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망막정맥폐쇄(RVO) QSP 모델 — 참고문헌

Retinal Vein Occlusion QSP Model — Annotated References

모든 PMID는 2026-08-05에 PubMed E-utilities로 조회하여 제목·저자·저널·연도를 확인했습니다. Every PMID below was resolved and verified against the PubMed E-utilities API on 2026-08-05; the title, first author, journal and year shown are the ones PubMed returned. Each entry states what the model actually took from it — a parameter, a structural assumption, or a calibration target.

1. 역학과 자연사 (Epidemiology and natural history)

Sets the phenotype prevalences, the baseline central subfield thickness and BCVA at presentation, and the untreated trajectories the model must reproduce.

  1. McIntosh RL, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1113-23. PMID 20430446 → the untreated CRVO trajectory used to check NAT_NONISCH / NAT_ISCH.
  2. Rogers SL, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1094-101. PMID 20430447 → the BRVO natural history; the reason OCC_RES for BRVO is 0.32 and not 0.55.
  3. Cugati S, et al. Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study. Arch Ophthalmol 2006;124:726-32. PMID 16682596
  4. Klein R, et al. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008;126:513-8. PMID 18413521 → fellow-eye risk over 5-15 years, quoted in the decision layer of the map.
  5. Hayreh SS, et al. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics. Am J Ophthalmol 1994;117:429-41. PMID 8154523
  6. Central Vein Occlusion Study Group. Baseline and early natural history report. Arch Ophthalmol 1993;111:1087-95. PMID 7688950 → baseline BCVA distribution; the ischaemic / non-ischaemic split.
  7. Central Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol 1997;115:486-91. PMID 9109757 → the conversion rate from non-ischaemic to ischaemic CRVO; K_NP.
  8. Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98:271-82. PMID 6383055 → grid laser as the pre-anti-VEGF comparator; the untreated BRVO arm.
  9. Cugati S, et al. Retinal vein occlusion and vascular mortality: pooled data analysis of 2 population-based cohorts. Ophthalmology 2007;114:520-4. PMID 17141315 → why the model treats RVO as a systemic vascular event, not only an eye event.

2. 압력항의 근거 — 망막 모세혈관 정수압 (The evidence for the pressure arm)

These are the papers that make the pressure arm a measurement rather than a metaphor. They are the reason PA = 40, RV0 = 0.25 and PC ≈ 21.6 mmHg in a normal eye, and the reason a venous occlusion drives Pc toward the arterial inlet pressure.

  1. Glucksberg MR, Dunn R. Direct measurement of retinal microvascular pressures in the live, anesthetized cat. Microvasc Res 1993;45:158-65. PMID 8361399 → the source of the pressure-arm numbers. Servo-null micropipette measurements across the retinal microvasculature; sets the arteriolar inlet and capillary pressures the model uses.
  2. Attariwala R, Giebs CP, Glucksberg MR. The influence of elevated intraocular pressure on vascular pressures in the cat retina. Invest Ophthalmol Vis Sci 1994;35:1019-25. PMID 8125712 → justifies P_v = IOP + 2 mmHg and the IOP → Pv → Pc feedback loop.
  3. Attariwala R, et al. The effect of acute experimental retinal vein occlusion on cat retinal vein pressures. Invest Ophthalmol Vis Sci 1997;38:2742-9. PMID 9418726 → direct measurement of what an experimental vein occlusion does to venous pressure. The basis for the OCC multiplier magnitudes.
  4. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res 2010;87:198-210. PMID 20200043 → the Starling form used in the model, including the role of the reflection coefficient σ and why interstitial oncotic pressure is not free to rise without limit.
  5. Michel CC, Woodcock TE, Curry FE. Understanding and extending the Starling principle. Acta Anaesthesiol Scand 2020;64:1032-7. PMID 32270491 → the glycocalyx / sub-glycocalyx interpretation of σ that the model encodes as SIGMA = SIGMAX * TJ^0.55.
  6. Ruffini A, et al. A mathematical model of interstitial fluid flow and retinal tissue deformation in macular edema. Invest Ophthalmol Vis Sci 2024;65:33. PMID 39254963 → an independent poroelastic treatment of retinal fluid; the closest published precedent for treating macular oedema as a filtration / clearance balance rather than as a permeability index.
  7. Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res 2005;24:493-519. PMID 15845346 → the argument that the haemodynamic state, not the mediator profile, defines the RVO phenotype. This paper is the closest prior statement of the model's central claim.
  8. Williamson TH. Central retinal vein occlusion: what's the story? Br J Ophthalmol 1997;81:698-704. PMID 9349161 → the lamina cribrosa anatomy and why CRVO has so few collateral options (COLL_MAX 0.45-0.70 for CRVO versus 2.2 for BRVO).

3. 혈전과 재개통 · 우회로 시계 (Thrombus, recanalisation, collaterals)

  1. Rehak M, Wiedemann P. Retinal vein thrombosis: pathogenesis and management. J Thromb Haemost 2010;8:1886-94. PMID 20492457 → the Virchow decomposition in cluster 3 and the K_LYS order of magnitude.
  2. Tsuboi K, et al. Collateral vessels in branch retinal vein occlusion: anatomic and functional analyses by OCT angiography. Ophthalmol Retina 2019;3:767-76. PMID 31167729 → the collateral clock made visible. OCT-A quantification of collateral formation in BRVO; the reason the collateral time constant is months (K_COLL = 0.0035 /d) and the reason BRVO crosses below Pc* and CRVO does not.
  3. Tsuboi K, et al. Longitudinal vasculature changes in branch retinal vein occlusion with projection-resolved optical coherence tomography angiography. Graefes Arch Clin Exp Ophthalmol 2019;257:1875-83. PMID 31165932
  4. Tsuboi K, et al. Chorioretinal shunt vessel in eyes with central retinal vein occlusion after radial optic neurotomy. Ophthalmology 2018;125:1332-3. PMID 30143093 → the surgical attempt to add conductance directly to the venous side.
  5. Opremcak EM, Bruce RA, Lomeo MD, et al. Radial optic neurotomy for central retinal vein occlusion: a retrospective pilot study of 11 consecutive cases. Retina 2001;21:408-15. PMID 11642369 → one of the very few interventions that targets R_v rather than L_p; included in the map precisely because that arrow is so rare.
  6. Glacet-Bernard A, et al. Hemodilution therapy using automated erythrocytapheresis in central retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2011;249:505-12. PMID 20953877 → viscosity as a lever on R_v; the other left-half arrow.

4. 혈액-망막 장벽과 투과성 (Barrier biology: the permeability arm)

  1. Klaassen I, Van Noorden CJ, Schlingemann RO. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog Retin Eye Res 2013;34:19-48. PMID 23416119 → the junction complex in cluster 11 and the paracellular / transcellular split.
  2. Daruich A, et al. Mechanisms of macular edema: beyond the surface. Prog Retin Eye Res 2018;63:20-68. PMID 29126927 → the single best synthesis of macular oedema as a balance of influx and clearance; the structural template for clusters 11-13.
  3. Antonetti DA, et al. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content. Diabetes 1998;47:1953-9. PMID 9836530 → occludin loss as the measurable correlate of TJ.
  4. Murakami T, et al. Protein kinase Cβ phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes 2012;61:1573-83. PMID 22438576 → the VEGF → PKCβ → occludin Ser490 → internalisation chain; the mechanistic content of KDIS_TJ * DRIVE * TJ.
  5. Bringmann A, et al. Müller cells in the healthy and diseased retina. Prog Retin Eye Res 2006;25:397-424. PMID 16839797 → AQP4 / Kir4.1 water handling; the saturable clearance term J_out.
  6. Jo AO, et al. TRPV4 and AQP4 channels synergistically regulate cell volume and calcium homeostasis in retinal Müller glia. J Neurosci 2015;35:13525-37. PMID 26424896 → why clearance saturates rather than scaling linearly with oedema.
  7. Wang T, et al. Anti-VEGF therapy prevents Müller intracellular edema by decreasing VEGF-A in diabetic retinopathy. Eye Vis (Lond) 2021;8:13. PMID 33865457
  8. Suzuma I, et al. Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2. Diabetes 2001;50:444-54. PMID 11272159 → the justification for the mechanotransduction term W_PRESS * (Pc - 28)/12 in DRIVE: pressure itself induces VEGF and opens junctions, so the pressure arm partially drives the permeability arm.
  9. Suzuma I, et al. Stretch-induced retinal vascular endothelial growth factor expression is mediated by phosphatidylinositol 3-kinase and protein kinase C. J Biol Chem 2002;277:1047-57. PMID 11694503

5. 매개체: VEGF, IL-6, Ang-2 (Mediators)

  1. Aiello LP, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-7. PMID 7526212 → the original human intraocular VEGF measurements; anchors VTONE.
  2. Noma H, et al. Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion. Eye (Lond) 2008;22:42-8. PMID 16826241 → the calibration source for VTONE, IL6 and their ratio to CST. Justifies aqueous sampling as a proxy for the vitreous compartment.
  3. Noma H, et al. Vitreous levels of interleukin-6 and vascular endothelial growth factor in macular edema with central retinal vein occlusion. Ophthalmology 2009;116:87-93. PMID 19118700 → normal ~50-100 pg/mL VEGF versus 1500-2500 pg/mL in ischaemic CRVO; the 13-fold induction 1 + E_HIF_V * HIF. IL-6 5 → ~85 pg/mL sets E_HIF_I = 16.
  4. Noma H, et al. Role of inflammation in previously untreated macular edema with branch retinal vein occlusion. BMC Ophthalmol 2014;14:67. PMID 24884703 → the reason IL-6 is a separate state and not folded into VEGF. IL-6 correlates with oedema independently of VEGF, so anti-VEGF leaves it standing.
  5. Noma H, et al. Vascular endothelial growth factor and interleukin-6 are correlated with serous retinal detachment in central retinal vein occlusion. Curr Eye Res 2012;37:62-7. PMID 21978265 → the separate SRF compartment and its distinct mediator dependence.
  6. Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov 2017;16:635-61. PMID 28529319 → Ang-2 as a Tie2 antagonist; the TIE2_BOOST term that makes Ang-2 blockade raise the junction repair rate constant rather than simply lower DRIVE.
  7. Campochiaro PA, Peters KG. Targeting Tie2 for treatment of diabetic retinopathy and diabetic macular edema. Curr Diab Rep 2016;16:126. PMID 27778249
  8. Shen J, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest 2014;124:4564-76. PMID 25180601 → the VE-PTP node in cluster 10.

6. 안구 약동학 (Ocular pharmacokinetics)

The TVIT half-lives, the penetration factor FPEN, and the systemic concentrations all come from this block.

  1. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol 2008;146:508-12. PMID 18635152 → aqueous half-life 9.82 d for bevacizumab.
  2. Krohne TU, Liu Z, Holz FG, Meyer CH. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol 2012;154:682-6. PMID 22818800 → aqueous half-life 7.19 d for ranibizumab; the model's TVIT for RBZ.
  3. Bakri SJ, et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179-82. PMID 18054637 → the source of the retina-to-vitreous partition that the model condenses into FPEN ≈ 0.08.
  4. Bakri SJ, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114:855-9. PMID 17467524
  5. Caruso A, et al. Ocular half-life of intravitreal biologics in humans and other species: meta-analysis and model-based prediction. Mol Pharm 2020;17:695-709. PMID 31876425 → the size-dependence of ocular half-life; the basis for brolucizumab 5.1 d and faricimab 7.5 d, which are not directly measured in humans.
  6. Hutton-Smith LA, et al. A mechanistic model of the intravitreal pharmacokinetics of large molecules and the pharmacodynamic suppression of ocular VEGF levels by ranibizumab in patients with neovascular age-related macular degeneration. Mol Pharm 2016;13:2941-50. PMID 26726925 → the direct QSP precedent for this model's PD layer, and the paper that frames the discrepancy the ALPHA parameter absorbs.
  7. Hutton-Smith LA, et al. Ocular pharmacokinetics of therapeutic antibodies given by intravitreal injection: estimation of retinal permeabilities using a 3-compartment semi-mechanistic model. Mol Pharm 2017;14:2690-6. PMID 28631484 → the retinal permeability estimates behind FPEN.
  8. Avery RL, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina 2017;37:1847-58. PMID 28106709 → the calibration target for the systemic arm. Plasma aflibercept ≈ 0.03 µg/mL with near-complete plasma free-VEGF suppression; ranibizumab plasma concentrations an order of magnitude lower with minimal suppression. The model reproduces both from a single flip-flop structure.
  9. Chang-Lin JE, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 2011;52:80-6. PMID 20702826 → K_REL_DEX, KEL_DEX and the ~900 ng/mL vitreous plateau.
  10. Chang-Lin JE, et al. Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes. Invest Ophthalmol Vis Sci 2011;52:4605-9. PMID 21421864 → the vitrectomy node in cluster 18.

7. 결합 친화도와 억제 지속시간 (Binding affinity and suppression duration)

  1. Papadopoulos N, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012;15:171-85. PMID 22302382 → the KDV values used verbatim: aflibercept 0.49 pM, ranibizumab 46 pM, bevacizumab 58 pM for VEGF-A165, and aflibercept's PlGF affinity.
  2. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92:667-8. PMID 18356264 → the calculation this model corrects. The affinity-and-half-life argument predicts months of VEGF suppression from one aflibercept injection. The model reproduces that arithmetic (96 days) and then shows that the retreatment interval is set by the pressure arm rather than by loss of suppression.
  3. Stewart MW. Pharmacokinetics, pharmacodynamics and pre-clinical characteristics of ophthalmic drugs that bind VEGF. Expert Rev Clin Pharmacol 2014;7:167-80. PMID 24483136
  4. Stewart MW. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept. Retina 2012;32:434-45. PMID 22374154
  5. Blanot M, et al. Aflibercept off-target effects in diabetic macular edema: an in silico modeling approach. Int J Mol Sci 2024;25:3621. PMID 38612432 → an independent in-silico treatment of aflibercept's multi-ligand binding.

8. 임상시험 — 항VEGF (Anti-VEGF trials: the calibration targets)

  1. Brown DM, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study (CRUISE). Ophthalmology 2010;117:1124-33. PMID 20381871 → target: +14.9 letters and −452 µm CST at month 6; sham +0.8 letters.
  2. Campochiaro PA, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study (BRAVO). Ophthalmology 2010;117:1102-12. PMID 20398941 → target: +18.3 letters at month 6 in BRVO.
  3. Campochiaro PA, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118:2041-9. PMID 21715011 → target: the deferred (sham → ranibizumab) arm reaches only +7.3 letters at month 12 and never catches up. This is the delay-response calibration.
  4. Heier JS, et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology 2012;119:802-9. PMID 22301066 → the loss of gains under reduced monitoring frequency.
  5. Campochiaro PA, et al. Long-term outcomes in patients with retinal vein occlusion treated with ranibizumab: the RETAIN study. Ophthalmology 2014;121:209-19. PMID 24112944 → target: about half of CRVO eyes still require injections at 4 years. In the model these are the eyes whose Pc never crosses below Pc*.
  6. Boyer D, et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology 2012;119:1024-32. PMID 22440275 → target: +17.3 letters and −457 µm at week 24.
  7. Heier JS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology 2014;121:1414-20. PMID 24679444 → target: +13.0 letters at week 100 for immediate treatment versus +1.5 for the deferred arm. The single strongest published statement that delay is paid permanently.
  8. Holz FG, et al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol 2013;97:278-84. PMID 23298885 → target: +18.0 letters at week 24.
  9. Korobelnik JF, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO study. Ophthalmology 2014;121:202-8. PMID 24084497
  10. Campochiaro PA, et al. Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study. Ophthalmology 2015;122:538-44. PMID 25315663 → target: +17.0 letters versus grid laser +12.2 at week 24.
  11. Scott IU, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the SCORE2 randomized clinical trial. JAMA 2017;317:2072-87. PMID 28492910 → the most important negative result in this model. Bevacizumab (KD 58 pM) is non-inferior to aflibercept (KD 0.49 pM): +18.6 versus +18.9 letters. A 118-fold affinity difference produces no difference in outcome. Any model in which effect scales with affinity is falsified by this trial; the log-dose structure of t_sup is what survives it.
  12. Scott IU, et al. Comparison of monthly vs treat-and-extend regimens for individuals with macular edema who respond well to anti-VEGF treatment (SCORE2 report 12). JAMA Ophthalmol 2018;136:337-45. PMID 29476687 → the treat-and-extend controller in the model, including the ±4-week step.
  13. Tadayoni R, et al. Efficacy and safety of faricimab for macular edema due to retinal vein occlusion: 24-week results from the BALATON and COMINO trials. Ophthalmology 2024;131:950-60. PMID 38280653 → target: faricimab non-inferior to aflibercept (+16.9 vs +17.5 letters). Six monthly loading doses, which is what the model's FAR_TAE scenario uses.
  14. Danzig CJ, et al. Faricimab treat-and-extend dosing for macular edema due to retinal vein occlusion: 72-week results. Ophthalmol Retina 2025. PMID 40107501 → the achievable extension intervals; the imax cap in the controller.
  15. Sahni J, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema (BOULEVARD). Ophthalmology 2019;126:1155-70. PMID 30905643 → the evidence that the Ang-2 arm contributes durability rather than peak effect.
  16. Lanzetta P, et al. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results. Lancet 2024;403:1141-52. PMID 38461841 → the high-molar-dose arm. The model predicts 8 mg extends suppression from 96 to 114 days — a 19% gain for a 4-fold dose, because duration is logarithmic.
  17. Dugel PU, et al. HAWK and HARRIER: ninety-six-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 2021;128:89-99. PMID 32574761 → brolucizumab's molar dose advantage (230.8 nmol per injection).
  18. Monés J, et al. Risk of inflammation, retinal vasculitis, and retinal occlusion-related events with brolucizumab. Ophthalmology 2021;128:1050-9. PMID 33207259 → the intraocular inflammation node in cluster 23.

9. 스테로이드 (Corticosteroids)

  1. Haller JA, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion (GENEVA). Ophthalmology 2010;117:1134-46. Trial report; see also PMID 24447389 for the pooled safety analysis → target: CST reduction and the ~16% rate of IOP rise ≥10 mmHg. The model reproduces the CST effect only after the steroid is allowed a direct junction effect (E_DEX_TJ) in addition to mediator suppression — VEGF suppression alone is not enough to match the trial.
  2. Kuppermann BD, et al. Onset and duration of visual acuity improvement after dexamethasone intravitreal implant in eyes with macular edema due to retinal vein occlusion. Retina 2014;34:1743-9. PMID 24830824 → the time course that constrains K_REL_DEX and the ~6-month re-dosing interval.
  3. Boyer DS, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema (MEAD). Ophthalmology 2014;121:1904-14. PMID 24907062 → the cataract calibration: ~68% cataract-related events over 3 years. The reason the model runs phakic and pseudophakic arms separately.
  4. Ip MS, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion (SCORE report 5). Arch Ophthalmol 2009;127:1101-14. PMID 19752419
  5. Scott IU, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion (SCORE report 6). Arch Ophthalmol 2009;127:1115-28. PMID 19752420
  6. Li X, et al. Safety and efficacy of dexamethasone intravitreal implant for treatment of macular edema secondary to retinal vein occlusion in Chinese patients. Graefes Arch Clin Exp Ophthalmol 2018;256:59-69. PMID 29119239
  7. Wecker T, et al. Real-life medium term follow-up data for intravitreal dexamethasone implant in retinal vein occlusion. Sci Rep 2021;11:8385. PMID 33859243

10. 허혈 · 신생혈관 · 신생혈관 녹내장 (Ischaemia, neovascularisation, NVG)

  1. Central Vein Occlusion Study Group. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion (report N). Ophthalmology 1995;102:1434-44. PMID 9097789 → the PRP node. Prophylactic PRP does not prevent iris neovascularisation better than prompt PRP at the first sign of it; the model reproduces this because PRP removes the VEGF source but not the ischaemia already present.
  2. Hayreh SS, Zimmerman MB. Ocular neovascularization associated with central and hemicentral retinal vein occlusion. Retina 2012;32:1553-65. PMID 22495331 → target: the incidence and timing of INV/ANV in ischaemic CRVO.
  3. Rong AJ, Swaminathan SS, Vanner EA, Parrish RK. Predictors of neovascular glaucoma in central retinal vein occlusion. Am J Ophthalmol 2019;204:62-9. PMID 31277883 → the NVG risk factors; KM_NVI_NP and the NVI > 0.5 & IOP > 25 criterion.
  4. Ou WC, et al. Longitudinal quantification of retinal nonperfusion in the macula of eyes with retinal vein occlusion. Ophthalmic Surg Lasers Imaging Retina 2018;49:249-56. PMID 29664983 → the growth rate of non-perfusion, which sets K_NP.
  5. Zhu ZY, et al. Effect of anti-VEGF treatment on nonperfusion areas in ischemic retinopathy. Int J Ophthalmol 2021;14:1647-54. PMID 34804852 → the partial, leukostasis-mediated protection anti-VEGF gives against non-perfusion progression, encoded via W_LEUK_V.
  6. Kadomoto S, et al. Nonperfusion area quantification in branch retinal vein occlusion: a widefield optical coherence tomography angiography study. Retina 2021;41:1210-7. PMID 33105300 → the disc-area units used for NP.
  7. Hayreh SS. Photocoagulation for retinal vein occlusion. Prog Retin Eye Res 2021;85:100964. PMID 33713810

11. 구조 바이오마커와 시력 (Structural biomarkers and visual function)

  1. Sun JK, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol 2014;132:1309-16. PMID 25058813 → the DRIL state and why thickness alone under-predicts acuity.
  2. Sun JK, et al. Neural retinal disorganization as a robust marker of visual acuity in current and resolved diabetic macular edema. Diabetes 2015;64:2560-70. PMID 25633419 → the evidence that the structural damage persists after the oedema resolves. This is the empirical content of L_pr being irreversible.
  3. Song Y, et al. Prognostic biomarkers in treatment-naïve central retinal vein occlusion with macular edema. Eur J Med Res 2025;30:559. PMID 40624719
  4. Hirano Y, et al. Multimodal imaging of microvascular abnormalities in retinal vein occlusion. J Clin Med 2021;10:405. PMID 33494354

12. 전신 위험인자와 혈압 (Systemic risk and blood pressure)

  1. O'Mahoney PR, Wong DT, Ray JG. Retinal vein occlusion and traditional risk factors for atherosclerosis. Arch Ophthalmol 2008;126:692-9. PMID 18474782 → hypertension in 63-73% of CRVO. The prior on PA in the virtual population, and the reason the blood-pressure arrow matters at a population level and not just in individuals.
  2. Voigt AM, et al. Incidence of retinal vein occlusion and its association with mortality: results from the Gutenberg Health Study. Ophthalmology 2025;132:—. PMID 39971137
  3. Yau JW, et al. Retinal vein occlusion: an approach to diagnosis, systemic risk factors and management. Intern Med J 2008;38:904-10. PMID 19120547

13. 실제 진료 결과 (Real-world outcomes and treatment intensity)

  1. Hunt A, et al. Central retinal vein occlusion 36-month outcomes with anti-VEGF: the Fight Retinal Blindness! registry. Ophthalmol Retina 2023;7:317-25. PMID 36371040 → the target for the REALWORLD scenario: injection counts and letter gains over 36 months outside a trial.
  2. Spooner KL, et al. Long-term outcomes of anti-VEGF treatment of retinal vein occlusion. Eye (Lond) 2022;36:1194-201. PMID 34117379
  3. Spooner K, et al. Prospective study of aflibercept for the treatment of persistent macular oedema secondary to retinal vein occlusion. Clin Exp Ophthalmol 2020;48:53-60. PMID 31498950 → the persistent-oedema population. In the model these are the eyes whose residual thickness is a pressure floor, and the trial's modest benefit from switching agent is exactly what the model predicts for them.
  4. Wecker T, et al. Five-year visual acuity outcomes and injection patterns in patients with pro-re-nata treatments for AMD, DME and RVO. Br J Ophthalmol 2017;101:353-9. PMID 27215744 → the letters-per-injection relationship the dose-response curve reproduces.
  5. Bhandari S, et al. Changes in 12-month outcomes over time for age-related macular degeneration, diabetic macular oedema and retinal vein occlusion. Eye (Lond) 2023;37:1145-54. PMID 35508721
  6. Ciulla TA, et al. Longer-term anti-VEGF therapy outcomes in neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion. Ophthalmol Retina 2022;6:796-806. PMID 35381391 → the treatment-intensity / outcome relationship across three indications.
  7. Kawakami S, et al. Healing rate of macular edema secondary to branch retinal vein occlusion in two years after initiation of anti-VEGF therapy. PLoS One 2023;18:e0280058. PMID 36595494 → the fraction of BRVO eyes that become injection-free; in the model, the fraction whose Pc crosses below Pc*.
  8. Akdemir SC, et al. Comparison of anti-VEGF results between non-ischemic and ischemic branch retinal vein occlusion. J Fr Ophtalmol 2022;45:1013-20. PMID 36127168 → the ischaemic / non-ischaemic response gap the model derives from Pc.

14. 주사 관련 안전성 (Injection-related safety)

  1. Chang-Lin JE (above, PMID 20702826) — steroid IOP kinetics.
  2. Abbas K, et al. Transient vision and intraocular pressure changes following anti-vascular endothelial growth factor injection. Can J Ophthalmol 2026. PMID 40987347 → the transient IOP spike from injecting 0.05 mL into a 4 mL cavity.
  3. Zhang C, et al. Rates of endophthalmitis in prefilled versus nonprefilled syringes for intravitreal injections. Ophthalmol Retina 2026;10:—. PMID 40816641 → the per-injection endophthalmitis rate that makes injection count a risk as well as a benefit.
  4. Hanna RM, et al. Intravitreal vascular endothelial growth factor inhibitors, hypertension, proteinuria, and renal injury: a concerning trend. Curr Opin Nephrol Hypertens 2022;31:47-56. PMID 34750330 → the systemic VEGF-suppression safety node; connects to the model's ASYS compartment and the aflibercept-versus-ranibizumab plasma difference.

15. 모델링 방법 (Modelling methodology)

  1. Park J, et al. Computational fluid dynamics modeling of intravitreal ranibizumab bolus versus subretinal gene therapy. Transl Vis Sci Technol 2025;14:—. PMID 41042032 → shows how much the well-mixed-vitreous assumption gives up; part of the justification for treating FPEN and ALPHA as lumped calibration factors.
  2. Franz M, et al. Injected eye, fellow eye and systemic pharmacokinetic modeling of intravitreally administered bevacizumab. Mol Pharm 2026;23:—. PMID 41925314
  3. Chowdhury JM, et al. Computational modeling of intravitreal ranibizumab kinetics: predicting macular drug concentration. PLoS One 2026;21:e0—. PMID 42096431
  4. Wohlfart S, et al. Vitrectomy status alters early intravitreal drug distribution: an ex vivo PET-CT study. Invest Ophthalmol Vis Sci 2026;67:—. PMID 42446480
  5. Jing Y, et al. Faricimab for retinal vein occlusion: a review of current evidence and future perspectives. Front Pharmacol 2025;16:—. PMID 41164764
  6. Chaudhary V, et al. Emerging clinical evidence of a dual role for Ang-2 and VEGF-A blockade with faricimab in retinal diseases. Graefes Arch Clin Exp Ophthalmol 2025;263:1345-58. PMID 39708087

모델 파라미터의 출처 요약 (Where each key parameter comes from)

파라미터 값 출처 / 근거
PA post-arteriolar inlet pressure 40 mmHg Glucksberg 1993 [10], Attariwala 1994 [11]
RV0 / RA0 0.25 / 1.0 chosen so that normal Pc = 21.6 mmHg [10]
PT, PI_C, PI_T0, SIGMA_MAX 12, 25, 4 mmHg, 0.92 Levick & Michel 2010 [13], Michel 2020 [14]
OCC0 per phenotype 5 – 32 scaled to Attariwala 1997 experimental occlusion [12]
OCC_RES residual stenosis 0.18 – 0.80 fitted to the natural-history reviews [1,2] and RETAIN [60]
K_COLL, COLL_MAX 0.0035 /d; 0.45 – 2.2 Tsuboi 2019 OCT-A collateral kinetics [19,20]
RV_VEGF, E_HIF_V 24 pM/d, ×12 Noma 2009 aqueous / vitreous VEGF [35], Aiello 1994 [33]
RI_IL6, E_HIF_I 30 pg/mL/d, ×16 Noma 2008/2014 IL-6 [34,36]
RA_ANG2, E_HIF_A 10 pM/d, ×7 Saharinen 2017 [38], Sahni 2019 [70]
TVIT per agent 5.1 – 9.8 d Krohne 2008/2012 [41,42], Caruso 2020 [45]
KDV per agent 0.49 – 58 pM Papadopoulos 2012 [51]
FPEN retina:vitreous 0.08 Bakri 2007 [43], Hutton-Smith 2017 [47]
ALPHA apparent-IC50 multiplier 120 calibrated, single global value; see [46,52,66]
K_NP non-perfusion growth 0.30 DA/d Ou 2018 [84], Kadomoto 2021 [86]
K_NVI, NVG criterion 0.030 /d; NVI>0.5 & IOP>25 Hayreh 2012 [82], Rong 2019 [83]
dexamethasone implant PK plateau ≈ 900 ng/mL Chang-Lin 2011 [49]
K_CAT_DEX 0.0024 /d MEAD 3-year cataract rate [76]
E_ED, KM_ED, E_PR 36 letters, 230 µm, 42 letters CRUISE [56], COPERNICUS [61], Sun 2014/2015 [88,89]
K_EZ photoreceptor damage 0.0018 /d fitted to the deferred arms of CRUISE [58] and COPERNICUS [62]

이 모델이 사용하지 않은 것 (What this model deliberately does not claim)

  • 개별 환자 예측 (individual prediction). The parameters are population-level and the calibration targets are trial means. Nothing here is fitted to any individual eye.
  • ALPHA는 기전이 아니라 보정 상수입니다. The 120-fold gap between an SPR affinity and an apparent in-vivo IC50 is a lumped stand-in for VEGFR2 competition, local interstitial flux and diffusional limitation. It is applied identically to every agent, so it cannot manufacture a difference between agents — but it is not a measured quantity, and any absolute suppression duration should be read as an order of magnitude.
  • 절대 두께 (absolute thickness). KF, VMAX_PUMP and KM_PUMP are fitted so that the CRVO baseline lands near the trial baselines. The differences between arms are the model's output; the absolute micrometres are calibration.
  • SIGMA = SIGMAX·TJ^0.55 관계. The functional coupling of the reflection coefficient to junction integrity is a modelling choice with the right qualitative behaviour, not a measured relationship. It matters, because it is what sets Pc*.