy

在人体研究中，据报道，各种类型的青光眼滤过手术后纤维化滤泡形成的发生率为2.5%至25%。这种趋势在瓣膜或非瓣膜装置手术后比小梁切除术后更为明显

. In canine studies, the incidence of fibrotic bleb formation as a long-term complication has ranged from 1 to 33% in patients undergoing drainage device surgeries alone or in combination with cyclodestructive procedures

在犬类研究中，单独或与睫状体破坏性手术联合进行引流装置手术的患者，纤维化滤泡形成作为长期并发症的发生率为1%至33%

. Fibrotic bleb formation following glaucoma surgeries has been shown to result from multiple factors, including preoperative, intraoperative, and postoperative influences in both human and veterinary medicine. Surgical trauma triggers an inflammatory cascade marked by the release of cytokines such as transforming growth factor-β (TGF-β), platelet-derived growth factor, and vascular endothelial growth factor (VEGF), which promote fibroblast activation, myofibroblast differentiation, and subsequent extracellular matrix remodeling.

青光眼手术后纤维化滤泡的形成已被证明是由多种因素引起的，包括术前，术中和术后对人类和兽医的影响。手术创伤引发炎症级联反应，其特征在于细胞因子如转化生长因子-β（TGF-β），血小板衍生生长因子和血管内皮生长因子（VEGF）的释放，其促进成纤维细胞活化，肌成纤维细胞分化和随后的细胞外基质重塑。

. In glaucomatous eyes, elevated levels of cytokines in the aqueous humor, including TGF-β2 and VEGF-A, have been linked to increased fibrosis, suggesting a more pronounced wound healing response compared to non-glaucomatous eyes

. Furthermore, preexisting conjunctival inflammation caused by long-term topical medication use or prior surgical interventions may predispose tissue to excessive scarring

此外，由长期局部用药或先前的手术干预引起的先前存在的结膜炎症可能使组织易于过度瘢痕形成

. Preventing fibrosis before its onset remains critical to maintaining the functionality of surgical implants; however, once fibrosis has formed, secondary interventions may be required to restore aqueous humor flow. In both fields, various approaches have been applied in such situations, including needling bleb revision with MMC or 5-fluorouracil, surgical removal of fibrotic tissue, or performing the same or different glaucoma surgeries in different quadrants of the eye.

.在发病前预防纤维化对于维持手术植入物的功能至关重要；然而，一旦纤维化形成，可能需要二次干预来恢复房水流动。在这两个领域中，已经在这种情况下应用了各种方法，包括用MMC或5-氟尿嘧啶进行针刺修正，手术切除纤维化组织，或者在眼睛的不同象限中进行相同或不同的青光眼手术。

. Needling revision has shown temporary reduction in IOP, but its long-term effectiveness is compromised by the recurrence of fibrosis

针刺修正术显示眼压暂时降低，但其长期有效性因纤维化的复发而受到损害

. Excisional revision of fibrotic tissue also presented challenges, as not only did the fast and aggressive fibrosis affect its effectiveness and economic advantages, but it further risked thinning Tenon’s capsule and rendering the conjunctiva fragile

纤维化组织的切除修复也提出了挑战，因为快速和侵袭性的纤维化不仅影响了其有效性和经济优势，而且进一步有可能使Tenon囊变薄并使结膜脆弱

. Reimplantation surgery offered advantages in terms of IOP reduction and long-term preservation of visual function compared to other methods, but it has raised concerns regarding implant-related complications such as corneal endothelial irritation or ocular motility disturbance, as well as the economic burden of the costly implant.

与其他方法相比，再植入手术在降低眼压和长期保存视功能方面具有优势，但它引起了人们对植入物相关并发症（如角膜内皮刺激或眼球运动障碍）以及昂贵植入物的经济负担的担忧。

Another approach to counteract fibrotic blebs has shown effectiveness in human subjects by facilitating the drainage of aqueous humor into the retrobulbar space using a bleb diversion device

另一种抵消纤维化滤泡的方法通过使用滤泡转移装置促进房水引流到球后空间，在人类受试者中显示出有效性

. This was achieved by utilizing a large-bore fenestrated silicone stent specifically designed to redirect the aqueous humor in cases where standard tube shunts failed due to fibrotic bleb formation. The study involved a cohort of 35 patients, and during each annual follow-up assessment, a significant reduction in the mean baseline IOP of 53–57% was observed.

这是通过使用大口径开窗硅胶支架来实现的，该支架专门设计用于在标准管分流由于纤维化泡形成而失败的情况下重定向房水。该研究涉及35名患者，在每次年度随访评估中，观察到平均基线眼压显着降低53-57%。

. However, applying a similar device in a study of five canine eyes with fibrotic blebs formed after AGV surgery did not yield successful outcomes, failing to maintain effective IOP control in three cases

然而，在一项对AGV手术后形成纤维化滤泡的五只犬眼进行的研究中，应用类似的装置并没有取得成功的结果，三例未能维持有效的眼压控制

In the current study, the TBD was crafted to have a flat rectangular prism-like shape with a short central lumen. This design allowed for adequate drainage of the aqueous humor, ensuring its efficient expulsion from the vast and flat lumen into the adjacent healthy Tenon’s and conjunctival tissues. The device acts as a protective barrier, preventing fibrotic tissue from obstructing the shunting space.

在目前的研究中，TBD被制作成具有短中心腔的扁平矩形棱柱状形状。这种设计允许房水充分引流，确保其从宽阔平坦的腔中有效排出到邻近的健康肌腱和结膜组织中。该装置起到保护屏障的作用，防止纤维化组织阻塞分流空间。

The presence of vertical protrusions on both sides at both ends of the lumen contributed to the ability of the device to maintain its flat structure and securely attach to the bleb wall. To address concerns related to conjunctival complications such as thinning or erosion, the outer protrusions on the outer side of the bleb were designed to be thinner.

管腔两端两侧都存在垂直突起，这有助于该装置保持其平坦结构并牢固附着在泡壁上。为了解决与结膜并发症有关的问题，例如变薄或侵蚀，将滤泡外侧的外部突起设计为更薄。

Although it was only 3 weeks, no detrimental effects on eye movement or conjunctival integrity were observed throughout the experimental period..

虽然只有3周，但在整个实验期间没有观察到对眼球运动或结膜完整性的不利影响。。

In human studies, larger surface areas have been generally associated with improved aqueous humor drainage, although this effect plateaus beyond an optimal range

在人体研究中，较大的表面积通常与改善房水引流有关，尽管这种影响超过了最佳范围

. In veterinary medicine, no such studies have been conducted in dogs. However, widely used glaucoma drainage devices typically feature surface areas ranging from 96 to 184 mm

在兽医学方面，尚未对狗进行此类研究。然而，广泛使用的青光眼引流装置通常具有96至184毫米的表面积

, which are thought to balance efficacy and safety

，被认为可以平衡疗效和安全性

. The AGV model used in this study had a surface area of 102 mm

。本研究中使用的AGV模型的表面积为102毫米

, and the TBD employed in this study added an additional surface area of 16.5 mm

，并且本研究中使用的TBD增加了16.5 mm的额外表面积

. While this contribution was relatively modest, it provided an opportunity to examine whether adjunctive devices like the TBD could enhance drainage efficiency by supplementing the primary implant. The small surface area of the TBD may have limited its independent efficacy in significantly lowering IOP, especially when compared to larger implants.

。TBD的小表面积可能限制了其显着降低眼压的独立功效，特别是与较大的植入物相比。

Nevertheless, the device’s ability to bypass fibrotic blebs and redistribute aqueous humor to adjacent tissues represented an alternative mechanism of action that complements existing implants..

然而，该装置绕过纤维化泡并将房水重新分布到邻近组织的能力代表了一种替代作用机制，可以补充现有的植入物。。

On histological examination, a fibrous membrane was formed surrounding the TBD and AGV, which were connected to each other. In addition, patency between the cavities of the TBD and AGV was confirmed without obstruction due to fibrosis or formation of granulation tissue. There were no significant differences in the general characteristics of the fibrotic capsules surrounding the AGV and TBD, although the small sample size might have limited the detection of subtle or statistically significant variations.

。此外，证实了TBD和AGV腔之间的通畅性，没有由于纤维化或肉芽组织形成而阻塞。AGV和TBD周围纤维化囊的一般特征没有显着差异，尽管样本量小可能会限制细微或统计学上显着变化的检测。

Specifically, in dog 2, the fibrotic tissue surrounding the TBD appeared more advanced in maturation compared to the AGV region. This may reflect the fact that the TBD was implanted at a later stage, potentially amplifying the impact of sequential surgical invasions on the tissue response. Alternatively, the difference could be attributed to variations in localized tissue dynamics, such as differing levels of aqueous humor exposure or mechanical stress around the devices..

具体而言，在狗2中，与AGV区域相比，TBD周围的纤维化组织成熟程度更高。这可能反映了TBD在后期植入的事实，可能会放大连续手术侵袭对组织反应的影响。或者，这种差异可能归因于局部组织动力学的变化，例如不同水平的房水暴露或设备周围的机械应力。。

The location of conjunctival incisions for both AGV implantation and TBD placement was considered important, as it could have influenced the integrity and functionality of the bleb and the surrounding tissues, ultimately affecting surgical outcomes. Although the chosen incision technique—a fornix-based flap placed approximately 5 mm posterior to the limbus—provided procedural and structural advantages, the incision’s proximity to the implant plate and its interaction with the additional TBD placement site may present specific challenges.

AGV植入和TBD放置的结膜切口的位置被认为是重要的，因为它可能会影响滤泡和周围组织的完整性和功能，最终影响手术结果。尽管选择的切口技术（位于角膜缘后约5 mm处的穹窿皮瓣）提供了程序和结构上的优势，但切口与植入板的接近程度及其与额外TBD放置部位的相互作用可能会带来特定的挑战。

Previous studies in human medicine have shown that incision location can influence long-term outcomes, such as implant stability, bleb morphology, and the risk of device extrusion .

先前的人类医学研究表明，切口位置会影响长期结果，例如植入物的稳定性，气泡形态和器械挤出的风险.

. For example, fornix-based approaches are often associated with easier visualization at the limbus during tube insertion and placement of the incision site away from the area of bleb formation, but they may also result in posterior visualization challenges, potentially leading to a higher risk of complications such as tube revision or endophthalmitis.

。

. Moreover, canine studies have highlighted species-specific considerations, such as the heightened inflammatory response and the tendency for external irritation

此外，犬类研究强调了特定物种的考虑因素，例如炎症反应加剧和外部刺激倾向

, which could further influence the success of glaucoma surgery. While the fornix-based approach, which involves making incisions at a distance from the limbus, provides certain advantages, the incision’s location near the plate and the additional TBD placement incision may exacerbate conjunctival scarring or impact the bleb’s absorptive capacity.

。虽然基于穹窿的方法（涉及在距离角膜缘一定距离处切开）具有一定的优势，但切口位于板附近和额外的TBD放置切口可能会加剧结膜瘢痕形成或影响滤泡的吸收能力。

These factors emphasize the importance of selecting an optimal incision technique tailored to both the patient’s anatomy and the surgical objectives. Future research should explore the comparative outcomes of limbal- and fornix-based approaches in canine patients, specifically evaluating the impact on long-term implant stability, bleb formation, and tissue healing..

这些因素强调了选择适合患者解剖结构和手术目标的最佳切口技术的重要性。未来的研究应该探索基于角膜缘和穹窿的方法在犬患者中的比较结果，特别是评估对长期植入物稳定性，气泡形成和组织愈合的影响。。

Interestingly, UBM examination following the application of TBD revealed shallowing of the aqueous cavity previously observed in blebs after AGV surgery, and no such cavities were found around the TBD. However, diffuse hypoechoic areas within the bleb tissue were observed, suggesting absorption of the aqueous humor through the surrounding tissues, including Tenon’s capsule and conjunctiva.

有趣的是，应用TBD后的UBM检查显示，AGV手术后先前在滤泡中观察到的水腔变浅，并且在TBD周围未发现此类腔。然而，观察到泡组织内弥漫性低回声区域，表明房水通过周围组织吸收，包括Tenon囊和结膜。

These findings indirectly imply that aqueous humor absorption occurred through the surrounding tissues without hindrance.

这些发现间接暗示房水吸收通过周围组织发生而没有阻碍。

. Additionally, shallowing of the cavity suggested that despite some degree of fibrosis following AGV surgery, the bleb retained the ability to absorb aqueous humor, which likely resulted in a relatively small amount of aqueous humor escaping through the TBD lumen after passing through the AGV bleb..

此外，空洞变浅表明，尽管AGV手术后出现了一定程度的纤维化，但滤泡仍保留了吸收房水的能力，这可能导致相对少量的房水在通过AGV滤泡后通过TBD腔逃逸。。

This study encountered a challenge in achieving an AGV outflow comparable to that of glaucomatous eyes, as the surgery was performed in normal eyes. To address this issue, two interventions were implemented: instilling atropine to maintain pupil dilation and performing digital ocular compression

这项研究在实现与青光眼眼相当的AGV流出方面遇到了挑战，因为手术是在正常眼睛中进行的。为了解决这个问题，实施了两种干预措施：滴注阿托品以维持瞳孔扩张和进行数字眼压

. Through these interventions, bleb formation was encouraged by ensuring a volume of aqueous humor drainage. Notably, a relatively low IOP was observed in the first 10 days after surgery, indicating the establishment of outflow. However, starting on day 10, similar IOP levels were consistently maintained in both eyes.

通过这些干预措施，通过确保房水引流量来鼓励气泡的形成。值得注意的是，在手术后的前10天观察到相对较低的眼压，表明建立了流出。然而，从第10天开始，两只眼睛的眼压水平一直保持相似。

It was hypothesized that the methods described have limitations in further increasing the outflow into the tube of the AGV due to the normal iridocorneal angle and outflow pathway, which hinder the observation of the effects of aqueous humor on the filtering site commonly observed in glaucomatous eyes.

据推测，由于正常的虹膜角膜角度和流出途径，所描述的方法在进一步增加进入AGV管的流出方面存在局限性，这阻碍了观察房水对青光眼眼中常见的过滤部位的影响。

Based on these considerations, the point at which the IOP became similar between both eyes was set as the endpoint of the study..

基于这些考虑，将双眼眼压相似的点设置为研究的终点。。

An additional approach was implemented to encourage the formation of fibrotic blebs, which involved avoiding the use of intraoperative MMC in AGV and TBD surgeries, as well as the omission of postoperative corticosteroids. While MMC is widely used to inhibit fibrosis and enhance surgical success, its exclusion was intended to observe the natural progression of bleb fibrosis.

实施了另一种方法来鼓励纤维化泡的形成，这涉及避免在AGV和TBD手术中使用术中MMC，以及省略术后皮质类固醇。虽然MMC被广泛用于抑制纤维化和提高手术成功率，但其排除旨在观察滤泡纤维化的自然进展。

Similarly, the omission of corticosteroids, commonly used to suppress inflammation and fibrosis, allowed for an unaltered evaluation of the TBD’s effects on aqueous humor drainage. These strategies provided a controlled environment to study the natural fibrotic response, but their absence may have influenced the severity and characteristics of the fibrotic tissue observed.

同样，省略通常用于抑制炎症和纤维化的皮质类固醇，可以对TBD对房水引流的影响进行不变的评估。这些策略为研究自然纤维化反应提供了受控环境，但它们的缺失可能影响了观察到的纤维化组织的严重程度和特征。

Future studies incorporating these agents could provide further clarity on their effects on surgical outcomes and device performance; For instance, the use of MMC or corticosteroids during or after TBD application could potentially extend the survival period of the bleb but might also influence the risk of late plate extrusion..

纳入这些药物的未来研究可以进一步阐明它们对手术结果和设备性能的影响；例如，在TBD应用期间或之后使用MMC或皮质类固醇可能会延长气泡的存活期，但也可能影响晚期平板挤压的风险。。

This study focused on examining the bleb fibrosis and the subsequent IOP reduction following TBD implantation, a direct comparison between AGV-alone and AGV with TBD conditions was not included. A previous study involving 10 clinically normal dogs undergoing single-piece Baerveldt glaucoma implant surgery reported a significant postoperative IOP reduction that returned to baseline within approximately 21 days and remained stable for 60 days thereafter, which aligns with the current study’s observations.

这项研究的重点是检查TBD植入后的滤泡纤维化和随后的眼压降低，不包括单独的AGV和具有TBD条件的AGV之间的直接比较。先前的一项研究涉及10只接受单件Baerveldt青光眼植入手术的临床正常狗，该研究报道术后眼压显着降低，在大约21天内恢复到基线水平，此后60天保持稳定，这与当前研究的观察结果一致。

. Such trends, along with the inherent limitations of normal eyes in replicating glaucomatous conditions, guided the decision to prioritize TBD implantation over including an AGV-alone group in this preliminary study.

这种趋势，以及正常眼睛在复制青光眼疾病方面的固有局限性，指导了在这项初步研究中优先考虑TBD植入而不是仅包括AGV组的决定。

Although this was a short-term study, the findings demonstrated that TBD could serve as an efficient and less invasive approach for managing elevated IOP in the presence of fibrotic blebs. The simplicity of TBD not only aids in cost reduction but also provides flexibility in its application. In this study, TBD was applied to the superior nasal quadrant of the bleb, but it could be adjusted according to needs, such as towards the superior temporal quadrant or the retrobulbar direction, and multiple TBDs could be implemented if required, even for fibrotic blebs formed around the first TBD.

尽管这是一项短期研究，但研究结果表明，TBD可以作为一种有效且侵入性较小的方法，用于在存在纤维化滤泡的情况下管理升高的眼压。TBD的简单性不仅有助于降低成本，而且为其应用提供了灵活性。在这项研究中，TBD被应用于气泡的上鼻象限，但可以根据需要进行调整，例如朝向颞上象限或球后方向，并且如果需要，可以实施多个TBD，即使对于在第一个TBD周围形成的纤维化泡也是如此。

The versatility of TBD suggests its potential utility in offering a different approach for managing bleb fibrosis following glaucoma surgery..

TBD的多功能性表明其在青光眼手术后提供治疗滤泡纤维化的不同方法方面的潜在效用。。

This preliminary study is limited by its small sample size and short follow-up period, which restricted the ability to evaluate the long-term efficacy and tissue response to the TBD. The results indicate that the TBD was tolerated in aqueous humor drainage up to 21 days after surgery, but did not provide conclusive evidence for its effectiveness beyond this period.

这项初步研究受到样本量小和随访期短的限制，这限制了评估TBD长期疗效和组织反应的能力。结果表明，TBD在手术后21天内可以耐受房水引流，但没有提供超过这一时期的有效性的确凿证据。

the study design included periodic ophthalmic evaluations to confirm encapsulated bleb formation and ensure the absence of functional abnormalities in the dogs’ eyes following tissue sampling, the experiment was designed with a minimal follow-up duration and small sample size to reduce experimental stress on the animals and minimize the number of animals sacrificed.

该研究设计包括定期眼科评估，以确认包裹的滤泡形成，并确保组织取样后狗眼中没有功能异常，该实验的设计具有最小的随访时间和较小的样本量，以减少对动物的实验压力，并尽量减少牺牲的动物数量。

From the perspective of conjunctival tissue healing, the three-week period included the initial clotting and vascular reactions within the first 5 days post-surgery, followed by the inflammatory phase and fibroplasia lasting approximately 15 days, including granulation tissue formation. However, this timeframe may have been insufficient to evaluate the subsequent remodeling phase and to gain a more detailed understanding of aqueous humor drainage dynamics and tissue adaptations.

从结膜组织愈合的角度来看，三周的时间包括手术后前5天内的初始凝血和血管反应，然后是持续约15天的炎症期和纤维增生，包括肉芽组织形成。然而，这个时间范围可能不足以评估随后的重塑阶段，也不足以更详细地了解房水引流动力学和组织适应。

. Despite employing various strategies to encourage bleb formation, the inherent differences between normal and glaucomatous eyes presented fundamental challenges, making it difficult to fully assess the long-term efficacy and stability of TBD. Additionally, while anti-inflammatory treatments were administered following both AGV and TBD surgeries, and distinct signs of uveitis including aqueous flare were absent, it is possible that surgically induced intraocular inflammation may have influenced the initial reduction in IOP..

尽管采用了各种策略来鼓励气泡的形成，但正常眼和青光眼眼之间的固有差异提出了根本性的挑战，因此很难充分评估TBD的长期疗效和稳定性。此外，虽然在AGV和TBD手术后均进行了抗炎治疗，并且没有明显的葡萄膜炎迹象，包括水性眩晕，但手术引起的眼内炎症可能影响了眼压的初始降低。。

In conclusion, TBD represents a novel approach to address bleb fibrosis in the aftermath of glaucoma surgery. The preliminary results of this study demonstrate its potential to restore aqueous humor flow and reduce IOP in the short term. However, limitations such as the small sample size, short follow-up period, and use of normal rather than glaucomatous eyes necessitate further research.

总之，TBD代表了一种解决青光眼手术后滤泡纤维化的新方法。这项研究的初步结果表明，它有可能在短期内恢复房水流量并降低眼压。然而，诸如样本量小，随访时间短以及使用正常眼而不是青光眼眼等局限性需要进一步研究。

Future studies should focus on evaluating the long-term effects of the TBD, including its impact on fibrotic blebs and IOP control over extended periods. Additionally, comparisons between TBD and other surgical techniques, the role of adjunctive agents such as MMC or corticosteroids, and the influence of incision site strategies on outcomes would contribute to a better understanding of its clinical utility and potential for broader application in glaucoma management.

未来的研究应侧重于评估TBD的长期影响，包括其对纤维化滤泡和长期眼压控制的影响。此外，TBD与其他手术技术之间的比较，MMC或皮质类固醇等辅助药物的作用以及切口部位策略对结局的影响将有助于更好地了解其临床实用性和在青光眼管理中更广泛应用的潜力。

Optimization of the device design to address challenges such as the risk of conjunctival complications and improving bleb survival would also be essential to maximize its efficacy..

优化设备设计以应对诸如结膜并发症风险和改善滤泡存活率等挑战，对于最大限度地提高其疗效也是至关重要的。。

Data availability

数据可用性

All data generated or analyzed during this study are included in this published article (and its Supplementary Information files).

本研究期间生成或分析的所有数据均包含在本文（及其补充信息文件）中。

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Funding

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This study was supported by the BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, the Research Institute for Veterinary Science (RIVS), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1I1A1A01058695)..

这项研究得到了BK21四未来兽医领先教育和研究中心，兽医科学研究所（RIVS）以及由教育部资助的韩国国家研究基金会（NRF）的基础科学研究计划（2021R1I1A01058695）的支持。。

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Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea

韩国首尔国立大学兽医学院兽医临床科学系

Songhui Lee, Eunji Lee, Kangmoon Seo & Seonmi Kang

Songhui Lee，Eunji Lee，Kangmoon Seo和Seonmi Kang

Department of Pathology, Biotoxtech Co., Ltd., Cheongju, Republic of Korea

大韩民国清州Biotoxtech有限公司病理学系

Du-Min Go

杜敏走

Laboratory of Veterinary Pathology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea

首尔国立大学兽医科学研究所兽医学院兽医病理学实验室，大韩民国首尔

Dae-Yong Kim

金大永

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Songhui Lee

李松辉（Songhui Lee）

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Contributions

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S.L. contributed to the conception and execution of experiments, device design and fabrication, data analysis, figure preparation, and manuscript writing. E.L. conceived and performed experiments, and data analysis. D.G. and D.K. conducted tissue examinations and manuscript writing. K.S. provided supervision and contributed to manuscript review and editing.

S、 L.为实验的概念和执行，器件设计和制造，数据分析，图形准备和手稿撰写做出了贡献。E、 L.构思并进行了实验和数据分析。D、。K、美国提供了监督，并为稿件审查和编辑做出了贡献。

S.K. contributed to the conception, conceived experiments, designed and fabricated the device, and supervised the entire research process, including data acquisition and interpretation. All authors reviewed and approved the final manuscript..

S、 K.为概念做出了贡献，构思了实验，设计和制造了设备，并监督了整个研究过程，包括数据采集和解释。所有作者都审查并批准了最终稿件。。

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善美，你

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Competing interests

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Seonmi Kang, Kangmoon Seo, and Songhui Lee are listed as inventors on the Korean patent application No. 10-2022-0082539 and PCT application No. KR2023/009331. This patent was derived from the findings of this study and was filed by Seoul National University R&DB Foundation. The other authors declare no competing interests..

Seonmi Kang、Kangmoon Seo和Songhui Lee被列为韩国专利申请号10-2022-0082539和PCT申请号KR2023/009331的发明人。该专利来源于这项研究的结果，由首尔国立大学R＆DB基金会提交。其他作者声明没有利益冲突。。

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Lee, S., Go, DM., Lee, E.

李，S.，Go，DM.，李，E。

et al.