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EP-3776566-B1 - TEST AND OPTIMIZATION OF MEDICAL TREATMENTS FOR THE HUMAN EYE

EP3776566B1EP 3776566 B1EP3776566 B1EP 3776566B1EP-3776566-B1

Inventors

  • Friedmann, Elfriede
  • Dörsam, Simon
  • Olkhovskiy, Vladislav

Dates

Publication Date
20260506
Application Date
20190402

Claims (10)

  1. A computer-implemented method for testing ocular drug delivery, wherein the ocular drug delivery is characterized by a set of delivery parameters comprising at least one of drug type, drug concentration, drug amount, injection position, penetration depth, the method comprising: - providing a model for the human eye, wherein the model comprises: a geometry equation defining a three-dimensional limacon for the geometry of the vitreous body; and a set of equations defining a drug convection in the vitreous body; - setting a target drug state in the vitreous body; - using the model to perform at least one simulation of the ocular drug delivery with a given set of values for the set of delivery parameters as initial conditions, wherein the set of equations models the evolution of the ocular drug delivery with time and the geometry equation is used for providing boundary conditions, wherein the at least one simulation provides a simulated drug state in the vitreous body; - comparing the target drug state and the simulated drug state; wherein the geometry equation is a parameterized geometry equation including a set of free geometry parameters, the geometry equation being x = R φ cosφ + m x y = R φ sinφcosθ z = R φ sinφsinθ with R ( φ ) = ( p 1 + p 2 cosφ + p 3 cosφ 3 ), θ∈ [0, π ), φ∈ [0,2 π ) , wherein p 1 ∈ [7.5,7.7] and p 2 ∈ [9.0,9.2]and p 3 ∈ [-2.5, -2.8] and m x ∈ [-1, -1.2]; wherein the set of equations is given by the system: ∂ t C t x → + v → t x → ⋅ ∇ C t x → − ∇ ⋅ D x → ∇ C t x → = f g ∇ ⋅ v → t x → = 0 , υ K v → t x → + ∇ p t x → = h g wherein C ( t, x ) is the concentration of the drug, v ( t , x )is the velocity of vitreous humor, D ( x ) is the diffusion coefficient, f g is the effect of the gravitational force on the drug concentration C ( t, x ) , p ( t, x ) is the pressure of the vitreous humor flow, h g is the effect of the gravitational force on the vitreous humor flow, v is the viscosity and K is the permeability of the vitreous body; wherein the boundary conditions are: C t x → = 0 on Γ c p t x → = 2000 Pa on Γ c ∂ n → C t x → = 0 on Γ l v → t x → = 0 on Γ l − D x → ∂ n → C t x → − PC t x → + n → x → ⋅ v → t x → 1 − k C t x → = 0 on Γ r n → x → ⋅ v → t x → = K R p t x → − P v L 0 on Γ r ; wherein Γ c is the boundary towards the ciliary body, Γ l towards the lens and Γ r towards the retina. P = 2.6 · 10 -7 m/s is the retinal permeability, n is the unit normal vector to the surface of the vitreous body, k = 7.9 is the partition coefficient between the vitreous body and the retina, K R is the hydraulic conductivity of the retina, choroid and sclera, equal to 1.5 · 10 -15 m 2 /(Pa s), P v = 1200 Pa is the pressure of the episcleral tissue and L = 3 · 10 -4 m is the thickness of retina, choroid and sclera; wherein the model is used to perform a plurality of simulations of the ocular drug delivery, each simulation being performed with a different set of values for the set of delivery parameters and each simulation providing a simulated drug state in the vitreous body; and wherein the method further comprises: - retrieving eye measurement data describing at least the shape of the vitreous body; - determining a set of values for the set of free geometry parameters by fitting the parameterized geometry equation to the eye measurement data; - computing a plurality of deviation scores for the plurality of simulations based on the comparison between the target drug state and the plurality of simulated drug states; - selecting an optimal set of values for the set of delivery parameters based on the deviation scores.
  2. The computer-implemented method according to claim 1, wherein retrieving eye measurement data further comprises collecting the eye measurement data by performing the measurements on one or more human eyes using an imaging technique.
  3. The computer-implemented method according to any one of the preceding claims, further comprising defining a performance factor characterizing a drug state, wherein: setting the target drug state comprises setting a target constraint for the performance factor; providing a simulated drug state comprises computing a simulated value for the performance factor; comparing the target drug state and the simulated drug state comprises comparing the simulated value with the target constraint; and wherein the performance factor is derived from C ( t, x ) .
  4. The computer-implemented method according to any one of the preceding claims, further comprising: generating a visual representation of the simulated drug state in the vitreous body; and outputting the visual representation via an output device.
  5. The computer-implemented method according to any one of the preceding claims, wherein the model for the human eye further comprises a plurality of geometry equations defining the geometry of all components of the human eye and the method further comprises: three-dimensionally printing the human eye using the plurality of geometry equations.
  6. A computer system for testing ocular drug delivery, wherein the ocular drug delivery is characterized by a set of delivery parameters comprising at least one of drug type, drug concentration, drug amount, injection position, penetration depth, the computer system comprising: - means for providing a model for the human eye, wherein the model comprises: a geometry equation defining a three-dimensional limacon for the geometry of the vitreous body; and a set of equations defining a drug convection in the vitreous body; - means for setting a target drug state in the vitreous body; - means for using the model to perform at least one simulation of the ocular drug delivery with a given set of values for the set of delivery parameters as initial conditions, wherein the set of equations models the evolution of the ocular drug delivery with time and the geometry equation is used for providing boundary conditions, wherein the at least one simulation provides a simulated drug state in the vitreous body; - means for comparing the target drug state and the simulated drug state; wherein the geometry equation is a parameterized geometry equation including a set of free geometry parameters, the geometry equation being x = R φ cosφ + m x y = R φ sinφcosθ z = R φ sinφsinθ with R ( φ ) = ( p 1 + p 2 cosφ + p 3 cosφ 3 ), θ∈ [0, π ), φ∈ [0,2 π ), wherein p 1 ∈ [7.5,7.7] and p 2 ∈ [9.0,9.2]and p 3 ∈ [-2.5, -2.8]and m x ∈ [-1, -1.2]; wherein the set of equations is given by the system: ∂ t C t x → + v → t x → ⋅ ∇ C t x → − ∇ ⋅ D x → ∇ C t x → = f g ∇ ⋅ v → t x → = 0 , υ K v → t x → + ∇ p t x → = h g wherein C ( t, x ) is the concentration of the drug, v ( t , x )is the velocity of vitreous humor, D ( x ) is the diffusion coefficient, f g is the effect of the gravitational force on the drug concentration C ( t, x ) , p ( t, x ) is the pressure of the vitreous humor flow, h g is the effect of the gravitational force on the vitreous humor flow, v is the viscosity and K is the permeability of the vitreous body; wherein the boundary conditions are: C t x → = 0 on Γ c p t x → = 2000 Pa on Γ c ∂ n → C t x → = 0 on Γ l v → t x → = 0 on Γ l − D x → ∂ n → C t x → − PC t x → + n → x → ⋅ v → t x → 1 − k C t x → = 0 on Γ r n → x → ⋅ v → t x → = K R p t x → − P v L on Γ r ; wherein Γ c is the boundary towards the ciliary body, Γ l towards the lens and Γ r towards the retina. P = 2.6 · 10 -7 m/s is the retinal permeability, n is the unit normal vector to the surface of the vitreous body, k = 7.9 is the partition coefficient between the vitreous body and the retina, K R is the hydraulic conductivity of the retina, choroid and sclera, equal to 1.5 · 10 -15 m 2 /(Pa s), P v = 1200 Pa is the pressure of the episcleral tissue and L = 3 · 10 -4 m is the thickness of retina, choroid and sclera; wherein the means for using the model to perform at least one simulation are configured to perform a plurality of simulations of the ocular drug delivery, each simulation being performed with a different set of values for the set of delivery parameters and each simulation providing a simulated drug state in the vitreous body; and wherein the system further comprises: - means for retrieving eye measurement data describing at least the shape of the vitreous body; - means for determining a set of values for the set of free geometry parameters by fitting the parameterized geometry equation to the eye measurement data; - means for computing a plurality of deviation scores for the plurality of simulations based on the comparison between the target drug state and the plurality of simulated drug states; - means for selecting an optimal set of values for the set of delivery parameters based on the deviation scores.
  7. The computer system according to claim 6, further comprising means adapted for collecting the eye measurement data by performing the measurements on one or more human eyes using an imaging technique.
  8. The computer system according to claim 6 or 7, wherein a performance factor characterizes a drug state and: setting the target drug state comprises setting a target constraint for the performance factor; providing a simulated drug state comprises computing a simulated value for the performance factor; comparing the target drug state and the simulated drug state comprises comparing the simulated value with the target constraint; and wherein the performance factor is derived from C ( t, x ) .
  9. The computer system according to any one of claims 6 to 8, comprising: means for providing a plurality of geometry equations describing the geometry of all components of the human eye; and means adapted for three-dimensionally printing the human eye using the plurality of geometry equations.
  10. A computer program product comprising computer-readable instructions, which, when loaded and executed on the computer system of any one of claims 6 to 9, cause the computer system to perform operations according to the method of any one of claims 1 to 5.

Description

Technical Field The following description relates to a computer-implemented method, a computer program product and a computer system for testing and optimizing medical treatments of the human eye. Background The human eye comprises a plurality of components, including the vitreous body, the lens, the ciliary body, the iris, the anterior chamber and the cornea. The individual components have different shapes and different properties, such as mechanical properties (e.g. consistency) and optical properties. Further, the characteristics of a given component may be affected by pathologies of the eye, such as glaucoma and retinal diseases, or conditions such as myopia. In order to treat the pathologies/conditions, the properties of the components, which determine at least partly the physiological processes occurring in the human eye, need to be understood. For example, the vitreous body acts as a mechanical damper and transmits stresses protecting the eye. However, although linked to several pathologies such as retinal detachment, the structure of the vitreous body is not well understood. Further, there is a problem with testing different therapeutic approaches for treating the pathologies/conditions, because in vitro or in vivo tests suffer from limitations in the tests that can be performed due to availability, costs and ethical considerations. Therefore, there is a need for an accurate understanding of the structure of the eye based on which tests of different therapeutic approaches can be correctly and efficiently performed. The document "Modeling and Simulations of Drug Distribution in the Human Vitreous" by S. Dörsam et al., 2017, discloses a mathematical model for the drug distribution in the vitreous body of a human eye. The drug is injected in the vitreous and used for the treatment of retinal diseases. The distribution of the drug is modelled with anisotropic diffusion which include the effect of the collagen fibers which have a certain orientation in the vitreous body. In addition to the diffusion the steady permeating flow of the aqueous humor is included and modeled with the Darcy equation driven by a pressure drop. The position of injection is analyzed by introducing specific output functionals which measure the mean or relative amount of the drug in the vitreous and in the area of action. The document "Computer Modeling of Drug Distribution after Intravitreal Administration" by N. Haghjou et al., 2011, discloses a computer model to predict intraocular concentrations and pharmacokinetics of intravitreally injected drugs. A finite volume model was created to predict distribution of two drugs with different physiochemical properties in the rabbit eye. The model parameters were obtained from literature review. To validate this numeric model, the in vivo data of spatial concentration profile from the lens to the retina were compared with the numeric data. The difference was less than 5% between the numerical and experimental data. The document "Finite element modeling of drug distribution in the vitreous humor of the rabbit eye" by S. Friedrich et al., 1997, discloses a study about drug distribution in the vitreous humor of the rabbit eye after an intravitreal injection, using a finite element model. Fluorescein and fluorescein glucuronide were selected as model compounds due to available experimental data. All required model parameters were known except for the permeability of these compounds through the retina, which was determined by fitting model predictions to experimental data. The location of the intravitreal injection in the experimental studies was not precisely known; therefore, several injection locations were considered, and best-fit retinal permeability was determined for each case. The document "Drug Distribution in the Vitreous Humor of the Human Eye: The Effects of Aphakia and Changes in Retinal Permeability and Vitreous Diffusivity" by S. Friedrich et al., 1997, discloses an examination of the effects of aphakia and changes in retinal permeability and vitreous diffusivity on drug distribution in the vitreous humor of the human eye. The study was performed using a finite element model that accurately accounts for the vitreous geometry and boundary conditions. Intravitreal injection was simulated using the models. Elimination from aphakic and phakic eyes was compared for four extreme injection locations and for two retinal permeabilities. US 2018/000339 A1 discloses a computer-implemented virtual eye analyzer & simulator system for diagnostic and intraoperative analysis of whole eye biomechanics, optics, physiology and function, comprising a computer based FEM and a processor operable to: manipulate structure, function and optics virtually; run MonteCarlo simulations, Al simulations and wherein the system includes an artificial neural network system of visual accommodation and visual acuity. Summary It is an object of the invention to allow for accurate and efficient testing of medical tr