This patent disclosure can contain material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.
All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described herein.
The present application relates to conduits that can be used for medical applications, such as tympanostomy conduits and subannular ventilation conduits, or for non-medical applications. More particularly, the present application relates to conduits with anti-fouling properties, guided fluid transport, minimal invasiveness, and/or programmable shape and chemistry information.
Acute otitis media (AOM), also known as an ear infection, and otitis media with effusion (OME) are the leading causes of healthcare visits worldwide. Otitis media (OM) occurs in the middle ear space behind the eardrum, usually after a cold or other upper respiratory infection has been present for several days. During this infection, the Eustachian tubes swell, preventing air from entering the middle ear and pulling fluid into the middle ear space. This trapped fluid, containing mucins, harbors bacteria and viruses.
Acute otitis media (AOM), also known as an ear infection, and otitis media with effusion (OME) are the leading causes of healthcare visits worldwide, and lead to considerable patient morbidity and significant annual healthcare burden of >$5B of direct and indirect costs in the US. Globally, AOM affects over 700 million people each year; children tend to be disproportionately affected relative to adults with estimates of global incidence peaking at 61% in ages 1-4. AOM, is the most common infection in pediatric patients, affecting over 8.8 million U.S. children and causing 12 to 16 million physician visits per year in the US. Acute OM has a prevalence of 60% within the first 5 years of life. OM occurs in the middle ear space behind the eardrum, usually after a cold or other upper respiratory infection has been present for several days. During this infection, the Eustachian tubes swell, preventing air from entering the middle ear and pulling fluid into the middle ear space. This trapped fluid, containing mucins, harbors bacteria and viruses. Since children younger than age 7 have shorter and more horizontal Eustachian tubes, these become blocked more easily, leading to a higher occurrence of ear infections.
Left untreated, OM can lead to symptoms including pain, fever, vomiting, loss of appetite, difficulty sleeping, dizziness, recurrent acute infections, hearing loss, and speech delays. Severe complications of acute OM include disabling acute mastoiditis, subperiosteal abscess, intracranial suppuration, meningitis, and facial nerve palsy. In the developing world, chronic OM frequently results in these permanent hearing sequelae, and when untreated, is estimated to result in more than 28,000 deaths worldwide due to the aforementioned complications according to a WHO report.
A total of $2.8 billion was spent on treatment of OM in 2006, not including over-the-counter medications. The current standard of care consists of a 10-day course of broad spectrum oral antibiotics. OM is the most common reason for prescribing antibiotics to US children. Treatment of acute otitis media in children under 2 years of age. Thus, OM treatment is believed to add to the ongoing increase in antibiotic resistance among pathogenic bacteria. Systemic antibiotic administration often results in side effects, including diarrhea, dermatitis, vomiting, and oral thrush. Even after the middle ear space is no longer infected, fluid can remain in the ear. Approximately 30% of children still have fluid in the middle ear one month after an ear infection and 20% still have fluid after two months. This fluid causes recurrent infections, with 40% of children having 4 or more episodes of acute OM.
To treat fluid buildup, a small incision can be made into the tympanic membrane, commonly known the ear drum, in a procedure known as a myringotomy. During tympanocentesis, the fluid can be removed with a needle by the surgeon. However, after the incision heals, OM can recur and the fluid can build up again. Thus, tympanostomy tubes, commonly called ear tubes, are used to create a semi-permanent channel for mucus to drain from the middle ear space and allow air to enter, equalizing the pressure and preventing pain. They can also help return the patient's hearing to normal, as the dampening effects of viscous fluid on the ossicles during “glue ear” is no longer present. Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. The lower amount of fluid in the ear can also prevent recurrent OM.
The placement of tympanostomy tubes is frequently recommended for patients with recurrent acute OM, commonly defined as 3 or more episodes of OM within a 6-month period. Tube placement can also be recommended for chronic OM where fluid is present in the middle ear continuously for over 4 months, fluid is causing a documented hearing loss greater than 20 dB, infection does not clear up after trying multiple antibiotics, or complications of ear infections occur including mastoid infection. Nearly 700,000 tympanostomy tube placements are performed each year in the US alone, making it the most common procedure for children under anesthesia. It is estimated that 26% of children require tympanostomy tube insertion before the age of 10. There is increasing prevalence of recurrent otitis media among children in the United States.
To place a tympanostomy tube, a small typically cylindrical grommet is inserted into a small perforation in the tympanic membrane formed during a myringotomy. Tympanostomy tubes are typically composed of silicone or fluoroplastic, although variations have been composed of titanium and stainless steel. They come in a variety of shapes and sizes, and the selection of tube by the surgeon is based on the pathophysiology, the patient's age, the number of previous sets of tubes, the surgeon's preference, and the duration of time for placement. Short-term tubes are smaller and typically stay in place for 2 to 18 months before falling out on their own. Long-term tubes are larger with flanges that secure them in place for up to three years and often require removal by an otolaryngologist.
In addition to being placed directly into a hole in the tympanic membrane, another option is subannular placement via a tunnel beneath the skin of the external ear canal and annulus, which is a bony ring that surrounds the tympanic membrane. This technique can be used for atrophic and retracted tympanic membranes where there can be insufficient fibrous tissue to retain a standard tympanostomy tube. It can also be beneficial for patients who have undergone a tympanoplasty, or a replacement of the tympanic membrane tissue. The materials and designs of subannular ventilation tubes are like those of tympanostomy tubes. For both types of tubes, antibiotic droplets are frequently recommended to allow for local delivery and treatment of recurrent infections.
The objects and advantages will be apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout, and in which:
In certain embodiments, the present disclosure is directed to providing guidelines for design of medical and fluidic conduits for medical and biological applications, microfluidic devices, membranes, nozzles, bioreactors, transport of coolant and other chemicals through machinery, drainage of waste products from reactions, sensors, food and beverage industry, cosmetics and perfumes, and other applications.
Certain embodiments of the present disclosure describes ventilation or tympanostomy tubes that reduce and/or prevent occlusion by various biofluids, debris, and cells and bacteria.
Certain embodiments of the present disclosure describe tubes that reduce and/or prevent growth of human cells on the outer surface of the tube and the flanges that would prevent early extrusion.
Certain embodiments of the present disclosure describes surfaces that reduce/or prevent the formation of biofilms on their surface to prevent the development of infection in general or otorrhea in the case of ear tubes.
Certain embodiments of the present disclosure recognize that ideal ventilation or ear tubes would be composed of materials with low advancing contact angles and optimized shapes with chosen antibiotic liquid suspensions as to not prevent these from entering the tubes. As described more fully below, this could be accomplished by either altering the material of the tubes, altering the shape of the tubes, and/or altering the composition of the therapeutic droplets themselves to include more surfactants or using oil-based droplets, in accordance with certain embodiments.
Certain embodiments of the present disclosure describe tube designs that allows water to be passively repelled or to actively induce swelling inside of the tube to close it prior to swimming or bathing to improve patient comfort and encourage ear tube use, including during summer months.
Certain embodiments of the present disclosure describe drops of various materials that can be used to temporarily change the shape or fluidic properties of the tube.
Certain embodiments of the present disclosure describe creation of ventilation tubes that can be easily inserted into smaller perforations through dynamic flanges or that include size changing abilities that would alleviate these issues and potentially make it easier for the surgeon to insert the tympanostomy or subannular ventilation tubes.
According to some embodiments, a system includes a device having a conduit having a proximal end, the proximal end having a proximal end radius, a distal end opposite the proximal end, the distal end having a distal end radius, an inner surface connecting the proximal end and the distal end, the inner surface forming a proximal angle at the proximal end and a distal angle at the distal end, the inner surface having surface properties, and an outer surface connecting the proximal end and the distal end; the distal end radius, the proximal end radius, the distal angle, the proximal angle, and the surface properties of the inner surface are selected to: allow entry of a first material to the distal end of the conduit, allow transport of the first material through the conduit along the inner surface toward the proximal end, and allow exit of the first material from the proximal end of the conduit, and resist entry of a second material into the proximal end of the conduit; and the Young-Laplace pressure for the first material is less than Young-Laplace pressure for the second material.
In some embodiments, the difference between the Young-Laplace pressure of the first material and the Young-Laplace pressure of the second material is in the range of 1 and 1,000 Pa.
In some embodiments, a selectivity of the conduit is between 1 and 10, the selectivity being a normalized pressure difference between the Young-Laplace pressure of the first material and the Young-Laplace Pressure of the second material.
In some embodiments, the at least one of an angle or a surface property of the inner surface vary to maintain a substantially constant or reducing Young-Laplace pressure of the first material from the distal end to the proximal end.
In some embodiments, at least one of an angle or a surface property of the inner surface varies such that there is substantially no pinning of the first material from the distal end.
In some embodiments, at least one of an angle or a surface property of the inner surface varies to maintain a Young-Laplace pressure of the first material from the distal end to the proximal end that varies by 10% or less.
In some embodiments, an advancing angle of the first material at the distal end as the first material enters the distal end is less than 90°.
In some embodiments, an advancing angle of the second material at the proximal end is as the second material enters the proximal end is greater than 90°.
In some embodiments, the proximal angle is increased to decrease the breakthrough pressure of the first material at the proximal end.
In some embodiments, the inner diameter of the conduit is 3 mm or less.
In some embodiments, the conduit is a tympanostomy or aeration tube.
In some embodiments, the shape of the conduit is selected from a group consisting of cylindrical, conical, and curved.
In some embodiments, the diameter of the proximal end is greater than the diameter of the distal end.
In some embodiments, the conduit includes a distal flange disposed on the distal end of the conduit.
In some embodiments, the conduit includes a proximal flange disposed on the proximal end of the conduit.
In some embodiments, the device is a tympanostomy tube and at least one of the proximal flange and the distal flange has a radial stiffness that matches a portion of a tympanic membrane.
In some embodiments, the device further includes a portion of the conduit provided with a slippery surface including: a partially or fully stabilized lubricating liquid layer on at least a portion of the inner surface or the outer surface of the conduit, the lubricating liquid layer wetting and adhering to at least a portion of the conduit to form the slippery surface over the portion of the conduit.
In some embodiments, the lubricating liquid decreases an advancing angle of the first material.
In some embodiments, the lubricating liquid increases an advancing angle of the second material.
In some embodiments, the spreading coefficient of the first material on the lubricating liquid is greater than zero, and wherein the lubricating liquid forms a wrapping layer around the first material.
In some embodiments, the lubricating liquid decreases the effective surface tension of the first material.
In some embodiments, the lubricating liquid increases the effective surface tension of the second material.
In some embodiments, the lubricating liquid is on the inner surface of the conduit.
In some embodiments, the lubricating liquid is on the outer surface of the conduit.
In some embodiments, the lubricating liquid is on the inner surface of at least one of the proximal flange and the distal flange.
In some embodiments, the lubricating liquid is one or more of silicone oil, partially or fully fluorinated oil, mineral oil, carbon-based oil, castor oil, fluocinolone acetonide oil, food-grade oil, water, surfactant/surfactant solution, organic solvent, perfluorinated hydrocarbons, as well as mixtures thereof.
In some embodiments, the surface properties include a chemical gradient or pattern on at least a portion of at least one of the inner surface and the outer surface.
In some embodiments, the chemical gradient or pattern is disposed on the inner surface of the conduit.
In some embodiments, the chemical gradient or pattern is disposed on the outer surface of the conduit.
In some embodiments, the chemical gradient or pattern is disposed on at least one of the proximal flange at the proximal end of the conduit and a distal flange at the distal end of the conduit.
In some embodiments, the chemical gradient or pattern decreases the effective surface tension of the first material when the first material is disposed on the chemical gradient.
In some embodiments, the chemical gradient or pattern increases the effective surface tension of the second material when the second material is disposed on the chemical gradient.
In some embodiments, the chemical gradient or pattern includes a wicking layer to configured to transport fluid along the wicking layer from one of the proximal end and the distal end to the other of the proximal end and the distal end or a center portion of the conduit.
In some embodiments, a portion of the conduit is provided with a gradient or pattern thereon.
In some embodiments, the gradient or pattern decreases the effective surface tension of the first material.
In some embodiments, the gradient or pattern increases the effective surface tension of the second material.
In some embodiments, the gradient or pattern is disposed on at least a portion of the inner surface of the conduit.
In some embodiments, the gradient or pattern is disposed on at least a portion of the outer surface of the conduit.
In some embodiments, the gradient or pattern is disposed on at least one of the proximal flange and the distal flange at the distal end of the conduit.
In some embodiments, the gradient or pattern is selected from a group consisting of geometrically patterned channels, macro-porous channels, micro-porous channels, three-dimensional periodic networks of pores, sponge-like networks of pores, surface roughness, grooves, ridges, indentations, micropillars, and microridges.
In some embodiments, the conduit includes a stimulus-responsive portion, the stimulus being selected from one or more of light, temperature, pressure, electric field, magnetic field, swelling, de-swelling, or chemical composition.
In some embodiments, the stimuli-responsive portion is selected from a group consisting of a thermostrictive, piezoelectric, electroactive, chemostrictive, magnetostrictive, photostrictive, swellable, or pH-sensitive material.
In some embodiments, the stimulus is the chemical composition, and the chemical composition includes a lubricating liquid.
In some embodiments, the stimulus-responsive portion includes a proximal flange disposed at or near the proximal end of the conduit; and wherein the distal flange is capable of transitioning between a first configuration and a second configuration in response to the stimulus.
In some embodiments, the distal flange changes at least one of a size of the distal flange or a shape of the distal flange when transitioning between the first configuration and the second configuration.
In some embodiments, one of the distal end and the distal flange includes a protrusion, the protrusion includes a shape constant material to facilitate insertion of the distal end of the conduit.
In some embodiments, the stimuli responsive portion is a valve disposed within the conduit, the valve being capable of closing in response to the stimulus.
In some embodiments, the valve is selected from one of a stimuli-responsive polymer, a gas-selective mobile membrane, stimuli-responsive cilia-like and hair-like fibers, platelets, pillars, reconfigurable tunable nano- or microstructures with functionalized tips, and combinations thereof.
In some embodiments, the stimulus-responsive portion further includes a proximal flange disposed at or near the proximal end of the conduit, and wherein the proximal flange is capable of transitioning between a first configuration and a second configuration in response to the stimulus.
In some embodiments, the stimuli-responsive portion includes a first layer of a first stimuli-responsive material and a second layer of a second stimuli-responsive material,
In some embodiments, the stimulus is swelling and the first stimuli-responsive material and the second stimuli-responsive material have different cross-linking densities.
In some embodiments, the conduit has a first diameter in the first configuration, and the conduit has a second diameter in the second configuration.
In some embodiments, the stimuli-responsive portion is disposed on the inner surface of the conduit.
In some embodiments, the stimuli-responsive portion swells in response to the stimuli.
In some embodiments, the conduit further includes a lumen defined by the inner surface and extending from the distal end to the proximal end, wherein the stimuli-responsive portion is disposed in the lumen.
In some embodiments, the stimuli-responsive portion includes pores disposed throughout the lumen and the pores close in response to the stimulus.
In some embodiments, the lumen is open to the first material in the first configuration and closed to the first material in the second configuration.
In some embodiments, the stimuli-responsive portion is disposed on the outer surface of the conduit.
In some embodiments, the stimulus causes the stimuli-responsive portion to separate from the conduit.
In some embodiments, the stimuli-responsive portion includes actuators that are configured to expand when exposed to the stimulus.
In some embodiments, the conduit includes a tube, and wherein the device further includes a second conduit, the second conduit including a tube having a proximal end and a distal end, the second conduit proximal end disposed near the proximal end of the conduit and the second conduit distal end disposed near the distal end of the conduit.
In some embodiments, the distal end radius, the proximal end radius, the distal angle, the proximal angle, and the surface properties of the inner surface are selected to allow entry of a third material to the proximal end of the conduit, allow transport of the third material through the conduit along the inner surface toward the distal end, and resist exit of the third material from the proximal end of the conduit; wherein the Young-Laplace pressure for the third material is less than the Young-Laplace pressure for the second material, but below the breakthrough pressure at the distal end.
In some embodiments, at least a portion of the inner surface is configured to pin the third material thereon.
In some embodiments, the at least portion includes one of a surface chemistry or a texture to facilitate pinning of the third material.
In some embodiments, the conduit further includes a valve configured to resist exit of the third material from the proximal end of the conduit.
In some embodiments, the difference between the Laplace pressure of the second material and the Laplace pressure of the third material is between 1 Pa and 1000 Pa.
In some embodiments, the distal end is configured to have breakthrough pressure of at least 1 Pa higher than the Young-Laplace pressure of the third material at the location of the distal end to prevent exit of the third material from the distal end.
In some embodiments, the advancing angle of the third material at the proximal end as the third material enters the proximal end is less than 90°.
In some embodiments, the angle of the inner surface at the distal end is decreased to increase the breakthrough pressure of the third material at the proximal end.
In some embodiments, the distal end radius, the proximal end radius, the distal angle, the proximal angle, and the surface properties of the inner surface are selected to allow entry of a fourth material to the proximal end of the conduit, allow transport of the fourth material through the conduit along the inner surface toward the distal end, and allow exit of the first material from the distal end of the conduit; and wherein the Young-Laplace pressure for the fourth material is less than the Yong-Laplace pressure for the second material.
In some embodiments, the difference between the Young-Laplace pressure of the second material and the Laplace pressure of the fourth material is in the range of 1 Pa to 1000 Pa.
In some embodiments, at least one of an angle or a surface property of the inner surface vary to maintain a substantially constant or reducing Young-Laplace pressure of the fourth material from the proximal end to the distal end.
In some embodiments, at least one of an angle or a surface property of the inner surface varies such that there is substantially no pinning of the first material from the proximal end to the distal end.
In some embodiments, an advancing angle of the fourth material at the proximal end as the fourth material enters the proximal end is less than 90°.
In some embodiments, the distal end is configured to have breakthrough pressure for the fourth material of at least 1 Pa lower than the Young-Laplace pressure of the forth liquid at the location of the distal end to enable its exit.
In some embodiments, the angle of the inner surface at the proximal end is increased to decrease the breakthrough pressure of the fourth material at the proximal end.
In some embodiments, the first material is selected from the group consisting of effusion, pus, blood, plasma, tears, breast milk, amniotic fluid, serum, synovial fluid, cerebrospinal fluid, urine, saliva, sputum, sweat, other bodily fluid, water, water containing surfactants, perilymph, endolymph, mucus, and any combination thereof.
In some embodiments, the second material is selected from the group consisting of water, aqueous solutions, foams and emulsions, ototoxic agents, soap, pool water, fresh water, salt-containing water, or precipitation, foams and emulsions, ototoxic agents.
In some embodiments, the third material is selected from a group consisting of lubricating liquids, cross-linkers, aqueous and oil-based solutions of antibiotics, antiseptics, anti-viral agents, anti-inflammatory agents, small molecules, immunologics, nanoparticles, genetic therapies including viral and lipid-based therapies, chemotherapeutics, stem cells, cellular therapeutics, growth factors, proteins, radioactive materials, other liquid or gas-based pharmaceutical compounds, and combinations thereof, cerumenolytic agents, e.g. squalene, chlorhexidine, and EDTA, deferoxamine, dihydroxybenzoic acid, glutathione, D methionine and N acetylcysteine, also in forms of foams and emulsions.
In some embodiments, the fourth material is selected from the group consisting of oil-based, water-based, and other solvent-based therapeutics containing at least one of antibiotics, antiseptics, anti-viral agents, anti-inflammatory agents, small molecules, immunologics, nanoparticles, air for ventilation, genetic therapies including viral and lipid based therapies, chemotherapeutics, stem cells, cellular therapeutics, growth factors, proteins, radioactive materials, other liquid or gas-based pharmaceutical compounds, and combinations thereof.
In some embodiments, the conduit includes one or more of a hydrogel, a chemically crosslinked polymer, a supramolecular polymer, a metal, a metal oxide, a porous material, geometrically-patterned pores or channels in a material, membranes and sponges, colloid- and surfactant-templated pores, grooves and ridges, periodic and aperiodic arrays of indentations, nano- and microstructures: nanoforest, nanoscale patterned films, microplatelets, micropillars, and microridges.
In some embodiments, the conduit includes one or more of biostable or bioabsorbable polymers, isobutylene-based polymers, polystyrene-based polymers, polyacrylates, and polyacrylate derivatives, vinyl acetate-based polymers and its copolymers, polyurethane and its copolymers, silicone and its copolymers, ethylene vinyl-acetate, polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics, polyamides, polyesters, polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose, collagens, alginates, gelatins, and chitins.
In some embodiments, the conduit includes one or more of dacron polyester, poly(ethylene terephthalate), polycarbonate, polymethylmethacrylate, polypropylene, polyalkylene oxalates, polyvinylchloride, polyurethanes, polysiloxanes, nylons, poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes, poly(amino acids), ethylene glycol I dimethacrylate, poly(methyl methacrylate), poly(2-hydroxyethyl methacrylate), polytetrafluoroethylene poly(HEMA), polyhydroxyalkanoates, polytetrafluorethylene, polycarbonate, poly(glycolide-lactide) co-polymer, polylactic acid, poly(γ-caprolactone), poly(γ-hydroxybutyrate), polydioxanone, poly(γ-ethyl glutamate), polyiminocarbonates, poly(ortho ester), polyanhydrides, alginate, dextran, chitin, cotton, polyglycolic acid, polyurethane, gelatin, collagen, or derivatized versions thereof.
In some embodiments, wherein the conduit includes one or more of Li, Be, B, Na, Mg, Al, Si, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, Rb, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, Cs, Ba, Hf, Ta, W, Re, Os, Ir, Pt, Au, Ti, Pb, Bi, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and their oxides.
According to some embodiments, a system includes tympanostomy or ventilation device having a conduit configured to be positioned in an ear, the conduit including an input port configured to be received in an ear canal, the input port configured to receive a first liquid; an output port configured to be received in a middle ear, the output port configured to output the first liquid received in the input port; an inner surface extending from the input port to the output port, at least a portion of the inner surface being a conical or curved geometry extending at least partially between the input port and the output port to allow the transport of the first liquid between the ports.
In some embodiments, the first liquid is a therapeutic.
In some embodiments, the conical or curved geometry is selected to allow the first liquid to pass from the input port to the output port and to prevent a second liquid to pass from the input port to the output port.
In some embodiments, the second liquid is selected from at least one of water, aqueous solutions, foams and emulsions, ototoxic agents, soap, pool water, fresh water, salt-containing water, or precipitation, foams and emulsions, ototoxic agents, and combinations thereof.
In some embodiments, a lubricating liquid layer is disposed on at least part of the inner surface, the lubricating liquid layer including a lubricating liquid that wets and adheres to the at least part of the inner surface to form a slippery surface over the at least part of the inner surface.
In some embodiments, the lubricating liquid and the conical or curved geometry are selected to allow the first liquid to pass from the input port to the output port and to prevent a second liquid to pass from the input port to the output port.
In some embodiments, a pattern is on at least part of the inner surface.
In some embodiments, the pattern includes a wicking layer, the wicking layer is configured to transport fluid along the wicking layer.
In some embodiments, the pattern includes a difference in surface properties of the at least part of the inner surface.
In some embodiments, the surface properties of the at least part of the inner surface change from being hydrophobic at the input port to less hydrophobic or hydrophilic at the output port.
In some embodiments, the pattern is selected from a group consisting of geometrically patterned channels, macro-porous channels, micro-porous channels, three-dimensional periodic networks of pores, sponge-like networks of pores, surface roughness, grooves, ridges, indentations, micropillars, and microridges.
In some embodiments, the lubricating liquid, the pattern, and the curve are selected to allow the first liquid to pass from the input port to the output port and to prevent a second liquid to pass from the input port to the output port.
In some embodiments, the lubricating liquid layer reduces the adhesion of microbes and cells.
In some embodiments, otitis media, puss, mucus can enter the output port in the middle ear, be transported through the tube and exit at the inner port into the ear canal.
In some embodiments, at least one of the input port further includes an input port flange configured to assist entrance of the first material into the input port, and the output port further comprise an output port flange configured to assist the entrance of a third material into the output port.
In some embodiments, the third material is selected from the group consisting of effusion, pus, blood, plasma, tears, breast milk, amniotic fluid, serum, synovial fluid, cerebrospinal fluid, urine, saliva, sputum, sweat, other bodily fluid, water, water containing surfactants, perilymph, endolymph, mucus, and any combination thereof.
In some embodiments, the conduit includes a shape, the shape being configured to change in response to a stimulus.
In some embodiments, the shape change is selected from one of closing of the input port, closing of the output port, closing of the inner surface between the input port or output port, and combinations thereof.
In some embodiments, the shape change includes one of increasing the size of the output port, increasing the size of the input port, increasing the size of the conduit, expanding of a flange at the input port, expanding of a flange at the output port, actuation of actuators on an external surface of the conduit, or combinations thereof.
In some embodiments, the shape change includes one of decreasing the size of the output port, decreasing the size of the input port, decreasing the size of the conduit, contracting of a flange at the input port, contracting of a flange at the output port, actuation of external actuators on the conduit, or combinations thereof.
Upon review of the description and embodiments provided herein, those skilled in the art will understand that modifications and equivalent substitutions can be performed in carrying out the invention without departing from the essence of the invention. Thus, the invention is not meant to be limiting by the embodiments described below.
I. Problems with Tympanostomy Tubes and Conduits
Problems with tubes, such as tympanostomy and subannular ventilation tubes, are common.
For example, to place a tympanostomy tube, a small typically cylindrical grommet is inserted into a small perforation in the tympanic membrane. Tympanostomy tubes can be composed of silicone or fluoroplastic, although variations have been composed of titanium and stainless steel. They come in a variety of shapes and sizes, and the selection of tube by the surgeon is based on the pathophysiology, the patient's age, the number of previous sets of tubes, the surgeon's preference, and the duration of time for placement. Short-term tubes are smaller and typically stay in place for 2 to 18 months before falling out on their own. Long-term tubes are larger with flanges that secure them in place for up to three years and often require removal by an otolaryngologist.
In addition to being placed directly into a hole in the tympanic membrane, another option is subannular placement via a tunnel beneath the skin of the external ear canal and annulus, which is a bony ring that surrounds the tympanic membrane. This technique can be used for atrophic and retracted tympanic membranes where there can be insufficient fibrous tissue to retain a standard tympanostomy tube. It can also be beneficial for patients who have undergone a tympanoplasty, or a replacement of the tympanic membrane tissue. The materials and designs of subannular ventilation tubes are like those of tympanostomy tubes. For both types of tubes, antibiotic droplets are frequently recommended to allow for local delivery and treatment of recurrent infections.
A. Occlusion of Tubes
It is estimated that 7% to 37% of implanted tympanostomy tubes fail due to occlusion. Occlusions can be formed by mucus, blood, keratinocytes, earwax, or bacteria and they prevent fluid from flowing through the tubes, rendering them ineffective. Many tube materials, including silicone and fluoroplastics, although having a low degree of wettability, do not resist adhesion of cells and require high sliding angles for water and mucus droplets to slide from the surfaces. When a tube becomes clogged, ear drops can be prescribed to help loosen the blockage. When possible, the ENT doctor can try to suction out the blockage. Sometimes the patient must undergo a painful procedure to remove the occluded tube. In addition to causing additional medical expenses and increased risk of scarring, tube replacement requires additional surgeon and patient time.
B. Premature Extrusion of Tubes
Keratinocytes are a basal epithelial cell type, forming a layer on the external side of the tympanic membrane. When a tympanostomy tube is placed on or into the tympanic membrane, the squamous layer of the tympanic membrane keratinizes on the outer flange, pushing out the tube posterior-inferiorly and causing extrusion of transtympanic ventilating tubes, relative to the site of insertion. Premature extrusion of tympanostomy tubes can occur, requiring the patient to undergo another tympanostomy tube placement surgery.
C. Failure to Self—Extrude and Medial Migration of the Tube
One of the most serious problems associated with tympanostomy tubes is persistent tympanic membrane perforation. Perforations can need surgical closure via a myringoplasty/tympanoplasty procedure. Higher complication rates, such as persistent otorrhea, formation of granulation tissue, or impending development of cholesteatomas, are observed in patients when tympanostomy tubes stay in the tympanic membrane longer than 2 years. Tympanic membrane perforation has been reported to be more common when the ventilation tube is removed (14.3%) than when it extrudes spontaneously (4.0%). A long-term T-tube with two long flanges usually remain in the eardrum for 24 months or longer and are associated with higher persistent tympanic membrane perforation.
Another rare complication is a medial migration of tympanostomy, in which the tube is displaced behind an intact tympanic membrane instead of following the natural path of extrusion towards the ear canal. Some hypotheses connect this complication with the formation of the biofilm on the outer surface of the tube, and with the dysfunction of the Eustachian tube.
D. Biofilm Formation on Tubes
Ventilation tubes can serve as a site for bacterial adhesion and biofilm formation. Bacterial biofilms are glycoprotein bacterial colonies that are resistant to antibiotic penetration. In addition to clogging, this can cause additional infections within the middle ear space. Otorrhea is the most common postoperative complication of middle ear ventilation tube insertion. Ootorrhea can form because of a biofilm in the middle ear, serving as a bacterial reservoir for bacteria to be continuously released into the middle ear. Postoperative otorrhea requires antibiotics and aggressive treatment, and often requires the tube to be removed because of permanent contamination of the tube. Thus, bacterial adherence to tympanostomy tube materials has been the focus of study for more than 30 years. In vitro studies have demonstrated that more inert tympanostomy tube materials and smoother surfaces can inhibit the adsorption of key bacterial binding proteins, such as fibronectin. Biofilms will form on each type of tympanostomy tube currently available on the market.
E. Delivery of Therapeutic Droplets Through Tubes
To prevent the negative side effects of systemic antibiotic usage, targeted therapeutic delivery to the site of infection would be ideal to solve recurrent OM. However, traversing the keratinized tissue of the tympanic membrane on its own to reach the middle ear space is impossible for most droplet formulations. Thus, ventilation tubes can be used to directly deliver antibiotic droplets into the middle ear. However, delivery of single droplets through these small orifices can be challenging. The current materials and geometric space for these tubes, including metals and various plastics, have not been able to solve these issues as the advancing contact angle of these materials with water and other fluids creates an extremely high-pressure resisting entrance of the droplet into the tube. Researchers found that without the use of slight tragal pressure, Cortisporin, TobraDex, and Cipro drops did not consistently pass through tympanostomy tubes.
Currently, for disorders like idiopathic sudden sensorineural hearing loss, clinicians will inject (via a needle) steroids into the middle ear that will ideally diffuse through the round or oval window into the inner ear. While there is an option to place a tube and apply steroid-based ear drops, most clinicians intuitively understand that based on current tube design and flow mechanics, the steroid concentration of drug will not consistently or reliably be high enough to treat the hearing loss. The creation of the tube that allows high flow will allow minimally invasive drug delivery and development of optimized formulations of topical medications, in accordance with certain embodiments.
F. Environmental Water Entering the Middle Ear Space
Environmental water encountered during swimming and bathing, particularly soapy water containing surfactants, can enter the middle ear space, causing pain and additional infections.
G. Invasive Insertion and Scarring
Many tympanostomy tubes require relatively large incisions due to their bulky flanges and surgical placement through the narrow and long ear canal. These large incisions can cause scarring, called tympanosclerosis, and incomplete perforation healing in approximately 5% of cases. Small perforations do not allow sound to be adequately captured and conducted, and scar tissue on the tympanic membrane causes it to be thicker and dampens the motion.
H. Reduced Fluid Flow Through Small Radius Tubes
Movement of fluids through small tubes such as tympanostomy tubes can be challenging. The advancing contact angle of tube materials and water other fluids contributes to an extremely high pressure that prevents fluid from entering and flowing along the length of tubes. Although tubes with small radii are desirable, the high pressures encountered create a lower limit for tube diameter. In addition, high pressures limit the utility of tympanostomy tubes for drug delivery to the middle ear.
In accordance with certain embodiments, disclosed herein are improved conduits for various application. In accordance with certain embodiments, disclosed herein are tympanostomy and/or subannular ventilation conduits. The geometry and/or surface properties of these tubes or conduits are optimized for controlled transport of various fluids. These conduits can be provided with any desired shape such as flat, curved, wavy, round, tubular, cylindrical, conical, sharpened, beveled, isotropic and anisotropic, mesh-like, membrane-like, catheter-like, flower-like, wire-like. The conduits can be all smooth or roughened, solid or porous, mono- or multilayered, soft or hard, hollow or filled with one or more additional functional materials or therapeutics. The conduits can include fully- or partially biodegradable parts. The conduits can have chemically or structurally patterned surfaces. The conduits can have one or more soft or hard flanges. The conduit can have one or more of the properties described in
Some of the exemplary design principles discussed in the present application include the reduction and/or prevention of occlusion on the lumen of the conduit, reduction of adhesion of the biofilm to the inner and outer surfaces of the conduit, enhanced guided flow of biological fluids and antibiotic drops, reduction and/or prevention of an early extrusion of the conduit, smoothing of the inner and outer surfaces of the tube by adding the lubricious or lubricating layer, inducing a wrapping layer on the biological fluids, antibiotic drops, cells and bacteria, on-demand replenishment of the lubricating overlayer, minimization of invasiveness, avoiding hearing loss and formation of the scarring tissue in the tympanic membrane, patient-specific customization of tube, patient-specific customization of drug, on-demand change of geometry and surface chemistry of the tube, controlled capture and release of biomarkers in the middle and outer ear, patterning of the tube to improve the fluid transport and bioadhesion, and remote monitoring of the middle ear condition through built-in sensors.
While certain embodiments of the present disclosure discuss tympanostomy conduits, and others discuss subannular ventilation conduits, it shall be understood that the tympanostomy conduit designs and principles herein can be used for subannular ventilation conduits, and the subannular ventilation conduits designs herein can be used for tympanostomy conduits. Additionally, the conduit designs herein can be used for other medical and biological purposes outside of the middle ear. Non-limiting examples include inner ear conduits, prostatic and biliary stents, sinus cavities, stents for sinus cavities, abdominally-based drains, such as drainage of gallbladder, pancrease, intestine.
Other non-limiting examples include eye tubes, such as glaucoma shunts or tear duct tubes. According to study by Worth Health Organization in 2002, glaucoma is the second leading cause of blindness. Glaucoma patients requiring surgical treatments often use glaucoma drainage devices such as Ahmed Glaucoma Valve (AGV), Baerveldt, or Molteno. Glaucoma drainage devices are designed to divert aqueous humor (fluid in the eye) from the anterior chamber to an external reservoir. Glaucoma drainage devices devices allow to control intraocular pressure (IOP) in eyes with previously failed trabeculectomy and in eyes with insufficient conjunctiva because of scarring from prior surgical procedures or injuries. Glaucoma drainage devices devices are available in different sizes, materials, and design with the presence or absence of an TOP regulating valve, yet they often face many postoperative complications such as hypotony due to a poor drainage regulation, occlusion, corneal scarring, and others. All these complications require more surgeries and treatment which can lead to unforeseen complications, and inoperable patients; while untreated postoperative hypotony can lead to blindness. Hence the move to minimizing repeated surgeries by improving the fluid flow regulation is a constant goal of certain embodiments.
In certain embodiments the conduits address the problem of tear duct clogging. Tear duct clogging occurs due to the obstruction of tear drainage system and can cause responses such as infection, swelling, allergic reaction, tumor, or injury. Tear duct clogging affects up to 5% of infants in United States. Many treatments currently exist to treat tear duct clogs depending on cause and severity. One of treatments includes the insertion of lacrimal stents (or canalicular stents). The two main divisions of stents are bicanalicular versus monocanalicular. Placement of nasolacrimal stents can also sometimes result in an occlusion and infection linked to biofilm production from organisms such as nontuberculous mycobacteria
A particular advantage of embodiments of this invention is that they can reduce the need for revision surgery and can be customized and optimized for a host of various specific clinical indications. The designer tympanostomy conduits discussed in the embodiments of the present disclosure can serve custom patient needs as seen in the Table 1, including important ones such as Eustachian tube dysfunction and sensorineural hearing loss and others, in a minimally-invasive fashion. Either one or two, or the synergy of benefits shown in the
In certain embodiments, the surface properties and shape of the tube are selected to meet certain patient needs. For patients with chronic serous otitis media (pediatric and adult), ventilation is a primary issue due to poor Eustachian tube function, thus the tube needs to stay clog-free, and, thus, to have low-adhesion surface and stay in the eardrum for a desired amount of time. Avoiding water is important in pediatric patients, thus selective permeability is of importance. For the recurrent acute otitis media, the ability to administer antibiotic ear drops (drug delivery) is critical, thus tubes can be optimized for flow in both direction: into and out of the middle ear. For Eustachian tube dysfunction in adults, ventilation is a primary issue, as well as the need for long term duration, thus tubes with low-adhesion properties are desired. For patients with inner ear diseases (adults with Sensorineural hearing loss, Meniere's, Autoimmune hearing loss, etc.), primary concern is the drug delivery. For short-term ventilation in adults an On/Off capacity of the tube is a primary concern, e.g. ‘open’ when going on airplane flight and ‘close’ tube when not concerned about barotrauma.
A particular advantage of certain embodiments of the invention is the ability to deliver drugs into infected area.
In certain embodiments a unique feature of dynamic, shape-changing tubes and their uses is described.
Additional advantages of the present embodiments of the invention will become readily apparent to those skilled in this art from the following detailed description, wherein only the preferred embodiment of the invention is shown and described, simply by way of illustration of one of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the embodiments of the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
In certain embodiments, medical conduits such as tympanostomy conduits and/or subannular ventilation conduits can be made with anti-fouling materials on the inside of the conduit to reduce and/or prevent occlusion and/or on the outside of the conduit, to reduce and/or prevent premature rejection, minimize the pervasiveness of the infection, and reduce inflammation, improve the smoothness of the tube, and provide a protective coating, e.g. in the form of a wrapping layer, over the impinging biofluid, microorganism, wax and dust. While the following description includes certain embodiments relating to tympanostomy conduits and/or subannular ventilation conduits, the designs can be used in other medical (catheters, inflation balloons, stents, drainages and other) or non-medical applications, such as microfluidic, membrane, bioreactors, transport of coolant and other chemicals through machinery, drainage of waste products from reactions, sensors, printing nozzles, food and beverage industry, cosmetics and perfumes, and other applications.
In certain embodiments, a material utilized in designs of tympanostomy tubes 201 makes use of an immobilized liquid interface that can contribute to low cell adhesion and high mobility of liquids on a solid swellable or non-swellable substrate, as shown in
A detailed discussion of the liquid-infused slippery surfaces can be found in U.S. Pat. No. 9,683,197—Issued Jun. 20, 2017, entitled “Dynamic and switchable slippery surfaces”, U.S. Pat. No. 9,121,306—Issued Sep. 1, 2015, entitled “Slippery surfaces with high pressure stability, optical transparency, and self-healing characteristic”, U.S. Pat. No. 9,630,224—Issued Apr. 25, 2017 entitled “Slippery liquid-infused porous surfaces having improved stability”, US Patent Application Publication No. 2015/0152270—Published Jun. 4, 2015, entitled “Slippery self-lubricating polymer surfaces”, US Patent Application Publication No. 2012/021929—Published Jul. 3, 2014, entitled “Slippery Liquid-infused Porous Surfaces and Biological Applications Thereof”, US Patent Application Publication No. 2015/0175814—Published Jun. 25, 2015, entitled “SLIPS Surface Based on Metal-Containing Compound”, US Patent Application Publication No. 20160032074—Published Feb. 4, 2016—entitled “Solidifiable composition for preparation of liquid-infused slippery surfaces and methods of applying”, US Patent Application Publication No. 2014/0342954—Published Nov. 20, 2014, entitled “Modification of surfaces for fluid and solid repellency”, US Patent Application Publication No. 2015/0173883—published Jun. 25, 2015—entitled “Modification of surfaces for simultaneous repellency and targeted binding of desired moieties”, the content of which is hereby incorporated herein by reference in its entirety. In certain embodiments, the lubricating liquid layer above the solid surface can be stabilized fully or partially or temporarily by many different effects, including capillary forces induced by micro/nanoscale topography (10 nm-1000 μm), molecular porosity, surface chemistry, Van der Waals interactions, and combinations thereof. Thus, the underlying solid can be smooth, possess roughness/porosity, and/or be capable of swelling with the lubricating phase. Further, in certain embodiments, the lubricant can be made dynamically stable by liquid flow. In certain embodiments, surfaces with partially stabilized lubricating liquid layers, or lubricating liquid layers that are only stable under flow, also improve performance. In certain embodiments, easily reconfigurable molecules possessing highly flexible long chains with low energy barriers for internal rotation (such as long polydimethylsiloxane polymers or other types of polymers and copolymers, including random or block silicone co-polymers with other siloxane co-monomers featuring alkyl, aryl, aralkyl substituents on silicon atoms) can be grafted to a solid surface and continue to exhibit liquid-like behavior, providing some of the benefits of surfaces with a stabilized lubricating liquid layer.
In certain embodiments, shown in
In certain embodiments, as shown in the
Synergistically with other benefits of the design space of
In certain embodiments, further modification of the surface of the tube through adding chemistries (or structures) will improve the benefits of adding the one or more benefit mechanisms from the designer toolbox (
Other non-limiting examples of surface modification include reconfigurable molecules possessing highly flexible long chains with low energy barriers for internal rotation (such as long polydimethylsiloxane polymers or other types of polymers and copolymers, including random or block silicone co-polymers with other siloxane co-monomers featuring alkyl, aryl, aralkyl substituents on silicon atoms) that can be grafted to a solid surface and continue to exhibit liquid-like behavior, providing some of the benefits of surfaces with a stabilized lubricating liquid layer. Other non-limiting examples include lithography, micropatterning, 3D printing, etching, or the plasma treatment, conjugation of proteins or short polymer chains, ionic bonding of small molecules, addition of hydrogen bonded moieties, or infusion of other liquids or gassesand etching.
In certain embodiments, other types of anti-fouling coatings can include hydrophobic and hydrophilic materials, some of which are discussed below regarding guided fluid transport.
In certain embodiments, directed fluid transport can be designed to occur through conduits, such as tympanostomy conduits, in more than one direction, as shown in
In certain embodiments, shown in
In certain embodiments, it is desirable for certain fluids to be transported from the distal end to the proximal end. In these embodiments, the distal end is the entrance, and the proximal end is the exit for that material. In other embodiments, it is desirable for other fluids to be transported from the proximal end to the distal end. In these embodiments, the proximal end is the entrance and the distal end is the exit for that material. In certain embodiments, it is desirable for other fluids to be prevented from entering the conduit.
In certain embodiments, the surface properties and shape of the conduit can be controlled such that a first material can exit the middle ear, be transported from the distal end to the proximal end of the conduit without pinning and exit the conduit, but not enter the middle ear, from the proximal end to the distal end of the conduit. In certain embodiments, shown in
In certain embodiments, the surface properties and shape of the conduit can be controlled so that a third material can enter the conduit at the proximal end, but not enter the middle ear. In certain embodiments, shown in
In certain embodiments, the surface properties and shape of the conduit can be selected so that a fourth material can be delivered to the middle ear by entering the proximal end and exiting the distal end. In certain embodiments, shown in
In certain embodiments, shown in
In certain embodiments, as shown for examples in
While the following description includes certain embodiments relating to tympanostomy conduits and/or subannular ventilation conduits, the designs can be used in other medical or non-medical applications, such as microfluidic, membrane, bioreactors, transport of coolant and other chemicals through machinery, drainage of waste products from reactions, sensors, additive manufacturing nozzles, funnels, food and beverage industry, cosmetics and perfumes, and other applications.
In certain embodiments, directionality features designed into the tympanostomy conduits can allow (1) mucus from the middle ear cavity that builds up from otitis media to pass through the conduit into the external auditory canal, and (2) oil- or water-based antibiotic drops delivered through the external auditory canal to pass through these conduits to enter the middle ear cavity, where they can treat the otitis media infection, (3) post-myringotomy blood drainage. A broad range of other liquids can be administered to pass through the conduit in the desired direction. In certain embodiments, directionality features can induce dynamic reversible or irreversible, local or on the whole changes in the tube geometry, surface structure, chemistry or size that can be used for a topical delivery of the drug, drainage of the bodily fluid, improved placement of the device, or structural reconfiguration of the device to aid its stability or extrusion at a desired time.
In some embodiments, the drops administered from one side can temporarily close the tube to temporarily prevent any liquid transport through the conduit. In certain embodiments, drops can block the tympanostomy tube before swimming/bathing to prevent the environmental water from entering the middle ear. In certain embodiments, other stimuli, such as light, temperature, electric or magnetic field, pH change, pressure gradient, and other induce physical or chemical transformation of the tube to serve a desired purpose, in certain embodiments. Exemplary cases are described throughout the disclosure.
In certain embodiments, geometric patterns can be used for preferential flow. In certain embodiments, the geometric pattern increases the advancing angle and contact angle hysteresis of a liquid entering the conduit, and in other embodiments, the pattern decreases the advancing angle and contact angle hysteresis of a liquid entering the conduit. In certain embodiments, the geometric pattern can induce the Cassie-Baxter. Young-Laplace or Wenzel states, or other intermediate states. In certain embodiments, the geometric pattern is disposed on the outer or inner surface of the conduit. In certain embodiments, the geometric pattern created by surface topography, for example surface roughness, grooves, ridges, indentations, micropillars, microridges, or pores, and other 3D tessellations.
In certain embodiments, various parameters of conduits such as radius, the angle of the flange (the horizontal piece at the end of distal or proximal end) or the lumen wall angle, surface tension, and lubricant can be tuned to either promote fluid flow entering proximal end and exiting distal end or restrict fluid flow in which the fluid is either trapped within the lumen unable to exit the distal end or unable to enter the proximal end.
A. Preventing Fluid from Entering the Proximal End of the Conduit
In certain embodiments, the surface of the conduit can be surface functionalized via chemistries such as but not limited to silanization, fluorination, hydroxylation, carboxylation, and esterification in which the resulting surface is either hydrophobic or hydrophilic. By the use of these surface functionalization, a fluid of hydrophilic or hydrophobic nature can be inhibited from entering at lower Young-Laplace pressures. In certain embodiments, the use of surface-active fluorinated conduit will dramatically increase the Young-Laplace pressure of water entering the conduit compared to a non-polar low surface tension liquid.
In certain embodiments, the radius of the proximal end can be greatly smaller than the distal end to prevent fluid entering the conduit from the proximal end. In certain embodiments, the proximal and distal end are separated by a membrane such as tympanic membrane, anterior chamber, etc. In certain embodiments, this geometry prevents fluid entrance in the proximal end and is preferential minimizing volumetric flow rate.
In certain embodiments, pinning of the liquid can be observed at the proximal end by irregularities in the entrance geometry and cusp within the conduit. The cusp at the entrance of the geometry will induce high Young-Laplace pressures and create potential pinning points.
B. Preventing Fluid from Exiting from the Distal End of the Conduit
In certain embodiments, the angle of the lumen at the distal end can be varied to have a sudden increase in Young-Laplace pressure for fluid exit. For example, in case of Collar Button geometry, the angle of the lumen is maintained as 0° from vertical and hence the sudden change in contact angle the fluid must experience, the fluid must change its contact angle at the distal end from its equilibrium contact angle to the lumen wall to 180°. In this embodiment, the change in angle caused by a discontinuity causes a sudden rise in Young-Laplace pressure for exit. In this embodiment the fluid is therefore within the conduit but barrier is unable to exit due to this sudden pressure.
In certain embodiments, the use of cilia like structures can be used as pinning points within the lumen. Pinning is a phenomenon of discontinuous motion of the meniscus. Pinning is typically induced by discontinuities in the geometry that the meniscus is in contact with, for example through roughness or cilia-like structures. Direction of the structures dictate the preferential direction of flow and hence can be oriented acute to the proximal end preventing fluid from exiting the distal end. Cilia-like structures can be used in combination with radial change through the lumen to prevent the fluid from exiting either end. In certain embodiments, a gradient of surface tension can be imposed on the conduit in which the fluid encounters higher energy barrier as it travels through the conduit reaching the distal end. In certain embodiments, this increase in Gibbs free energy prevents or increases the barrier of the fluid from exiting the distal end. In certain embodiments this can be achieved via gradient of lubricant overlayer thickness, surface tension, density, Young's modulus, or heterogeneity of materials.
C. Conduits Tuned to Induce Optimal Fluid Flow
In certain embodiments, the conduit lumen wall is continuously curved from the proximal end to the distal end to minimize the sudden pressure jump experience by fluid to exit the conduit. In certain embodiments, the summation of the advancing angle and the lumen flange angle at the distal end will be 180° such that the pressure has no discontinuities, hence avoiding any pinning of fluid.
In certain embodiments, the lumen of the conduit is infused with lubricant (or other low surface tension fluid) in which a wrapping layer assist a the flow of fluid through the conduit and out the distal end. In certain embodiments, the wrapping layer allows for the minimization of surface interactions between high surface tension liquid and air. In certain embodiments, a wrapping layer reduces pinning, reducing the Young-Laplace pressure for exit.
In certain embodiments, the conduit is surface functionalized according to the fluid's hydrophilicity or hydrophobicity. In certain embodiments, the fluid is water, and the surface is modified by modifying the lumen wall with metallic elements. In certain embodiments, the fluid preferentially wets the lumen wall without pressure gradients required. In this embodiment, by tuning this surface modification with respect to the fluid to transport, the Young-Laplace pressure of exiting the distal end can be minimized. In other embodiments, the length of the conduit is tuned below the capillary height of the fluid wetting the lumen walls and the radius is below the capillary length of the fluid, allowing the fluid to spontaneously wet and approach the distal end against forces of gravity. In certain embodiments, the fluid is able to flow through the conduit and exit the distal end optimally without the addition of an applied pressure gradient.
D. Tympanostomy Conduits with Optimized Architectures and Surface Chemistry
In certain embodiments, to optimize the flow transport through the conduit, to induce or prevent liquid pinning in the tube and thus enable or prevent liquid passage, the shape and surface chemistry of both conduit proximal and distal end is considered. The ability of the liquid to be pinned or be transported inside the tube can most effectively be described in terms of capillary pressure, ΔP, sustained across the interface between two static fluids (e. g. water and air or oil and air, or mucus and air) in the conduit. Pressure can be described by using the Young-Laplace equation:
where γeff is the effective surface tension of the liquid entering the conduit, rint is the inner radius of the conduit, and the θadv is the advancing contact angle of the liquid, which is a characteristic of the wettability or chemical properties of the surface. Transport through the conduit is constrained by the highest-pressure barrier in the system, which can occur in different areas of the conduit depending on the conduit design (i.e. local geometry and local advancing contact angle along the conduit), direction of liquid transport, shape and curvature of the conduit and flanges, and material properties. When high pressure barriers appear in certain regions, the liquid will pin at these locations and be unable to move within or exit the conduit. In certain embodiments, by keeping the conduit substantially free of significant pressure jumps, as described in non-limiting examples below, liquid pinning can be avoided and transport through the tube can be enabled. As is described below in certain embodiments, such pressure jumps can occur at the entrance or the exit of the tubes, such as when the fluid enters and exits the tube. In certain embodiments the break-through pressure at the conduit ends is optimized and reduced by local changes in chemistry or geometry of the conduit or flanges. A few non-limiting examples are shown in
1. Surface Properties, Size and Shape of the Conduit and Flanges
In certain embodiments, as can be seen in
where rint(z)=rint,0+∫0z tan θflange dz and the precise shape is numerically optimized to minimize the maximum breakthrough pressure of a given liquid by ensuring
In certain embodiments, for a flat flange,
and breakthrough pressure depends only on the radius of the tube and the effective surface tension. In certain embodiments, when θadv+θflange≥180° for a curved or angled flange, the pressure barrier becomes
In this embodiment, rint(z) is larger than the radius of the lumen due to the angled flange, thus decreasing the pressure barrier compared to sharp flange angles. For hydrophilic conduits, certain embodiments shall consider the first breakthrough pressure and a second breakthrough pressure. The first breakthrough pressure is the pressure at which the fluid exits the conduit, and the second breakthrough pressure is the pressure at which the liquid wets the entire area of the flange, as shown in
As described herein, the dimension and shape of the tube, flange, and surface properties of the conduit material play a significant role in guiding or suppressing the flow of liquids.
In certain embodiments, membranes with pore sizes (rpore) ranging from hundreds of nanometers to tens of microns are incorporated into the tympanostomy conduits to increase the pressure barrier associated with fluid transport. The discussion above holds, with rint=rpore, and only highly wetting liquids are able to permeate the ear-conduit. This effect could be beneficial for allowing, for example, silicone oil transport carrying medication while reducing and/or preventing the transport of aqueous liquids into the inner-ear cavity.
In certain embodiments, the pores can rapidly and repeatedly open and close, enabling precise, dynamic modulation of gas/liquid sorting and controllable separation of a three-phase system of air/water/oil mixture, complex solutions and suspensions such as proteins and blood. In certain embodiments, a liquid-filled pore can provide a gating strategy which offers a unique combination of dynamic and interfacial behaviors, according to US 2018/0023728 published on Jan. 25, 2018, the contents of which are incorporated herein by reference. These embodiment can be used to design gated transport systems starting from a wide variety of pore sizes, geometries, and surface chemistries as well as gating liquids, according to certain embodiments. In certain embodiments, the substrate can contain pores that are about in average 10 nm to about 3,000 microns in size or of any combination of sizes in between, such as 20 nm to 2 microns, 100 nm to 10 microns, 100 nm to 1.2 microns, 80 nm to 1 micron, 200 nm to 5 microns, 10 nm to 10 microns, and 100 nm to 50 microns.
In certain embodiments, the geometry and chemistry of the device that is built from a dynamic, environmentally responsive material can be temporarily changed by applying the external stimulus, such as light, temperature, or chemical environment, to allow for a provisional transport or delivery through the tube, according to certain embodiments, and as discussed in further detail throughout this disclosure.
2. Surface Tension of Lubricating Liquids
In certain embodiments, lubricating liquids can alter the surface tension of the surface of the conduit. In certain embodiments, conduit low surface tension lubricating liquids (˜19 mN/m) form a 0-degree advancing contact angle on tympanostomy conduits to allow for essentially barrier-less transport of oil drops through the conduit. Water droplets, depending on the presence of the lubricating liquid wrapping layer, have a much larger surface tension (60 mN/m with the wrapping layer and 72 mN/m without wrapping layer), and a high advancing angle. Thus, in certain embodiments, it can be more challenging to drive water through the conduit. Mucus, which has surface tension on the order of ˜50 mN/m, is therefore easier to transport through the conduit than water in this embodiment. The immobilized liquid interface facilitates the transport of water into the ear through the conduits with certain dimensions (<1 mm ID). The selection of lubricant can be optimized in order to reduce effective surface energy and lower the contact angle of a certain fluid in order to promote transport, or, conversely, increase the contact angle and inhibit transport, in accordance with certain embodiments. Introducing surfactants to water also alters fluid transport through the conduit, according to certain embodiments.
3. Geometry Optimization for Enhanced Preferential Flow
In certain embodiments, an optimization of conduit geometries can be performed to allow selectively preferential flow of one or more liquids. The parameters for such optimization are provided by the Young-Laplace equation governing the maximum pressure for the fluid:
where, ΔP is the pressure difference across the meniscus of the fluid. One could modify: a) the effective surface tension of the phase in contact with air (γeff), b) the radius of the tube (r), c) the advancing angle of the three-phase front, d) lumen wall tilt angle and θflange), e) the surface properties of the tube, f) the bevel of the tube and flanges. The effective surface tension is dictated by the spreading coefficient of lubricant on the fluid: SLD=γDV−γDL−γLV, where, SLD is the spreading coefficient of lubricant on droplet, and γDV, γDL, and γLV are the interfacial tensions of droplet-vapor, droplet-lubricant, and lubricant-vapor, respectively. When spreading coefficient is larger than 0, it is favorable for the formation of a wrapping layer due to the minimization of energy. The effective surface tension is the lower of the values between γDV, and γDL+γLV. Such optimization can be performed for various materials, smoothened, chemically patterned, or morphologically textured of the tube in accordance with certain embodiments.
In certain embodiments, preferential flow is the preferential unidirectional flow of one material relative to another. In certain embodiments, preferential flow is the preferential unidirectional flow of therapeutic drops versus environmental water. One route for the optimization can be performed numerically by keeping the Young-Laplace pressure of an antibiotic solution constant throughout the length of the lumen. In certain embodiments, the angle of the inner surface of the conduit can be varied to maintain a constant Young-Laplace pressure. By continuously changing the flange angle (e.g., the distal angle of a distal flange or the proximal angle of a proximal flange) and radius in infinitesimal increments (dr and dθflange) one can achieve an azimuthal symmetric or axisymmetric geometry with an optimal curvature, which maintains constant Young-Laplace fluid pressure:
The same pressure is realized through the conduit's lumen where θadv+θflange,final=180°. In certain embodiments, the final flange angle can be tuned by adjusting material properties. In certain embodiments, conduits with improved performance incorporating straight-angled or curved flanges can be achieved by allowing the pressure in the flange to vary by up to ±1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or any intermediate values. In certain embodiments, these shapes are determined by considering the initial pressure in the flange:
Throughout the length of the flange z, one can impose the condition
for all z until the end of the flange, where x=0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 and x is the allowable pressure variance in the flange.
In certain embodiments, the Young-Laplace pressure of a material does not vary along the tube or conduit. In certain embodiments, the Young-Laplace pressure of the material only varies by 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less. In certain embodiments, the material can be the first material traveling from the distal end to the proximal end. In certain embodiments, the material can be the fourth material traveling from the proximal end to the distal end.
The flow model can be optimized through an interplay of various parameters: Young-Laplace fluid pressure (ΔP), initial radius (r), initial flange angle (θflange,initial) (e.g., the distal angle of a distal flange or the proximal angle of a proximal flange), and length of the lumen (L). These degrees of freedom can be swept and optimized to (1) maximize Young-Laplace pressure for water, (2) minimize Young-Laplace pressure for drug solution and (3) minimize deviance from the prescribed tube length. As shown in certain embodiments, in
In certain embodiments, the radii are in the range between 10 nm and 1500 μm (capillary length of water). In certain embodiments, the radii are 10 nm, 50 nm, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 800 nm, 1 μm, 10 μm, 50 μm, 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1000 μm, 1100 μm, 1200 μm, 1300 μm, 1500 μm, or any value in between. In certain embodiments, the radii are 1 mm, 2 mm, 3 mm, or any value in between
Advantageously, tubes with an optimized design have significantly smaller (by 1.5-10 times) radii but similar or much lower maximum antibiotic Young-Laplace pressures and higher water Young-Laplace pressures as compared to any of control cylindrical or conical tubes with larger radii independently of its shape, as shown in the
Similarly, in some embodiments the tubes can be optimized for a broad variety of liquids, for example water and antibiotics. For the calculations for
In certain embodiments, shown in
In certain embodiments, shown in
In certain embodiments, the selectivity between materials, such as the first and second materials, is in the range of 1 to 1.2, 1.2 to 1.5, 1.5 to 1.7, 1.7 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 8, 8 to 10, 1 to 10, 1.2 to 10, 1.5 to 10, 1.7 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 1 to 10, 1.2 to 8, 1.5 to 6, 1.7 to 5, and 2 to 4.
In certain embodiments, the difference between the Young-Laplace pressure of two materials, (such as the difference between the first, third or fourth materials and second material), is greater than 1 Pa, greater than 5 Pa, greater than 10 Pa, greater than 25 Pa, greater than 50 Pa, greater than 100 Pa, or in the range of 1 MPa to 1000 MPa, 5 MPa to 1000 MPa, 10 MPa to 1000 MPa, 25 MPa to 1000 MPa, 50 MPa to 1000 MPa, 100 MPa to 1000 MPa, or 500 MPa to 1000 MPa.
The following example further describes and demonstrates embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
In some embodiments, experimental results of tubes with approximately the same inner radius of 0.275 mm and length of 2 mm shows that the Young-Laplace pressure for fluid transport of antibiotic drop mimicking solution is reduced significantly more than for water for curved-infused tubes compared to Collar Button non-infused tubes as measured using the apparatus as shown in
The pressure reduction from a non-infused Collar Button tube to an optimally curved tube according to certain embodiments with infusion for antibiotic drop-mimicking solution is 77%, as seen from the
In certain embodiments, shown in
Such properties can enable the topical administration of drugs, such as antibiotics, which currently could not be delivered effectively through existing devices as they cannot pass from a proximal end of the tubes through the distal end to the inner ear.
In certain embodiments, the conduit provides for controllable flow of aqueous humor of the eye from the anterior chamber into subconjunctival spaces to reduce intraocular pressure (IOP) in controllable fashion and reduce the need for further treatments in glaucoma patients.
In certain embodiments, the use of a curved geometry for a conduit transporting aqueous humor of the eye will reduce the minimum gradient of pressure across the anterior chamber and subconjunctival spaces required for flow. In certain embodiments, this reduction in pressure gradient allows for lower difference in opening and closing pressures of the AGV shunt and reduced opening pressures. Higher opening pressures leads to inadequate IOP control in long term placements and can be worsen from increased flow resistance from tissue around the glaucoma drainage device.
In certain embodiments, conduits have of switchable slippery surfaces. In these embodiments, the conduit can switch between slippery and non-slippery states to restrict surplus flow of aqueous humor preventing postoperative hypotony.
In certain embodiments, the conduit has switchable pinning sights for controllable flow of fluid. In certain embodiments, when eye pressures are in normal ranges of 12-20 mmHg, the pinning sights are inactivated. In certain embodiments, when the eye pressure drops below 12 mmHg, the flow of aqueous humor is inhibited by a stimuli which increases the effect of pinning sights and naturally allows the eye pressure to equalize into normal ranges.
In certain embodiments, the conduit has surface modified lumen in which the flow is reduced or completed restricted via stimuli to prevent postoperative hypotony.
4. Chemical and Geometric Patterns for Enhanced Preferential Flow
In certain embodiments, tympanostomy conduits or subannular ventilation conduits contain wicking materials or chemical gradients on the flanges of the conduit to guide or enhance the flow of fluids. In certain embodiments, the chemical gradient increases the effective surface tension of the conduit, and in other embodiments, the chemical gradient decreases the effective surface tension of the conduit. In certain embodiments, multimaterial printing or other manufacturing methods can allow two or more materials (shown in different shades of gray) to be patterned into the same device for gathering or wicking the liquid as shown in the designs in
Non-limiting examples of materials for a wicking layer include hydrophilic polymers or hydrogels, such as poly(ethylene glycol), poly(acrylic acid), poly(N-isopropoylacrylamide) (PNIPAM), poly(vinylpyrrolidone), poly(2-oxazoline), cellulose, or alginate. Materials could also include hydrophobic polymers, such as poly(dimethyl siloxane), polyurethanes, acrylics, carbonates, polyesters, polyethers, or fluorocarbons that can have surface modifications. The material could also be proteins, including collagen, gelatin, fibronectin, laminin, or any RGD-conjugated natural or synthetic material.
In certain embodiments, a solution includes a dual-channel conduit with patterned chemical properties, for example as shown in
In certain embodiments, geometric patterns can be used for preferential flow. In certain embodiments, the geometric pattern increases the advancing angle and contact angle hysteresis of a liquid entering the conduit, and in other embodiments, the pattern decreases the advancing angle and contact angle hysteresis of a liquid entering the conduit. In certain embodiments, the geometric pattern increases the advancing angle and contact angle hysteresis of a liquid entering the conduit. In other embodiments, the pattern decreases the advancing angle and contact angle hysteresis of a liquid entering the conduit. In certain embodiments, the geometric pattern can induce the Cassie-Baxter, Young-Laplace or Wenzel states, or other intermediate states. In certain embodiments, the geometric pattern is disposed on the outer or inner surface of the conduit. In certain embodiments, the geometric pattern created by surface topography, for example surface roughness, grooves, ridges, indentations, micropillars, microridges, pores, or other 3D tessellations.
In certain embodiments, as can be seen in, for example,
5. Use of Gravity for Preferential Flow
In certain embodiments, gravity plays a role in trying to transport the antibiotic droplets into the middle ear and the mucus out of the ear, for example as shown in
In certain embodiments, the fluidic properties can be achieved or enhanced by synergistic utilization of shape/size change benefit from
E. Tympanostomy Conduits with Pinning to Reduce and/or Prevent Environmental Water Entrance
In certain embodiments, environmental water can be reduced and/or prevented from entering by increasing the pinning area for the water droplet, for example as shown in
F. Replenishment and Administration of the Lubricating Liquid to the Conduits
In certain embodiments, the lubricant drops can be administered to replenish the reservoir and re-create the anti-bacterial and improved transport properties of the conduit when the lubricating oil on the surface of the device is exhausted. For the tympanostomy conduits, replenishment can be done, for example, by applying an otic oil-based formulation which has high or low chemical affinity to the material of the conduit to induce long- or short-term longevity of the lubricating liquid on the conduit. The administration of the lubricating liquid can be targeted towards replenishment of a) only outer or b) only inner surfaces, c) only proximal or d) only distal ends of the conduit, or e) only the flange(s), or any combination thereof. The tube material can contain pores and channels that serve as lubricating liquid replenishment reservoirs.
In other embodiments, excessive lubricating liquid can be applied that either makes the flanges slippery or makes the flanges expand, swell, twist, roll, collapse, or induces appearance of periodic or aperiodic arrays of features (wells, bumps, holes, etc) or is used to enable controlled extrusion of the tubes at a desired timepoint. In certain embodiments, controlled extrusion can be done by inducing a size or shape transformation of the outer surface of the conduit, or peeling off an external thin layer around the conduit. More details are in additional sections of this disclosure.
In certain embodiments, tympanostomy conduits and/or subannular conduits can be designed to be minimally invasive and avoid tissue damage. While the following description includes certain embodiments relating to tympanostomy conduits and/or subannular ventilation conduits, the designs can be used in other medical or non-medical applications, such as such as microfluidic, membrane, bioreactors, transport of coolant and other chemicals through machinery, drainage of waste products from reactions, sensors, printing nozzles, food and beverage industry, cosmetics and perfumes, and other applications. Non-invasive designs can also be combined, for example, with antifouling, guided fluid transport, therapeutic delivery, and other aspects described throughout the disclosure. In certain embodiments, the conduit includes a shape changing or stimuli-responsive portion that facilitates insertion, extrusion, guided transport, or therapeutic delivery.
In certain embodiments, shape-changing materials change their shape and/or dimensions in response to one or more stimuli through external influences: the effect of light, temperature, pressure, an electric or magnetic field, or a chemical stimulus. In certain embodiments, the chemical stimulus is a cross-linking agent or a swelling agent. In certain embodiments, the swelling agent is the lubricating liquid. In certain embodiments, the conduit has a first configuration before exposure to the stimulus and second configuration after exposure to the stimulus.
A. Tympanostomy Conduits with Shape-Changing Features
In certain embodiments, a shape/size-changing feature can facilitate the ease of insertion of the tube into the eardrum and show better post-insertion performance. In certain embodiments, this shape and dimensional change during shape change can be utilized to fabricate conduits in smaller or otherwise different dimensions that reach their desired dimension after soaking, as shown in for example in
The mechanical integrity is analyzed in the
According to certain embodiments, the material's shape-changing behavior described can be implemented into the commercial software ABAQUS/Standard through user defined material subroutines and to solve the inverse problem, namely, to investigate the full deformation response of the final 3D tube, in order to back-calculate the original shape/size of the manufactured tube that will undergo shape transformation. This will enable a customized approach to developing customized manufacturing of the tube, according to certain embodiments. In some embodiments, the tube can be exposed to a tailored shape-changing agent for a host of desired medical indications. In order to simulate the mechanical deformation of the tube during the swelling process, a Finite Element Analysis (FEA) model of the swelling geometry was created using the commercial ABAQUS/Standard software. The FEA model was created by taking the final desired geometry as an input and solving the inverse swelling problem to obtain the fabrication geometry necessary to achieve the final geometry. The FEA model accounts for the anisotropic swelling varying linearly along the radial direction. A linear elastic material model is used for the simulations, while the strain is imposed via a uniform swelling coefficient. The model is radially subdivided into various concentric cuts with varying expansion coefficients that are fit to data that was empirically measured from the experimental procedure. Given the axisymmetric nature of the problem, the final output of the numerical model provides a cross sectional description of the geometry that can then be used for fabrication prior to the swelling operation.
In certain embodiments, tympanostomy conduits are made of programmable materials that change shape and size on demand. The shape-changing properties are particularly beneficial for an intelligent design of flanges to minimize the invasiveness of the conduits pre- and post-myringotomy. Shape-changing materials change their shape and/or dimensions in response to one or more stimuli through external influences: the effect of light, temperature, pressure, an electric or magnetic field, or a chemical stimulus. Among these, certain materials change their shape without changing their dimensions, and other materials retain their shape but change their dimensions. Some also change both parameters at the same time. Shape changes can take place in all dimensions to equal or unequal extents. In certain embodiments, the shape-changing materials can be of thermostrictive, piezoelectric, electroactive, chemostrictive, magnetostrictive, photostrictive, or pH-sensitive nature. An embodiment of shape-changing ear conduit is demonstrated in
In certain embodiments, shown in
In certain embodiments, shown in
In certain embodiments, the conduit design mimics expandable stent architecture with or without the delivery balloon. For example,
In certain embodiments, the changes of the geometry occur in the conduit or flange to induce temporal reconfigurations that improve or reduce or redirect or block liquid transport as described in the previous section. In other embodiments, dynamic structural or chemical changes can be used for the extrusion, targeted delivery, or other guided fluid transport purposes.
B. Insertion Mechanisms for Inducing Shape Change
In certain embodiments, the insertion mechanism for the conduit includes two stages. An example of the two-stage insertion mechanism is shown in
C. Tympanostomy Conduits with Anisotropic Mechanical Properties
As shown, for example, in
D. Tympanostomy Conduits with Controllable Extrusion.
Grommet-type tympanostomy tubes tend to extrude between 9 and 18 months after insertion. Tympanic membrane epithelial migration can produce a more or less orderly sequence of events including 1) accumulation of squamous debris under the outer tube flange, 2) elevation and rotation of the tube, 3) extrusion of the inner flange, 4) closure of the tympanic perforation, and 5) outward migration of the tube with cerumen. In ˜20% of children, this does not occur. Some tubes remain in place despite the accumulation of surrounding squamous debris for years. Tubes that can remain in place can result in persistent conductive hearing loss, infection, or tympanic membrane perforation. Further, tubes that remain in place in children can result in the need to return to the operating room for removal, adding risks associated with general anesthesia.
In certain embodiments, shown in
In some embodiments, actuators 4508 formed of shape-changing material can also be placed on the outer surface of a conduit for a built-in control of the conduit extrusion process from the tympanic membrane through external stimuli. For example, the actuators can expand or collapse, or undergo another type of size/shape and/or chemical transformation to induce the extrusion from the membrane as shown in the
In some embodiments, passive extrusion can take place whereby the grommet extrudes following de-swelling of one or more components on the device. This mechanism can control the extrusion by discontinuing administration of the lubricant or other liquid. As the lubricant or other liquid seeps from the device into surrounding materials and tissues, the swollen components can gradually de-swell until the device is loosened from the hole through which the conduit is placed, allowing it to fall out or be easily removed. To speed up this process, another liquid can be placed on the tube that displaces the original lubricant and rapidly evaporates or leaves the tube, allowing the material to be de-swelled. In this manner, a patient or provider will be able to control extrusion time by controlling gradual or controlled de-swelling of the implant.
E. Tympanostomy Conduits with Sensing Components
In certain embodiments, shown in
In certain embodiments, the conduit with an antenna collects data from the patient tracking at least one of various relevant bodily biomarkers: temperature, moisture level, osmolarity, pH, pressure difference, drug concentration, surfactants, viscosity of the fluid and others that will allow for a remote monitoring of child's condition, and transfer the results to a computer or a mobile device or a wearable health tracking device. In some embodiments, the conduit can do so via antenna 3502 and/or sensor 3503.
In certain embodiments, shown in
In certain embodiments, the conduit undergoes on-demand enabled shape and chemistry transformations for temporary point-of-care applications where the local or “as a whole” transformation takes place for limited or unlimited amount of time for enhancing, reducing, redirecting or blocking liquid transport (for example, for drug delivery and protection of the middle and/or inner ears from external conditions) or used for the controlled extrusion purposes. While the following and above description includes certain embodiments relating to tympanostomy conduits and/or subannular ventilation conduits, the designs can be used in other medical or non-medical applications, such as microfluidic devices, membrane, bioreactors, nozzles, transport of coolant and other chemicals through machinery, drainage of waste products from reactions, sensors, food and beverage industry, cosmetics and perfumes, and other applications. porous networks, conjugated particles, nanotextured surfaces, or enzymes.
In certain embodiments, the conduit provides solutions for treating a number of middle and inner ear diseases and disorders. In certain embodiments, a conduit is specifically designed to enable an efficacious “first-in-class” drug delivery and thereby decrease time of treatment and morbidity, and direct and indirect costs associated with failed treatment.
A. Tympanostomy Conduits Guiding Therapeutics into the Middle Ear
A number of ear diseases can be treated with topical therapeutics, including bacterial infections, sensorineural hearing loss, and Meniere's disease. Characteristic of topical delivery systems is the absence of systemic effects, which is an advantage if no systemic effect is required. For example, systemic administration of antibiotics for otitis media can result Clostridium difficile (C. diff) infections and antibiotic resistant organisms, such as Methicillin-resistant Staphylococcus aureus (MRSA). Systemic steroids for sensorineural hearing loss has a host of significant side effects, ranging from anxiety and reflux, to avascular necrosis of the hip and psychosis. Systemic reaction to topical antibiotics and steroids is extremely uncommon. Further, the use of topical agents allows for the simultaneous modification of the local microenvironment. The pH of the external auditory canal, for example, is normally slightly acidic. The administration of an antibiotic in an acidic drop helps restore and fortify this normal host defense mechanism. Ototopical medications are generally less expensive than systemic medications.
Another example of an ear disease that would benefit from the topical drug administration is the Meniere's disease, which is treated with gentamicin and steroids. For example, the gentamicin and/or steroids can be injected into the tympanum, or middle ear, through the ear drum. This can be done with a minor surgical procedure performed in the office. Gentamicin is used in patients to stop attacks of vertigo. It is a medication which is toxic to the inner ear but is more toxic to the vestibular cells than the hearing cells of the inner ear. This can allow elimination of enough vestibular cells to stop vertigo attacks without a significant change in hearing.
Placement of a short- or long-term tympanostomy conduit with designs can decrease the need for repeated procedures. Indeed, in some patients, a tympanostomy conduit placed in to the eardrum can replace the intratympanic injection, instead, the medication is injected through the conduit or the patient can self-treat with drops at home. A number of therapeutics can be delivered more efficiently through the conduit disclosed herein, by means of non-limiting example, including: antibiotics, antiseptics, anti-viral agents, anti-inflammatory agents, small molecules, immunologics, nanoparticles, genetic therapies including viral and lipid based therapies, chemotherapeutics, stem cells, cellular therapeutics, growth factors, proteins, radioactive materials, or other liquid and gas-based pharmaceutical compounds.
In some embodiments, a conduit includes a single-, dual- or multi-channel conduit with patterned chemical properties and texture, as shown in other sections of this disclosure. In certain embodiments, different channels of conduits are optimized for the transport of topical medication into the middle ear (for example, as shown in
In certain embodiments, a conduit includes porous material within the lumen representing a) an array of channels, or three-dimensional b) periodic or a) aperiodic (sponge-like) interconnected network of pores of sizes ranging from 0.01 to 1000 μm, with specific chemical modification of the pores allowing for selective therapeutic delivery into the tympanum. The tailored surface functionalities can include: perfluorooctyltrichlorosilane triethoxsilylbutyraldehyde, bis(2-hydroxyethyl)-3-aminopropyltriethoxysilane, 3 chloropropyltriethoxysilane, 3-(trihydroxysilyl)-1-propanesulfonic acid, n-(triethoxysilylpropyl)-alpha-poly-ethylene oxide urethane, n-(trimethoxysilylpropyl)ethylene diamine triacetic acid, n-octyltriethoxysilane, n-octadecyltriethoxysilane, (3-trimethoxysilylpropyl)diethylenetriamine, methyltriethoxysilane, hexyltrimethoxysilane, 3-aminopropyltriethoxysilane, hexadecyltriethoxysilane 3-mercaptopropyltrimethoxysilane, dodecyltriethoxysilane; or chiral functionalities, such as N-(3-Triethoxysilylpropyl)gluconamide or (R)-N-Triethoxysilylpropyl-O-Quinineurethane).
In certain embodiments, shown in
In certain embodiments, the surface chemistry 3811 of the walls can change in response to the stimulus to open the lumen. In this embodiment, the fluid can be unable to pass through the lumen when the tube is first inserted but able to pass through the lumen after the surface chemistry change. Non limiting examples of surface chemistry change include hydrophobicity, hydrophilicity, omniphobicity or peptide or polymer conjugation. In certain embodiments, shown in
In certain embodiments, the stimuli-responsive materials can be of thermostrictive, piezoelectric, electroactive, chemostrictive, magnetostrictive, photosensitive and photostrictive, or pH-sensitive nature. These materials can utilize light-driven therapeutic cargo control, where UV light triggers cargo flow through the conduit. In certain embodiments, materials can utilize controlled electric conduction. In certain embodiments. the top layer of the liquid medium is conductive, or the liquid medium has a solid conductive confining surface on the top of device. In other embodiments, the tips of microstructures are also modified with conductive materials. In certain embodiments using electrical conduction, the electric conduction of the surface or the whole system can be controlled by chemically-induced mechanical actuation of the microstructures.
In certain embodiments, the self-modulated adaptively reconfigurable tunable nano- or microstructures with appropriately functionalized (chemically or physically) tips embedded in a hydrogel, as described in U.S. Pat. No. 9,651,548 “Self-regulating chemo-mechano-chemical systems” issued on May 16, 2017, which is incorporated herein by reference. This dynamic system incorporates the movement of “skeletal” high-aspect-ratio microstructures (posts, blades, etc.) by a polymeric “muscle” provided by the swelling/contracting capabilities of the hydrogel in which the microstructures are embedded. In certain embodiments, the layers are arranged vertically, one stacked over the other. In certain embodiments, the system can be also designed horizontally with these two layers positioned side-to-side.
B. Tympanostomy Conduits with Vascular Networks for Drug Delivery to the Tympanic Membrane Surface
OM can present itself either as an infection inside the middle ear space due to a buildup of fluid or as an infection on tympanic membrane itself. In certain embodiments, shown in
A number of therapeutics can be delivered efficiently through the vascular network, including, but not limited to antibiotics, antiseptics, anti-viral agents, anti-inflammatory agents, small molecules, immunologics, nanoparticles, genetic therapies including viral and lipid based therapies, chemotherapeutics, stem cells, cellular therapeutics, growth factors, proteins, radioactive materials, and other liquid and gas-based pharmaceutical compounds.
C. Drug Delivery Though the Lubricant Overlayer
Certain embodiments relate to a medical device for delivering a therapeutic agent to the body tissue of a patient, and methods for using such a medical device. For example, in some embodiments, drug eluting tubes incorporate synthetic slippery lubricant-infused surfaces for repelling fluids of biological origin while allowing for effective drug release from the tube. In certain embodiments, Drugs to be included in the drug eluting tubes disclosed herein can either be incorporated in the solid matrix supporting the entrapped liquid or other liquid-like matrix and then diffuse over time through the lubricating liquid layer into the surrounding tissue or the drugs can be incorporated within the lubricating liquid layer and then diffuse into the surrounding tissue. In accordance with certain embodiments, the drugs can be incorporated in both the solid matrix and the lubricating liquid layer. In certain embodiments, drugs used in these applications can be either extremely hydrophobic or hydrophilic and can be difficult to dissolve in the lubricating liquid layer. Therefore, even if drugs can be introduced into the underlying solid substrate, the drugs cannot be able to diffuse through the lubricating liquid layer and will remain trapped. Lubricants useful in the embodiments related to delivery though the lubricant overlayer should allow for sufficiently low surface energy while allowing for effective drug release from the tube. Non-limiting examples of an entrapped liquid include oils, hydrogels, organogels, or reconfigurable molecules possessing highly flexible long chains such as long polydimethylsiloxane polymers or other types of polymers and copolymers, including random or block silicone co-polymers with other siloxane co-monomers featuring alkyl, aryl, aralkyl substituents on silicon atoms that can be grafted to a solid surface.
A range of surface structures with different feature sizes and porosities can be used. Feature sizes can be in the range of tens of nanometers to microns (e.g., 10 to 1000 nm), and have aspect ratios from about 1:1 to 10:1. In certain embodiments, the surface has a large surface area that is readily wetted by the lubricating liquid and which entrains lubricating liquid and retains it on the substrate surface.
In certain embodiments, ore than one drug or biologically active component can be used in accordance with certain aspects. The compounds can be released from the lubricating layer by diffusion, degradation or other mechanism or combination of mechanisms, which provide for the desired release profile. Other suitable drugs, therapeutic materials, etc. for including in stents are disclosed in U.S. Pat. No. 8,147,539 to McMorrow et al., issued on Apr. 3, 2012, the contents of which are hereby incorporated by reference.
In certain embodiments, drugs can be incorporated into the lubricating layer, the solid matrix supporting the entrapped liquid, or any combination thereof. Drug eluting stents can be prepared by mixing the drug with the polymer melt and then casting the melt to form the stent, according to certain embodiments. The drugs can also be encapsulated in particles or micelles and then dispersed in an oil in certain embodiments. Examples of such dispersions of encapsulated drugs include forming complexes with cyclodextrin and oil to create these particles. In certain embodiments, the drug can also be encapsulated in carriers made of lipid molecules, block co-polymers or both. In certain embodiments, the drug can also be encapsulated in particle carriers made of lipid molecules, polymers, or a combination or both and these particles can be added into the drug suspension that is applied to the outer lumen of the tube.
The following example further describes and demonstrates embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
In certain embodiments, release of drug is intermediate, and the profile can be tuned by reducing the drug loading in the lubricating liquid layer and tuning the lubricating liquid layer thickness. If slow drug release over the course of a few months is desired, one possibility is to load the underlying substrate with the drug and have the drug diffuse slowly through the lubricating liquid layer over time. In one non-limiting example, the drug is paclitaxel and the lubricating liquid layer is castor oil. If the lubricating liquid layer depletes over time, the drug can also possibly be released from the substrate of the conduit after this depletion takes place. Many parameters can be tuned to achieve a desired release profile. For example, the following parameters can be taken into consideration to develop a certain drug release profile: Oil layer thickness, oil layer viscosity, drug concentration within the oil layer, surface area of tube coated with the oil layer, drug concentration within the porous matrix/substrate, and material used for porous matrix/substrate.
D. Tympanostomy Conduits for Drug Delivery to the Inner Ear
The round window (RW) and oval window (OW) are two openings from the middle ear into the inner ear, including cochlea. The round window membrane (RWM) and oval window membrane (OWM), vibrate with acoustic energy transmitted from the tympanic membrane to the ossicular change, allowing conversion of mechanical energy to electrical neuronal potentials at the level of hair cells in the inner ear. Given anatomic location, the RWM can be a site for drug delivery to the inner ear. The RWM can be used as the site of cochlear implantation. The RWM can act as a barrier to ototoxic substances in the middle ear and participate in the secretion and absorption of substances. Animal experiments show that the RWM behaves like a semipermeable membrane. Many substances with both low and high molecular weights have been demonstrated to penetrate through the RWM when placed in the round window niche. These substances include sodium ions, antibiotics, antiseptics, arachidonic acid metabolites, local anesthetics, toxins and albumin. The permeability of the RWM can be influenced by the factors such as size, configuration, concentration, liposolubility and electrical charge of the substance, and the thickness and the condition of the RWM.
In certain embodiments, the distal end 4005 of this conduit can either rest near the tissue, be chemically attached to the tissue via an adhesive agent, or be mechanically attached to the tissue via mechanisms including at least one hook, macro-needle, or micro-needle 4006 to enable drug delivery into the inner ear via the round window. In certain embodiments, such mechanisms, as shown in
In certain embodiments, the interaction of an administered drug-containing solution with the lubricating liquid layer or physical structure of the implant can cause a physically or chemically-induced phase transition of the solution. In some embodiments, mechanisms could be used to increase the viscosity of the solution to remain within the middle ear space. Non-limiting examples of such mechanisms include foaming, gelation, or increased cross-linking. These mechanisms can be useful to prevent the solution from leaking through the Eustachian tubes or back out of the tympanostomy tube after it traverses the tympanic membrane.
In certain embodiments, the lumen could contain a porous network that introduces a phase into the liquid to produce a foam-like composition in a physically-induced phase transition. In other embodiments, surface features on the lumen surface could cause turbulent mixing of the solution with air, producing a foam-like composition. Surfactants could be incorporated into the administered solution or the lubricant overlayer to aid in stabilization of the air bubbles within these foams.
In certain embodiments, molecular organogelators convert oils into gels by forming self-assembled fibrous networks in a chemically-induced phase transition. In certain embodiments, gelation can be activated by contacting the oil with an immiscible solvent (water). Synthetic small-molecules known as organogelators have the ability to self-assemble into long fibers when introduced into organic liquids (oils). These fibers entangle and interconnect into a three-dimensional (3-D) network, thereby converting the oil into an elastic organogel. Gelation can be achieved in response to external stimuli or environments such as temperature, redox states, pH, ultrasound, or light. Upon irradiation with light, the gelator can be photoisomerized, whereupon it becomes an active gelator. Thus, light can be used as a “switch” to activate the gelator, according to certain embodiments. In other embodiments, the lubricant could contain a crosslinking mechanism introduces covalent, ionic, van der Waals, or other increased interactions between molecules in the solution. Non-limiting examples of a crosslinking mechanism include calcium ions for an alginate solution, poly(2-hydroxyethyl methacrylate) crosslinking, hydrogen bonding of phospholipid polymers, alkyne-azide click reactions.
In certain embodiments, shown in
E. Tympanostomy Conduits with Pinning to Reduce and/or Prevent Environmental Water Entrance
In certain embodiments, the lumen of the tympanostomy conduit can be gated by another material that allows for transport of certain fluids or fluids under certain conditions into the conduit while keeping out other fluids. In certain embodiments, shown in
In other embodiments, the lumen of the tympanostomy conduit is gated by another material that allows for transport of certain fluid and gas exchange between the environment and middle ear space. In certain embodiments, for example shown in
A. Animal Model
The chinchilla (Chinchilla lanigera) animal model is the most widely utilized animal in middle ear research due to size and anatomy of the tympanic membrane (TM). Female chinchillas Lanigera (total number of 6) were anesthetized in routine fashion to undergo auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) testing. To perform ABR/DPOAE, the anesthetized animals were placed in a sound-treated booth. Needle ABR leads were placed in standard, stereotypical fashion and bilateral ABR and DPOAE thresholds were obtained at 0.5, 1, 2, 4, 8, and 16 kHz using the Eaton-Peabody Laboratories cochlear function test suite (EPL CFTS) written in LabVIEW. EPL CFTS was used to control digital stimulus generation and data acquisition utilizing the input/output boards installed on the PXI chassis. Thresholds in the same animals have been measured on separate occasions with highly reproducible values. The difference between ABR and DPOAE testing can indicate a conductive hearing loss.
Following the ABR/DPOAE tests, tympanostomy tubes were placed into both ears in the surgical sterile facility, as shown in
Prior to placement, all test TTs were sterilized with an autoclave at 121° C. with a 25 min wet and a 15 min dry cycle, and then exposed to ultraviolet germicidal irradiation, prior to the myringotomy procedure to insertion into the TM. After the TT placement, the animals were allowed to recover for 2 weeks, and TT were closely monitored by weekly otoendoscopy.
After the 2-week recovery period, the animal underwent a second round of general anesthesia to for ABR/DPOAE testing, as described above. After ABR/DPAOE testing, TTs were removed from the TM. For this, the ear canal was first evaluated with a 30° Storz Hopkins® rod endoscope. Then, using a sterile rosen needle, the tube was gently teased out of the prior myringotomy. Alligator forceps were used to grasp the tube gently, lift it from the ear canal under direct visualization and deliver it into a vial with PBS for further analysis. Otoendoscopic images were obtained of the TM before and after the removal of the TT. The same procedure was done on the contralateral ear. The animal was then permitted to recover for an additional 10 weeks. Photographs of the TM obtained by the endoscope were obtained with the animal awake on a weekly basis to document the healing of the perforation.
B. Evaluation of Hearing Loss
Throughout the duration of the study the observational logs did not reveal any signs of distress in any Chinchilla subjects either from the experimental group or control group. As shown in the
C. Tissue Response to Tympanostomy Tubes
Ear canals hosting the control tube normally had a wet environment adjacent to the tube. The immediate area around the tube as well as some of the tympanic membrane glistened and sometimes showed mucus. The degree of inflammation visible on otoscopy was notable. Five out of six ear canals which hosted test tubes had, on the other hand, a dry environment. The degree of inflammation was visibly less in these animals. Several animals whose tympanic membrane hosted the non-oil-infused control tube had signs of inflammation or buildup around the tube, compared to animals with the implanted test tubes that were oil-infused that had no signs of inflammation or granulation. The tympanic membranes healed well around all the test tubes within 12 weeks of removal, as opposed to some of the control tubes. All control and sample tubes remained patent (unobstructed and affording free passage) when observed during extraction surgeries.
D. Bacterial Adhesion on Tympanostomy Tubes
Surgically removed TTs from chinchillas were placed in a vial with 1.2 mL of PBS and sonicated at 40 kHz for 2 min to remove bacteria. The sonicated solution was 10-fold serially diluted and 100 μL of the pure solution and dilutions (up to 10-3) plated on blood, chocolate, and Sabouraud agar (Becton Dickinson) plates in triplicate. The blood and chocolate agar plates were incubated in a 5% CO2 incubator at 37° C. The Sabouraud agar plates were incubated at 37° C. in atmospheric air. The number of colonies forming units per mL was determined after incubation for 24 hours. Different colonies were sampled and re-streaked on new plates for DNA extraction and sequence-based identification.
Bacterial colonies of interest sampled from the in vivo assay plates were grown on a separate plate of the same type they were found on for an additional 24 hours. The 16S rDNA sequence was amplified using primers 8F and 1493R, which flank all 16S variable regions. Amplified products were purified and sequenced (Genewiz). The obtained sequences were aligned and edited using Geneious 8.0. Sequence identity was searched in GenBank using the BLAST (blastn algorithm) program with default parameters.
A. Conduit Materials
Polymers that can be used for forming the tube include without limitation biostable or bioabsorbable polymers, according to certain embodiments. Non-limiting examples include isobutylene-based polymers, polystyrene-based polymers, polyacrylates, and polyacrylate derivatives, vinyl acetate-based polymers and its copolymers, polyurethane and its copolymers, silicone and its copolymers, ethylene vinyl-acetate, polyethylene terephtalate, thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics, polyamides, polyesters, polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose, collagens, alginates, gelatins, chitins, and combinations thereof.
Other non-limiting examples of polymers that can be used for forming the tubes, or for example the tubes used as stents, include without limitation dacron polyester, poly(ethylene terephthalate), polycarbonate, polymethylmethacrylate, polypropylene, polyalkylene oxalates, polyvinylchloride, polyurethanes, polysiloxanes, nylons, poly(dimethyl siloxane), polycyanoacrylates, polyphosphazenes, poly(amino acids), ethylene glycol I dimethacrylate, poly(methyl methacrylate), poly(2-hydroxyethyl methacrylate), polytetrafluoroethylene poly(HEMA), polyhydroxyalkanoates, polytetrafluorethylene, polycarbonate, poly(glycolide-lactide) co-polymer, polylactic acid, poly(γ-caprolactone), poly(γ-hydroxybutyrate), polydioxanone, poly(γ-ethyl glutamate), polyiminocarbonates, poly(ortho ester), polyanhydrides, alginate, dextran, chitin, cotton, polyglycolic acid, polyurethane, gelatin, collagen, or derivatized versions thereof, i.e., polymers which have been modified to include, for example, attachment sites or cross-linking groups, e.g., RGD, in which the polymers retain their structural integrity while allowing for attachment of cells and molecules, such as proteins, nucleic acids, and combinations thereof.
In certain embodiments, tubes can also be made with non-polymers. Non-limiting examples of useful non-polymers include sterols such as cholesterol, stigmasterol, β-sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; C12-C24 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; C18-C36 mono-, di- and triacylglycerides such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C16-C18 fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate; anhydrides of fatty acids such as stearic anhydride; phospholipids including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and lysoderivatives thereof sphingosine and derivatives thereof sphingomyelins such as stearyl, palmitoyl, and tricosanyl sphingomyelins; ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures thereof. Particularly useful non-polymers include cholesterol, glyceryl monostearate, glycerol tristearate, stearic acid, stearic anhydride, glyceryl monooleate, glyceryl monolinoleate, acetylated monoglycerides, and combinations thereof.
The materials for the conduit designs listed in these embodiments can be selected from a group consisting of FDA-approved materials, such as silicones and fluoroplastics, Nylon, polyethylene terephthalate, Polycarbonate, Acrylonitrile Butadiene Styrene, Poly(p-phenylene oxide), Polybutylene terephthalate, Acetal, Polypropylene, Polyurethane, Polyetheretherketone, hydroxylpatite, Ultra-high molecular weight polyethylene, High Density Polyethylene, Low Density Polyethylene, Polystyrene High Impact, Polysulfone, Polyvinylidene fluoride, polystyrene, polymethylmethacrylate, latex, polyacrylate, polyalkylacrylate, substituted polyalkylacrylate, polystyrene, poly(divinylbenzene), polyvinylpyrrolidone, poly(vinylalcohol), polyacrylamide, poly(ethylene oxide), polyvinylchloride, polyvinylidene fluoride, polytetrafluoroethylene, and mixtures thereof. In addition, they can include polyelectrolyte hydrogels: ionic (including anionic or cationic) and ampholytic (including both anionic and cationic), for which incorporating more hydrophilic or hydrophobic monomers in hydrogel composition would allow for regulation of the volume transition behavior of the hydrogel. Non-limiting examples include hydrogel-forming materials such acrylate, polyacrylate, methacrylic acid, (dimethylamino)ethyl methacrylate, hydroxyethyl methacrylate, poly(vinyl alcohol)/poly(acrylic acid), 2-acrylamido-2-methylpropane sulfonic acid, [(methacrylamido)-propyl]trimethyl ammonium chloride, poly(N-vinyl-2-pyrrolidone/itaconic acid). Another category of materials can be represented by nonionic hydrogels. Non-limiting examples include poly(ethylene glycol), ethylene glycol diacrylate, polyethylene glycol diacrylate poly(ethylene oxide), diacrylate, acrylamide, polyacrylamide, methylenebisacrylamide, N-isopropylacrylamides, poly(vinyl alcohol) and mixtures thereof. In some embodiments, the hydrogel can be made of natural materials, such as proteins (e.g. collagen and silk) and polysaccharides (e.g. chitosan, dextran and alginate), and combinations thereof. In some embodiments, the tubes can be made of metals or metal oxides.
In certain embodiments, the materials can also contain colloidal particles that are dispersed or suspended in another substance. Non-limiting examples of suitable colloidal particles that can be used in the hydrogel-based sensors include polystyrene and polymethylmethacrylate, melamine resins (having a large number of reactive amino and imino groups for immobilization of different metal ions or metal nanoparticles), silica and polydivinylbenzene microparticles. In some embodiments the colloidal particles are made of one or more of the following polymers: poly(methyl methacrylate), polyacrylate, polyalkylacrylate, substituted polyalkylacrylate, polystyrene, poly(divinylbenzene), polyvinylpyrrolidone, poly(vinylalcohol), polyacrylamide, poly(ethylene oxide), polyvinylchloride, polyvinylidene fluoride, polytetrafluoroethylene, other halogenated polymers, hydrogels, organogels, or combinations thereof. Other polymers of different architectures can be utilized as well, such as random and block copolymers, branched, star and dendritic polymers, and supramolecular polymers. In certain embodiments, the colloidal particles are of natural origin (biopolymer colloid), such as a protein- or polysaccharide-based material, silk fibroin, chitin, shellac, cellulose, chitosan, alginate, gelatin, or a mixture thereof. In certain embodiments, the colloidal particles include one or more metals, such as gold, palladium, platinum, silver, copper, rhodium, ruthenium, rhenium, titanium, osmium, iridium, iron, cobalt, or nickel, or a combination thereof. In certain embodiments, the colloidal particles include one or more oxides, such as silica, alumina, beryllia, noble metal oxides, platinum group metal oxides, titania, tin oxide, zirconia, hafnia, molybdenum oxide, tungsten oxide, rhenium oxide, vanadium oxide, tantalum oxide, niobium oxide, chromium oxide, scandium oxide, yttria, lanthanum oxide, ceria, thorium oxide, uranium oxide, other rare earth oxides, or a combination thereof. Other class of particles to include is ferromagnetic, ferrimagnetic or superparamagnetic particles (diameter usually 10 nanometers or less). Exemplary nanoparticles include iron, nickel and cobalt containing particles, such as magnetite or hematite, Colloidal particles useful in the conduits described herein can be charged, or uncharged, hydrophilic, hydrophobic, or amphiphilic. In some embodiments, the conduits can contain two or more colloidal particles.
In any of these preceding embodiments, the precursor composition can comprise one or more additives selected from the group consisting small molecules, dispersed liquid droplets, or microparticle fillers, nanoparticle fillers, such as anti-oxidants, UV stabilizers, plasticizers, anti-static agents, porogens, slip agents, processing aids, foaming or antifoaming agents, nucleating agents and fillers to enhance mechanical properties or roughness, and to control optical properties or viscosity and uniformity of application, according to certain embodiments.
In certain embodiments, for medical and non-medical fluidic applications, the materials for the conduit designs listed in this innovation can include metals selected from the group of Li, Be, B, Na, Mg, Al, Si, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, Rb, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, Cs, Ba, Hf, Ta, W, Re, Os, Ir, Pt, Au, Ti, Pb, Bi, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and their oxides or a combination thereof. In certain embodiments, the metal-containing conduit contains aluminum and the roughened metal-containing surface contains boehmite. In certain embodiments, the metal-containing sol-gel precursor contains a porogen.
The materials for the conduit designs can include metal foams or porous metallic substrates. In certain embodiments, these porous substrates can be formed typically by the solidification process of a mixture of pre-melted metals with injected gas/gas-releasing blowing agents, or by compressing metal powders into special tooling to form different shapes and forms (e.g., sheet, cylindrical shape, hollow cylinders etc.). Metal foams can be manufactured either in closed-cell or open-cell structures (i.e., interconnected network of metals). Metal foams of different materials, such as aluminum, titanium, nickel, zinc, copper, steel, iron, or other metals and alloys, can be used, and have been produced by various methods, such as direct foaming and powder compact melting methods, which have been extensively discussed in J. Banhart, Prog. Mater. Sci 46, 559-632 (2001), which is incorporated herein by reference.
B. Surface Properties
A range of surface structures with different feature sizes and porosities can be used for conduit design, according to certain embodiments. Feature sizes can be in the range of hundreds of nanometers to microns (e.g., 100 to 1000 nm), and have aspect ratios from about 1:1 to 10:1. In certain embodiments, the surface has a large surface area that is readily wetted by the lubricating liquid and which entrains lubricating liquid and retains it on the substrate surface. The roughened surface material can be selected to be chemically inert to the lubricating liquid and to have good wetting properties with respect to lubricating liquid. In addition, the roughened surface topographies can be varied over a range of geometries and size scale to provide the desired interaction, e.g., wettability, with lubricating liquid. In certain embodiments, the roughened surface can be the surface of a three-dimensionally porous material. The porous material can be any suitable porous network having a sufficient thickness to stabilize lubricating liquid, such as a thickness from about 5 μm to about 1 mm. Moreover, the porous material can have any suitable pore sizes to stabilize the lubricating liquid, such as from about 10 nm to about 100 μm.
In other embodiments, a roughened surface is further functionalized to improve wetting by lubricating liquid. Surface coating can be achieved by methods well known in the art, including plasma assisted chemical vapor deposition, chemical functionalization, solution deposition, and vapor deposition. For example, surfaces containing hydroxyl groups (i.e., —OH) can be functionalized with various commercially available fluorosilanes (e.g., (1H,1H,2H,2H-tridecafluorooctyl)-trichlorosilane) to improve wetting by low surface tension fluids. In certain embodiments, many materials having native oxides can be activated to contain —OH functional groups using techniques such as plasma treatment. After activation, either vapor or solution deposition techniques can be used to attach silanes so that surfaces with low surface energy can be produced. For vapor deposition, the deposition can be carried out by exposing the surface to silane vapors. For solution deposition, the deposition can be carried out by immersing the surface in a silane solution, followed by rinsing and blow-drying after deposition. For layered deposition, layered deposition of a primer is followed by application of a mixture of sacrificial beads and the lubricating liquid, which is dried and cured. The beads are removed to produce a contiguous porous surface.
In certain embodiments, the roughened surface can have pores that are comparable or smaller than the material to be repelled. For example, pore sizes that are smaller than the size of protozoa (e.g., 10 μm), bacteria (e.g., 1 μm), viruses (e.g., 0.1 μm), and the like can be utilized.
C. Lubricating Liquids
Lubricating liquid can be selected from a number of different fluids. These fluids can be selected based on their suitability for biocompatibility, low toxicity, anti-fouling performance, drug release and chemical stability under physiological conditions. In one or more aspects, the lubricating liquid is a chemically inert, high-density biocompatible fluid, non-limiting examples of which include castor oil, silicone oil, fluocinolone acetonide oil, olive oil and mineral oil.
The lubricating liquid infiltrates, wets, and stably adheres to the substrate. Moreover, it is chemically inert with respect to the solid substrate and the fluid to be repelled. The lubricating liquid is non-toxic. Further, the lubricating liquid in accordance with certain aspects is capable of repelling immiscible fluids of any surface tension. In one or more aspects, the lubricating liquid is a chemically-inert and high-density biocompatible fluid. Further, the lubricating liquid is capable of repelling immiscible fluids, and in particular biological fluids of any surface tension. For example, the enthalpy of mixing between the fluid to be repelled and lubricating liquids be can be sufficiently high (e.g., water and oil) that they phase separate from each other when mixed together. In one or more embodiments, lubricating liquid is inert with respect to the solid surface and biological fluid. Lubricating liquid flows readily into the recesses of the roughened surface and generally possesses the ability to form an ultra-smooth surface when provided over the roughened surface. Some exemplary suitable lubricating liquid includes perfluorinated hydrocarbons, organosilicone compound (e.g. silicone elastomer), hydrophobic materials, and the like. In particular, the tertiary perfluoroalkylamines (such as perfluorotri-npentylamine, FC-70 by 3M, perfluorotri-n-butylamine FC-40, etc), perfluoroalkylsulfides and perfluoroalkylsulfoxides, perfluoroalkylethers, perfluorocycloethers (like FC-77) and perfluoropolyethers (such as KRYTOX family of lubricants by DuPont), perfluoroalkylphosphines and perfluoroallcylphosphineoxides as well as their mixtures can be used for these applications, as well as their mixtures with perfluorocarbons and any and all members of the classes mentioned. In addition, long-chain perfluorinated carboxylic acids (e.g., perfluorooctadecanoic acid and other homologues), fluorinated phosphonic and sulfonic acids, fluorinated silanes, and combinations thereof can be used as the lubricating liquid. The perfluoroalkyl group in these compounds could be linear or branched and some or all linear and branched groups can be only partially fluorinated. In certain embodiments, hydrophobic materials such as olive oil, silicone oil, hydrocarbons, and the like can be utilized as the lubricating liquid. In certain embodiments, ionic liquids can be utilized as the lubricating liquid.
In certain embodiments, the lubricating liquids used to facilitate repellency are selected to create a fluid surface that is intrinsically smooth, stable, and defect free. The lubricating liquid of certain embodiments infiltrate, wet, and stably adhere to the substrate. Moreover, the lubricating liquid of certain embodiments should be chemically inert with respect to the solid substrate and the fluid to be repelled. The lubricating liquid of certain embodiments should provide for adequate release of the drug and be non-toxic. Further, the lubricating liquid in accordance with certain aspects is capable of repelling immiscible fluids of any surface tension. In one or more aspects, the lubricating liquid is a chemically-inert and high-density biocompatible fluid.
Lubricating liquid can be selected from a number of different fluids according to certain embodiments. These fluids can be selected based on their suitability for drug release, biocompatibility, low toxicity, anti-clotting performance, and chemical stability under physiological conditions. In one or more aspects, the lubricating liquid is a chemically inert, high-density biocompatible fluid, non-limiting examples of which include vegetable oils. Vegetable oil refers to oil derived from plant seeds or nuts. Exemplary vegetable oils include, but are not limited to, almond oil, borage oil, black currant seed oil, castor oil, corn oil, safflower oil, soybean oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, coconut oil, palm oil, canola oil, etc. Vegetable oils are typically “long-chain triglycerides,” formed when three fatty acids (usually about 14 to about 22 carbons in length, with unsaturated bonds in varying numbers and locations, depending on the source of the oil) form ester bonds with the three hydroxyl groups on glycerol. In certain embodiments, vegetable oils of highly purified grade (also called “super refined”) are generally used to ensure safety and stability of oil-in-water emulsions. In certain embodiments, hydrogenated vegetable oils, which are produced by controlled hydrogenation of the vegetable oil, can be used in the systems disclosed herein.
Other oils can also be used but it can be necessary to modify the composition to provide for adequate solubilization of the drug in the oil. For example, perfluorinated hydrocarbons or organosilicone compound (e.g. silicone elastomer) and the like can be utilized. In particular, in certain embodiments the tertiary perfluoroalkylamines (such as perfluorotri-n-pentylamine, FC-70 by 3M, perfluorotri-n-butylamine FC-40, etc), perfluoroalkylsulfides and perfluoroalkylsulfoxides, perfluoroalkylethers, perfluorocycloethers (like FC-77) and perfluoropolyethers (such as KRYTOX family of lubricants by DuPont), perfluoroalkylphosphines and perfluoroalkylphosphineoxides as well as their mixtures can be used for these applications, as well as their mixtures with perfluorocarbons and any and all members of the classes mentioned. In addition, long-chain perfluorinated carboxylic acids (e.g., perfluorooctadecanoic acid and other homologues), fluorinated phosphonic and sulfonic acids, fluorinated silanes, and combinations thereof can be used as lubricants in certain embodiments. The perfluoroalkyl group in these compounds could be linear or branched and some or all linear and branched groups can be only partially fluorinated in certain embodiments. To improve drug solubility in these other oils, surfactants can be included in the compositions in certain embodiments.
For applications in certain non-medical applications, the lubricant can be selected from the group consisting of fluorinated lubricants (liquids or oils), silicones, mineral oil, plant oil, water (or aqueous solutions including physiologically compatible solutions), ionic liquids, polyolefins, including polyalpha-olefins (PAO), synthetic esters, polyalkylene glycols (PAG), phosphate esters, alkylated naphthalenes (AN) and silicate esters or any mixture thereof.
In certain embodiments, the lubricant has a high density. For example, lubricant that has a density that is more than 1.0 g/cm3, 1.6 g/cm3, or even 1.9 g/cm3 can be used.
In certain embodiments, the lubricant has a low freezing temperature, such as less than −5° C., −25° C., or even less than −80° C. Having a low freezing temperature will allow the lubricant to maintain its slippery behavior at reduced temperatures and to repel a variety of liquids or solidified fluids.
In certain embodiments, the lubricant can have a low evaporation rate, such as less than 1 nm/s, less than 0.1 nm/s, or even less than 0.01 nm/s. Taking a typical thickness of lubricant to be about 10 μm and an evaporation rate of about 0.01 nm/s, the surface can remain highly liquid-repellant for a long period of time without any refilling mechanisms.
In certain embodiments, the viscosity of the oil is in the range of about 1 to 2000 cSt. In certain embodiments, the viscosity of the oil is in the range of about 1 to 500 sCt.
In certain embodiments, the viscosity of the oil is in the range of about 8 to 1500 cSt. In certain embodiments, the viscosity of the oil is in the range of about 10 to 550 cSt. In certain embodiments, the viscosity of the oil is in the range of about 8 to 80 cSt. In certain embodiments, the viscosity of the oil is in the range of about 8 to 350 cSt. In certain embodiments, the viscosity of the oil is in the range of about 80 to 350 cSt. In certain embodiments, the viscosity of the oil is in the range of about 80 to 550 cSt
D. Stimuli-Responsive Materials
The simuli-responsive valves for the conduit lumen or the conduits themselves can comprise a nematic, smectic, chiral, dicotic, bowlic liquid crystals with thermotropic, lyotropic and metallotropic phases. Liquid crystal can also be a cholesteric (chiral nematic) liquid crystal, a smectic A, smectic C, or smectic C* (chiral smectic C), a ferroelectric or antiferroelectric smectic liquid crystal, a liquid crystal compound comprising a bent-core molecule, a columnar mesophase liquid crystal, a discotic liquid crystalline porphyrin, or a lyotropic liquid crystal, or any combination thereof. Next example would be a photo-responsive liquid crystal composition composed of a liquid crystalline compound and a gelling agent mixed with the liquid crystalline compound to form a gelling mixture, wherein the liquid crystalline compound is capable of being controlled in a state oriented in one direction by an irradiation of light. As the specific liquid crystalline compound, can be used those exhibiting a nematic phase at room temperature such as, cyanobiphenyl compounds, phenylcyclohexane compounds, benzylideneaniline compounds, phenylbenzoate compounds, phenylacetylene compounds and phenylpyrimidine, cyanobiphenyl compounds such as 4-pentyl-4′-cyanobiphenyl, benzylideneaniline compounds such as 4-methoxybenzylidene-4′-butylaniline, phenylcyclohexane compounds such as 4-(trans-4-pentylcyclohexyl)benzonitrile. In addition, isoleucine derivatives having an azobenzene structural part, BDH-17886 from Merck Ltd., liquid crystal composition p-meth-oxy-n-p-benzilidene butylaniline (MBBA) can be used. Liquid crystal mixtures with polymers can include polyurethane (PU), polyethylene oxide (PEO), polyacrylonitrile (PAN), polyvinyl acetate (PVA), cellulose acetate; polyaniline, polypyrrole, polythiophene, polyphenol, polyacteylene, polyphenylene, poly(lactic acid) (PLA), poly(methyl methacrylate) (PMMA), poly(glycolic acid) (PGA), poly(ethylene oxide), polyacrylate, polyester, polyamide, polyolefin, polyvinylchloride (PVC), poly(amic acid), polyimide, polyether, polysulfone, and any combination thereof.
In one embodiment, the shape-responsive layer comprises a liquid crystal elastomer. Shape-changes in monodomain LCEs, which have a uniformly aligned liquid crystal (LC) director, can range from 10% to 400% of the initial LCE size. In some embodiments, the LCE is a polydomain liquid crystal elastomer. In some embodiments, the LCE includes a nematic director and a mesogen (liquid crystal molecule) associated with a polymer. In some embodiments, the mesogen content of the LCE ranges from about 20% molar content to about 90% molar content of the liquid crystal elastomer. In some embodiments, the mesogen is generally a molecule that produces a liquid crystal phase at room temperature and can include at least one of aromatic rings, aliphatic rings, poly aromatic rings, poly aliphatic rings, phenyls, biphenyls, cyanobiphenyls, benzenes, and combinations thereof. In some embodiments, the mesogen is functionalized with one or more functional groups, such as alkenes, alkanes, alkynes, carboxyl groups, esters, halogens, and combinations thereof. In certain embodiments, the mesogen is 4-methoxyphenyl 4-(3-butenyloxy) benzoate.
In some embodiments, mesogens in LCEs are cross-linked polymers. In some embodiments, the polymer includes at least one of polysiloxanes, poly(methyl) siloxanes (PMS), poly(dimethyl) siloxanes (PDMS), polymethylhydrosiloxane (PMHS), poly(methyl methacrylate), polyethylene, polypropylene, poly(butylacrylate) network chains and combinations thereof.
The polymers can be associated with mesogens in various arrangements. For instance, in some embodiments, the mesogens can be cross-linked to polymers. The crosslinker can be any reactive molecule that produces a physically or chemically crosslinked, elastomeric network. For example, a di(methacrylate) crosslinker is used or a diacrylate crosslinker. The crosslinker concentration can be varied to increase or decrease the elastomer modulus, at higher or lower crosslinker contents, respectively. Other catalysts or methods can be used to crosslink the network, including thermal annealing or platinum catalysts that are more or less reactive. The solvent content can also be varied during synthesis.
In some embodiments, a plurality of mesogens can be covalently coupled to a single polymer chain. In some embodiments, a plurality of mesogens can be covalently coupled to multiple polymer chains. In some embodiments, the mesogens and polymers can be intertwined within a matrix. LCEs can be made using methods known in the art.
In yet another embodiment, conductive material can be added to the shape-responsive layer. The conductive filler can provide the LCE nanocomposite with an electrical, magnetic, or light-induced response, as examples. For example, the LCE can comprise one or more wires. Alternatively or in addition to, carbon nanoconduits, carbon black nanoparticles, or conductive gold nanoparticles can be used.
In addition to tympanostomy conduits, the embodiments of the present disclosure can also enhance the field of other conduit-like medical implants, such as but not limited to surgical drains, vascular stents, catheter, dialysis tubing, feeding conduits, colostomy conduits, and eustachian implants.
Filing Document | Filing Date | Country | Kind |
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PCT/US19/23276 | 3/20/2019 | WO | 00 |
Number | Date | Country | |
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62645629 | Mar 2018 | US |