Systems and methods for treating blepharitis using tissue stress application

Abstract

A dermal conditioning device for generating at least one pressure point on at least the outer surface of an eyelid, comprising at least one skin tissue damage generator, at least one controller, a power source and a housing, wherein the controller is connected to the skin tissue damage generator, the power source is connected to the skin tissue damage generator and the controller, and the housing encloses the skin tissue damage generator and the controller, wherein the controller controls the skin tissue damage generator to generate at least one signal and applies the signal to apply stress to the outer surface of the outer layer of the eyelid, wherein the stress causes the pressure point to be formed on the eyelid without tissue coagulation, thereby activating at least one of the corneal reflex, threat reflex and tear reflex of the eyelid by activating at least one nociceptor on the eyelid.

Description

Technical Field

[0001] The disclosed technology relates generally to systems and methods for treating blepharitis, and in particular, to systems and methods for inducing ocular reflexes through the eyelids while preventing permanent damage to the skin tissue of the eyelids. Background Art

[0002] The skin is a dynamic, multi-layered organ that is in a constant state of flux as the top outer layer of cells is shed and replaced by inner cells that move up to the skin's surface. Although the overall structure of the body is consistent, the thickness of the skin varies depending on the anatomical site and the age of the individual. Anatomically, the epidermis is the outermost layer that acts as a physical and chemical barrier between the internal body and the external environment; the dermis is a deeper layer that provides structural support for the skin; and the subcutis or hypodermis is a layer deeper than the dermis that serves as an important fat reserve. The dermis is a layer composed of loose connective tissue.

[0003] The mammalian eye is a complex organ that enables mammals to have vision, including the conscious perception of light, color distinction, and depth perception. The eye is generally composed of three layers surrounding various anatomical structures. The outermost layer, called the fibrous membrane, is composed of the sclera and the cornea. The sclera is called the white of the eye in vernacular and covers most of the outer surface of the eye. The cornea is the transparent part of the eye that allows light to enter the eyeball and reach the optic nerve. Below the fibrous membrane is the uvea, which is the middle layer that includes the iris, and below the uvea is the retina, which is the innermost layer of the eye connected to the optic nerve.

[0004] The cornea and sclera are exposed to the environment and surrounding conditions, and are protected from irritants and debris by the eyelids and eyelashes. Generally similar to the skin, the cornea and sclera are lubricated by a body substance called tears (commonly referred to as tears), which is generally used to clean and lubricate the eyes in response to irritation. Tears are produced by the lacrimal glands, which are located on the upper lateral area of ​​the eye socket in the skull of mammals. When blinking, tears spread on the exposed sclera and cornea (i.e., the surface of the eye), thereby gathering in the area called the tear lake in the inner corner of the eye. Tears are discharged from the tear lake into the lacrimal sac. The tears spread on the surface of the eye are medically called tear film or precorneal membrane, and constantly coat and lubricate the sclera and cornea. The tear film itself has three different layers: the outermost lipid layer containing mainly oil, the middle water layer containing electrolytes, amino acids and proteins, and the inner mucus layer containing mainly mucin. The lipid layer of the tear film, called meibum or sebum, is produced by the meibomian glands (one per eye), which are located within the tarsus at the edge of the eyelid. The lipid layer coats the aqueous layer, preventing it from evaporating and spilling onto the cheeks. The aqueous layer of the tear film is produced by the lacrimal glands (one per eye) and forms the bulk of the tear film, while also facilitating its spread over the surface of the eye. The mucous layer is produced by the conjunctival goblet cells, directly coating the cornea and enabling the tear film to be evenly distributed over the surface of the eye.

[0005] Reference is now made to FIG. 1A , which shows a schematic diagram of an eye (generally labeled 10 and 40 ) showing the organs involved in the production of the tear film, as is known in the art. The reference 10 of FIG. 1A shows a cross-section of the eye, while the reference 40 of FIG. 1A shows a front view of the eye. Referring to the reference 10 of FIG. 1A , an eyeball 12 having a pupil 14 and a cornea 16 is shown. Above the surface of the cornea 16 is a tear film 18 , which includes three layers. As indicated by the box 20 , the three layers of the tear film 18 are shown in an expanded view as including a lipid layer 22 , an aqueous layer 24 , and a mucus layer 26 . The lipid layer 22 is the outermost layer, while the mucus layer 26 is located directly on the cornea 16 . The top and bottom portions of the eyeball 12 are covered by eyelids 27A and 27B , which have a plurality of eyelashes 28 extending therefrom. The upper eyelid 27A includes the lacrimal gland 30 and the meibomian gland 32A, while the lower eyelid 27B includes only the meibomian gland 32B. Although not explicitly shown, the eyelids 27A and 27B include the orbicularis oculi muscle, which forms the body of the eyelids 27A and 27B, between the skin (not shown) of the eyelids 27A and 27B and the gland shown in FIG. 1A. The orbicularis oculi muscle substantially surrounds the eye and is the muscle responsible for opening and closing the eyelids 27A and 27B. Therefore, the orbicularis oculi muscle enables the eye to blink and contract and relax when the eye reflex that causes blinking is activated. The conjunctiva 34 lines the inner side of the eyelids 27A and 27B, and as shown, the lacrimal gland 30 and the meibomian glands 32A and 32B are connected to the conjunctiva 34. A plurality of goblet cells 36 are located on the conjunctiva 34. The lacrimal gland 30, the meibomian glands 32A and 32B, and each of the plurality of goblet cells 36 together produce the components that constitute the tear film 18. The meibomian glands 32A and 32B produce the lipid layer 22, the lacrimal gland 30 produces the aqueous layer 24, and the plurality of goblet cells 36 produce the mucus layer 26. As shown in more detail at 40 of FIG. 1A, each time the eyelids 27A and 27B open and close via the orbicularis oculi muscle in an action known as blinking, the tear film 18 is excreted from the combination of fluids produced by the lacrimal glands 30, the meibomian glands 32A and 32B, and the plurality of goblet cells 36 and travels across the cornea, thereby keeping the surface of the cornea fluid and clean.

[0006] Reference is now made to reference 40 of FIG. 1A , which shows a front view of the eye. Eyelids 42, cornea 44, and iris 46 are shown. Lacrimal glands 48, meibomian glands 50, and a plurality of alveoli and ducts 52 connecting the meibomian glands 50 to the surface of the cornea 44 are hidden under the skin but are shown in reference 40 of FIG. 1A . The eye shown also includes a caruncle 54 and two canaliculi 56 connected to a lacrimal sac 58 (also called a tear sac) and a lacrimal duct 60. The lacrimal glands 48 supply the aqueous layer to the tear film, while the meibomian glands 50 provide the lipid layer to the tear film via a plurality of alveoli and ducts 52. Each time the eye is blinked, as the eyelids 42 move downward in the direction of arrow 62, the secretions of the lacrimal glands 48 and meibomian glands 50 that form the tear film spread on the cornea 44 in the direction of arrow 64 toward the caruncle 54. The liquid in the tear film is injected into the lacrimal sac 58 via the canaliculi 56 and then discharged via the lacrimal duct 60. The canaliculus 56, lacrimal sac 58, and lacrimal duct 60 are subcutaneous and are not normally visible.

[0007] The tear film covers the ocular surface. The functions of the tear film include providing nutrition to the ocular surface, lubricating the ocular surface, and acting as a chemical barrier to the external environment. The tear film forms a layer about 8 μm thick and, as mentioned above, is generally formed by three layers: an outer or lipid layer, a central or aqueous layer, and an inner or mucin layer. The tear film can also be viewed more as a lipid boundary layer, with mucins incorporated into the entire aqueous phase at varying concentrations. The meibomian glands and ciliary glands produce the lipid components of the tear film, including wax esters, triglycerides, free fatty acids, and neutral diesters. The lacrimal glands produce the aqueous component. Goblet cells located in the conjunctiva secrete mucus and contain film-associated glycoproteins. The proteins contained in the tear film are involved in other body processes and, in addition to providing mechanical protection for the surface of the cornea, can, for example, act as antibacterial agents, anti-inflammatory agents, and also contribute to the healing process after trauma.

[0008] Human tears contain a complex of proteins that have a dramatic effect on tear film stability and ocular surface integrity. At least 500 proteins have been identified in the tear film. These proteins in turn possess a range of functions, including bactericidal, virucidal and fungicidal activity, specific and nonspecific immune capabilities, and lipid transport capabilities. Human tear proteins can also minimize autolytic damage, attenuate ultraviolet B radiation-induced effects, inhibit serine and cysteine ​​proteases, promote ocular surface wound healing, and regulate the proliferation, motility and differentiation of corneal and / or conjunctival epithelial cells. The sources of these proteins are the lacrimal glands, ocular surface epithelium, conjunctival blood vessels and meibomian glands, as mentioned above.

[0009] The tears that form the tear film are secretions, and their main function is to lubricate the cornea and prevent the cornea from drying, to wash away foreign particles from the ocular surface, and to distribute immunoglobulins (IgA and IgG) and antimicrobial proteins to the ocular surface to prevent infection. The innate immune system of the cornea is composed of various types of cells, including epithelial cells, fibroblasts and Langerhans cells. Epithelial cells are responsible for secreting proteins such as TNF-α, IL-1, IL-6 and IL-8. Meibomian glands are larger sebaceous glands, and sebaceous glands are known to secrete a variety of proteins in non-ocular environments, such as IgA and proinflammatory cytokines (e.g., TNF-α and IL-1a). In addition, the meibomian glands are secreted by a whole plasma secretion mechanism. When the mature epithelial cells lining the tarsal ducts decompose and release their protein lipid contents into the ducts and on the ocular surface, secretion occurs.

[0010] Blepharitis is a general term for common eye diseases characterized by inflammation, sloughing, reddening and crusting of the eyelids. Blepharitis has many types and can be classified according to the apparent source of the disease. In any case, blepharitis is usually caused by any of bacterial infection in the eyelids, tear gland obstruction (which leads to the production of tears that reduce the aqueous layer of the tear film) or meibomian gland obstruction (which causes the aqueous layer of the tear film to evaporate due to the lack of sebum). In the case of insufficient supply of sebum to the eyes, blepharitis can be clinically referred to as dry eye (abbreviated as DES in this article) and is characterized by dysfunctional meibomian glands. This disease may also be referred to as meibomian gland dysfunction (abbreviated as MGD in this article), and may be the result of another meibomian gland abnormality in which the meibomian glands cannot produce enough sebum, the alveoli and / or ducts in the eyelids from the meibomian glands to the surface of the eyes are blocked, or the meibomian glands are prevented from secreting and producing enough sebum in the lipid layer of the tear film. No matter how MGD itself behaves, the result is that the lipid layer of the tear film lacks sebum, thereby causing the tear film to evaporate and causing DES.

[0011] Reference is now made to FIG. 1B , which shows a schematic diagram of a cross-section of a sample of the epidermis (generally labeled 80 ), as is known in the art. The epidermis 80 is a stratified squamous epithelium whose principal cells are called keratinocytes, which synthesize the protein keratin. The keratinocytes are in a state of constant transfer from the deeper layers of the skin to the uppermost layer of the skin. Protein bridges called desmosomes connect the keratinocytes. The epidermis 80 includes four separate layers formed by keratinocytes at various stages of keratin maturation. Moving from the outermost surface to the deeper layers, the four layers of the epidermis are: the outermost layer 82A, referred to herein as the stratum corneum 82A; the stratum granulosum 82B (also referred to as the granular cell layer); the stratum spinosum 82C (also referred to as the spinous cell layer or the thorny cell layer) and the stratum basale 82D (also referred to as the basal cell layer or the germinal cell layer).

[0012] The stratum corneum 82A is composed of a layer of hexagonal, non-viable cornified cells (called corneocytes). In most areas of the skin, there are 10-30 layers of stacked corneocytes. Each corneocyte is surrounded by a protein envelope and is full of keratin that retains water. The cell shape and orientation of keratin increase the strength of the stratum corneum 82A. Surrounding the cells are stacked layers of lipid bilayers. The resulting structure of the stratum corneum 82A provides a natural physical and water-retaining barrier for the skin. The upward movement of epidermal cells, such as from the basal layer 82D to the stratum corneum 82A, usually takes about 28 days, and this time is called the epidermal transit time.

[0013] Methods and systems for treating blepharitis, including DES and MGD, are known in the art. A common treatment includes controlling the environment in which patients with DES and MGD spend their time. This may include, for example, avoiding areas with smoke and dust, avoiding the use of hair dryers, heaters, air conditioners, and fans (especially when such devices are directed toward the eyes), and using humidifiers to add moisture to dry indoor environments. Another common treatment involves manually applying a lubricant to the eye to hydrate the eye, such as applying eye drops. More complex treatments include applying anti-inflammatory drugs to the eyelids to reduce inflammation of the meibomian glands and ducts. Surgery may also be used in extreme cases to prevent the eyelids from opening completely, which may result in reduced tear film evaporation.

[0014] Heating systems have also been suggested as a method for unclogging the ducts of the meibomian glands. For example, U.S. Patent No. 9,510,972 to Badawi, assigned to SightSciences, Inc., relates to a software-controlled device that can deliver targeted thermal energy to the meibomian glands while allowing the eyelids to blink naturally. This dry eye treatment typically includes a patch or strip that is attached to the skin of the upper and / or lower eyelids to deliver heat or other forms of energy, pressure, medication, moisture, etc. (alone or in combination) to one or more meibomian glands contained in the underlying skin. One or more treatment strips include one or more strips that are configured to adhere to an underlying area of ​​the skin near one or both eyes of a subject so that the one or more strips allow the subject to blink naturally without being restricted by the patch. The strip is configured to emit energy to the underlying area of ​​the skin and is shaped to follow the location of the meibomian glands contained in the underlying area of ​​the skin.

[0015] U.S. Patent No. 8,083,787 to Korb et al., assigned to TearScience, Inc., relates to a method of treating dry eye in a person in which the flow of naturally occurring secretions to the eye is obstructed by the presence of an obstruction in a meibomian gland in the eyelid. The method includes the steps of lifting the eyelid away from the eye and softening the obstruction by applying thermal energy to heat the obstruction to a temperature between about 37° C. and about 47° C. The method also includes the steps of clamping the eyelid between a backing plate and a force applicator such that a regulated force is applied to the eyelid to squeeze the softened obstruction out of the meibomian gland.

[0016] Other systems and methods for treating MGD and DES can be found at https: / / tearscience.com / patents. Summary of the invention

[0017] The purpose of the disclosed technology is to provide a novel method and system for treating blepharitis, meibomian gland dysfunction (MGD) and dry eye syndrome (DES) by actively inducing eye reflexes through the eyelids. The generation of skin tissue damage can enhance the induction of eye reflexes. Optionally, heat can also be applied to activate the inflammatory healing process of the eyelids.

[0018] According to the disclosed technology, a dermal conditioning device is provided for generating at least one pressure point in at least the outer surface of the eyelid without tissue coagulation. The dermal conditioning device comprises: at least one skin tissue damage generator, at least one controller, a power supply and a housing. The controller is connected to the skin tissue damage generator, and the power supply is connected to the skin tissue damage generator and the controller. The housing encloses the skin tissue damage generator and the controller. The controller controls the skin tissue damage generator to generate at least one signal and applies the signal to apply stress to the outer surface of the outer layer of the eyelid. The stress causes a pressure point to be formed on the eyelid without tissue coagulation, thereby activating at least one of the corneal reflex, threat reflex and tear reflex of the eyelid by activating at least one nociceptor on the eyelid.

[0019] According to some embodiments of the disclosed technology, the skin tissue injury generator includes at least one protrusion, and the at least one protrusion is used to generate at least one mechanical injury on the outer surface of the eyelid.

[0020] According to some embodiments of the disclosed technology, the controller controls the skin tissue damage generator to additionally apply the signal to heat the outer surface of the eyelid.

[0021] According to some embodiments of the disclosed technology, the dermis conditioning device generates a signal wherein a distal end of the dermis conditioning device is at least 37 degrees Celsius.

[0022] According to some embodiments of the disclosed technology, the dermal conditioning device generates a signal having pulses having a duration ranging between 2 milliseconds and 60 milliseconds.

[0023] According to some embodiments of the disclosed technology, the controller controls the signal by controlling a first parameter of the signal. The first parameter may be selected from the group consisting of timing, intensity, frequency, duration and phase of the signal. If heat is additionally applied, the first parameter may also be temperature.

[0024] According to some embodiments of the disclosed technology, the skin tissue damage generator comprises a heat generator.

[0025] According to some embodiments of the disclosed technology, the skin tissue damage generator includes a stress application generator.

[0026] According to some embodiments of the disclosed technology, the skin tissue injury generator includes an actuator mechanically coupled to a distal end of the dermal conditioning device and configured to apply the signal to apply stress to the outer surface of the eyelid.

[0027] According to some embodiments of the disclosed technology, the dermal conditioning device further comprises a position sensor coupled to the skin tissue damage generator for determining a depth of at least one protrusion into the outer surface of the eyelid.

[0028] According to another aspect of the disclosed technology, a method for generating at least one pressure point on at least an outer surface of an eyelid is provided. The method includes the following procedure: generating at least one pressure point on an outer surface of at least one eyelid epidermis. The method also includes the following procedure: continuously generating the pressure point until at least one of a tear reflex, a hand-blink reflex, and a blink reflex occurs in the eyelid, thereby re-initiating the function of at least one of a meibomian gland and a lacrimal gland.

[0029] According to some embodiments, the pressure point creates at least one lesion having a depth ranging between 5% and 90% of the thickness of the eyelid epidermis.

[0030] According to some embodiments of the disclosed technology, the method further comprises the procedure of activating an immune system response of the eyelid, thereby further reinitiating the function of the meibomian gland and the lacrimal gland. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The disclosed technology will be more fully understood and appreciated through the following detailed description taken in conjunction with the accompanying drawings, in which:

[0032] FIG. 1A shows a schematic diagram of the eye illustrating the organs involved in tear film production, as is known in the art;

[0033] FIG1B is a schematic diagram of a cross-section of a sample of epidermis, as known in the art;

[0034] FIG. 2A to FIG. 2C is a schematic diagram of a dermal conditioning device constructed and operative in accordance with an embodiment of the disclosed technology;

[0035] FIG. 3A to FIG. 3C Taken together are schematic diagrams of an embodiment of a dermal conditioning device of the disclosed technology, constructed and operative in accordance with another embodiment of the disclosed technology;

[0036] FIG. 3D to FIG. 3E is through FIG. 3A to FIG. 3C A schematic diagram of a sample of eyelid skin undergoing mechanical injury treatment with a dermal conditioning device constructed and operated in accordance with another embodiment of the disclosed technology;

[0037] Figure 4A Shows passing through FIG. 3A to FIG. 3C two images of a skin area after mechanical injury treatment with a dermal conditioning device constructed and operative in accordance with another embodiment of the disclosed technology;

[0038] Figure 4B is an example of a response to using FIG. 3A to FIG. 3C a graph of thermal wave penetration depth of skin treated by a dermal conditioning device constructed and operative in accordance with another embodiment of the disclosed technology;

[0039] Figure 4C It is shown in the FIG. 3A to FIG. 3C A graph of skin temperature at different skin depths within 15 ms after a pulse treatment lasting 8 milliseconds by a dermal conditioning device constructed and operated according to another embodiment of the disclosed technology;

[0040] Figure 4D It is shown in the FIG. 3A to FIG. 3C A graph of skin temperature at different skin depths within 30 ms after a 14 millisecond pulse treatment by a dermal conditioning device constructed and operated according to another embodiment of the disclosed technology;

[0041] Figure 4E is shown in response to the general Figure 2A Dermal conditioning devices, and in particular Figure 3Aa graph of the temperature of applied skin at various depths during a heating phase of a dermal conditioning device constructed and operative in accordance with another embodiment of the disclosed technology;

[0042] Figure 4F Shown in Figure 3A a dermal conditioning device that continuously performs a heating phase of 8 millisecond pulses to provide a temperature gradient of the skin at various depths, the dermal conditioning device being constructed and operated in accordance with another embodiment of the disclosed technology;

[0043] FIG. 5A to FIG. 5C is a schematic diagram of a dermal conditioning device of the disclosed technology using an optical emitter to generate heat, the dermal conditioning device being constructed and operative according to another embodiment of the disclosed technology;

[0044] FIG. 5D to FIG. 5E is a schematic diagram of a dermal conditioning device of the disclosed technology using a dry stream to generate heat, the dermal conditioning device being constructed and operative according to another embodiment of the disclosed technology;

[0045] FIG. 6A to FIG. 6B is a schematic diagram of a dermal conditioning device of the disclosed technology using an RF transmitter to generate heat, the dermal conditioning device being constructed and operative according to another embodiment of the disclosed technology;

[0046] Figure 6C is through FIG. 6A to FIG. 6B an image of a skin area after mechanical injury treatment with a dermal conditioning device constructed and operative in accordance with another embodiment of the disclosed technology; and

[0047] Figure 7 is a schematic diagram of a method for operating a leather conditioning device constructed and operated in accordance with another embodiment of the disclosed technology. DETAILED DESCRIPTION

[0048] The disclosed technology overcomes the shortcomings of the prior art by providing a novel system, device and method for treating blepharitis and inducing eye reflexes via the eyelids to thereby activate the meibomian glands and lacrimal glands to increase the sebum supply to the tear film of the eye. In particular, the disclosed technology causes the activation of the corneal reflex as well as the tear reflex and the threat reflex. The corneal reflex, also known as the blink reflex, is an involuntary blink of the eyelid caused by corneal irritation and may be caused by any external stimulus. The corneal reflex mainly protects the eye from foreign objects that attempt to touch and enter the cornea. The tear reflex, also known as the tear reflex, is usually accompanied by the blink reflex, resulting in the involuntary production of tears in response to irritants or foreign particles in or near the eye. The threat reflex, also known as the wave-blink reflex, is a blink reflex in response to the rapid movement of an object toward the eye. All of these reflexes cause the orbicularis oculi muscle to be activated, thereby causing the eyelids to open and close quickly (i.e., blink), and thereby exert a large amount of pressure on the meibomian glands and lacrimal glands. The systems, devices, and methods of the disclosed technology can further enhance the activation of the meibomian glands through optional activation of the body's inflammatory healing process. The systems and methods of the disclosed technology use a non-invasive and non-ablative process. According to the disclosed technology, sufficient pressure is applied to at least one eyelid of the eye (upper eyelid, lower eyelid, or both), that is, at at least one pressure point, thereby directly activating the nociceptors in the skin of the eyelid. The activation of the nociceptors in the skin of the eyelid when sufficient pressure is applied also leads to the activation of nociceptors on the cornea and sclera, thereby causing the activation of the eye reflex (i.e., at least one of the corneal reflex, the tear reflex, and the threat reflex), which applies pressure to the meibomian glands and the lacrimal glands when the eye blinks due to the reflex. According to the disclosed technology, the pressure on the eyelid can also produce micro-mechanical damage on the eyelid epidermis to further activate at least one of the corneal reflex, the tear reflex, and the threat reflex of the eye via the eyelid, and also activate the immune function of the eye through excessive tear production in the lacrimal gland. Activation of these eye reflexes causes the orbicularis oculi muscle to contract (ie, flex) and relax, applying pressure to the meibomian glands to secrete sebum and thereby restore gland function by flushing any blocked alveoli and ducts in the eyelid.

[0049] The orbicularis oculi muscle is located on the outside of the tarsal plate in the eye. The orbicularis oculi muscle itself can be subdivided into an orbital region surrounding the eye and a palpebral region forming the eyelid. The palpebral region includes the Riolan muscle (muscle of Riolan) surrounding the terminal portion of the meibomian gland near the end of the eyelid. When the orbicularis oculi muscle contracts to cause blinking, the Riolan muscle is also activated, which helps to keep the eyelids (when closed) tightly apposed. The activation of these two muscles (orbicularis oculi and Riolan muscles) can apply additional compression to the meibomian glands to expel any oil or debris in the alveoli, ducts and orifices of the meibomian glands into the marginal lipid reservoir, where the oil or debris can eventually become part of the lipid layer of the tear film. The activation of the body's inflammatory healing process in the eye also activates the meibomian glands to increase the production of sebum (comprising a combination of lipids and proteins) that it normally produces in order to protect the corneal tear film from damage. The minimal pressure applied to the eyelid and eye and the optional non-permanent damage caused to the eyelid and eye by the systems and methods of the disclosed technology are sufficient to cause activation of at least one of the corneal reflex, the tear reflex, and the threat reflex and signal the immune system about potential damage to the cornea, and thereby activate the release of pro-inflammatory proteins and other proteins related to the immune system produced by the lacrimal gland as part of the healing process.

[0050] According to the disclosed technology, a method of activating at least one of the corneal reflex, tear reflex and threat reflex in addition to potentially activating the immune system of the eyelid is to activate nociceptors in the epidermis of the eyelid by applying pressure to the eyelid (e.g., at at least one pressure point), which can also indirectly activate nociceptors in the cornea and sclera. The system of the disclosed technology can further apply pressure on the eyelid by generating micro-mechanical damage in the eyelid. The pressure applied to the eyelid by the disclosed technology, which is converted into mechanical pressure and optional micro-damage on the eyelid, is the cause of the activation of nociceptors on the eyelid and indirectly on the cornea and sclera. The pressure and optional micro-mechanical damage in the eyelid must be sufficient to cause the nociceptors in the epidermis of the eyelid and, relatedly, the cornea and sclera to react as if a foreign particle or object is entering the eye, near the eye, or as if an object is moving rapidly toward the eye to cause the central nervous system to initiate the corneal reflex, tear reflex and / or threat reflex. During the impact of the eyelid by the disclosed technique, the activation of nociceptors does not produce a high degree of pain. The disclosed technique can further be used to produce micro-mechanical injuries on the eyelid without causing tissue coagulation.

[0051] According to the disclosed technology, a dermal conditioning device is provided, which includes at least one non-invasive eyelid epidermis and / or epidermis / dermis mechanical injury generator, at least one controller, a power source and a housing. The controller is used to control the mechanical injury generator to apply pressure on the eyelid, and optionally to produce micro-injuries on the eyelid, which does not cause significant pain (and therefore does not cause tissue coagulation), does not cause any permanent damage to the eyelid (including the skin of the eyelid) or the eye, cornea or sclera, but does induce at least one of the corneal reflex, tear reflex and threat reflex and optionally also the inflammatory healing process of the eyelid skin that heals the damaged epidermis of the eyelid. The activation of the above-mentioned eye reflexes relieves DES and MGD by applying compression on the meibomian glands by the orbicularis oculi muscle during blinking and causing sebum to be secreted from the glands. The activation of the inflammatory healing process of the skin (e.g., due to the production of micro-injuries on the eyelid) (which also heals the damaged epidermis and dermis of the eyelid) can further relieve DES and MGD. The inflammatory healing process can be further activated by activating thermal nociceptors on the eyelids by optionally applying heat to the eyelids by the disclosed techniques. The amount of mechanical stress and heat applied to the eyelids using the disclosed techniques can affect the length of time the above-mentioned reflexes occur (implying an increase in activation of the orbicularis oculi and riolar muscles) and the length of time the body's inflammatory healing process is particularly active in the eyelids. An increase in the amount of mechanical stress and / or heat applied to the eyelids (which can also result in a slight increase in pain) can enhance relief of DES and MGD (to a certain extent). According to the disclosed techniques, the amount of mechanical stress and / or heat applied should not exceed the limit at which pain indicates potential permanent damage to the eyelids. The application of heat can induce slight tissue coagulation due to the activation of thermal nociceptors in the eyelids, which can further enhance the treatment of DES and MGD due to increased blinking of the eye.

[0052] Therefore, it is important to note that the disclosed technology activates nociceptors in the eyelid as well as the eye in order to treat DES and MGD without ever touching the eye. The devices and systems of the disclosed technology achieve this activation through a carefully controlled mechanism that can apply stress and optionally heat so that damage or injury to the eye itself (e.g., sclera and / or cornea) is prevented during treatment. In addition, even if application of the devices and systems of the disclosed technology increases the intraocular pressure in the eye, any change in intraocular pressure is instantaneous and short-lived, thereby preventing damage to the retina and optic nerve. Typical treatment and use of the device according to the disclosed technology can be between a few seconds to a few minutes per eye, thus avoiding any prolonged increase in intraocular pressure.

[0053] According to the disclosed technology, a system and method are provided in which the skin of the eyelid where the lacrimal glands and meibomian glands are located is subjected to mechanical stress and optional small mechanical damage, such as between 50-700 microns in depth or between 20-1000 microns in depth. The eyelid thickness ranges between 800-1500 microns in depth. According to the disclosed technology, damage with a depth between 5%-90% of the eyelid thickness (e.g., between 20-1000 microns) can be formed. A depth of 20 microns deep into the eyelid is essentially the starting point of the living epidermis (i.e., midway into the stratum corneum), while a depth of 1000 microns deep into the eyelid reaches the dermis and is adjacent to the threshold of significant pain upon further penetration. The damage can be formed by using strain or by mechanical force. The damage can also be formed by the additional use of heat. Thus, the disclosed technology causes epidermal damage similar to burning on the eyelid without causing coagulation of the skin tissue, but causes relatively long periods of mild pain and irritation, which may last for about 1 to 144 hours after treatment (i.e., short-term mild pain or mild pain for up to several days). In one embodiment of the disclosed technology, increased heat can be used, which can cause mild tissue coagulation, and due to the activation of thermal nociceptors in the eyelid, the relief of DES and MGD provided to the eyelid can be enhanced by causing an additional blink reflex due to the pain caused by the mild burning caused by the applied heat. In this embodiment as well, the pain can last for 1 to 144 hours. The strain and / or mechanical force applied to the eyelid by the disclosed technology causes activation of the corneal reflex, the threat reflex, and the tear reflex, as well as epidermal damage. These reflexes cause blinking and exert pressure on the meibomian glands (e.g., due to contraction of the rioron muscle). Epidermal damage also activates the body's natural inflammatory healing process, which induces the activation of epidermal growth factor (referred to herein as EGF) in the meibomian gland alveoli and ducts, thereby leading to the regeneration of glandular function. At the same time, epidermal damage together with the applied strain and / or mechanical force is not sufficient to change the viscosity of the sebum of the tear film. This is due to the working range of the dermal conditioning device of the disclosed technology, including parameters related to intensity, time, force, depth, etc., and because the strain and / or mechanical force applied to the eyelid is applied in an instantaneous manner to prevent any permanent damage to the eyelid (including changing the viscosity of the sebum of the tear film).

[0054] It should be noted that the medical model explaining the mechanism of DES shows that EGF and other tear film components such as proteins, vitamins (like vitamin A), other growth factors and hormones work in a closed-loop control system controlled by the tear glands. The tear glands balance the chemical composition of the tear film to control the behavior and function of the meibomian glands. For example, an increase in vitamin A in the chemical composition of the tear film by the tear glands will cause the meibomian glands to reduce the secretion of sebum. Conversely, a decrease in vitamin A in the chemical composition of the tear film by the tear glands will cause the meibomian glands to increase the secretion of sebum and an increase in the amount of EGF.

[0055] The corneal reflex, threat reflex, and tear reflex cause the orbicularis oculi muscles (including the ioral muscles) to contract and relax, thereby causing blinking, thereby causing tears to spread over the exposed sclera and cornea of ​​the eye. Contraction of the orbicularis oculi muscles also exerts physical pressure on the lacrimal and meibomian glands, thereby causing them to excrete tears, sebum, and meibum. According to the disclosed technology, by actively inducing the corneal reflex, threat reflex, and tear reflex, the pressure exerted by the contraction and relaxation of the orbicularis oculi muscles causes the orifices, alveoli, and ducts in both glands to be flushed, thereby clearing any blocked ducts, resetting glandular function, and providing treatment for DES and MGD.

[0056] Reflex tearing (or tear reflex as modified above) in the body is produced by strong physical or emotional stimulation of the tear glands. The tears thus produced contain essential components for the proliferation and differentiation of the corneal and conjunctival epithelium, such as vitamin A and EGF. If reflex tearing is present, they can provide the ocular surface epithelium with substances required for proper epithelial wound healing, even when basic tearing is reduced (such as during DES and / or MGD), thereby accelerating the drying of the ocular surface. According to the disclosed technology, the generation of mechanical damage in the eyelids additionally causes the body to produce the same reaction in reflex tearing. Reflex tearing leads to blinking, which is a mechanism for the spread of the tear film over the ocular surface. By slightly injuring the eyelids using the disclosed technology, the eye reflex is activated and an inflammatory healing process occurs in the epidermis and dermis of the eyelids. During this process, the tear glands produce many proteins, as mentioned above, including an increase in EGF. Tear production of EGF has a strong impact on the function of the meibomian glands, and according to the disclosed technology, the production of EGF in the tear glands leads to an inflammatory healing process in the meibomian glands, which can treat MGD as well as DES.

[0057] According to the disclosed technology, the increase of EGF present in the corneal reflex, threat reflex, tear reflex and eyelid induces the meibomian glands to secrete more meibum and sebum, thereby cleaning any blocked alveoli and ducts and alleviating the symptoms of MGD and DES. The presence of EGF has been shown to restore the normal function of the meibomian glands, including the proper production and secretion of meibum and the cleaning of alveoli and ducts. Therefore, the disclosed technology induces the lacrimal glands and meibomian glands to produce more meibum and sebum, and achieves non-invasive and non-ablative treatment of MGD and DES. According to the disclosed technology, pressure can be applied to the lower eyelid when the eyes are kept open, pressure can be applied to the upper eyelid when the eyes are closed, or pressure can be applied to both the lower eyelid and the upper eyelid when the eyes are closed. Applying pressure to the lower eyelid by the disclosed technology is sufficient to activate the threat reflex (in addition to the corneal reflex and tear reflex). As mentioned above, the amount of pressure applied is controlled and sufficient to activate the nociceptors in the eyelids and eyes, while also not significantly affecting the intraocular pressure (which may damage the retina and optic nerve). This is achieved in part by limiting the treatment time of the disclosed technology to from a few seconds to a maximum of several minutes. This is also achieved by precisely controlling the depth (in micrometers) to which the elements of the device and system of the disclosed technology can be pressed into the eyelid. Optionally, this is further achieved by precisely controlling parameters related to the amount of heat provided to the eyelid (including the amount of contact time between the heated element and the eyelid). When the eyes remain open, when the device and system of the disclosed technology moves over the lower eyelid, the moving mechanism of the disclosed technology is perceived by the eyes as a potential danger and thereby activates the threat reflex, the blink reflex, and the tear reflex. In one embodiment, as described below, the perception of the eye to the movement of the device and system of the disclosed technology can be enhanced by manufacturing certain elements of the disclosed technology from transparent materials. In addition, even if the eyes can be kept open overall when using the disclosed technology, the movement of the system of the disclosed technology is sufficient to cause the nociceptors in the eyelid to send signals to the central nervous system to activate the threat reflex, just as an object is moving rapidly toward the eye. According to the disclosed technology, in embodiments where pressure is applied to the eyelid and mechanical damage is also formed, only the epidermis and / or dermis of the eyelid is subjected to minor and non-traumatic damage. According to the disclosed technology, it is required that the skin tissue of the eyelid does not evaporate and remains intact. In one embodiment of the disclosed technology, sufficient epidermal damage is caused on the eyelid to activate the production of EGF. The body's inflammatory healing process can therefore repair the epidermis and dermis of the eyelid, while also providing treatment for MGD and DES.

[0058] The stratum corneum of the skin can absorb up to three times its weight in water and is flexible and elastic when moist, but when the water content drops significantly, the stratum corneum becomes brittle and easily breaks. This property is applicable to both humans and animals. In one embodiment of the disclosed technology, this property is used to induce the inflammatory healing process of the skin of the eyelid while maintaining the cellular integrity and activity of the skin tissue of the eyelid. According to this embodiment of the disclosed technology, the epidermis and / or dermis are fully dehydrated to make it brittle. Then stress (i.e., force per cross-sectional area) is applied to the brittle stratum corneum, which produces strain on the stratum corneum, thereby causing damage. The strain causes multiple lesions to be formed in the stratum corneum but does not ablate it. The damage induces the inflammatory healing process of the skin. In addition, the lesions formed in the upper skin layer enable water to evaporate from the deeper skin layer in response to the heat continuously applied to the outer surface of the skin, that is, the epidermis of the skin and part of the dermis below the epidermis are dehydrated. This embodiment is an optional embodiment of the disclosed technology. This embodiment may cause mild tissue coagulation through the continued application of heat, which may enhance the relief provided by the disclosed technology for DES and MGD by activating thermal nociceptors in the eyelids, thereby leading to further prolonged periods of blinking.

[0059] The conditioning of the epidermis and / or dermis includes a stress application phase or a mechanical force generation phase, which does not penetrate the skin and is therefore non-invasive. The conditioning of the epidermis and / or dermis may optionally include a mechanical injury formation phase, a heating phase, or both. The heating phase causes dehydration of the skin, and the stress application phase produces strain on the skin, thereby causing surface deformation of the skin and inducing the natural healing process of the skin. The heating phase may also cause slight tissue coagulation, thereby causing the activation of thermal nociceptors in the eyelid. For example, the amount of heat applied may be a minimum of 37°C and higher. In addition, the stress application phase may involve the use of a microneedle array that does not penetrate the epidermis. Optionally, the microneedle array can penetrate the skin in a controlled and regulated manner to no more than 20-1000 microns, thus penetrating between 5%-90% of the minimum thickness of the eyelid. As mentioned above, 20 microns is the starting point of the live epidermis of the eyelid (i.e., halfway through the stratum corneum), while 1000 microns penetrate the dermis of the eyelid and are at the boundary where the patient may feel significant pain when penetrating beyond the depth. The stress is applied to produce just enough strain on the skin surface to form a fissure, but without inducing trauma. Thus, in contrast to conventional prior art techniques, the disclosed non-ablative techniques result in minimal coagulation or denaturation of skin cells. The optional tissue coagulation phase and the non-invasive strain application phase may be applied sequentially, successively, or as a combination thereof. Additionally, unlike known prior art techniques, the disclosed techniques cause repairable skin damage without causing permanent damage to the skin, while also providing treatment for DES and MGD.

[0060] It should also be noted that the disclosed technology is described with reference to the human eye and the treatment of blepharitis in humans.

[0061] Reference now FIG. 2A to FIG. 2B , which are schematic illustrations of a dermal conditioning device, generally designated 200, constructed and operative in accordance with an embodiment of the disclosed technology. Figure 2A , dermal conditioning device 200 is shown positioned proximate to an area of ​​skin 250. The layers of area of ​​skin 250 are indicated as stratum corneum 252, stratum granulosum 254, stratum spinosum 256, and stratum basale 258. Stratum granulosum 254, stratum spinosum 256, and stratum basale 258 may be collectively referred to as the deeper layers of the skin. Figure 2A An area of ​​skin 250 is shown prior to conditioning by dermal conditioning device 200, wherein the stratum corneum 252 remains completely intact.

[0062] The dermal conditioning device 200 includes a stressor 206, a controller 208, and a power supply 210, all of which are enclosed in a housing 212. The dermal conditioning device 200 also optionally includes a heater 204. A handle 214 is attached to the housing 212. The stressor 206, the controller 208, and the power supply 210 are each electrically connected to each other via a communication bus 216, which transmits data therebetween using known techniques including any one of a wired, optical fiber, and software (e.g., communication protocol) channel. The heater 204 (if used) is also electrically connected to other elements in the housing 212 via the communication bus 216. The communication bus 216 can transmit data serially, in parallel, or in a combination thereof. The stressor 206 generates stress for applying to an area of ​​the skin 250 according to one or more stress control parameters as determined by the controller 208. The stress can be a mechanical stress, a pressure applied by an airflow, a mechanical force, etc. The stressor 206 is connected to the distal end of the dermal conditioning device 200 so that when an area of ​​the skin 250 is positioned sufficiently close to the distal end of the dermal conditioning device 200, the stress generated by the stressor 206 is applied to the area of ​​the skin 250. The applied stress produces strain on the area of ​​the skin 250 and may optionally result in the formation of multiple fissures or injuries. The applied stress also produces a corneal reflex, a threat reflex, and a tear reflex of the orbicularis oculi muscle (not shown) that exceeds the basal layer 258 of the skin 250. The stressor 206 can be considered as a mechanical damage generator for applying pressure and also for optionally producing damage in the skin tissue (e.g., in the eyelid). As mentioned above, the housing 212 can be made of a transparent material (such as a transparent plastic), thereby enabling an area of ​​the skin 250 (e.g., in terms of the lower eyelid) to sense the movement of the dermal conditioning device 200, thereby enhancing the activation of the threat reflex and the corneal reflex.

[0063] As mentioned above, optionally, the heater 204 generates heat for coagulating the area of ​​skin 250 according to one or more thermal control parameters as determined by the controller 208. The heater 204 is thermally coupled to the distal end of the dermal conditioning device 200 such that when the area of ​​skin 250 is positioned sufficiently close to the distal end of the dermal conditioning device 200, the heat generated by the heater 204 is delivered to the area of ​​skin 250. The delivered heat causes water to evaporate from the area of ​​skin 250. In this embodiment, the heater 204 and the stressor 206 can be viewed as a mechanical injury generator for generating injuries in skin tissue (e.g., in the eyelid).

[0064] like Figure 2A As shown, before the skin 250 is conditioned by the dermal conditioning device 200, the stratum corneum 252 of the area of ​​the skin 250 is smooth and completely intact without obvious cracks. In this state, the stratum corneum 252 forms a barrier between the deeper skin layers 254, 256 and 258 and the outer surface of the stratum corneum 252 facing the distal end of the dermal conditioning device 200. Therefore, the stratum corneum 252 prevents the living cells within the deeper skin layers 254, 256 and 258 from absorbing the externally applied solution.

[0065] Reference now Figure 2B , which is constructed and operated according to an embodiment of the disclosed technology Figure 2A The controller 206 and the stressor 206 and the optional heater 204 ( Figure 2A ) is a schematic block diagram of the controller 208. The controller 208 includes at least one processor 218, a memory 220, a transceiver 222, and a communication bus 224. The processor 218, the memory 220, and the transceiver 222 are electrically connected to each other via the communication bus 224. The communication bus 224 uses known techniques including any one of wired, optical fiber, and software (e.g., communication protocol) channels to transmit data. The communication bus 224 can transmit data serially, in parallel, or in a combination thereof. The transceiver 222 receives data by any known communication means, wired, wireless, or both, such as by infrared technology, technology, Ethernet technology, etc. The data may include one or more program code instructions, one or more parameters for controlling the operation of the leather conditioning device 200, etc. The memory 220 is a computer readable medium that operates to store one or more program code instructions, data, and operating parameters. The processor 218 applies the parameters to control the operation of the leather conditioning device 200 when executing the one or more program code instructions, such as controlling Figure 2A Operation of the heater 204, the stressor 206, or both.

[0066] The controller 208 controls the operation of the heater 204 and the stressor 206 to apply their respective heat and strain to the area of ​​the skin 250 sequentially, simultaneously, or in combination thereof. For example, the controller 208 may first control the implementation of the dehydration phase through the heater 204, and then control the implementation of the stress application and strain generation phase through the stressor 206. In another embodiment, the controller 208 may synchronize the operation of the heater 204 and the stressor 206 so that the dehydration phase and the stress application and strain generation phase can be implemented simultaneously. The heater 204 and the stressor 206 can work together to produce epidermal damage on the skin tissue of the eyelid. The damage can be a mechanical injury or a small burn to the eyelid.

[0067] The heater 204 includes a heat generator 224 and a heat emitter 226. The heat generator 224 is electrically coupled to the controller 208 and the power source 210 ( Figure 2A ). The heat emitter 226 is thermally coupled to the heat generator 224 and the dermis conditioning device 200 ( Figure 2A ). The heat generator 224 generates heat according to one or more heat control parameters such as temperature (in degrees Celsius - ° C), wavelength (in nanometers - nm), energy level (in joules - J), timing (in seconds), etc. The controller 208 controls the operation of the heat generator 224 according to the heat control parameters. When the area of ​​skin 250 is positioned close to the distal end of the dermis conditioning device 200, the heat emitter 226 emits the heat generated by the heat generator 224 from the distal end of the dermis conditioning device 200 onto the area of ​​skin 250. The controller 208 controls the generation of heat by the heat generator 224 and the emission of heat by the heat emitter 226 to cause dehydration of the area of ​​skin 250, so that the water content of the stratum corneum 252 is less than 10% and the water content of the granular layer 254 is less than 70%. For example, the controller 208 controls any of the timing, frequency, temperature and intensity of the heat emitted by the heat emitter 226. Controller 208 may receive feedback from one or more sensors (not shown) regarding the state of area of ​​skin 250 and adjust the generation of heat by heat generator 224 and the emission of heat by heat emitter 226 accordingly.

[0068] According to the disclosed technology, the following formula is used to determine the parameters for operating the heater 204. For a constant heat capacity, the amount of energy required to evaporate water can be calculated as:

[0069] Energy = (mass) × (temperature difference) × (specific heat capacity) (1)

[0070] Even though living skin tissue does not have a constant heat capacity, the variation in specific heat of skin tissue over a fairly narrow temperature range below 100°C is quite small, and the error resulting from assuming a constant heat capacity is correspondingly small. For example, at atmospheric pressure, the specific heat capacity at constant pressure varies from 4.183 kJ / (kg·K) at 20°C to 4.194 kJ / (kg·K) at 80°C, a variation of only 0.3%. For other substances, such as superheated water, the variation in heat capacity with respect to temperature and pressure can be significant. At 350°C (200 bar), the heat capacity is 8.138 kJ / (kg·K), almost twice the heat capacity at 20°C at the same pressure. Therefore, the amount of heat required to evaporate water from living skin tissue can be calculated as the sensible heat (Q sh ) and latent heat (Q lh ). In the context of the disclosed technology, sensible heat refers to the amount of heat required to heat a tissue so that its surface temperature (usually 32°C) is about 100°C. Latent heat is the amount of heat required to change the state of the heated water from liquid to vapor. Therefore, the amount of heat required, Q Th The sum of the sensible heat and the latent heat is given by:

[0071] Q Th =Q sh +Q lh (2)

[0072] The sensible heat is calculated as the specific heat capacity of water multiplied by the temperature change. The latent heat is calculated as the specific latent heat of water multiplied by the amount of water (which is measured as the mass of water). Therefore, the amount of heat required can be rewritten as:

[0073] Q Th =C m (T2-T1)+mL (3)

[0074] Where L is the specific latent heat (for water, the specific latent heat is 2264.76 kJ / (kg·K)), m is the mass (kg), C m is the specific heat capacity of water (4.2 kJ / (kg·K)); T2 is the final temperature of the skin (°C), and T1 is the initial temperature of the skin (°C). The direct heat transfer (flow) from the distal end of the dermal conditioning device 200 to the different layers of the skin 250 can be determined by the following general equation:

[0075]

[0076] More specifically, the thermal potential difference is expressed by the temperature difference T i -T j Multiplying the thermal conductivity k and the thermal conductivity area A gives, and the thermal resistance is given by the thickness of the skin. Therefore, direct heat transfer is determined by the following more specific equation:

[0077]

[0078] Where q is the heat flow, T i -T i-1 is the temperature difference within each cortex, Δx a , Δx b is the thickness of layers a and b, A is the thermal conductivity area of ​​the skin, and k a , k b are the thermal conductivities of skin layers a and b, respectively.

[0079] The amount of heat absorbed by an area of ​​skin 250 is a function of the distance between the thermal emitter 228 positioned at the distal end of the dermal conditioning device 200 and the skin 250 and the thermal properties of the skin 250. Because the skin 250 is relatively large compared to the distal tip of the dermal conditioning device 200, the distal tip of the dermal conditioning device 200 can be analyzed as a concentrated mass. In a concentrated mass, the internal temperature remains essentially consistent throughout the heat transfer process, and the temperature (T) can be considered to be a function of time (t) only, thus obtaining T(t). The heat transfer of the concentrated mass model is the amount of heat transferred to the area of ​​skin 250 within the time interval dt, which is equal to the energy increase of the area of ​​skin 250 within the time interval dt, and can be mathematically expressed as the contact area (A) of the dermal conditioning device 200 with the area of ​​skin 250. s ) multiplied by the temperature difference (T ∞ -T). This is equivalent to the mass (m) of the area of ​​skin 250 being treated multiplied by the specific heat of skin 250 c p , and can be expressed as the following formula:

[0080] H s (T ∞ -T)dt=mc p dT (6)

[0081] Where h is the heat transfer coefficient (W / (m 2 ·K)), A s is the contact area of ​​the dermal conditioning device 200 with the area of ​​the treated skin 250, T ∞ is the final temperature of the area of ​​skin 250 (° C.), T is the initial temperature of the area of ​​skin 250 (° C.), m is the mass of the area of ​​skin 250 treated (kg), and c p is the specific heat of the skin 250 area (Kg·m 2 / (K·s 2 )). Note that m=ρV, where ρ is the density of the area of ​​skin 250 (kg / m 3 ), V is the volume of the treated skin 250 area (m 3 ), equation (5) can be rewritten as:

[0082]

[0083] It can be solved as follows:

[0084]

[0085] in

[0086]

[0087] Heat generator 226 may be implemented using any known technology for generating heat according to the following examples:

[0088] The heat generator 226 may be a mechanical heat generator that generates heat via friction;

[0089] The heat generator 226 may be a heat generating element thermally coupled to a thermally conductive element forming a heat emitter 228 disposed at the distal end of the dermis conditioning device 200;

[0090] The heat generator 226 may be a heat producing element coupled to an air pressurizer fluidly coupled to the distal end of the dermis conditioning device 200 via a plurality of air channels forming a heat emitter 228;

[0091] The heat generator 226 may be an infrared (herein IR) or near IR laser emitter optically coupled to a heat emitter 228 configured as a plurality of fiber optic channels disposed at the distal end of the dermal conditioning device 200; and

[0092] The heat generator 226 may be an RF signal transmitter electrically coupled to a heat emitter 228 configured to conduct the RF signal from the distal end of the dermal conditioning device 200 .

[0093] Regardless of how the heat is generated, the amount of heat generated is applied in an instantaneous manner (i.e., non-continuously) so as not to distort or permanently damage the skin tissue of the eyelid. This is achieved by applying heat intermittently according to how the heat is generated. In the case of heat transfer via radiation (like in the case of laser or RF signals), the pulse repetition rate (e.g., between 2-60ms) is such that each individual pulse does not distort the skin tissue but is strong enough to cause skin tissue damage. In the case of heat transfer via convection or conduction, heat is applied instantaneously to the eyelid (again, for example, at a pulse rate between 2-60ms) via on-off switching (such as with pressurized air) or via advancement and retraction of the element and the skin (such as with a heated element). As described above, the above description of the heater 204 represents an embodiment of the disclosed technology, in which heat is applied to the skin tissue of the eyelid in addition to applying mechanical stress or force. However, the disclosed technology does not require heat to work and can be achieved only by applying mechanical stress or force (as described below) to the skin tissue of the eyelid.

[0094] The stressor 206 includes an actuator 230 and a stress applicator 232. The actuator 230 and the stress applicator 232 are coupled to each other so that when the area of ​​skin 250 is positioned sufficiently close to the distal end of the dermal conditioning device 200, the force actuated by the actuator 230 is transmitted by the stress applicator 232 to the area of ​​skin 250. For example, the actuator 230 may be mechanically coupled, electrically coupled, or fluidically coupled to the stress transmitter 232. FIG. 5A to FIG. 5E Exemplary embodiments are described in more detail in , however, these examples are not intended to be limiting. The actuator 230 is electrically coupled to the controller 208 and the power source 210 ( Figure 2A ). The actuator 230 generates stress according to one or more stress control parameters, such as force (in Newtons-N), energy level (in Joules-J), frequency (in Hertz-Hz), phase (in seconds), timing (in seconds), etc. The actuator 230 can be any known stress actuator, such as an electric motor (e.g., a brushed DC motor, a brushless DC motor, a linear motor, etc.), a piezoelectric element, an RF transmitter, etc., and embodiments thereof are described below. FIG. 6A to FIG. 6B. The actuator 230 may also be embodied as any type of piston or actuator, such as a hydraulic piston, a pneumatic piston, a magnetic piston, a piezoelectric piston, an electromagnetic actuator (e.g., a linear electromagnetic actuator, a rotary electromagnetic actuator, etc.), a voice coil actuator, etc. In some embodiments of the disclosed technology, the actuator 230 may be any type of piston or actuator for precisely moving an element over a small distance. The controller 208 controls the operation of the actuator 230 according to the stress control parameters mentioned above. The stress applicator 232 transmits the stress generated by the actuator 230 from the distal end of the dermal conditioning device 200 to the area of ​​the skin 250. In response to the applied stress, strain is generated on the area of ​​the skin 250, resulting in the formation of multiple injuries. The depth to which the stress applicator 232 extends into the area of ​​the skin 250 is controlled by the controller 208, which may additionally include a motion controller (not shown). The stressor 206 may also include a position sensor (not shown) for determining the depth to which the stressor 232 has extended into the area of ​​the skin 250. The position sensor may be embodied as an encoder (such as a magnetic encoder, an optical encoder, etc.) or a Hall Effect sensor (analog or digital). As mentioned above, Figure 2A and Figure 2B The dermal conditioning device can be used on the upper eyelid with the eyes closed, on the lower eyelid with the eyes open, or on both eyelids (upper and lower) with the eyes closed.

[0095] refer to Figure 2C, the dermal conditioning device 200 is shown adjacent an area of ​​skin 250 after treatment by the dermal conditioning device 200. The area of ​​skin 250 is slightly damaged, exhibiting multiple lesions 260 within the dehydrated stratum corneum 252 and down to the first skin layer 254 among the deeper skin layers. The stratum corneum 252 may be thinner after treatment by the dermal conditioning device 200 than before treatment. The multiple lesions 260 are caused by the strain produced on the skin 250 due to the stress applied by the stress applicator 232. The multiple lesions 260 may be enhanced by the additional application of heat applied by the thermal emitter 228. Each of the multiple lesions 260 provides sufficient damage so that the thermal nociceptors report enough pain to the central nervous system to trigger the body's inflammatory healing process in the eyelid, but not so severe that significant tissue coagulation occurs. It should be noted that after conditioning by the dermal conditioning device 200, the cellular structure within the stratum corneum 252 and the deeper cortical layers 254, 256 and 258 remains substantially intact, thereby showing minimal trauma. In the case of being applied to the eyelid, the cellular structure of the stratum corneum and the deeper cortical layers shows sufficient structural changes to induce the body's healing process, thereby leading to the production of EGF that helps treat DES and MGD. The stress applied by the disclosed technology on the eyelid is sufficient to indirectly cause the corneal and scleral nociceptors to report the possibility that foreign objects or particles are approaching the eye or are moving rapidly toward the eye, thereby causing the central nervous system to trigger any one of the corneal reflex, threat reflex and tear reflex. As mentioned above, this can be achieved by the stressor 206, but without producing micro-damage, but only applying pressure on the lower eyelid, upper eyelid or both. The stressor 206 can additionally cause micro-damage in the eyelid, thereby further activating the above-mentioned reflex and also causing the inflammatory healing process of the eyelid to be activated. The inflammatory healing process may be further activated by applying heat to the eyelid, optionally by the heater 204. The stressor 206 thus activates nociceptors in the eyelid and eye to treat DES and MGD without touching the eye itself. The stressor 206 may be applied to the eyelid at various locations to cover the outer surface of the eyelid in a range between 10%-80% of the total outer surface of the eyelid. The stressor 206 may generate a pulse train for a total time period of 1-30 seconds, 1-4 minutes, 2-3 minutes, or any other time range from seconds to minutes. The application of the stressor 206 to the eyelid is thus instantaneous and brief (relatively speaking), thereby not causing any prolonged changes in the intraocular pressure of the eye and preventing damage to the retina and / or optic nerve.

[0096] Controller 208 controls the heating of the skin 250 by controlling heater 204 to generate sufficient heat to dehydrate the area of ​​skin 250 without causing thermal damage to any surface or deeper layers of the area of ​​skin 250. Figure 2A and Figure 2CConditioning of the indicated skin 250. The heater 204 generates heat and applies the heat to the outer surface of the stratum corneum 252 of the skin 250, thereby causing the water stored therein to evaporate. In one embodiment, the controller 208 controls the temperature, intensity, and timing of the heat generated by the heater 204 to cause water to evaporate from the epidermal layers (e.g., the stratum corneum 252 and the deeper dermal layers 254, 256, and 258) of the skin 250 until the corresponding water content of the stratum corneum 252 is less than about 10% and until the corresponding water content of the extracellular matrix (abbreviated herein as ECM) of the granular layer 200B is less than about 70%.

[0097] The controller 208 also controls the stressor 206 to generate stress, which, when applied to the stratum corneum 252 from the outside, causes strain on the stratum corneum 252, thereby activating the corneal reflex, threat reflex and tear reflex of the eye. In the case of optionally using the heater 204, the stress generated by the stressor 206 can additionally cause strain on the dehydrated stratum corneum 252 sufficient to rupture the dehydrated stratum corneum. The stressor 206 generates stress and applies the stress to the outer surface of the stratum corneum 252, but does not penetrate the stratum corneum 252. The stressor 206 can also generate stress that penetrates the outer surface of the stratum corneum, thereby causing multiple lesions 260 to form and trigger an immune response. Therefore, the conditioning of the skin 250 by the dermal conditioning device 200 is non-invasive or minimally invasive. The size and depth of the multiple lesions 260 can be within the depth range of 20 to 1000 microns and can have a diameter of up to about 700 microns. The depth mentioned corresponds to about 5%-90% of the minimum thickness of the skin tissue of the eyelid. The ratio of damaged tissue to undamaged tissue in the conditioned stratum corneum 252 may be in the range of between 1% and 30%. The ratio may be, for example, the ratio of the width of the plurality of lesions 260 to the width of the intact area of ​​the stratum corneum 252. In another embodiment of the disclosed technology, the stressor 206 may be embodied as a plurality of heated tips that may be advanced and retracted into the skin 250. In this embodiment, the plurality of heated tips are used to pierce the stratum corneum and granular layer in a controlled and regulated manner to a depth of between 20-1000 microns. The plurality of heated tips may be embodied as an array of heated needles. The following is a description of the invention in detail. FIG. 3A to FIG. 3C This is described in more detail in . In general, when the dermal conditioning device 200 is used on the eyelid, the housing 212 can be placed up to 3 mm from the lash line.

[0098] Reference now FIG. 3A to FIG. 3C , which together are schematic diagrams of one embodiment of a leather conditioning device of the disclosed technology, generally designated 300, which is constructed and operated in accordance with another embodiment of the disclosed technology. In the following description, the leather conditioning device 300 is understood to be operable to perform the above-mentioned FIG. 2A to FIG. 2CAny of the procedures and / or functions described in the dermis conditioning device 200. Figure 3A , the dermal conditioning device 300 includes a controller 308, a power source 310, corresponding communication buses 316A, 316B and 316C, a heater 304 (which includes: a heat generator 326, shown as a thin element at the distal end of the housing 312; and a heat emitter 328, shown as a thermally conductive surface of a set of pyramidal teeth at the distal end of the dermal conditioning device 300), an actuator 330, a shaft 334, an actuator tip 332, and a rangefinder 336. Review FIG. 2A to FIG. 2B , while still referring to Figure 3A , controller 308 corresponds to controller 208, power supply 310 corresponds to power supply 210, heater 304, heat generator 326, and heat emitter 328 correspond to heater 204, heat generator 226, and heat emitter 228, respectively, and actuator 330 and actuator tip 332 correspond to actuator 230 and stress applicator 232, respectively. Therefore, heater 304, heat generator 326, heat emitter 328, actuator 330, and actuator tip 332 together may be considered an epidermal injury generator.

[0099] The controller 308, the actuator 330, and the power source 310 are electrically coupled via a communication bus 316A. The controller 308 and the power source 310 are electrically coupled to the heat generator 326 via communication buses 316B and 316C, respectively. The actuator 330 is mechanically coupled to the actuator tip 332 via a shaft 334. The actuator 330 is a linear motor that is operable according to a stress parameter to extend the actuator tip 332 distally beyond the rangefinder 336 in alignment with the longitudinal axis (Y) of the dermal conditioning device 300, and to retract the actuator tip 332 proximally behind the rangefinder 336. A more detailed description of the actuator tip 332 is provided below. Figure 3B Given in.

[0100] The heater 304 is positioned at the distal end of the dermis conditioning device 300, near the actuator tip 332. The heater 304 can be embodied using any suitable technology known in the art. For example, the heat generator 326 of the heater 304 can be a thermal heater, such as a ceramic heater. Alternatively, the heat generator 326 of the heater 304 can be a laser light source. The heater 304 provides constant heat to the distal end of the dermis conditioning device 300. In one embodiment, the heat emitter 328 is a thermally conductive coating on the actuator tip 332, so that the heat emitter 328 forms the distal end of the dermis conditioning device 300 together with the actuator tip 332. In this embodiment, the heat generator 326 of the heater 304 is thermally coupled to the heat emitter 328, such as by using a spring (not shown) or alternatively by using a thermally conductive adhesive, and the spring presses the heat generator 326 against the proximal base of the heat emitter 328 and the actuator tip 332 to ensure thermal matching. The controller 308 controls the operation of the heat generator 326 of the heater 304 to maintain the heat emitter 328 at a constant effective temperature of approximately 600°C during operation of the dermal conditioning device 300. In another embodiment of the disclosed technology, the temperature of the heat emitter 328 is maintained at a constant effective temperature of at least 37°C during operation of the dermal conditioning device 300. In terms of the eyelids, an effective temperature of at least 37°C during operation will cause sufficient cauterization to the eyelids to induce the body's natural healing process while nevertheless avoiding permanent damage and trauma to the eyelids. Higher temperatures can induce tissue coagulation via activation of thermal nociceptors in the eyelids (without causing permanent damage or trauma to the eyelids, nor damaging the eye itself). In embodiments of the disclosed technology that also use heat, the higher temperature of the heat emitter 328 can also enable the actuator tip 332 to be in contact with the eyelid for a shorter time. In general, it should be noted that the actuator tip 332 transfers heat to the eyelid in an instantaneous manner. According to the disclosed technology, dermal conditioning of the eyelid is performed by transient (i.e., time-dependent) heat transfer rather than a steady-state heat transfer mechanism. This is achieved by a harmonic oscillatory motion of the actuator tip advancing and then retracting, thus resulting in transient heat transfer. As mentioned above, application of heat to the eyelid is optional, and the disclosed technology primarily uses mechanical stress or force on the eyelid to induce corneal reflexes, threat reflexes, and tear reflexes that do not require heat. The use of heat on the eyelid can enhance the treatment of DES and MGD by the disclosed technology.

[0101] refer to Figure 3B , showing a perspective view of the dermis conditioning device 300. An actuator tip 332 is disposed at the distal end of the dermis conditioning device 300. The actuator tip 332 includes an array of pyramidal protrusions 338 aligned with the longitudinal axis (Y) of the dermis conditioning device 300. Figure 3B, protrusion 338 is shown as a pyramidal protrusion with a square base. This is merely an example, as protrusion 338 may have different geometries and shapes. For example, the base shape of protrusion 338 may be triangular, circular, oval, and other known geometric shapes. Protrusion 338 may also have a conical shape, a rod shape, a rectangular shape, etc. The apex of the array of protrusions 338 forms the distal end of the dermal conditioning device 300. As shown, the apex of protrusion 338 is sharp. However, in another embodiment of the disclosed technology, the apex (i.e., the distal end) of protrusion 338 may be blunt, for example, having a flat surface or a rounded surface, wherein each distal end of protrusion 338 covers 0.01-5mm 2 In one embodiment, the actuator tip 332 includes an area covering approximately 1 cm 2 The surface area of ​​the distal end of each protrusion 338 (e.g., the surface area of ​​the stratum corneum 252 ( Figure 2A The surface area of ​​the contact is about 1.27x10 -4 m 2 . The spacing between the contact area of ​​the skin 250 and the array of protrusions 338 of the actuator tip 332 is sufficient so that at any point in time, the temperature of any one of the contact areas of the skin 250 with any one of the array of protrusions 338 is thermally affected by only one of the array of protrusions 338. Therefore, throughout the treatment process, there is an area between the areas of the skin 250 that are in contact with the array of protrusions 338 that is maintained at normal body temperature (i.e., 37°C). The protrusions 338 can be made of a biocompatible, thermally conductive, and thermoelastic material, such as gold-plated titanium, tungsten, tantalum, or gold-plated stainless steel. In one embodiment of the disclosed technology, the thermal conductivity of the protrusions 338 is less than the thermal conductivity of gold-plated copper so that the stratum corneum 252 ( Figure 2A ) is sufficient to cause dehydration but not to cause skin 250 ( Figure 2A ) in the area of ​​the eyelid. With respect to the placement of the array of protrusions 338, in the case where the dermal conditioning device 300 is used on the eyelid, the edge of the array of protrusions 338 can be placed up to 3 mm from the eyelash line.

[0102] It should be noted that all materials in the dermis conditioning device 300 that come into contact with the body (human or animal) need to be biocompatible. Since biocompatibility may depend on temperature (because some materials lose their biocompatibility when a threshold temperature is exceeded), the materials in the disclosed technology that come into contact with the body need to be such that they maintain their biocompatibility within the temperature range (e.g., between 37° C.-600° C.) in which the dermis conditioning device 300 can be used. It should be noted that in the case where the heater 304 is embodied as a laser, the dermis conditioning device 300 can use even higher temperatures.

[0103] The rangefinder 336 of the dermal conditioning device 300 is disposed at the respective distal end of the dermal conditioning device 300. When the dermal conditioning device 300 is not in use, the rangefinder 336 encompasses the array of protrusions 338. During treatment, the actuator 330 advances the actuator tip 332 distally so that the distal end of the protrusion 338 extends distally beyond the rangefinder 336 by approximately 400 microns (abbreviated herein as μm). In another embodiment of the disclosed technology, the actuator 330 advances the actuator tip 332 distally so that the distal end of the protrusion 338 extends distally beyond the rangefinder 336 by approximately 20-1000 μm. The actuator 330 may advance and retract the actuator tip 332 in a harmonic pulsating motion according to a predetermined pulse duration and a predetermined number of pulses for each treatment as controlled by the controller 308, thereby causing frictional heat on the stratum corneum 252 in addition to stress. For example, to fully advance and retract the actuator tip 332, the duration of the harmonic pulsating motion may be 2-60 milliseconds. It should be noted that in one embodiment of the disclosed technology, the rangefinder 336 may be made of a transparent material so that the eye may more easily perceive the advancement and retraction of the actuator tip 332 (or any other moving element of the dermal conditioning device 300) when the actuator tip 332 is applied to the lower eyelid while the eye remains open. The eye's enhanced perception of the movement of the actuator tip 332 may enhance the activation of the threat reflex (i.e., the wave-wink reflex) and the corneal reflex (i.e., the blink reflex) because the eye may more easily perceive an object moving toward it. In another embodiment of the disclosed technology, the housing 312 ( Figure 3A ) is made of transparent material to achieve the same effect.

[0104] During contact of the plurality of protrusions 338 with an area of ​​the skin 250, the distal ends of the array of protrusions 338 depress the surface of the skin 250 but do not penetrate the stratum corneum 252 ( Figure 2A). Multiple protrusions 338 depress the surface of the skin 250 in a non-invasive manner. The depth of depression is in the range of 0.1 millimeter (mm) to 1mm, or 0.05 to 1.2mm, or 0.2mm to 0.8mm, or 0.3mm to 0.7mm, or 0.4 to 0.6mm or 0.05mm to 0.7mm. Therefore, the conditioning of the skin 250 by the dermal conditioning device 300 is non-invasive. The contact time between the protrusion 338 and the skin 250 varies between 1-20 milliseconds (abbreviated as ms in this article) to allow sufficient heat transfer between the array of protrusions 338 and the skin 250, thereby causing sufficient dehydration of the skin 250 without substantially condensation or burning. Typical pulse durations may be in the range of 8ms to 14ms, or 5ms to 20ms, or from 10ms to 15ms, or 5ms to 15ms, or 6ms to 16ms, or 2ms to 60ms. In one embodiment, the distance of the harmonic pulsating motion of the actuator tip 332 can be in the range of between 0.02 mm and 1.50 mm along the longitudinal axis of the dermal conditioning device 300. As mentioned above, the pulsating motion of the actuator tip 332 can last for as short as a few seconds and as long as a few minutes during the treatment. The combination of the pulsating motion of the actuator tip 332 and the heating of the heater 304 causes the area of ​​the skin 250 to heat up rapidly, thereby causing water to evaporate from the surface of the skin 250 and the stratum corneum 252 to rupture. In addition, once the stratum corneum 252 ruptures, the continued application of heat by the heater 304 draws water from the deeper skin layers 254, 256, and 258 ( Figure 2A ) evaporates. It should be noted that in one embodiment, the rangefinder 336 can be replaced by a position sensor in the housing 312 (as described above in Figure 2A and Figure 2B As described in ), the position sensor is connected to the controller 308 and the actuator 330 to accurately determine the distance that the protrusion 338 extends into the stratum corneum 252.

[0105] Reference now Figure 3C , it is Figure 3A Schematic diagram of another embodiment of the distal end of the dermis conditioning device 300. The heater 304 ( Figure 3A) includes a heat generator 326 positioned proximal to the actuator tip 332. The heat generator 326 can be an optical emitter, such as an intense pulsed light (abbreviated herein as IPL) light source, an IR or near-IR light source, a solid-state laser diode, etc., and the heat emitter 328 includes a plurality of optical channels embedded in a plurality of protrusions 338, which guide light from the heat generator 326 to the distal end of the dermal conditioning device 300. The heat generator 326 can thus generate heat by emitting radiation. The heat generator 326 can be implemented as a fractional CO2 laser having a tissue penetration depth of 25μm, 50μm, or 100μm. The heat generator 326 can emit light having a wavelength of 2.94μm, which corresponds to the maximum absorption peak of water. Alternatively, the optical channel of the heat emitter 328 can be positioned outside and adjacent to the array of protrusions 338. The controller 308 ( Figure 3B ) synchronizes the harmonic pulsating motion of the actuator tip 332 with the light emission of the heat generator 326. For example, the controller 308 may control the IR laser emission of the heat generator 326 so that the IR laser is emitted only when the array of protrusions 338 is in physical contact with the area of ​​skin 250. This may provide a safety measure that prevents IR laser emission unless the device is in physical contact with the surface of the area of ​​skin 250. Alternatively, a sensor (not shown) may sense contact between the actuator tip 332 and the area of ​​skin 250 and notify the controller 308 to activate the heat generator 326. When no contact is detected between the actuator tip 332 and the area of ​​skin 250, the sensor may similarly notify the controller 308 to deactivate the heat generator 326. The heat generator 326 may also be embodied as a non-radiative emitting heating device and may transfer heat via convection or conduction.

[0106] Reference now FIG. 3D to FIG. 3E , they are used FIG. 3A to FIG. 3C Schematic diagram of a sample of eyelid skin being treated for mechanical damage using a dermal conditioning device (generally designated 300), which is constructed and operated according to another embodiment of the disclosed technology. Figure 3D shows an area of ​​skin 250 prior to conditioning by dermal conditioning device 300, and Figure 3E An area of ​​skin 250 is shown after being conditioned by dermal conditioning device 300. Figure 3D , the surface temperature of skin 250 is 37°C (normal skin temperature) and skin 250 is very hydrated. Stratum corneum 252 is intact, acting as a barrier between the outer surface of skin 250 and the deeper dermal layers 254, 256 and 258. Figure 3E , the skin 250 is damaged. There are multiple injuries 260 in the stratum corneum 252 and deeper skin layers 254, which serve to activate the corneal reflex, threat reflex and tear reflex of the eye and optionally induce the body's inflammatory healing process.

[0107] In one embodiment, to achieve this conditioning of the skin area 250, the controller 308 controls the heat generator 326 to increase the temperature of the distal end of the dermal conditioning device 300 to as high as 600°C. The temperature can also be increased to a minimum of 37°C. The higher temperature of the distal end of the dermal conditioning device 300 can reduce the contact time between the distal end and the skin 250. The controller 308 sends a control signal to the actuator 330 to drive the actuator tip 332 with a pulse in the range of 2ms to 60ms. This pulse range is given as an example only, and the pulse range can vary from 2ms to 60ms. According to the disclosed technology, the duration of the stress pulse and the surface temperature of the distal end of the dermal conditioning device 300 are calculated based on the following equations between the penetration depth of the heat wave and the thermal characteristics of the area of ​​the skin 250 (which are analyzed using the lumped system analysis given above in equations (6)-(9)):

[0108]

[0109] where δδ is the penetration depth of the thermal wave in meters; α is the thermal diffusivity in m 2 / s; t is time in seconds; k is thermal conductivity in W / m·°K; ρ is density in Kg / m 3 As a unit; and C p is the heat capacity at constant pressure, expressed in J / (Kg·°K).

[0110] Table 1 below gives the thermal conductivity properties of a region of skin 250 .

[0111]

[0112] Table 1: Thermal conductivity of different layers corresponding to tissue density and heat capacity of the area of ​​skin 250

[0113] The heat transfer from the actuator tip 332 to the area of ​​the skin 250 can be calculated according to the following equation:

[0114] hot 通量 =∫∫(total heat flux)dA (11)

[0115] Equation (11) describes the heat flux of each protrusion 338 array corresponding to the area of ​​skin 250. According to equation (11), the heat flux is calculated by integrating the heat flux per protrusion 338 over the contact surface area A of each protrusion 338 with the surface skin 250. Therefore, the total energy transferred to the area of ​​skin 250 can be expressed by the following equation:

[0116]

[0117] This equation describes the amount of energy delivered to the skin 250 from each protrusion 338 for each pulse of duration t, and it is expressed by the heat 通量 (calculated in the above equation (11)) is calculated by integrating.

[0118]

[0119] This equation describes the amount of energy delivered from the actuator tip 332 to the skin 250 per pulse, which is calculated by multiplying the amount of energy delivered per protrusion 338 per pulse by the number of protrusions 338, n, Figure 3B In the illustrated embodiment, the number n is 81. The plurality of protrusions 338 may be arranged as desired. For example, the plurality of protrusions 338 may be arranged in a 4×6 array, a 12×12 array, a 10×10 array, a 15×15 array, a 10×15 array, and the like.

[0120] Table 2 below shows the amount of heat transferred from the actuator tip 332 to the skin 250 and the depth of heat penetration for each of a pulse of 8 ms duration and a pulse of 14 ms duration, as determined by finite element analysis of the dermal conditioning device 300 (as described above in equations (6)-(9)):

[0121] Pulse duration (ms) Heat transfer (J) Heat penetration(μm) 8 0.024 76 14 0.035 100

[0122] Table 2: Amount of heat (J) transferred to the skin 250 through the actuator tip 332 at different pulse durations (8 ms and 14 ms) and the thermal penetration depth (μm) of the applied heat

[0123] As mentioned above, the plurality of lesions 260 may also be formed by simply advancing and retracting the protrusions 338 into the stratum corneum 252 to a predetermined depth using sufficient mechanical stress and force without applying heat.

[0124] Reference now 4A to 4D , which illustrate the effects of skin 250 on the skin using an embodiment of the disclosed technology in which heat is applied at pulse durations of 8 ms and 14 ms. FIG. 3A to FIG. 3E The response of the dermal conditioning device 300 to treatment was obtained from a finite element analysis of the skin using equations (6)-(9) as given above. Figure 4A , showing that after using FIG. 3A to FIG. 3E Two images of a skin area after mechanical injury treatment by a dermal conditioning device, generally designated 250, constructed and operated in accordance with another embodiment of the disclosed technology. It should be noted that Figure 4AThe images shown are given as examples only, and the examples shown are from pig skin. Skin 250 is shown as having lesions extending through stratum corneum 252, stratum granulosum 254, and partially into stratum spinosum 256. As shown, lesion 260A has a width of 172.56 μm and a depth of 156.15 μm, and lesion 260B has a width of 297.81 μm and a depth of 212.04 μm. The width and depth of lesions 260A and 260B are given as examples only, and according to the disclosed technology, deeper and wider lesions are possible, for example, with a depth of between 20-1000 μm and a width of up to 700 μm. Skin 250 is punctured by protrusions 338 ( Figure 3B ) mechanical penetration. The skin 250 may also be dehydrated and treated by the dermal conditioning device 300 ( FIG. 3A to FIG. 3E ) is produced by a combination of non-invasive compressive loads / stresses applied to the stratum corneum 252, and the resulting strain on the stratum corneum 252 is caused by this stress.

[0125] It should also be noted that Figure 4A (and also the following Figure 6C ) may produce different results compared to the actual lesion depth and width shown in ). Changes in the thermal properties used in the model may explain these differences. Therefore, according to the disclosed technology, when using the thermal model presented above to determine the parameters of the heater used to produce lesions in the skin tissue of the eyelid, the thermal properties of the skin tissue of the eyelid and the thermal properties of the actual materials used in the dermal conditioning device of the disclosed technology need to be considered and appropriately adjusted.

[0126] refer to Figure 4B , showing an example response to FIG. 3A to FIG. 3C Graph 406 depicts the depth of thermal wave penetration of skin treated by a dermal conditioning device, generally designated 400, constructed and operated in accordance with another embodiment of the disclosed technology. Graph 400 includes a horizontal axis 402 showing tissue depth in microns and a vertical axis 404 showing temperature in degrees Celsius. Curve 406 depicts the depth of thermal wave penetration of skin treated by a dermal conditioning device 300 ( FIG. 3A to FIG. 3C ) for a treatment with a pulse duration of 8 ms, while curve 408 depicts the thermal wave penetration depth into the skin 250 in response to the dermal conditioning device 300 ( FIG. 3A to FIG. 3C) The penetration depth of the thermal wave to the skin 250 under the treatment at the pulse duration of 14 ms. With respect to the curve 406 corresponding to the pulse duration of 8 ms, at a depth of 0 μm, the temperature of the skin 250 reaches 400°C, at a depth of 5 μm, the temperature of the skin 250 reaches 350°C, at a depth of 10 μm, the temperature of the skin 250 reaches 300°C, and at a depth of 30 μm, the temperature of the skin 250 reaches 150°C. With respect to the curve 408 corresponding to the pulse duration of 14 ms, at a depth of 0 μm, the temperature of the skin 250 reaches 400°C, at a depth of 5 μm, the temperature of the skin 250 reaches 360°C, at a depth of 10 μm, the temperature of the skin 250 reaches 320°C, and at a depth of 30 μm, the temperature of the skin 250 reaches 180°C. As can be seen from the curves 406 and 408, the most significant temperature increase occurs at the surface of the skin 250 at a depth of 0 μm. The deeper layers of the skin 250 (e.g., FIG. 3D to FIG. 3E The temperature of the layers 254, 256 and 258 of the cortex decreases sharply at a steep slope and gradually decreases at about 50 μm, where the temperature decreases at a gentle slope. This feature prevents ablation and tissue damage at the deeper cortical layers, thereby maintaining the activity of these cells.

[0127] Reference now Figure 4C , it is shown by FIG. 3A to FIG. 3C A graph of the temperature of the skin at different skin depths within 15 ms after treatment with a dermal conditioning device with a pulse of 8 ms duration, generally labeled 420, is constructed and operated according to another embodiment of the disclosed technology. The graph 420 includes a horizontal axis 422 showing time in milliseconds and a vertical axis 424 showing temperature in degrees Celsius. The topmost curve labeled 426 illustrates the change in surface temperature of the skin 250 (in other words, the outside of the stratum corneum 252) within 15 ms after treatment with an 8 ms pulse by the device 300. At the beginning of the pulse, the surface temperature of the skin 250 rises rapidly, reaching a peak temperature of 400°C within 1 ms. The surface of the stratum corneum 252 is maintained at a constant temperature of 400°C during the 8 ms pulse duration, after which the temperature begins to drop, reaching 320°C after 10 ms, and reaching approximately 260°C after 30 ms.

[0128] The curve labeled 428 illustrates the temperature change of the skin 250 at a depth of 5 μm (corresponding to the middle area of ​​the stratum corneum 252) within 15 ms after being treated with an 8 ms pulse by the dermal conditioning device 300. At the beginning of the pulse, the temperature rises rapidly within the first 2 ms to reach approximately 300° C., after which the temperature continues to rise at a slower rate, reaching a peak temperature of nearly 350° C. at 8 ms. After 8 ms, the temperature drops quite rapidly, dropping to approximately 250° C. at 10 ms, and continues to drop to below 160° C. after 15 ms.

[0129] The curve marked as 430 illustrates the temperature change of the skin 250 at a depth of 10 μm (corresponding to the boundary between the stratum corneum 252 and the stratum granulosum 254) within 15 ms after being treated with an 8 ms pulse by the dermal conditioning device 300. At the beginning of the pulse, the temperature rises rapidly within the first 3 ms to 260°C, after which the temperature continues to rise at a slower rate, reaching a peak temperature of nearly 300°C at 8 ms. After 8 ms, the temperature drops quite quickly, dropping to about 240°C at 10 ms, and continues to drop to below 160°C after 15 ms. Curves 430 (10 μm) and 428 (5 μm) converge after about 12 ms. The curve marked as 432 illustrates the temperature change of the skin 250 at a depth of 30 μm (corresponding to the boundary between the epidermis and dermis of the skin)) within 15 ms after being treated with an 8 ms pulse by the dermal conditioning device 300. At the beginning of the pulse, the temperature rises almost linearly, reaching nearly 150°C after 8ms. After 8ms, the temperature drops almost linearly, but slower than the rise, reaching 120°C after 15ms.

[0130] The curve labeled 434 illustrates the temperature change of tissue beneath skin 250 at a depth of 100 μm within 15 ms after treatment with an 8 ms pulse by dermal conditioning device 300. At the beginning of the pulse, the temperature of the deep tissue barely changes from the normal human body temperature of 37°C, reaching 40°C after 15 ms.

[0131] As can be seen from graph 420, only the surface temperature of skin 250 (represented by curve 426) is maintained at 400°C throughout the pulse duration, allowing significant dehydration and fissure formation. The temperature of deeper skin layers 254 and 256 at depths of 5 μm and 10 μm, represented by curves 428 and 430, respectively, increases somewhat, allowing dehydration without causing damage to living cells. However, the temperature of deep tissue below 30 μm and up to 100 μm, represented by curves 432 and 434, respectively, increases only slightly, preventing damage to these areas.

[0132] Reference now Figure 4D , which is achieved through FIG. 3A to FIG. 3CGraph 440 of skin temperature at different skin depths within 30 ms after treatment with a 14 ms duration pulse by a dermal conditioning device, generally designated 440, constructed and operated in accordance with another embodiment of the disclosed technology. Graph 440 includes a horizontal axis 442 showing time in milliseconds and a vertical axis 444 showing temperature in degrees Celsius. The uppermost curve designated 446 illustrates the temperature of the skin at different skin depths after treatment with a 14 ms duration pulse by a dermal conditioning device 300 ( FIG. 3A to FIG. 3C ) The surface temperature change of the skin 250 (i.e., the outer side of the stratum corneum 252) within 30 ms after the treatment with a 14 ms pulse. At the beginning of the pulse, the surface temperature of the skin 250 rises rapidly, reaching a peak temperature of 400° C. within 1 ms. The surface of the stratum corneum 252 is maintained at a constant temperature of 400° C. within the 14 ms pulse duration, after which the temperature begins to drop, reaching 370° C. after 15 ms, and just below 260° C. after 30 ms.

[0133] The curve labeled 448 illustrates the temperature change of the skin 250 at a depth of 5 μm (corresponding to the middle area of ​​the stratum corneum 252) within 30 ms after being treated with a 14 ms pulse by the dermal conditioning device 300. At the beginning of the pulse, the temperature rises rapidly within the first 3 ms to reach approximately 320° C., after which the temperature continues to rise at a slower rate, reaching a peak temperature of nearly 360° C. at 14 ms. After 14 ms, the temperature drops quite rapidly, dropping to approximately 240° C. at 17 ms, and continues to drop to below 120° C. after 30 ms.

[0134] The curve marked 450 illustrates the temperature change of the skin 250 at a depth of 10 μm (corresponding to the boundary between the stratum corneum 252 and the stratum granulosum 254) within 30 ms after treatment with a 14 ms pulse by the dermal conditioning device 300. At the beginning of the pulse, the temperature rises rapidly within the first 3 ms to 260°C, after which the temperature continues to rise at a slower rate, reaching a peak temperature of about 310°C at 17 ms. After 14 ms, the temperature drops quite rapidly, dropping to about 240°C at 17 ms, and continues to drop to below 120°C after 30 ms. The 10 μm curve 450 and the 5 μm curve 448 converge after about 17 ms.

[0135] The curve labeled 452 illustrates the temperature change of the skin 250 at a depth of 30 μm (corresponding to just below the basal layer 258) within 30 ms after being treated with a 14 ms pulse by the dermal conditioning device 300. At the beginning of the pulse, the temperature gradually increases throughout the pulse duration, reaching a peak temperature of nearly 180° C. at 14 ms, after which the temperature gradually decreases to just below 110° C. at 30 ms.

[0136] The curve labeled 454 illustrates the temperature change of tissue beneath skin 250 at a depth of 100 μm over 30 ms after treatment with a 14 ms pulse by dermal conditioning device 300. At the beginning of the pulse, the temperature of the deep tissue has barely changed from the normal human body temperature of 37°C, reaching just below 45°C after 30 ms.

[0137] As can be seen from the graph 440, the temperature rise and decay patterns are similar to those of the graph 420 ( Figure 4C ) is similar. Throughout the pulse duration, only the surface temperature of skin 250 (represented by curve 446) is maintained at 400°C, allowing significant dehydration and formation of cracks in the stratum corneum. The temperature of deeper skin layers 254 and 256 at depths of 5 μm and 10 μm, represented by curves 448 and 450, respectively, is increased, allowing partial dehydration without causing damage to living cells therein. However, the temperature of deep tissues below 30 μm and up to 100 μm, represented by curves 452 and 454, respectively, is only slightly increased, thereby preventing damage to these areas.

[0138] In general, by means of the dermis conditioning device 300 ( Figure 3A ) and more generally by the dermal conditioning device 200 ( Figure 2A) Applying a heating phase to the skin 250 causes the stratum corneum 252 and the deeper skin layers 254, 256, and 258 to dehydrate. The dehydration results in a concentration gradient between the solution subsequently introduced to the outer surface of the skin 250 and the dehydrated stratum corneum 252 and the deeper skin layers 254, 256, and 258. The concentration gradient is greater than any concentration gradient that exists in other areas of the skin 250 that have not been treated by the dermal conditioning device 200. The concentration gradient caused by the conditioning of the skin 250 by the dermal conditioning device 200 helps to accelerate the absorption of the introduced solution through the stratum corneum 252 into the living cells in the deeper skin layers 254, 256, and 258. In addition, when the stratum corneum 252 is dehydrated, the concentration gradient outside the stratum corneum 252 of the skin is large. For example, the water content of the solution may be in the range of 75% to 100%, or 80% to 90%, or 60% to 100%, and the water content of the dehydrated stratum corneum 252 may be in the range of 0% to 10%, or 5% to 15%, or 10% to 20%. In contrast, the concentration gradient inside the stratum corneum 252 is smaller. For example, the stratum granulosum 254 may be dehydrated to reach a water content corresponding to the heat penetration depth, which may be 70%, or 75%, or 65%, or 80%. As the distance between the stratum granulosum 254 and the dehydrated stratum corneum 252 decreases, the water content level of the stratum granulosum gradually decreases from the current level, i.e., moving upward through the partially dehydrated stratum corneum 254, transitioning through 50%, 40%, 30%, and 20% water content to reach the dehydrated stratum corneum 252 with a water content in the range of 0% to 10%, or 5% to 15%. The difference between the concentration gradient outside the skin 250 and the concentration gradient inside the skin 250 may further accelerate the absorption of the externally applied solution.

[0139] Additionally, during treatment, the dermal conditioning device 300 ( Figure 3A ) and more generally by the dermal conditioning device 200 ( Figure 2A ) The total amount of heat energy applied to the skin 250 is relatively small. In general, the heat energy applied is a function of the physical size and design of the dermal conditioning device 200. The heat transfer analysis described above in Equations 11-13 describes the heat transfer for the dermal conditioning device 300 ( Figure 3A ). The heat transfer analysis takes into account the size, shape, and material of the actuator tip 332, and also takes into account the method by which the controller 308 controls the application of heat by the heat emitter 328 according to the heating parameters (e.g., 8 ms and 14 ms pulses, heating the actuator tip to 400° C., etc.). However, such analysis is not intended to be limited to FIG. 3A to FIG. 3E It will be appreciated that similar heat transfer analysis may be performed for each of the embodiments disclosed herein to achieve the desired thermal energy transfer to the skin 250 that causes the stratum corneum 252 to break, but does not cause excessive condensation, based on heat transfer analysis as known in the art.

[0140] Therefore, compared with the conventional technology, the dermis conditioning device 300 ( Figure 3A ) and generally by the dermal conditioning device 200 ( Figure 2A ) treatment, the amount of coagulated tissue within the skin 250 was significantly reduced. By comparing the skin 80 treated by the prior art (FIG. 1B) with the skin treated by the dermal conditioning device 300 ( Figure 3A ) and more generally by the dermal conditioning device 200 ( Figure 2A ) Treated skin 250( Figure 4A ) is significantly reduced in skin coagulation. As can be seen by comparing these images, the coagulation present in skin 80 (FIG. 1B) is significantly greater than that in skin 250 ( Figure 4A ) Any coagulation present in the dermis. This reduction in tissue coagulation weakens the barrier caused by such tissue coagulation, thereby further enhancing the ability of the living cells of the deeper cortical layers 254, 256 and 258 to absorb the introduced solution.

[0141] Reference now Figure 4E , it is shown that the response to the general Figure 2A Dermal conditioning device 200 ( Figure 2A ) and a special leather conditioning device 300 ( Figure 3A ), generally designated 471, is a graph of the temperature of the applied skin at multiple depths during the heating phase of any of the dermal conditioning devices constructed and operated in accordance with another embodiment of the disclosed technology. The applied heat is indicated on the vertical axis 472, labeled "Temperature" as measured in °C, and the skin depth is indicated on the horizontal axis 474, labeled "Skin Depth" as measured in μm. Curve 476A shows the temperature of the skin 250 at the surface corresponding to a depth of 0 microns (μm), curve 476B shows the temperature of the skin 250 at a depth of 5 μm, and curve 476C shows the temperature of the skin 250 at a depth of 10 μm. Curves 476A, 476B, and 476C are associated with the stratum corneum 252. Therefore, the temperature of the stratum corneum 252 rises sharply in response to the heating phase and is maintained at an elevated temperature in the range of 400°C to 340°C. Curve 476D shows the temperature of the skin 250 at a depth of 30 μm. At this depth, the temperature of the skin rises more slowly and does not exceed 250° C. Curve 476E shows the temperature of skin 250 at a depth of 100 μm. At this depth, the temperature of the skin hardly rises, reaching 50° C.

[0142] Reference now Figure 4F , which is shown in the leather conditioning device 300 ( Figure 3A ) of the protrusion 338( Figure 3A) Temperature gradients of skin 250 at various depths during a heating phase with 8 ms pulses, generally designated 478, the dermal conditioning device is constructed and operated according to another embodiment of the disclosed technology. Although the dermal conditioning device 300 ( Figure 3A ) on the skin 250, but this is not intended to be limiting, and it is understood that a similar effect is produced on the skin 250 by the application of a heating phase by the dermal conditioning device 200. Dashed line 482 indicates the boundary between the stratum corneum 252 and the deeper skin layers 254, 256 and 258. The indication of skin depth is merely exemplary and not to scale. The thermal gradient of the area above the dashed line 482 corresponds to Figure 4E The thermal gradient of the region below the dashed line 482 corresponds to Figure 4E 476D and 476E. Thus, the heating phase has a dual effect on the skin 250. The stratum corneum 252 is heated to a relatively high temperature, as shown by curves 476A, 476B and 476C ( Figure 4F ), thereby affecting its elasticity. When the relative humidity of the stratum corneum 252 is 100% before the heating stage, its elongation in response to the applied stress is 200%. However, when the relative humidity of the stratum corneum 252 is close to 0% after the heating stage, its elongation in response to the applied stress decreases to less than 10%. In contrast, the deeper skin layers 254, 256 and 258 are heated to a lower temperature, as shown in curves 476D and 476E ( Figure 4E ) as shown.

[0143] Reference now FIG. 5A to FIG. 5C , which are schematic diagrams of a dermal conditioning device (generally designated 500) of the disclosed technology that generates heat using an optical emitter, the dermal conditioning device being constructed and operated in accordance with another embodiment of the disclosed technology. The dermal conditioning device 500 generates heat using an optical emitter, and generates stress by using a rotatable roller that operates to roll over the surface of the skin (not shown) and generate strain on the skin. In the following description, the dermal conditioning device 500 should be understood to include at least the hardware components ( Figure 2A 2E ), and is operable to perform any of the procedures and functions described above with respect to skin 250. As mentioned above, dermal conditioning device 500 can function without generating heat and only via stress generated by the use of a rotatable roller, and without having to generate micro-mechanical trauma in the eyelid. Dermal conditioning device 500 includes a controller (not shown) and a power source (not shown), an actuator 530 and a roller 532, and a heat generator 526 and a heat emitter 528. The controller and power source correspond to controller 208 and power source 210 (both from Figure 2B). Heat generator 526 and heat emitter 528 correspond to heat generator 226 and heat emitter 228 (both from Figure 2B ). Actuator 530 and roller 532 correspond to actuator 230 and stress transmitter 232 (both from Figure 2B ). The controller, power supply and heater 526 can be integrated into the body of the dermis conditioning device 500.

[0144] The roller 532 is a rotatable roller that forms the distal end of the dermal conditioning device 500 and is operable to directly contact and touch the skin 250. The actuator 530 is electrically coupled to a power source and a controller. The actuator 530 is mechanically coupled to the roller 532 via an axis 534. The axis 534 is oriented orthogonal to the longitudinal y-axis of the dermal conditioning device 500 and passes through a central rotational axis position of the dermal conditioning device x-axis parallel to the roller 532, thereby enabling the roller 532 to rotate around the axis 534. FIG. 5A to FIG. 5C An axis guide 540 of the dermis conditioning device is shown in FIG. The actuator 530 may be embodied as a rotatable motor operable to rotate the roller 532 about the axis 534 .

[0145] The heat emitter 528 is formed by a plurality of channels, which connect the heat generator 526 to the distal end of the dermis conditioning device 500 formed by the roller 532. The heat generator 526 can be positioned at any suitable position in the dermis conditioning device 500, such as inside the roller 532. The channels of the heat emitter 528 can be arranged in a plurality of rows, thereby forming parallel rings 542 covering the surface of the roller 532. The roller 532 can be provided with 1, 2, 3 ... n parallel rings 542 forming the channels of the heat emitter 528. The distance between the rings can be in the range of tens of microns to millimeters, such as 0.05mm, 0.2mm or 1mm. The distance between any two channels can be in the range of 0.1mm to 0.5mm, 0.5mm to 1mm, 1mm to 1.5mm, 1.5mm to 2mm, 2mm to 2.5mm or 2.4mm to 3mm. All these distances are given as examples only.

[0146] refer to FIG. 5A to FIG. 5B , shows a dermal conditioning device 500 having a heat generator 526 configured as an optical emitter operable to emit light suitable for evaporating water from living tissue, as described above with respect to Figure 3CThe heat generator 526 does not cause evaporation or condensation of the skin tissue itself. The heat generator 526 can be an IPL light source, an IR light source, or a solid-state laser diode, and can emit laser light with a wavelength of about 2.94 μm. The heat emitter 528 is formed by a plurality of optical channels, which are configured to transmit the optical signal emitted by the heat generator 526 to the outer surface of the roller 532 at the distal end of the dermal conditioning device 500. The optical signal emitted by the heat emitter 528 causes water to evaporate from the skin 250. When the heat generator 526 is an IPL light source or an IR light source, one or more reflectors (not shown) may be installed between the heat generator 526 and the heat emitter 528 to focus the emitted light into a narrower beam within a certain range (approximately twice the diameter of each channel of the heat emitter 528). When the heat generator 526 is a solid-state laser, the heat generator 526 includes a plurality of small-diameter lasers (not shown), each of which is installed in one of the optical channels of the heat emitter 528. Heat emitter 528, along with heat generator 526 and roller 532, may be considered an epidermal injury generator.

[0147] refer to Figure 5A , the heat emitter 528 is constructed as a plurality of optical channels embedded in a plurality of protrusions 538 covering the roller 532. The heat generator 526 and the heat emitter 528 of the dermis conditioning device 500 are similar to the dermis conditioning device 300 ( Figure 3C ) heat generator 326 ( Figure 3C ) and thermal emitter 328 ( Figure 3C ) is substantially similar to the roller 532, the main difference being that the heat generator 526 and the heat emitter 528 are disposed on the surface of the roller 532. The protrusion 538 may be formed of any suitable biocompatible, thermally conductive and thermoelastic material, such as that described above with respect to the protrusion 338 ( Figure 3B) is described in detail with reference to an array of embodiments of the present invention. Similarly, the size, shape and material of the protrusions 538 and the distances therebetween may correspond to the size, shape and material of the protrusions 338 of the dermal conditioning device 300 and the distances therebetween. The plurality of protrusions 538 depress the surface of the skin 250 in a non-invasive manner in synchronization with the rotation of the roller about the axis 534. The protrusions 338 are blunt enough not to penetrate the skin 250 when treated by the dermal conditioning device 500, and the depth of depression of the skin 250 ranges from 0.1 millimeters (mm) to 1 mm, or 0.05 mm to 1.2 mm, or 0.2 mm to 0.8 mm, or 0.3 mm to 0.7 mm, or 0.4 mm to 0.6 mm, or any other suitable range, such as 0.025 mm to 0.05 mm or 0.05 mm to 0.7 mm. However, when used on the eyelids, the depression of the plurality of protrusions 538 on the surface of the skin 250 is sufficient to cause activation of the corneal reflex, the threat reflex, and the tear reflex. The vertical movement of the plurality of protrusions 538 over the eyelid causes activation of nociceptors in the eyelid, which may trigger any of the corneal reflex, the threat reflex, and the tear reflex via indirect activation of nociceptors in the cornea and / or sclera. In another embodiment, the protrusions 338 may be sharp enough to penetrate the skin 250 when treated by the dermal conditioning device 500, and thereby cause micro-mechanical damage in the eyelid. In one embodiment, the diameter of each protrusion in the array of protrusions 338 may be in the range of 0.05mm, 0.1mm, 0.15mm, and up to 1.0mm. The height of the protrusions 338 as measured from the outer periphery of the roller 532 may be in the range of 0.05mm, 0.1mm, 0.15mm, and up to 1.0mm. Although the protrusions 338 are FIG. 5A to FIG. 5B are shown as pins, but they may have any suitable shape for applying stress to the skin, such as described above with respect to FIG. 3A to FIG. 3C The pyramid shape may serve as a plurality of evaporation needles.

[0148] refer to Figure 5B , the thermal emitters 528 are configured as multiple optical channels embedded directly on the surface roller 532 between the protrusions 538. Therefore, during treatment, there is a small distance (indicated via reference numeral 544) between the thermal emitters 528 and the surface of the stratum corneum, which corresponds to the height of the protrusions 538. FIG. 5A to FIG. 5B The illustrated embodiment is intended for illustrative purposes. Therefore, features such as the handle and housing of the leather conditioning device 500 are shown as conceptual diagrams only. Figure 5A The optical channel of the heat emitter 528 of the dermis conditioning device 500 is embedded in the plurality of protrusions 538 to form Figure 5B The optical channel of the heat emitter 528 of the dermis conditioning device 500 is arranged on the surface of the roller 532 between the plurality of protrusions 538. Figure 5AThe areas of the skin affected by the thermal emitters 528 correspond to those areas of the skin directly affected by the plurality of protrusions 538. In addition, Figure 5A The heat emitter 528 of the dermal conditioning device 500 is in direct contact with the skin. Figure 5B The area of ​​the skin affected by the heat emitter 528 of the dermal conditioning device 500 is between those areas of the skin directly affected by the plurality of protrusions 538. In addition, the heat emitter 528 may not be in direct contact with the skin, and the distance from the skin corresponds to the height of the plurality of protrusions 538.

[0149] Reference now Figure 5C , which shows another embodiment of a leather conditioning device 500 that is constructed and operated in accordance with an embodiment of the disclosed technology. In this embodiment of the leather conditioning device 500, the stress applicator 232 ( Figure 2B ) is formed as a plurality of elongated ridges spanning the width of the roller 532. The thermal emitters 528 are formed of a plurality of optical channels embedded directly on the roller 532 and arranged in rows 554 spanning the width of the roller 532. The rows 554 of thermal emitters 528 are staggered with the ridges of the stress applicators 552. The width of the roller 532 may be in the range of 0.5 cm to 4 cm. The rows 554 of channels forming the thermal emitters 528 are positioned between the elongated ridges 552. The height of the ridges 552 from the surface of the roller 532 may be in the range of 0.5 mm to 2 mm. In one embodiment, Figure 5C The height of ridge 552 may be approximately 1.25 mm, similar to Figure 3B The size of the protrusion 538. Similarly, with the protrusion 338 ( Figure 3B )Same, Figure 5C The ridge 552 may be made of a suitable thermally conductive and biocompatible material.

[0150] The rotation of the roller 532 by the actuator 530 determines the exposure time of the area of ​​the skin 250 to the light emitted by the heat generator 526. Therefore, the level of epidermal dehydration of the skin is a function of the rotation frequency of the roller 532 and the power and wavelength of the optical signal emitted by the heat generator 526. According to the disclosed technology, a controller (not shown) controls the rotation speed of the roller 532 about the axis 534, as well as the pulse duration and intensity of the light emitted by the heat generator 526 to dehydrate the skin while avoiding ablation. In the case where the heat generator 526 is embodied as an IPL or solid-state laser, the controller can synchronize the light pulses emitted by the heater 526 with the rotation speed of the actuator 538 to ensure that light is emitted from the optical channel of the heat generator 528 only when the optical channel is within the line of sight of the area of ​​the skin 250. The controller 508 controls the speed of the roller 532 over the skin. For example, the speed can be in the range of 1 mm / s to 5 mm / s. About FIG. 5A to FIG. 5B , the combination of the spacing between the optical channels of the thermal emitters 528 on the roller 532 and the rotational frequency of the roller 532 as controlled by the controller is calibrated so that at any given time, the temperature of the area of ​​contact of the skin 250 with any one of the protrusions 538 is substantially affected by a single one of the protrusions 538, so that there is a region maintained at normal human body temperature of 37°C between the areas of skin making contact with the protrusions 538. Similarly, with respect to Figure 5C The combination of the spacing between the optical channels of the thermal emitters 528 on the roller 532 and the rotational frequency of the roller 532 as controlled by the controller is calibrated so that at any given time, the temperature of the area of ​​contact between the skin 250 and any one of the ridges 552 is substantially affected by a single one of the ridges 552, so that there is a region between the areas where the skin comes into contact with the ridges 552 that is maintained at normal human body temperature of 37°C.

[0151] After the skin is dehydrated, such as can be determined by a timer, sensor, etc., the controller controls the rotation of the roller 532 to cause the protrusions 538 ( FIG. 5A to FIG. 5B ) or alternatively ridge 552 ( Figure 5C ) applies a non-invasive compressive load or stress on the dehydrated skin, thereby generating strain on the skin that causes the formation of multiple fissures. The controller calibrates and controls the rotation speed of the roller 532 and the rotation speed of the protrusion 538 ( FIG. 5A to FIG. 5B ) or alternatively ridge 552 ( Figure 5C ) is applied to the skin so as not to pierce or penetrate the skin. Therefore, the conditioning of the skin 250 by the dermal conditioning device 500 is non-invasive. It should be noted that the dehydration of the skin and the application of stress on the skin by the dermal conditioning device 500 can be performed simultaneously or sequentially under the control of the controller. By driving the rotation of the roller 532 via the actuator 530 and controlling the operation of the heater 526, the controller controls the combined application of heat and stress to the skin, thereby generating subsequent strain on the skin and causing the stratum corneum to split. As mentioned above, the disclosed technology may only include applying stress on the skin by the dermal conditioning device 500.

[0152] Reference now FIG. 5D to FIG. 5E , which are schematic diagrams of a disclosed technology leather conditioning device (generally designated 550) that uses a dry stream to generate heat, the leather conditioning device being constructed and operated according to another embodiment of the disclosed technology. The leather conditioning device 550 is understood to include at least the leather conditioning device 200 ( Figure 2A 2E) and is operable to perform any of the procedures and functions described above with respect to skin 250. Dermal conditioning device 550 is substantially similar to FIG. 5A to FIG. 5CThe dermal conditioning device 500 has a roller 532 and an actuator 530 operating as described above. The dermal conditioning device 550 includes a heat generator 556 and a heat emitter 558 connected via a manifold 560. The manifold 560, together with the heat generator 556 and the heat emitter 558, is operable to cause a flow of dry air or gas (referred to herein as a "dry flow") from the heat generator 556 to be discharged from the distal end of the dermal conditioning device 550 toward the skin 250. The dry flow has a dual purpose, which not only dehydrates the stratum corneum and deeper skin layers, but also applies stress as a stabilizing fluid pressure, thereby producing strain on the skin that causes the stratum corneum to crack. The combination of dehydration and the stress application of the roller 532, the heat generator 556, and the heat emitter 558 can cause the stratum corneum to peel off, further promoting the dehydration of the deeper skin layers, thereby conditioning the living cells residing therein to subsequently absorb any of the hydrophilic, lipophilic, or hydrophobic solutions.

[0153] The heat emitter 558 is formed by a plurality of perforations on the surface of the roller 532, which guide the dry flow generated by the heat generator 556 to the outer surface of the roller 532 via the manifold 560. The heat generator 556 generates the dry flow, for example, by using an air dryer that heats the air to a temperature in the range of 20°C to 600°C. The manifold 560, illustrated as a plurality of tubes, guides the dry flow from the heat generator 556 to the roller 532, where the dry flow is discharged from the heat emitter 558 (which is shown as a perforation (not marked) on the surface of the roller 532). In some embodiments, the size of the manifold 560 may be in the range of 0.5mm and 0.6mm up to 3mm. The diameter of the perforations of the heat emitter 558 on the outer surface of the roller 532 may be in the range of 0.1mm to 0.5mm and up to 1mm. The perforations of the heat emitter 558 are aligned as a plurality of parallel rows or parallel rings on the surface of the roller 532. The distance between perforations within a row may range between 0.1 mm and 3 mm. The distance between rows may range between 0.5 mm and 3 mm.

[0154] The roller 532 is operable to apply pressure on the surface of the skin in addition to the pressure applied by the dry stream on the skin. Thus, the stress applied to the skin is a combination of both the dry stream and the pressure from the roller 532. The controller controls the timing, temperature, and pressure of the dry stream and the rotational speed of the roller 532 about the axis 534, thereby controlling the heat and stress levels delivered to the skin and the resulting strains produced on the skin. As described in the heat calculations given in equations 6-13 above, the heat levels are calibrated to sufficiently dehydrate the skin to produce fissures without inducing trauma.

[0155] refer to Figure 5E, shows another embodiment of a dermal conditioning device 550 that is constructed and operated in accordance with an embodiment of the disclosed technology. In this embodiment of the dermal conditioning device 550, the roller 532 is additionally provided with one or more ridges 562 that span the width of the roller 532, such as described above with respect to Figure 5C The rows of channels forming the heat emitters 558 are positioned between the elongated ridges 562. In some embodiments, the speed of the roller 532 over the skin can be in the range of 1 mm / s to 5 mm / s. The temperature of the dry stream emitted from the dermal conditioning device 500 can be in the range of 10° C. to 50° C. The humidity of the dry stream emitted from the dermal conditioning device 550 can be in the range of 0% to 10% humidity.

[0156] FIG. 5A to FIG. 5E Each of the illustrated dermal conditioning devices may be used on the eyelid to induce lesions in the epidermis and / or dermis of the eyelid, thereby inducing the body's corneal reflex, threat reflex, and tear reflex and otherwise inducing the body's inflammatory healing process. FIG. 5A to FIG. 5E The heat generator and heat emitter (which are optional elements) in any of the dermal conditioning devices shown, together with the roller shown, can constitute an epidermal and / or dermal damage generator. The damage or slight burning caused to the epidermis is sufficient to cause mild coagulation, thereby activating the production of EGF. As previously mentioned, any perforation or penetration of the stratum corneum of the eyelid in this embodiment does not exceed 20-1000 μm, and the maximum width is about 700 μm. The depth of the perforation is determined by a sensor, pad or other mechanism (as described above in Figure 3A The dermal conditioning device of the disclosed technology is controlled and adjusted to ensure that the depth of any tip, needle or evaporation element of the dermal conditioning device entering the epidermis does not exceed 20-1000 μm. In addition, in embodiments using heat, the amount of heat applied to the epidermis of the eyelid to cause epidermal damage or slight burning needs to be at least 37°C. The application of the dermal conditioning device of the disclosed technology to the eyelid is non-invasive, while causing minimal trauma to induce the body's corneal reflex, threat reflex and tear reflex and the body's natural inflammatory healing process. The above-mentioned reflexes cause contraction and relaxation of the orbicularis oculi muscle, thereby causing blinking and applying physical pressure on the lacrimal and meibomian glands in the eyelid, which can treat DES and MGD. The body's natural inflammatory healing process includes the production of EGF, which can treat DES and MGD by increasing the production of meibum and sebum supply to the tear film of the eye, thereby opening any blocked alveoli and ducts in the eyelid from the meibomian glands to the surface of the eye. The dermal conditioning device of the disclosed technology in this embodiment is to be used only on the eyelid and should not come into contact with the surface of the eye (ie, the sclera).

[0157] It should be noted that regarding the mechanical damage to the eyelid caused by the disclosed technology, the healing process of the skin may take up to about three months to fully recover. Therefore, it can be concluded that the therapeutic effect of the inflammatory healing process induced by the disclosed technology can last for at least several weeks.

[0158] Reference now FIG. 6A to FIG. 6B , which are schematic diagrams of a leather conditioning device (generally labeled 600A and 600B, respectively) of the disclosed technology that uses an RF transmitter to generate heat, and the leather conditioning device is constructed and operated according to another embodiment of the disclosed technology. Fig. 6A An embodiment using a monopolar electrode is exemplified, and Figure 6B An embodiment using a set of bipolar electrodes is exemplified. In the following description, the dermal conditioning device 600 should be understood to include at least Figure 2A 2E, and are operable to perform any of the procedures and functions described above with respect to skin 250. In particular, dermal conditioning devices 600A and 66B each include a housing 620, a controller 608, a power source 610, a linear motor 630, an RF generator 626, and a single electrode 628A ( Fig. 6A ) or a pair of electrodes 628B ( Figure 6B ) and communication bus 616. Controller 608 corresponds to controller 208 ( Figure 2B ), power supply 610 corresponds to power supply 210 ( Figure 2A ), the linear motor 630 corresponds to the actuator 230 ( Figure 2B ), RF generator 626 corresponds to the heat generator ( Figure 2B ), Fig. 6A The single electrode 628 corresponds to the thermal emitter 228 ( Figure 2B ), and a pair of electrodes 628B ( Figure 6B ) corresponds to the thermal emitter 228 ( Figure 2B ). The controller 608, power supply 610, motor 630 and RF generator 626 are integrated within the housing 620 of the respective dermis conditioning devices 600A and 600B. Fig. 6A Electrode 628A is a monopolar electrode, and Figure 6B The electrodes 628B are a set of bipolar electrodes. The controller 608, power supply 610, motor 630 and RF generator 626 are electrically coupled via a communication bus 616.

[0159] refer to Fig. 6A, the electrode 628A is electrically connected to the motor 630 and the RF generator 626 of the dermal conditioning device 600A. The electrode 628A is disposed at the distal end of the dermal conditioning device 600A. The motor 630 is a linear motor that is operable to gently push the electrode 628A toward the skin 250, thereby applying stress to the dehydrated skin 250 to produce strain, thereby forming cracks on the surface of the skin 250. The RF generator 626 generates a high-frequency alternating current that agitates the ions within the stratum corneum 252 and the deeper skin layers 254, 256, and 258, thereby causing the water stored therein to be heated via frictional heat, as indicated by the dashed area 623A. Based on the experimental results, which show that water begins to evaporate from the tissue starting at a tissue temperature of 70°C, and when the tissue temperature reaches 104°C, about half of the tissue water is lost, the controller 608 controls the heating of the stratum corneum 252 and the deeper skin layers 254, 256 and 258 via the RF generator 626 to heat the skin 250 to a temperature of up to 100°C. The controller 608 controls the pulse duration of the RF signal emitted by the RF generator 604A between 30-50 seconds. At this rate, the expected temperature increase of the skin 250 is very low. At a frequency range of 460KHz, the maximum power delivered to the skin 250 is 25W / m2·°K. When a single electrode is used, the heat penetrates a narrow deeper area, i.e., reaches the spinous layer 256. The combination of precisely controlled heating and stress application results in the formation of cracks in the stratum corneum 252, but does not substantially damage or change the pre-existing immune and integrity of the skin 250.

[0160] refer to Figure 6B, the electrode 628B is electrically connected to the motor 630 and the RF generator 626 of the dermal conditioning device 600B. The electrode 628B is disposed at the distal end of the dermal conditioning device 600B. The motor 630 is a linear motor operable to gently push the electrode 628B toward the skin 250, thereby applying stress to the dehydrated skin 250 to produce strain, thereby forming cracks on the surface of the skin 250. The combination of precisely controlled heating and stress application results in the formation of cracks in the stratum corneum 252, but does not substantially damage or change the pre-existing immune and integrity state of the skin 250. The RF generator 626 generates a high-frequency alternating current that agitates the ions within the stratum corneum 252 and the deeper skin layers 254, 256, and 258, thereby causing the water stored therein to be heated via frictional heat, as indicated by the dashed area 623B. The controller 608 controls the heating of the stratum corneum 252 and the deeper skin layers 254, 256 and 258 via the RF generator 626 to heat the skin 250 to a temperature of up to 100°C. The controller 608 controls the pulse duration of the RF signal emitted by the RF generator 604A to between 30-50 seconds. At this rate, the expected temperature increase of the skin 250 is very low. At a frequency range of 460 KHz, the maximum power delivered to the skin 250 is 25 W / m2·°K. When two electrodes are used, such as Figure 6B As shown, the heat penetrates a relatively wide shallow area, i.e., the heat does not penetrate beyond the stratum granulosum 254. The combination of precisely controlled heating and stress application results in the formation of fissures in the stratum corneum 252, but does not substantially damage or alter the pre-existing immune and integrity status of the skin 250.

[0161] Reference now Figure 6C , it is after using FIG. 6A to FIG. 6B An image of an area of ​​skin after mechanical injury treatment performed by a dermal conditioning device (generally designated 640) constructed and operated in accordance with another embodiment of the disclosed technology. Figure 4A The area of ​​skin shown, Figure 6C Shown is a lesion 642 that is 100.02 μm in width and 168.25 μm in depth, thus extending into the upper region of the stratum spinosum and deep enough to elicit an inflammatory response. Figure 6C picture Figure 4A The same is given as an example only and shows the damage produced by RF energy on pig skin.

[0162] It should be noted that part of the disclosed technology relies on the body's process of nociception via nociceptors, which are specialized peripheral sensory neurons that warn humans of potentially damaging stimuli to the skin by detecting extremes of temperature and pressure and chemicals associated with injury. Nociceptors convert these stimuli into long-distance electrical signals that are relayed to higher brain centers. The activation of functionally different populations of skin nociceptors and the processing of the information they convey provide a rich variety of pain characteristics. In the disclosed technology, the activation of the corneal reflex, threat reflex, and tear reflex are triggered by corneal and scleral nociceptors, which are triggered by skin nociceptors in the eyelids. In addition, the activation of the immune system's inflammatory response is triggered by eyelid skin nociceptors. However, from the perspective of the patient receiving this treatment, the pain produced is very small due to the extremely short pulse duration (2-60ms) used to prevent tissue coagulation (i.e., ablation of the epidermis of the eyelid) and the low energy used.

[0163] Reference now Figure 7 , which is a schematic diagram of a method for operating a dermal conditioning device that operates according to another embodiment of the disclosed technology. In procedure 700, pressure is applied to the outer surface of at least one eyelid epidermis. The pressure may be applied with a blunt tip or surface, thereby not causing mechanical damage to the eyelid epidermis, or may be applied with at least one tip, protrusion, and / or needle that is sharp enough to cause mechanical damage to the eyelid epidermis, as described above in Figure 3B The mechanical injury may be produced such that it affects the epidermis or epidermis and dermis of the eyelid. The pressure may be applied using the pressure described above. FIG. 5A to FIG. 5E and FIG. 6A to FIG. 6B Mechanical damage may be caused by direct contact, as described above in FIG. 5A to FIG. 5E and FIG. 6A to FIG. 6B As described in . The mechanical damage according to the disclosed technology should have a maximum depth of 1000 μm and a maximum width of 700 μm, thereby covering between 10-100% of the outer surface of the eyelid. As mentioned above, the mechanical damage generator (such as a heating or stressor with an actuator tip, needle and / or protrusion) is located at least 3 mm from the eyelash line. Therefore, there is no direct contact between the device of the disclosed technology and any of the meibomian glands and / or lacrimal glands. The device of the disclosed technology can be applied to the lower eyelid, the upper eyelid, or both.

[0164] refer to Figure 2A, the controller 208 controls the generation of at least one signal by the heater 204 and the stressor 206. The controller 208 controls any of the timing, intensity, temperature, frequency, duration, and phase of the at least one signal. In one embodiment, the heater 204 and the stressor 206 are separate components. In one embodiment, the heater 204 is not included in the dermis conditioning device 200. Figure 3A , controller 308 controls the generation of heat by heater 304, and controller 308 also controls the generation of stress by stressor 306. Heater 304 can maintain the distal end of dermal conditioning device 300 at 600 degrees Celsius. Stressor 306 can generate pulses with a duration ranging from 8 milliseconds (ms) to 14 ms, or from 6 ms to 16 ms, or from 5 ms to 20 ms, or from 8 ms to 20 ms, or from 2 ms to 60 ms. In another embodiment, heater 204 and stressor 206 are implemented as a single component. Reference FIG. 5D to FIG. 5E , the controller 508 controls the heat generator 556 to generate the main flow.

[0165] In procedure 702, pressure is applied continuously until the tear reflex (i.e., tearing reflex), the hand-flap-blink reflex (i.e., threat reflex), and the blink reflex (i.e., corneal reflex) occur. All tear production is apparently caused by some external or internal stimulus. The continuous application of pressure on the eyelid surface acts as an external stimulus for inducing contraction and relaxation of the orbicularis oculi muscle. This results in a tear reflex as well as a blink reflex that stimulates both the meibomian and lacrimal glands.

[0166] As mentioned above, reflex tearing is produced by strong physical and emotional stimulation of the lacrimal glands. The tears produced thereby contain essential components for the proliferation and differentiation of the corneal and conjunctival epithelium, such as vitamin A and EGF. As mentioned above, according to the disclosed technology, the production of EGF has the following effects on the meibomian glands. Based on evidence from in vitro cell culture, EGF can regulate meibomian gland morphogenesis. Adding EGF to cultured immortalized human meibomian gland epithelial cells leads to significant time-dependent cell proliferation by upregulating genes for cell cycle, DNA replication, ribosomes, translation, and significantly reducing those genes related to cell differentiation, tissue development, lipid metabolic processes, and peroxisome proliferator-activated receptor signaling.

[0167] It should also be noted that the effect of the treatment on the eyelid does not affect the viscosity of the meibomian gland sebum or tear production by any mechanical or chemical means (i.e., not by temperature or vibration). The meibomian and lacrimal glands produce increased upper tear layer lipids and proteins by activating the tear reflex, threat reflex, and corneal reflex of the eye to protect the cornea and tear film structure. As mentioned above, the activation of the eye's reflexes is sufficient to reinitiate the function of the meibomian and lacrimal glands, thereby alleviating and treating DES and MGD.

[0168] The pressure applied in procedure 702 may also cause micro-mechanical trauma, thereby further activating the tear reflex, threat reflex, and corneal reflex of the eye. The generation of micro-mechanical trauma may also lead to the activation of the inflammatory healing process of the eyelid.

[0169] In procedure 704, which is an optional procedure, the immune system is activated (i.e., the inflammatory healing process) to further reinitiate the function of the meibomian and lacrimal glands. Activating the immune system by creating mechanical damage to the eyelid activates the meibomian and lacrimal glands in addition to causing the tear reflex and the blink reflex. The immune system can also be activated by applying heat to create mechanical damage to the eyelid. Together, these further reinitiate the function of the meibomian and lacrimal glands for a period of at least two weeks or even longer.

[0170] As mentioned above, pressure can be applied and mechanical damage can be generated by generating a stress signal, wherein generating a stress signal includes performing any of the following: generating a dry flow, generating a radio frequency (abbreviated herein as RF) signal, generating a series of mechanical pulses, and generating mechanical rotation. Stress is applied non-invasively to depress the outer surface of the stratum corneum. In some embodiments, the depth to which the outer surface of the stratum corneum is depressed is between 0.1 mm and 1 mm, or 0.05 mm to 1.2 mm, or 0.2 mm to 0.8 mm, or 0.3 mm to 0.7 mm, or 0.4 mm to 0.6 mm, or 0.025 mm to 0.05 mm or 0.05 mm to 0.7 mm. Mechanical damage can be further enhanced by applying heat (e.g., between 20°C-600°C). Reference FIG. 5D to FIG. 5E , the heat generator 556 generates a dry current that exerts stress on the stratum corneum 252. FIG. 6A to FIG. 6B , the RF generator 626 generates a high frequency alternating current, which exerts stress on the stratum corneum 252. FIG. 3A to FIG. 3C , the actuator 330 advances and retracts the actuator tip 332 in a harmonic pulsating motion according to a predetermined pulse duration and a predetermined number of pulses for each treatment as controlled by the controller 308. The plurality of protrusions 338 depress the surface of the skin 250 in a non-invasive manner in synchronization with the pulsating motion. The depression depth is in the range of 0.1 millimeters (mm) to 1 mm, or 0.05 mm to 1.2 mm, or 0.2 mm to 0.8 mm, or 0.3 mm to 0.7 mm, or 0.4 mm to 0.6 mm, or 0.025 mm to 0.05 mm, or 0.05 mm to 0.7 mm. Reference FIG. 5D to FIG. 5E , the actuator 530 is mechanically coupled to the roller 532 via the shaft 534. The actuator 530 is a rotatable motor that rotates the roller 532 about the shaft 534. The plurality of protrusions 538 depress the surface of the skin 250 in a non-invasive manner in synchronization with the rotation of the roller about the shaft 534.

[0171] In some embodiments of the disclosed technology, generating at least one signal further comprises controlling any of the timing, intensity, temperature, frequency, duration, and phase of the at least one signal. Figure 2A , the controller 208 controls any of the timing, intensity, temperature, frequency, duration, and phase of the signal generated by any of the heater 204 and the stressor 206 .

[0172] As described above, the disclosed technology can be used on the eyelids to treat DES and MGD. In addition, in some embodiments, the disclosed technology also allows the stratum corneum to be opened for application of solutions while keeping the barrier function of the skin intact. Applying strain (and optionally applying heat and optionally producing micro-mechanical damage) on the eyelids using the disclosed technology as described above induces the body's corneal reflex, threat reflex and tear reflex without causing trauma or permanent damage to the eyelids. The optional application of heat and the generation of micro-mechanical damage can also induce the body's inflammatory healing process without causing trauma or permanent damage to the eyelids. The contraction and relaxation of the orbicularis oculi muscle and the induction of the body's inflammatory healing process lead to an increase in the production of EGF, which can increase the flow of meibum and sebum, dredge the alveoli and ducts in the meibomian glands and lacrimal glands, and thereby treat DES and MGD.

[0173] Those skilled in the art will appreciate that the various embodiments disclosed above are intended to be examples. The disclosed technology is not limited to the specific combination and arrangement of the above elements. In particular, additional embodiments of heaters, heat generators, heat emitters, stressors, actuators, and stress applicators as known in the art can be combined in any suitable manner to implement the disclosed technology.

[0174] Those skilled in the art will appreciate that the disclosed technology is not limited to what has been particularly shown and described above. Instead, the scope of the disclosed technology is limited only by the following claims.

Claims

1. A device for activating nociceptors on an eyelid of an eye for activating at least one of a corneal reflex, a threat reflex, and a tear reflex of the eye, comprising: at least one skin tissue pressure generator, the at least one skin tissue pressure generator being configured to generate at least one pressure signal; at least one controller coupled to the at least one skin tissue pressure generator for controlling the at least one skin tissue pressure generator; a power source coupled to the at least one skin tissue pressure generator and the at least one controller; a position sensor coupled to the at least one skin tissue pressure generator; as well as a housing enclosing the at least one skin tissue pressure generator and the at least one controller, wherein the at least one controller controls the at least one skin tissue pressure generator to apply the at least one pressure signal to stress the outer surface of the eyelid in a controlled manner, the at least one pressure signal activating the nociceptors on the eyelid and the nociceptors on the eye without tissue coagulation on the eye, thereby activating at least one of the corneal reflex, the threat reflex and the tear reflex of the eyelid, wherein the at least one skin tissue pressure generator comprises an actuator electrically coupled to the at least one controller and mechanically coupled to a distal end of the at least one skin tissue pressure generator, the actuator being configured to apply the at least one pressure signal to stress the outer surface of the eyelid and to stress the eye; wherein the distal end of the at least one skin tissue pressure generator is provided with at least one protrusion, the at least one protrusion being configured to apply the at least one pressure signal to apply stress to the outer surface of the eyelid; and Wherein the position sensor is used to determine the penetration depth of the at least one protrusion into the outer surface of the eyelid.

2. The device of claim 1, wherein the at least one protrusion is also used to create at least one mechanical injury on the outer surface of the eyelid.

3. The device according to claim 1 further includes a heat generator, which is used to heat the distal end of the at least one skin tissue pressure generator and is further used to apply heat to the outer surface of the eyelid using the at least one pressure signal.

4. A device according to claim 3, wherein the heat generator maintains the distal end of the at least one skin tissue pressure generator at at least 37 degrees Celsius.

5. The apparatus of claim 1, wherein said generating said at least one pressure signal comprises generating a pulse of said at least one pressure signal having a duration ranging between 2 milliseconds and 60 milliseconds.

6. An apparatus according to claim 1, wherein the at least one controller also controls the at least one pressure signal by controlling a first parameter of the at least one pressure signal, the first parameter being selected from the group consisting of: timing, intensity, temperature, frequency, duration and phase of the at least one pressure signal.

7. The device of claim 3, wherein the at least one controller also controls the temperature of the distal end of the at least one skin tissue pressure generator.

8. The device of claim 3, wherein the heat generator is selected from the group consisting of: i. Main stream generator; ii. Radio frequency generator; iii. Optical transmitter; and iv. Thermal heater.

9. The device of claim 1, wherein the at least one skin tissue pressure generator further comprises a stress applying generator selected from the group consisting of: i. Mainstream generator; and ii. Radio frequency generator.

10. The device of claim 1, wherein the actuator is configured to perform one of: a) operating the at least one skin tissue pressure generator using a harmonic pulsating motion, and b) rotating a roller located at the distal end of the at least one skin tissue pressure generator.

11. The device of claim 1, wherein the at least one protrusion has an optical channel embedded therein, the optical channel configured to apply the at least one pressure signal to stress the outer surface of the eyelid.

12. The device of claim 1, wherein the at least one skin tissue pressure generator comprises a plurality of heated tips.

13. The device of claim 1, wherein the actuator is selected from the list consisting of: i. Electric motor; ii. Piezoelectric element; iii.RF transmitter; iv. Hydraulic piston; v.Pneumatic piston; vi. Magnetic piston; vii. Piezoelectric piston; viii. electromagnetic actuator; and ix. Voice coil actuator.

14. The apparatus of claim 1, wherein the at least one controller controls the penetration depth of the at least one protrusion applying stress to the outer surface of the eyelid to a depth ranging between 0.05 mm and 0.7 mm.

15. The device of claim 1, wherein the position sensor is selected from the list consisting of: i. Encoder; ii. Magnetic encoder; iii. Optical encoder; and iv. Hall effect sensor.

16. The device of claim 1, wherein the housing is made of a transparent material.

17. The device of claim 1, further comprising a rangefinder positioned at a distal end of the housing for limiting a distance of the harmonic pulsating motion of the at least one skin tissue pressure generator.

18. The device of claim 17, wherein the rangefinder is made of a transparent material.

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