CN115068166A

CN115068166A - Method of producing nasal implants

Info

Publication number: CN115068166A
Application number: CN202110275913.4A
Authority: CN
Inventors: 梅颜昌; 谢尧钦
Original assignee: National University of Singapore
Current assignee: National University of Singapore
Priority date: 2021-03-15
Filing date: 2021-03-15
Publication date: 2022-09-20
Also published as: CN117897122A

Abstract

A method of producing an implant for supporting a nasal passage is disclosed. The method comprises the following steps: forming a structure comprising a plurality of layers having at least an inner layer and an outer layer, and at least one of the inner layer and the outer layer comprising a shape memory material; and shaping the structure such that the shape memory material will assume a predetermined shape when positioned in the nasal passage.

Description

Method of producing nasal implants

Technical Field

The present invention relates to an implant for supporting an internal nasal valve of a nose. More particularly, the present invention relates to methods for forming such implants.

Background

In recent years, attention has been paid to the correction of nasal septum malformation. The nasal septum is the cartilage of the nose that separates the nostrils. Typically, the nasal septum is centered and evenly separates the nostrils. However, many people have a non-uniform nasal septum that makes one nostril larger than the other. Severe unevenness is called nasal septum deviation. It may lead to health complications such as nostril blockage or dyspnea.

Nasal septum deviation may be caused by injury to the nose or congenital defects. Depending on the size of the nose and the shape of the cartilage, such defects may cause the size of the nostrils, the shape of the nose, and the shape of the nasal passages or airways to vary. Nasal septum deflection may also worsen with age.

The inner nares and their path may be one of the narrowest passages that may affect airway flow. A significant proportion of the inspiratory resistance is caused by the misshapen inner naris shape. Collapse of the struts in one or both of the inner nares is a common cause of nasal airway obstruction. This can lead to dyspnea and snoring as well as other respiratory related diseases such as sleep apnea.

Internal nasal inflammation also commonly occurs. It may cause a change in shape and may be the result of previous surgery, trauma, aging, or primary weakening of the upper or lower cartilage. Sometimes these conditions may be asymptomatic during active periods, but may cause sleep apnea at rest.

Severe deflection may be accompanied by facial pain or frequent nosebleed or sinus infections. Severe excursions can also lead to dyspnea, which affects quality of life. Surgery is often the primary method of correcting nasal septum deflection. The bone and cartilage under the skin give the nose most of its size and shape. Other structures inside and behind the nose help with breathing.

Collapse and weakening of the nasal cartilage can also lead to changes in the appearance of the nose and external deformities. Loss of support and volume of the lower cartilage, the middle nasal portion or the back may result in undesirable cosmetic changes. Opposing tissue defects on the back of the nose can result in irregular nasal contours.

The present invention seeks to address or mitigate at least one of the above difficulties.

Disclosure of Invention

Disclosed herein is a method of producing an implant for supporting a nasal passage, comprising:

forming a structure comprising a plurality of layers having at least an inner layer and an outer layer, and at least one of the inner layer and the outer layer comprising a shape memory material;

the structure is shaped such that the shape memory material will assume a predetermined shape when positioned in the nasal passage.

As used herein, the term "shape memory" refers to a structure having a first (typically expanded) shape and a second (typically contracted, reduced or diminished) shape, for example, to facilitate delivery of an implant. The structure is generally formed into a first shape and is forced to a second shape, for example under pressure and heat treatment. The structure then returns to the first shape if certain conditions are met, such as warming the structure. For example, the implant may be formed into a first shape, reduced in cross-section to a second shape to allow delivery or injection into the nasal airway, and then expanded back to the first shape when heated/warmed by a heating element, device, or body. Upon returning to the first (i.e. predetermined) shape, the implant may have a desired shape, for example may conform to the desired shape of the nasal airway, particularly in the case of a custom-made implant, or may then undergo further shaping from the predetermined shape to the desired shape. It is noted that the second shape may be the same as the first shape, but of a different size (e.g., reduced), or may have a different form (e.g., a curved first shape may be straightened into the second shape for ease of transport).

Forming the structure may include: the inner layer is formed thicker than the outer layer and includes a shape memory material.

Forming the structure may include: the inner layer is formed from at least one crystalline polymer having an intrinsic viscosity between 3.0 and 10.0.

The inner layer may be formed on the substrate. In embodiments, the matrix may be a fluoropolymer. The inner layer may be formed of a plurality of layers of aliphatic polyester polymers having different crystal structures, and laminated on the fluoropolymer.

The fluoropolymer may then be removed after the temperature treatment. In such embodiments, the matrix is used in the forming step, the shaping step, or both the forming and shaping steps, but does not form a part of the implant.

Forming the structure may include: the inner and outer layers are formed from respective polymers having respectively different Intrinsic Viscosities (IV). In other words, the layers are formed of different polymers, and those polymers have different IV. The inner and outer layers may be formed from respective polymers such that the ratio of IV is at least 1.05. Forming the structure may include: forming a first layer of the inner and outer layers to be thicker than a second layer of the inner and outer layers, the first layer having a higher intrinsic viscosity than the second layer and being at least twice as thick as the second layer. The outer layer has a lower viscosity than the inner layer, the lower viscosity being less than 1.0.

The method may further comprise: controlling a drying time of one or both of the inner and outer layers to control crystal formation of the one or both of the inner and outer layers.

Shaping the structure may include: the structure is formed into a cylindrical shape with the inner layer disposed inside the outer layer. The structure has a length, and shaping the structure may further include shaping the structure to have different diameters along the length.

Shaping the structure may include: one or both of the inner and outer layers are extruded.

Forming the structure may include: the inner and outer layers are formed by one or more of molding, dip coating, and solution casting. It is noted that the forming step and the shaping step may occur in any order, such as shaping before forming or forming before forming, or may be performed simultaneously.

The method may further comprise: controlling at least one of the following parameters:

(ii) temperature;

a rate of distance of the solution of one of the inner and outer layers relative to the already formed layer of the other of the inner and outer layers divided by time;

structural surface adhesion properties;

the rate of evaporation of the solvent from the wetting zone;

an environmental mixture; and

relative humidity.

The method may further comprise: a plasticizer is applied to set one or both of the inner and outer layers. Applying a plasticizer to set one or both of the inner and outer layers may include: the plasticizer is applied after the implant is inserted into the nasal passage.

One or both of the inner and outer layers may be formed of a bioabsorbable material.

Also disclosed is an implant for nasal passage support, comprising: a structure comprising a plurality of layers having at least an inner layer and an outer layer, at least one of the inner and outer layers comprising a shape memory material, the structure being shaped such that the shape memory material will assume a predetermined shape when positioned in a nasal passage.

The implant may be formed by a method as described above.

The structure may be formed into a tubular shape having a varying diameter along its length.

Drawings

Embodiments of the invention will be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

FIG. 1 illustrates a method for forming an implant according to the present teachings.

Fig. 2 depicts a tube formed from multiple layers and having different diameters.

Fig. 3 depicts a form of PTFE used for solution layering.

FIG. 4 illustrates an exemplary polymer having a lower intrinsic viscosity (caprolactone) with a thickness of 90 μm relative to a total polymer thickness with a higher intrinsic viscosity of 120 μm. This results in a ratio of 3: 4.

Detailed Description

The present disclosure relates to a method of manufacturing an implant or implant device for internally supporting a nasal passage. Some embodiments may focus on supporting the nasal valve through its natural orifice. Some implants act as dilators and may achieve an external aesthetic change to the shape of the nose. Since the device is intended for insertion or firing through a natural orifice, procedures involving the device are minimally invasive. The implants described herein may also be introduced via other means generally known to those skilled in the art.

Treatment of the internal nasal valve includes firing an implant into the nasal passage to abut lateral tissue of the patient. Typically, the implant will perform a dilating function, opening the patient's internal nasal valve. Injection of the present implant (which term is used interchangeably with "firing" and similar terms) into the tissue surrounding the internal nasal valve will cause a change or alteration in the angle of the internal nasal valve.

In an embodiment, the present disclosure relates to a method of manufacturing a shaped prosthetic substrate having different crystalline structure layers or component layers. Such a method 100 of producing an implant for supporting a nasal passage is shown in fig. 1. Broadly, the method 100 includes:

102: a substrate is formed comprising a plurality of layers.

104: the matrix is shaped.

Step 102 includes forming a plurality of layers. There may be any number of layers from two layers to more than two layers depending on the application and desired properties of the implant. The parameters are controlled at step 106 and may be adjusted during the execution of step 102 of forming the plurality of layers, and may also be adjusted during the execution of step 104 if any post-treatment of the layers is applied, e.g. in case the implant is to be subjected to drug elution, controlling the temperature to heat treat the outer layer of the matrix or to ensure that the drug compound is ideally temporarily attached to the outer structure of the matrix. Currently, the implant produced by the method 100 includes at least an inner layer and an outer layer. In effect, the outer layer is positioned between the inner layer and the skin of the nasal passage. Thus, the term "outer" refers to the skin that is outermost and thus abuts the nasal passages when the implant is in use. Conversely, the term "inner" refers to the inner layer being positioned closer to the inside of the nasal passage than the outer layer.

At least one of the inner layer and the outer layer includes or is formed from a shape memory material. This allows the implant to assume a predetermined shape when in place in the nasal passage. The predetermined shape may conform to a desired shape of the inner surface of the nasal passage-e.g., the outer diameter OD (see fig. 2) of the implant has a shape that is desired to be imparted to or maintained in the nasal passage.

Step 104 includes shaping the substrate such that the shape memory material assumes a predetermined shape when positioned in the nasal passage. The phrase "when positioned in the nasal passage" may refer to being just positioned in the nasal passage, or may refer to after the implant absorbs heat and the shape memory material is thus able to return from some contracted shape to a predetermined shape-i.e. the shape memory material or corresponding layer (typically the inner layer/matrix) has an expanded state when in use, a contracted state when in storage, and moves from the contracted state to the expanded state when in the nasal passage.

One or more layers and substantially all layers of the implant may be made of a polymer. In this regard, Intrinsic Viscosity (IV) has been found to be important for maintaining the position of the implant in the nasal passage and for allowing mucus, air and other substances to pass along the nasal passage. The polymer may be a biopolymer.

The choice of polymer, the IV ratio between layers and the thickness ratio between layers are important for the shape memory properties. In particular, step 102 may include forming the matrix by forming the inner and outer layers from respective polymers having respectively different IVs. Alternatively, step 102 may include sandwiching one or more layers of a first IV between layers of a second IV — the second IV may be higher or lower than the first IV. In other words, the IV of the inner layer is different from the IV of the outer layer. For example, the ratio between the IV of the two layers may be 1.05 or greater. Similarly, the inner layer may be made thicker than the outer layer and comprise a shape memory material. Thus, the shape memory properties imparted by the shape memory material to the inner layer will exert sufficient force during recovery back to the predetermined shape such that the sufficient force can force the outer layer to assume the necessary shape — for example, the outer layer can be extended, deformed, or otherwise become reshaped to an expanded state by movement of the inner layer.

The method 100 may also include controlling fabrication parameters (step 106) to control the properties of the implant. For example, step 106 may include controlling the drying time of one or both of the inner and outer layers, thereby controlling crystal formation in the respective inner and outer layers. Step 106 may also or alternatively include controlling the fabrication parameters to impart desired porosity characteristics to a particular layer, or to avoid porosity. In this way, the shaped prosthesis or implant may have porosity or lack thereof at any layer to control the strength and degradation of the implant. Similarly, step 106 may include controlling the temperature in the vicinity of the prosthesis during the addition or formation of the multiple layers. Although fig. 1 only shows that step 106 is performed during step 102, control step 106 may be performed during step 102 and/or step 104.

The entire manufacturing process may be controlled to produce a prosthesis of any desired form/shape, although such a prosthesis will typically be cylindrical (with the inner layer radially inward of the outer layer) to ensure that the inner air passageway is maintained. The implant may have different diameters along its length (L-see fig. 2) as the desired shape will be intended to maintain the shape of or reshape the nasal passage.

The result of method 100 is that an implant (which may be interchangeably referred to as a prosthesis) with a self-expandable design can be produced that, due to its shape memory, is able to maintain excellent stiffness for the inner nasal valve wall support when inflated, expanding the cartilage to improve breathing and resist migration. In embodiments, the implant device can increase the internal valve angle and support the structural strength of the tissue surrounding the valve in the nasal passage. This prevents tissue collapse during inspiration. The implant will affect the lateral structure of the nose, which results in an adjustment of the position of the lateral aspect of the lateral nasal cartilage, thereby affecting the external nasal valve.

According to an embodiment, the method of treatment includes inserting an implant device near the lower cartilage, dorsum of the nose, mesial tissue of the dorsum of the nose, or columella, as needed, to change the outer shape of the nose. The size is selected so that the implant can fit within the core of the hollow tube or introducer for delivery. The implant is introduced into the nasal tissue by inserting the tube into the desired location. The implant is then maintained in this position by the advancing shaft exerting a slight pressure on the implant as the hollow tube is withdrawn. Thus, the method 100 may also include the step of inserting/firing the implant into the desired location, step 110, shown in phantom, since this is not strictly a step of producing the implant itself.

The implant may have variable and various physical properties depending on the particular application it is desired to accomplish in the nasal passage, e.g., support, reshaping, drug delivery, etc., whether or not the implant is required to be recyclable or resorbable/bioabsorbable. The implant may have a rigid or flexible shape, in particular provided in different layers, or a configuration at different regions of the tubular shape. Furthermore, different layers or regions may be applied-the coating will typically be applied to an outer layer which may have a single coating along its length, may have different coatings at different portions of its length, or may be formed of different materials at different portions of its length which are adapted to promote or inhibit tissue growth or deliver different drug compounds to different extents.

The shape of the insert may be moldable such that the shape is altered and maintained just before or after implantation. The implant can then be modified as desired by the patient or as needed to be at its glass transition temperature (T) _g ) The above achieves the desired results.

Each layer of the implant may be made of any suitable material, such as a biodegradable and/or bioabsorbable polymer. This may include polymers such as one or more of Polylactide (PLA), Polyglycolide (PGA), lactide-glycolide copolymers (PLGA), PLA-PCL copolymers, poly e-caprolactone, polydioxanone, polyanhydrides, trimethylene carbonate, poly β -hydroxybutyrate, poly g-glutamic acid ethyl ester, poly DTH iminocarbonate, poly bisphenol a iminocarbonate, polyorthoesters, polycyanoacrylates and polyphosphazenes, and copolymers, terpolymers and combinations and mixtures thereof, which may be used to make implant materials via a multi-layered process.

There are also many biodegradable polymers derived from natural sources, such as modified polysaccharides (cellulose, chitin, chitosan, dextran) or modified proteins (fibrin, casein), which can be selected alone or in combination with other polymer(s) mentioned herein.

These examples of polymers that may be used to form the implant matrix are not intended to be limiting or exhaustive, but rather to illustrate potential polymers that may be used.

In some embodiments, the method 100 may include forming or attaching sutures at one or more locations on the substrate. The suture may be at one or both ends of the base. The method 100 may include pushing the suture(s) through the substrate before or after insertion into the nasal passage. The method 100 may also include adjusting the position of the implant in the hollow tube using sutures, which may reduce the diameter of the largest diameter portion of the implant adjacent the lateral cartilage. This may be accomplished by loading the implant into a transmitter tube where the implant is reduced in diameter in situ until a predetermined period of time (e.g., up to 20 minutes). The time limit is defined by an amount that facilitates a desired deflation or contraction of the implant, e.g., to a size that facilitates storage into the nasal airway, and/or a time that is short enough not to cause plastic deformation of the implant, i.e., to cause the implant to still expand back to a desired shape. Thus, the predetermined period of time prevents creep of the implant prior to its being launched out of the emitter tube. The smaller diameter portion of the implant serves as a handle and allows the implant to be pulled into the launcher — one or more sutures may similarly be used to pull the implant into the introducer, or otherwise reposition the implant once it is within the introducer. The emitter tube or introducer will be a device that will be apparent to the skilled artisan in view of the present teachings and introducers used in other applications.

The attached sutures may then be used to guide implantation of the implant, and/or to adjust the position of the implant within or on tissue immediately after implantation. The suture can then be trimmed as desired.

The above-described method 100 may be used to produce implants to improve nasal patency. Nasal patency is critical to the airway, and nasal obstruction can cause snoring, sleep apnea, and sleep disruption. Good patency of the nasal airway is also crucial for an increasing number of people who use Continuous Positive Airway Pressure (CPAP) for sleep apnea.

Depending on the device settings used in the method 100, the mechanical properties of the implant, such as the stiffness of the expansible portion of the implant, may be manipulated, notably, the shape memory material may be set along the length of the implant or only along one or more predetermined portions of the implant to achieve the desired predetermined shape. For example, the manufacture of a polymeric prosthesis for an implant, such as in the form of a stepped diameter tubular shape, may include manufacturing steps to produce a matrix form via extrusion, molding, and/or solution casting methods. The original matrix form or single diameter cylindrical tube used to produce essentially the inner layer or both the inner and outer layers may be produced by extrusion, molding or solution casting methods prior to forming its final form, for example by heating and expansion/reshaping. Some substrates are capable of achieving a relatively high level of geometric accuracy, and the mechanical strength is generally determined by the combination of the base materials and processes used.

In other embodiments, dip coating or solution casting may be used. Dip coating involves depositing a liquid film via precise and controlled removal of the substrate from solution. This is typically done using an instrument known as a "dip coater". Most dip coaters have a motorized arm that moves vertically and holds a frame with multiple spindles. A substrate is mounted on each mandrel and a solution holder is positioned below the substrate. The motorized arm immerses the mandrel and its substrate in the solution at a controlled immersion speed and time. The substrate was taken out at a prescribed speed, and a wet film was formed on the substrate.

The desired properties of the substrate may be achieved by dip coating multiple layers. The molecular weight of the polymer is often one of the factors that determine mechanical properties such as ductility of the matrix. The method 100 may include controlling the rate of removal of the substrate to control the thickness of each layer. When the starting material is selected in the form of a resin, its IV is not the only criterion for determining the mechanical properties of the matrix formed by the resin. Alternatively, the entire process from the polymer resin mixing process to the formation of the first layer (whether it is the inner or outer layer) and its intermediate layering is affected by the manufacturing parameters. For example, the method 100 may include controlling one or both of pressure and temperature to control the porosity (or others) of each layer. Similarly, this will affect the mechanical strength of the tube before the implant is collapsed to fit inside the delivery device or tool. Relatedly, for some implant materials, it is desirable to: the implant is contracted for less than 20 minutes to avoid creep to avoid plastic deformation of the implant that may inhibit the ability of the implant to move to the expanded state.

The supporting main columns of the substrate (e.g., thick inner layers) can be used to solution layer the polymer solution or dip coat the polymer solution such that after multiple layering steps, a polymer shell with multiple layers is formed from the solution by controlling solvent evaporation. The dip coater setup assembly may have at least two rail axes such that the vertical movement direction slide moves the slide holding the solution layered substrate up and down at a desired speed of mm/s driven by a motor. With two rail axes, the sliding forces are better distributed. The vertically moving slide may hold a frame that holds several posts via an interference fit that are inserted into the internal cavity of the base to perform layering of the solution. Placing the structural support main column in a closed chamber allows control of the drying time, chamber temperature and inert gas environment to which the coating is exposed.

Each of the impregnation processes contributes to the formation of the matrix by layering and will contribute to its final mechanical strength. For all or many of the coating steps, the impregnation may be only partial (i.e., partial immersion of the substrate) such that the entire tube has a predetermined uniform form, or has a fusion of different polymers at different sections along the length of the predetermined form. Pharmaceutical coatings, growth factor components or other compounds may also be added to promote cartilage growth and reduce inflammation of the mucosa. The addition may include coating the finished substrate during formation or mixing the drug or active compound into the substrate. The IV value of the outermost layer, i.e. the layer deposited last, is high enough to attach to the compound and ensure that it remains in the implant, but low enough to allow the compound to diffuse into the surrounding tissue when in contact with that tissue, e.g. at a desired rate.

In other embodiments, the preparation parameters require environmental control to reduce porosity at low temperatures, for example, at 20 degrees celsius or less, during preparation of the prosthetic substrate. In addition, different polymers, particularly when formed under controlled manufacturing parameters, will have different degrees of crystallinity. Different degrees of crystallinity can be achieved by layering methods and controlling the evaporation of the solvent by maintaining the temperature below the boiling point. In some embodiments, the temperature is maintained above the boiling point of the solvent for drying each layer, or the temperature may be varied between temperatures above and below the boiling point.

For example, step 102 may include forming the inner layer as a crystalline polymer having an intrinsic viscosity between 3.0 and 10.0. The ability to control the evaporation rate of the solution during the solution layering process and withdrawal is critical to producing coatings without porosity and with desirable mechanical properties.

Where porosity in the layer is desired, the method may include controlling environmental conditions such as air or gas mixtures, relative humidity, and temperature. This will result in a layered film with voids that will affect the adhesion of the next layer in the multi-layer prosthesis and its mechanical strength before cutting or final forming of the prosthesis for its intended function.

As should be understood from the present teachings: solution layering is not limited to vertical dip coating processes. For example, a polymer dissolved in a solvent may be dispensed along the length of a rotating substrate-e.g., an outer layer may be deposited in liquid form on an inner layer-as the substrate is displaced longitudinally along its length and rotated horizontally about its longitudinal axis relative to gravity or ground zero. Step 102 may include controlling one or more of the spin speed, machine or cross direction speed, intrinsic viscosity of each polymer layer, solvent type. Controlling these parameters will determine the wall thickness of the implant, and the ambient temperature and pressure will determine the evaporation rate of the solvent, and thus the formation of a solvent meniscus during the layering of each multilayer. This will determine the overall mechanical properties of the implant, such as expansion properties and ductility for expansion, i.e. expansion back to the expanded state.

The desired surface properties of the substrate are important for adhering the first base layer to the impregnation tool or substrate onto which the first base layer is to be applied. The first layer thickness, i.e., the thickness of the first base layer or the innermost layer of the implant, and the IV of the first base layer should result in a crystalline polymer having an IV greater than IV3.0 and less than IV 10.0. This enables the first base layer to adhere to the impregnation tool or impregnation base to form a layer according to step 102, while being low enough to enable the layer to be separated from the impregnation tool or impregnation base once formed. In an embodiment, the first layer is formed from PLLA having an IV of 6.0. A thickness of 60 μm to 80 μm can be obtained by moving the substrate into the PLLA solution. This may require at least one, preferably two, such cycles: the substrate is moved into the PLLA solution and lifted upward at a speed of 4mm/s to 5 mm/s. This allows the solution to be layered on the surface of the substrate in a low humidity environment below 50% RH with a dwell time while maintaining a temperature of at least 20 degrees celsius for each layer for less than an hour. In this case, the intermediate layer does not generate voids.

In another embodiment, the first layer thickness may be: the PLC formed a layer with a dry thickness of 10 μm, followed by a PLLA with an IV of 6.0 to form a layer of 30 μm, as shown in fig. 4. Using PLC, flexibility and shape memory are imparted to the implant, while PLA provides structure.

In embodiments, it is preferred to use a higher IV polymer PLLA, which will provide the strength, rigidity and toughness needed to promote shape memory, and an extensible PLC will provide malleability.

The matrix material used for the first layer adhesion (e.g., the impregnated matrix) should have surface properties that can be custom etched by chemical etching, irradiation, machining, and/or polishing to have a moderately elevated contact angle (deionized water) in the range of 50 to 140 degrees. These processing steps, such as etching, affect the way in which the polymer solution used for the first layer (i.e. the first layer or first base layer to be deposited on the impregnated substrate) interacts with the solid surface of the substrate material. This in turn will affect the dimensional aspects of the subsequent layers.

Some examples of suitable matrix materials (impregnated matrix) include fluoropolymers such as Polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), or Fluorinated Ethylene Propylene (FEP), among others. For example, PTFE matrices typically have a water contact angle of 120 degrees and can be etched in sodium solution to reduce the water contact angle to less than 100 degrees. The water contact angle cannot be too small, or less than 70 degrees, or hydrophilic, as it enhances the adhesion of the first polymer layer (first base layer) to the substrate. This can pose a challenge in breaking the bond to remove the polymer layer from the PTFE matrix. This is also due in part to the rigidity of the PTFE matrix with an average wall thickness of 0.22mm ± 0.02. The wall thickness of the PTFE matrix may be in the range of about 100 μm to 250 μm.

Having too high a water contact angle is also undesirable. With a PTFE surface having a lower hydrophobicity (i.e., water contact angle less than 140 degrees), a first layer having an intrinsic viscosity less than IV10.0 (e.g., a poly L-lactide (PLLA) solution extracted from a PLLA polymer solution) will have better adhesion and form a more uniform wet thickness layer on the substrate. The dry thickness will be formed by controlling the evaporation of the solvent of the initial wet film formed. Obviously, the dry thickness will be less than the wet thickness.

Compatibility of the solvent with the solute (polymer) used to dissolve the polymer resin having a typical intrinsic viscosity is important. The polymer does not dissolve immediately. Dissolution is controlled by the disentanglement of polymer chains or by the diffusion of chains through the boundary layer adjacent to the polymer-solvent interface. For example, PLLA resins are generally compatible with solvents such as chloroform or Dichloromethane (DCM). There are a myriad of bioabsorbable polymers that can be used in solution layering or dip coating. Each bioabsorbable polymer is soluble in a respective, possibly different, solvent. The weight ratio of polymer to solvent and the time for stirring will for example influence the solubility of the resin, which in turn will influence the mechanical properties of the layer-by-layer formed matrix. In this embodiment, the ratio of polymer to solvent is between 1 and 100 in a w/v ratio. In this case, a polymer such as poly L-lactide (PLLA) or PDLA (poly DL-lactide) (IV2.0 to IV10.0) may be used to form a first base layer on the substrate to adhere the first multilayer, which has the known 85 degree contact angle property. Of all resorbable polymers used in implants, this base layer will generally have the highest modulus. However, this may vary depending on how the layers of the implant should degrade and in what order the layers of the implant should be. In an embodiment, the formation, thickness, and material of the first layer may be as discussed above with reference to fig. 4.

In embodiments where the substrate involves a multi-layer process, the first layer or first base layer may be formed from PLLA having an IV of 6.0 mixed with methylene chloride in a ratio of 1/16w/v for a substrate 100mm in length with an OD of 1.0 mm. It was stirred at about 2000rpm at room temperature (between 20 and 30 degrees celsius) for up to 60 hours. Another PLA-PCL copolymer (polylactic acid/polycaprolactone biodegradable block copolymer-although other biodegradable polymers may be used) solution of IV3.8 was mixed with dichloromethane at a ratio of 1/30w/v to form the next layer on top of the first layer. This may be, for example, a GMP grade copolymer of L-lactide and epsilon-caprolactone in a molar ratio of 70/30 with a midpoint of intrinsic viscosity of 3.8 dl/g.

The solution became visually clear and was shown to completely dissolve all the resin.

In an embodiment, the same mixture solution may be stirred at 20 degrees celsius. Undissolved particles of PLLA were observed after 18 hours. In this case, ambient temperature affects the dissolution of PLLA in dichloromethane. If chloroform is used as the solvent, it will take more than 24 hours. If the PLLA resin is not completely dissolved, the layer coating applied to the substrate will not be homogenous and will not have undissolved resin particles. Since the matrix is built up layer by layer from a completely dissolved polymer solution, the time and ambient temperature of the PLLA solution mixture are critical for the solubility which will partially affect the mechanical properties. Its IV also affects the time it takes for the PLLA to dissolve completely. A lower intrinsic viscosity PLLA of IV4.0 will take a shorter 12 hours between 20 degrees celsius and 25 degrees celsius to achieve a clear mixed solution for solution layering. The ambient temperature, which affects the temperature of the solution, is critical to achieve a clear mixed solution after stirring for several hours.

In an alternative embodiment, the method 100 may include insulating a container, such as a glass ware, holding the polymer resin and the solvent using an insulating material during agitation. The heat transferred from the magnetic stirrer base can improve the solubility of the resin in the solvent in a temperature range of about 15 degrees celsius below the boiling point of the solvent.

In embodiments, where a vertical tower former (dip coater) is used, the stage of removing the substrate from the polymer solution can be viewed simply as the interaction of several sets of forces. These forces can be put into one of two categories: expulsion forces and entrainment forces. The expulsion force is used to draw the liquid away from the substrate and back into the plating solution. Instead, the entrainment force is the force used to hold the fluid on the substrate. The balance between these sets of forces determines the thickness of the wet film applied to the substrate.

The dynamic meniscus and the flow of solution in this region determine the thickness of the wet film. This is influenced by three main parameters: the rate of the distance of the solution relative to the substrate divided by the time at vertical withdrawal; influence the substrate surface adhesion properties of the meniscus of the solution; and evaporation of the solvent from the wet zone. Therefore, it is important to understand the physical principles that support the dynamic meniscus curvature and thickness of the stagnation point. This is an example of a first solution layering on a substrate, i.e. forming the first layer of the 10 μm PLA layer in fig. 4. In subsequent layers on top of the first layer, the evaporation control of the first layer will affect the wet thickness of the subsequent layers as well as the wet thickness of the final dry layer forming a shell membrane to maintain the thickness of the implant.

Another important factor is the length of travel of the solution layering, which accounts for the adhesion of each layer to the first deposited layer and the evaporation of solvent from the first layer. If the first layer on the substrate is still semi-wet or if the solvent is still evaporating from the first layer, this will affect the adhesion between the layers. This in turn will affect the mechanical strength of the layered matrix of the implant. This problem is exacerbated if the environment causes porosity due to condensation of water moisture as the solvent evaporates on the surface of the layer exposed to the environment.

In the experiments, using a PTFE matrix with a starting diameter of 0.82mm, wall thicknesses of 60 μm to 80 μm can be achieved after 2 to 3 such cycles, as follows: the substrate was moved into a PLLA IV6.0 solution at a ratio of 1/16w/v and lifted upward at a speed of 4mm/s to 5mm/s to allow the solution to layer on the surface of the substrate in a low humidity environment below 50% Relative Humidity (RH) and maintained at a temperature of at least 20 degrees celsius with a dwell time of less than 1 hour for each layer. In this process, no pores were found in the intermediate layer. A second biopolymer, such as PLLA-PCL copolymer with an intrinsic viscosity of 3.8 at a ratio of 1/30w/v, can be laminated for four cycles (15 μm each) on top of the previously formed PLLA layer by moving the matrix with the PLLA layer into the PLLA-PCL copolymer solution and lifting the matrix up at a speed of 4mm/s to 5mm/s to allow the solution to laminate on the surface of the PLLA to provide some malleability for the nasal valve infrastructure support (i.e., the tissue wall and cartilage of the nasal septum). If the rigidity is too high, the nasal septum cartilage may shift.

After the solution layering process, the resulting cylindrical shaped implant with an OD 1.06mm was left mounted on the substrate and support posts in a low temperature (i.e. below 20 degrees celsius) and DCM filled environment. The implant may have any desired shape, such as an oval cross-section, a circle, or other desired shape, to properly support or form the shape of the internal nasal passage. With N ₂ The chamber in which the implant was stored was gas flushed to evaporate residual solvent for at least 15 hours, then passed to a convective air circulation oven to heat at 85 degrees celsius for up to 80 hours to remove any residual solvent formed by solution layering under the outermost or outer layer of the formed implant. This results in a layer having a reduced thickness in dry thickness compared to wet thickness. The modulus of the obtained pipe is more than 3000MPa, and the elongation at break is more than 40%. The PTFE matrix will later be removed when the biopolymer is dried.

In another experiment, wall thicknesses of 30 μm to 50 μm can be achieved after 2 to 3 such cycles, as follows: the substrate was moved into a PLLA solution with IV6.0 at a ratio of 1/20w/v and lifted upward at a speed of 4mm/s to 5mm/s to allow the solution to layer on the surface of the substrate with a dwell time of less than 1 hour for each layer in a low humidity environment below 50% RH and at a temperature maintained at least 20 degrees celsius. In this case, the intermediate layer was found to have no pores. A second biopolymer, such as PLLA-PCL copolymer with intrinsic viscosity of 3.8 at a ratio of 1/30w/v, can be layered on top of the previously formed PLLA layer for six (or a predetermined number of) cycles (15 μm per layer) by moving the matrix with the PLLA layer into the PLLA-PCL copolymer solution and lifting the matrix up at a speed of 4mm/s to 5mm/s to allow the solution to layer on the surface of the PLA. After the solution layering process, the formed OD 1.1mm [ PLLA + PLC ] in the form of multiple layers and multi-biopolymer cylindrical shapes will be left mounted on its substrate and support posts in a low temperature (i.e., below 20 degrees celsius) environment and a DCM filled environment.

With N ₂ The chamber in which it was stored was gas flushed to evaporate residual solvent for at least 15 hours, then passed to a convective air circulation oven to heat at 75 degrees celsius for up to 80 hours to remove solvent formed or collected under the outermost layer of the shaped implant. This results in a layer having a reduced thickness in dry thickness compared to wet thickness. The modulus of the obtained pipe is more than 3000MPa, and the elongation at break is more than 60%. With this configuration, the entire device would completely degrade within 36 months. For this purpose, the PLA-PCL copolymer will degrade from the inner layer before pressing against the PLA layer on the wall of the cartilaginous nasal septum. Thus, the implant is designed to degrade outward from the inner layer. This maintains support of the nasal passages in the desired shape.

In some embodiments, the implant may be malleable, or the outer layer may be malleable. This allows the shape of the implant to be adjusted before or after implantation. To fix the shape of the implant once the desired shape is confirmed, whether before or after implantation into the nasal passage, one or more plasticizers, such as polyethylene glycol (PEG), may be added as needed to adjust or fix the shape according to step 108 of fig. 1. For example, less than 5% PEG may be added to the PLA layer during formation of the layer. Although not required, polymers or polymers of the type having shapes may be preferably usedImplants made of a material with shape memory properties, which polymer can induce shape memory, is layered by solution and is above the glass transition temperature T _g Preferably body temperature or higher in the nasal passages. This property will allow the shape memory property to be activated or adjusted after implantation by applying an external condition, such as temperature.

For example, N must be mixed with a solvent in a closed inert gas environment ₂ Gas, control the evaporation of solvent from the wet film. The humidity and temperature of the closed environment are set to, for example, a humidity of less than or equal to 25% RH and a temperature between 4 and 20 degrees celsius to allow the shape and thickness of each layer of dry film to be set during the solution layering process. This will affect the mechanical strength properties of the coating.

The formed tube (implant) of the two polymers is further processed into its final form, as shown in fig. 2. Implant 200 includes a substrate that includes an inner layer 202 and an outer layer 204, one or both of which include a shape memory material as described above.

The formed tube 200 may be cut to a length of 25mm or any length to suit a particular application. The distal end portion may be flared to a larger diameter, for example between 160 degrees celsius to 210 degrees celsius to up to 2mm, using a heated rod of 2mm diameter, 24mm length, and tapered end to 0.9 mm. The slot design is cut to produce fins from the larger diameter portion formed to enable the implant to expand (i.e., enlarge the nasal airway and/or expand the implant beyond its initially formed diameter at step 104) to provide expansion support to the internal nasal valve. This ensures that the implant can reach the size (e.g., diameter) required to support and contact the nasal cavity wall. A drug eluting coating, such as mometasone furoate, on the surface layer(s) (i.e., the layer/surface of the implant that contacts the nasal cavity wall (s)) may elute anti-inflammatory drugs and/or reduce polyps. Preferably, the pharmaceutical product will be applied after the layer has been baked in an air circulation oven to a reduced thickness. This also reduces the likelihood that the drug product may be denatured by heat exposure. Aliphatic polyester polymers having, for example, IV < 1.0 may be usedSurface-to-wall coating of compounds, such as PDLA, to allow the drug to be properly eluted. Thus, applying the compound to the outer layer of the implant may include applying (e.g., by spraying) a coating having an IV from which the compound may suitably elute — the IV of the coating may be about 1.0. Slots may be formed or cut into one or more portions of the implant, such as: larger portion or larger diameter portion or having an outer diameter OD in FIG. 2 ₁ I.e. portion 202. Currently, although three slots are shown, any number of slots may be present as desired. The slots may be equally spaced around the perimeter of the implant, as shown, or may be unevenly/unequally spaced. Typically, there will be a sufficient number of slots to achieve a smooth contraction and expansion of the implant (e.g., portion 202 thereof). Thus, the number of grooves may depend on the size or diameter of the implant or on the size or diameter of the portion of the implant in which the grooves are formed.

Depending on the size of the diameter of the base matrix (i.e., the infusion matrix) used, different wall thicknesses and different polymers may be layered on top of each other along the length of the device. For example, two diameter sections of PTFE tubing (i.e., two sections of tubing having different diameters respectively) may be used as the substrate, the smaller diameter being 1mm, the larger diameter section being 2mm, and the overall length being 28mm, as shown in fig. 3. For this reason, the finished tube does not need to be subjected to a hot forming process to obtain a 2mm diameter enlargement. The impregnated substrate and the resulting implant may have one, two, three, or any other number of different diameters.

Similarly, the first layer was formed from PLLA having an IV of 6.0 mixed with methylene chloride in a ratio of 1/16 w/v. It is stirred at up to 2000rpm at room temperature (between 20 ℃ and 30 ℃) up to 60 hours. Another solution of the PLA-PCL copolymer of IV3.8 was mixed with dichloromethane at a ratio of 1/30w/v, stirred at 2000rpm at the same temperature until 48 hours. The solution was visually clear and was shown to completely dissolve all the resin.

The total length of the base body from the larger diameter D2 to D1 was 24 mm. The PLLA may be coated over the entire length, while the PLA-PCL copolymer may be coated only starting from a 1mm diameter section (i.e., a smaller section) to 2/3 of the length. This will give 2 layers of PLA over the entire length, which will have an average modulus over 3000MPA, while the PLA-PCL copolymer will have only 2 layers starting from the 1mm diameter proximal edge up to 2/3 of length. This is another configuration and the degradation time is about 36 months. Thus, step 102 may include forming each layer over the entire length of the implant, forming one layer or multiple layers over less than the entire length of the implant, or wherein the implant includes multiple sections of respectively different diameters, forming one layer or multiple layers over one or more (but not all) sections. A solid tube with a double diameter may be formed or cut in any design to allow for application of a drug coating and elution to control mucosal inflammation. Growth factors such as I-GF1 may be added to promote cartilage growth. More layers can be laminated to a thickness of 200 μm if desired.

In another embodiment, as shown in fig. 3, a fully resorbable implant for insertion into the nose may be 2.4cm long, 0.12mm thick and have an expandable region of 2mm diameter made of two polymers from layers of PLLA poly L-lactide and PLA-PCL copolymer.

The implant may be introduced using a tool having a hollow tube to launch the implant into the nasal valve. The angle at which the larger diameter can be folded into the hollow tube is important. It is desirable to reduce the size (e.g., diameter) of the larger diameter portion 202 prior to firing into the nasal airway. This makes it easier to correctly position the implant without causing damage to the nasal airway. By pulling in or delivering the implant to have a specific outer diameter OD ₁ This reduction in size is achieved in a hollow tube (e.g., tube 203) of small inner diameter 205. Inner diameter 205 may be at OD ₁ And OD ₂ Or in some cases may be equal to or less than OD ₂ . When the implant is pulled into the hollow tube 203, the diameter OD of the implant is larger than the diameter of the tube 203 ₁ Is compressed. The degree of this compression depends on the ability of the implant 200 to collapse by cutting a groove 207 in the portion 202 of the implant 200 having the larger diameter (as seen in an end view of the implant 200 in fig. 2)Reflective), which imparts a degree of flexibility on the portion 202.

The design of the delivery device will later be entered to accommodate the size and type of device needed to lift the inner nasal valve upward and provide proper placement and anchoring (e.g., via sutures). The polymer layer is bioabsorbable. The implant may be percutaneously inserted through the natural orifice of the nose over the middle portion of the nose.

The larger diameter distal portion may be heat formed and flared to 2 mm. The implant may be shaped to provide an upward force on a portion of the nasal passage, e.g., the middle portion of the superior cartilage. The implant has structural strength from the PLLA layer and by providing an upward force on the middle portion of the superior cartilage, it will support the inner nasal valve, preventing it from collapsing. The PLA-PCL copolymer layer will provide it with shape-conforming flexibility and extensibility properties. The solid tube may be formed or cut in any design to allow the drug coating to be applied on or in one or more layers of the substrate and eluted to control mucosal inflammation. Growth factors such as I-GF1 may be added to promote cartilage growth. These implants may be placed adjacent to the superior cartilage below the nasal surface. This will apply a lateral force to the middle portion of the lateral nasal cartilage, thereby flaring the inner nasal valve.

The implant may be placed adjacent the lateral edge of the inferior cartilage. The implant may extend to the bony prominences of the anterior maxilla. This secures the lateral cartilage more firmly to the maxilla, preventing the lateral nose from collapsing.

A post-insertion check is performed to visually confirm that the desired structural and shape changes to the nose have been achieved. Diagnostic imaging is not typically used at this stage because the implant should be in a non-surgical area where no diagnostic tools are needed.

The implant is typically guided into position by the diagnostic device. The method 100 may further include providing a detectable marker at a predetermined location on the implant to facilitate detection of proper placement. For example, the implant may include a radiopaque material, such as a marker at one or both of the distal and proximal portions of the implant device, or may be mixedBaSO into bioabsorbable polymer layers ₄ . The radiopaque or MRI visible material may be in the form of one or more markers (e.g., a band of a rare metal such as platinum).

According to another embodiment, the ratio of the IV of the at least two polymers used to make should be greater than 1.05, for example IV4.0/IV3.8, which is important for shape memory, where the higher IV polymer is formed from a polymer such as PLLA or L-lactide-co-glycolide acid (PLGA) and the lower IV polymer is formed using a layer having a total thickness of at least 2/3.

For example, fig. 4 illustrates a lower IV polymer of 3/4 thickness. In this embodiment, the lower intrinsic viscosity polymer is caprolactone, which has 3/4 of the total thickness of the higher IV polymer. The higher intrinsic viscosity polymer can be 6.0 PLA sandwiched between layers of L-lactide-caprolactone copolymer (PLC) with IV 3.8. In other words, the lower IV layer-labeled inner and outer layers of the PLC-constitutes 90um of the total thickness of the implant 120um, while the higher IV polymer-labeled PLLA-constitutes the remaining 30um of the total thickness.

Due to the solution layering process, the mechanical strength of the formed tube will have sufficient toughness without interlayer porosity. This means that the implant is not limited to a particular shape of the substrate or to the total number of layers. The implant may be cut to size and used as a stent. The mechanical strength is determined by the number of layers formed on top of the substrate or the number of layers of the same material or different materials, the compatibility of the solvent with the solute, the time it takes for the resin particles to dissolve in the solvent, and the rate at which the solution peels from the polymer dissolved in the solvent. These factors affect the evaporation rate, the thickness of the wet coated film during the stripping of the solution from the meniscus of the solution, and the resulting dry film properties. A low IV outer layer for drug loading, e.g. mometasone furoate or dexamethasone, having a thickness of less than 50 μm, with an IV of less than 1.0, will be used for controlled release at 370 μ g of drug for anti-inflammatory therapy for up to 28 days.

Porosity due to ambient relative humidity and temperature also affects the mechanical strength of the form obtained by solution layering. Evaporation of the solvent during the drying stage cools both the substrate and the film. This cooling may cause problems during subsequent film formation, leaving pit-like marks in the fine structure of the film. On a macroscopic scale, this would produce a hazy coating where a clear coating should be present. Under the wrong conditions, there will be the formation of pores on the surface of the layer. Determining the amount of porosity is complex, but controllable by control of environmental settings, such as temperature and humidity. Porosity not only changes the density of the layer compared to the raw material itself, but also affects the drying kinetics. As previously described, at the point of contact between the dry film and the wet film at the dry front, the wet film will be drawn into the dry film via capillary action. The porosity of the membrane also has a large effect on this, determining the rate at which the solution will be drawn into the dry film, the distance the solution will travel into the dry film, and the rate at which the absorbed material will dry.

The implant may be made of a solid material, a composite of materials, and may be a single material itself, or may be a composite of one or more materials laminated in multiple layers to form the full thickness of the implant. The implant may be in the form of a hollow tube or a layered structure, or may have a woven or braided structure made of multiple layers. The implant may be woven or braided from several materials. Alternatively, the implant may be made of a biodegradable material.

The material, including biodegradable materials, may have shape memory properties, allowing the implant to assume a predetermined shape after implantation. The use of an insert made of a material having shape memory properties allows the implant to assume a preset shape after insertion. Alternatively, certain conditions may be applied, such as applying heat, pressure, vacuum forming by using different layers passing above their T _g To induce higher crystallinity to provide its shape memory and toughness to allow the material to assume a desired fixed or altered shape after implantation. The requirements needed to assume the memorized shape will depend on the inherent properties of the shape memory material selected for the production of the implant. The fixed shape of the implant may also be advanced before or after insertionAnd (6) adjusting the rows. The implant may be composed of a biodegradable material with or without shape memory.

Claims

1. A method of producing an implant for supporting a nasal passage, comprising:

shaping the structure such that the shape memory material will assume a predetermined shape when positioned in the nasal passage.

2. The method of claim 1, wherein forming the structure comprises: the inner layer is formed thicker than the outer layer and includes the shape memory material.

3. The method of claim 1 or 2, wherein forming the structure comprises: the inner layer is formed from at least one crystalline polymer having an intrinsic viscosity between 3.0 and 10.0.

4. A method according to claim 1 or 2, wherein the inner layer is formed on a removable substrate.

5. The method of claim 4, wherein the removable substrate is a fluoropolymer.

6. The method of claim 1, wherein forming the structure comprises: the inner layer and the outer layer are formed from respective polymers having respectively different Intrinsic Viscosities (IV).

7. The method of claim 6, comprising: forming the inner layer and the outer layer from respective polymers such that the ratio of the intrinsic viscosities is at least 1.05.

8. The method of claim 7, wherein forming the structure comprises: forming a first layer of the inner and outer layers thicker than a second layer of the inner and outer layers, the first layer having a higher intrinsic viscosity than the second layer and being at least twice as thick as the second layer.

9. The method of claim 7, wherein the outer layer has a lower viscosity than the inner layer, the lower viscosity being less than 1.0.

10. The method of claim 1 or 2, further comprising: controlling a drying time of one or both of the inner layer and the outer layer to control crystal formation of the one or both of the inner layer and the outer layer.

11. The method of claim 1 or 2, wherein shaping the structure comprises: forming the structure into a cylindrical shape, wherein the inner layer is disposed inside the outer layer.

12. The method of claim 11, wherein the structure has a length and shaping the structure further comprises shaping the structure to have different diameters along the length.

13. The method of claim 1 or 2, wherein shaping the structure comprises: extruding one or both of the inner layer and the outer layer.

14. The method of claim 1 or 13, wherein forming the structure comprises: forming the inner layer and the outer layer by one or more of molding, dip coating, and solution casting.

15. The method of claim 1, further comprising: controlling at least one of the following parameters:

(ii) temperature;

a rate of distance divided by time of the solution of one of the inner and outer layers relative to the already formed layer of the other of the inner and outer layers;

structural surface adhesion properties;

the rate of evaporation of solvent from the wetting zone;

an environmental mixture; and

relative humidity.

16. The method of claim 1, further comprising: applying a plasticizer to set one or both of the inner layer and the outer layer.

17. The method of claim 16, wherein applying a plasticizer to set one or both of the inner layer and the outer layer comprises: applying the plasticizer after inserting the implant into the nasal passage.

18. The method of claim 1 or 2, wherein one or both of the inner layer and the outer layer are formed of a bioabsorbable material.

19. The method according to claim 1 or 2, further comprising: one or more slots are formed in a portion of the implant to allow the portion to expand.

20. An implant for nasal passage support, comprising: a structure comprising a plurality of layers having at least an inner layer and an outer layer, at least one of the inner layer and the outer layer comprising a shape memory material, the structure being shaped such that the shape memory material will assume a predetermined shape when positioned in the nasal passage.

21. The implant of claim 20, wherein the structure forms a tubular member having a varying diameter along its length.

22. An implant for nasal passage support, the implant formed according to the method of claim 1 or 2.