Thomas Potentier
email: thomas.potentier@ec-nantes.fr

Emmanuel Guilmineau

Arthur Finez

Colin Le Bourdat

Caroline Braud

High-Reynolds-number wind turbine blade equipped with root spoilers -Part 2: Impact on energy production and turbine lifetime

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Introduction

Thanks to a steady rotor size increase over the last decades, the wind energy sector managed to grow. In the onshore wind sector, due to various limitations, the rotor diameter remains constrained, but blades over 60 m long are now common. Larger blades require more attention to detail during the design phase to reduce the cost. The maintenance cost during the turbine lifetime increases too, and a good understanding of the turbine ageing is necessary.

In order to reduce the levellized cost of energy (LCOE), turbine manufacturers had to imagine solutions to increase the energy output of existing turbines. Among such solutions, there are aerodynamic add-ons (AAOs), which are mostly passive devices attached to the blade surface to either lower the acoustic emission or increase the power extraction locally.

With the increasing rotor diameter and hub height, turbine manufacturers are now facing aeroelastic challenges where tower and blades can deform over large distances. Before several extensive measurement campaigns of scaled models in large wind tunnels or in the field were performed (see [START_REF] Hand | Unsteady Aerodynamics Experiment Phase VI: Wind Tunnel Test Configurations and Available Data Campaigns[END_REF][START_REF] Simms | NREL Unsteady Aerodynamics Experiment in the NASA-Ames Wind Tunnel: A Comparison of Predictions to Measurements[END_REF]Snel et al., 2007;Boorsma and Schepers, 2014;[START_REF] Madsen | The DAN-AERO MW Experiments: Final report[END_REF][START_REF] Trodborg | DANAERO MW II Final Report[END_REF], the physical phenomenon of wind loading unsteadiness was poorly understood and large safety factors were used to ensure the turbine robustness and design lifetime. High-fidelity tools such as computational fluid dynamics (CFD) could perform that task, but the computational cost would render the turbine's time to market too important. In another hand, turbine designers using quicker engineering tools such as blade element momentum (BEM) lacked, at first, the necessary unsteady models. Now, it is common knowledge to be using unsteady models to simulate wind turbines, and it is referenced in many textbooks [START_REF] Hansen | Aerodynamics of Wind Turbines[END_REF][START_REF] Burton | Wind energy: handbook[END_REF]. The large-scale unsteadiness investigated showed that the atmospheric boundary layer, turbulent wind, yawed inflow or even blade pitching can have a serious impact on the turbine if not properly accounted for, as found in [START_REF] Potentier | Analysis of the DANAERO wind turbine field database to assess the importance of different state-of-the-art blade element momentum (BEM) correction models[END_REF]. One of the remaining challenges to predict the turbine loads even more accurately is to account for the local unsteadiness, self generated by the flow travel-ling around an aerofoil, which can interact with large-scale unsteadiness. As detailed in Potentier et al. (2022), where thick blade profiles equipped with blade root AAO were studied with 2D CFD with low-turbulence-intensity free-stream conditions, the spoiler produces the desired higher lift by reorganizing the flow and pressure distribution around the aerofoil. In consequence the unsteady behaviour (vortex shedding) behind the aerofoil is vastly different from the bare blade.

ENGIE Green is a French exploiting party of renewable energy sources. During routine maintenance, some cracks have been noted at the blade root near the spoiler installation. The present paper aims at understanding the aerodynamic causes of the structural failure, using state-of-the-art calculation methods and proposing a novel way of predicting the impact of spoiler on the blade structure lifetime. The AEP gain will also be evaluated. Because performing fatigue calculation using CFD would be too computationally expensive, and BEM cannot directly account for aerodynamic unsteadiness, in this paper we propose bridging the gap by utilizing the strengths of both simulation methods. First the methodology to build the aeroelastic model is explained in Sect. 2. The use of 2D CFD associated with aeroelastic BEM simulation will allow us to compare between the two configurations the aerodynamic parameters such as lift coefficient (C L ), axial induction (a), rotor loads, power and energy production (Sect. 3.1). A novel way of accounting for polar unsteadiness in the fatigue lifetime calculation is proposed in Section 3.2. A validation using 3D CFD, for a single wind speed, is currently being done to assess the vortex shedding behaviour on the rotor.

Methodology

Wind turbine blade and aerofoil shape

The wind turbine geometry used in the present study was acquired during a scanning campaign on an operating 2 MW turbine (see [START_REF] Dambrine | Impact of Blade Aging on Wind Turbine Production[END_REF]; the rotor diameter is 92 m and the maximum height reach is 150 m above ground. During the scan post-treatment the chord, twist and thickness were also extracted, defining the blade geometry (see Fig. 2). One can note the typical "de-twist" toward the blade tip to alleviate the blade loading. The blade geometry is discretized more densely at the root of the blade since the spoiler is installed at this location. More details about the scan posttreatment are available in Potentier et al. (2022). The scanned blade was originally equipped with root spoilers. The blade without spoiler was generated by manually removing parts of the cloud points corresponding to the spoiler location; consequently wherever the spoiler is not present both aerofoils geometries are identical (see Fig. 1). For the rest of the study, the simulations will take place on the real scale, i.e. using the scan outputs as blade geometry.

Unsteady aerodynamic BEM inputs

The tools used to perform the spoiler impact assessment are CFD for the polar generation and blade element momentum (BEM) theory for the aerodynamic calculations. BEM is used to calculate associated loads and compute the turbine annual energy production (AEP). The BEM solver used is the AeroDyn module (see [START_REF] Jonkman | AeroDyn v15 User's Guide and Theory Manual[END_REF] from Open-FAST (https://openfast.readthedocs.io/en/main/website, last access: 8 November 2021). OpenFAST can produce a large variety of sensors, which are calculated outputs during the simulation.

AeroDyn is a well-known tool developed by NREL and has been used in many international or academic projects. A thorough explanation of the BEM theory is available in textbooks such as [START_REF] Hansen | Aerodynamics of Wind Turbines[END_REF] or [START_REF] Burton | Wind energy: handbook[END_REF]. A brief step-by-step approach written below summarizes the iterative BEM procedure. 2. Then, the inflow angle ϕ is estimated from the instantaneous velocity inflow V w , the rotor rotational speed ω and the local radius r.

3. The angle of attack, α, is computed using the blade element theory (BET) with θ the local twist angle and β the blade pitch angle. 6. To account for the finite blade span, the Prandtl tip correction factor is calculated.

7. The initial induction coefficients, a and a , are updated accounting for highly loaded rotors.

8. The unsteady BEM equations can be applied: yaw models, dynamic wake model, blade acceleration due to its deflection and tower shadow effect. 9. A convergence criterion, , is defined, and the iteration process restarts from step 2, using the updated induction values, until the convergence criterion is reached.

10. After convergence, the local loads (aerofoil level) can be calculated.

11. Once all elements are converged, the integrated loads (rotor and turbine level) can be computed.

The procedure described relies on steady polar to perform the iterative steps; it is an inherent BEM limitation. However, as highlighted in Potentier et al. (2022), aerodynamic properties become highly unsteady at the blade root when a spoiler is present. To overcome the single steady polar limitation and use the unsteady coefficient, we decided to generate three steady polars corresponding to the mean, minimum and maximum C L , C D and C M for each turbine case: "no spoiler" and "spoiler" (see Table 1). Those mean, minimum and maximum coefficients are representative of the states reached by the aerodynamic coefficients during the time series calculated using 2D CFD as found in Potentier et al. (2022) (see e.g. Fig. 3).

Turbine structure scaling

The scan does not give any information on the blade's material, since only the outer skin was measured. Material properties are a crucial element for turbine design, and as part of an academic or wind turbine exploiting party, we do not have access to this information. Therefore, for the rest of the aeroelastic study, the blade and tower mechanical properties will be scaled using the open-source NREL 5 MW turbine (see [START_REF] Jonkman | Definition of a 5-MW Reference Wind Turbine for Offshore System Development[END_REF]. Some hypotheses and assumptions had to be made and will be explained below. Usually, scaling is made to reach the same level of stress or reach similarity in physical phenomena: Mach number, Reynolds number and Froude number (see [START_REF] Campagnolo | Wind Tunnel Testing Of Scaled Wind Turbine Models: Aerodynamics And Beyond[END_REF]. Here, since the stress target values are unknown and the physics similarity is already achieved (Mach, Reynolds and Froude numbers close enough between the NREL turbine and the ENGIE Green turbine), we decided to scale the turbine based on geometric properties. The NREL turbine has a 63 m long blade and its tower is 87.6 m high. In comparison the ENGIE Green turbine has a blade length of 45 m and the tower height is 80 m. Several scaling procedures exist and have been described in [START_REF] Loth | Gravo-Aeroelastically Scaling for Extreme-Scale Wind Turbines[END_REF] and Canet et al. (2021). The authors aimed at creating a sub-scale model for wind tunnel or field testing, where the difference between both models is large (reduction factor up to 90). In our case, we desired to use known mechanical properties and adjust them based on the smaller blade and tower length, so that the ENGIE Green turbine behaves similarly to the NREL one. Therefore, the method used varies slightly compared to the literature and is described below. The blade structural properties needed are the edgewise and flapwise local stiffnesses along the radius: EI xx and https://doi.org/10.5194/wes-7-1771-2022

Wind Energ. Sci., 7, 1771-1790, 2022 EI yy , as well as the linear mass M L . E is the Young modulus while I xx and I yy are respectively the in-plane and out-ofplane sectional moment of inertia. Assuming identical material is used to manufacture both blades, only the sectional inertiae I xx and I yy vary. Since the sectional inertia varies based on geometric properties, we decided to use the chord as the main driver for the change in properties. The thickness could also have been chosen, but the chord was preferred because of its larger absolute value. Also, the edgewise stiffness could have been scaled based on the chord thickness and thickness for the flapwise stiffness. It was decided to only use the chord as a basis for the scaling for simplicity. Further studies could be done to assess the validity of the assumption.

In our geometric scaling we multiply the NREL 5 MW stiffnesses EI xx and EI yy by the ratio of the local chord along the radius to the power of 4 (see Eq. 1), thanks to dimensional analysis. Following the same reasoning, we assume an identical material, and the NREL 5 MW linear mass needs to be multiplied by the chord ratio at the power of 1 (see Eq. 2).

The same methodology is applied to the tower stiffnesses and mass.

EI EG xx j = EI NREL xx j × c NREL r/R j c EG r/R j 4 EI EG yy j = EI NREL yy j × c NREL r/R j c EG r/R j 4 (1)
Here, E is the material Young modulus, I EG

M EG L j = M NREL L j × c NREL r/R j c EG r/R j , (2)
where M EG L j and M NREL L j are the linear mass of both blades and the subscript j shows the analysed station.

Moreover, the blade and tower modal shapes, necessary OpenFAST inputs, have been recalculated using the scaled mechanical properties. A Campbell diagram illustrates that despite the difference in length and mass, both turbines behave similarly, as desired (see Fig. 4). All ENGIE Green blade modes follow the NREL baseline turbine trend with a little offset due to the shorter blade. Regarding the tower, the first modes (fore-aft and side-to-side) are identical between both turbines; only the second modes show a clear offset towards the highest frequencies.

A final sanity check was performed on the mass to assess the validity of the scaling. The blade and tower mass where respectively 0.6 % and 1.3 % off compared to the manufacturer's design specifications, which is small enough to be acceptable. Figures 5 and6 show the mechanical property comparison with the original NREL 5 MW turbine. Finally, the turbine characteristics publicly available and necessary for OpenFAST are gathered (see Appendix A).

Unsteady polar generation

The grid independence study and polar generation methodology have already been performed and presented in Potentier et al. (2022). Then, all 16 profiles listed in Table 2 were computed to extract aerofoil aerodynamic coefficients (lift, drag and moment coefficients) for OpenFAST computations. Thus producing six different steady polars for the turbine (see Table 1). Figures 7 and8 show representative sections for the lift and drag coefficient along the blade span. The solid lines show the mean aerodynamic coefficient values, while the shaded areas illustrate the range of variation reached during each angle of attack calculation. Consequently, the polar using the maximum aerodynamic coefficients corresponds to the upper limit, and the polar using the minimum aerodynamic coefficient follows the lower limit.

Initial BEM simulations showed that high angles of attack can be reached (α > 50 • ) for the inner sections; for this reason the inboard section polars have been simulated up to α = 60 • . Each polar has then been extrapolated using the Viterna extrapolation method from [START_REF] Viterna | Theoretical and experimental power from large horizontal-axis wind turbines[END_REF] to cover the full 360 • range (-180 ≤ α ≤ 180). Then, to account for the rotational effects, the 3D correction model derived by Chaviaropoulos was used (see [START_REF] Chaviaropoulos | Investigating Three-Dimensional and Rotational Effects on Wind Turbine Blades by Means of a Quasi-3D Navier-Stokes Solver[END_REF].

BEM simulation set-up

The following sections will detail the model set-up used during the aeroelastic simulations. The first goal of the present paper is to determine the maximum aerodynamic potential of spoilers compared to a bare blade, free of any constraints. A second goal is to assess the impact of the spoiler, on the turbine lifetime, when running at maximum power extraction.

Pitch settings for maximal power production

The pitch settings for maximum power extraction are unknown. The turbine manufacturers may not recommend maximum power generation pitch settings due to potential noise, stall or load issues. Therefore, using SCADA measurements is not sufficient, and an optimization study is necessary. In order to reduce the optimization space to only a single varihttps://doi.org/10.5194/wes-7-1771-2022

Wind Energ. Sci., 7, 1771-1790, 2022 able (the pitch settings), we assume that the turbine's rotational speed available thanks to averaged field measurements is optimized and will not vary. Then, a search for the optimum pitch settings was carried out for each wind speed between cut-in (3 m s -1 ) and cut-out (20 m s -1 ), by increments of 0.5 m s -1 , and for each turbine configuration (see Table 1). The optimization constraints are described as follows: below rated wind speed (here 10.5 m s -1 ), the power production has to be maximal, whilst from rated wind speed until cut-out the turbine must regulate the generated power in order to maintain rated power (here 2.05 MW). A sweep of pitch settings for a range between -10 and 10 • below rated and between 0 and 20 • above rated was tried. Figure 9 shows the outcome of the trials for the turbine with spoiler using the mean aerodynamic coefficient polar: the response surface of the optimization procedure. The black line shows the optimal pitch settings for maximal power production. Table 3 shows that the blade with spoiler needs a higher pitch to achieve rated power, thus reducing the angle of attack. Figure 10 shows the outcome of the study for all configurations tested. As can be seen, the difference between both the no spoiler and spoiler is small. Power surface response with varying pitch settings for different wind speeds for the spoiler case using mean aerodynamic polar. The black dotted line is the turbine's optimal pitch settings for maximum power generation.

Rigid turbine simulations

In the first analysis, the turbine is considered rigid (i.e. not flexible) with the hub height 80 m above ground using the standalone AeroDyn module. The aerofoils associated with the CFD-calculated polars precisely define the blade dis-

U (Z) = U × Z H H κ , (3)
where U (Z) is wind speed distribution along the vertical direction, U is the reference wind speed at a hub height, Z is the height varying between the ground and the top of the turbine, H H is the hub height, and κ is the wind shear exponent (here 0.2). The air density in the BEM calculations is considered constant in space and time and is equal to the one used for the CFD polar calculation (ρ = 1.225).

Flexible turbine simulations

The second analysis is a fully flexible turbine with turbulent wind using OpenFAST. The tool TurbSim (see [START_REF] Jonkman | TurbSim User's Guide[END_REF]

Results

After running all the turbine configurations, a deep aerodynamic analysis is possible as many sensor outputs are available. For brevity reasons only a small sample of all the available results will be presented. The multiple polar "states" (mean, maxi, mini) allow assessment of the variation around the mean value, giving a measure of unsteadiness. First, the rigid turbine loads, power and AEP are analysed. Secondly, the flexible turbine fatigue impact is analysed.

Rigid turbine

In Figs. 11 to 13, the x axis represents the blade radius, the yaxis represents the considered sensor output and each subplot represents a wind speed whose value is given in the title, from 6 to 11 m s -1 .

Aerodynamic parameters

The lift coefficient of the no-spoiler case shows very low values inboard, as expected from very thick aerofoils. After the radial position R7.2 ( r R = 16 %), both curves merge, describing the end of the spoiler effect. For the spoiler case, the mean C L increases to relatively high values, especially for such in- board sections, (C spoiler L mean ≈ 1). However, the associated variation increases drastically. Indeed, the variation for the nospoiler case was C no spoiler L mean ± 0.3 while in the spoiler case the variation is close to C spoiler L mean ± 1 (see Fig. 11). A similar outcome is seen for the drag coefficient (not shown here). The large variation in C L is a consequence of the polar unsteadiness.

The axial induction, a, is a key aerodynamic metric for turbine analysis. Through this parameter it is possible to have information about the sectional energy extraction and the sectional turbine loading. The energy extraction is at its maximum when a = 1 3 , according to the Betz limit, and the loads increase significantly beyond a = 0.4 following the highly loaded rotor relationship (Glauert correction). Therefore, most turbine manufacturers aim for an induction factor value close to the optimal a = 1 3 , when in power production mode. After the pitch optimization, the turbine runs close to optimal axial induction for the outer part of the blade.

The no-spoiler case show very low induction values at the root of the blade due to the cylinder shape: low lift coefficient and high drag values. The blade's inboard is not efficient to extract energy but the expected load level is consequently low. Where the spoiler is installed the induction increases, and similarly to the lift coefficient the upper band of the variation due to the polar unsteadiness is close to the optimal induction. The average induction level at the spoiler location is close to a = 0.2, which is a significant improvement compared to the no-spoiler case where the induction level is close to 0 (see Fig. 12). The relative variation area is similar compared to the lift coefficient: a spoiler mean ± 0.1 and still a lot larger than the no-spoiler case.

Interestingly, for 6, 7 and 8 m s -1 , the axial induction after the radial position R10 is lower for the spoiler than for the no-spoiler case. This is due to the pitch optimization. The objective function was to maximize power and not try to reach optimal induction. The best trade-off between the spoiler power generation and the blade outboard power generation is when the blade outboard is not at its optimal point to allow for the blade inboard to play a more important role. It also means that the blade tip is slightly less loaded, as can be seen in Sect. 3.1.2. However, the axial induction is still very close to its optimal value (a = 0.3).

Aerodynamic static loads

The local out-of-plane force (F X ) is calculated, and its evolution against the radius for several wind speeds is shown in Fig. 13. Through the momentum theory and the axial induction, F X is directly proportional to the power production. The bare blade design intent showed very low normal forces at blade root level with an almost constant increase along the span past R10. After the spoiler installation the local force increases significantly, despite being significantly lower than the outer part of the blade. Due to the different pitch settings between both blades, the spoiler case shows a slightly lower force towards the blade tip.

Integrated load: root bending moment

The previous figures showed the results at the aerofoil level, and the next phase of the analysis will focus on the integrated values.

https://doi.org/10.5194/wes-7-1771-2022

Wind Energ. Sci., 7, 1771-1790, 2022 The flapwise root bending moment (RBM) is a critical parameter for blade design and is directly linked to F X through Eq. ( 4):

RBM = R 0 r × F X (r)dr, ( 4
)
where F X (r) is the local out-of-plane force and r the local radius considered.

The unsteadiness caused by the spoiler does not seem to be reflected at rotor level, and the coloured area around the mean value is almost nonexistent. Also, because the change is very small, both curves seem overlapped in Fig. 14. The vertical bars show the difference between the mean RBM values for the spoiler and no-spoiler case. Except around 5 m s -1 , the use of a spoiler tends to decrease the RBM slightly (righthand side vertical axis).

The lower RBM value in the spoiler case is explained thanks to the pitch settings, and the same explanation as for the out-of-plane force F X holds for the RBM. The spoiler case pitch settings are less "aggressive" due to the higher power produced thanks to the blade inboard. The blade outboard, where most of the power is generated, experiences a lesser angle of attack than the no-spoiler case. Therefore, the local load generated by the outer part of the blade is smaller in the no-spoiler case than in the spoiler case. After the integration, performed using Eq. ( 4), the RBM no spoiler is higher than RBM spoiler .

Power curve and energy production

The mean power curves for the no-spoiler and spoiler configuration can be plotted (see Fig. 15). Both curves are very close to each other; the vertical bars shows that the spoiler does produce more energy on average, albeit a small amount (power difference on the right-hand axis). The error bars show the variation in power due to the different polar states used; i.e. the top of the error bar is the power difference between the spoiler and the no-spoiler case using the maximum aerodynamic coefficient polar. It is to be noted that, interestingly, the power gain of approximately 1 %, for wind speeds up to up to 8 m s -1 , is similar to the C L gain thanks to the spoiler presented in Fig. 11. Closer to rated power, the power gain reduces.

After integrating the mean power curves over a year simulating a wind site condition IEC class II (Weibull shape factor = 0.2 and average wind speed = 8.5 m s -1 ), the AEP impact can be seen in the Table 4. On average, the spoiler produces 0.49 % AEP more than the no-spoiler case, assuming maximum power extraction settings.

Turbine unsteadiness definition

When using BEM, one cannot use a time-varying description of each angle of attack during the iterative procedure. Using several steady-state polars representing the different possible aerodynamic coefficients allowed for a first estimation of the variation due to the unsteadiness. Analysing the loads or the different aerodynamic metrics (such as presented in Sect. 3.1.1 and 3.1.2) using three different polar states independently is acceptable because the data represent instantaneous "snapshot" values. However, to integrate the results in time, to calculate the mean thrust or the AEP, this assumption cannot hold. Indeed, assuming that the aerodynamic coefficient time variation is periodic, as illustrated in Fig. 3, then after integration all oscillations cancel out. Therefore, the unsteadiness caused by the spoiler on time-integrated quantities cannot be assessed. For this reason, the following method has been applied to give a measure of the variation caused by the spoiler, using the AEP as an example.

The total variation in power for each wind speed is found by P WS = P WS max -P WS min . Then, knowing the Weibull site characterization it is possible to calculate the probability of each wind speed occurring over a year: pr(WS). Combining both, the weighted Weibull average total variation around the mean value is found (see Eq. 5).

δP = WS=20 WS=3 P WS × pr(WS), ( 5
)
where δP is the Weibull weighted average power variation, P WS is the power range over a wind speed, WS is the conhttps://doi.org/10.5194/wes-7-1771-2022 Wind Energ. Sci., 7, 1771-1790, 2022 sidered wind speed and pr(WS) is the wind speed occurrence probability.

Table 5 shows that the spoiler addition increases the inherent variation around the mean value for the AEP.

Figure 16 gives more details about the AEP variation than Table 5, which gives the overview. The central symbol represents the AEP calculated using the mean aerodynamic coefficient polar. The error bars represent the AEP calculated when using the minimum and maximum aerodynamic coefficient polar as explained in Table 1. Comparing each configuration (black lines), the AEP gain using mean aerodynamic coefficients polar is 0.49 %, the AEP gain using minimum aerodynamic coefficients polar is 0.17 % and the AEP gain using maximum aerodynamic coefficients polar is 0.68 %. Within each configuration (blue and orange arrows) the overall variation due to the unsteadiness also changes: the spoiler increases the variation in the AEP calculation. The AEP variation is ±0.4 % in the spoiler case, while in the no-spoiler case, the variation is approximately halved (+0.23 % and -0.09 %).

One should note that performing AEP calculation should "smooth out" any variation due to the polar unsteadiness since the power is integrated over a year. Nevertheless, we have chosen to treat each result for each polar state independently in order to define boundaries for the spoiler's poten-tial. The gains presented assume a single turbine operating at maximum power production, as detailed in Sect. 2.5.1, which is unrealistic. Consequently, the actual expected gains will be smaller.

Flexible turbine

As seen in the previous sections, the rigid modelling shows little AEP benefit of installing the spoiler. However, due to the large increase in the mean local loads and its associated variation introduced by the spoiler, it seems interesting to investigate the damage and fatigue on the turbine. The aeroelastic calculations will be performed by OpenFAST with a fully flexible turbine. The fatigue analysis will focus on the blade only but can be extended to the whole turbine.

Combination method

A method to account for unsteadiness on a rigid turbine has been presented in Sect. 3.1.4, but it can only simulate integrated load. In order to further analyse the spoiler unsteadiness, impact fatigue analysis is necessary. However, the same BEM limitations arise. Here again, we chose to calculate each configuration (no spoiler and spoiler) using the three polars for each wind speed (from 3 to 20 m s -1 ). Then, thanks to a previously calculated vortex shedding frequency (VSF) for each aerofoil section, a new time series is generated, as detailed below.

Vortex shedding frequency (VSF)

In Potentier et al. (2022), the authors showed that a VSF can easily be found for a single aerofoil at a single angle of attack using 2D CFD velocity (or load) time series. Applying the same methodology for all aerofoils and for all angles of attack, 2D CFD load time series were post processed, thereby creating a database of VSF (see Fig. 17). Using the BEM hypothesis of 2D flow, we assume that neither the blade rotation nor the blade deflection change the VSF. Moreover, the turbulent wind speed frequency spectrum is independent from the VSF, and we can therefore perform the interpolation in the time domain between time series rather than in the frequency domain.

Because of the sampling theorem, the OpenFAST sampling output rate must be at least 2 times higher than the highest VSF. The highest calculated VSF of all sections is approximately 60 Hz. To add safety margin, the OpenFAST output is set to be at 160 Hz, which is equivalent to a time step of t OF = 0.0063 s.

New OpenFAST time series creation

Once all aeroelastic results are available (Fig. 18), a mean VSF (VSF mean ) is determined by interpolating at the mean angle of attack of the mean time series result of the VSF (blue square in Fig. 17). Inverting it leads to a representative time step for the considered wind speed t = 1 VSF mean . Then, the original results calculated using maximum, mean or minimum polars are interpolated at new time steps using t (Fig. 19).

An intermediate time series is generated, for each sensor. Again, supposing a periodic variation in the lift and drag coefficients, we assume that the first aerodynamic coefficient "seen" by the aerofoil is from the maximum polar, and it then changes to the mean polar and finally the minimum polar and https://doi.org/10.5194/wes-7-1771-2022

Wind Energ. Sci., 7, 1771-1790, 2022 varies following this cycle for 600 s. Such behaviour leads to the creation of the pink curve in Fig. 20. One final numerical manipulation is necessary because all intermediate time series created possess different VSF and therefore different t values by re-sampling them at the same OpenFAST sampling rate ( t OF = 0.0063 s). Because the turbulent wind speed frequency spectrum is independent of the VSF, we can perform the interpolation in the time domain rather than in the frequency domain. We thus ensure possible further analysis (Fig. 21).

This method is repeated for each radial position, each wind speed and all local loads. The results presented in the next sections use the data generated by this method.

Normal force results

Figure 22 shows the force normal to the rotor plane (F X ) for a 600 s long OpenFAST simulation with an average horizon-tal wind speed of 8 m s -1 (hub height). Each subplot shows a radial location, from R = 3.6 to R = 7.5 (from r R = 8 % to r R = 16.7 %), and the horizontal axis shows the time spent in the simulation. F X is clearly higher in the spoiler case regardless of the spanwise location. Figure 23 compares the power spectral density (PSD) for the spoiler case using either the mean aerodynamic polar results or the combination method results. At low frequencies the PSDs are overlapped, since the same turbulent wind speed was used in all aeroelastic simulations. However after the VSF mean is reached, the combination method shows clear peaks and harmonics. The curve trend also shows the same downward behaviour at higher frequencies. The higher energy in the spectrum for the combination method hints at higher fatigue loads for the combination method than using the OpenFAST results directly. OpenFAST output normal force to the rotor plane for an average horizontal wind speed of 8 m s -1 (hub height). The blue square (blue ) shows the blade results without spoiler using the combination method, and the orange dot (orange •) shows the blade results with spoiler using the combination method. Each subplot shows the results for a radial location (m) whose value is given in the title.

Fatigue results

After running in OpenFAST all wind speeds for both turbine configurations and generating the new time series as described in Sect. 3.2.1, it is possible to determine the lifetime impact of the spoiler and its associated unsteadiness on the turbine. The tool used is Mlife, also developed by NREL (see [START_REF] Hayman | Mlife user's guide[END_REF]. Similarly to the AEP calculation, we assume that the generated OpenFAST outputs follow a Weibull distribution of an IEC site B (shape factor = 2 and average wind speed = 8.5 m s -1 ).

The method developed can only account for sectional loads since it relies on vortex shedding frequency. The integrated load such as RBM cannot be associated with any particular VSF.

In order to calculate the blade lifetime with the predefined pitch and RPM settings, an ultimate load before rupture for each analysed sensor must be given. Since the material properties are unknown, we used MExtreme (see [START_REF] Hayman | MExtreme User's Guide[END_REF] to extract the highest sectional loads of interest (here F X and F Y ) seen by the turbine of both cases as first approximation. To assess the evolution of lifetime with respect to the https://doi.org/10.5194/wes-7-1771-2022

Wind Energ. Sci., 7, 1771-1790, 2022 of the analysis (see Appendix B). The Wöhler exponent was kept constant throughout the study to a representative wind turbine blade material: m = 10 (see [START_REF] Lloyd | Guideline for the Certification of Wind Turbine[END_REF].

Because of the different hypotheses taken, we are only analysing trends and not presenting the direct Mlife results. Therefore a life index (L i ) is created by normalizing the outputs of the no-spoiler case to create a baseline; i.e. for each sensor L no-spoiler i = 1. Then the spoiler case results are normalized by the previously created baseline. Table 6 summarizes the outcome of the fatigue calculation. The second column shows the life index impact of the considered sensor when adding a spoiler. Here, L i is the life index of the no-spoiler or spoiler case, and j is the section considered.

As suspected in Sect. 3.1.2, all local forces see a negative impact after installing the spoilers, and L spoiler i < L no spoiler i indicates that this specific section will fail before the nospoiler turbine. Despite the hypotheses and assumptions, the method employed captures the negative impact of the spoiler on the local sections well, which is in line with the blade failures (cracks), seen at the spoiler's end in the field by the ENGIE Green maintenance team. It is to be noted that BEM aeroelastic simulations can model neither the spoiler's glue joint nor the internal elements of the blade (such as spar or web). A dedicated finite element analysis (FEA) would be The authors built an aeroelastic BEM model for a commercial 2 MW turbine retrofitted with root spoilers using a 3D blade scan. The turbine was chosen to address a maintenance problem where blades cracked after installing the spoilers. Regarding the AEP gain and rotor integrated load, the spoiler impact is marginal. The AEP increases by a small amount (≈ 0.5 %) with a large variation associated. So far, all the efforts made to measure the AEP in the field led to inconclusive results due to the small absolute difference and large dispersion in the power curve measuring method. The integrated loads remain approximately constant, and a small decrease in flapwise root bending moment has even been noted. However, the local loads increase significantly with a large variation around the mean value.

A fatigue analysis has been performed using a novel way of capturing the aerodynamic unsteadiness due to the aerofoil's behaviour. It uses 2D CFD flow characteristics (vortex shedding frequency) as well as the results calculated from three different steady polars (maximum, mean and minimum aerodynamic coefficients). The spoiler increases the already locally present unsteadiness and should not be neglected in the turbine's structural design. The spoiler can be detrimental to the turbine lifetime: retrofitting such devices should be done with care, and the turbine's mechanical properties should be re-evaluated prior to installing the spoiler.

A similar conclusion could be drawn for other aerodynamic add-ons generating a similar amount of unsteadiness; however dedicated studies would be necessary. Also, more studies would be required to quantify the impact height and chordwise position of the spoiler.

Finally, the presented method currently relies on 2D assumptions and BEM calculations, and further studies involving 3D CFD are being carried out to assess the vortex shedding behaviour on a rotor.

Figure 1 .

 1 Figure 1. Overimposed aerofoil shapes at radial position R6 ( r R = 13 %): the blue square (blue ) shows the no-spoiler coordinates while the orange dot (orange •) shows the spoiler coordinates.

Figure 2 .

 2 Figure 2. The scanned blade geometry: chord, twist and relative thickness distribution against the normalized radius.

  1. The axial induction factor a and the tangential induction factor a are first estimated (typically a = a = 0) only during the first loop. For the following loops the induc-Wind Energ. Sci., 7, 1771-1790, 2022 https://doi.org/10.5194/wes-7-1771-2022 tion values used are those from the previous iteration (see step 7).

4.

  Read the C L , C D (drag coefficient) and C M (moment coefficient around the one-fourth chord position) from the polar associated with the analysed radius. 5. Calculate the loads in the rotor plane using C L , C D and ϕ.

Figure 3 .

 3 Figure 3. Spoiler case C L evolution in time α = 6 • and Re c = 3 × 10 6 . The blue triangle (blue ) corresponds to the minimum C L , the red square (red ) corresponds to the maximum C L and the orange dot (orange •) corresponds to the mean C L .

Figure 4 .

 4 Figure 4. Campbell diagram comparison between the NREL reference turbine and the ENGIE Green scaled one. The solid lines show the NREL response, and the dashed lines show the ENGIE Green turbine's response. The dark shaded area illustrates the ENGIE Green's turbine range of operation.

  xx and I EG yy are the ENGIE Green blade local inertiae, and I NREL xx and I NREL yy are the NREL's 5 MW turbine initial local inertiae. c NREL r/R and c EG r/R are the NREL's 5 MW and ENGIE Green's blade chords at the same spanwise location, and the subscript j shows the analysed station.

Figure 5 .

 5 Figure 5. Blade stiffness properties. The blue lines (blue -) show the scaled blade and the orange lines (orange -) the original NREL 5 MW blade properties. The symbols and show the different stiffness directions.

Figure 6 .

 6 Figure 6. Tower stiffness properties. The blue lines (blue -) show the scaled tower and the orange lines (orange -) the original NREL 5 MW tower properties. Because fore-aft and side-to-side stiffnesses are identical only a single curve per tower is shown.

Figure 7 .

 7 Figure 7. The blue dot (blue •) shows the C L for a representative root section without spoiler, the orange triangle (orange ) shows the C L for a representative root section with spoiler, the purple square (violet ) shows the C L for a representative middle section and the cyan diamond (cyan ) shows the C L for a representative tip section. The shaded areas illustrate the range of variation (maximum and minimum) reached during each angle of attack calculation. The plotted polars have not been corrected with a rotational model.

Figure 8 .

 8 Figure 8. The blue dot (blue •) shows the C D for a representative root section without spoiler, the orange triangle (orange ) shows the C D for a representative root section with spoiler, the purple square (violet ) shows the C D for a representative middle section and the cyan diamond (cyan ) shows the C D for a representative tip section. The shaded areas illustrate the range of variation (maximum and minimum) reached during each angle of attack calculation. The plotted polars have not been corrected with a rotational model.

Figure 9 .

 9 Figure9. Power surface response with varying pitch settings for different wind speeds for the spoiler case using mean aerodynamic polar. The black dotted line is the turbine's optimal pitch settings for maximum power generation.

  developed by NREL is used to generate 10 min long three-dimensional turbulent wind fields for each wind speed. The box representing the wind field is 150 m wide and high subdivided in 50 points and 600 s long. The IEC Kaimal model is used as the spectral model thanks to the directly available IEC class requirements (here IEC class II chosen). The underlying assumption is that the atmospheric conditions are considered neutral following the Monin-Obukhov similarity theory as detailed in Wharton https://doi.org/10.5194/wes-7-1771-2022 Wind Energ. Sci., 7, 1771-1790, 2022

Figure 10 .

 10 Figure 10. The blue square (blue ) shows the pitch evolution with respect to the wind speed without spoiler, and the orange dot (orange •) shows the pitch with respect to the wind speed with spoiler.

Figure 11 .

 11 Figure 11. The blue square (blue ) shows the C L evolution along the blade radius without spoiler, and the orange dot (orange •) shows the C L evolution along the blade radius with spoiler. Each subplot shows the results for a wind speed (m s -1 ) whose value is given in the title.

Figure 12 .

 12 Figure 12. The blue square (blue ) shows the a evolution along the blade radius without spoiler, and the orange dot (orange •) shows the a evolution along the blade radius with spoiler. Each subplot shows the results for a wind speed (m s -1 ) whose value is given in the title.

Figure 13 .

 13 Figure13. The blue square (blue ) shows the force normal to the rotor plane evolution along the blade radius without spoiler, and the orange dot (orange •) shows the normal force to the rotor plane evolution along the blade radius with spoiler. Each subplot shows the results for a wind speed (m s -1 ) whose value is given in the title.

Figure 14 .

 14 Figure 14. The blue square (blue ) shows the flapwise root bending moment evolution without spoiler, and the orange dot (orange •) shows the flapwise root bending moment evolution with spoiler. The black bars show the difference between the spoiler and no-spoiler case for each wind speed.

Figure 15 .

 15 Figure 15. Power curve close-up for the low wind speeds. The blue square (blue ) shows the power curve without spoiler, and the orange dot (orange •) shows the power curve with spoiler. The black bars show the difference between the mean spoiler and mean no-spoiler case.

Figure 16 .

 16 Figure 16. Detailed AEP gain and variation for all configurations assuming a wind class IEC II.

Figure 17 .

 17 Figure 17. Plot of the angle of attack versus the vortex shedding frequency for the no spoiler and spoiler cases, with radial position R6 ( r R = 13.3 %) calculated in 2D CFD. The blue square (blue ) shows the no-spoiler VSF, and the orange dots (orange •) show evolution of the spoiler VSF depending on the angle of attack. The black crosses mark the mean VSF (interpolated VSF at the mean angle of attack of the time series) for each case. The shaded area shows the standard deviation of the angle-of-attack time series.

Figure 18 .

 18 Figure 18. OpenFAST time evolution of 0.5 s of the local out-of-plane force (F X ) using the maximal, mean and minimal aerodynamic polars.

Figure 19 .

 19 Figure 19. Interpolated OpenFAST results of the local out-of-plane force (F X ).

Figure 20 .

 20 Figure 20. Creation of the intermediate time series by alternating between the different interpolated time series.

Figure 21 .

 21 Figure 21. Generation of the final time series using the sampling rate from OpenFAST ( t OF = 0.0063 s).

Figure

  Figure22. OpenFAST output normal force to the rotor plane for an average horizontal wind speed of 8 m s -1 (hub height). The blue square (blue ) shows the blade results without spoiler using the combination method, and the orange dot (orange •) shows the blade results with spoiler using the combination method. Each subplot shows the results for a radial location (m) whose value is given in the title.

Figure 23 .

 23 Figure 23. OpenFAST output normal power spectral density of the normal force to the rotor plane for an average horizontal wind speed of 8 m s -1 (hub height). The blue square (blue ) shows the blade results with the combination method for the spoiler, and the orange dot (orange •) shows the blade results for the mean spoiler. Each subplot shows the results for a radial location (m) whose value is given in the title.

Figure 24 .

 24 Figure 24. Lifetime expectancy evolution with respect to out-of-plane local load. The blue square (blue ) shows the blade results without spoiler, and the orange dot (orange •) shows the blade results with spoiler, and each symbol represents a blade nodal output (8.0 % < r R < 16.7 %).

Figure 25 .

 25 Figure 25. Lifetime expectancy evolution with respect to the in-plane local load. The blue square (blue ) shows the blade results without spoiler, and the orange dot (orange •) shows the blade results with spoiler, and each symbol represents a blade nodal output (8.0 % < r R < 16.7 %).

Table 1 .

 1 Turbine configurations analysed.

	Spoiler	Aerodynamic coefficient values
	configuration
	No spoiler	Mean aerodynamic coefficients
	No spoiler	Maximum aerodynamic coefficients
	No spoiler	Minimum aerodynamic coefficients
	Spoiler	Mean aerodynamic coefficients
	Spoiler	Maximum aerodynamic coefficients
	Spoiler	Minimum aerodynamic coefficients

Table 2 .

 2 CFD-calculated blade section polars defining the BEM model assuming an inflow between 8 and 8.5 m s -1 .

	Spanwise	Relative	Aerofoil	Local
	location	spanwise	relative Reynolds number
	from the	location thickness	[-]
	hub [m]	from the	[%]
		hub [%]
	2.1	4.4 %	93 %	1.35 × 10 6
	3.0	6.7 %	86.8 %	1.53 × 10 6
	3.6	8.0 %	81.2 %	1.67 × 10 6
	4.2	9.3 %	74.9 %	1.86 × 10 6
	4.5	10.0 %	71.9 %	1.95 × 10 6
	5.1	11.3 %	66.2 %	2.17 × 10 6
	5.4	12.0 %	63.4 %	2.29 × 10 6
	6.0	13.3 %	58.6 %	3.05 × 10 6
	6.6	14.7 %	53.9 %	2.79 × 10 6
	7.2	16.0 %	49.6 %	3.05 × 10 6
	7.5	16.7 %	47.9 %	3.18 × 10 6
	10	22.2 %	35.8 %	4.17 × 10 6
	13	28.9 %	29.8 %	4.92 × 10 6
	20	44.4 %	24.2 %	5.90 × 10 6
	27	60.0 %	21.2 %	6.09 × 10 6
	43	95.6 %	17.3 %	4.06 × 10 6

Table 3 .

 3 Optimal pitch settings for both no spoiler and spoiler cases using mean aerodynamic polars.

	Wind	No	Spoiler Difference
	speed	spoiler	pitch between no
	[m s -1 ]	pitch settings spoiler and
		settings	[ •	]	spoiler [ •	]
		[ •	]
	3.0	-0.164 -0.059	-0.105
	4.0	-0.9 -0.872	-0.028
	5.0	-1.621 -1.565	-0.056
	6.0	-1.549 -1.494	-0.055
	7.0	-1.453 -1.405	-0.048
	8.0	-1.568 -1.517	-0.051
	9.0	-2.1 -2.062	-0.039
	10.0	-3.046 -3.025	-0.021
	11.0	0.829	0.969	-0.141
	12.0	4.46	4.563	-0.104
	13.0	6.998	7.095	-0.097
	14.0	9.144	9.237	-0.093
	15.0	11.025	11.117	-0.092
	16.0	12.73	12.821	-0.092
	17.0	14.322	14.417	-0.095
	18.0	15.839	15.937	-0.098
	19.0	17.305	17.406	-0.101
	20.0	18.684	18.785	-0.102

cretization as detailed in Table

2

. As the standalone AeroDyn module can only simulate steady wind profiles, we chose to use the power law relation as seen in Eq. (3):

Table 4 .

 4 Spoiler impact on the AEP.

	Turbine	AEP	AEP
	configuration [MWh] gain
			ratio
			[%]
	No spoiler	8256.5	n/a
	Spoiler	8269.9	0.49

n/a: not applicable.

Table 5 .

 5 Spoiler total AEP variation around the mean value.

	Turbine	AEP	AEP
	configuration variation variation
		[MWh]	[%]
	No spoiler	27.6	0.31
	Spoiler	70.4	0.83

WindEnerg. Sci., 7, 1771-1790, 2022 https://doi.org/10.5194/wes-7-1771-2022

Acknowledgements. The authors would like to acknowledge the ANRT (Association Nationale de Recherche Technologique) for their financial support.

Code and data availability. Codes and data sets are available on demand.

required to answer the question fully, but such a study is out of the scope of the present paper.

To compare the results of the proposed method, Table 7 shows the same life index calculation when using the steady polar. In some cases the fatigue calculation predicts much higher residual lifetime when adding a spoiler. It appears in contradiction with the analysis performed so far and the damaged blades in the field. It highlights the risk of installing such AAO without knowing the aerodynamic impact and structural consequences. Author contributions. TP performed the scans post-processing, CFD pre-processing and post-processing, BEM model building, calculations and analysis, and writing of the paper. EG performed CFD verification and helped set up the CFD model. CLB and AF provided feedback from the industrial point of view, and CB helped with proofreading a previous version of the manuscript and physical analysis of the results.

Competing interests. The contact author has declared that none of the authors has any competing interests.

Disclaimer. Publisher's note: Copernicus Publications remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Financial support. This research has been supported by CIFRE (grant no. 2019/1426).

Review statement. This paper was edited by Alessandro Bianchini and reviewed by two anonymous referees.


Laurence Legeai-Mallet
email: laurence.legeai-mallet@inserm.fr

Ravi Savarirayan
email: ravi.savarirayan@vcgs.org.au

Novel therapeutic approaches for the treatment of Achondroplasia

Keywords: Achondroplasia, FGFR3, therapeutic approaches, preclinical studies, mouse models, clinical trials

Achondroplasia is the most common form of human dwarfism. The molecular basis of achondroplasia was elucidated in 1994 with the identification of the fibroblast growth factor receptor 3 (FGFR3) as the causative gene. Missense mutations causing achondroplasia result in activation of FGFR3 and its downstream signalling pathways, disturbing chondrogenesis, osteogenesis, and long bone elongation. A more accurate understanding of the clinical and molecular aspects of achondroplasia have allowed new therapeutic approaches to be developed. These are based on: clear understanding of the natural history of the disease; proof-of-concept preclinical studies in mouse models; and the current state of knowledge regarding FGFR3 and related growth plate homeostatic pathways. This review provides a brief overview of the preclinical mouse models of achondroplasia that have led to new, nonsurgical therapeutic strategies being assessed and applied to children with achondroplasia through pioneering clinical trials.

Introduction

Skeletal dysplasia represents 5% of all birth defects and comprise 461 different diseases [START_REF] Mortier | Nosology and classification of genetic skeletal disorders: 2019 revision[END_REF]. Among them, achondroplasia (ACH, OMIM# 100800) is the most common form of human dwarfism and affects over 250, 000 individuals worldwide. It is associated with a recognizable pattern of growth, medical complications over the lifespan, and related functional and psychosocial challenges [START_REF] Ireland | Optimal management of complications associated with achondroplasia[END_REF][START_REF] Horton | Achondroplasia[END_REF]. This condition remains the most readily recognizable phenotype consequent to abnormalities in growth plate biology.

The molecular basis of achondroplasia has been elucidated with the identification of Fibroblast Growth Factor Receptor 3 (FGFR3) as the causative gene [START_REF] Rousseau | Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia[END_REF][START_REF] Shiang | Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia[END_REF]. Missense mutation causing ACH result in activation of FGFR3 and its downstream signaling pathways that can be enhanced in the presence FGF ligands [START_REF] Naski | Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia[END_REF]. During infancy and childhood, bone growth occurs, progressively, over 15-18 years with an active phase before puberty. The bone elongation is essentially driven by the activity of the various growth plates, and formation of the ossification centers, both affected in ACH by the FGFR3 gain-of-function mutation.

The management and the treatment of ACH are major challenges of many centers involved in rare skeletal disorders. The only current therapy (approved in Japan) that is offered to ACH patients is treatment with recombinant human growth (r-hGH). No clear long term benefit has been established with this treatment, which does not address the underlying pathogenetic mechanisms [START_REF] Miccoli | Height Outcome of Recombinant Human Growth Hormone Treatment in Achondroplasia Children: A Meta-Analysis[END_REF]. Surgical limb lengthening is also a therapy employed for achondroplasia, primarily by distraction osteogenesis. Complications are, however, common including infection, muscle contractures, increase risk of fractures, pain, and potential adverse psychological outcomes. The use of intramedullary nails might improve outcomes and is now recommended as the implant of choice of femoral lengthening [START_REF] Paley | PRECICE intramedullary limb lengthening system[END_REF].

This review provides a brief overview of the clinical and molecular aspects of achondroplasia, and focuses on new therapies, developed from insights gained from the ACH mouse models.

FGFR3 and dwarfism

ACH is caused by a heterozygous, activating mutation localized in the transmembrane domain of Fibroblast Growth Factor Receptor 3 (FGFR3) gene. FGFR3 is a member of the receptor tyrosine kinases (RTK). The protein is comprised of extracellular, ligand-binding transmembrane, and intracellular kinase domains [START_REF] Belov | Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology[END_REF]. Mutations that cause ACH (approximately 99%) arise in the same nucleotide, and result in a glycine to arginine substitution (Gly380Arg) in the transmembrane domain of the FGFR3 protein. This missense mutation is fully penetrant and can show a modest variability in clinical features. Most cases (80%) of achondroplasia arise as new, spontaneous mutation, and the high frequency of this condition is partially due to a paternal age effect [START_REF] Wilkin | Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome[END_REF]. During antenatal development, the most visible impact related to dysregulation of FGFR3 signaling is in the skeleton. Prenatal ultrasound can often detect common characteristics of achondroplasia such as shortened limbs, frontal bossing, depressed nasal bridge, short cranial base and narrow thorax, but it is important to note that these features usually develop after 26 weeks of gestation [START_REF] Savarirayan | Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia[END_REF] and are

often not present at the routine ultrasound check (performed at 20 weeks of gestation). [START_REF] Naski | Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3[END_REF]; or where a Fgfr3 promoter drive the expression of human mutant cDNA (Fgfr3 G380R ). These were followed by the generation of numerous knock-in mouse models variably expressing the G380R mutation [START_REF] Wang | A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3[END_REF][START_REF] Lee | Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia[END_REF] G375C mutation [START_REF] Chen | Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis[END_REF], Y367C mutation [START_REF] Pannier | Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia[END_REF], K644E mutation [START_REF] Li | A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors[END_REF], and K644M mutation [START_REF] Iwata | Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice[END_REF]. The deep phenotyping of the Fgfr3 mouse models highlighted the role of the receptor in several tissues. The Fgfr3 gain-of-function mutation is ubiquitously expressed in mice and impairs bone formation and elongation. In the appendicular skeleton, examination of the growth plate showed that the high activation of FGFR3 induces the disorganization of the skeletal growth plate [START_REF] Naski | Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3[END_REF][START_REF] Wang | A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3[END_REF][START_REF] Lee | Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia[END_REF][START_REF] Chen | Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis[END_REF][START_REF] Pannier | Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia[END_REF][START_REF] Li | A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors[END_REF][START_REF] Iwata | Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice[END_REF]. FGFR3 signaling inhibits chondrocyte proliferation and differentiation into pre-hypertrophic and hypertrophic chondrocytes. The size of hypertrophic chondrocytes in the Fgfr3 mutant growth plate were extremely reduced as a consequence of this abnormal differentiation, confirming the important contribution of hypertrophic chondrocytes to bone elongation. Bone maturation delay at age 1 week followed by an accelerated secondary ossification center formation was also reported in these mice [START_REF] Pannier | Delayed bone age due to a dual effect of FGFR3 mutation in Achondroplasia[END_REF]. The axial skeletal is also affected, with the size of the pedicles of the lumbar vertebrae reduced, and anomalies of the intervertebral discs, specifically the nucleus pulposus and annulus fibrosus [START_REF] Komla-Ebri | Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model[END_REF]. Membranous and endochondral ossification were affected in craniofacial development, and skull dysmorphology is observed in Fgfr3 mouse models, with abnormal cartilage and premature fusion of the synchondroses at the skull base leading to abnormalities of foramen magnum shape and size, as well as premature fusion of the coronal sutures [START_REF] Di Rocco | FGFR3 mutation causes abnormal membranous ossification in achondroplasia[END_REF].

FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel's) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis [START_REF] Biosse Duplan | Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible[END_REF]. In addition, a deafness phenotype was also reported in the Fgfr3 Y367C/+ mouse model [START_REF] Pannier | Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia[END_REF].

Fgfr3 knock-out mouse models confirm the key role of FGFR3 in controlling bone elongation. In mice that lack Fgfr3, the proliferative and hypertrophic zones of the growth plate are expanded with bone elongation observed [START_REF] Colvin | Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3[END_REF][START_REF] Deng | Fibroblast growth factor receptor 3 is a negative regulator of bone growth[END_REF]. This phenotype was also described in humans, and termed CATSHL syndrome (camptodactyly, tall stature and hearing loss), with patients being heterozygous for a missense FGFR3 mutation that inactivates the receptor [START_REF] Brassington | A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome[END_REF][START_REF] Escobar | A second family with CATSHL syndrome: Confirmatory report of another unique FGFR3 syndrome[END_REF]. With respect to achondroplasia, it was necessary to take into consideration that the FGFR3 mutation is active from the early stages of prenatal skeletal development until skeletal maturity and possibly beyond.

Activation
The progress in understanding of the FGFR3 mechanism of action and pathological bases of Fgfr3-related dwarfism gained from mouse models have led to potential therapeutic strategies in humans, which are now in active clinical development. Current therapeutic approaches are many and varied, and include targeting the FGFR3 receptor or the FGF ligand, inhibiting the tyrosine kinase activity of FGFR3, and antagonization of FGFR3 downstream signaling pathways (Figure 1).

Fibroblast Growth Factor aptamer (APT-F2P/RBM 007)

An aptamer is a short, single-stranded nucleic acid molecule, raised against a range of targets and antigens. Their characteristics are their strong and specific neutralizing activities, medium size, and low antigenicity. An aptamer targeting FGF2 has been generated (APT-F2P/RBM007; Ribomic Inc.), that blocks the binding of FGF2 to its receptors (FGFR1-4), inhibiting FGFR downstream signaling pathways.

Preliminary data demonstrated that APT-F2P is effective for the treatment of FGF2dependent lung cancers [START_REF] Hamamoto | The FGF2 aptamer inhibits the growth of FGF2-FGFR pathway driven lung cancer cells[END_REF]. The efficacy of this aptamer was demonstrated in bone using mouse and rat models of arthritis and osteoporosis. APT-F2P blocked the disruption of the epiphyseal growth plate, and restored bone quality [START_REF] Jin | Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain[END_REF]. It was hypothesized that the action of APT-F2P on the growth plate could be a potential therapeutic approach for achondroplasia.

Preclinical studies are currently ongoing to evaluate the effect of RBM007 on bone development and its safety in ACH mouse models.

5.2 Soluble FGFR3 as a decoy receptor (TA-46/ Recifercept) Soluble receptors exert their biological effects through mechanisms of action that are defined by their relationship to ligands and membrane-bound receptors. In oncology, soluble receptors have been generated in order to suppress tumor angiogenesis as a therapeutic approach in numerous forms of cancer.

As FGFR3 activation requires ligand binding, it was hypothesized that preventing the FGF fixation to its receptor would promote the bone growth of ACH mice. A soluble form of FGFR3 (TA-46, now called recifercept) acting as a decoy receptor was generated, and prevents FGF binding to mutant FGFR3. Transgenic Fgfr3 Ach/+ mice were treated with TA-46 twice a week, and the defective maturation of the growth plate and bone growth were restored. These data supported the idea that the ACH mutation requires FGF-binding to be activated [START_REF] Garcia | Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice[END_REF]. Currently, phase I studies employing this molecule (recifercept; Pfizer Ltd.)

have been completed in healthy male volunteers without ACH. An observational study to document the baseline characteristics and growth in children with ACH aged 0-10 years (ClinicalTrials.gov number, NCT03794609; Dreambird) is now recruiting, and will likely form the basis of a phase 2 clinical drug trial commencing in the near future.

Anti-FGFR3 antibody (B-701/ Vofamatab)

Monoclonal antibody therapy is also used routinely in oncology. The mechanism of action of FGFR3 antibodies is to bind to the extracellular domain of FGFR3, in order to block ligand binding, interfere with co-factor receptor interaction, and inhibit dimerization of the receptor.

Generation of FGFR3 antibodies were produced for the treatment of bladder cancers. Various studies have reported the efficacy of B-701 on bladder cancer lines, which are FGFR3-dependent tumors [START_REF] Rauchenberger | Human combinatorial Fab library yielding specific and functional antibodies against the human fibroblast growth factor receptor 3[END_REF][START_REF] Trudel | The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells[END_REF][START_REF] Yin | Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody[END_REF]. In the future, FGFR3-specific monoclonal antibodies will potentially be an additional therapeutic option for ACH patients.

Tyrosine kinase Inhibitor (BGJ398/ Infigratinib)

Many oncologic treatments use small molecule tyrosine kinase inhibitors (TKI) to inhibit the activity of receptor tyrosine kinases. Several TKI were generated for the treatment of bladder cancers and FGFR3-induced myeloma, such as CHIR-258 [START_REF] Trudel | CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma[END_REF], PD173074, SU5402, ARQ087, and NVP-BGJ398. NVP-BGJ398, which is more selective for FGFR3 over other FGFRs [START_REF] Kunova Bosakova | Fibroblast growth factor receptor influences primary cilium length through an interaction with intestinal cell kinase[END_REF], was used in preclinical murine models for treating rhabdoid tumors [START_REF] Wöhrle | Fibroblast growth factor receptors as novel therapeutic targets in SNF5-deleted malignant rhabdoid tumors[END_REF], hepatocellular carcinoma [START_REF] Scheller | mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma[END_REF], and FGF23-mediated hyphosphatemic rickets [START_REF] Wöhrle | Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets[END_REF]. In a mouse model mimicking ACH (Fgfr3 Y367C/+ ), the efficacy of NVP-BGJ398 was demonstrated

showing improvement of many of the affected skeletal elements in ACH such as the long bones, vertebrae, intervertebral discs, craniofacial morphology, and the foramen magnum [START_REF] Komla-Ebri | Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model[END_REF][START_REF] Di Rocco | FGFR3 mutation causes abnormal membranous ossification in achondroplasia[END_REF][START_REF] Biosse Duplan | Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible[END_REF]. Relatively low doses of NVP-BGJ398 reduced FGFR3 phosphorylation and its downstream signaling pathways and rescued the disorganization of the growth plate and resulted in bone elongation.

Currently, this TKI (infigratinib; QED therapeutics), is in clinical development with The primary endpoints of this study are to determine the incidence of treatment-emergent adverse effects and evaluate the change from baseline in annualized height velocity.

Recently, (July 2020), the first child with achondroplasia was dosed orally with infigratinib, and this phase II clinical trial is now ongoing.

Drug repurposing: meclozine

Drug repurposing is also a proposed strategy for achondroplasia. Meclozine, an antihistamine and motion sickness drug was considered as putative treatment, as it was demonstrated that meclozine downregulated the phosphorylation of ERK, a downstream FGFR3 pathway. Preclinical studies were conducted in transgenic Fgfr3 Ach/+ mice, and the preliminary data demonstrated an improvement of the skeletal phenotype of the mutant mice

[42]. To date, no clinical trials have been conducted.

Statins, a class of cholesterol-lowering drugs, were also tested in transgenic Fgfr3 Ach/+ mice. The preliminary data showed that statins corrected the skeletal phenotype [START_REF] Yamashita | Statin treatment rescues FGFR3 skeletal dysplasia phenotypes[END_REF].

However, others studies showed that statins retard cartilage development and reduce the expression of the key regulators of growth plate cartilage [START_REF] Bush | A new prescription for growth? Statins, cholesterol and cartilage homeostasis[END_REF]. This strategy has not progressed beyond the animal model currently.

5.6 Drugs that modulate growth plate homeostasis: CNP analog (BMN111/Vosoritide) and

TransCon CNP.

The C-natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor B (NPR-B) are recognized as key regulators of longitudinal bone growth [START_REF] Chusho | Dwarfism and early death in mice lacking C-type natriuretic peptide[END_REF]. Loss of function mutations in NPR-B are responsible for acromesomelic dysplasia, Maroteaux type, a disproportionate form of dwarfism [START_REF] Bartels | Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux[END_REF]. Mutant mice with a disruption of CNP (Nppc -/-) also show disproportionate dwarfism with short limbs [START_REF] Chusho | Dwarfism and early death in mice lacking C-type natriuretic peptide[END_REF]. The CNP signaling pathway promotes bone growth through inhibition of MAPK signaling. Tall statures with elongated bones are observed in patients with activating Npr3 mutations [START_REF] Hannema | An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities[END_REF], and in patients that overexpress CNP [START_REF] Bocciardi | Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation[END_REF][START_REF] Moncla | A cluster of translocation breakpoints in 2q37 is associated with overexpression of NPPC in patients with a similar overgrowth phenotype[END_REF]. CNP overexpression in the cartilage or continuous delivery of CNP by intravenous infusion normalizes the dwarfism of Fgfr3 Ach/+ mice [START_REF] Yasoda | Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway[END_REF][START_REF] Yasoda | Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias[END_REF]. An analog of CNP, BMN111, with an extended plasma half -life due to its resistance to neutral endopeptidase was recently generated (vosoritide; BioMarin). Proof of principle studies were conducted in human ACH cells and a mouse model (Fgfr3 Y367C/+ ) and confirmed the beneficial effect of BMN111 on long bone growth and the skull [START_REF] Lorget | Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia[END_REF]. In parallel, studies to assess the hemodynamic effects of BMN111, given its structural similarity to atrial natriuretic peptide, were performed in juvenile cynomolgus monkey. No clinical signs of hypotension or distress were observed in this model [START_REF] Wendt | Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism[END_REF]. A multicenter, open-label, dose escalation, clinical trial using vosoritide in 35 patients with ACH aged 5 to 14 years was initiated in 2014 (Clinicaltrials.gov, number NCT02055157). The results of dose-finding and extension study (ClinicalTrials.gov number, NCT02724228) were reported in 2019 [START_REF] Savarirayan | C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia[END_REF]. Vosoritide was given as a once daily, subcutaneous injection. A sustained increase of annualized growth velocity of 1.5cm/year above baseline was observed for up to 42 months in children receiving 15mcg/kg/day of vosoritide. Given these promising phase 2 data, a phase 3, randomized placebo-controlled, double-blind, multicenter trial (ClinicalTrials.gov number, NCT03197766), was undertaken in 121 children with achondroplasia aged 5 to less than 18 years [START_REF] Savarirayan | Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial[END_REF]. This study confirmed a mean increase of 1.57cm/year in annual growth velocity in children receiving vosoritide as compared to placebo with a similar side effect profiles in vosoritide and placebo arms. The children recruited to this trial will be followed until final assess its safety and effect on annual growth velocity in these children.

Future perspectives

The main challenge of drug development for achondroplasia resides in characterization of the balance of harms and benefits of any proposed therapy in growing individuals based on anticipated natural history, preclinical data and clinical trials. Treating pediatric patients with achondroplasia presents challenges that relate to potential harms as, 1) some organ systems (e.g. CNS, reproductive organs, heart) are still developing, and 2) treatment is likely required to be administered for prolonged periods, often to the end of skeletal maturation/linear growth. The earliest time after birth that management and, now, treatment of ACH can be instituted is paramount to offer the best chances of ameliorating the features that cause morbidity and mortality. During infancy, the management of the foramen magnum is crucial for ACH patients as is management of sleep-disordered breathing. The combination of these two features in infants with achondroplasia is thought to contribute significantly to the increased risk of sudden death in this condition observed before age 5 years. Orthopedic concerns that need to be managed in childhood and adolescence include spinal kyphosis, exaggerated lordosis, leg bowing, and the high prevalence of spinal stenosis leading to reduced walking distance and pain [START_REF] White | Best practice guidelines for management of spinal disorders in skeletal dysplasia[END_REF].

In the future, treating adult achondroplasia patients will also be an important consideration. The aim of such therapy will be to reduce the clinical impact of the FGFR3 activating mutation on spinal stenosis, intervertebral disc disease, bone homeostasis, and other non-skeletal complications that might affect life span (i.e. cardiovascular).

Today, several major milestones for the precision treatment of achondroplasia have been achieved, best demonstrated by the results from the phase 2 and 3 clinical trials of oncedaily, subcutaneous CNP therapy in children with ACH aged 5 to 18 years [START_REF] Savarirayan | C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia[END_REF][START_REF] Savarirayan | Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial[END_REF]. Several other therapeutic options for ACH are emerging, and we will soon have the clinical trial data to assess their safety and efficacy profiles.

It is likely that a better understanding of the multiple signalling pathways activated by the FGFR3 gain-of function mutation in ACH, based on preclinical animal studies and the natural history of the disease will facilitate more precision therapeutic strategies to be developed. As further understanding of the benefits and harms of these drugs is gathered, these treatments can be further tailored, to provide the right therapy, at the right time and dose, to achieve maximum benefits for each individual with ACH. Combination therapy, or the sequential use of different therapies, might also become a future possibility, to first promote and control chondrogenesis and osteogenesis during early infancy and childhood and then minimize progression of the condition in adolescence and beyond skeletal maturity.

It is hoped that these new, disruptive therapies will give better, non-surgical options for individuals with ACH to optimize their health and well-being, and minimize the medical impacts of their condition.

Legend figures

Drug development process for achondroplasia.

1. The natural history of the disease needs to be understood, with a focus on complications related to abnormality of the endochondral ossification process.

phase 1

 1 studies completed, and an observational natural history study recruiting (ClinicalTrials.gov number, NCT04035811; PROPEL) children with ACH aged 2.5 to 10 years to learn more about their growth and medical complications. In addition, a phase 2, multicenter, open-label, dose escalation and expansion study (ClinicalTrials.gov number, NCT04265651; PROPEL-2) to evaluate the safety, tolerability and efficacy of infigratinib has commenced in children who have completed at least 6 months of the PROPEL lead-in study.

2 .

 2 Relevant preclinical studies in well-characterized ACH mouse models (and cynomolgus monkeys) in order to study key disease features and proof-of-concept of drug safety and efficacy. 3. Overview of the drugs and their targets currently in clinical development (green denotes the compound in clinical trial, red denotes no clinical trial are ongoing (as of July 2020).

  The spectrum of chondrodysplasia phenotypes associated with FGFR3 missense mutations range from mild to severe. Hypochondroplasia, the mildest form of FGFR3-related dwarfism, is caused by mutations localized in the tyrosine kinase domain I of the protein;

	long bone elongation begin during embryonic development and mostly occurs through
	endochondral ossification, a process in which mesenchymal cells differentiate into
	chondrocytes that form the cartilage template for future bone. This template is replaced
	following vascular invasion by bone cells. FGFR3 is expressed in proliferating and pre-
	hypertrophic chondrocytes and bone during embryonic and post-natal development [14]. The
	generation of Fgfr3 mouse models have significantly contributed to deciphering the impact of
	Fgfr3 gain-of-function mutations on bone development. Several Fgfr3 mouse models have
	been developed: a transgenic mouse (Fgfr3 Ach/+ ) model in which a Col2a1 promoter drives
	expression of the ACH mutation in chondrocytes
	radiographic findings and confirmed by molecular analysis of the FGFR3 gene.
	Approximately 80% of cases arise as a new mutation and individuals with ACH experience a
	variety of medical (i.e. foramen magnum stenosis with cord compression, spinal stenosis,
	sleep apnea, increased risk of sudden death), functional (i.e. limitation with activities of daily
	living, self-care, and access to the environment) and psychosocial issues (i.e. issues with self-
	esteem and discrimination based on their physical appearance) [2,3,4, 13]
	Until very recently, the treatment options for individuals with ACH have been limited
	to surgical or expectant ("wait and watch") modalities, with variable outcomes. Therapeutic
	options for ACH that address the underlying pathology have been a longstanding and unmet
	need. The recent advent of clinical trials in children with ACH, has been made possible by the
	deeper understanding of the pathogenesis of ACH provided by studies of animal (mouse)
	models of ACH.
	4. Preclinical models of Fgfr3-related dwarfism: lessons from the mouse
	The understanding of the control of bone elongation was partially elucidated with the
	discovery of FGFR3 as the gene, that when dysregulated causes ACH. Bone formation and

SADDAN syndrome (Severe Achondroplasia with Developmental Delay and Acanthosis

Nigricans) by a specific mutation (K650M) localized in the tyrosine kinase domain II of FGFR3; and thanatophoric dysplasia, an almost uniformly lethal skeletal dysplasia, by mutations localized primarily in the extracellular domain of FGFR3

[START_REF] Ornitz | Achondroplasia: Development, pathogenesis, and therapy. Developmental dynamics : an official publication of the[END_REF]

.

3. Diagnosis, clinical features and natural history

The diagnosis of ACH is made by the combination of clinical features and

  of FGFR3 is induced by high affinity ligand binding, which results in dimerization of the tyrosine kinase domains and trans-phosphorylation of tyrosine residues, inducing tyrosine kinase activity Interestingly, FGFR3 gain of function mutations result in constitutive activation of FGFR3 and its signaling pathways that can be further modulated by the presence or absence of FGF ligands. In growth plate chondrocytes, it has been well demonstrated that mutated FGFR3 dysregulated many downstream signaling pathways that directly affect chondrocyte proliferation and differentiation in various Fgfr3 mouse models[START_REF] Naski | Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3[END_REF][START_REF] Wang | A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3[END_REF][START_REF] Lee | Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia[END_REF][START_REF] Chen | Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis[END_REF][START_REF] Pannier | Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia[END_REF][START_REF] Li | A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors[END_REF][START_REF] Iwata | Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice[END_REF].

FGFR3 signaling can activate several MAP kinases (e.g. ERK1/2 and P38) and other protein phospholipases (i.e., Phospholipase Cg (PLCg) and signal transducer and activator of transcription (STAT1, 3, 5)

[START_REF] Ornitz | Fibroblast growth factors in skeletal development[END_REF]

.

5. Current therapeutic strategies for achondroplasia: from mouse to human model

Aberrant FGF signaling is involved in both developmental disorders (e.g. dwarfism) and a wide range of cancers, including bladder, myeloma, lung, cervical, prostate, and testicular. Some potential treatments for ACH have been informed by protocols used in oncology, and adapted to target bone tissues affected by FGFR3 gain-of-function mutations.

  adult height is achieved (ClinicalTrials.gov number, NCT03424018) to asses durability of drug response. It is envisaged that this randomized controlled trial (level 1) evidence will form the basis of regulatory approval of vosoritide as the first precision treatment for children with achondroplasia in this age group. In addition, a phase 2 randomized, double-blind,

	placebo-controlled trial is ongoing to assess the effects of vosoritide given to children aged 3
	months to less than 5 years (ClinicalTrials.gov number, NCT03583697).
	Another CNP derivative called, TransCon CNP, has also been engineered (Ascendis
	Pharma). TransCon CNP is a pro-drug consisting of CNP-38 conjugated via a cleavable linker
	to a polyethylene glycol carrier molecule. It is designed to provide continuous CNP exposure
	at the growth plate, with the goal of optimizing efficacy, with its longer half-life allowing
	weekly subcutaneous dosing. Preclinical data in mice and cynomolgus monkeys have shown
	efficacy of CNP on bone growth without cardiovascular side effects. Phase 1 studies have
	completed and an observational study (ClinicalTrials.gov number, NCT03875534; ACHieve)
	has been recruiting children with ACH aged 0-8 years to document natural history. Recently,
	(June 2020), the first child with achondroplasia was recruited into a multicenter, double-blind,
	randomized placebo-controlled, dose-escalation clinical trial of TransCon CNP in children
	with ACH aged 2-10 years (ClinicalTrials.gov number, NCT04085523; ACcomplisH) to


A Damecourt
email: a-damecourt@chu-montpellier.fr

N Nieto

S Galmiche

R Garrel

M De Boutray

planning for mandibular reconstruction by free fibula flap in cancer: Our technique

Keywords: mandibular reconstruction, computer-aided design, CAD/CAM, 3D printing, microsurgery

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The free fibula flap (FFF), described by Hidalgo in 1989, is the gold standard for mandibular reconstruction [START_REF] Hidalgo | Fibula free flap: a new method of mandible reconstruction[END_REF]. Conformation of this free bone flap, without using a model, is often imprecise, resulting in a prolonged operative ischaemia time. One of the solutions currently used by surgical teams is the creation of resection guides, pre-drilling guides and custommade fixation plates [START_REF] Zhang | Evaluation of computer-assisted mandibular reconstruction with vascularized fibular flap compared to conventional surgery[END_REF][START_REF] Antony | Use of virtual surgery and stereolithography-guided osteotomy for mandibular reconstruction with the free fibula[END_REF]. These guides and custom-made plates are designed by CAD (computer-aided design) and CAM (computer-aided manufacturing), in collaboration with biomedical engineers, thereby allowing planning of conformation and fixation prior to surgery.

The objective of this article is to describe a method of in-house treatment planning of mandibular reconstruction by FFF to determine the number and angulation of osteotomies and to preconform the fixation plates. This method is performed entirely and exclusively by the surgical team using a dedicated 3D printer.

Technique

Planning technique

1.1. Printing of 3D models (Fig. 1) All patients scheduled to undergo FFF were assessed by preoperative CT angiography of the lower limbs to evaluate the donor fibular pedicle less than two weeks before the reconstruction. CT scan of the facial bones was also performed to provide recent data to plan the mandibular resection.

These radiological data, in DICOM (Digital Imaging and Communication in Medicine) digital format, were then used for 3D modelling of the patient's fibula and mandible, an essential prerequisite to 3D printing.

We use free software: 3D Slicer ® and OsiriX Lite ® for this procedure, allowing semiautomatic segmentation of the region of interest (mandible or fibula) by grayscale thresholding. After completing this segmentation, 3D modelling is performed by the software and this modelling is then converted to the STL (stereolithography) format used for 3D printing. A final preparation step can be performed in the presence of imperfections on the model using Meshmixer ® software, allowing smoothing and artefact suppression.

The prepared STL file is then imported into the printing software. A Raise3D ® model N2+ printer, at a cost of €4,450, is used. IdeaMaker ® printing software is provided with the printer. PLA (polylactic acid) is used as thermoplastic printing material. The position of the model on the print bed can be determined and print supports can be added to ensure stability during printing. After several trials using various settings, we adopted the following parameters:

for the mandible: anatomical position -support beyond an overhang of 30° -printing precision: 150 µm.

for the fibula: horizontal position -support beyond an overhang of 60° -printing precision: 150 µm.

The printing time is between 4 and 6 hours for the mandibular model and between 6 and 10 hours for the fibula. 1.2. Osteotomy planning and pre-conformation of fixation plates (Fig. 2) This step consists of planning the mandibular bone resection and fibula osteotomies to allow preconforming of the fixation plates and creation of fibula osteotomy guides. This planning is performed exclusively by the patient's surgeon 48 to 72 hours before the operation.

Resection margins are determined by the team on the basis of physical examination and recent mandibular CT scan (< 2 weeks). Resection margins are marked on the printed mandibular model (Fig. 2A) with a safety margin of at least 1 cm around the tumour, including the inferior alveolar canal, when it is involved.

A silicone impression of the basilar margin of the mandibular model is then performed to allow constant determination of the bigonial distance and the shape of the mandibular arch during simulation (Fig. 2B).

The zone to be resected is then sectioned together with its planned margins, and planning of the lateral and intermediate osteotomies of the fibula cutting guide can then be performed.

The length and angulations of fibular fragments are progressively adapted with the saw and the drill until the mandibular arch to be reconstructed has been precisely reproduced (Fig. 2C, 2D, 2E and 2F).

After completion of these steps, the "reconstructed" model is definitively repositioned in the silicone impression to allow conformation of the fixation plates, 1 to 1.25 mm thick with at least two holes on either side of the bridge. The conformed plates are then sent to the sterilization unit to be sterilized in the autoclave and packaged prior to surgery (Fig. 2G and2H).

Finally, paper tracings are performed to guide the fibula osteotomies during surgery. These tracings are cut to reproduce the osteotomy lines on the lateral, anterior and possibly posterior surfaces of the fibular fragments. They are then annotated to indicate their directions to avoid any confusion during surgery (Fig. 3). Intraoperative use of these guides is described in section 2.

2. Surgical technique (Fig. 4) Flap dissection and harvesting are performed according to classical techniques. Conformation osteotomies are systematically performed before harvesting the fibula flap, using paper tracing to guide these osteotomies, as a real cutting and predrilling guide is not available with this technique. The paper tracings, placed in a sterile adhesive, are then positioned on their respective surfaces of the fibula, to guide the osteotomies on at least two surfaces of the fibula (Figs. 4A and4B). The length of the bone fragment and the direction of the osteotomies are plotted on the fibula to reproduce those planned on the 3D printed fibular model.

Preconformed plates during planning are then used for fixation of the FFF.

Discussion

Conformation of the fibula performed extemporaneously presents several limitations, such as a long learning curve [START_REF] Hidalgo | Aesthetic improvements in free-flap mandible reconstruction[END_REF], a long conformation time, resulting in longer operating and ischaemia times and imprecise conformation, responsible for cosmetically and functionally suboptimal mandibular reconstruction.

The introduction of preoperative virtual planning has facilitated in situ conformation of the fibula before flap division [START_REF] Eckardt | Virtual planning of composite mandibular reconstruction with free fibula bone graft[END_REF]. More recently, the development of CAM has allowed the creation of custom-made cutting and pre-drilling guides with good results and excellent reproducibility [START_REF] Foley | Mandibular Reconstruction Using Computer-Aided Design and Computer-Aided Manufacturing: An Analysis of Surgical Results[END_REF].

In practice, these processes are often reserved for the most complex cases, especially for secondary reconstruction or for benign diseases, as most teams can only perform a limited number of procedures due to their high unit cost, ranging between €2,000 and about €6,000 depending on the study [START_REF] Toto | Improved operative efficiency of free fibula flap mandible reconstruction with patient-specific, computerguided preoperative planning: Preoperative modeling for free fibula flaps[END_REF]. Furthermore, the time required for design and manufacture of custom-made guides and plates is often incompatible with the need for urgent management of malignant lesions.

The major advantage of the technique described in this article is to allow very rapid planning of mandibular reconstruction by FFF at a limited cost. This technique therefore allows:

• A planning time of less than 72 hours after imaging.

• A medical planning time of less than one hour, compatible with the surgeon's clinical activity. 3D printing does not affect this parameter, as it does not require any particular surveillance and can be performed at night.

• Intraoperative conformation on the leg, before flap division, thereby allowing a shorter ischaemia time.

• A short modelling, printing and planning learning curve. This technique is also a good simulation teaching tool for junior surgeons, who are able to acquire experience on inexpensive models.

• A low planning cost: purchase price of the printer of €4,450, then price per patient of €2 to €4.

Seven patients with squamous cell carcinoma invading the mandible have been managed by this in-house planning method, with at least one fibular conformation osteotomy. The mean planning time was 53 minutes [range: 15-75]. The mean intraoperative conformation time was 89 minutes [range: 68-110] versus 104 minutes in a previous series of 25 patients operated without 3D planning and the mean ischaemia time was 55 minutes versus 101 minutes.

Our method does not allow the manufacture of real cutting and pre-drilling guides. Paper tracings are helpful, but cannot be used to guide osteotomies in three dimensions and osteotomies sometimes need to be corrected by drilling.

It must be stressed that this method remains less precise than other procedures described in the literature. For example, Bosc et al. use CAM cutting guides with preoperative conformation of fixation plates. They use Polyjet printing technologies and Fused Deposition Modeling (FDM), with mostly free software. All steps are performed entirely by the surgical team within the hospital department. The mean design time is longer (5.1 days), but with a trend towards marked reduction with learning (3 days for the last patient) [START_REF] Bosc | Mandibular reconstruction after cancer: an in-house approach to manufacturing cutting guides[END_REF].

Dupret-Bories et al. have established a partnership with a bioengineering school, also allowing the manufacture of CAM cutting guides in an average of 5 days [START_REF] Dupret-Bories | Contribution of 3D printing to mandibular reconstruction after cancer[END_REF].

Although the cost per patient for these two authors remained higher than that of our method, they demonstrated a marked cost saving compared to industrial processes (about €1,000 per patient) and the manufacture of true cutting guides ensures a higher degree of precision.

However, these cutting guides are considered to be "surgically invasive devices" (Annex IX of Directive 93/42/EEC). Each device used, particularly the planning software, must be validated by a CE mark, which is not the case for most free software reported in the literature.

As our method is not at all invasive, it is not subject to this regulation The procedure described here is not designed to replace more sophisticated methods, but it simply and inexpensively allows customized surgery, with a gain of time compared to the manufacture of cutting guides.

Conclusion

This in-house planning technique is not designed to replace cutting and pre-drilling guides, but constitutes a simple, inexpensive complementary method that can be performed routinely in the context of the surgeon's activity to plan bone fragment modelling by using a hospitalbased 3D printer, which facilitates conformation prior to flap division.

Figure 1 .

 1 Figure 1. OsiriX ® DICOM volume rendering image. B. OsiriX ® DICOM image after segmentation. C. Meshmixer ® STL image before cleaning D. Meshmixer ® STL image after cleaning. E. IdeaMaker ® STL image of the mandible on the printer bed with print supports. F.

Figure 2 .

 2 Figure 2. A. Marking of resection margins. B. Mandible model placed in the impression to

Figure 3 .

 3 Figure 3. Preparation of tracings that are cut to reproduce the osteotomy lines on the lateral,

Figure 4 .

 4 Figure 4. Identification and marking of the surfaces of the fibula. B. The tracing is positioned

Acknowledgements

The authors would like to thank the surgeons involved in this planning project: the Montpellier university hospital maxillofacial surgery and head and neck surgery teams.

Conflicts of interest:

None