Abstract
Background
The non-human primate (NHP) model is ideal for pre-clinical testing of novel therapies for human retinal diseases due to its similarity to the human visual system. However, intra-ocular delivery of gene therapy or cell transplantation to the retina gets hampered by the sticky vitreous body and poorly permeable inner limiting membrane (ILM) in primates. Although vitrectomy and ILM peeling are commonly performed in patients, many pitfalls exist in carrying out these procedures in the rhesus macaque, which have not been reported previously.
Methods
We summarised common surgical pitfalls after performing vitrectomy and ILM peeling in four eyes of two rhesus macaques (one male and one female). We provided corresponding hands-on technical tips based on our surgical experience and literature search. Orbital CT scans were compared between adult rhesus macaques and humans. High-resolution surgical videos were recorded to demonstrate each critical surgical step.
Results
Due to size difference, poor post-operative compliance, and high-standard requirements of a controlled experiment, there were eleven common surgical pitfalls during vitrectomy and ILM peeling in rhesus macaque. Falling into these pitfalls may produce discomfort, add fatigue, cause surgical complications, or even lead to the exclusion of the NHP from an experimental group.
Conclusion
Recognition and circumvention of these pitfalls during vitrectomy and ILM peeling in NHP are essential. By focusing on these surgical pitfalls, we can better carry out preclinical tests of novel therapies for retinal diseases in the NHP model.
Subject terms: Retinal diseases, Vitreous detachment
Introduction
Non-human primates (NHP) such as rhesus macaque play an essential role in translational medicine of retinal diseases and optic neuropathies. Unlike rodent or other mammals, NHP has a unique, human-like visual system, including [1] macular structure for high visual acuity [1, 2] distinct retinal ganglion cells (RGCs) subtypes, and transcriptomic expression [2, 3] specific optic nerve projection pattern [3]. Furthermore, pathophysiological responses in the primate central nervous system (CNS) are different from rodents [4]. These features endow the NHP model with great value for developing novel therapeutic strategies to save and restore vision.
Moreover, unlike the rodent model, vitrectomy and inner limiting membrane (ILM) peeling are often required in the NHP model to promote intravitreally delivered therapeutic agents to the retina [5, 6]. The vitreous body is a gel-like substance placed before the retina. In a young, healthy NHP eye, the vitreous body is sticky, acting as a trap and preventing therapeutic agents from diffusing to the retina. Studies have found that before the intravitreal injection of adeno-associated virus (AAV), vitrectomy significantly promotes the transduction of RGCs in NHP retinas [7]. ILM is the base membrane at the vitreoretinal interface, formed by the extracellular matrix excreted by retinal Müller cells [5]. Cumulative evidence has shown that the ILM acts as a physical barrier for intravitreal retinal therapeutic strategies in primates, including viral vectors, cell transplantation, nanoparticles, and anti-VEGF therapy [5, 6, 8]. Accordingly, ILM peeling dramatically increase inner retina transduction by AAV [5–7] and significantly promotes retinal integration of intravitreally transplanted cells [9].
Although vitrectomy and ILM peeling are commonly performed in human patients, many pitfalls with monkeys result in surgical or experimental failure. Due to the rare availability and high cost of the NHP model, it is highly desirable to avoid these pitfalls to achieve a high surgical success rate. However, to our best knowledge, these surgical pitfalls have not yet been reported.
This current study detailed the surgical preparation and procedures, summarised eleven common pitfalls and provided corresponding technical tips and surgical videos based on our surgical experience and literature review. Therefore, our work can help basic science researchers understand the surgery, the surgical team in the animal facility prepare the surgery, and vitreoretinal surgeons bypass the pitfalls to achieve a high success rate of vitrectomy and ILM peeling in the NHP model.
Methods and materials
Aim
This study aimed to help basic science researchers and retinal surgeons to facilitate pre-clinical tests of novel therapies for retinal diseases in the NHP model.
Study design
In this study, vitrectomy and ILM peeling were performed in four eyes of two rhesus macaques (one male and one female). One surgeon performed all surgery. OCT and colour fundus photography were performed to evaluate post-operative structure. We also compared the CT skull scans of three male human adults with those of three male rhesus macaques which met the lowest requirement of statistical comparison. Due to the preciousness of rhesus macaques, we minimised the use of animals as much as possible.
Non-human primate experiments were conducted following The ARRIVE Guidelines and the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research guidelines. Protocols were approved by the Joinn Laboratory (Suzhou, China, Ethics ID number: ACU20-1698). Vitrectomy and ILM peeling were performed in four eyes of two rhesus macaques (one male and one female), aged 5–7 years at the weight of 5–7 kg. The monkeys were housed in the animal facility of the Joinn Laboratory under 12 h/12 h light/dark cycle with food ad libitum.
Anaesthesia
General anaesthesia was induced using Zoletil50 (4–8 mg/kg, IM, tiletamine/zolazepam) and maintained with isoflurane (2%, 1 L/minute). After tracheal intubation (PVC 6-0, Henan Tuoren Medical Device Group Co. LTD, China), mechanical ventilation was maintained at 15 cycles per minute (Tidal volume: 70 ml, max pressure: 260 mm water). In addition, a pulse oximeter was connected to the finger, a blood pressure cuff was tied to a lower extremity, and 3-lead electrocardiogram clips were connected onto the limbs for the cardiopulmonary monitoring.
Surgical preparation
Prophylactic steroids (Dexamethasone, 0.25 mg/Kg, IM) and antibiotic (Cefazolin, 25 mg/Kg, IM) were administered [10]. In addition, a tear drainage test was carried out to exclude monkeys with dacryocystitis (blockage of tear duct due to the presence of pus).
After general anaesthesia, the monkey’s eyelid margin and eyelashes were carefully scrubbed three times using cotton swabs soaked in povidone-iodine (5%, Zhejiang Apeloa Inc., China). The periocular skin was prepared with povidone-iodine in an outward circular motion three times for skin asepsis. The operative eye was draped with sterile surgical drapes, and the ocular surface was covered with a sterile adhesive plastic drape. A flexible eyelid speculum was applied (Note: the eyelashes should be completely wrapped by the drape and excluded from the surgical field to decrease the microbial contamination from the periocular area). Afterwards, the povidone-iodine solution was instilled into the conjunctival sac, retained for 1 min [11], and washed with a balanced saline solution.
Surgical procedure
Vitrectomy and ILM peeling in rhesus macaque were similar to those in human patients. The pitfalls and tips for procedures in monkeys are detailed in the Results section; management of common surgical complications are detailed in the Discussion section; the major steps and entire surgical process are shown in Supplementary Movies 1–9. Briefly, 23-gauge trocar-cannula entries were established 3 mm away from the corneal limbus by 3-port vitrectomy (Supplementary Movie 1), followed by the core vitrectomy (Supplementary Movie 2). Next, posterior vitreous detachment (PVD) creation was made, facilitated with triamcinolone staining (Supplementary Movie 3) or end-grasping forceps (Supplementary Movie 4). Then peripheral vitrectomy was carried out using a 45-degree prism contact lens (Supplementary Movie 5). Next, Indocyanine green (ICG) staining was used to visualise and peel the ILM (Supplementary Movie 6) within the vascular arcade area (ILM peeling in the right and left eye by a dominant right-hand surgeon is shown in Supplementary Movie 7, 8, respectively). After intravitreal injection of triamcinolone to reduce the inflammatory response [12, 13], trocar-cannulas were removed one by one from sclerotomy ports, with the infusion trocar-cannula removed at last (Supplementary Movie 9). In case of wound leakage or severe hypotony, scleral suturing was performed. The whole surgical time from sclerotomy to wound closure was around 30 minutes (Supplementary Movie 10).
Post-operative management
Post-operative steroids (Dexamethasone, 0.25 mg/Kg, IM) was detailed previously [10]. Cefazolin (25 mg/Kg, IM) was applied for 3 days after surgery. In addition, tobramycin dexamethasone eye drops and ofloxacin eye ointment were administered three times a day for 1 week.
Retinal OCT imaging with the dense scan pattern
The monkey was anaesthetised with Zoletil50. Macular OCT imaging was obtained by using the Heidelberg Spectralis OCT system with an 870 nm wavelength light source and an objective lens system at a 30-degree angle of view. A dense scan pattern was applied with 100 frames averaged.
Colour fundus photography
The monkey was anaesthetized with Zoletil50. Colour fundus images were captured with a fundus Camera (ASP-CER, Chongqing Kanghuaruiming S&T CO, LTD.).
Skull CT scan and CT measurement
Cranial CT scans with a slice thickness of 2.5 mm in humans and 0.8 mm in macaques were obtained (human, GE Optina660, General Electric Company, Boston, USA; macaques, Philip Brilliance iCT, Royal Philips Company, Amsterdam, Holland). The monkey was anaesthetised with Zoletil50 before CT scan. The horizontal orbital length was measured manually between the medial and the lateral orbital wall manually with a Philips DICOM Viewer R3.0-SP15 software. The measurer was blinded to the species of CT images. Informed consent was obtained from all human subjects.
Statistical analysis
The data was analysed by GraphPad (9.0) software. Normality tests were used to analyse the distributions of data. Welch’s t-test (two-tailed) was used to compare two groups of data. Data were presented as mean ± s.e.m. The effect size had a 95% confidence interval. No data were excluded.
Results (pitfalls and tips)
Head tilt during general anaesthesia
Most of the vitreoretinal surgeries in patients are performed under local anaesthesia, provided that the patients are cooperative and keep their face up in a supine position. However, after tracheal intubation and general anaesthesia, the monkey’s head tilted to one side. Therefore, we need to keep the monkey facing up using a pad positioner or donut-shaped pillow made of surgical drapes or other materials (Fig. 1A).
Fig. 1. Pitfalls and tips 1–5.
A Face-up position of the rhesus macaque. B CT scan of the forehead of the rhesus macaque. C CT scan of the forehead of humans. D Recommended hand position to decrease discomfort and fatigue during surgery. E Microscopic view of the custom-made cotton ring. F Scheme of sutureless techniques. G Microscopic view of conjunctival displacement.
Narrow forehead
Vitreoretinal surgeons are used to placing their hypothenar eminence, little and ring fingers on the patient’s forehead to stabilise their hands and reduce fatigue. However, compared with humans, the height of the forehead in monkeys is much smaller (Fig. 1B, C). The narrow forehead may cause discomfort and increase fatigue during the procedure. Instead, surgeons can rest their eminence, little and ring fingers on the forehead and periorbital area (Fig. 1D), or bring an additional wrist rest to support their hands [14].
Need for smaller contact lens mounting rings
Contact lenses visualise the vitreous and retina by eliminating corneal refraction. To stabilise the contact lens during vitrectomy, a suitable contact lens mounting ring is necessary. The corneal diameter of the adult rhesus macaque, 10.6 mm on average [15], is smaller than that of humans, which is around 12 mm. Therefore, a conventional contact lens mounting ring for an adult human is too large and often blocks the sclerotomy sites (3 mm from the corneal limbus). Additionally, conjunctival suture is needed to fasten the ring. To solve the problem, the surgeon can customise a cotton ring using the cotton swab to stabilise the prism lens without suturing (Fig. 1E).
Poor post-operative compliance (need to protect corneal epithelium)
It is important not to injure the corneal epithelium during the surgery since the monkey may scratch its eye in case of foreign body sensation, increasing the risk of intraocular infection. The following measures can be taken to protect the corneal epithelium: (1) use a lower concentration (5%, rather than 10%) of povidone-iodine for a shorter time (1 min, rather than 3 min) [16–18], (2) irrigate the cornea frequently to prevent the epithelium from drying up during the surgery, (3) do not remove the corneal epithelium.
Poor post-operative compliance (need for sutureless wound closure)
Conjunctival or scleral suture, potentially causes foreign body sensation, may be scratched by the monkey post-surgery. This increases the risk of wound leakage or endophthalmitis. Thus, a 23-gauge or smaller trocar-cannula is recommended. Sutureless techniques are as follows (Fig. 1F, Supplementary Movie 1): (1) conjunctival displacement: displace conjunctiva first, then perform conjunctival and scleral incisions (Fig. 1G); [19] (2) tunnelled scleral incision: make an initially oblique, then perpendicular scleral incision to achieve a valve-like effect [19, 20]. These techniques prevent direct communication of tear film with the vitreous body through the sclerotomies, thereby reducing endophthalmitis risk.
In case of wound leakage or extensive conjunctival bleb formation following the withdrawal of the infusion cannula, scleral suture or air-liquid exchange are still needed to seal the wound [21]. It is noteworthy that air/gas-liquid exchange may hamper the access of intravitreally delivered therapeutic agents to the retina, opacify vision (making it hard to evaluate the therapeutic effect in the experimental monkeys), and it may take several weeks to completely absorb the gas [22]. An alternative way is to perform partial (1/3-1/2) fluid-air exchange to seal the sclerotomy, which only takes a few days to absorb the air.
Small palpebral fissure (narrow eye-opening)
As shown in Fig. 2B, C, the horizontal orbital diameter (distance between medial and lateral orbital wall, as an analogue to palpebral fissure length) in rhesus macaque (~24 mm) was much smaller than adult humans (~38 mm) [23].
Fig. 2. Small palpebral fissure in the rhesus macaque.
A CT scan of orbit in humans. B CT scan of orbit in rhesus macaque. C Comparison of horizontal orbital length between human and macaque. Data was demonstrated as mean ± s.e.m, n = 3 adult male humans and 3 adult male rhesus macaques with 0.3% and 4% coefficient of variation, respectively. Data was at normal distribution with significantly different variances. Welch’s t-test, two-tailed, **p < 0.01. D, E The microscopic view showed the eyelid covered the sclerotomy sites and some of the trocar-cannula ports. F Microscopic view of exposing the port with a forceps. G, H Illustration of the fundus and lens injury by inserting surgical tools.
To circumvent small palpebral fissure, we preferred a flexible wire eyelid speculum to an adjustable rigid one because the former was smaller and occupied even less space (Fig. 2D). Besides, due to narrow eye-opening, the sclerotomy sites and some of the trocar-cannula ports are covered by the eyelids (Fig. 2D, E). To expose the port, the surgical assistant can rotate the eyeball with forceps when necessary (Fig. 2F).
Short axial length
The axial length is around 24 mm in adult humans and 19 mm in adult rhesus macaques (Fig. 2A) [24], which is similar to a human infant aged from 3–12 months [25]. Therefore, special attention should be taken not to injure the fundus or lens while inserting surgical tools intravitreally, especially for the first time (Fig. 2G, H).
Difficulty in PVD creation
Like young, healthy adult humans, young, healthy adult rhesus macaques have their posterior vitreous cortex firmly attached to the retina [26]. Here, we used two techniques to create PVD. (1) Triamcinolone (TA) assisted PVD creation: TA was injected intravitreally to identify the posterior vitreous cortex following core vitrectomy (Fig. 3A, Supplementary Movie 3). After removal of floating TA particles with a vitreous cutter (Fig. 3B), we induced vitreo-papillary PVD by aspiration alone around the optic disc (with a vacuum pressure of 300–500 mm Hg), carefully and patiently (Fig. 3C). This process of induction took a few minutes. Afterwards, we enlarged PVD and then removed the TA labelled posterior hyaloid (Fig. 3D). This TA-assisted PVD creation worked well in three out of four eyes of the rhesus macaque. (2) End grasping forceps assisted PVD creation. In one eye, PVD was not induced successfully by TA-assisted aspiration. Therefore, we used fine end-grasping forceps to grab and carefully lift the posterior hyaloid in the peripapillary area (Fig. 3E, Supplementary Movie 4). After several patient attempts, PVD was induced (Fig. 3F), and enlarged by aspiration alone (Fig. 3G). Afterwards, the detached hyaloid was removed with the vitreous cutter (Fig. 3H).
Fig. 3. Scheme of PVD under microscopic surgical view.
A TA labelled posterior vitreous. B Microscopic view of removing floating TA particles. C Microscopic view of vitreo-papillary PVD. D Microscopic view of removing TA labelled posterior vitreous membrane. E Microscopic view of the posterior vitreous membrane without TA-assisted aspiration. F Microscopic view of PVD creation. G Microscopic view of aspirating alone to enlarge PVD area. H Microscopic view of removing the detached vitreous membrane.
Difficulty in ILM peeling
The ILM was firmly attached to the neural retina in the young adult rhesus macaque. To facilitate ILM peeling, indocyanine green was injected (0.25% ICG, a few drops) intravitreally to stain the ILM for about 30 s as in human patients (Fig. 4A, Supplementary Movie 6). If the ILM was not well stained, ICG staining was repeated. To prevent ICG retinal toxicity, alternative dyes such as trypan blue or brilliant blue G can be used to stain the ILM.
Fig. 4. Scheme of ILM peeling under microscopic surgical view.
A ILM staining. B Creation of the first ILM strip. C, D Peeling of ILM within the vascular arcades. E–H Peeling of ILM with passive aspiration.
There were three major steps in ILM peeling. First, we gently created an ILM edge outside of the maculo-papillary bundles with a “pinch” technique (Fig. 4A, Supplementary Movie 7, 8). Creating the first ILM strip might take multiple attempts and a few minutes (Fig. 4B). One can initiate the peel in any direction and at any clock hour which allows a comfortable hand position. Secondly, the ILM edge was peeled radially to create a thin strip with a long edge. Afterwards, the long edge of the ILM flap was gently grasped and peeled circumferentially within the vascular arcades (Fig. 4C, D). Since a large piece of ILM might be torn by the forceps during peeling, we continued to peel ILM using passive aspiration (Fig. 4E, F, G, H). However, it was not rare that the peel was not completed in one strip in the rhesus macaque.
Colour fundus photography and OCT retinal imaging were performed at 2 weeks post-surgery with successful ILM peeling at the posterior pole (Fig. 5A, B). We also found tiny residual ILM remnants (Fig. 5C) and subtle outer retinal deficits (interrupted IS/OS junctions) (Fig. 5D, E) in OCT retinal images.
Fig. 5. Retinal photography and OCT images after surgery.
A, B Colour fundus photography and OCT retinal at 2 weeks post-surgery. C OCT imaging of residual ILM. D, E OCT imaging of subtle outer retinal deficits.
Interfacial tension management is undesirable
Intravitreal injection of silicone oil or gas may decrease the access of therapeutic agents to the retina. Additionally, air-liquid mix or emulsified silicone oil in the vitreous body reduces the ocular transparency and thus prevents post-operative retinal examinations. Besides, emulsified silicone oil needs to be removed using additional surgery.
Lens injury is undesirable
Be careful to protect the lens during peripheral vitrectomy (Supplementary Movie 5). Although it is common to combine lens surgery and vitrectomy in human patients, lens surgery was not desirable due to the following reasons: (1) increase in experimental variation, (2) increase in experimental budget, (3) shortage of special ophthalmic devices (for determining the power of an intraocular lens (IOL)), custom-made IOL for monkey, and PHACO surgical tools in the animal research facility.
Discussion
This study summarises detailed procedures and common pitfalls of vitrectomy and ILM peeling in the monkey. Our work can help retinal surgeons bypass these pitfalls and increase the surgical success rate. At the same time, basic research scientists can learn more surgical details from this current work.
Advanced tools
A wide-angle viewing system provided the panoramic view of fundus even in eyes with small pupils and corneal opacity, which improves the safety and efficacy of vitrectomy [27]. The Oculus BIOM noncontact lens system offered corneal epithelial protection and flexibility during the surgery, however, had a relatively lower resolution and contrast of fundus image compared to contact lens system [28].
23-gauge or 25-gauge?
We preferred 25-gauge over 23-gauge for vitrectomy in monkeys because the former had lower rates of sclerotomy suturing, postoperative hypotony [29, 30] and post-operative intraocular inflammation [31]. On the contrary, other studies suggested that 25- and 23-gauge vitrectomies had similar safety profiles, scleral suturing rates and sclerotomy closure rate [32]. As such, gauge selection can be made according to the availability of appropriate instruments in the animal facility; a 25-gauge vitrectomy might be better if both are available [10].
When to deliver intravitreal therapy?
It often takes a few weeks for the sclerotomies to close [33]. Besides, the vitrectomy-induced immune response was detectable up to 1 month after surgery [34]. Therefore, to prevent potential leakage of the therapy through the wound and to alleviate the potential effect of post-operative intraocular inflammation on retinal therapies, therapeutic reagents can be delivered intravitreally a few weeks after surgery.
Management of common mild surgical complications
Mild surgical complications are tolerable, such as transient post-operative hypotony, subtle cataracts, limited pre-retinal haemorrhage, and small retinal holes.
Transient post-operative hypotony is a common complication in 23-gauge sutureless vitrectomy [29, 30]. Mild post-operative hypotony does not cause severe complications such as endophthalmitis and thus does not require additional treatment [29, 30]. A traumatic focal cataract may likely be caused by surgical mis-manipulation, such as accidentally cutting the posterior lens cortex. A subtle cataract does not require combined or secondary lens surgery as long as it does not affect the quality and reliability of post-operative ocular examinations. Limited retinal bleeding might occur during ILM peeling and can be left without treatment. Smaller retinal holes can be sealed by photocoagulation during the surgery.
Alternatives to vitrectomy (microplasmin)
Pharmacological vitreolysis with microplasmin can effectively induce the PVD without altering the retina’s morphology in animal studies [35]. However, clinical studies have shown some disadvantages of microplasmin, including relative low success rates of PVD (~13%) and association with a higher incidence of ocular adverse events such as transient loss of visual acuity, abnormal electroretinogram test, a loss of the ellipsoid zone in the outer retina [36]. Furthermore, enzymatic vitreolysis with microplasmin preserves ILM [37]; therefore, ILM peeling is still required after microplasmin injection. Additionally, microplasmin is expensive (roughly costs $3000 per eye), which further prevents it from being used in monkey vitrectomy and ILM peeling.
Alternatives to ILM peeling
Sub-retinal injection following vitrectomy can deliver AAV or stem cells into sub-retinal space after penetrating the entire neural retina. However, this procedure is invasive and focuses on the outer retina. Sub-ILM injection, another alternative, effectively delivers the AAV to the primate inner retina [10]. However, it is technically challenging to surgically induce “a hydrodissected space” between ILM and the neural retina since these tissues are firmly attached to the young, healthy primate. Additionally, compared to intravitreal injection, the sub-ILM injection has much more limited retinal surface coverage. Another potential alternative is using an exosome-associated intravitreal drug delivery [38]. However, according to our best knowledge, its effect on NHP has not been studied yet.
Conclusion
This study listed the required surgical materials and tools, demonstrated essential surgical procedures, summarised common surgical pitfalls and corresponding hands-on technical tips, using high-resolution surgical vitrectomy videos and ILM peeling in the NHP model (rhesus macaque). Our work aimed to promote mutual understanding between basic science researchers and retinal surgeons to facilitate pre-clinical tests of novel therapies for retinal diseases in the NHP model.
Summary Table
What was known before
Although vitrectomy and ILM peeling are commonly performed in patients, many pitfalls exist for carrying out these procedures in the rhesus macaque, which have not been reported previously.
What this study adds
Due to size difference, poor post-operative compliance, and high-standard requirements of a controlled experiment, there were eleven common surgical pitfalls during vitrectomy and ILM peeling in rhesus macaque.
Supplementary information
Acknowledgements
The sponsor or funding organisation had no role in the design or conduct of this research. We thank MJEditor (www.mjeditor.com) for language editing.
Author contributions
Conceptualisation: YZ, QP; Data curation: YZ, SL, ML; Formal Analysis: SL, ML, HP, LW, YM; Funding acquisition: YZ, WW; Methodology: YZ, QP; Visualisation: YZ, QP, SL, ML. Writing – original draft: YZ, QP, SL, ML; Writing – review & editing: YZ, QP, WW.
Funding
National Key R&D Program of China [2021YFA1101200]. National Key R&D Program of China [2016YFC1101200]. National Natural Science Foundation of China [81770926;81800842]. Key R&D Program of Zhejiang Province [2019C03009; 2021C03065]. Key R&D Program of Wenzhou Eye Hospital [YNZD1201902]. National Key R&D Program of China [2019YFC0119300].
Data availability
Data available within the article or its supplementary materials.
Competing interests
The authors declare no competing interests.
Ethics approval
The research followed the principles of the Declaration of Helsinki, and was approved by the ethics committees of Wenzhou Eye Hospital, Wenzhou Medical University (Ethics ID number: KYK (2017) 53). Patient consents from three male adults were obtained before analysis of their orbital CT scan data in this study.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Qintuo Pan, Shengjian Lu, Mengyun Li.
Contributor Information
Wencan Wu, Email: wuwencan@wmu.edu.cn.
Yikui Zhang, Email: zhang.yikui@wmu.edu.cn.
Supplementary information
The online version contains supplementary material available at 10.1038/s41433-022-02327-5.
References
- 1.Picaud S, Dalkara D, Marazova K, Goureau O, Roska B, Sahel JA, et al. The primate model for understanding and restoring vision. Proc Natl Acad Sci USA. 2019;116:26280–7. doi: 10.1073/pnas.1902292116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Peng YR, Shekhar K, Yan W, Herrmann D, Sappington A, Bryman GS, et al. Molecular classification and comparative taxonomics of foveal and peripheral cells in primate retina. Cell. 2019;176:1222–37. doi: 10.1016/j.cell.2019.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jeffery G, Levitt JB, Cooper HM. Segregated hemispheric pathways through the optic chiasm distinguish primates from rodents. Neuroscience. 2008;157:637–43. doi: 10.1016/j.neuroscience.2008.09.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Friedli L, Rosenzweig ES, Barraud Q, Schubert M, Dominici N, Awai L, et al. Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates. Sci Transl Med. 2015;7:302ra134. doi: 10.1126/scitranslmed.aac5811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Peynshaert K, Devoldere J, Minnaert AK, De Smedt SC, Remaut K. Morphology and composition of the inner limiting membrane: species-specific variations and relevance toward drug delivery research. Curr Eye Res. 2019;44:465–75. doi: 10.1080/02713683.2019.1565890. [DOI] [PubMed] [Google Scholar]
- 6.Zhang KY, Johnson TV. The internal limiting membrane: Roles in retinal development and implications for emerging ocular therapies. Exp Eye Res. 2021;206:108545. doi: 10.1016/j.exer.2021.108545. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Tshilenge KT, Ameline B, Weber M, Mendes-Madeira A, Nedellec S, Biget M, et al. Vitrectomy before intravitreal injection of AAV2/2 vector promotes efficient transduction of retinal ganglion cells in dogs and nonhuman primates. Hum Gene Ther Methods. 2016;27:122–34. doi: 10.1089/hgtb.2016.034. [DOI] [PubMed] [Google Scholar]
- 8.Peynshaert K, Devoldere J, De Smedt SC, Remaut K. In vitro and ex vivo models to study drug delivery barriers in the posterior segment of the eye. Adv Drug Deliv Rev. 2018;126:44–57. doi: 10.1016/j.addr.2017.09.007. [DOI] [PubMed] [Google Scholar]
- 9.Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Investigative Ophthalmol Vis Sci. 2010;51:2051–9. doi: 10.1167/iovs.09-4509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Gamlin PD, Alexander JJ, Boye SL, Witherspoon CD, Boye SE. SubILM injection of AAV for gene delivery to the retina. Methods Mol Biol. 2019;1950:249–62. doi: 10.1007/978-1-4939-9139-6_14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Nguyen CL, Oh LJ, Wong E, Francis IC. Povidone-iodine 3-minute exposure time is viable in preparation for cataract surgery. Eur J Ophthalmol. 2017;27:573–6. doi: 10.5301/ejo.5000964. [DOI] [PubMed] [Google Scholar]
- 12.Siqueira RC, Dos Santos WF, Scott IU, Messias A, Rosa MN, Fernandes Cunha GM, et al. Neuroprotective effects of intravitreal triamcinolone acetonide and dexamethasone implant in rabbit retinas after pars plana vitrectomy and silicone oil injection. Retina. 2015;35:364–70. doi: 10.1097/IAE.0000000000000284. [DOI] [PubMed] [Google Scholar]
- 13.Konstantinidis L, Berguiga M, Beknazar E, Wolfensberger TJ. Anatomic and functional outcome after 23-gauge vitrectomy, peeling, and intravitreal triamcinolone for idiopathic macular epiretinal membrane. Retina. 2009;29:1119–27. doi: 10.1097/IAE.0b013e3181ac23da. [DOI] [PubMed] [Google Scholar]
- 14.Li Y, Wolf MD, Kulkarni AD, Bell J, Chang JS, Nimunkar A, et al. In situ tremor in vitreoretinal surgery. Hum Factors. 2021;63:1169–81. doi: 10.1177/0018720820916629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zurawski CA, McCarey BE, van Rij G, Fernandes A. Corneal biometrics of the rhesus monkey (Macaca mulatta) J Med Primatol. 1989;18:461–6. doi: 10.1111/j.1600-0684.1989.tb00413.x. [DOI] [PubMed] [Google Scholar]
- 16.Zamora JL. Chemical and microbiologic characteristics and toxicity of povidone-iodine solutions. Am J Surg. 1986;151:400–6. doi: 10.1016/0002-9610(86)90477-0. [DOI] [PubMed] [Google Scholar]
- 17.Jiang J, Wu M, Shen T. The toxic effect of different concentrations of povidone iodine on the rabbit’s cornea. Cutan Ocul Toxicol. 2009;28:119–24. doi: 10.1080/15569520903080511. [DOI] [PubMed] [Google Scholar]
- 18.Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology. 1991;98:1769–75. doi: 10.1016/S0161-6420(91)32052-9. [DOI] [PubMed] [Google Scholar]
- 19.Warrier SK, Jain R, Gilhotra JS, Newland HS. Sutureless vitrectomy. Indian J Ophthalmol. 2008;56:453–8. doi: 10.4103/0301-4738.43364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.López-Guajardo L, Pareja-Esteban J, Teus-Guezala MA. Oblique sclerotomy technique for prevention of incompetent wound closure in transconjunctival 25-gauge vitrectomy. Am J Ophthalmol. 2006;141:1154–6. doi: 10.1016/j.ajo.2006.01.037. [DOI] [PubMed] [Google Scholar]
- 21.Yamane S, Kadonosono K, Inoue M, Kobayashi S, Watanabe Y, Arakawa A. Effect of intravitreal gas tamponade for sutureless vitrectomy wounds: three-dimensional corneal and anterior segment optical coherence tomography study. Retina. 2011;31:702–6. doi: 10.1097/IAE.0b013e3181f0d2e6. [DOI] [PubMed] [Google Scholar]
- 22.Kanclerz P, Grzybowski A. Complications associated with the use of expandable gases in vitrectomy. J Ophthalmol. 2018;2018:8606494. doi: 10.1155/2018/8606494. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Gupta V, Prabhakar A, Yadav M, Khandelwal N. Computed tomography imaging-based normative orbital measurement in Indian population. Indian J Ophthalmol. 2019;67:659–63. doi: 10.4103/ijo.IJO_1187_18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Fernandes A, Bradley DV, Tigges M, Tigges J, Herndon JG. Ocular measurements throughout the adult life span of rhesus monkeys. Invest Ophthalmol Vis Sci. 2003;44:2373–80. doi: 10.1167/iovs.02-0944. [DOI] [PubMed] [Google Scholar]
- 25.Bach A, Villegas VM, Gold AS, Shi W, Murray TG. Axial length development in children. Int J Ophthalmol. 2019;12:815–9. doi: 10.18240/ijo.2019.05.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Uchino E, Uemura A, Ohba N. Initial stages of posterior vitreous detachment in healthy eyes of older persons evaluated by optical coherence tomography. Arch Ophthalmol. 2001;119:1475–9. doi: 10.1001/archopht.119.10.1475. [DOI] [PubMed] [Google Scholar]
- 27.Inoue M. Wide-angle viewing system. Dev Ophthalmol. 2014;54:87–91. doi: 10.1159/000360453. [DOI] [PubMed] [Google Scholar]
- 28.Virata SR, Kylstra JA, Singh HT. Corneal epithelial defects following vitrectomy surgery using hand-held, sew-on, and noncontact viewing lenses. Retina. 1999;19:287–90. doi: 10.1097/00006982-199907000-00003. [DOI] [PubMed] [Google Scholar]
- 29.Sheng Lim K, Garg A, Cheng J, Muthusamy K, Beltran-Agullo L, Barton K. Comparison of short-term postoperative hypotony rates of 23-gauge vs 25-gauge needles in formation of the scleral tract for Baerveldt tube insertion into the anterior chamber. J Curr Glaucoma Pr. 2018;12:36–9. doi: 10.5005/jp-journals-10028-1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Ho LY, Garretson BR, Ranchod TM, Balasubramaniam M, Ruby AJ, Capone A, Jr, et al. Study of intraocular pressure after 23-gauge and 25-gauge pars plana vitrectomy randomized to fluid versus air fill. Retina. 2011;31:1109–17. doi: 10.1097/IAE.0b013e31820b5b9b. [DOI] [PubMed] [Google Scholar]
- 31.Inoue Y, Kadonosono K, Yamakawa T, Uchio E, Watanabe Y, Yanagi Y, et al. Surgically-induced inflammation with 20-, 23-, and 25-gauge vitrectomy systems: an experimental study. Retina. 2009;29:477–80. doi: 10.1097/IAE.0b013e31819a6004. [DOI] [PubMed] [Google Scholar]
- 32.Sedova A, Steiner I, Matzenberger RP, Georgopoulos M, Scholda C, Kriechbaum KF, et al. Comparison of safety and effectiveness between 23-gauge and 25-gauge vitrectomy surgery in common vitreoretinal diseases. PLoS One. 2021;16:e0248164. doi: 10.1371/journal.pone.0248164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Sawada T, Kakinoki M, Sawada O, Kawamura H, Ohji M. Closure of sclerotomies after 25- and 23-gauge transconjunctival sutureless pars plana vitrectomy evaluated by optical coherence tomography. Ophthalmic Res. 2011;45:122–8. doi: 10.1159/000318875. [DOI] [PubMed] [Google Scholar]
- 34.Barth H, Crafoord S, Arner K, Ghosh F. Inflammatory responses after vitrectomy with vitreous substitutes in a rabbit model. Graefes Arch Clin Exp Ophthalmol. 2019;257:769–83. doi: 10.1007/s00417-019-04242-0. [DOI] [PubMed] [Google Scholar]
- 35.Chen W, Mo W, Sun K, Huang X, Zhang YL, Song HY. Microplasmin degrades fibronectin and laminin at vitreoretinal interface and outer retina during enzymatic vitrectomy. Curr Eye Res. 2009;34:1057–64. doi: 10.3109/02713680903308487. [DOI] [PubMed] [Google Scholar]
- 36.Grinton M, Steel DH. Cochrane Corner: Ocriplasmin-why isn’t it being used more? Eye (Lond) 2019;33:1195–7. doi: 10.1038/s41433-019-0407-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Gandorfer A, Rohleder M, Sethi C, Eckle D, Welge-Lüssen U, Kampik A, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthalmol Vis Sci. 2004;45:641–7. doi: 10.1167/iovs.03-0930. [DOI] [PubMed] [Google Scholar]
- 38.Wassmer SJ, Carvalho LS, György B, Vandenberghe LH, Maguire CA. Exosome-associated AAV2 vector mediates robust gene delivery into the murine retina upon intravitreal injection. Sci Rep. 2017;7:45329. doi: 10.1038/srep45329. [DOI] [PMC free article] [PubMed] [Google Scholar]
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