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In Search of Excellence: From a Small Clinical Unit to an Internationally Recognized Center for Orbital Diseases Research and Surgery at the Department of Ophthalmology, Shanghai Ninth People's Hospital, China

Song, Xuefei MD, PhD∗,†; Zhou, Huifang MD, PhD∗,†; Wang, Yi PhD candidate∗,†; Yang, Muyue PhD candidate∗,†; Fang, Sijie MD, PhD∗,†; Li, Yinwei MD, PhD∗,†; Li, Yongyun PhD candidate∗,†; Fan, Xianqun MD, PhD∗,†

Author Information
Asia-Pacific Journal of Ophthalmology: September-October 2021 - Volume 10 - Issue 5 - p 432-436
doi: 10.1097/APO.0000000000000435
  • Open

Abstract

The Department of Ophthalmology of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (The Department), has made significant progress since 2 decades ago in 1995. From a humble beginning of a subdivision with less than 10 ophthalmologists in the 90s, it has evolved to a highly specialized expert team of more than 80 eye surgeons and visual scientists today. The Department is now well recognized in China and beyond with a multitude of key affiliated subsidiary institutes, including the Institute of Ophthalmology attached to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and National Key Clinical Specialty of China.

The Department positions itself as a pioneering ophthalmic institution in the field of orbital diseases and surgery in China. The Department has excelled remarkably in 3 areas:

  • (1) Revealing the pathogenesis of orbital diseases, including thyroid-associated ophthalmopathy (TAO), orbital vascular malformation (OVM), and orbital tumors;
  • (2) Developing biomaterials for orbital bone defect repair;
  • (3) Innovating the orbital surgical technique, following the trend of the establishment of digital orbital surgical planning platform and endoscope-navigation system.

By virtue of the concerted efforts of a committed team of orbital surgeons and visual scientists, the team has been at the forefront of orbital disease pathogenesis research. The team further utilizes up-to-date results derived from their research to develop and advance surgical methodology and technology. Ultimately, this division strives to translate innovative research into clinical practice to provide safe and quality orbital surgeries for patients in need.

PART 1: REVEALING ORBITAL DISEASE PATHOGENESIS

The Role of Th17 Cell Immunity in TAO

Proinflammatory and Profibrotic Function of Th17 Cells in TAO

Researchers at The Department focused on elucidating the dysregulated T-cell immune responses in TAO. The team discovered the first evidence of the proinflammatory and profibrotic roles of T helper (Th) 17 cells in the pathogenesis of TAO.1 They reported an upregulated proportion of circulating interleukin (IL)-17A-producing Th17 cells in TAO patients, and unraveled IL-17A-mediated extracellular matrix synthesis by orbital fibroblasts (OF) which culminated in orbital tissue fibrosis in TAO.1 The team also showed a CD40–CD40L interaction mediated by Th17 cells which propagated cell-cell mediated autoimmunity in TAO.2 Furthermore, it was also shown that IL-17A also regulates orbital fibrosis and adipogenesis in TAO by promoting differentiation of OF subsets by promoting differentiation of CD90+ OF into myofibroblasts and CD90- into lipid-bearing adipocytes, respectively.3

Pathogenicity and Plasticity of Th17 Cells in TAO

It is recently known that Th17 cells have an important pathogenic role in TAO development.7 The team has revealed a distinct orbital immune microenvironment in TAO, where OFs produced prostaglandin E2 to upregulate IL-23R and IL-1R expression on orbit-infiltrating Th17 cells through the EP2/EP4/cAMP signaling pathway,4 and the interaction between OFs and Th17 cells promotes pro-inflammatory responses in OFs and further attracts Th17 cells to propagate such responses.5 Recently, they also observed a potential immunological transition process from Th1 cells to Th17 cells, which provided new insights into the development of very severe TAO in Graves’ disease.6 These findings laid the scientific foundation for the development of novel therapeutic strategies which target pathways to attenuate disease severity in TAO.

Glycosylphosphatidylinositol Anchor Attachment Protein 1 (GPAA1), BMP9, and Novel Diagnostic Markers in Orbital Vasculature Malformations

OVM is a common disease of the orbit that can severely impair vision and cosmesis. The pathogenesis and etiology of OVM are incompletely elucidated and treatment is often intractable, rendering it a long-standing clinical problem for orbital surgery. The research team at The Department has recently discovered novel genetic and molecular aberrancy in the pathogenesis of OVM, which could potentially become future therapeutic targets.

GPAA1 Variation in Hereditary Venous Malformation

A rare non-synonymous variant (c.968A > G) in GPAA1 was recently identified by the research team of The Department using whole-exome sequencing in patients with hereditary OVM. The study revealed that expression of the GPAA1 variant protein in vascular endothelial cells (ECs) could result in a loss of the quiescent status, and lead to overgrowth and over migration of EC which culminate in OVM. This hypothesis was further confirmed in a GPAA1-deficient zebrafish model which demonstrated vascular dysplasia.8

Dysregulation of BMP9 in Sporadic VM

It was further shown that serum and tissue bone morphogenetic protein 9 (BMP9) expression was significantly lower in OVM patients than in healthy participants. BMP9 maintains the quiescent status of ECs and strengthens vessel wall via the BMP9/ALK1/SMAD1/5/ID1 axis. Besides, BMP9 had a potential effect on attenuating VM progression in a mouse model.9–12

Pathogenic Mechanism and Diagnostic Markers

The team has also explored potential diagnostic markers of OVM. High-throughput transcriptional profiling combined with angiogenesis antibody array analysis was used for detection OVM. It was observed from OVM specimens that autophagy and VEGF pathways were upregulated, whereas Wnt, Hippo, hedgehog, and vascular smooth muscle contraction signaling pathways were downregulated. Furthermore, plasma EGF and leptin levels were significantly elevated in patients with OVM.13 These findings laid the foundation for future development of surrogate biomarkers for OVM disease detection and diagnosis, and also revealed the altered molecular pathways in OVM.

Pathogenesis and Imaging Technology in Orbital Tumors

By reviewing data and pedigrees of patients with orbital/periorbital plexiform neurofibroma (OPPN), researchers at The Department showed that successive generations of OPPN patients presented with earlier onset and more severe ocular signs than their predecessors did. Furthermore, they have identified 6 novel mutations of this orbital tumor. These findings are essential to clinicians who offer genetic counseling to patients from affected families.14 The team also revealed clinically significant oncological outcomes data on lacrimal gland adenoid cystic carcinoma treated by eye-spring tumor resection protocol and adjuvant multimodal therapy in Chinese patients, which laid the important groundwork to guide future studies in this area.15

Besides clinical research, the team also took great strides in preclinical cancer research to explore new pharmacological therapy for ocular malignancies. By means of patient-derived xenograft (PDX) models which are highly authentic to the microenvironment of the host tumor,16,17 the orbital surgery unit at the Shanghai Ninth People's Hospital and its local partner drug development company are jointly exploring novel targets of drug therapy for the treatment of ocular neoplasms. The team also explored the potential of fluorinated-functionalized polysaccharide-based nanoparticles to enhance the hypoxic effect of photodynamic therapy in the amelioration of ocular choroidal melanoma.18 Recently, the group has also validated an innovative imaging strategy based on nitrogen-doped carbon dots as fluorescent probes aimed at early detection of tumorigenesis in patients with a clinical diagnosis of malignancy.19

PART 2: DEVELOPING THE BIOMATERIALS FOR ORBITAL BONE DEFECT REPAIR

The scaffolds currently used for bone defect repair and orbital reconstruction have key limitations, including poor degradation performance and the inability to induce new bone formation. The use of such scaffolds is also associated with serious surgical complications such as infection, material displacement, and rejection. In some cases, these adverse outcomes necessitate additional revision procedures, which could pose huge psychological and financial burdens on patients affected. Toward the goal of developing optimal biomaterials for orbital bone defect repair, the group investigated the biological pathways which regulate the differentiation of bone mesenchymal stem cells (BMSC). Through this, they discovered the key regulatory roles of the miR-31, Runx2, and Satb2 molecules on the differentiation of BMSCs, which offer new perspectives on the utilization of stem cells in orbital bone defect repair.20 Furthermore, 9 functional biomaterials, including chitosan-grafted graphene oxide with CMA certification and four authorized patents, were newly developed for the first time.21 These prefabricated functional materials were proven to enhance osteoinductivity and promote upregulation of osteogenesis-related genes to achieve bone reparative effects.22,23 Based on the team's unique knowledge of stem cell technology and biomaterials, new orbital prosthetic scaffolds have been developed, and key patents were attained. Ultimately, the success of the team's research in regenerative medicine would transform into clinical practice to benefit patients with orbital bone defects.

Delicate Regulation of Osteogenic Differentiation

The Runx2/miR-31/Satb2 loop was first revealed by the research team at The Department to regulate the osteogenic differentiation of BMSCs. Runx2, an osteogenic transcription factor, can inhibit miR-31 expression and target Satb2 to promote the osteogenic differentiation of BMSCs. These findings provide a scientific foundation for the future application of microRNAs in osteogenic stem cell therapy for orbital bone defects.20 The team also investigated the SMC1 protein, which bears a critical role in programming host cells into induced pluripotent stem cells (iPSCs). The findings were published in Cell Stem Cell and could guide future studies on the induction of iPSCs, which have potential applications in orbital regenerative medicine and beyond and are critically recommended by the editor-in-chief as the current research hotspot.23

Novel Degradable Biomaterials for Orbital Bone Defect Repair

Currently-in-use biomaterials for orbital bone repair are nondegradable, nonbioactive, and foreign to orbital structures. They are prone to serious complications such as rejection and infection, therefore there exists a very real demand for biomaterials that are capable of producing optimal clinical outcomes. Researchers at The Department have pioneered the new, degradable, functionalized materials poly fumarate (PFM) polyethylene oxide maleate and polyglyceride sebacate (PSED). These materials possess good biocompatibility, osteoconductivity, and osteoinductivity. PFM and PSED harbor structures such as naked hydroxyl and carboxyl groups and can be functionalized through various methods, including photo/thermal crosslinking, chemical conjugation, physical adsorption, and biological ligation. The physicochemical and biological properties of these newly developed biomaterials can be effectively molded to provide new scaffolds for personalized orbital bone repair.24,25

Vascularized Tissue Engineering Bone Construction

Degradable scaffolds composed of BMSCs were first used in studies conducted at The Department to repair orbital bone defects and achieve autologous bone regeneration in animal experiments.26 Furthermore, the team showed that BMSCs engineered with chemically modified RNAs (modRNA) encoding the hBMP-2 and VEGF-A genes27 demonstrate synergistically osteogenic and angiogenic properties upon inoculation onto in vivo bone defect models, resulting in superior healing efficacy. Such work led to a national invention patent, and could potentially be applied clinically as a stem cell therapeutic strategy to enhance clinical outcomes of orbital bone defect repair.

PART 3: INNOVATING THE ORBITAL SURGICAL TECHNIQUE

Experimenting Innovative Technology and Artificial Intelligence in Orbital Surgery

Modern medicine has entered the digital era. The Orbital Surgery of Shanghai Ninth People's Hospital pioneered the application of image data resampling, multimodal data fusion, and 3D modeling techniques to construct digital orbital 3D models, achieve accurate orbital measurements, and establish the normal reference values of Chinese orbital multiparametric measurements.28–30 The team established for the first time a digital orbital surgery planning platform to design orbital defect reconstruction which enabled simulations of virtual repositioning of bone fragments and postoperative outcome predictions.31–32

Riding on the rapid development of artificial intelligence,33–35 the Orbital Surgery Division of Shanghai Ninth People's Hospital has completed the development and preliminary clinical validation of an artificial intelligence computed tomography screening model for TAO to determine the active and quiescent stages of TAO. This could eventually transform into digital and automated diagnosis and clinical evaluation of the disease.36–37

The team has also pioneered the application of 3D printing technology to utilize its advantages in material development to meet clinical needs, and has developed the technical capability to apply next-generation treatments.38–41 The Orbital Surgery Division has treated patients with orbital injuries by using the contralateral orbit as a template to reconstruct the orbital morphology and restore the globe position, which could accurately restore the orbital volume and eye position to resemble its original state.42 The use of preoperative, computer-aided design and fabrication provide precise guidance in the reconstruction of complex orbital injuries and defects.43–44

Exploration of Endoscope-Navigation System

Based on the interdisciplinary collaborations between clinicians and engineers, an authentic orbital surgery navigation system was designed and developed by the Orbital Surgery Division of Shanghai Ninth People's Hospital and Shanghai Jiao Tong University. The system adopted high-precision infrared positioning, point-surface combination registration, and soft and hard tissue weighted registration to achieve accurate positioning and guidance in orbital surgery, with an accuracy of 0.30 mm.45

The deep orbital space, in particular the orbital apex, is narrow and houses various important tissues, rendering tissue dissection and operating in such region technically challenging. The team has the experience of applying the endoscopic system in orbital fracture repair, orbital decompression, and other typical orbital surgery to improve the safety and effectiveness of orbital surgery, and witnessed significant improvements in surgical outcomes and safety.

Although endoscopic surgery has the advantage of a surgical field, image magnification and peripheral distortion can mislead the surgeon, resulting in inadvertent damage to the optic nerve or other vital structures. The Orbital Surgery Division first put forward the concept of “endoscope-navigation”. This is founded upon visual calibration and enhanced reality technology to integrate endoscopy and navigation technologies to develop an endoscope-navigation surgical system. By virtue of this new system, a series of complicated orbital surgeries were successfully performed by the team, including complex orbital fracture repair, deep orbital decompression in patients with TAO, precise retroorbital foreign body retrieval, and transnasal ethmoid minimally invasive surgical treatment of traumatic optic neuropathy.46–49 These authentic surgical technologies have great potentials to become game-changers in the field, and have currently been recognized with national patents.

The Orbital Surgery Division of Shanghai Ninth People's Hospital has reached key milestones despite its short history. It is a unit committed to translating laboratory research performed at the bench to solutions to clinical challenges encountered at the bedside. It will continue advancing the development of orbital surgery to benefit the many patients in need of safe and quality orbital surgical treatments. The field shall be excited to bear witness to its development in the years ahead!

REFERENCES

1. Fang S, Huang Y, Wang S, et al. IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO. J Clin Endocrinol Metab 2016; 101:2955–2965.
2. Fang S, Huang Y, Zhong S, et al. IL-17A promotes RANTES expression, but not IL-16, in orbital fibroblasts via CD40-CD40l combination in thyroid-associated ophthalmopathy. Invest Ophthalmol Vis 2016; 57:6123–6133.
3. Fang S, Huang Y, Zhong S, et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in graves orbitopathy. J Clin Endocrinol Metab 2017; 102:4273–4283.
4. Fang S, Huang Y, Wang N, et al. Insights into local orbital immunity: evidence for the involvement of the Th17 cell pathway in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2019; 104:1697–1711.
5. Fang S, Huang Y, Liu X, et al. Interaction between CCR6+ Th17 cells and CD34+ fibrocytes promotes inflammation: implications in graves’ orbitopathy in Chinese population. Invest Ophthalmol Vis Sci 2018; 59:2604–2614.
6. Fang S, Zhang S, Huang Y, et al. Evidence for associations between Th1/Th17 “hybrid” phenotype and altered lipometabolism in very severe Graves’ orbitopathy. J Clin Endocrinol Metab 2020; 105:dgaa124.
7. Taylor PN, Zhang L, Lee R, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol 2020; 16:104–116.
8. Li Y, Yang L, Yang J, et al. A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes. Hum Genet 2020; 139:1499–1511.
9. Yla B, Qsa B, Peng L, et al. BMP9 attenuates occurrence of venous malformation by maintaining endothelial quiescence and strengthening vessel walls via SMAD1/5/ID1/(-SMA pathway - ScienceDirect. J Mol Cell Cardiol 2020; 147:92–107.
10. Chai P, Yu J, Wang X, et al. BMP9 promotes cutaneous wound healing by activating Smad1/5 signaling pathways and cytoskeleton remodeling. Clin Transl Med 2021; 11:e271.
11. Yang Z, Li P, Shang Q, et al. CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression. Sci Adv 2020; 6:eabc5022.
12. Li P, Li Y, Zhu L, et al. Targeting secreted cytokine BMP9 gates the attenuation of hepatic fibrosis. Biochim Biophys Acta Mol Basis Dis 2018; 1864:709–720.
13. Chai P, Yu J, Li Y, et al. High-throughput transcriptional profiling combined with angiogenesis antibody array analysis in an orbital venous malformation cohort. Exp Eye Res 2020; 191:107916.
14. Chai P, Luo Y, Zhou C, et al. Clinical characteristics and mutation Spectrum of NF1 in 12 Chinese families with orbital/periorbital plexiform Neurofibromatosis type 1. BMC Med Genet 2019; 20:158.
15. Yang J, Zhou C, Wang Y, et al. Multimodal therapy in the management of lacrimal gland adenoid cystic carcinoma. BMC Ophthalmol 2019; 19:125.
16. Shi J, Li Y, Jia R, et al. The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance. Int J Cancer 2020; 146:2078–2088.
17. Chai P, Yu J, Jia R, et al. Generation of onco-enhancer enhances chromosomal remodeling and accelerates tumorigenesis. Nucleic Acids Res 2020; 48:12135–12150.
18. Li J, Xue Y, Tian J, et al. Fluorinated-functionalized hyaluronic acid nanoparticles for enhanced photodynamic therapy of ocular choroidal melanoma by ameliorating hypoxia. Carbohydr Polym 2020; 237:116119.
19. Yuan D, Si W, Zhou H, et al. Effects of a miR-31, Runx2, and Satb2 regulatory loop on the osteogenic differentiation of bone mesenchymal stem cells. Stem Cells Dev 2013; 22:2278–2286.
20. Ruan J, Wang X, Yu Z, et al. Enhanced physiochemical and mechanical performance of chitosan-grafted graphene oxide for superior osteoinductivity. Adv Funct Mater 2016; 26:1085–-1097.
21. Xie Q, Zi W, Zhou H, et al. The role of miR-135-modified adipose-derived mesenchymal stem cells in bone regeneration. Biomaterials 2016; 75:279–294.
22. Zhang D, Ni N, Wang Y, et al. CircRNA-vgll3 promotes osteogenic differentiation of adipose-derived mesenchymal stem cells via modulating miRNA-dependent integrin (5 expression. Cell Death Differ 2021; 28:283–302.
23. Zhang H, Jiao W, Sun L, et al. Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. Cell Stem Cell 2013; 13:30–35.
24. You Z, Bi X, Fan X, et al. A functional polymer designed for bone tissue engineering. Acta Biomater 2012; 8:502–510.
25. Zhou H, Xiao C, Wang Y, et al. In vivo efficacy of bone marrow stromal cells coated with beta-tricalcium phosphate for the reconstruction of orbital defects in canines. Invest Ophthalmol Vis Sci 2011; 52:1735–1741.
26. Zhou H, Yuan D, Bi X, et al. Orbital wall repair in canines with beta-tricalcium phosphate and induced bone marrow stromal cells. J Biomed Mater Res B Appl Biomater 2014; 101:1340–1349.
27. Geng Y, Duan H, Xu L, et al. BMP-2 and VEGF-A modRNAs in collagen scaffold synergistically drive bone repair through osteogenic and angiogenic pathways. Commun Biol 2021; 4:82.
28. Zhou H, Fan X, Xiao C. Direct orbital manometry in normal and fractured orbits of Chinese patients. J Oral Maxillofac Surg 2007; 65:2282–2287.
29. Hu Y, Luo M, Ni N, et al. Reciprocal actions of microRNA-9 and TLX in the proliferation and differentiation of retinal progenitor cells. Stem Cells Dev 2014; 23:2771–2781.
30. Ji Y, Lai C, Gu L, et al. Measurement of intra-orbital structures in normal Chinese adults based on a three-dimensional coordinate system. Curr Eye Res 2018; 43:1477–1483.
31. Li Y, Su Y, Song X, et al. What is the main potential factor influencing ocular protrusion? Med Sci Monit 2017; 23:57–64.
32. Zhai G, Yin Z, Li L, et al. Automatic orbital computed tomography coordinating method and quantitative error evaluation based on signed distance field. Acta Radiol 2021; 62:87–92.
33. Ruamviboonsuk P, Cheung CY, Zhang XL, et al. Artificial intelligence in ophthalmology: evolutions in Asia. Asia Pac J Ophthalmol (Phila) 2020; 9:78–84.
34. Cheng CY, Soh ZD, Majithia S, et al. Big data in ophthalmology. Asia Pac J Ophthalmol (Phila) 2020; 9:291–298.
35. He M, Li Z, Liu C, et al. Deployment of artificial intelligence in real-world practice: opportunity and challenge. Asia Pac J Ophthalmol (Phila) 2020; 9:299–307.
36. Song X, Liu Z, Li L, et al. Artificial intelligence CT screening model for thyroid-associated ophthalmopathy and tests under clinical conditions. Int J Comput Assist Radiol Surg 2021; 16:323–330.
37. Lin C, Song X, Li L, et al. Detection of active and inactive phases of thyroid-associated ophthalmopathy using deep convolutional neural network. BMC Ophthalmol 2021; 21:39.
38. Fan X, Zhou H, Lin M, et al. Late reconstruction of the complex orbital fractures with computer-aided design and computer-aided manufacturing technique. J Craniofac Surg 2007; 18:665–673.
39. Chen L, Yan D, Wu N, et al. 3D-printed poly-caprolactone scaffolds modified with biomimetic extracellular matrices for tarsal plate tissue engineering. Front Bioeng Biotechnol 2020; 8:219.
40. Li J, Chen M, Fan X, et al. Recent advances in bioprinting techniques: approaches, applications and future prospects. J Transl Med 2016; 14:271.
41. Chin JKY, Yip W, Young A, et al. A six-year review of the latest oculoplastic surgical development. Asia Pac J Ophthalmol (Phila) 2020; 9:461–469.
42. Markiewicz MR, Dierks EJ, Potter BE, et al. Reliability of intraoperative navigation in restoring normal orbital dimensions. J Oral Maxillofac Surg 2011; 69:2833–2840.
43. Zavattero E, Ramieri G, Roccia F, et al. Comparison of the outcomes of complex orbital fracture repair with and without a surgical navigation system: a prospective cohort study with historical controls. Plast Reconstr Surg 2017; 139:957–965.
44. Bell RB, Markiewicz MR. Computer-assisted planning, stereolithographic modeling, and intraoperative navigation for complex orbital reconstruction: a descriptive study in a preliminary cohort. J Oral Maxillofac Surg 2009; 67:2559–2570.
45. Fan X, Li J, Zhu J, et al. Computer-assisted orbital volume measurement in the surgical correction of late enophthalmos caused by blowout fractures. Ophthalmic Plast Reconstr Surg 2003; 19:207–211.
46. Zhang S, Li Y, Wang Y, et al. Comparison of rim-sparing versus rim-removal techniques in deep lateral wall orbital decompression for Graves’ orbitopathy. Int J Oral Maxillofac Surg 2019; 48:461–467.
47. Shu Z, Li Y, Fan X. Application of endoscopic techniques in orbital blowout fractures[J.]. Frontiers of Medicine 2013; 7:328–332.
48. Shi W, Jia R, Li Z, et al. Combination of transorbital and endoscopic transnasal approaches to repair orbital medial wall and floor fractures. J Craniofac Surg 2012; 23:71–74.
49. Zhao Y, Li Y, Li Z, et al. Removal of orbital metallic foreign bodies with image-guided surgical navigation. Ophthalmic Plast Reconstr Surg 2020; 36:305–310.
Keywords:

endoscope-navigation; ocular oncology; orbital diseases and surgery; thyroid-associated ophthalmopathy

Copyright © 2021 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.