Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/483—Physical analysis of biological material
  • G01N33/4833—Physical analysis of biological material of solid biological material, e.g. tissue samples, cell cultures
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N3/00—Investigating strength properties of solid materials by application of mechanical stress
  • G01N3/02—Details
  • G01N3/06—Special adaptations of indicating or recording means
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N3/00—Investigating strength properties of solid materials by application of mechanical stress
  • G01N3/08—Investigating strength properties of solid materials by application of mechanical stress by applying steady tensile or compressive forces
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N3/00—Investigating strength properties of solid materials by application of mechanical stress
  • G01N3/24—Investigating strength properties of solid materials by application of mechanical stress by applying steady shearing forces
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2203/00—Investigating strength properties of solid materials by application of mechanical stress
  • G01N2203/0058—Kind of property studied
  • G01N2203/0089—Biorheological properties
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2203/00—Investigating strength properties of solid materials by application of mechanical stress
  • G01N2203/02—Details not specific for a particular testing method
  • G01N2203/025—Geometry of the test
  • G01N2203/0252—Monoaxial, i.e. the forces being applied along a single axis of the specimen
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2203/00—Investigating strength properties of solid materials by application of mechanical stress
  • G01N2203/02—Details not specific for a particular testing method
  • G01N2203/025—Geometry of the test
  • G01N2203/0254—Biaxial, the forces being applied along two normal axes of the specimen

Definitions

• the present disclosure relates to the field of measuring the mechanical properties of a sample of human or animal skin.
• the skin has a complex multi-layered structure, stratified by three main layers from the surface to the depth: the epidermis, the dermis and the hypodermis.
• the structural complexity of the skin gives it mechanical properties: anisotropy, elastic behavior, viscoelastic behavior, heterogeneity.
• the skin can thus be seen as a complex material whose mechanical response depends on very
• the extensometer which makes it possible to carry out uniaxial tensile tests in vivo, by fixing two pads to the skin and causing them to move in opposite directions.
• the pads are glued to the skin in vivo. Bonding is carried out with double-sided adhesive strips or with suitable glues.
• this technique has drawbacks. Indeed, the use of powerful glues to obtain an effective anchor point can for example damage the superficial layer of the skin during the removal of the pads. Thus, it is difficult to propose it for carrying out tests carried out at the same place of the skin in vivo to evaluate the evolution of the mechanical properties over time.
• Adhesive strips are less invasive and better tolerated by the patient's skin. However, they do not make it possible to obtain sufficiently strong anchoring points, thus generating a risk of displacement between the pad in contact with the skin and the measurement zone, thus causing erroneous measurements.
• the current devices are imprecise for monitoring the evolution of the mechanical behavior of the same area of the skin in vivo over time.
• the current devices are mainly developed for mechanical characterization of the skin in vivo. Indeed, the skin, once removed, loses its mechanical characteristics over time. Also, currently, it is not possible to correctly assess the evolution over time of mechanical properties in skin in vitro. However, in the case of mechanical characterization of the skin in vivo, the devices and methods must be non-invasive, which leads to limitations in the study of mechanical behavior. In the study of the non-linearity of the force-displacement relationship for example, it is not possible to study the phase corresponding to the rupture phase in the case of a characterization of the skin in vivo.
• the invention proposes to overcome these drawbacks.
• Another object of the invention is to provide a measuring device capable of performing measurements in different possible directions in the plane of the skin.
• Another object of the invention is to provide a measuring device capable of performing mechanical tensile stresses parallel to the surface of the ex vivo skin, of which the mechanical properties are maintained over time and to achieve reproducible measurements of the mechanical properties.
• the subject of the present disclosure is a system for measuring the mechanical properties of an ex vivo or in vitro skin sample
• a measuring device comprising at least one mechanical stress module suitable for applying to the skin a tensile force in a direction parallel to the surface of the skin sample, said at least one mechanical stress module comprising:
• traction means being provided with a fixing head capable of being fixed in a zone of the skin sample in order to induce a deformation of the skin sample by axial displacement of said zone of the skin sample;
• control unit configured to control the means of displacement
• a calculation unit configured to receive the signals transmitted by the measuring device and to calculate the mechanical properties of the skin from said signals.
• a plurality of mechanical stress modules being arranged around a center of the device and configured to each exert a tensile force in a radial direction and parallel to the surface of the sample of skin, the axial displacement means and the translation arms are aligned in pairs so as to displace two traction means along a common axis of displacement.
• the aligned axial displacement means are synchronized so as to simultaneously move two traction means along the common axis.
• the axial displacement means comprises a piezoelectric nano-positioning table, one end of the translation arm being fixed to a movable part of the piezoelectric nano-positioning table.
• each biasing module further comprises a manual micrometric displacement table configured to manually adjust the position of the translation arm along one of the axes of displacement.
• a manual micrometric displacement table configured to manually adjust the position of the translation arm along one of the axes of displacement.
• the piezoelectric nano-positioning table and the micrometric displacement table are arranged relative to each other so as to have the same axis of displacement.
• the fixation head is in the form of a rod provided with a thread capable of engaging in the thickness of the skin sample to produce a fixation point in the skin sample.
• the fixing head is in the form of a straight cylindrical body, one of the bases of the straight cylindrical body being provided with a layer of glue to fix the fixing head to the surface of the skin sample.
• the traction means comprises a cylindrical fixing body intended to be received in a housing formed in one end of the translation arm and locked in position by means of a clamping element.
• the measuring device further comprises at least one traction force sensor able to measure the traction force exerted by a traction means.
• the measuring device further comprises at least one position measuring sensor capable of measuring the position of a translation arm during its movement.
• the measuring device further comprises at least one imaging means configured to observe the deformation zone of the skin sample generated by the displacement of the fixing heads, the optical axis of said imaging means being oriented along a direction normal to the surface of the skin.
• FIG. 1 shows a top view of a device for measuring the mechanical properties of a skin sample according to one embodiment
• FIG. 2 shows a sectional view of the device of FIG. 1 along the axis (BB');
• FIG. 3 shows a perspective view of the device of Figure 1;
• FIG. 4 shows an enlarged and perspective view of zone (B) of FIG. 3;
• FIG. 5 shows an enlarged view of an area (A) of Figure 2;
• FIG. 6 shows another bottom view of Figure 4.
• FIG. 7 shows a perspective view of a traction means according to two embodiments of the invention.
• FIG. 8 schematically represents a sectional view showing two fixation heads in a fixation configuration in the skin
• FIG. 9 schematically represents the translation of one of the two fixing heads of FIG. 8 along a direction parallel to the surface of the skin, causing a deformation of the fixing zone of the skin by axial displacement;
• FIG. 10 shows a system for measuring mechanical properties comprising the measuring device according to one embodiment of the invention connected to a control unit and to a calculation unit.
• FIG. 11 shows the evolution of the complex modulus measured for a sample of pigskin as a function of the stress frequency.
• the term "mechanical properties” means the physical parameters that can be defined from the deformation of the skin subjected to mechanical stress. Indeed, by analyzing the mechanical responses to the imposed deformation, it is possible to trace the elastic, viscoelastic and plastic properties of the skin.
• ex vivo skin sample means a sample of skin taken from a living body and which is kept alive throughout the duration of the measurement of the mechanical properties by a nutritional solution. . Therefore, the ex vivo skin sample functions normally like the in vivo skin for a fixed period of time.
• sample of skin in vitro means a sample of synthetic skin produced in the laboratory.
• studies on the skin in vitro do not make it possible to characterize the natural functioning of the skin which is no longer alive.
• FIG. 1 schematically represents a top view of the device 10 for measuring the mechanical properties of a skin sample ex vivo or in vitro according to one possible embodiment.
• the device of the present disclosure can be used on any type of skin sample.
• the device of the present disclosure has more particularly been designed with the aim of characterizing the mechanical properties of an ex vivo skin sample maintained in a fixed position on a nutritional medium which makes it possible to maintain the mechanical properties of the skin sample for a duration of at least seven days.
• the technique of life maintenance of an ex vivo skin sample is described in the document WO2013164436.
• the measuring device of Figure 1 comprises four mechanical stress modules 20, 40, 70, 80 which are each capable of applying traction in a direction parallel to the surface of the skin, thus making it possible to exert at least four tensile tests simultaneously in the plane of the skin.
• the mechanical stress modules operate in pairs.
• the module 20 and the module 40 are arranged opposite and exert traction along a common axis (BB') in the opposite direction.
• the mechanical stress modules 70 and 80 are arranged opposite and exert traction along a common axis (AA') in the opposite direction.
• the axes (AA') and (BB') are parallel to the surface of the skin.
• the four mechanical load modules 20, 40, 70 and 80 are supported by a frame 100 intended to be placed and stabilized on a horizontal surface of a table for example.
• the frame comprises a base 103 forming a substantially horizontal surface which extends in a horizontal plane (XY).
• the center of the base 103 is provided with a substantially circular opening 104.
• the two axes (AA') and (BB') intersect at a point located approximately at the center of the opening.
• Base 103 also includes a passageway 105 that extends from central opening 104 to an edge of the base.
• the measuring device 10 comprises a sample holder 5 visible in FIG. 2 in which the skin sample is positioned post mortem, ex vivo or in vitro.
• the sample holder is mounted on a platen 60 movable in a vertical direction (Z Z') normal to the surface of the skin and slidably mounted in a sliding means 61 such as a rail in a direction parallel to the plane (XY) of the horizontal surface 1.
• the rail extends along the axis (YY'), in the passage 105.
• the skin sample is placed in the center of the opening 104 using two positioning adjustments, along the axis (YY') in a horizontal direction and along the axis (ZZ') in a vertical direction.
• the frame 100 comprises fixing means 101, 102 to fix the base 103 by suction cup effect on the horizontal surface 1. Any other fixing means can be envisaged.
• the function of the base 103 is to provide stability to the mechanical stress modules 20, 40, 70, 80 when using the device.
• the skin sample is placed under traction means.
• Figure 2 are visible the traction means 30, 50 belonging respectively to the mechanical stress modules 20, 40.
• the first mechanical stress module 20 comprises a first translation arm 21 connected on the one hand to a first traction means 30 and on the other hand to a first displacement means 24.
• the first traction means 30 comprises a attachment head 31 (visible in Figure 4) intended to be attached to the skin sample during the tensile test.
• the first moving means 24 moves the translation arm 21, the latter also moves the traction means 30 along the axis (BB').
• the first traction means 30 makes it possible to induce a deformation of the skin sample by axial displacement of a first attachment point of the skin sample along the axis (BB').
• the second mechanical stress module 40 comprises a second translation arm 41 connected on the one hand to a second traction means 50 and on the other hand to a second displacement means 44.
• the second traction means 50 comprises a attachment head 51 (visible in FIG. 4) intended to be attached to the skin sample during the tensile test.
• the second moving means 44 moves the translation arm 41, the latter also moves the traction means 50 along the axis (BB').
• the second traction means 50 makes it possible to induce a deformation of the skin sample by axial displacement of a second point of attachment of the sample along the axis (BB').
• the third module 70 and the fourth module 80 are structurally identical to the second module 40 and to the first module 20 respectively. fixation of the sample along the axis (AA').
• the function of the two modules 20, 40 is to exert an opposing tensile force along a common axis (BB').
• the two modules 70, 80 have the function of exerting an opposing traction force along a common axis (AA').
• the mechanical stress modules 20, 40, 70, 80 are arranged around the center of the base 100. More specifically, they are aligned two by two along the 'axis (BB') and the axis (AA') with the traction means positioned opposite and positioned substantially at the center of the base 103. It is noted that the two horizontal translation axes (AA') and (BB') intersect at a point located substantially in the center of the opening 104 of the base 103. The skin sample is placed in the center of the opening of the base, under the traction means carried by the four mechanical stress modules.
• the moving means comprises a piezoelectric nano-positioning table 24, 44, 74, 84.
• One end of the translation arm 21, 41, 71, 81 is fixed to a movable part of the piezoelectric nano-positioning table for moving the traction means.
• the piezoelectric nano-positioning table makes it possible to control the deformation of the sample by axial displacement of the translation arm.
• the piezoelectric nano-positioning tables of the aligned mechanical stress modules are also aligned in pairs with respect to each other so as to have the same axis of shift.
• the piezoelectric nano-positioning table 24 associated with the module 20 and the piezoelectric nano-positioning table 44 associated with the module 40 have the same displacement axis (BB').
• the nano-positioning table piezoelectric 74 associated with the module 70 and the piezoelectric nano-positioning table 84 associated with the module 80 have the same axis of movement (AA').
• the aligned piezoelectric displacement tables are synchronized so that the displacements of the traction means are synchronized.
• the pulling force exerted by the opposing displacements of the aligned piezoelectric tables has the same value at any point on the axis of displacement.
• only one traction force sensor is needed to measure the traction force per axis of displacement between the two aligned piezoelectric nano-positioning tables.
• the measuring device comprises a single traction force sensor 22, 82 per pair of aligned mechanical stress modules, in other words per axis of displacement.
• the force sensor 22, 82 is arranged at the level of the translation arm 21, 81 which comprises a first part 21 A, 81 A and a second part 21 B, 81 B. The two parts are connected together by the through a force sensor.
• the translation arms of the other two modules are formed in one piece in one piece.
• the measuring device further comprises a position measuring sensor 27, 87 per pair of aligned mechanical stress modules, in other words per displacement axis.
• a position measuring sensor 27, 87 per pair of aligned mechanical stress modules, in other words per displacement axis.
• the position measurement sensor is a laser sensor. The laser sensor thus makes it possible to deduce the actual deformation of the skin sample under the effect of an axial displacement of a fixation point of the skin sample.
• each solicitation module further comprises a manual micrometric displacement table 25, 45, 75, 85 which makes it possible to manually adjust the position of the arm of translation along one of the translation axes before the start of the tensile test.
• the piezoelectric nano-positioning table and the micrometric displacement table are arranged relative to each other so as to have the same axis of displacement.
• the nano table piezoelectric positioning is fixed on a movable part of the manual micrometric displacement table.
• the micrometric displacement table is itself fixed to the base 103 of the frame 100.
• the two manual micrometric displacement tables 25, 45 are also aligned relative to each other so as to have the same axis of movement.
• the four displacement tables 24, 44, 25, 45 are aligned along the axis (BB').
• the traction means 30, 50 comprises a main axis Z1, Z2 oriented in a vertical direction substantially normal to the surface of the skin.
• the traction means 30, 50 comprises a substantially cylindrical body 34, 54 having at one end provided with a fixing head 31, 51, intended to be fixed to the skin 3 during the operation of the measuring device 10.
• the traction means 30, 50 is fixed by mechanical fixing means to the tip 23, 43 of the translation arm 21, 41.
• a housing 28, 48 is made in the tip 23, 43.
• the cylindrical body 34 , 54 of the traction means 30, 50 is received in the housing 28, 48 and locked in position using a clamping element 29, 49.
• the traction means 30, 50 further comprises a bearing surface ring 32, 52 located at the end of the cylindrical body which is provided with the fixing head. This bearing surface 32, 52 is able to bear against the periphery of the housing 28, 48 when the cylindrical body 34, 54 of the traction means 30, 50 is inserted into the housing.
• the traction means 30, 50 is removably and interchangeably mounted relative to the translation arm 21, 41. As shown in Figure 5, once mounted on the tips 23, 43 of the translation arms 21, 41, the two fixing heads 31, 51 are spaced apart by a distance D which can be adjusted manually using the micrometric displacement table 25, 45 which are visible in Figure 3.
• the fixing head is in the form of a fixing rod provided with a thread 33, 53 allowing the rod to be fixed in the thickness of the skin by effect of screwing.
• the fixing head 91 is in the form of a substantially cylindrical body 93, the base 95 of which is provided with a layer of glue making it possible to fix the fixing head to the surface of the skin.
• This layer of glue can be, for example, a layer of epoxy or any other glue suitable for fixing the fixing head to the surface of the skin.
• this second embodiment of the fixation head is used to obtain a fixation point on the skin sample
• the traction means 30, 50 are then taken out of the measurement zone, that is to say the center of the base with the fixing heads glued on the surface of the skin sample.
• Figure 8 an ex vivo skin sample 3 held in a fixed position in a nutritional medium 2.
• the assembly is contained in the sample holder or container 5.
• Two fixing heads 31 and 51 are fixed by screwing effect in the thickness of the skin.
• the two fixing heads are moved by the moving means along a common axis along a direction parallel to the surface of the skin.
• the displacement of each fixing head is represented by a double arrow.
• the measuring device also comprises an imaging means 110 configured to observe and record the deformation zone of the surface of the skin generated by the movement of the fixing heads.
• the imaging means 110 can be a color camera positioned above the skin of the surface with the optical axis (Z3) oriented in a direction normal to the surface of the skin, with magnifications adaptable but can also be a more precise microscopy device.
• Figure 9 is shown the movement of one of the fixing heads from an initial position Lo to a position Li in which the fixing head exerts a tensile force on the skin, causing a deformation or an extension of the skin which is represented in FIG. 9 by the distance AL traveled by the fixing head.
• the skin displacement is measured by the laser position sensor 27 (visible in Figure 3) without short-range contact projected and aligned with the axis of the translation arm 21 which moves the fixation head 31 .
• FIG. 10 schematically represents a system 200 for measuring the mechanical properties comprising the device 10 for measuring the mechanical properties, a unit 202 for controlling the means of displacement and a calculation unit 203.
• the system 200 also includes other means that make it possible to characterize the skin sample, for example a radiation diffusion system, an ellipsometer or an epi-fluorescence microscope.
• the control unit 202 comprises a control program which controls the moving means 24, 44, 74, 84 of the measuring device 10 to move the translation arms, which move the corresponding fixing head in translation in the plan of the skin sample.
• the traction force sensors 22, 42, the position measurement sensors 27, 47 and the imaging means 110 are connected to the control unit 202.
• the control unit is configured to control the displacement means according to a stress frequency of between 0.1 mHz and 1 Hz.
• the shape of the stress frequency can be sinusoidal, triangular or rectangular. More precisely, the control unit 202 is configured to control the displacement of the translation arm in a sinusoidal or triangular or rectangular manner, by varying various parameters such as the frequency of stress and the deformation of the sample.
• the stress frequency can vary between 0.1 mHz and 1 Hz, preferably between 0.1 Hz and 1 Hz and the deformation of the sample can vary between 0.001% and 10%.
• the calculation unit 203 is configured to receive signals transmitted by the sensors of the measuring device. All of the signals measured by the sensors of the measuring device are then processed by the calculation unit 203 to calculate the mechanical properties of the skin, in particular to plot the stress as a function of the deformation.
• the measurement of the complex modulus as a function of the stress frequency allows a breakdown into two values: the real part in phase with the solicitation signal makes it possible to characterize the elastic properties of the skin and the imaginary part makes it possible to characterize the dissipation properties of the skin.
• Figure 11 represents, by way of example, the measurements of the two values at different stress frequencies on a sample of pigskin at a temperature of 25°C.
• the round dots correspond to the storage modulus and the square dots correspond to the dissipation modulus.
• the device 10 of the present disclosure has been designed to make it possible to measure the mechanical properties of a sample of human skin ex vivo or in vitro as a function of several parameters.
• the device makes it possible to impose a deformation on the sample and measure the stress resulting from this deformation.
• the mechanical stresses are carried out with tractions in different directions in the plane of the skin and with different frequencies.
• the stress-strain curves obtained by the device at different frequencies make it possible to probe the elastic, plastic and viscoelastic properties of the skin subjected to stress.
• the device of the present disclosure is particularly suitable for monitoring the evolution over time of the mechanical properties of an ex vivo skin sample kept fixed on a nutritional medium for a period of several days and for establishing a link with any changes in the mechanical properties of the skin or the structure of the skin induced by an external product.
• the fact of maintaining the skin ex vivo on a nutritional medium allows the skin to keep its mechanical properties as described in the document in the document WO2013164436, unlike an in vitro sample.
• the device makes it possible to continuously monitor over time over several days the deformation of the skin and the return of the skin to its state of equilibrium by maintaining attachment points in position on the same area of the skin for throughout the duration of the test, making it possible to obtain precise and reproducible measurements of the mechanical properties of the skin.
• the device of the present disclosure can find application in the field of cosmetics and medicine and any field relating to human skin.
• the device makes it possible, for example, from measurements of mechanical properties, to evaluate the modifications of healthy skin over time due to the effect of cosmetic products such as moisturizing creams, sunscreens or anti-aging creams.
• measurements of mechanical properties make it possible, for example, to monitor the effect of products applied to promote healing or to treat an injured area. It is also possible to follow the evolution of the mechanical behavior of an area of the skin damaged by various actions such as confinement under a dressing, bedsores under the effect of friction.
• the device also makes it possible to follow the evolution of the mechanical properties of the skin in the face of environmental aggressions such as environmental pollution or the aggression of the sun's rays.

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• 2020
  • 2020-12-19 FR FR2013764A patent/FR3118180A1/fr active Pending
• 2021
  • 2021-12-17 EP EP21854928.5A patent/EP4264225A1/de not_active Withdrawn
  • 2021-12-17 WO PCT/FR2021/052389 patent/WO2022129813A1/fr not_active Ceased
  • 2021-12-17 US US18/258,089 patent/US20240053239A1/en not_active Abandoned

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