METHOD FOR EVALUATING A FILLER GEL

Description

technical field

[0001] The present invention relates to filler gels, particularly those based on polysaccharide, used in the aesthetic and / or medical field to fill wrinkles and / or give more relief to certain areas of the face. Previous technique

[0002] Dermal fillers, for example, are hydrogels based on polysaccharides, particularly hyaluronic acid (HA), and are injected under the skin using a syringe.

[0003] Manufacturers offer dermal fillers with varying rheological properties depending on the injection site. For example, when injected into the superficial layers of the skin, the gels must gently fill fine lines and wrinkles and easily move with the face. Gels intended for filling deeper folds and wrinkles, and / or for creating volume (known as "volumizers"), must maintain their thickness within the skin layers over time, even under the stress of facial movements.

[0004] The rheology of the gel and its behavior over time are therefore essential elements that must be mastered if one seeks to obtain filling gels with optimal results.

[0005] The most commonly used rheological measurements of gels are those of the moduli G' and G", with the phase shift angle δ being related to these measurements (tan δ = G" / G'). These measurements are typically performed under low oscillatory stress with a small amplitude, within their linear viscoelastic range. These measurements do not fully reflect the mechanical and deformation stresses that a filling gel undergoes. in vivo.

[0006] These measurements do not allow us to predict the gel's compression behavior. However, in the case of deep implantation, the gel is compressed between layers of tissue, and its ability to create relief depends on its capacity not to spread or lose excessive thickness over time.

[0007] In order to characterize the behavior of the gel under compression, it is known to measure its cohesivity by performing a compression test consisting of subjecting a bolus of gel to the pressure of a plate moving with a constant forward motion and measuring the reaction force of the gel at the end of the advance.

[0008] Jimmy Faivre et al.: "Advanced Concepts in Rheology for the Evaluation of Hyaluronic Acid-Based Soft Tissue Fillers", DERMATOLOGIC SURGERY, vol. 47, no. 5, February 22, 2021, pages e159-e167 and "Original Article - Supplemental Digital Content Advanced Concepts in Rheology for the Evaluation of Hyaluronic Acid-based Soft Tissue Fillers", pages 1-5, disclose a method for evaluating the mechanical performance of a known filler gel.

[0009] However, this test does not allow for a completely reliable prediction of the behavior of the gel in tissues.

[0010] Furthermore, there remains an interest in having tools for characterizing and selecting gels in the laboratory, thus limiting the need for testing. in vivo at the product development stage. Description of the invention

[0011] Therefore, there is a need to facilitate the evaluation, characterization, and development of new dermal fillers, and in particular to easily differentiate between several gels to select the one(s) with the most suitable properties for the desired result, and especially, for volumizing products, to evaluate in vitro their ability to maintain their thickness within tissues. Tests in vivo are also known but are lengthy and expensive and require animal sacrifice. The invention offers a method for directly characterizing the behavior of a gel when subjected to a predefined stress. in vitro.This method makes it possible to measure the gel's ability to maintain its initial thickness under a constant, fixed normal stress, and thus to take into account the forces applied by surrounding tissues to a gel in or under the skin, for example, those related to facial movements. For the purposes of this invention, the term "skin" includes the skin of the face, décolletage, hands, scalp, abdomen, and / or legs, as well as the lips. Summary of the invention

[0012] The invention achieves this objective through a method for evaluating the mechanical performance of a filler gel, comprising the steps of: 1) subject a bolus of this gel, initially thickened by a predefined thickness d0 between two pressure surfaces, to a predefined compressive force F, 2) record the evolution of the thickness variation of the compressed gel over time, 3) parameterize a mathematical model approximating the observed evolution from the data acquired, 4) determine a limiting thickness from the model d ∞ towards which the gel tends to evolve over time, 5) generate information relating to the gel's ability to maintain its thickness in tissues, in particular a projection index, by comparing the limiting thickness d ∞ to the initial thickness d 0 .

[0013] Thanks to the invention, we have information representative of the actual behavior of a gel bolus subjected to a compressive force within the tissues; the greater the capacity to maintain its thickness, the closer the limiting thickness will be to the initial thickness. Compared to a compression test, the method according to the invention relies on a mechanical stress on the gel that more closely reflects what it can withstand. in vivo.

[0014] The method according to the invention has the advantage of being rapid, reproducible, and requiring only a small amount of gel to perform the measurement. Indeed, a small quantity of gel, for example 1 gram or less, is sufficient to obtain a result with this method, whereas prior art compression characterization methods required larger quantities.

[0015] In the following, the term "deep application" refers to the administration of a gel into the deepest layers of the skin, the hypodermis and the deepest part of the dermis, and / or under the skin (above the periosteum) to "volumize" soft tissues, such as for filling the deepest wrinkles and / or partially atrophied areas of the contour of the face and / or body.

[0016] The term "superficial application" refers to the administration, for example by mesotherapy, of a composition superficially into or onto the skin, for the treatment of the superficial layers of the skin, the epidermis and the most superficial parts of the dermis, to reduce superficial wrinkles and / or improve skin quality (such as its radiance, density or structure) and / or rejuvenate the skin.

[0017] The term "mid-surface application" refers to the administration of a composition to the mid-surface of the skin to treat the middle layers and reduce mid-surface wrinkles. For such mid-surface applications, gels with intermediate properties are chosen—that is, properties between those of gels intended for deep and superficial applications. Such gels are sometimes called "utility fillers" or "mid-surface fillers."

[0018] The "degree of modification" (MoD%) of a polysaccharide, such as hyaluronic acid, corresponds to the molar amount of crosslinking agent, i.e., the amount of crosslinking agent bound to the polysaccharide at one or more of its ends, expressed per 100 moles of repeating units of the polysaccharide. It can be determined by methods known to those skilled in the art, such as Nuclear Magnetic Resonance (NMR) spectroscopy.

[0019] The "molar crosslinking ratio" (TR), expressed as a percentage, denotes the molar ratio of the amount of crosslinking agent to the amount of polysaccharide repeat unit introduced into the crosslinking reaction medium, expressed per 100 moles of polysaccharide repeat units in the crosslinking medium.

[0020] According to the invention, the polysaccharide can be any polymer composed of monosaccharides joined together by glycosidic bonds. Preferably, the polysaccharide is selected from pectin and pectic substances; chitosan; chitin; cellulose and its derivatives; agarose; glycosaminoglycans such as hyaluronic acid, heparosane, dermatan sulfate, keratan sulfate, chondroitin and chondroitin sulfate; and mixtures thereof.

[0021] Preferably, the polysaccharide is hyaluronic acid, particularly in salt form, specifically in a physiologically acceptable form such as sodium, potassium, zinc, calcium, magnesium, silver, or calcium salt, and mixtures thereof. More specifically, hyaluronic acid is in its acidic form or as a sodium salt (NaHA). The filler gel can therefore be a gel based on hyaluronic acid and / or its salts.

[0022] The phase angle δ characterizes the degree of viscoelasticity of a material; it varies from 0° for a 100% elastic material (all the deformation energy is returned by the material, meaning that the gel is able to regain its initial shape after the application of a given deformation) to 90° for a 100% viscous material (all the deformation energy is lost by the material, meaning that it flows and totally loses its initial shape when it undergoes deformation).

[0023] The "projecting" characteristic or the ability to "project" of a gel is defined by maintaining its thickness over time, including under stress.

[0024] The predefined force is preferably constant but can also vary cyclically over time around an average value. The predefined force can vary cyclically over time by around 10%, preferably 5%, and even more preferably 2%, relative to the average value. This force F can be applied between a fixed plate and a moving plate that is displaced towards the fixed plate, this moving plate preferably applying a fixed force F.

[0025] The aforementioned mathematical model can be chosen from among the Maxwell, Kelvin, Kelvin-Voigt and Burgers models.

[0026] The mathematical model is preferably the generalized Maxwell model for viscoelastic materials, which expresses the gel thickness as a function of time in the form: d gel t = d ∞ + ∑ A i . e − t / τ i Or d ∞ is the limiting thickness obtained at equilibrium (after an infinite time for a force within the linear range of freezing) or after a sufficiently long predefined time (for a force outside the linear range), Ai a constant, Ti a relaxation parameter, the number of members i of the equation preferably being greater than 1 and less than or equal to 3; in particular, good results are already obtained for a value of i of 2 in the expression above, that is to say for a model expressed in the form: d gel t = d ∞ + A 1 . e − t / τ 1 + A 2 . e − t / τ 2

[0027] A parameter called the projection index P Idx, expressed as a percentage, can be defined by the ratio d ∞ / d 0 * 100 .

[0028] The step of generating information relating to the ability of the gel to retain its thickness may include the calculation of the projection index P Idx.

[0029] The initial thickness d 0 can be chosen between 100 and 3000 microns, preferably between 200 and 2000 microns, preferably between 500 and 1000 microns, preferably between 600 and 900 microns, better between 600 and 800 microns, being for example equal to 700 microns.

[0030] The force F can be chosen between 0.1 and 10N, preferably between 1 and 5N, preferably between 1 and 3N, better between 1.5 and 2.5N, being for example equal to 2N. Such a force value is particularly well suited to so-called volumizing filler gels and / or for deep application.

[0031] The invention advantageously allows for the simulation of different implantation conditions and thus the prediction of a gel's behavior in various implantation configurations by varying the applied force. In this sense, for example, for a volumizing gel, it is possible to increase the compression force F to represent an injection into an area within and / or subdermally, potentially resulting in higher pressures.

[0032] According to the invention, when gels are intended for deep application, a force F between 0.1 and 10N, preferably between 1 and 5N, more preferably between 2 and 4N, will preferably be chosen.

[0033] According to the invention, when gels are intended for surface application, a force F between 0.1 and 5N, preferably between 0.5 and 2N, more preferably between 0.5 and 1N, will preferably be chosen.

[0034] According to the invention, when the gels are intended for a median application, a force F between 0.1 and 10N, preferably between 1 and 4N, more preferably between 1 and 2N, will preferably be chosen.

[0035] Thus, during the implementation of the process, at least two evaluations can be carried out at different respective forces F depending on the intended application for the gels, in particular either at a force F between 1 and 5N, preferably between 2 and 4N, or at a force F between 0.5 and 2N, preferably between 0.5 and 1N, or at a force between 1 and 4N, preferably between 1 and 2N.

[0036] The quantity of gel can be chosen between 0.1 and 10g, preferably between 0.5 and 5g, more preferably between 0.5 and 2g, better between 0.75 and 1g, being for example equal to 1g.

[0037] In vivo,The surrounding tissues relax, the skin layers stretch, and the normal force exerted by these layers decreases over time. This prevents the gel from completely running or flattening. All gels eventually reach equilibrium.

[0038] With the method in vitro According to the invention, the gel is preferably not completely enclosed and can therefore eventually flow out of the rheometer, depending on the geometry of the rheometer's measuring cell. The duration of force application is chosen to account for this flow and is preferably less than 10 hours.

[0039] Thus, the duration of the aforementioned acquisition is preferably greater than or equal to 5 minutes, better greater than or equal to 30 minutes, better greater than or equal to 1 hour, in particular between 30 minutes and 10 hours, in particular between 30 minutes and 2 hours, for example 60 minutes.

[0040] The method may include the step of determining whether the compression occurs within the linear viscoelastic deformation region (LVER) of the gel. Advantageously, this step consists of an oscillatory strain sweep measurement in compression mode at a given oscillation frequency to determine the linear viscoelastic region and bracket the applied normal force. This measurement is applied over a defined strain range. Preferably, the strain range covers 0.1 to 10%, at 1 Hz at 25°C.

[0041] The method may include the emission of an alert information when the force F is not within the linear viscoelastic deformation range and / or when E' <E", E' désignant le module d'élasticité et E" le module de perte.

[0042] The modulus of elasticity E', also called the conservation modulus, corresponds to the energy released by the gel after being subjected to compression. This measurement is expressed in Pa. The loss modulus E", corresponds to the energy dissipated by the gel after being subjected to compression. This measurement is also expressed in Pa.

[0043] The process can be implemented using a test bench with an automated system equipped with a processor programmed to control the force F and measure the distance over time between the bearing surfaces, as well as to parameterize the model and calculate the limiting thickness. d ∞ , and provide information relating to the gel's ability to retain its thickness, in particular the projection index P Idx.

[0044] The projection index thus calculated can be printed or displayed on an information medium, including a leaflet, gel packaging, information or advertising panel, commercial or medical brochure, television, computer or mobile phone screen, or on an automated screen, for example the automated screen of a rheometer.

[0045] The invention further relates to a method for selecting a filling gel in which the evaluation method according to the invention is implemented for a set of gels to be tested, and the gel is selected based at least on the result of the evaluation, in particular the calculated projection index.

[0046] The gels according to the invention can be used for deep application or for superficial application, as mentioned above.

[0047] From a set of gels, the gel(s) with the highest projection index(es) can be selected. For example, gels with projection indices greater than or equal to 60%, or even 70%, 75%, or 85% or more, can be selected.

[0048] The projection index value can be used to discriminate between gels whose cohesivenesses would be close, for example gels for which the cohesiveness measurements differ by less than 10% (relative to the lowest measurement), or even less, for example 8% or less, 5% or less or 2% or less, or even 1% or less.

[0049] The invention also relates to a method for classifying a set of filling gels according to their mechanical performance, in which the evaluation method according to the invention as defined above is implemented for each of these gels, and the gels are classified according to the projection index values ​​obtained.

[0050] The invention further relates to a method for manufacturing a filling gel, in which a candidate gel is manufactured in a small quantity, then its projection index is evaluated by implementing the evaluation method according to the aforementioned invention, and the gel is manufactured in a quantity greater than that of the candidate gel, for example at least if the projection index exceeds a predefined threshold.

[0051] This process may involve reformulating the gel and comparing the projection index of the gel after reformulation with that before reformulation.

[0052] The reformulation may involve modifying the polysaccharide concentration and / or the amount of crosslinking agent bound to the polysaccharide in the gel.

[0053] The process may include the step of automatically determining, by iteration, parameters of the manufacturing process of the filler gel such as the values ​​of polysaccharide concentration and quantity of crosslinking agent to obtain the best performance, given the dependence of the projection index on these parameters of the manufacturing process of the filler gel.

[0054] The invention further relates to a method for manufacturing a filler gel, in which several candidate gels are manufactured in small quantities, then their projection index is evaluated by implementing the evaluation method according to the aforementioned invention, a gel is selected based on the results of the evaluation, and the selected gel is manufactured in a quantity greater than that of the candidate gel.

[0055] The invention further relates to a method for supervised learning of a neural network, in which the input values ​​are provided for the concentration of the polysaccharide, in particular hyaluronic acid of the gel, the degree of modification MoD%, the molar crosslinking ratio TR, G', G", the phase angle δ, and the width of the linear viscoelastic domain LVER, as well as the value of the limiting thickness d ∞ for tested gels, and the network is taught to deliver the limit thickness value at the output d ∞ depending on the aforementioned input parameters. Brief description of the drawings

[0056] The invention will be better understood upon reading the detailed description that follows, the non-limiting examples of its implementation, and upon examination of the attached drawing, on which: [ Fig 1 ] there figure 1 is a block diagram of an example of a method according to the invention, [ Fig 2 ] there figure 2illustrates the step of applying a constant fixed force to the gel sample, [ Fig 3 ] there figure 3 illustrates the evolution of gel thickness values ​​over time during measurement for five gel examples, [ Fig 4 ] there figure 4 represents the projection index as determined by the implementation of the invention for several different filling gels, and [ Fig 5 ] there figure 5 represents in bar chart form the results of cohesiveness measurement and projection index for several filling gels. Detailed description

[0057] The method according to the invention may include, as illustrated in the figure 1 , a step 1 of preparing the sample to be tested.

[0058] In particular, as illustrated in the figure 2For example, a bolus of mass M of the filling gel is deposited onto a base plate 10, and then a parallel and horizontal pressure plate 11 is lowered into contact with it. During this step 1, this pressure plate applies a constant force to the sample until the thickness of the material, given by the distance between plates 10 and 20, is equal to a predefined value d0, for example, 700 microns.

[0059] Once the thickness reaches this predefined value d0 and the gel resistance force is less than or equal to the value of the force F to be applied, data acquisition can begin, taking this instant as the origin of time for the acquisition. Then, in step 2, the continued evolution of the thickness over time can be measured, with the pressure applied by the pressure plate remaining, for example, fixed and constant.

[0060] Depending on the behavior of the gel, its thickness may change only slightly during the measurement, as illustrated under a) in the figure 2 , or more markedly, as illustrated under b).

[0061] There figure 3 represents the result of measurements for five different hyaluronic acid-based filler gels, labeled E1 to E5.

[0062] Once the acquisition is complete, the process includes a step 3 in which the values ​​to be given to the parameters of a mathematical model are sought in order to have the best fit of the model with the evolution of the observed thickness.

[0063] In the example considered, the model used is the generalized Maxwell model, which gives the evolution of the gel thickness as a function of time t by the formula: d gel t = d ∞ + ∑ A i . e − t / τ i

[0064] Good results are obtained even with the presence of two exponential terms: d gel t = d ∞ + A 1 . e − t / τ 1 + A 2 . e − t / τ 2

[0065] To find the parameter values d ∞ , A i and τ i which allow obtaining the best fit, any suitable software can be used to determine the values ​​of these parameters by iterations, for example the OriginPro ®< software.

[0066] In this simulation, d ∞ corresponds to the thickness at equilibrium after an infinite time, assuming that the applied force F is in the linear deformation range.

[0067] To perform the compression and acquisition of a gel bolus, preferably equal to 1g, a DHR2 rheometer (TA Instruments ®< ) is used for example with a 40 mm wide anodized aluminum pressure plate, with a parallel plate geometry, at a temperature of 25°C.

[0068] On the figure 3We plotted the C curves obtained after adjusting the model parameters. We can see that we obtain a fairly accurate approximation of the thickness evolution by the model, with, for example, an R² regression greater than 0.99.

[0069] Once the parameters have been adjusted, a limit thickness value is obtained in step 4. d ∞ , which can be used in step 5 to calculate the projection index P Idx = d ∞ / d 0 * 100

[0070] The mathematical model is best suited to gels for which the test is carried out in the linear viscoelastic LVER range, but the invention also provides useful information when applied to gels tested outside their linear elastic range.

[0071] In this latter case (excluding LVER), for the simulation and calculation of d ∞ We consider a time period that is not infinite but sufficiently long, for example, greater than 1 hour, preferably greater than 5 hours, preferably greater than 10 hours, more preferably greater than 30 hours, and even more preferably greater than 72 hours. Advantageously, we will consider a time period of less than 7 days, preferably less than 5 days, and more preferably less than 4 days.

[0072] The process may include a verification step to ensure that the filling gel is properly tested within its linear viscoelastic range (LVER).

[0073] To do this, we can determine the values ​​E' and E" by subjecting them to a dynamic mechanical analysis, with an oscillatory mechanical stress in compression evolving in amplitude, for example 0.1 to 10%, 1Hz at 25°C.

[0074] Before implementing step 1, it is possible to verify that the force F applied in the evaluation process is within the LVER range of the gel being evaluated and that the modulus E' is greater than the modulus E'. For the purposes of this invention, the linear LVER range is considered to be the range of deformations from an initial value of elastic modulus E' up to the value of the elastic modulus E' reduced by 10% of its initial value.

[0075] This confirms that among the gels E1 to E5, gels E3 and E4 are not stressed within their linear range for an applied stress of 2N. This corresponds to a rapid collapse on the figure 3 .

[0076] Comparisons of the projection indices of different filling gels can be made, as illustrated in the figure 4 , in order to obtain useful information for selecting the best gels for a given application.

[0077] For example, gel E1 has a projection index of 78%, meaning that it is able to maintain 78% of its initial thickness after an infinite time under the stress of 2N, while gel E5 is able to maintain 47% of its initial thickness.

[0078] On the figure 5 , the projection index values ​​obtained with the invention of commercial hyaluronic acid-based gels known as "volumizers" are compared to the cohesiveness values ​​obtained with the prior art constant velocity compression test of these same gels.

[0079] The legend of commercial hyaluronic acid gels tested at figures 3, 4 And 5 is as follows: E1: RHA 4 (Teoxane), E2: Restylane Volyme (QMED), E3: Restylane Lyft (QMED), E4: Juverderm Voluma (Allergan), E5: Boletero Volume (Merz).

[0080] The exemplified projection index values ​​are measured at 25°C using a DHR2 rheometer equipped with a parallel flat plate geometry (40 mm diameter, anodized aluminum, TA Instruments®) coupled with TRIOS software (TA Instruments®). One gram of gel is applied between the plates, and the gap between these plates corresponds to an initial thickness (dinitial) of 700 µm. A compressive force of 2 Newtons is applied for 1 hour, and the change in gel thickness is recorded. The parameter d ∞ is calculated using OriginPro® software by determining it via the generalized Maxwell model d gel t = d ∞ + ∑ A i . e − t / τ i Or d ∞ is the limiting thickness obtained at equilibrium (after an infinite time for a force within the linear domain of the gel) or after a sufficiently large predefined time (for a force outside the linear domain), A i a constant, Ti a relaxation parameter, the number of members i of the equation is equal to 2.

[0081] The projection index values ​​are then calculated as follows: P Idx % = d ∞ d initial .100

[0082] Cohesiveness was measured at 25°C using a DHR2 rheometer equipped with a parallel flat plate geometry (40 mm diameter, anodized aluminum, TA Instruments®) coupled with TRIOS software (TA Instruments®). Two grams of gel were deposited in the center of the Peltier plate. The initial gap between the plates was set at 2.60 mm, and the gel was then compressed at a constant rate of 100 µm / s. The compressive strength of the gel was measured at the end of the compression cycle, when the gap reached 1.82 mm (70% of the initial gap).

[0083] The E5 gel has a better cohesive value than the E2 gel (9N vs 7N) and has a lower projection index than E2 (47% vs 64%), and will therefore be less suitable in its ability to sustainably maintain its thickness in the layers of the skin and to retain its thickness, including under the stress of facial movements.

[0084] The invention thus makes it possible to predict the behavior of the frost more reliably and accurately in situ than the simple measure of cohesiveness.

[0085] For gels tested within their linear LVER range, PIdx is a direct measure of their ability to maintain their initial thickness under a given compressive stress. For those tested beyond their linear LVER range, PIdx indicates their ability to maintain their thickness over a certain period; theoretically, in an unconfined geometry, these gels would continue to flow, but in reality, the surrounding tissues provide some confinement, blocking gel creep, and thus PIdx remains a useful indicator for predicting gel behavior. in vivo.

[0086] It is possible to implement the method according to the invention to calculate the projection index P Idx for several candidate gels, and to select the one or those with the highest value of P Idx for deep applications, for example.

[0087] P Idx measurement can also be used as an aid in the formulation of a new gel, by adjusting certain manufacturing parameters such as the molar crosslinking rate TR or the amount of polysaccharide, particularly hyaluronic acid, according to the impact of modifying these manufacturing parameters on the P Idx value to iteratively arrive at the best result.

[0088] It is therefore possible to classify gels according to the PIdx value obtained for each of them, or even to perform several evaluations at different respective strengths, corresponding to different intended applications, for example, superficial, mid-surface, and / or deep injection, and to classify gels for each of these applications. The gels are, for example, ranked in ascending or descending order.

[0089] Several candidate gels can be manufactured in small quantities, then evaluated in vitro their projection index by implementing the evaluation process described above, and select a gel based on the evaluation results; the selected gel can then be manufactured in a larger quantity for commercial use.

[0090] We can use the results of measurements of the parameter d ∞ to feed a neural network in order to have a tool to predict the value of d ∞ for different input parameters, and thus to free oneself, once a sufficient amount of data has been collected, from the measurement in vitro.

[0091] This allows for supervised learning of a neural network, where the input during training includes, for example, the concentration values ​​of polysaccharides, particularly hyaluronic acid, the degree of modification (MoD%), the molar crosslinking ratio (TR, G', G"), the phase angle δ (tan δ = G" / G'), the width of the linear viscoelastic domain (LVER), and the limiting thickness value. d ∞ for tested gels.

[0092] Once the network is trained, the same input parameters are provided, namely the polysaccharide concentration values, particularly hyaluronic acid, the degree of modification MoD%, the molar crosslinking ratio TR, G', G", the phase angle δ (tan δ = G'' / G'), the width of the linear viscoelastic domain LVER, and the network outputs a prediction of the limiting thickness value. d ∞ .

[0093] The expression "between" should be understood to include bounds, unless otherwise specified.

Claims

1. Method for evaluating the mechanical performances of a filler gel, comprising the steps consisting in: - 1) subjecting a bolus of this gel, present with a predefined initial thickness d0 between two pressure surfaces, to a predefined compressive force F, - 2) capturing the change in the variation of the thickness of the gel thus compressed over time, - 3) parameterizing a mathematical model approximating the observed change on the basis of the capture performed, - 4) determining, from the model, a limiting thickness d toward which the gel tends to change over time, - 5) generating information relating to the ability of the gel to maintain its thickness in the tissues, in particular a projection index, by comparing the limiting thickness d to the initial thickness d0.

2. Method according to Claim 1, in which the force F is constant or changes cyclically over time around an average value, the force F preferably being constant, the force F preferably being selected between 0.1 and 10 N.

3. Method according to either of the preceding claims, the mathematical model being selected from Maxwell, Kelvin, Kelvin-Voigt and Burgers models, the mathematical model preferably being the generalized Maxwell model for viscoelastic materials, which expresses gel thickness as a function of time in the form: d gel t = d + ∑ A i . e − t / τi where d is the thickness at equilibrium, Ai a constant, τi a relaxation parameter, better still the mathematical model being expressed in the form: d gel t = d + A 1 . e − t / τ 1 + A 2 . e − t / τ 2 4. Method according to any one of the preceding claims, in which a parameter, referred to as the projection index PIdx, expressed in %, defined by the following ratio is calculated d / d 0 * 100 .

5. Method according to any one of the preceding claims, in which the initial thickness d0 is selected between 500 and 1000 microns, preferably between 600 and 900 microns, better still between 600 and 800 microns, being in particular equal to 700 microns, and / or the amount of gel being selected between 0.1 and 10 g, better still between 0.5 and 5 g, even better still between 0.5 and 2 g, being in particular equal to 1 g.

6. Method according to any one of the preceding claims, in which at least two evaluations are carried out at different respective forces F depending on the intended application for the gels, in particular either at a force F of between 1 and 5 N, preferably between 2 and 4 N, or at a force F of between 0.5 and 2 N, preferably between 0.5 and 1 N, or at a force of between 1 and 4 N, preferably between 1 and 2 N.

7. Method according to any one of the preceding claims, comprising the step consisting in determining whether the compression takes place in the linear viscoelastic deformation region (LVER) of the gel; preferably, the step consisting in determining whether the compression takes place in the linear viscoelastic deformation region of the gel being carried out by subjecting the gel to a sweep of compressive oscillatory stresses, preferably covering the range (0.1 to 10%, 1 Hz, at 25°C), and better still comprising the emission of warning information when the force F is not in the linear viscoelastic deformation region and / or when E'<E", E' denoting the modulus of elasticity and E" the loss modulus.

8. Method for classifying a set of filler gels according to their mechanical performance, in which the evaluation method according to any one of the preceding claims is carried out for each of these gels, and the gels are classified according to the result of the measurements, in particular according to projection index values obtained.

9. Method according to any one of the preceding claims, which is carried out using a test bench comprising an automated device having a processor programmed to control the force F and to measure the distance over time between the contact surfaces, and also to parameterize the model, calculate the limiting thickness, and deliver the information relating to the capacity of the gel to retain its thickness.

10. Method according to any one of the preceding claims, in which the projection index is printed or displayed on an information medium, in particular a notice, packaging of the gel, an information or advertising panel, a commercial or medical brochure, a television screen, a laptop computer screen or a mobile telephone screen, or on a screen of an automated device.

11. Method according to any one of the preceding claims, in which the filler gel is a gel based on a hyaluronic acid and / or salts thereof.

12. Method according to any one of the preceding claims, in which the force F is applied between a fixed plate and a movable plate which is moved towards the fixed plate, this movable plate preferably applying a fixed force F.

13. Method for selecting a filler gel, in which the evaluation method according to any one of Claims 1 to 7 for a set of filler gels to be tested is carried out, and the gel is selected according to at least the results of the evaluation, in particular projection index values, a projection index value preferably being used to distinguish between gels for which the compression test results are close.

14. Method for manufacturing a filler gel, in which a candidate gel is manufactured in a small amount, and its projection index is then evaluated by carrying out the evaluation method according to any one of Claims 1 to 7, and the gel is manufactured in an amount greater than that of the candidate gel, at least if the projection index exceeds a predefined threshold.

15. Method for manufacturing a filler gel, in which several candidate gels are manufactured in a small amount, and their projection index is then evaluated by carrying out the evaluation method according to any one of Claims 1 to 7, a gel is selected on the basis of the evaluation results, and the selected gel is manufactured in an amount greater than that of the candidate gel.

16. Method for supervised learning of a neural network, in which the polysaccharide concentration values, in particular the hyaluronic acid concentration values, the degree of modification MoD%, the degree of molar crosslinking DC, G', G", the phase angle δ (tan δ = G" / G'), the width of the linear viscoelastic region LVER and also the value of the limiting thickness d are provided as input for gels tested by carrying out the evaluation method according to any one of Claims 1 to 7, and the network is trained to deliver as output the value of the limiting thickness d .