The North American porcupine has ˜30,000 quills on the dorsal surface and when it encounters a predator, the release of quills is facilitated by direct contact with the predator. Each quill tip contains microscopic backward facing barbs, whereas other mammals such as the African porcupine, hedgehog, and echidna have smooth quills (or spines). If the tip of a quill strikes the skin of a predator, the resulting reaction force exerted on the shaft of the quill may be strong enough to shear the quill's root from surrounding tissue, which may help the porcupine to escape from the enemy. It has been well documented that it is difficult to remove porcupine quills from the predator once the quills are lodged within tissue (typically through both skin and muscle). However, the forces involved in penetration and pull-out have yet to be described and a comprehensive mechanism remains elusive. The biomimicry of the North American porcupine should be of interest to both scientific and industrial communities.
Although a variety of needles and their derivatives have been used, it would be beneficial to promote innovations mimicking and improving natural systems, for example, the North American porcupine's quills. More generally, there remains a need for devices and methods that facilitate penetrating and/or sticking to a substrate.
The present disclosure provides a device for penetrating a substrate and uses thereof. Such a device comprises one or more tips, wherein the one or more tips are designed and constructed to initiate penetration by the device; and one or more protrusions in a region adjacent to each tip. In some embodiments, one or more protrusions can be constructed and arranged so that the required penetration force is reduced as compared with that observed for an otherwise identical device lacking the one or more protrusions. Additionally or alternatively, one or more protrusions can be constructed and arranged such that the required pull-out force is increased as compared with that observed for an otherwise identical device lacking the one or more protrusions.
In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification.
The term “biodegradable” is understood to refer to any material that it changes its chemical composition (e.g., degrades) after being placed into a live animal or live cell-containing medium, resulting in an eventual decrease in number average molecular weight.
The term “tip” as used herein typically refers to the smaller end region of an object that at least two different dimensions or a pointed region of an object that contains a projection.
The term “shaft” as used herein typically refers to a long, narrow region of an object.
The term “needle” as used herein typically refers to an object that pierces a substrate.
The term “microneedle” as used herein typically refers to a sharp object with at least one dimension on the order of 10 nanometers to 1,000 microns.
The term “Hypodermic needle” is understood in the art to refer to objects (whether solid, or containing one or a plurality of lumens) that is adapted for and capable of penetrating the epidermis of any species.
The term “barb” as used herein refers to an object that has at least one sharp pointed region that is affixed to a main body such as a shaft.
The drawing is for illustration purposes only, not for limitation.
A device for penetrating a substrate used in accordance with the present disclosure, in theory, can be of any shape or design. For example, a device or a body of the device can be or comprise a film, a sheet, a tape, a needle, an array, a hook, and/or a probe.
A tip of a device, in general, refers to an end and/or pointed region of an object that is sufficiently sharp to initiate penetration. Typically, a tip is an extremity of something slender or tapering and may contain a shaft of any shape (e.g., a tapered region) that connects with a body of a device used in accordance with the present disclosure. A device may contain one or more tips.
Each tip may independently have one or more protrusions in a region adjacent to the apex of tip. Such one or more protrusions can be constructed and arranged so that the required penetration force is reduced as compared with that observed for an otherwise identical device lacking the one or more protrusions. In some embodiments, a device described herein can be characterized by the required penetration force being reduced to or less than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 75% or 90%, as compared with that observed for an otherwise identical device lacking the one or more protrusions. In some embodiments, a device described herein can be characterized by the required penetration force being reduced to in a range of any two values above, as compared with that observed for an otherwise identical device lacking the one or more protrusions. In addition or alternatively, such one or more protrusions can be constructed and arranged such that the required pull-out force is increased as compared with that observed for an otherwise identical device lacking the one or more protrusions. In some embodiments, a device described herein can be characterized by the required pull-out force being increased to or more than 1500%, 1000%, 500%, 400%, 300%, 250%, 200%, 150%, or 125%, as compared with that observed for an otherwise identical device lacking the one or more protrusions. In some embodiments, a device described herein can be characterized by the required pull-out force being increased to in a range of any two values above, as compared with that observed for an otherwise identical device lacking the one or more protrusions. In some embodiments, the diameter of the penetration point of each tip can be less than 140%, 120%, 110% or 105% of that observed for an otherwise identical device lacking the one or more protrusions.
In some embodiments, intended for biological applications, dimensions or dimensional ratios of a device are on the order of those exhibited by North American porcupine quills. In some embodiments, dimensions or ratios may be significantly smaller or larger than those of the quills, even by orders of magnitude.
Protrusions
In general, devices described herein comprises one or more tips and one or more protrusions extending from the tip surface, in a region adjacent to each tip.
In certain embodiments, devices described herein may comprise a single protrusions. In various embodiments, a plurality of protrusions includes two or more protrusions. In some embodiments, the number of protrusions can be up to the order of a billion. Typically, the number of protrusions utilized in a particular device may depend on the spacing and the area having protrusions protrude from. For example, protrusions can be spaced from one another about or less than 1 cm, 5 mm, 1 mm, 500 microns, 200 microns, 100 microns, 50 microns, or 10 microns. A spacing between protrusions can be in a range of 1 cm to 5 mm, 5 mm to 1 mm, 500 microns to 200 microns, 200 microns to 100 microns, 100 microns to 50 microns, 50 microns to 10 microns, 10 microns to 1 micron, or between any two values above.
In accordance with the present disclosure, a device can be arranged and constructed so that one or more protrusions protrude from the a region adjacent to each of one or more tips in different directions in three-dimensional space. For example, protrusions can protrude radially from the surface of a region adjacent to a tip, each independently having at an angle relative to the tangent to the surface or relative to a shaft from which it protrudes. In some embodiments, protrusions are projected outward in the opposite direction of the tip that the protrusions are adjacent to. Each protrusion of the plurality can independently have an angle of 90 degrees or any others less than 90 degrees. In some embodiments, such an angle can be about or less than 80 degrees, 70 degrees, 60 degrees, 50 degrees, 40 degrees, 30 degrees, 20 degrees, 10 degrees, 5 degrees, 4 degrees, 3 degrees, 2 degrees, 1 degree or even 0 degree. In some embodiments, such an angle can be in a range of 0-90 degrees, 1-60 degrees, 1-50 degrees, 1-30 degrees, 1-20 degrees, 1-10 degrees, 1-5 degrees, 1-3 degrees, or 1-2 degrees. In certain embodiments, protrusions can be unidirectional. In certain embodiments, protrusions (e.g., pyramidal protrusions) may not be directed inward or outward.
In some embodiments, the dimensions and/or shape of a protrusion, or protrusions of a plurality thereof, are designed for the particular way in which a device is to be used. Without wishing to be bound by any particular theory, parameters such as the dimensions of an individual protrusion (e.g., a length, width, thickness), and/or the shape of the protrusion (e.g., barb-shaped, etc.) may influence the penetration and/or pull-out of the tip where the protrusion is placed adjacently to, and thus the efficiency and functions of the device.
Dimensions of a protrusion generally includes a length, a width and a thickness. In some embodiments, a protrusion is barb-shaped or in any other shape, and can has a maximum width. Protrusions can be designed in different shapes independently depending on applications. In general, shapes that locally maximize stress concentrations at fine points around the periphery can be used in accordance with the present disclosure as good cutting shapes with reduced insertion force. Shapes that spread the tissue around larger features will help raise removal force. For example, a protrusion may be barb-shaped, hemisphere, pyramid, harpoon-shaped, triangle, conical, hook-shaped, oval or Y-shaped.
In some embodiments, at least one dimension of an individual protrusion may be about or less than 1 cm, 5 mm, 2 mm, 1 mm, 500 μm, 300 μm, 250 μm, 200 μm, 150 μm, 120 μm, 100 μm, 90 μm, 80 μm, 70 μm, 60 μm, 50 μm, 40 μm, 30 μm, 20 μm, 10 μm, 5 μm, 1 μm, or even 500 nm. In some embodiments, the length of an individual protrusion may be more than 500 nm, 1 μm, 5 μm, 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 120 μm, 150 μm, 200 μm, 250 μm, 300 μm, 500 μm, 1 mm, 2 mm, 5 mm, or even 1 cm. In some embodiments, at least one dimension of an individual protrusion may be in a range of 1 cm to about 1 μm. In some embodiments, at least one dimension of an individual protrusion may be in a range of 1 mm to 10 μm. In some embodiments, at least one dimension of an individual protrusion may be in a range of 500 μm to 100 μm. In some embodiments, at least one dimension of an individual protrusion may be in a range of 200 μm to 100 μm. In some embodiments, at least one dimension of an individual protrusion may be in a range of 120 μm to 100 μm. In some embodiments, at least one dimension of an individual protrusion may in a range of 70 μm to about 50 μm. In some embodiments, at least one dimension of an individual protrusion may be in a range of 50 μm to 10 μm. In some embodiments, at least one dimension of an individual protrusion may be in a range of any two values above. It may be desirable, in certain embodiments, to adjust at least one dimension of a protrusion according to the application/use of the device.
In some embodiments, an aspect ratio of one dimension to another dimension (e.g., length/width) of an individual protrusion may be about, less than or more than 50, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.2, or even 0.1. In some embodiments, an aspect ratio of one dimension to another dimension may be in a range of 50-1. In some embodiments, an aspect ratio of one dimension to another dimension may be in a range of 10-1. In some embodiments, an aspect ratio of one dimension to another dimension may be in a range of 5-1. In some embodiments, an aspect ratio of one dimension to another dimension may be in a range of 2-1. In some embodiments, an aspect ratio of one dimension to another dimension may be in a range of any two values above. It may be desirable, in certain embodiments, to adjust an aspect ratio of one dimension to another dimension of a protrusion according to the application/use of the device.
In some embodiments, protrusions may overlap with one another. In some embodiments, protrusions can have an overlap of about, less than or more than 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or even 90% of the protrusion size. In some embodiments, an overlap may be in a range of 1-50% of the protrusion size. In some embodiments, an overlap may be in a range of 5-30% of the protrusion size. In some embodiments, an overlap may be in a range of 10-20% of the protrusion size. In some embodiments, an overlap may be in a range of any two values above of the protrusion size. Without being bound by any particular theory, it is proposed that in some embodiments, when protrusions have overlapped features, they may affect the functions of a device cooperatively. It may be desirable, in certain embodiments, to adjust an overlap according to the application/use of the device.
As noted above, a tip described herein may include a shaft that connects with a body of a device. Typical shafts have a tapered region. For example, a shaft can a tapered column, cone, pyramid, hemisphere, or triangle. The dimension of a cross section of a tip, typically on its shaft, may vary depending on the design/use of a device used in accordance with the present disclosure. In some embodiments, the dimension of a cross section may be about, less than or more than 10 cm, 5 cm, 4 cm, 3 cm, 2 cm, 1 cm, 5 mm, 1 mm, or even 500 lam. In some embodiments, the dimension of a cross section may be in a range of 1 cm and 1 mm. In some embodiments, the dimension of a cross section may be in a range of any two values above.
Protrusions in accordance with the present disclosure can be arranged and constructed to protrude from a region adjacent to each tip. In some embodiments, protrusions are located in a tapered region adjacent to each tip. An adjacent region depending on design and application can be in a distance away from the apex of a tip. For example, to mimic a porcupine quill as illustrated in Example below, the distance may be a relative distance observed from a porcupine quill. In some embodiments, an adjacent region is about, less than or more than 0.01 mm, 0.1 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1 cm, 2 cm, 4 cm, 5 cm, or even 10 cm away from the apex of a tip. In some embodiments, an adjacent region may be in a range of 0-10 mm, 1-5 mm, 0-2 mm, 2-4 mm, or 3-4 mm away from the apex of a tip. In some embodiments, an adjacent region may be in a range of any two values above away from the apex of a tip. Depending on the size/use of a device, a distance away from the apex of a tip can be adjusted and relative to the dimension of the cross section of the tip's shaft where protrusions locate. For example, a distance away from the apex of a tip can be about or less than 0.1 fold, 0.5 fold, 1 fold, 2 fold, 5 fold, 10 fold, or even 20 fold of the dimension of a cross section. Without being bound to any particular theory, protrusions located near the apex of a tip may exhibit a great impact on required pull-out force of a device while protrusions located next to and away from the tip apex may exhibit substantial impact on minimizing the required penetration force.
In addition to the above discussion on protrusion dimensions, in some embodiments, at least one dimension of an individual protrusion can be adjusted and relative to the dimension of the cross section of the tip's shaft where protrusions locate. For example, at least one dimension of an individual protrusion can be about or less than 0.1 fold, 0.5 fold, 1 fold, 2 fold, 5 fold, 10 fold, or even 20 fold of the dimension of a cross section.
Materials
A device including one or more tips and one or more protrusions as described herein can be made of or comprise one or more materials. Different portions can be made of or comprise different materials for different properties. For example, a device may have a body that is made of or comprising a non-swelling material. A body of a device can be anti-adhesive or repellant. Additionally or alternatively, a body of a device can be non-erodible or non-degradable.
Exemplary materials include, but are not limited to, metals (e.g., gold, silver, platinum, steel or other alloys); metal-coated materials; metal oxides; plastics; ceramics; silicon; glasses; mica; graphite; hydrogels; and polymers such as non-degradable or biodegradable polymers; and combinations thereof. In general, materials can be utilized in any form and/or for different purposes and/or in different regions (e.g., one or more tips and their adjacent regions).
Without being bound to any particular theory, varying compositions of materials used in accordance with the present disclosure (e.g., components, weight percentages, molecular weight, etc.) can affect properties of the materials for different functions/applications. For example, a substrate that a device penetrates into can be compliant and one or more tips/protrusions according to the present disclosure can be made and characterized by a stiffness being greater than that of the substrate. In certain embodiments, the stiffness of tips/protrusions can be about or more than 2 fold, 5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, or 100 fold of that of the substrate.
In some embodiments, a device can be made of or comprise deformable materials. As an example, a portion of a device (e.g., one or more protrusions) can be made of or comprise a pliable polymer, which may have a low bending modulus. A deployable protrusion may be able to deploy or bend and the deployment/bending may affect penetration and/or pull-out of the device. Exemplary deployable protrusions are illustrated in
To give another example, a deformable material (e.g., hydrogels, thermoplastics, shape memory materials) can change shape/size depending on pressure or temperature, and can be used in different portions of a device. In certain embodiments, one or more tips of a device can be made of or contain a water-swellable material (e.g., hydrogel). In certain embodiments, one or more protrusions of a device can be made of or contain a shape memory material. Shape memory materials can change to a trained shape in response to an activation signal. Exemplary shape memory materials include, but not limited shape memory alloys (SMA) and shape memory polymers (SMP), as well as shape memory ceramics, electroactive polymers (EAP), ferromagnetic SMAs, electrorheological (ER) compositions, magnetorheological (MR) compositions, dielectric elastomers, ionic polymer metal composites (IPMC), piezoelectric polymers, piezoelectric ceramics, and various combinations thereof. Suitable shape memory alloy materials include, without limitation, nickel-titanium based alloys, indium-titanium based alloys, nickel-aluminum based alloys, nickel-gallium based alloys, copper based alloys (e.g., copper-zinc alloys, copper-aluminum alloys, copper-gold, and copper-tin alloys), gold-cadmium based alloys, silver-cadmium based alloys, indium-cadmium based alloys, manganese-copper based alloys, iron-platinum based alloys, iron-platinum based alloys, iron-palladium based alloys, and the like. Alloys can be binary, ternary, or any higher order so long as the alloy composition exhibits a shape memory effect, e.g., change in shape orientation, damping capacity, and the like. More discussion of shape memory materials can be found in US Patent Application US 20090241537, the contents of which are incorporated by references. In certain embodiments, a shape memory materials used in accordance with the present disclosure is nitinol. Without being bound to any particular theory, a deformable protrusion utilizing a shape memory material, upon increasing temperature by insertion into a substrate, can deploy by reverting back to a shape memory annealed form.
In some embodiments, a device can be made of or comprise adhesive materials (e.g., adhesive polymers). As examples, bioadhesives such as chitosan and carbopol can be used. Use of an adhesive material may be beneficial in penetrating and retaining in a substrate.
In some embodiments, a device can be made of or comprise erodible and/or degradable materials. To give an example, a tip may contain a shaft that can degrade to release the very pointed tip portion from the device body. In addition or alternatively, a protrusion can be detached from a tip after penetration, and it may remain in a substrate or erode/degrade so that the required penetration force of the device can be achieved without increased pull-out force. In certain embodiments, tips and/or protrusions can be erodible and/or degradable and a device body can degrade/erode more slowly that the tips or protrusions. Erodible and/or degradable materials can be used to coat a device or any portion of it described herein.
In some embodiments, a device can be made of or comprise one or more polymers. For example, a portion of the device (e.g., tips and/or protrusions in a region adjacent to tips) as discussed below used in accordance with the present disclosure can be made of or comprise one or more polymers. Various polymers and methods known in the art can be used. Polymers may be natural polymers or unnatural (e.g. synthetic) polymers. In some embodiments, polymers can be linear or branched polymers. In some embodiments, polymers can be dendrimers. Polymers may be homopolymers or copolymers comprising two or more monomers. In terms of sequence, copolymers may be block copolymers, graft copolymers, random copolymers, blends, mixtures, and/or adducts of any of the foregoing and other polymers.
A polymer used in accordance with the present application can have a wide range of molecular weights. In some embodiments, the molecular weight of a polymer is greater than 5 kDa. In some embodiments, the molecular weight of a polymer is greater than 10 kDa. In some embodiments, the molecular weight of a polymer is greater than 50 kDa. In some embodiments, the molecular weight of a polymer ranges from about 5 kDa to about 100 kDa. In some embodiments, the molecular weight of a polymer ranges from about 10 kDa to 50 kDa.
In some embodiments, polymers may be synthetic polymers, including, but not limited to, polyethylenes, polycarbonates (e.g. poly(1,3-dioxan-2-one)), polyanhydrides (e.g. poly(sebacic anhydride)), polyhydroxyacids (e.g. poly(β-hydroxyalkanoate)), polypropylfumarates, polycaprolactones, polyamides (e.g. polycaprolactam), polyacetals, polyethers, polyesters (e.g. polylactide, polyglycolide), poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes, and polyamines and copolymers thereof. In some embodiments, polymers include polymers which have been approved for use in humans by the U.S. Food and Drug Administration (FDA) under 21 C.F.R. §177.2600, including, but not limited to, polyesters (e.g. polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(1,3-dioxan-2-one)); polyanhydrides (e.g. poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; polycyanoacrylates; copolymers of PEG and poly(ethylene oxide) (PEO).
PEGs may be useful, in some embodiments, in accordance with the present application since they are nontoxic, non-immunogenic, inert to most biological molecules (e.g. proteins), and approved by the FDA for various clinical uses. PEG polymers can be covalently crosslinked using a variety of methods to form hydrogels. In some embodiments, PEG chains are crosslinked through photopolymerization using acrylate-terminated PEG monomers. In addition to chemical modification, block copolymers of PEG, such as triblock copolymers of PEO and polypropylene oxide) (henceforth designated as PEO-b-PPO-b-PEO), degradable PEO, poly(lactic acid) (PLA), and other similar materials, can be used to add specific properties to the PEG.
In some embodiments, polymers used herein can be a degradable polymer. Such a degradable polymer can be hydrolytically degradable, biodegradable, thermally degradable, and/or photolytically degradable polyelectrolytes.
Degradable polymers known in the art, include, for example, certain polyesters, polyanhydrides, polyorthoesters, polyphosphazenes, polyphosphoesters, certain polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, poly(amino acids), polyacetals, polyethers, biodegradable polycyanoacrylates, biodegradable polyurethanes and polysaccharides. For example, specific biodegradable polymers that may be used include but are not limited to polylysine, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(caprolactone) (PCL), poly(lactide-co-glycolide) (PLG), poly(lactide-co-caprolactone) (PLC), and poly(glycolide-co-caprolactone) (PGC). Another exemplary degradable polymer is poly (beta-amino esters), which may be suitable for use in accordance with the present application.
Suitable degradable polymers, and derivatives or combinations thereof, as discussed above can be selected and adapted to have a desired degradation rate. Alternatively or additionally, a degradation rate may be fine-tuned by associating or mixing other materials as previously described (e.g., non-degradable materials) with one or more of degradable polymers.
In general, a degradation rate as used herein can be dictated by the time in which a material degrades a certain percentage (e.g., 50%) in a certain condition (e.g., in physiological conditions). In some embodiments, the degradation time of a device or a portion of the device as described herein can have a wide range. In some embodiments, the degradation time may be greater than 1 minute, 5 minutes, 30 minutes, 1 hour, 2 hours. 5 hours, 12 hours, 24 hours, 1.5 days, 2 days, 5 days, 7 days, 15 days, 30 days, 2 months, 6 months, 1 year, 2 years, or even 5 years. In embodiments, the degradation time may be about or less than 10 years, 5 years, 2 years, 1 year, 6 months, 2 months, 30 days, 15 days, 7 days, 5 days, 2 days, 1.5 days, 24 hours, 12 hours, 5 hours, 2 hours, 1 hour, 30 minutes or even 5 minutes. The degradation time may be in a range of 12-24 hours, 1-6 months, or 1-5 years. In some embodiments, the degradation time may be in a range of any two values above.
In addition or alternatively, suitable shape memory polymers as mentioned above include thermoplastics, thermosets, interpenetrating networks, semi-interpenetrating networks, or mixed networks. The polymers can be linear or branched thermoplastic elastomers with side chains or dendritic structural elements. Suitable polymer components to form a shape memory polymer include, but are not limited to, polyphosphazenes, poly(vinyl alcohols), polyamides, polyester amides, poly(amino acid)s, polyanhydrides, polycarbonates, polyacrylates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyortho esters, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyesters, polylactides, polyglycolides, polysiloxanes, polyurethanes, polyethers, polyether amides, polyether esters, and copolymers thereof. Examples of suitable polyacrylates include poly(methyl methacrylate), poly(ethyl methacrylate), ply(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate). Examples of other suitable polymers include polystyrene, polypropylene, polyvinyl phenol, polyvinylpyrrolidone, chlorinated polybutylene, poly(octadecyl vinyl ether) ethylene vinyl acetate, polyethylene, poly(ethylene oxide)-poly(ethylene terephthalate), polyethylene/nylon (graft copolymer), polycaprolactones-polyamide (block copolymer), poly(caprolactone) dimethacrylate-n-butyl acrylate, poly(norbornyl-polyhedral oligomeric silsequioxane), polyvinylchloride, urethane/butadiene copolymers, polyurethane block copolymers, styrene-butadiene-styrene block copolymers, and the like. In some embodiments, some multiblock copolymers that are made of or comprise (1) methylenebis(4-phenylisocyanate)/1,4-butanediol and poly(∈-caprolactone), (2) poly(ethylene terephthalate) and poly(ethylene oxide), (3) poly(2-methyl-2-oxazoline) and poly(tetrahydrofuran), (4) methylenebis(4-phenylisocyanate)/1,4-butanediol and poly(tetrahydrofuran), (5) methylenebis(4-phenylisocyanate)/1,4-butanediol and poly(ethylene adipate), (6) carbodiimide-modified diisocyanates and poly(butylene adipate), (7) ethylene glycol and poly(tetrahydrofuran) or any combination thereof.
Making and Uses
Devices in accordance with the present disclosure can be made using exemplary materials as discussed above and by suitable methods. For example, a device or any portion of it (e.g., protrusions) may be fabricated by a technique including, but not limited to, laser cutting, dry etching, wet etching, imprint coating, molding, stamping, embossing, two-photon lithography, three dimensional printing, electrospinning, imprinting, interference lithography and any combination thereof.
An example of a device or a portion of a device (e.g., a tip) suitable for use in accordance with the present disclosure can be or comprise a hypodermic needle. A tip can have at least one hole and at least one lumen. Such a hole can be used to communicate between a lumen and an exterior.
An exemplary hypodermic needle with one or more barb-shaped protrusions is illustrated in
In some embodiments, a hypodermic needle is laser cut, machined, or etched to create protrusions. For example, hypodermic needles can be prepared to remove material from the shaft to create hooked needles. A hook can be covered with a sacrificial polymer layer that is present upon insertion and absent during pull-out to increase mechanical interlocking.
In some embodiments, to create raised features on the surface of a device, holes of any shape can be laser cut, machined, or etched into a hypodermic needle. A liquid material can then be introduced in a controlled fashion into the lumen of the needle, while the tip is plugged forcing material through the holes. A material can then be solidified by any one of the following including, but not limited to cooling, cross-linking by heat or exposure to ultraviolet radiation. In some embodiments, a material upon solidification is at least as compliant as the material into which it will be inserted. In some embodiments, holes are on the order of 100 microns in width or diameter as observed in the barbed region of the quill most directly correlated with decreased penetration force. In some embodiments, the holes are made at a distance from the tip of the needle that mimics the relative distance observed for a porcupine quill (e.g., 3-4 mm). In another preferred embodiment, the holes are made in the tapered portion of the needle.
In some embodiments, the morphology of protrusions can be imprint coated, laser cut, machined, or etched into a hypodermic needle. In some embodiments, the morphology can be achieved by molding one or a plurality of existing porcupine quills to create a negative mold. A negative mold can then be filled with a liquid material that upon solidification yields a positive cast of the porcupine quill.
Devices and methods described herein can be used in various applications including, but not limited to, medical devices, drilling, nailing, fishing, fastening, sewing, clothing manufacture, textiles, hair clips, holding devices, assembling layered systems, industrial adhesives, skin piercing (including ear piercing), shoemaking, or industrial puncturing devices.
In some embodiments, a device can be dimensioned and constructed for use as a needle, a microneedle array, a patch, a hook, a probe, a trocar, an implant, etc. A substrate can be compliant or non-compliant. In some embodiments, a substrate can be a tissue at a target site. Exemplary tissues includes, but are not limited to, skin, muscle, heart, spleen, liver, brain, intestine, stomach, gall bladder, blood vessels, fascia, dura, the eye, lips, tongue, mucosa, lungs, kidney, pancreas, and ears.
Provided devices and methods, in some embodiments, may be used in accessing sites in the body. In some embodiments, devices and methods described here can be used to insert into a site containing bodily fluids. Such devices and methods may be used in sampling bodily fluids or may further in processing for diagnostic purposes, acupuncture, tacking a film or mesh for treating hernia, ulcers, and burns, sealing internal or external wounds (suture/staple replacements/supplements).
In some embodiments, provided devices and methods can be used in applications of devices/tubes/monitoring systems/drug delivery devices to the skin or muscle or other tissues, preventing air leaks following lung resection procedures, delivering drugs, laparoscopically placing a tissue adhesive or buttress, obtaining vascular hemostasis, creating adhesion to the opthamalogic epithelium, and/or creating temporary surgical retraction.
In some embodiments, devices and methods described herein can be used in or as a mechanical adhesive. In addition or as an alternative, devices and methods described herein can be used as or in a delivery system and can release payloads after penetration to a substrate. In addition or as an alternative, devices and methods disclosed herein can be used for sampling and/or diagnostics.
Materials and Methods
Material:
North American (specifically, Pacific Northwest) porcupine quills and African porcupine quills were purchased from Minute Bear Trading, USA. Fluorescein (sodium salt, dye content ˜70%, Aldrich), rhodamine B (dye content ˜90%, Sigma-Aldrich), ethanol (ACS reagent, ≧99.5%, 200 proof, Sigma-Aldrich), Sylgard® 184 silicone elastomer kit (Dow Corning, Corp., USA), UV-curable polyurethane acrylate (Minuta Tech., Korea), Irgacure 2959 (Ciba Specialty Chemicals Corporation), 18 gauge, 19 gauge, and 25 gauge 7/8 needles (Becton Dickinson Company), artificial human skin (SynDaver™ Labs), muscle tissue of domesticated fowl (Shaw's, Inc.), gelatin powder (Difco™, BD), sand paper (3M wet or dry sandpaper 413Q 400 and Norton MultiSand™, 60), cyanoacrylate glue (Loctite 495, Loctite Corp.), industrial razor blades (surgical carbon steel, single edged No. 9, VWR), polyether ether ketone (PEEK) hex nuts (Small Parts), silicone rubber film with backing adhesive (McMaster-Carr), pin mount stubs (25.4 mm in diameter, 9.5 mm in height, and 3.2 mm in pin diameter, Ted Pella, Inc.), 5 min and 60 min epoxy glues (ITW Performance Polymers) were used as received. The fresh porcine skin was purchased from a local butcher shop. The thin copper wire (˜0.2 mm in diameter) was extracted from electrical wire (Type AWM, RadioShack).
Penetration-Retraction Tests with Muscle Tissue and Gelatin Gel:
Penetration-retraction tests were performed with the mechanical tester (Model 5540, Instron Corporation). Only quills with a barbed region of 4 mm in length were selected for testing, as measured with a millimeter ruler and a dissecting optical microscope (SZ-6 PLUS, Cambridge Instruments). The muscle tissue was cut into specimens with 3-4 cm width, 2-3 cm length, and 4-5 mm thickness using a razor blade. The tissue specimens were mounted within the lower grips at the base of the mechanical tester. During fixation, care was taken not to excessively compress the tissue. After the specimen was fixed between the grips, the exposed excess tissue over the grips was cut with a blade, generating a flat tissue surface. The quill was fixed between the upper grips and the tip adjusted to contact the tissue surface. The quill was penetrated into the muscle tissue to the desired depth, typically 10 mm, at a rate of 1 mm/sec and was pulled out at a rate of 0.033 mm/sec to study how the barbs function during removal from tissue. For the duration of all experiments, the tissue was kept moist with phosphate buffered saline. Each quill was used for a single measurement. The experiments with gelatin gel, used as a control for a non-fibrous tissue were performed with an alternative set-up, as gelatin gel could not be gripped. Compression stage instead of the lower grips was used to fix the gelatin gel during measurements. In other words, gelatin gel was fixed onto the stage without compression. Considering this experimental set-up, we performed another test with muscle tissue by placing a thick section of tissue between lower grips without compression. To minimize any movement of muscle tissue, we prepared the chicken breast tissue that can fit with the available space between lower grips without compression. Gelatin gel was prepared with the same density as that of muscle tissue by dissolving gelatin powder into distilled water at 40° C. and letting it cool to room temperature. For the tissue and gelatin gel, the mean penetration force and mean pull-out force were measured from n=5 different samples.
Measurement of the Density of Muscle Tissue:
Tissue density was measured using previously described methods: Briefly, the tissue density was determined using a 25 ml glass pycnometer with the following equation (1).
d
s
=sd
w/(mpf−mt+s) (1)
where ds is density of the tissue (g/mL), dw is density of water (g/mL), s is weight of the dried tissue (g), mpf is weight of pycnometer and water (g), and mt is weight of pycnometer, water and tissue. To obtain the weight of the dried tissue, the tissue had been dried in an oven at 60° C. until the weight plateaued after 7 days.
Preparation of the Stained Quills for Visualization During Adhesive Measurements:
Porcupine quills were immersed into 0.01% aqueous fluorescein or rhodamine B solution. After 1 h, quills were removed from the staining solution and washed thoroughly with water. The stained quills were dried overnight before use.
Penetration-Retraction Tests with Porcine Skin:
Fresh porcine skin was cut into specimens with 3-4 cm width and 3 cm length using a razor blade. For adhesive measurements, porcupine quills were inserted into porcine skin, vertically aligned within the lower grips, with a penetrating depth of 4 mm. The remainder of the test followed the procedure previously described for muscle tissue.
Characterization of the Mechanical Properties of Porcine Skin:
The specimen was cut into a dog bone shape (2 cm×5 cm). The length of skin for measurement (the distance between grips) was 6 mm. To prevent the porcine skin from slipping from the grips, the porcine skin was covered with sand paper (grit number: P60) except the measured area. The sand paper was tightly affixed to the porcine skin using cyanoacrylate glue and staples. A uniaxial tensile test was performed to measure mechanical properties of the prepared porcine skin using an eXpert 760 mechanical tester (ADMET, Inc.). The rate for the tensile test was 1 mm/min and the obtained data was fitted using the inverse Langevin model of finite elasticity.
Measurement of the Young's Modulus and Tensile Strengths for the Base and Tip of Porcupine Quills:
For measurements of the base, tensile tests were performed. In order to grip the base structure without crushing the ends, small steel needles (a tip part of 19 gauge needle) were inserted into both ends to maintain the cylindrical geometry. Copper wire and epoxy glue were then used on the exterior to prevent the samples from slipping from the grips. To accurately measure the Young's modulus of the tip, the top 1 mm near the apex was gripped with bottom grips leaving 2 mm exposed for measurement. We made the assumption that the cross-sectional diameter (˜0.30 mm) of the exposed 2 mm-long region between the grips remained constant. The prepared base and tip samples were mounted between lower grips and upper grips of the mechanical tester. The distance between lower grips and upper grips was 8 mm and 2 mm for base and tip, respectively. Measurements were performed at a rate of 1 mm/min for n=5 different samples.
Amino Acid Analysis:
Clean porcupine quills were cut and divided into 4 mm-length tip (i.e. only barbed region) and base, and 3 mg of each were gathered for analysis. Liquid phase hydrolysis of the samples was performed with 200 μL of 6N hydrochloric acid (HCl) added with 0.1% phenol at 110° C. for 24 h. After acid hydrolysis, the samples were dried for 1 h and then dissolved in Norleucine dilution buffer to a final volume as 20 or 40 mL. The final solution was thoroughly mixed with a vortexer and 50 μL was loaded into the analyzer (L-8800 Na Amino Acid Analyzer by Hitachi). The injected 50 μL contained 2.0 nmol of Norleucine as an internal standard.
Additional analysis was performed to obtain the concentration of cysteine which can be destroyed during hydrolysis with 6N HCl. Briefly, cysteine was oxidized to cysteic acid through incubating base and tip samples in 1.0 mL of performic acid at 4° C. overnight. The samples were then dried and prepared for amino acid content analysis as described above.
Buckling Resistance Tests:
To measure the buckling resistance of the shaft of the porcupine quill, 28 quills were randomly selected for uniaxial compression testing. The tip was trimmed slightly to provide a shaft with a near uniform cross sectional area and the resulting length and diameter were precisely measured with calipers. Quills were mounted in the mechanical tester between indented aluminum blocks to provide pivot connections at both ends of the quill. The mechanical tester was lowered at a rate of 100 mm/min and the resulting load was recorded. The critical load was determined by recording the load at buckling failure and plotted versus the slenderness ratio of the quill.
Surface Characterizations of the Quills:
The microstructures of the porcupine quills before and after penetration-retraction tests were examined with field-emission scanning electron microscope (FE-SEM, JEOL 5910) following a 30 nm-thick gold sputter coating. Light and fluorescence images were obtained with a Nikon Eclipse TE-2000-U microscope (Nikon Digital Sight DS-QiMC camera, Japan). The length of barbed region of each quill was examined with a dissecting optical microscope (SZ-6 PLUS, Cambridge Instruments) and optical digital images were obtained (IXY Digital, Canon, Japan).
Fabrication of Polyurethane (PU) Quills and Quill-Mimetic Needles:
Poly(dimethylsiloxane) (PDMS) pre-polymer was prepared by mixing the base material and curing agent in a 10:1 ratio. After vigorous mixing and degassing, PDMS molds of natural barbed and barbless quills were prepared by thermal curing at 70° C. overnight. To make quill-mimetic needle, a 25 gauge needle was inserted into the quills at this stage. After curing PDMS, the quill and needle were removed to produce PDMS molds. The polyurethane acrylate, which was mixed with 0.1% photo-initiator, was added into the PDMS molds. To fabricate a quill-mimetic needle, a 25 gauge needle was again inserted into the molds at this stage allowing the polyurethane to bond to the needle. Then, the samples were placed in a vacuum desiccator in the dark to degas the samples for 1-2 hours. The samples were then cured under UV (254 nm) for 90 min and removed from the molds.
Measurement of Penetration Force of PU Quills and Needles with Tissue:
A thick section of muscle tissue was prepared to fit with the available space between the lower grips of mechanical tester. The prepared tissue was placed between the grips without compression. The PU quill was fixed between the upper grips of mechanical tester and the tip adjusted to contact the tissue surface. The quill was penetrated into the muscle tissue to the desired depth, 4 mm, at a rate of 1 mm/sec. For the duration of all experiments, the tissue was kept moist with phosphate buffered saline. Each quill was used for a single measurement. The mean penetration force was measured from n=5 different samples.
The penetration force of quill-mimetic PU needle was examined with artificial skin (SynDaver Labs) that mimics the property of human skin. The fabricated PU needle was connected with a force gauge (Model FGV-5XY, Nidec-Shimpo Corp., Japan), and inserted manually into the skin tissue. The force gauge reads the required penetration force. Each needle was used at least 4 times. The mean penetration force was obtained from n=3 different samples.
Fabrication of Quill-Mimetic Patch with a Hexagonal Array of PU Quills:
The tip (5 mm-length) of natural quills was replicated with a hex nut base and arranged in a hexagonal array with a silicone backing layer using 60 min epoxy glue. Following generation of PDMS molds of barbed or barbless quills, we followed the same procedure descried previously to produce replica molded PU quills. The 7 PU barbed/barbless samples were then assembled with silicone backing layer. The hex base of PU quills allowed for simple alignment of a hexagonal array. To ensure that the array was stable, another backing layer was attached to the assembled sample using 5 min epoxy glue. All PU quills within the patch were perpendicular to the backing layer.
Measurement of Tissue Adhesion Force of Quill-Mimetic Patch:
A modification of ASTM F2258-05 was used to measure the tissue adhesion force of quill-mimetic patches. A flat section of muscle tissue was affixed using cyanoacrylate glue to test fixtures (i.e. pin mount stub with diameter of 25.4 mm). The prepared tissue sample was mounted within the lower grips at the base of the mechanical tester. The quill-mimetic patch was glued onto another fixture, and the prepared patch was fixed between the upper grips of mechanical tester. The tips of quills within the patch was adjusted to contact the tissue surface. The patch was penetrated into the muscle tissue to a depth of 4 mm at a rate of 1 mm/sec and was pulled out at a rate of 0.033 mm/sec to study how the barbs function during removal from tissue. For the duration of all experiments, the tissue was kept moist with phosphate buffered saline. The mean tissue adhesion force was measured from n=5 different samples.
Finite Element Analysis (FEA):
For the finite element simulation of the two-barbed quill penetrating through skin, we employed a two-dimensional approximation of the geometry with an initial mesh shown in
For the finite element simulation of the whole barbless quill penetration into porcine skin, we employed a two-dimensional approximation of the geometry, which is based on a natural quill, with an initial mesh shown in
Comparison Between Fibrous Tissue and Non-Fibrous Gelatin Gel to Examine Mechanical Interlocking of Tissue Fibers to Achieve Tissue Adhesion:
To examine if mechanical interlocking through hooking tissue fibers contributes to the tissue-holding force, we performed penetration-retraction tests using gelatin gel as a model of a non-fibrous tissue. To match the gelatin gel density with that of muscle tissue, we initially determined the fibrous component of muscle tissue to be 0.237±0.006 g/mL by obtaining the dry mass and wet volume (examined with a pycnometer) as previously described. Using the gelatin gel, we performed the tests with a penetrating depth of 4 mm. To prevent damage of the gelatin gel by gripping, the gel was placed on the mechanical tester without compression. This setup was repeated with muscle tissue accordingly to allow comparison of the gelatin and muscle data. As shown in
Results and Discussion
The first step of biomimicry is to understand the mechanism that mediates the biological function. To this end, we have elucidated mechanisms for how the North American porcupine quill optimally interacts with tissue exhibiting both minimal penetration force and maximal pull-out force.
North American porcupine quills have two distinct regions that are demarcated by black (tip) and white (base) colors (
As an additional control for the presence of barbs, we performed penetration-retraction tests using the African porcupine quill that has a smooth surface as described in
To understand the reduction of both penetration force and work of penetration required for the barbed quills, a simplified finite element model was developed (
To penetrate into tissue, the quill must tear tissue at the tip as well as expand the hole circumferentially through stretching and tearing tissue fibers. To analyze the effect of barbs on this process, we looked at the strain distribution in the tissue using finite element analysis (FEA) for both barbless and two-barbed quills (
Another natural system that utilizes stress concentration to ease penetration is the mosquito's proboscis. Compared to the porcupine quill, it has a complicated mechanism utilizing three distinct needles that collectively ease penetration into tissue. The process involves first stretching the surface of an object with smooth labium, and then two jagged-shaped maxillas are inserted into the tissue, resulting in stress concentration between the two maxillas. Finally, the labrum, the blood drawing needle inserts into the object between the two maxillas. This operation of stretching and penetrating is repeated 30,000 times a second, gradually advancing the proboscis further into the tissue. In contrast to the mosquito that utilizes the coordinated movement of 5 structures to penetrate tissue, the porcupine quill is remarkably simple, requiring only its barbed geometry to reduce penetration force. In addition, the porcupine quill is unique in that it is geometrically optimized for both easy penetration and high tissue adhesion.
Further simplified modeling of the quill penetration using FEA revealed that the geometry of the quill tip is optimized for both easy passage through tissue and high resistance for removal (
The presence of barbs contributes 0.33 N of pull-out force (comparing quills with a 4 mm barbed region, quill 2, to barbless quills, quill 1; Δ12=0.33), 0.11 N was attributed to the first 1 mm of the barbed region (quill 3) at the tip (
To examine how barbs generate mechanical adhesion with tissue, we examined quill removal from both fibrous tissue and a non-fibrous control in
The modulus of the quill may be optimized for penetration and adhesion as shown by the enlarged strain energy in the quill (
It is important to consider how the deployment of barbs affects penetration force and tissue adhesion. Our data suggests that the deployment of barbs is not critically important to reduce penetration force, as the penetration force of natural quills and PU barbed quills are similar (
The efficient penetration of the porcupine quill into tissue is facilitated by the mechanical properties of the quill. In addition to Young's modulus, which is described in
In addition to the porcupine quill's sharp tip and wide base with an inner foam core, a stiff tip likely aids in insertion into the flesh of predators by resisting buckling: the amino acid composition of the porcupine quill is dominated by cysteine, glycine, serine, and glutamine/glutamate. Interestingly, the porcupine quill tip contains significantly higher cysteine than the quill base, likely leading to an increased number of disulfide bridges that can confer increased strength through permanent and thermally stable cross-links (
Herein we report how the North American porcupine quill is optimized for polar opposite functions including ease of penetration into tissue while retaining significant tissue adhesion force through the presence of backwards facing deployable barbs. Barbs located near the first transition zone exhibit the most substantial impact on minimizing the force required for penetration by facilitating ease of tissue fracture via the stress concentration at barbs, while barbs at the tip of the quill independently exhibit the greatest impact on tissue holding force. We have shown cooperation between barbs in the 0-2 mm and 2-4 mm regions that appear important to enhance pull-out forces. The tip of the porcupine quill is architecturally and chemically optimized for maximum stiffness to facilitate ease of penetration into tissue while the base's foam structure deems it light-weight, yet able to resist buckling during penetration into tissue.
All literature and similar material cited in this application, including, patents, patent applications, articles, books, treatises, dissertations and web pages, regardless of the format of such literature and similar materials, are expressly incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including defined terms, term usage, described techniques, or the like, this application controls.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described in any way.
While the present disclosures have been described in conjunction with various embodiments and examples, it is not intended that they be limited to such embodiments or examples. On the contrary, the disclosures encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. Accordingly, the descriptions, methods and diagrams of should not be read as limited to the described order of elements unless stated to that effect.
Although this disclosure has described and illustrated certain embodiments, it is to be understood that the disclosure is not restricted to those particular embodiments. Rather, the disclosure includes all embodiments that are functional and/or equivalents of the specific embodiments and features that have been described and illustrated.
The present application claims priority to U.S. provisional patent applications, U.S. Ser. No. 61/433,934, filed Jan. 18, 2011; and U.S. Ser. No. 61/453,521, filed Mar. 16, 2011, the contents of which are incorporated herein by reference.
The work described herein was supported, in part, by grants from the National Institutes of Health (grant GM086433) and the American Heart Association (grant 0835601D), the National Science Foundation (Grant NIRT 0609182) and National Institutes of Health (grant DE013023). The Government of the United States has certain rights in this application.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US12/21778 | 1/18/2012 | WO | 00 | 8/20/2013 |
Number | Date | Country | |
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61433934 | Jan 2011 | US | |
61453521 | Mar 2011 | US |