Porous material with microscale structures

Abstract

To provide a porous material including a microscale structure, a porous material with a microscale structure, a manufacturing method for a drug delivery vehicle, and a related kit, a system and use.SOLUTION: In some embodiments, a porous film material comprises a microscale structure and a porosity of 60 vol% or more. In some embodiments, the microscale structure is a channel having an aspect ratio of 100 or more. In some embodiments, the porous film material is a polymer. In some embodiments, the porous film material is a biocompatible polymer. In some embodiments, the porous film material is polyester.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] This specification provides materials comprising microscale and / or nanoscale structures, particularly, but not limited to, porous materials including microscale structures, porous materials comprising microscale structures, methods of manufacturing drug delivery vehicles, and related kits, systems, and uses.

Background Art

[0002] Microscale structures (e.g., in the range of about 10 μm to 1 mm) and inherently porous materials having a high aspect ratio are difficult to manufacture at scaled-up production volumes and / or with high throughput. There are methods for producing materials comprising structures in the microscale range, but these existing techniques are limited in their utility. For example, conventional machining methods can create various structures over a wide range of scales and materials, but machining methods cannot be applied to create three-dimensional high aspect ratios in the microscale range, and moreover, they do not function well for many polymeric materials. Further, extrusion techniques can create high aspect ratios in a variety of shapes, which is applicable to many polymers. However, extrusion cannot produce materials having a high porosity (%) (e.g., greater than about 30 vol%) while maintaining microscale structures. Furthermore, extrusion techniques have a limited complexity of shape that can be formed. Three-dimensional printing techniques are increasingly moving towards microscale production, but without a doubt, the most common type of three-dimensional printing technique, UV curing technology, is hampered particularly by the "bleed" of structures at the microscale. Thus, three-dimensional printing techniques are limited in both the size of structures that can be achieved and the aspect ratio of the printed materials. Using dip coating methods, microscale structures can be produced from high aspect ratio porous polymers, but this is limited to forming simple shapes in batch steps and is not high throughput. Accordingly, there is a need for new methods of manufacturing porous materials comprising microscale structures. [Overview of the project] [Means for solving the problem]

[0003] Accordingly, this specification provides materials comprising microscale and / or nanoscale structures, in particular, porous materials comprising microscale and / or nanoscale structures, methods for producing porous materials comprising microscale and / or nanoscale structures, and related kits, systems, and uses. In some embodiments, the technique includes the step of embossing a polymer composition to produce a porous material comprising microscale and / or nanoscale structures. In some embodiments, the technique includes the step of embossing a thin film (e.g., a thin polymer film). In some embodiments, the material produced according to the technique provided herein has a homogeneous structure and / or a wall thickness of less than 100 μm (e.g., less than about 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10 μm). In some embodiments, the technique produces a material comprising a first composition and a second composition. In some embodiments, the second composition is a pologen. In some embodiments, embodiments of the embossing technique described herein produce a material comprising a functional composition and / or another composition, i.e., a second composition which is a layer added to the first composition. Conversely, in some embodiments, the second composition is removed from the first composition after the material has been formed, thereby creating voids in the first composition (e.g., in the material comprising the first composition). Thus, in some embodiments, the material produced by the technique described herein has a large hollow lumen volume, a high surface area-to-volume ratio, and / or a high permeability to fluid (e.g., gas and / or liquid) flow. In some embodiments, the material produced by this technique comprises porous scaffold walls, and therefore these materials have a structure of aligned microchannels with a high aspect ratio and excellent flexibility.

[0004] This technology offers advantages over existing technologies (e.g., extrusion and dip coating). For example, in some embodiments, materials manufactured according to the technology provided herein have reproducible and homogeneous microscale structures and / or channels (e.g., in the range of about 1 μm to 1 mm (e.g., about 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 42 0, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 74 This includes structures having sizes of 0, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm). In some embodiments, the materials produced by the techniques described herein include, for example, pores having hierarchical porosity. In some embodiments, the materials produced by the techniques described herein have a high percentage of interconnected porosity in the microchannel walls (e.g., 0 to 80 vol% (e.g., 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 vol%)).

[0005] In some embodiments, the materials produced by the technology described herein have a particle size in the range of approximately 100 nm to 10 μm (for example, approximately 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 190 0, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 470 0, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200, 7300, 7400, 750 It contains pores that are 0, 7600, 7700, 7800, 7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900, or 10000 nm.

[0006] In some embodiments, this technology uses a roll-to-roll processing method (for example, a high-throughput roll-to-roll method). In some embodiments, the material produced by the technique described herein comprises a plurality of compositions. For example, in some embodiments, the material produced by the technique described herein comprises a first composition and a second composition. In some embodiments, the first composition comprises a second composition which is a pologen (e.g., encapsulation). In some embodiments, the first composition comprises a second composition (e.g., encapsulation), and the second composition is later removed to impart voids to the first composition (e.g., providing a material comprising the first composition and voids). The technique is not limited to the compositions used to produce the material. For example, in some embodiments, the method includes the use of polymer compositions (e.g., polycaprolactone (PCL), poly(lactic acid-coglycolic acid) (PLGA), etc.).

[0007] In some embodiments, the materials produced by the techniques described herein are in the range of about 1 μm to 1 mm (for example, about 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310 ,320,330,340,350,360,370,380,390,400,410,420,430,440,450,460,470,480,490,500,510,520,530,540,550,560,570,580,590,600,610,620,630,640,650,660,670,680,690,700,710,720,730,74 It is equipped with a structure of 0, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm, and has a high hollow lumen volume (for example, about 30% to 90% (for example, 30, 31, 32, 33, 34, 35, 3 It has 6, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90%).

[0008] In some embodiments, the materials produced by the techniques described herein are in the range of about 1 μm to 1 mm (for example, about 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 6 A structure comprising 70, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm, and a thin poly Remar film (for example, having a thickness of less than 100 μm (e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or less than 150 μm) is manufactured by embossing.

[0009] In some embodiments, the materials manufactured by the techniques described herein are in the range of about 1 μm to 1 mm (for example, about 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, The present invention comprises a first composition comprising a structure of 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm, and a second composition which is a pharmaceutical and / or therapeutic agent.

[0010] In some embodiments, the steps of forming a structure in the material and imparting functionality to the material are separated. For example, in some embodiments, the material includes a composition (e.g., a polymer film) that is embossed and has chemical modifications on one side.

[0011] This technology is useful in several fields. For example, embodiments of the materials described herein are useful in tissue engineering, such as tissue engineering scaffold technology. In certain embodiments, this technology is useful for nerve repair. In some embodiments, this technology is useful in other engineering fields using materials having similar structure, permeability, and fluid (e.g., gas and / or liquid) flow, such as catalysts and fuel cells. In some embodiments, this technology is suitable for scalable batch sizes. In some embodiments, this technology is useful in the manufacture of medical devices (e.g., tissue scaffolds) to be introduced into patients. In some embodiments, this technology includes the step of matching the size (e.g., length, width, diameter, etc.) of a medical device to be fitted to a particular patient.

[0012] Accordingly, in some embodiments, embodiments of microscale structures and porous film materials having a porosity of 60% vol or more are provided herein. In some embodiments, the microscale structure is a channel having an aspect ratio of 100 or more. In some embodiments, the porous film material is a polymer. In some embodiments, the porous film material is a biocompatible polymer. In some embodiments, the porous film material is a polyester. In some embodiments, the porous film material comprises polycaprolactone and / or poly(lactide co-glycolide). In some embodiments, the porous film material comprises two polymer layers surrounding the microscale structure. In some embodiments, the porous film material comprises a filler. In some embodiments, the filler comprises an inorganic material. In some embodiments, the filler comprises fibers, particles, or nanoparticles. In some embodiments, the filler comprises metals, salts, calcium phosphate, oxides, ceramics, and / or graphite. In some embodiments, the porous film material comprises pologens. In some embodiments, the porous film material has a thickness of 50 to 200 μm. In some embodiments, the microscale structures of the porous film material have dimensions of 1 to 1000 μm.

[0013] Further embodiments provide a method for producing microscale structures and porous film materials having a porosity of 60% vol or more. For example, in some embodiments, the method includes the steps of preparing a polymer film and embossing the polymer film to produce the porous film material having microscale structures. In some embodiments, the polymer film has a porosity of 60% vol or more. In some embodiments, the embossing step includes pressing the polymer film against an embossing block having microscale structures. In some embodiments, the embossing block is heated to 20°C or higher. In some embodiments, the pressing step includes applying a force of at least 0.1 metric tons. In some embodiments, the pressing step includes the use of a hydraulic press. In some embodiments, the step of preparing the polymer film includes molding a composition containing a polymer and a pologen. In some embodiments, the step of preparing the polymer film includes washing the film containing the polymer and a pologen to minimize and / or remove the pologen. In some embodiments, the method further includes a step of washing the microscale structures and the porous film material having a porosity of 60% vol or more to minimize and / or remove pologens. In some embodiments, the method further includes a step of bringing the polymer film into contact with a spacer. In some embodiments, the embossing step further includes pressing the polymer film against the spacer to form the microscale structures in the polymer film. In some embodiments, the polymer film comprises a biocompatible polymer. In some embodiments, the polymer film comprises polyester. In some embodiments, the polymer film comprises polycaprolactone and / or poly(lactide co-glycolide). In some embodiments, the method further includes a step of reacting the surface of the polymer film with a reagent.

[0014] In some embodiments, a method for producing a microscale structure and a porous film material having a porosity of 60% vol or more includes the steps of: preparing a first polymer film and preparing a second polymer film; placing a spacer between the first polymer film and the second polymer film; and embossing the first polymer film and the second polymer film to produce the microscale structure and the porous film material having a porosity of 60% vol or more. In some embodiments, the method further includes the step of removing the spacer from the porous film material to leave voids. In some embodiments, the first polymer film and / or the second polymer film comprises polymers and pologens. In some embodiments, the step of preparing the first polymer film includes the step of washing the first polymer film to minimize and / or remove pologens, and / or the step of preparing the second polymer film includes the step of washing the second polymer film to minimize and / or remove pologens. In some embodiments, a plurality of methods include the step of washing the microscale structure and the porous film material having a porosity of 60% vol or more to minimize and / or remove pologens. In some embodiments, the first polymer film has a porosity of 60% vol or more, and / or the second polymer film has a porosity of 60% vol or more.

[0015] In some embodiments, the present technology provides a microscale structure and a porous film material having a porosity of 60% vol or more, formed by the method described herein. For example, in some embodiments, the present technology provides a microscale structure and a porous film material having a porosity of 60% vol or more, formed by a method comprising the steps of: preparing a polymer film; and embossing the polymer film to produce the porous film material having a microscale structure. In some embodiments, the present technology provides a microscale structure and a porous film material having a porosity of 60% vol or more, formed by a method comprising the steps of: preparing a first polymer film and a second polymer film; placing a spacer between the first polymer film and the second polymer film; and embossing the first polymer film and the second polymer film to produce the microscale structure and the porous film material having a porosity of 60% vol or more.

[0016] In some embodiments, the technology provides a device comprising a microscale structure and a roll-shaped porous film material having a porosity of 60% vol or more. In some embodiments, the device further comprises a sheath around the roll-shaped porous film material. In some embodiments, the device comprises a biocompatible polymer. In some embodiments, the device further comprises cells or tissue. In some embodiments, the device further comprises nerve tissue, and for example, in some embodiments, the device is fixed to the nerve tissue.

[0017] In some embodiments, the device includes a catalytic material. This technology is useful in a variety of fields. For example, in some embodiments, the technology relates to the use of microscale structures and porous film materials having a porosity of 60% vol or more as tissue scaffolds. In some embodiments, the technology relates to the use of microscale structures and porous film materials having a porosity of 60% vol or more as catalysts. In some embodiments, the technology relates to the use of microscale structures and porous film materials having a porosity of 60% vol or more for the purpose of manufacturing biomedical devices to support tissue growth. In some embodiments, the technology relates to the use of microscale structures and porous film materials having a porosity of 60% vol or more for the purpose of treating subjects requiring tissue repair or growth.

[0018] In some embodiments, the technology provides a system for manufacturing microscale structures and porous film materials having a porosity of 60% vol or more. For example, in some embodiments, the system includes a polymer film and an embossing block comprising a microscale structure. In some embodiments, the system further includes one or more spacers. In some embodiments, the system further includes a pologen. In some embodiments, the polymer includes a water-soluble salt pologen. In some embodiments, the polymer includes a filler. In some embodiments, the system further includes a sheath. In some embodiments, the polymer film has a porosity of 60% vol or more. Also, in some embodiments, the system further includes a hydraulic press.

[0019] In some system embodiments for producing microscale structures and porous film materials having a porosity of 60% vol or more, the system includes a polymer-containing composition; and an embossing block comprising the microscale structure. In some embodiments, the system further includes one or more spacers. In some embodiments, the system further includes a pologen. In some embodiments, the system further includes a pologen containing a water-soluble salt. In some embodiments, the system includes a filler.

[0020] Furthermore, some embodiments of this technology relate to devices and materials comprising therapeutic-loaded nanoparticles, for example, intended for use as implantable devices for therapeutic drug delivery. In some embodiments, the technology provides implantable devices that achieve spatial and temporal control of therapeutic drug delivery. Accordingly, in some embodiments, the method provides porous film materials described herein, further comprising therapeutic-loaded nanoparticles (e.g., therapeutic-loaded porous silicon nanoparticles). In some embodiments, the porous film material has a viscosity of 0.01 to 99% wt (e.g., 0.01, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 Therapeutic loaded nanoparticles (88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% wt), 0.01-50% wt (e.g., 0.01, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8, 9, Therapeutic loaded nanoparticles of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50% wt), or 1-30% wt (e.g., 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.Contains therapeutic load nanoparticles of 0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, or 30.0% wt). .

[0021] In related embodiments, several methods include the steps of preparing a polymer film containing therapeutic drug-loaded nanoparticles; and embossing the polymer film to produce the porous film material having microscale structures. In some embodiments, several methods include the step of loading therapeutic drugs into nanoparticles. In some embodiments, the technology provides a method for producing a porous film material having microscale structures and a porosity of 60% vol or more, the method including the steps of preparing a first polymer film and a second polymer film; placing a spacer between the first polymer film and the second polymer film; and embossing the first polymer film and the second polymer film to produce the porous film material having microscale structures and a porosity of 60% vol or more, where the first and / or second polymer film contains therapeutic drug-loaded nanoparticles. In some embodiments, the method includes the step of loading therapeutic drugs into nanoparticles.

[0022] Related embodiments provide a device comprising a microscale structure and a roll-shaped porous film material having a porosity of 60% vol. or more, wherein the porous film material comprises therapeutic agent-loaded nanoparticles. In some embodiments, the device comprises a porous film material including a first region containing a first therapeutic agent and a second region containing a second therapeutic agent. In some embodiments, the device comprises a porous film material including a first region containing a therapeutic agent at a first concentration and a second region containing the therapeutic agent at a second concentration. In some embodiments, the technology relates to the use of the device as a transplantable therapeutic agent delivery device.

[0023] In some embodiments, the technology provides a system for manufacturing a porous film material comprising a microscale structure and having a porosity of 60% vol. or more. In some embodiments, the system comprises a polymer film and an embossing block comprising a microscale structure, wherein the polymer film contains therapeutic agent-loaded nanoparticles. In some embodiments, the technology provides a system for manufacturing a porous film material comprising a microscale structure and having a porosity of 60% vol. or more. In some embodiments, the system comprises a composition comprising a polymer and an embossing block comprising a microscale structure, wherein the composition contains therapeutic agent-loaded nanoparticles.

[0024] Additional embodiments will be apparent to those of ordinary skill in the relevant art based on the teachings contained herein. These and other features, aspects, and advantages of the technology will be better understood with reference to the following drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] [Figure 1] FIG. 1 is a schematic diagram showing elements related to an embodiment of a technique for manufacturing an embossed polymer film. The figure shows a film pressed against an embossing block comprising a linear structure. A backing layer is disposed between the film and the element applying pressure to the film. [Figure 2]A series of micrographs showing cross-sections of PCL films embossed at different temperatures (21 °C, 40 °C, and 60 °C). Panels (a)-(c) show the film during embossing; panels (d)-(f) show the embossed film after rinsing away the porogen; panel (g) shows the embossed film after rinsing away the porogen at a greater magnification to show the porosity of the embossed film. The scale bars in panels (a)-(c) indicate a distance of 300 μm; the scale bars in panels (d)-(f) indicate a distance of 150 μm; the scale bar in panel (g) indicates a distance of 50 μm. [Figure 3] A series of micrographs showing a succession of spacers in an embossed sheet. Panel (a) shows a side view, and panel (b) shows a plan view. Panel (c) shows the embossed film after removing the spacers to form voids. The scale bar in panel (a) indicates a distance of 250 μm; the scale bar in panel (b) indicates a distance of 500 μm; the scale bar in panel (c) indicates a distance of 300 μm. [Figure 4] A series of micrographs showing devices fabricated from porous PCL to have linear microchannels. The device shown in panel (a) was fabricated by a conventional dip-coating method, and the device shown in panel (b) was fabricated by an embodiment of the embossing method described herein. The device shown in panel (a) fabricated by the conventional dip-coating method had a hollow lumen volume of 52 vol%, and the device shown in panel (b) fabricated according to the described technique had a hollow lumen volume of 62 vol%. The scale bar indicates a distance of 250 μm. [Figure 5]Panel (a) shows a schematic diagram of one embodiment of the method described herein. The method represented by Panel (a) includes the steps of assembling a polymer film, a spacer, and an embossing block; embossing the polymer film; removing the embossing film from the embossing block; rolling the embossed polymer film; assembling the rolled polymer film into a sheath; and removing the spacer. Panel (b) is a micrograph showing a side view of an embossing block comprising a microscale structure. Panel (c) is a micrograph showing a cross-section of a device manufactured according to one embodiment of the technique described herein. The device comprises voids to provide a linear microchannel. The scale bars in Panels (b) and (c) indicate a distance of 250 μm. [Figure 6] These are a series of micrographs illustrating embodiments of devices manufactured according to the techniques described herein. These devices have a 300 μm linear structure and a porosity of 70 vol%. The devices shown in panels (a) and (b) are manufactured from polycaprolactone (PCL), and the devices shown in panels (c) and (d) are manufactured from a combination of PCL and poly(lactide-co-glycolide) (PLGA). The micrographs shown in panels (a) and (c) show microscopic cross-sections of the devices. The micrographs shown in panels (b) and (d) show the inherent porosity and the close physical bonding between the film layers. The scale bars in panels (a) and (c) represent a distance of 250 μm. The scale bars in panels (b) and (d) represent a distance of 50 μm. [Figure 7]This panel shows bar graphs of measurements characterizing the mechanical properties of hydration devices manufactured by the dip-coating method (left bars in panels (a) and (b)) and according to embodiments of the technique described herein (center and right bars in panels (a) and (b)). Panel (a) shows compression measurements, and panel (b) shows three-point bending measurements. These data demonstrate that hydration devices manufactured by the embossing method described herein were easily compressed (panel (a)) and bent (panel (b)). Microchannel devices manufactured according to embodiments of the embossing method exhibited compliance (e.g., a measure of how easily the material can be compressed) equal to or better than that of dip-coated devices. A wide variety of properties were observed depending on the material used. The tested devices had a diameter of 1.5 mm and a length of 15 mm. Inserted photographs illustrate the tests performed. [Figure 8] These are a series of micrographs of scaled-up devices. Panel (b) shows an embossed device holding a microscale structure. Panel (a) shows a device manufactured using a traditional manufacturing method (dip coating). The scale bars in panels (a) and (b) represent distances of 500 μm. [Figure 9A] This shows the release of lysozyme and pSiNPs from a polymer film containing lysozyme loads (pSiNPs) as the polymer film degrades under physiological conditions over time. [Figure 9B]This plot shows the dynamics of lysozyme release from polymer films containing 5, 10, and 15 wt% pSiNP nanoparticles. The data plotted in Figure 9B show that PLGA films containing lysozyme-loaded pSiNPs released lysozyme over a 60-day period, and that the amount of lysozyme released depended on the initial weight percentage of pSiNPs in the film. Data plotted as squares were measured for PLGA films containing 5 wt% lysozyme-loaded pSiNPs. Data plotted as triangles were measured for PLGA films containing 10 wt% lysozyme-loaded pSiNPs. Data plotted as × were measured for PLGA films containing 15 wt% lysozyme-loaded pSiNPs. Data plotted as circles were measured for PLGA films containing lysozyme only (not loaded onto pSiNPs). [Figure 9C] This is a reflection scanning electron microscope image of a porous PLGA film containing embedded pSiNPs. The arrows indicate pSiNPs incorporated into the porous matrix of the polymer film. The scale bar indicates a distance of 10 μm. [Figure 10] The images on the left show the roughness of polymer films containing 0 wt% pSiNPs, and the images on the right show the roughness of polymer films containing 15 wt% pSiNPs. Roughness was measured using white light interferometry. [Figure 11] This is a plot of the dynamics of growth factor (BDNF) release from a porous polymer (PLGA) film containing 15 wt% pSiNPs. [Figure 12](a) Bar graph showing the bioactivity of growth factor (BDNF) released from PLGA films containing either 0% or 15 wt% drug-loaded pSiNPs. A significant difference was measured in neurite outgrowth (normalized for cell migration); **P<0.05. (b) Fluorescence micrograph of neurite outgrowth from mouse spinal dorsal root ganglia (DRGs) grown on polymer films without BDNF-loaded pSiNPs. Neurites were visualized using TUJ1 fluorescence staining. Scale bar indicates a distance of 500 μm. (c) Fluorescence micrograph of neurite outgrowth from mouse spinal dorsal root ganglia (DRGs) grown on polymer films containing 15 wt% BDNF-loaded pSiNPs. Neurites were visualized using TUJ1 fluorescence staining. Scale bar indicates a distance of 500 μm. [Figure 13] (a) An image showing a cross-section of an implantable device manufactured from a polyester film containing pSiNP according to the embossing technique described herein. The addition of pSiNP changes the polymer color from white to brown (appearing as a darker gray in Figure 13A). The image of the implantable device shows an embossed scaffold with a microchannel structure. The scale bar indicates a distance of 250 μm. (b) An enlarged image showing a cross-section of an implantable device manufactured from a polyester film containing pSiNP according to the embossing technique described herein. The addition of pSiNP changes the polymer color from white to brown (appearing as a darker gray in Figure 13B). The enlarged image of the implantable device shows microchannels and pSiNP incorporation. [Figure 14] This is a schematic diagram showing a device manufactured according to one embodiment of the embossing technique described herein. The device achieves both temporal and spatial delivery of a therapeutic agent in a single implant. The schematic diagram shows regions within the device containing various types of therapeutic agents (shown in varying shades of gray), whose release is controlled by one or more of the polymer layer thickness, polymer degradation kinetics, pSiNP quantity, pSiNP size, pSiNP pore diameter, and porosity, or any combination thereof. [Figure 15A]This is an image of a device manufactured according to one embodiment of the embossing technique described. The embossed implantable device was manufactured from a polyester film containing pSiNPs. These films were manufactured to have a 300 μm linear structure and a porosity of 70 vol%. The device was designed and manufactured to include separate regions containing therapeutic load pSiNPs (dark gray) and regions not containing therapeutic load pSiNPs (light gray). The image is a macroscopic image of the device, revealing three distinct regions of the device: two regions containing therapeutic load pSiNPs at the ends and one region in the center that does not contain pSiNPs. The scale bar indicates a distance of 1 mm. [Figure 15B] This image shows the boundary between a region containing a therapeutic load pSiNP (left, dark gray area) and a region not containing a therapeutic load pSiNP (right, light gray area) in a device manufactured according to the technology described herein. The device includes a coherent structure and a physical bond between two adjacent film layers that form the two regions. The scale bar indicates a distance of 250 μm. [Figure 16] These are in vivo results from the embossed multi-channel scaffold (Neurospan Bridge) of this disclosure, transplanted into a 1 cm long sciatic nerve defect in rats, compared to sural nerve autografts or open-tube implants. [Modes for carrying out the invention]

[0026] It should be understood that the figures are not necessarily drawn to a consistent scale, and the objects in the figures are not necessarily drawn to a consistent scale relative to each other. The figures are depictions intended to provide clarity and understanding of the various embodiments of the apparatus, systems, and methods disclosed herein. Where possible, the same reference numerals are used throughout the drawings to refer to the same or similar parts. Furthermore, it should be understood that the drawings are not intended to limit the scope of this teaching.

[0027] This specification provides materials comprising microscale and / or nanoscale structures, in particular, porous materials comprising microscale structures, methods for producing porous materials comprising microscale structures, and related kits, systems, and uses. In the detailed description of various embodiments, several specific details are provided for illustrative purposes to enable a full understanding of the disclosed embodiments. Those skilled in the art will understand that these various embodiments may be carried out with or without these specific details. In other examples, structures and devices are shown in the form of block diagrams. Furthermore, those skilled in the art will readily understand that the specific order in which multiple methods are shown and carried out is illustrative, and that these orders may vary but may still be included in the spirit and scope of the various embodiments.

[0028] All documents and similar materials cited herein, including but not limited to patents, patent applications, papers, books, academic papers, and internet web pages, are expressly incorporated herein by reference in their entirety for all purposes. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the field to which the various embodiments described herein belong. If the definition of a term in an incorporated reference appears to differ from the definition given herein, the definition given herein shall prevail. Section headings used herein are for systematization purposes only and should not be construed as limiting the subject matter described herein in any way. definition To facilitate understanding of this technology, several terms and phrases are defined below. Additional definitions will be provided throughout the detailed explanation.

[0029] Throughout the specification and claims, the following terms have their obviously related meanings unless the context explicitly requires otherwise. The phrase “in one embodiment” as used herein may refer to the same embodiment, but not necessarily the same embodiment. Furthermore, the phrase “in another embodiment” as used herein may refer to a different embodiment, but not necessarily a different embodiment. Thus, various embodiments of the present invention, as described below, can be readily combined without departing from the scope and spirit of the invention.

[0030] In addition, as used herein, the term “or” is an inclusive “or” operator and is equivalent to the term “and / or” unless the context requires a different interpretation. The term “based on” is not exclusive and may be based on another element not mentioned unless the context requires a different interpretation. Furthermore, throughout this specification, the meanings of “a,” “an,” and “the” include multiple demonstratives. The meaning of “in” includes “in” and “on.”

[0031] As used herein, the terms “about,” “approximately,” “substantially,” and “significantly” are to be understood by those skilled in the art and may vary to some extent depending on the context in which they are used. When these terms are used in a way that is not clear to those skilled in the art, considering the context in which they are used, “about” and “approximately” mean an increase or decrease of 10% or less of a given term, while “substantially” and “significantly” mean an increase or decrease of more than 10% of a given term.

[0032] As used herein, a range disclosure includes all values, as well as disclosures of further subdivided ranges within the entire range, including endpoints and subranges given for these ranges. As used herein, the suffix "-free" refers to an embodiment of a technique that omits a base root feature of the word to which "-free" is attached. That is, as used herein, the term "X-free" means "without X," where X is the technical feature that is omitted in the "X-free" technique. For example, a "calcium-free" composition does not contain calcium, and a "mix-free" method does not include a mixing step, etc.

[0033] When we say that an element, composition, material, or layer is "on top of," "fitted with," "connected to," or "joined with" another element, composition, material, or layer, it means that it is directly on top of, fitted with, connected to, or joined to the other element, composition, material, or layer, or that there may be an intervening element or layer. In contrast, when we say that an element, composition, material, or layer is "directly on top of," "directly fitted with," "directly connected to," or "directly joined with" another element, composition, material, or layer, there is no intervening element, composition, material, or layer. Other words used to express relationships between elements, compositions, materials, or layers should be interpreted similarly (e.g., "between" vs. "directly between," "adjacent" vs. "directly adjacent," etc.).

[0034] Terms such as “First,” “Second,” and “Third” are used herein to describe various steps, elements, compositions, components, areas, layers, and / or sections, but these steps, elements, compositions, components, areas, layers, and / or sections should not be limited to these terms unless otherwise indicated. These terms are used to distinguish one step, element, composition, component, area, layer, and / or section from another step, element, composition, component, area, layer, and / or section. Terms such as “First,” “Second,” and other numerical terms, when used herein, do not mean a single sequence or order unless otherwise explicitly stated in the context. Accordingly, a first step, element, composition, component, area, layer, or section described herein may be called a second step, element, composition, component, area, layer, or section without departing from the art.

[0035] Spatial or temporally relative terms such as "front," "back," "inside," "outside," "down," "below," "upper," and "upper" may be used herein to facilitate descriptions of the relationship between one element or feature and another element or feature. Spatial or temporally relative terms may be intended to include different directions of the device or system being used or operated, other than the direction depicted in the figures.

[0036] As used herein, the term “channel” refers to a structure that includes a longitudinal axis and has a hollow lumen. In some embodiments, the channel has a longitudinal axis that is longer than other dimensions of the channel (e.g., diameter or width). In some embodiments, the channel has more than 100 (e.g., 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or more than 1000); more than 1000 (e.g., 1000; 1500; 2000; 2500; 3000; 3500; 4000; 4500; 5000; 5500; 6000; 6500; 7000; 7500; 8000) Having an aspect ratio of ;8500;9000;9500; or greater than 10,000); or greater than 10,000 (for example, 10,000;15,000;20,000;25,000;30,000;35,000;40,000;45,000;50,000;55,000;60,000;65,000;70,000;75,000;80,000;85,000;90,000;95,000; or greater than 100,000).

[0037] As used herein, the term “aspect ratio” refers to the length of the longest axis of a structure or feature (e.g., a channel) divided by the diameter of the structure or feature (e.g., a channel). In some embodiments, the aspect ratio of a structure or feature (e.g., a channel) is greater than 100 (e.g., 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or greater than 1000). In some embodiments, the aspect ratio of a structure or feature (e.g., a channel) is greater than 1000 (e.g., 1000; 1500; 2000; 2500; 3000; 3500; 4000; 4500; 5000; 5500; 6000; 6500; 7000; 7500; 8000; 8500; 9000; 9500; or greater than 10,000). In some embodiments, the aspect ratio of a structure or feature (e.g., a channel) exceeds 10,000 (e.g., 10,000; 15,000; 20,000; 25,000; 30,000; 35,000; 40,000; 45,000; 50,000; 55,000; 60,000; 65,000; 70,000; 75,000; 80,000; 85,000; 90,000; 95,000; or greater than 100,000).

[0038] As used herein, the terms "micro" (for example, "micro-sized," "microscale," "microstructure," or "micrometer-sized") refer to less than approximately 1000 micrometers (μm) (for example, approximately 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400) ,410,420,430,440,450,460,470,480,490,500,510,520,530,540,550,560,570,580,590,600,610,620,630,640,650,660,670,680,690,700,710,720, This refers to sizes of 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or less than 1000 μm.

[0039] As used herein, the terms "nano" (for example, "nano-sized," "nanoscale," or "nanometer-sized") mean less than approximately 1000 nanometers (nm) (for example, approximately 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 4) This refers to sizes of 30, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or less than 1000 nm.

[0040] As used herein, the term "microchannel" refers to a channel having at least one spatial dimension less than approximately 1000 μm. As used herein, the term “biocompatible” means that a material is capable of contact with cells or tissues (e.g., in vitro or in vivo) or is capable of use in animals (e.g., mammals) and has acceptable toxicity for contact with and / or beneficial use of such cells, tissues, and / or animals. For example, in some embodiments, a biocompatible material is a material suitable for transplantation into a subject without causing adverse consequences and / or substantial toxicity or acute or chronic inflammatory reactions and / or acute rejection of the material by the immune system (e.g., via the subject's T-cell response). The term “biocompatible” is relative, and even materials that are highly compatible with living tissues should be expected to have some degree of inflammatory and / or immune response. However, non-biocompatible materials are typically highly toxic, inflammatory, and / or severely rejected by the immune system. For example, a non-biocompatible material implanted in a subject may trigger such a severe immune response that the immune system cannot adequately control its rejection of the material, and in some cases, this can also occur with the use of immunosuppressants, potentially requiring the removal of the material from the subject. In certain embodiments, biocompatible materials are approved for human use by the appropriate regulatory body, such as the U.S. Food and Drug Administration (FDA), the European Commission (EC) / European Medicines Agency (EMEA), or the Health Products and Food Branch (HPFB) of Canada. In some embodiments, biocompatible materials are biodegradable. For example, in some embodiments, biocompatible materials are biocompatible polymers.As used herein, the term “biocompatible polymer” means any artificial or natural biodegradable or non-biodegradable polymer, for example, but not limited to, collagen, gelatin, chitosan, carrageenan, alginates, hyaluronic acid, dextran, poly(lactic acid), poly(glycolic acid) (PGA), poly(coglycolic acid lactate) (PLGA), poly(ε-caprolactone), poly(anhydride), polyorthoesters, polyvinyl alcohol, poly(ethylene glycol), polyurethane, poly(acrylic acid), poly(N-isopropylacrylamide), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) copolymer (Pluronic®), copolymers thereof, or mixtures thereof.

[0041] As used herein, the term “porosity” refers to a measurement of the void space in a material, expressed as the ratio of the volume of total void space to the total volume of the material (e.g., the sum of total voids and total non-void spaces). Porosity is expressed as a decimal (fraction) between 0 and 1 or as an equivalent ratio indicated as “vol%”. In some embodiments, the non-void volume is occupied by solid material, and the void volume is occupied by fluid (e.g., gas and / or liquid). For example, as used herein, the term “hollow lumen volume” refers to the volume within the material (e.g., the scaffold) not occupied by scaffold walls.

[0042] As used herein, the terms “porous tissue scaffold” and “porous scaffold” are interchangeable and refer to a three-dimensional molecular matrix of biocompatible polymers for the adhesion and growth of tissue cells.

[0043] As used herein, the term “in vitro culture system” refers to a system designed for growing cells, tissues, organs, or parts of organs ex vivo. As used herein, the term “biocompatible product” refers to a material used for the treatment of a medical condition or for cosmetic correction, in which case the material is placed in or within a human or animal, and does not cause a harmful immune response. In some embodiments, biocompatible products include materials that decompose over time and / or are absorbed by the body. In some embodiments, biocompatible materials are bandages, powders, sponges, hemostatic agents, sutures, implants, injectable particles, microspheres, microcarriers, gels, or putties.

[0044] As used herein, the terms “pluripotent,” “pluripotency,” “pluripotent cells,” and equivalent expressions refer to cells capable of both proliferation and self-regeneration in cell cultures, as well as differentiation into various cell populations, including those exhibiting multipotency. For example, pluripotent embryonic stem (ES) cells can give rise to each of the three embryonic cell lineages. Pluripotency can be demonstrated by providing evidence of stable developmental ability, such as forming derivatives of all three germ layers from single-cell offspring and generating teratomas after injection into immunosuppressed mice. Other signs of pluripotency include the expression of genes known to be expressed in pluripotent cells and having a specific morphology. This technique is not limited to the use of any particular pluripotent cells and includes pluripotent cells obtained by any method well known to those skilled in the art. For example, in some embodiments, "pluripotent cells" may include stem cells, induced pluripotent stem cells (iPS cells) (e.g., human induced pluripotent stem cells (hiPSCs), human embryonic stem cells (hESCs), pathogenic cells, etc.).

[0045] As used herein, the term “pluripotent” refers to the ability of a cell to develop into any type of cell, including extraembryonic tissue (e.g., placenta), and to give rise to an entire organism (e.g., mouse or human).

[0046] As used herein, the term “calender” refers to a device used, for example, to stretch, coat, or thin a material by passing it between calender rolls under high temperature and pressure.

[0047] As used herein, the terms “therapeutic” or “therapeutic” refer to a compound that, when administered to a mammal in a therapeutically effective dose, provides a therapeutic benefit to the mammal. Therapeutic is also referred to herein as a drug. Those skilled in the art will understand that the term “therapeutic” is not limited to drugs approved by regulatory authorities. Therapeutic may be a peptide, protein, antibody, antibody fragment, or small molecule (e.g., a drug).

[0048] Embodiments of this technology provide materials useful for tissue repair (e.g., nerve repair). In some embodiments, the materials provide support for tissue repair and a high-hollow lumen (e.g., a volume available for tissue (e.g., nerve) regeneration). In some embodiments, a device comprising the material described herein is placed at the site of injury to achieve tissue regeneration. Accordingly, in some embodiments, a device comprising the material described herein is sufficiently flexible to allow placement of the device comprising the material at the site of injury without twisting when the object moves.

[0049] In some embodiments, the materials provided herein include synthetic polymers that maintain their shape without undergoing swelling over time that reduces the hollow lumen volume (e.g., as seen in natural polymers or hydrogels) (for example, Pawelec et al., (2018), "Microstructure and In Vivo Characterization of Multichannel Neural Induction Scaffolds," as incorporated herein). See "Viovary characterization of multi-channel nerve guidance scaffolds" Biomedical Materials 13:p.044104; Shahriari et al., (2017) "Hierarchically ordered porous and high-volume polycaprolactone microchannel scaffolds enhanced axon growth in transected spinal cords" Tissue Engineering Part A 23(9~10):415~25). In some embodiments, the synthetic polymer is harder than the hydrogel (and, in some embodiments, native nerve tissue), possesses high strength and rigidity that reduces wall thickness, and therefore provides a higher hollow lumen volume (see, for example, Chen et al., (2011), "Comparison of polymer scaffolds in rat spinal cord: A step toward quantitative assessment of combinatorial approaches to spinal cord repair," Biomaterials 32:8077-86, incorporated herein). The technique is not limited to the polymers used in the manufacture of the materials described herein. Embodiments of the technique include a wide variety of polymers that result in appropriate mechanical and degrading behavior. In some embodiments, the technique includes the use of FDA-approved polymers (e.g., useful in medical implants). In some specific embodiments, the technique provides materials or devices comprising poly(lactidoglycolide) (PLGA) and / or poly(caprolactone) (PCL).The chemical and glass transition temperatures of these two polymers provide specific mechanical properties that are advantageous to the embodiments of materials and devices described herein (as incorporated herein, Chen et al., (2011) "Comparison of polymer scaffolds in rat spinal cord: A step toward quantitative assessment of combinatorial approaches to spinal cord repair," Biomaterials 32:8077-86). Furthermore, the technology is not limited to the degradation rates (e.g., in vivo) of the materials and devices described herein. For example, embodiments provide materials containing PLGA (e.g., degrading over a period of several weeks to several months depending on the ratio of lactide to glycoside), and some embodiments provide materials containing PCL (which is resistant to degradation (e.g., maintaining its body for 24-36 months)). For example, the following are referenced herein: de Ruiter et al., (2008) "Methods for in vitro characterization of multichannel nerve tubes," Journal of Biomedical Materials Research, Part A 84A:643-51; Woodruff and Hutmacher, (2010) "The return of polycaprolactone, a forgotten polymer in the 21st century." of a forgotten polymer-polycaprolactone (See Progress in Polymer Science 35:1217-56).

[0050] Embodiments of this technology provide a device, for example, a multi-channel scaffold. In some embodiments, the device includes linear microchannels within a larger conduit. For example, the following are referenced herein: Yao et al., (2010) "Controlling dispersion of axonal regeneration using a multichannel collagen nerve conduit," Biomaterials 31:5789-97; Pawelec et al., (2018) "Microstructure and in vivo characterization of multi-channel nerve guidance scaffolds," Biomedical Materials 13:p.044104; Shahriari, (2017) "Peripheral nerve growth within a hydrogel microchannel scaffold supported by a kink-resistant conduit," Journal of Biomedical Materials Research. Materials Research) Part A 105(12):3392-99; Wang et al. (2017) "Design and Optimization of Biodegradable Porous Zein Conduits Using Microtubules as Guides for Rat Sciatic Nerve Repair" See "and optimization of a biodegradable porous zein conduit using microtubes as a guide for rat sciatic nerve defect repair" (Biomaterials 131:145-59). In some embodiments, linear microchannels physically induce recurrent generation (e.g., in some embodiments, regeneration mimics the microtubule configuration of the native neural tube), reducing misalignment and increasing functional recovery. Furthermore, in some embodiments, the technology provides materials and devices having monodisperse microchannel diameters, which are useful for manufacturing densely packed materials and devices, thereby resulting in high hollow lumen volume.

[0051] In some embodiments, the technology provides a multichannel scaffold comprising two elements, for example, a multichannel array and a conduit. In some embodiments, the conduit provides an anastomosis (e.g., between a nerve stump and a microchannel) when placed, for example, in tissue or a patient. Thus, in some embodiments, the technology provides a biocompatible, flexible, and / or sutureable conduit. For example, in some embodiments, the technology provides a conduit (e.g., a biocompatible, flexible, and / or sutureable conduit) comprising porous PCL. In some embodiments, the technology provides a hierarchical multichannel array (e.g., comprising two levels of structure (e.g., microstructure of the scaffold wall and channel configuration)). The technology provides a multichannel array that increases and / or maximizes the hollow lumen volume (e.g., by minimizing and / or reducing the microchannel wall thickness) while conferring appropriate structural support to the material or device, despite minimizing and / or reducing the microwall channel thickness.

[0052] In some embodiments, porosity is introduced into the microchannel walls. In some embodiments, increased porosity increases permeability, thereby achieving greater nutrient diffusion throughout the device (for example, for axonal regeneration in some embodiments). However, increasing porosity also reduces the mechanical stiffness and strength of the channel walls. Furthermore, the number and size of the channels also affect the maintenance of the scaffold's mechanical integrity and hollow lumen volume.

[0053] In some embodiments, the number of microchannels affects the scaffold mechanics of scaffolds containing synthetic and / or natural polymers. During the fabrication steps of embodiments of the techniques provided herein, experiments were conducted to test the mechanical properties of materials and devices manufactured according to the techniques described herein. For example, materials and devices were tested with lateral compression and three-point bending assays to simulate several typical loading conditions after in vivo implantation.

[0054] As described herein, embodiments of the technology provided herein relate to an embossing method for forming microstructures (e.g., 1 to 1000 μm) in a polymer or composite film while maintaining the inherent porosity (e.g., 0 to 90 vol%) of the starting film. In some embodiments, the method includes the steps of preparing a pre-formed film, a mold (for example, heated to about 20-200°C (for example, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200°C)), and an optionally flexible backing layer (for example, foam); and embossing the pre-formed film by applying pressure (for example, using hydraulics).

[0055] In some embodiments, films, materials, scaffolds, and devices described herein (e.g., manufactured by the methods described herein) are provided, further comprising nanoparticles loaded with a therapeutic agent. Compositions, materials, and devices In some embodiments, this technology is used for particles from 1 to 1000 μm (e.g., 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 5 The present invention provides materials containing structures in the range of 10, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm. In some embodiments, the technology provides materials including structures in the range of 5 to 500 μm (e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 μm). In some embodiments, the technology provides a material comprising structures in the range of 10 to 400 μm (e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 μm). In some embodiments, the technology provides a material comprising structures in the range of 1 to 1000 μm, as well as a material comprising therapeutically loaded nanoparticles (e.g., pSiNPs). See, for example, the experimental examples described herein.

[0056] In some embodiments, this technology uses 0.01 to 90 vol% (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 3 The present invention provides a material having a porosity of 5, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 vol%) (for example, manufactured from a porous film). In some embodiments, this technology is used in concentrations of 0.1 to 80 vol% (e.g., 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 3 The present invention provides a material having a porosity of 8, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 vol%) (for example, manufactured from a porous film).In some embodiments, this technology is 1-75 vol% (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, The present invention provides materials having a porosity of 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 vol%) (e.g., manufactured from a porous film). In some embodiments, the present invention provides materials having a porosity of 0.01 to 90 vol% and containing therapeutically loaded nanoparticles (e.g., pSiNPs) (e.g., manufactured from a porous film). See, for example, the experimental examples described herein.

[0057] In some embodiments, the technology provides a material manufactured from a first composition (e.g., a polymer) and a second composition (e.g., an inorganic component). In some embodiments, the technology provides a material comprising a first composition (e.g., a polymer) and a second composition (e.g., an inorganic component). In some embodiments, the technology provides a material comprising a first composition (e.g., a polymer) and 0.01 to 70% (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) in the material. The present invention provides a material comprising a second composition (e.g., an inorganic component) present in weight % of 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70% wt. In some embodiments, the technology comprises a first composition (e.g., a polymer) and 0.1 to 60% (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, The present invention provides a material comprising a second composition (e.g., an inorganic component) present in weight percent of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% wt).In some embodiments, the technology provides a material comprising a first composition (e.g., a polymer) and a second composition (e.g., an inorganic component) present in the material at a weight percentage of 1 to 50% (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50% wt). In some embodiments, the technology provides a material comprising a first composition (e.g., a polymer), a second composition (e.g., an inorganic component) present in the material at a weight percentage of 0.01 to 70, and nanoparticles loaded with a therapeutic agent (e.g., pSiNPs). See, for example, the experimental examples described herein.

[0058] This technology is not limited to polymers used to manufacture porous films. In some embodiments, the porous film includes polyesters (e.g., polycaprolactone (PCL), poly(lactidocoglycolide) (PLGA), and combinations thereof). In some embodiments, the porous film includes polymers that are polyesters (e.g., polycaprolactone (PCL), poly(lactidocoglycolide) (PLGA), poly(lactic acid), poly(glycolic acid), poly(butylene succinate), poly(ethylene terephthalate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(butylene terephthalate), poly(hydroxybutyrate), poly(ethylene adipate), poly(hydroxyalkanoate), and / or poly(ethylene naphthalate)), polyamides, polypyrroles, polyethylene, polyethylene glycol, chitosan, poly(vinyl alcohol) (PVA), or any combination thereof. In some embodiments, the polymer is selected based on characteristics related to its behavior in vivo. For example, in some embodiments, polymers are selected based on biocompatibility. In some embodiments, polymers are selected based on degradation and / or stability properties (e.g., in vivo degradation rate).

[0059] In some embodiments, the technology provides materials comprising polymers. In some embodiments, the technology provides scaffold structures comprising microchannels formed from biocompatible and / or biodegradable polymers. In some embodiments, the technology provides scaffold structures comprising microchannels formed from biocompatible and / or biodegradable polymers and comprising therapeutically loaded nanoparticles (e.g., pSiNPs). In some embodiments, the biocompatible and / or biodegradable polymer is a polyester polymer. The technology is not limited to biodegradable polymers used to produce the materials described herein. For example, in some embodiments, the biodegradable polymer is polylactic acid, polycaprolactone (PCL), polyglycolic acid, poly(lactide-co-glycolide) polymer (PLGA), or copolymers, derivatives, and / or mixtures thereof. In some embodiments, the biocompatible and / or biodegradable material is polycaprolactone (PCL), poly(lactide-co-glycolide) (PLGA), or a combination thereof. In some embodiments, the polymer is modified by chemical and / or physical methods (e.g., crosslinking, heat treatment, photochemical treatment, and / or changes in the chemical or physical environment). In some embodiments, a polymer film is used. The modification is performed at a limited location (e.g., on a surface, on a selected area, or within one or more microchannels). In some embodiments, the technique allows for control over the degree of modification of a polymer (e.g., a polymer film) to produce materials with diverse characteristics and / or material reactions (e.g., by controlling the time of the modification reaction, or by controlling the ratio of the modified reactant to the polymer (e.g., a polymer film)). In some embodiments, polymer modification and / or treatment results in a variety of degradation or release kinetics. In some embodiments, surface modification, e.g., differences in hydrophilicity, charge, or other physical properties, promotes cell adhesion.

[0060] In some embodiments, the polymer film is treated with a bioactive agent or active ingredient (e.g., a drug or other bioactive agent). In some embodiments, the polymer film is designed to have specific surface properties (e.g., surface roughness). In some embodiments, the polymer is conjugated with functionality such as inducing cell proliferation, promoting cell or tissue adhesion, and / or facilitating the release of a bioactive agent into the surrounding environment, with a surface including exposed portions.

[0061] As described herein and illustrated in the examples, in some embodiments, the polymer film and / or the material comprising the polymer film comprises nanoparticles. In some embodiments, the nanoparticles are silicon nanoparticles (e.g., porous silicon nanoparticles (pSiNPs)). In some embodiments, the nanoparticles comprise therapeutic agents (e.g., drugs (e.g., small molecules), peptides, proteins (e.g., enzymes), nucleic acids (e.g., siRNA, antisense nucleic acids, CRISPR-guided RNA), lipids, carbohydrates, etc.). In some embodiments, the technology provides a device comprising a polymer film containing therapeutic agent-loaded nanoparticles (e.g., an implantable device).

[0062] In some embodiments, the material includes a biodegradable material that decomposes, for example, by physical decay, corrosion, destruction, and / or dissolution. In some embodiments, the biodegradable material or its decomposition products are reabsorbed by living organisms. In some embodiments, the decomposition of the biodegradable material releases therapeutic agents (e.g., from nanoparticles).

[0063] In some embodiments, the materials provided herein include biodegradable polymer materials that decompose or corrode when exposed to solvents containing high concentrations of water, such as blood, serum, growth or culture media, body fluids, saliva, etc. Therefore, after implantation, the material decomposes or disintegrates into small pieces, releasing therapeutic agents in some embodiments. For structural scaffold membranes, the degradation rate (e.g., the rate at which the material or its degradation products are reabsorbed by surrounding cells) may be designed so that sufficient cell proliferation occurs before structural degradation or disintegration by the reabsorption process. In some embodiments, the dissolution rate is designed and / or selected to deliver therapeutic agents at a specific delivery rate to cells, tissues, and / or organs.

[0064] In some embodiments, the material is designed to have a degradation time (e.g., the time it takes for more than 95, 96, 97, 98, 99, 99.5, 99.9% of the material to degrade) or degradation rate (e.g., the mass of degraded material produced per unit of time) that matches the amount of time required for appropriate tissue (e.g., nerve tissue) regrowth from the scaffold to the target tissue. Depending on the time required for the recovery and regeneration of the target tissue, as a non-limiting example, the degradation time may range from approximately 1 month to approximately 3 years (e.g., 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5). 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5 , 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, or 36.0 months), approximately 1 month or more to approximately 1 year or less (for example, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4. The incubation period may be 5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, or 12.0 months), or approximately 1 month to approximately 6 months (e.g., 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0 months). Thus, the material (e.g., a scaffold containing the material) supports and promotes cell growth, cell proliferation, cell differentiation, cell repair, and / or three-dimensional cell regeneration (e.g., for nerve tissue proliferation).

[0065] In some embodiments, the technology provides a material comprising a composite film containing, for example, a polymer matrix and a filler. In some embodiments, the filler includes an inorganic component. In some embodiments, the filler is, for example, in the form of fibers, particles (e.g., porous or non-porous particles), and / or nanoparticles. In some embodiments, the technology provides a material comprising a first composition (e.g., a polymer) and a second composition (e.g., a filler (e.g., an inorganic component)). In some embodiments, the material comprises a filler (e.g., an inorganic component), which is, for example, a metal (titanium, tantalum, aluminum, iron, platinum, gold, silver, and / or palladium), a salt (e.g., NaCl and / or CaCO3), calcium phosphate, an oxide (e.g., zirconia, alumina, titania, and / or silica), a ceramic, and / or graphite (e.g., graphite nanotubes and / or graphene). In some embodiments, the technology provides a material comprising a composite film containing, for example, a polymer matrix, a filler, and nanoparticles loaded with a therapeutic agent.

[0066] In some embodiments, the technology provides a material comprising spacers or pologens (e.g., gels, aerogels, particles, sponges, foams, rods or multiple rods, fibers, textiles, aqueous dissolved substances (e.g., salts), and / or meshes). In some embodiments, the material is manufactured to include spacers or pologens, and then the spacers or pologens are removed, minimized, and / or eliminated from the material (e.g., to form holes, voids, and / or structures in the material). Accordingly, embodiments provide a method for removing spacers or pologens after embossing to form open voids in the material. In some embodiments, the technology provides a material comprising spacers or pologens (e.g., gels, aerogels, particles, sponges, foams, rods or multiple rods, fibers, textiles, aqueous dissolved substances (e.g., salts), and / or meshes) and nanoparticles loaded with a therapeutic agent.

[0067] The embodiments include the use of a mold (e.g., an embossing block) for embossing a polymer film. In some embodiments, the mold is heated. In some embodiments, the mold includes a heat and pressure-resistant material used for embossing a polymer film. In some embodiments, the mold is a material that can form surface structures in the mold material by machining, etching, etc., for the purpose of introducing structures into the polymer to be embossed. In some embodiments, the mold includes a metal (e.g., aluminum). In some embodiments, the mold includes a polymer (e.g., acetal).

[0068] In some embodiments, the technology includes an embossing method that can be scaled for high-throughput manufacturing and / or roll-to-roll processes. In some embodiments, the technology provides an embossing process in which the inherent porosity of the starting film is (e.g., 0.01 to 90 vol%) (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 2) While maintaining 8, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 vol%), spacers or gaps (e.g., 1-1000 μm (example) For example, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 5 A material having a size of 80, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm is incorporated and / or encapsulated between two layers of polymer or composite film.Accordingly, in some embodiments, the technology includes the steps of preparing a first film, a second film, a spacer material, a mold (e.g., heated to about 20-200°C (e.g., 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200°C)), and optionally a flexible backing layer (e.g., foam); and applying pressure to emboss the first and / or second pre-formed films (e.g., using hydraulic pressure). In some embodiments, the spacer material is fitted between the structures of the patterned mold. In some embodiments, the spacer material is physically trapped between the first and second films after embossing. In some embodiments, the spacer material includes, for example, gels, aerogels, particles, sponges, foams, rods or multiple rods, fibers, textiles, aqueous dissolved substances (e.g., salts), and / or meshes. In some embodiments, the material is manufactured to include the spacer material, and then the spacer material is removed, minimized, and / or eliminated from the material (e.g., to form holes, voids, and / or structures in the material). Thus, several embodiments provide a method for removing the spacer material after embossing to form open voids in the material. In some embodiments, the first and / or second films contain nanoparticles loaded with a therapeutic agent.

[0069] In some embodiments, the technology provides materials and / or devices containing materials. In some embodiments, the technology provides devices manufactured from polymers or composite materials. In some embodiments, the technology provides embossed structures (e.g., 1 to 1000 μm (e.g., 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, (Having a size of 970, 980, 990, or 1000 μm) and 0.01 to 90 vol% (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 2 The present invention provides a device having an intrinsic porosity of 9, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 vol%).

[0070] In some embodiments, the technology provides a material containing therapeutic drug-loaded nanoparticles and / or a device comprising a material containing therapeutic drug-loaded nanoparticles. In some embodiments, the technology provides a device manufactured from a polymer or composite material containing therapeutic drug-loaded nanoparticles. In some embodiments, this technology applies to embossed structures (e.g., 1 to 1000 μm (e.g., 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 9 (Having a size of 90 or 1000 μm) and 0.01 to 90 vol% (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, The present invention provides a device having an intrinsic porosity of 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 vol%) and containing nanoparticles loaded with a therapeutic agent.

[0071] In some embodiments, the technology provides a material manufactured from an embossed sheet containing a spacer material. In some embodiments, the technology provides a material manufactured by the steps of embossing a polymer sheet containing a spacer material to produce an embossed sheet, and rolling the embossed sheet into a cylinder. In some embodiments, the technology includes the step of joining the cylinder at the edge using, for example, heat, pressure, chemicals, or a combination thereof (for example, temporarily fixing the end of a roll of embossed sheets so that the roll of embossed sheets does not unfold and so that the roll of embossed sheets can be inserted into a sheath).

[0072] In some embodiments, the technology provides a material manufactured from an embossed sheet containing therapeutic drug-loaded nanoparticles and a spacer material. In some embodiments, the technology provides a material comprising the steps of manufacturing an embossed sheet containing therapeutic drug-loaded nanoparticles by embossing a polymer sheet containing therapeutic drug-loaded nanoparticles and a spacer material, and rolling the embossed sheet into a cylinder. In some embodiments, the technology includes the step of joining the cylinder at its edges using, for example, heat, pressure, chemicals, or a combination thereof (for example, temporarily fixing the end of a roll of embossed sheet so that the roll of embossed sheet does not unfold and so that the roll of embossed sheet can be inserted into a sheath).

[0073] In some embodiments, the spacer is a wire (e.g., a wire mandrel (e.g., a round object for shaping a form rod and / or material that is placed inside the workpiece to be formed)). In some embodiments, the spacer (e.g., wire) is removed to form a void. In some embodiments, relating to the manufacture of a material useful as a biomedical scaffold (e.g., for tissue growth and / or regeneration), the material comprises structures (e.g., channels, holes, ridges, grooves, depressions, ridges, etc.) that are linear structures.

[0074] In some embodiments, the technology provides a material and / or device comprising a scaffold wall having interconnected pores (e.g., to allow nutrients and oxygen to pass along the sides of the material (e.g., between microchannels and the outer edge of the scaffold)). In some embodiments, the technology provides a material and / or device comprising a scaffold wall having interconnected pores (e.g., to allow nutrients and oxygen to pass along the sides of the material (e.g., between microchannels and the outer edge of the scaffold)) and comprising nanoparticles loaded with a therapeutic agent. In some embodiments, pologen is used to form pores in the material by introducing volume into the polymer as the polymer polymerizes / coagulates. In some embodiments, the pologen is provided in the form of particles. In some embodiments, the pologen is selectively decomposed by immersing the pologen / polymer composition in a solvent to form pores after polymerization is complete. In some embodiments, the pologen is sodium chloride (NaCl). In some embodiments, the technology includes a step of reducing the particle size of the pologen. In some embodiments, the technology includes a step of manufacturing a material using pologen having reduced pologen dimensions. Accordingly, in some embodiments, the technology provides a material comprising a synthetic polymer scaffold wall containing a large number of interconnected pores having an average pore diameter of about 10 to 50 micrometers (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 micrometers) or less. In some embodiments, the technology provides a material comprising a synthetic polymer scaffold wall containing a large number of interconnected pores having an average pore diameter of about 15 to 30 micrometers (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 micrometers) or less.In some embodiments, the technology provides a material comprising a synthetic polymer scaffold wall containing a large number of interconnected pores having an average pore diameter of about 17 to 25 micrometers (e.g., 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, or 25.0 micrometers) or less.

[0075] In some embodiments, the technology relates to a method for producing porous materials having microscale and / or nanoscale structures. In some embodiments, the technology includes the step of mixing one or more types of pologens with a polymer precursor solution. In some embodiments, the ratio of polymer to pologen determines the volume % of the polymer, which can be selected based on the target porosity and mechanical properties. The polymer precursor solution may contain a polymer precursor and a first solvent. In some embodiments, the polymer precursor solution includes nanoparticles loaded with a therapeutic agent.

[0076] In some embodiments, the pologen has an average particle size or particle size of approximately 40 μm or less, approximately 30 μm or less, approximately 20 μm or less, or approximately 10 μm or less. In some embodiments, the pologen is a material that is brittle and / or soluble in the second solvent but insoluble in the first solvent / polymer precursor solution. Roughly speaking, the ratio of the bulk modulus to the shear modulus indicates the ductile / brittle behavior of a solid. According to Pugh's criteria, the critical value for the transition from brittle to ductile behavior is 1.75. Therefore, to facilitate fine grinding by mechanical grinding, pologens having a Pugh ratio of less than 1.75 (e.g., less than 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, or less than 1.75) can be selected. In some embodiments, the pologen is sodium chloride, calcium chloride, potassium chloride, sugars (e.g., sucrose, maltose, lactose, fructose, glucose, galactose, or a combination thereof), or a combination thereof. In some embodiments, the pologen is NaCl. NaCl is a particularly preferred pologen due to its insolubility in solvents used to dissolve biocompatible polymers (e.g., polycaprolactone (PCL) and polylactic acid coglycolic acid (PLGA)), and its solubility in water, which does not readily dissolve PCL or PLGA.

[0077] Some embodiments include a step of reducing the size of the pologen. In some embodiments, mechanical grinding techniques are used to grind or pulverize the pologen particles (e.g., NaCl). In some embodiments, the method includes a step of reducing the particle size of the pologen precursor by ball milling it before mixing the precursor with the polymer solution. In some embodiments, a planetary ball mill is used to reduce the powder particle size. Grinding can take anywhere from about 1 minute to several hours (for example, 1 to 360 minutes (for example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, It can be carried out in 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, or 360 minutes), approximately 2 hours or less (for example, less than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 minutes), or approximately 1 hour or less (for example, less than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes).The grinding speed is 100 RPM to 1000 RPM (for example, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 54 The grinding can be carried out at 0, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 RPM. In some embodiments, grinding is carried out by alternating between mixing time and non-mixing (e.g., rest) time.

[0078] In some embodiments, the technology provides an implantable device. In some embodiments, the implantable device delivers a continuous release of a therapeutic agent over a period of up to 60 days under physiological conditions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days). In some embodiments, the implantable device comprises therapeutic agent-eluting nanoparticles embedded in a polymer matrix. In some embodiments, the portable device is a microscale structure (e.g., 1-600 μm (e.g., 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 2 70, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 μm) and high hollow lumen The device includes a scaffold having a volume (more than 50% (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% hollow lumen volume)). In some embodiments, the implantable device includes therapeutic elution nanoparticles containing porous silicon. In some embodiments, the implantable device includes therapeutic elution nanoparticles containing oxidized porous silicon. In some embodiments, the implantable device includes polyester (e.g., polycaprolactone, poly(lactidoglycol), poly(lactic acid), etc.), chitosan, polyethylene, polyethylene glycol, polyamide, polypyrrole, and / or poly(vinyl alcohol).

[0079] In some embodiments, the portable device has a weight of 0.01 to 99% wt (e.g., 0.01, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 The polymer film contains therapeutic load nanoparticles of 3, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% wt). In some embodiments, the portable device has a weight of 0.01 to 50% wt (e.g., 0.01, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8) The polymer film contains therapeutic load nanoparticles in 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50% wt.In some embodiments, the portable device has a weight of 1-30% wt (e.g., 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 1 The polymer film contains therapeutic load nanoparticles in the following concentrations: 6.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, or 30.0% wt). In some embodiments, the portable devices have a viscosity of 0.01 to 99% (e.g., 0.01, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) It has a porosity of 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% porosity.In some embodiments, the portable device has a viscosity of 0.1-80% (e.g., 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, It has a porosity of 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80% porosity. In some embodiments, the implantable device is subjected to physiological conditions for 10 days or more (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 The present invention provides a release rate for a therapeutic agent, which is a releasing therapeutic agent / mg polymer, of 0.01 to 100,000 ng (e.g., 0.01; 0.02; 0.05; 0.1; 0.2; 0.5; 1; 2; 5; 10; 20; 50; 100; 200; 500; 1000; 2000; 5000; 10,000; 20,000; 50,000; or 100,000 ng) over 56, 57, 58, 59, or 60 days.In some embodiments, the implantable device is kept under physiological conditions for 10 days or more (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, The present invention provides a release rate for a therapeutic agent, which is a releasing therapeutic agent / mg polymer, of 0.1 to 10,000 ng (e.g., 0.1; 0.2; 0.5; 1; 2; 5; 10; 20; 50; 100; 200; 500; 1000; 2000; 5000; 1000; 2000; 5000; or 10,000 ng) over 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days. In some embodiments, the implantable device provides a therapeutic drug release rate of 1 to 1000 ng (e.g., 1;2;5;10;20;50;100;200;500;or 1000 ng) of the therapeutic drug / mg polymer over 10 days or more (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days) under physiological conditions.

[0080] In some embodiments, the implantable device includes a first region whose porosity and structure are continuous with a second region, wherein the first region contains a first therapeutic agent, and the second region contains a second therapeutic agent. In some embodiments, the implantable device includes a first region whose porosity and structure are continuous with a second region, wherein the first region contains a first concentration of the therapeutic agent, and the second region contains a second concentration of the therapeutic agent (e.g., including a concentration of 0 (e.g., no therapeutic agent)). The technology is not limited to including the first and second regions. Accordingly, in some embodiments, the technology provides an implantable device including 1, 2, 3, 4, 5 or more regions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more regions) whose porosity and / or structure are continuous. In some embodiments, each of the 1, 2, 3, 4, 5, or more regions (for example, regions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more regions) containing a therapeutic agent may or may not contain a therapeutic agent. In some embodiments, each of the 1, 2, 3, 4, 5, or more regions containing a therapeutic agent (for example, regions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more regions) may contain the same or different therapeutic agents and may contain therapeutic agents in various concentrations.

[0081] Accordingly, some embodiments provide an implantable device comprising multiple therapeutic drug delivery sites. In some embodiments, the therapeutic drug delivery sites contain the same therapeutic drug (e.g., present at the same or different concentrations), and in some embodiments, the therapeutic drug delivery sites contain different therapeutic drugs. In some embodiments, the implantable device comprises multiple therapeutic drug sites that release the loaded therapeutic drug substantially and / or practically simultaneously, in chronological order, spatial order, and / or any combination thereof. In some embodiments, the implantable device is manufactured from two or more polymer films described herein, one or more of the polymer films containing therapeutic drug eluting nanoparticles. In some embodiments, the film is embossed with spacers (e.g., wire mandrels) which are later removed to form open voids. In some embodiments, the film is rolled in a cylinder. In some embodiments, the film is rolled and joined at the ends (e.g., using heat, pressure, chemicals, or a combination of these three). method Related embodiments provide methods for manufacturing polymer films and / or devices comprising polymer films. In some embodiments, a plurality of methods include the step of obtaining a polymer material and / or preparing a polymer material. In some embodiments, a plurality of methods include the step of dissolving the polymer material in a solvent (e.g., an organic solvent, an aqueous solvent). In some embodiments, a plurality of methods include the step of obtaining and / or producing a solution of the polymer material in a solvent. In some embodiments, multiple methods involve polymers ranging from approximately 0.1% wt% to approximately 50% wt% (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4 The method includes the step of obtaining and / or preparing a solution of a polymer containing 0.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 wt). In some embodiments, the method includes the step of obtaining, preparing, and / or manufacturing a polymer material containing therapeutic agent-loaded nanoparticles. See, for example, U.S. Patent No. 7,713,778, incorporated herein.

[0082] In some embodiments, the methods include the step of adding a pologen to a polymer solution. In some embodiments, the methods include the step of obtaining, generating, and / or preparing a slurry containing the polymer solution and the pologen. In some embodiments, the methods include the step of obtaining, generating, and / or preparing a slurry containing the polymer solution, the pologen, and nanoparticles loaded with a therapeutic agent. Some embodiments include the step of loading the therapeutic agent onto the nanoparticles. See, for example, the examples described herein. Also, see, for example, U.S. Patent No. 7,713,778 incorporated herein.

[0083] In some embodiments, the methods include a step of physically altering the pologen (for example, by machining the pologen) before adding it to the polymer solution. For example, in some embodiments, the methods include a step of producing pologen of a specific size or a specific range of size by subjecting the pologen to screening, grinding, crushing, and / or other machining. In some embodiments, the porogen, after machining, is approximately 0.1 to 100 μm (e.g., 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, It has a size of 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 μm.In some embodiments, the pologen has a size within a specific range, where the size distribution has a peak, maximum, median, and mean, and / or the mode of the size distribution is approximately 0.1 to 100 μm (e.g., 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 11, 12, 1 3, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 5 (8, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 μm).

[0084] In some embodiments, machining of the porogen involves the use of a ball mill. In some embodiments, machining of the porogen is performed at approximately 50-1000 rpm (e.g., 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 5 The process includes the step of ball milling the porogen at 20, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, and 1000 rpm. In some embodiments, the machining of the porogen takes approximately 20 to 600 minutes (for example, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310) The process includes the step of ball milling the porogen for 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, or 600 minutes.In some embodiments, the machining of the porogen is performed for a predetermined time (e.g., 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0 minutes) Mechanically processed pologen The number of steps to be performed and the predetermined time (for example, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16 0.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0 minutes) Includes a step in which the pologen is not machined. In some embodiments, the time for machining the pologen and the time for not machining the pologen are repeated alternately several times during the ball mill grinding step, for example, the ball mill grinding includes time for performing ball mill grinding (the time described above) and each time a time for not performing ball mill grinding (the “pause” time described above).

[0085] Multiple embodiments provide a slurry containing a polymer and pologen in a predetermined range of ratios. For example, multiple embodiments provide a solubilized polymer solution and pologen in a ratio of about 5 vol% / 95 vol% polymer:pologen to 95 vol% / 5 vol% polymer:pologen (e.g., 5 to 95 vol% (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, The present invention provides a slurry containing a solubilized polymer solution containing 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 vol%) of pologen.

[0086] The embodiment provides a slurry containing a polymer and a pologen in a predetermined range of ratios, and further comprising nanoparticles loaded with a therapeutic agent. For example, the embodiment provides a slurry containing a solubilized polymer solution and a pologen in a ratio of about 5 vol% / 95 vol% polymer:pologen to 95 vol% / 5 vol% polymer:pologen (e.g., 5 to 95 vol% (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 5 It contains a solubilized polymer solution containing 4, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 vol%) of pologen, and also contains 0.01 to 99% wt (for example, 0.01, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.5 0, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 6 Therapeutic loaded nanoparticles of 5, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% wt), 0.01-50% wt (e.g., 0.01, 0.02, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.Therapeutic loaded nanoparticles of 90, 0.95, 1.00, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50% wt) or 1-30% wt (e.g., 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5) The present invention provides a slurry further containing therapeutic load nanoparticles of 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, or 30.0% wt.

[0087] In some embodiments, a slurry containing a solubilizing polymer and a pologen (and optionally, nanoparticles loaded with a therapeutic agent) is mixed. In some embodiments, the mixing step includes the use of a ball mill to mix the slurry. In some embodiments, the slurry mixing step is 1 to 600 minutes (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 27 The process includes a step of mixing over 0, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, or 600 minutes.In some embodiments, the step of mixing the slurry is performed for a predetermined time (e.g., 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14 (0.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0 mins) Slurry The steps involve mixing the ingredients and letting them sit for a predetermined time (for example, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 1 6.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0 minutes) The process includes a step in which the slurry is not mixed. In some embodiments, the time spent mixing the slurry and the time spent not mixing the slurry are repeated several times alternately during the mixing step, for example, the mixing step includes a time spent mixing (the time described above) followed each time by a time spent not mixing (the “pause” time described above).

[0088] In some embodiments, the process includes the step of producing a polymer film from a slurry containing a polymer and a pologen (and optionally further containing nanoparticles loaded with a therapeutic agent). In some embodiments, the polymer film production step includes the step of shaping the slurry to produce a polymer film containing a pologen. In some embodiments, the polymer film production step includes the step of spreading the slurry onto a substrate to produce a polymer containing a pologen. In some embodiments, the polymer film production step includes the step of drying the slurry spread on the substrate to produce a polymer containing a pologen. In some embodiments, the final dry thickness of the polymer film is approximately 10-1000 μm (for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, These are 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm. In some embodiments, the embodiment includes a step of removing the dried polymer film from the substrate (for example, using a wetting solution (e.g., alcohol (e.g., ethanol) or water)). In some embodiments, the polymer film is calendered to produce the final film.In some embodiments, the polymer film is calendered by a step (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 47 A polymer film having a thickness of 0, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm is manufactured.

[0089] In some embodiments, the method includes a step of removing pologen from a polymer film containing pologen (and optionally further containing pharmacokinetic-loaded nanoparticles). In some embodiments, the pologen removal step includes a step of bringing the pologen-containing polymer film into contact with a solvent (e.g., an aqueous solution) that dissolves pologen but not polymer (e.g., an aqueous solution) (e.g., immersion, soaking, washing). In some embodiments, the pologen-containing polymer film is left for 10 minutes to 10 hours (e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 14 5, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 48 Contact (e.g., immerse, soak, wash) for 0, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, or 600 minutes). In some embodiments, the washing step of the pologen-containing polymer film includes replacing (e.g., changing) one or more times a solvent that dissolves the pologen but not the polymer (e.g., an aqueous solution) with a fresh solvent that dissolves the pologen but not the polymer (e.g., an aqueous solution).

[0090] In some embodiments, this method produces polymers having a porosity of more than 50 vol%. In some embodiments, this method produces polymers having a porosity of more than 60 vol% (see the examples below). In some embodiments, this method produces polymers with a porosity of 0.01 to 90 vol% (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 3 To manufacture a material having a porosity of 5, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 vol%) (for example, manufactured from a porous film). In some embodiments, this method uses 0.1 to 80 vol% (for example, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 3 To manufacture a material having a porosity of 8, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 vol%) (for example, manufactured from a porous film).In some embodiments, this method uses 1 to 75 vol% (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, A material having a porosity of 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 vol) is manufactured (for example, manufactured from a porous film). See, for example, the experimental examples described herein. In some embodiments, the method manufactures a polymer film and / or material having the aforementioned porosity and further containing nanoparticles loaded with a therapeutic agent.

[0091] In some embodiments, the method includes the step of embossing a polymer film (e.g., a porous polymer as described herein, a porous polymer containing therapeutic load nanoparticles as described herein, and / or one manufactured according to embodiments of the method described herein). In some embodiments, the step of embossing a polymer film includes the step of preparing a polymer film manufactured according to the methods described in the Preamble and / or above. In some embodiments, the step of embossing a polymer film includes the steps of obtaining, manufacturing, and / or preparing a polymer film as described herein (e.g., having an intrinsic porosity of 0.01 to 90 vol%, 0.1 to 80 vol%, 1 to 75 vol%, greater than 50 vol%, or greater than 60 vol%); and the step of preparing an embossing block (e.g., a mold) having a certain structure (e.g., a linear structure) on its surface (e.g., a surface designed to contact the polymer film). In some embodiments, the method includes the step of embossing a plurality of polymer films arranged such that each film overlaps an adjacent film by about 1 mm (e.g., 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, or 1.2 mm). In some embodiments, the step of embossing the polymer films includes the step of preparing a plurality of polymer films manufactured according to the methods described in the preamble and / or above. In some embodiments, the step of embossing the plurality of polymer films includes the step of obtaining, manufacturing, and / or preparing a plurality of polymer films as described herein.

[0092] In some embodiments, the embossing block is 1 to 1000 μm (for example, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 4 Includes structures in the range of 90, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm. In some embodiments, the embossing block includes a structure in the range of 5 to 500 μm (e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 μm). In some embodiments, the embossing block includes a structure in the range of 10 to 400 μm (e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 μm). See, for example, the experimental examples described herein.

[0093] In some embodiments, the embossing step includes pressing a polymer film described herein (e.g., having intrinsic porosity and optionally containing therapeutic load nanoparticles) or a plurality of adjacent, overlapping polymer films into an embossing mold. In some embodiments, the step of pressing a polymer film into an embossing mold includes pressing the polymer film into the embossing mold using a force of about 0.1 to 10 metric tons (e.g., a force of 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 metric tons). In some embodiments, the embossing block is heated to a temperature of approximately 20-200°C (for example, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200°C). In some embodiments, a hydraulic press is used to press the polymer film into the embossing mold.

[0094] In some embodiments, a backing layer is placed between the pressure source and the polymer film. In some embodiments, the backing layer comprises a foam, gel, or other compressible material. In some embodiments, the method includes the steps of obtaining, manufacturing, and / or providing a spacer or a plurality of spacers. The technology is not limited to the shape of the spacer. For example, in some embodiments, the spacer is a rod, a sphere, a prism, a sheet, a slab, or other three-dimensional shape. In some embodiments, the spacer is 1 to 1000 μm (for example, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 51 It has 1, 2, and / or 3 dimensions in the range of 0, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm. In some embodiments, the spacer has a shape complementary to the structure of the embossing block (for example, the spacer has a shape similar to the structure of the embossing block, and in some embodiments, the shape fits with the structure of the embossing block).

[0095] This technology is not limited to the material of the spacer. In some embodiments, the spacer is made of metal. In some embodiments, the spacer is made of polymer. In some embodiments, the spacer is made of glass, ceramic, or graphite material.

[0096] In some embodiments, the embossing step includes placing one or more spacers in contact with the polymer sheet before pressing the polymer film into the embossing mold. In some embodiments, the embossing step includes placing one or more spacers in contact with the polymer sheet during the step of pressing the polymer film into the embossing mold. In some embodiments, the spacers are placed between the polymer film and the embossing mold. In some embodiments, the spacers are placed between the polymer film and a pressure source. In some embodiments, the spacers are treated (e.g., coated, washed, stripped, functionalized, etc.) before contact with the polymer film. In some embodiments, the spacers are coated with polymer.

[0097] In some embodiments, multiple spacers are used (for example, multiple methods include the step of bringing a polymer film into contact with multiple spacers that are positioned to contact the polymer film (for example, to form a pattern of a structure on the polymer film after embossing)). In some embodiments, the multiple spacers are arranged at regular intervals along one dimension (for example, see Figure 3, panels (a) and (b); for example, see Figure 5, panel (a)). In some embodiments, the multiple spacers are arranged at regular intervals along two dimensions (for example, an array). In some embodiments, the number of spacers is 1 to 100 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, Includes spacers numbering 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100). In some embodiments, the number of spacers includes spacers numbering 1 to 1000.

[0098] In some embodiments, the method includes the steps of preparing, manufacturing, and / or obtaining a first polymer film and a second polymer film. In some embodiments, the method includes the steps of placing the first polymer film on an embossing block and embossing the first polymer film using pressure as described above (for example, a force of about 0.1 to 10 metric tons (e.g., a force of 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 metric tons)). Next, in some embodiments, the method includes the steps of, after releasing the pressure, placing a plurality of spacers on the first polymer film, placing the second polymer film on the plurality of spacers, and applying pressure to the first polymer film, spacers, and second polymer film (for example, as described herein and below). In some embodiments, the method includes the steps of placing a first polymer film on an embossing mold, placing a plurality of spacers on the first polymer film, and placing a second polymer film on the plurality of spacers (see, for example, Figure 5, panel (a)). In some embodiments, the embossing mold and / or block used to apply pressure to the polymer film are preheated to a temperature of approximately 20 to 200°C (e.g., (e.g., 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200°C). In some embodiments, a backing layer is placed in contact with the first polymer film and the second polymer film. Multiple embodiments further include the step of pressing the first polymer film, spacers, and the second polymer film into the embossing mold to produce a material having linear channels occupied by the spacers.In some embodiments, the step of pressing a first polymer film, a spacer, and a second polymer film into an embossing mold includes the use of a hydraulic press. In some embodiments, the step of pressing a first polymer film, a spacer, and a second polymer film into an embossing mold includes the step of applying a pressure of about 0.1 to 10 metric tons (for example, a force of 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 metric tons).

[0099] In several embodiments, the polymer film retains its inherent porosity after embossing. In some embodiments, spacers are removed to produce a material with linear channels that retains the inherent porosity of the polymer material. In some embodiments, the linear channels are essentially, substantially, or practically parallel to each other.Accordingly, multiple embodiments of the present invention are as follows: 1) wall thickness of less than 100 μm (e.g., about 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or less than 10 μm); 2) reproducible and homogeneous microscale structures and / or channels (e.g., in the range of about 1 μm to 1 mm (e.g., about 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, Structures having a size of 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μm); and / or 3) 0.01~90 vol% (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 A polymer material is manufactured that has interconnected porosity of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 vol%).

[0100] In some embodiments, the technology provides a method for manufacturing devices containing polymer materials. In particular, several methods are available for microscale structures and / or channels (e.g., in the range of about 1 μm to 1 mm (e.g., about 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 43 0, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980 Structures having a size of 990 or 1000 μm); and / or 0.01 to 90 vol% (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3 The process includes the step of manufacturing a device comprising a polymer material having interconnected porosity of 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 vol%).

[0101] In some embodiments, the methods include the step of preparing, manufacturing, and / or obtaining an embossed polymer material (e.g., having microchannels and inherent porosity) as described herein. In some embodiments, the embossed polymer material contains pologens. In some embodiments, the embossed polymer material has had the pologens removed. In some embodiments, the embossed polymer material contains one or more spacers. In some embodiments, the embossed polymer material has had the spacers removed. In some embodiments, the methods include the step of manufacturing a device from the embossed polymer material. For example, in some embodiments, the steps include rolling the embossed polymer material into a cylindrical shape (see, for example, Figure 5, panel (a)). In some embodiments, the methods include the steps of rolling the embossed polymer material into a prismatic shape (e.g., having a final shape such as a triangle, square, pentagon, hexagon, etc.). In some embodiments, the methods include the steps of folding the embossed polymer material one or more times (e.g., into a meandering pattern). In some embodiments, the device is approximately 0.1 to 10 mm in size (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8) It has a diameter of 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0 mm.

[0102] In some embodiments, rolled and / or folded devices are pressed in a press mold. Accordingly, in some embodiments, multiple methods include the step of pressing the devices described herein in a press mold. In some embodiments, the press mold is at about 20 to 200°C (for example, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 19 The press mold is preheated to a temperature of 5 or 200°C. In some embodiments, a force of 0.1 to 10 metric tons (e.g., 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 metric tons) is applied to the press mold.

[0103] In some embodiments, the method includes a step of cleaning the device to remove the pologen. In some embodiments, the method includes a step of removing the pologen from a device containing pologen (e.g., a polymer containing pologen). In some embodiments, the pologen removal step includes a step of bringing the device containing the pologen into contact with a solvent (e.g., an aqueous solution) that dissolves the pologen but not the polymer of the device (e.g., immersion, soaking, washing). In some embodiments, the device containing the pologen is treated for 10 minutes to 10 hours (e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 1 50, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 31 5, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480 Contact (e.g., immerse, soak, wash) for 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, or 600 minutes). In some embodiments, the cleaning step of a device containing a pologen includes replacing (e.g., changing) one or more times a solvent that dissolves the pologen but not the polymer of the device (e.g., an aqueous solution) with a fresh solvent that dissolves the pologen but not the polymer (e.g., an aqueous solution). In some embodiments, multiple methods include removing a spacer from the device to create a channel in the device.In some embodiments, the method includes the step of inserting the device into the sheath. In some embodiments, the method includes the step of drying the device and / or polymer material. Treatment drugs Several embodiments of this technology relate to the delivery of therapeutic agents. Accordingly, in some embodiments, the technology considers the use of any biologically active therapeutic agent (e.g., intended for loading onto nanoparticles and for incorporation into films, materials, and devices described herein). Whereas described herein, a therapeutic agent is a substance that, when taken up or introduced into a living organism (e.g., the human body or the body of another animal), may have medical, toxic, performance-enhancing, or other effects, such as a chemical substance used to treat, cure, prevent or diagnose a disease, or otherwise modulate (e.g., enhance) physical or mental well-being. Such agents include, but are not limited to, toxins, enzymes, antibodies (or fragments or derivatives of antibodies), aptamers, inhibitors, small molecules, metabolites, cofactors, vitamins, hormones, neurotransmitters, stimulants, neurotransmitter modifiers (e.g., cholinergic, dopaminergic, serotonergic), antagonists and agonists of biological targets. The therapeutic agent may be a natural compound, an analogue of a natural compound, or a synthetic compound. Specific exemplary therapeutic agents include, but are not limited to, statins, opioids, enzyme inhibitors, analgesics, stimulants, benzodiazepines, steroids, receptor antagonists, sedatives, agonists, calcium channel blockers, antidepressants, enzymes, hormones, narcotics, barbiturates, antibiotics, anabolic steroids, nutritional supplements, beta-blockers, inhibitors, proteins, diuretics, antipsychotics, calcium, insulin, anticonvulsants, vitamins, hallucinogens, nonsteroidal anti-inflammatory drugs, anti-inflammatory drugs, ACE inhibitors, anesthetics, antidiabetic drugs, antivirals, angiotensin II receptor blockers, chemotherapeutic agents, antibodies, hypnotics, anticoagulants, antipsychotics, anxiotensin II receptor blockers, antihypertensive drugs, estrogens, corticosteroids, vaccines, anticholinergics, and / or antiarrhythmics. use In some embodiments, the technology is useful in tissue engineering scaffold technology. For example, in some embodiments, the technology is useful in nerve repair. In some embodiments, the technology provides a scaffold comprising microchannels (e.g., parallel high-aspect-ratio structures). In some embodiments, the technology provides a flexible scaffold. In some embodiments, the technology provides a scaffold comprising a porous scaffold wall. In some embodiments, the technology provides a scaffold having an increased hollow lumen volume compared to existing technologies. In particular, several embodiments of the present technology provide materials with a hollow lumen volume of 60 vol% or more (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 vol%), in contrast to existing technologies (e.g., dip coating) that are limited to the production of materials with a hollow lumen volume of less than 52 vol% (e.g., 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30 vol%). For example, some conventional techniques are limited to the production of materials having a hollow lumen volume of 45–52 vol% (see, for example, Pawelec et al., (2019), "The mechanics of scaling-up multichannel scaffold technology for clinical nerve repair," Journal of the Mechanical Behavior of Biomedical Materials 91:247–254, which is incorporated herein by reference).

[0104] Therefore, this technology improves tissue (e.g., nerve) regeneration compared to existing technologies. In particular, this technology provides materials and / or scaffolds that have an increased hollow lumen volume compared to existing technologies, thereby providing an increased volume available for tissue (e.g., nerve tissue) regeneration. For example, see Pawelec et al., (2018), "Microstructure and in vivo characterization of multi-channel nerve guidance scaffolds," Biomedical Materials 13: p.044104, which is incorporated herein by reference in its entirety.

[0105] In some embodiments, this technology is useful for use as a catalyst and / or for producing catalysts. Existing designs of flow catalysts, such as those used in automotive exhaust systems, rely on mass and heat transfer. However, none of these transfer processes are efficient with current state-of-the-art honeycomb structures. In recent years, porous open-cell catalysts have been manufactured, all of which have a wider surface-to-volume ratio than previous catalysts, thus increasing mass transfer and improving the catalyst, while the amount of expensive catalyst reagents (e.g., platinum) included is less than 25% of the amount used to produce previous catalysts. For example, see Papetti et al., (2018), “Additive manufactured open cell polyhedral structures as substrates for automotive catalysts,” International Journal of Heat and Mass Transfer 126:1035-1047, which is incorporated herein by reference in its entirety.

[0106] Both the amount of porosity and the structure of the porous structure itself (e.g., strut size, strut shape) affect the transfer of heat and mass during the reaction. For example, see Ulpts et al., (2018), "3D Characterization of Gas Phase Reactors with Ordered and Disordered Monolithic Catalysts by NMR Imaging and Modeling," each of which is incorporated herein by reference. See "Characterization of gas phase reactors with regularly and irregularly structured monolithic catalysts by NMR imaging and modeling" Catalysis Today 310:176-186; and Papetti (cited above). These parameters of porous structures are difficult to control with most manufacturing methods. In contrast, embodiments of embossing techniques offer improved control over the size of the structure, the shape of the structure, and / or the surface-to-volume ratio within open structures. In addition, while existing open-cell structures and forms have potential, there is no cost-effective method for manufacturing forms from suitable materials, including metals and / or ceramic oxides. For example, see Monno et al., (2018), "Cost-Efficient Aluminum Open-Cell Foams: Manufacture, Characterization, and Heat Transfer Measurements," Advanced Engineering Materials (Adv.Eng.Mater.) 20:1701032, which is incorporated herein by reference in its entirety.

[0107] Embodiments of the technology described herein, for example, compositions produced by the embossing method described herein, provide materials having a distinct open-cell structure and produced from a variety of raw materials and / or material systems. Furthermore, embodiments of the method are suitable for high-throughput manufacturing methods for scaling up to commercial production. Another advantageous structure of the technology described herein is that, in some embodiments, the surface is made functional before the structure is formed, for example, by applying a homogeneous coating of an expensive reactant (e.g., platinum) to the surface, thereby further reducing the amount of catalytic reagent used in the production of the catalyst.

[0108] In some embodiments, the technology provides a method for delivering a therapeutic agent (e.g., for achieving sustained release of the therapeutic agent over time). In some embodiments, the technology provides a delivery vehicle that achieves localized release of the therapeutic agent over time. In some embodiments, the technology provides a delivery vehicle that targets the release of the therapeutic agent to specific organs, tissues, and / or cell types. Furthermore, in some embodiments, the technology provides a delivery technology without an initial "burst phase" release of the therapeutic agent, in which a large amount of the therapeutic agent (e.g., more than 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85% of the therapeutic agent initially supplied by the device) is released over a short period of time (e.g., less than 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of the total release time of the therapeutic agent by the delivery technology). In some embodiments, the therapeutic agent is a drug (e.g., a small molecule), a peptide, a nucleic acid (e.g., siRNA, antisense RNA, guide RNA for CRISPR), an enzyme, a lipid, or a carbohydrate.

[0109] In some embodiments, the delivery device includes a microscale and / or nanoscale structure and embedded nanoparticles (e.g., porous silicon nanoparticles) containing the therapeutic agent. In some embodiments, the porous silicon nanoparticles (pSiNPs) confine the therapeutic agent molecules within the nanoparticle pores, keeping the therapeutic agent active for days, weeks, months, or years until release. pSiNPs typically release the therapeutic agent over a period of about 1-2 days, and by imparting a polymer layer around the pSiNPs, the release of the therapeutic agent can be slowed down, achieving sustained release over, for example, 1-7 days (e.g., 1, 2, 3, 4, 5, 6, or 7 days), 1-4 weeks (e.g., 1, 2, 3, or 4 weeks), and / or 1-12 months (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). For example, see the following, each incorporated herein: Zuidema et al., (2018), "Oriented Nanofibrous Polymer Scaffolds Containing Protein-Loaded Porous Silicon Generated by Spray Nebulization," Advanced Materials.)30:1706785; Moller et al., (2016) "Highly efficient siRNA delivery from core-shell mesoporous silica nanoparticles with multifunctional polymer caps" Nanoscale 8(7):4007-19; Xu et al., (2015) "Smart Porous Silicon Nanoparticles with Polymeric Coatings for Sequential Combination Therapy" Mol.Pharm. 12(11):4038~4047; Irani, (2015) "A novel pressed porous silicon-polycaprolactone composite as a dual-purpose implant for cell and drug delivery to the eye" "Implant for the delivery of cells and drugs to the eye" Experimental Eye Research 139:123-131; Nan et al., (2014) "Porous silicon oxide-PLGA composite microspheres for sustained delivery of daunorubicin to the eye. "Microspheres for sustained ocular delivery of daunorubicin" Acta Biomater. 10(8):3505~3512; Coffer, (2014) "Porous silicon and related composites as functional tissue engineering scaffolds" Porous Silicon for Biomedical Applications (Santos, ed.), pp.470~485; Meng, (2011) "Use of Size and a Copolymer Design Feature to improve the in vivo distribution of doxorubicin-loaded mesoporous silica nanoparticles and increase their permeability and retention effect in a mouse xenograft tumor model" "To Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model" ACS Nano 5(5):4131~4144; Bonanno and Segal, (2011) "Nanostructured porous silicon-polymer-based hybrids from biosensing to drug delivery" Nanomedicine 6(10):1755~1770; Serda et al., (2010) "Cellular association and assembly of multi-step delivery systems" "of a multistage delivery system" Small 6(12):1329~1340; Perelman et al., (2010) "Preparation and characterization of pH- and temperature-responsive poly(N-isopropylacrylamide-co-acrylic acid) / porous SiO(2) hybrids "A nanostructured hybrid material based on polymer-infiltrated porous silicon" by Kashanian et al. (2010) "Evaluation of mesoporous silicon / polycaprolactone composites as ophthalmic implants" by Acta Biomater. 6(9):3566~3572; "A nanostructured hybrid material based on polymer-infiltrated porous silicon" by De Stefano et al. (2010) Applied Physics A-Materials Science and Processing (Appl.Phys A-Mater.Sci.Process.)98(3):525~530; Xia et al. (2009) "Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of "siRNA and DNA Constructs" ACS Nano 3(10):3273~3286; Wu and Sailor (2009) "Chitosan Hydrogel-Capped Porous SiO2 as a pH-Responsive Nano-Valve for Triggered Release of Insulin" Advanced Functional Materials 19:733~741; McInnes and Voelcker (2009) "Silicon-polymer hybrid materials for drug delivery" Future Medical Chemistry Chem.)1(6):1051~1074: McInnes et al., (2009) "New biodegradable materials produced by ring opening polymerisation of poly(L-lactide) on porous silicon substrates" Journal of Colloid Interface Sci. 332(2):336~344; Whitehead et al., (2008) "High-porosity poly(epsilon-caprolactone) / mesoporous silicon scaffolds: Calcium phosphate deposition and biological "Response to bone precursor cells" Tissue Engineering Part A 14(1):195~206; Anglin et al., (2008) "Porous silicon in drug delivery devices and materials" Advanced Drug Delivery Reviews 60(11):1266~1277; Coffer et al., (2007) "Degradable electrospun porous silicon-biopolymer composites for orthopedic tissue engineering" Abstract American Chemistry Society 2007:233; Mukherjee et al., (2006) "Biorelevant mesoporous silicon / polymer composites: directed assembly, disassembly, and controlled release," Biomed. Microdevices 8(1):9~15; Coffer et al., (2005) "Porous silicon-based scaffolds for tissue engineering and other biomedical applications." (Scaffolds for tissue engineering and other biomedical applications) Physical Status Solidi A - Applied Materials Appl. Mat.) 202(8):1451~1455; Li et al., (2003) "Polymer Replicas of Photonic Porous Silicon for Sensing and Drug Delivery Applications," Science 299(5615):2045~2047. See also U.S. Patent No. 7,713,778, incorporated herein.

[0110] In some embodiments, the thickness of the polymer layer and / or the degradability of the polymer itself control the release of the therapeutic agent. Those skilled in the art can select and / or test polymers and polymer thicknesses to achieve desired release characteristics.

[0111] This technology offers the advantage of localized (as opposed to systemic) release of therapeutic agents. It also offers the advantage of containing an increased amount of therapeutic agent per unit mass of polymer compared to conventional devices.

[0112] In some embodiments, the technology provides a homogeneous polymer including implantable pSiNPs and associated devices for use in regenerative medicine. Embodiments of the technology provide a delivery device having a high hollow lumen volume and increased permeability. Embodiments of the technology provide a delivery device that has sufficient mechanical stability for surgical implantation and integrates with tissue while delivering a therapeutic payload. Embodiments of the technology provide a delivery device that achieves spatially patterned therapeutic release by having spatial variations in the concentration and / or amount of the therapeutic on the surface of the device. Embodiments of the technology provide a delivery device that achieves temporal control of therapeutic release. Thus, the technology provides a device for delivering one or more therapeutic drugs to a region of a lesion site within the same implant by spatial and temporal adjustment, and which has a release profile adjusted to a specific stage of the healing process where it may be most beneficial.

[0113] The polymer film delivery vehicles described herein offer several advantages over the use of pSiNPs alone for therapeutic drug delivery. For example, embodiments of the technology include a wide variety of biocompatible polymer materials (e.g., polycaprolactone (PCL) and / or poly(lactide-co-glycolide) (PLGA)) and can release therapeutic drugs over several days to several months without a burst phase. In some embodiments, the technology provides a delivery vehicle having a taut release time, which can be adjusted by, for example, changing the polymer thickness, polymer degradation, the amount of pSiNPs, the pSiNP size, the pSiNP pore diameter, and / or porosity. In some embodiments, the technology provides a delivery vehicle that delivers a high amount of therapeutic drug per unit mass of polymer (e.g., more than 1 ng of therapeutic drug per mg of polymer). In some embodiments, the technology provides a technique for localized release of therapeutic drugs. In some embodiments, the delivery vehicle provides an implantable device specific to the medical intervention required by the subject. In some embodiments, the delivery vehicle extends the bioactive lifetime of the therapeutic agent (e.g., by slowing, eliminating, and / or minimizing the denaturation of biomolecules). In some embodiments, the delivery vehicle achieves spatial and temporal control of therapeutic agent delivery.

[0114] While this disclosure refers to certain exemplary embodiments, it should be understood that these embodiments are presented as examples only and not as limitations. [Examples]

[0115] During the fabrication steps of the embodiments of this technology, linear structures and embossed polymer sheets with inherent porosity were manufactured and tested, materials containing embossed polymers were manufactured and tested, and experiments were conducted to manufacture devices containing embossed polymers. Materials and methods Material Preparation: A slurry was prepared using poly(ε-caprolactone) (Sigma Aldrich, number-average molar mass: 80 kDa; PCL). PCL was solubilized in 3 wt% chloroform. Porosity was introduced by adding pulverized NaCl as a pologen. NaCl crystals were prepared by ball milling NaCl at 400 rpm for 2 hours (Retsch PM100) (alternating between 5 minutes of milling and 5 minutes of rest). Milling yielded NaCl with a particle size of approximately 17-20 μm. This NaCl was added to the solubilized PCL to produce a polymer and salt slurry with a ratio of 30 vol% / 70 vol% polymer / salt. The slurry was mixed in a ball mill for 20 minutes (alternating between 2 minutes of mixing and 2 minutes of rest). Subsequently, films and open tubes were formed using the PCL + salt slurry.

[0116] To manufacture polymer films, a PCL+salt slurry was formed using an automated tape coater (MTI Corporation). The slurry was poured onto copper foil (McMaster) and spread using a blade to produce films with a final dry thickness of 130-150 μm. These films were air-dried and then peeled off the copper foil by wetting them in ethanol. Before embossing, the films (PCL+salt) were pressed in a continuous process using an automated calender to a final thickness of 80-90 μm.

[0117] Open tubes were fabricated by dipping stainless steel (grade 304, McMaster) with an outer diameter of 1.6 mm into a polymer + salt slurry. After drying, the coated rods were immersed in ethanol and the rods were removed from the PCL + salt tubes to form the tubes.

[0118] Embossing of material preparation: Stainless steel wire (304 stainless steel, annealed; California Fine Wire Company) with an outer diameter of 280 μm was cleaned with ethanol. The clean wire was dipped in a 12 wt% poly(vinyl alcohol) solution (Sigma Aldrich, 80% hydrolyzed; PVA) preheated to 60°C. After the coated wire was suspended to dry, it was inspected for coating drips or inhomogeneities. If any coating drips or inhomogeneities were found, the wire was removed from the manufacturing step. An acetal embossing mold (DELRIN) was machined to form linear grooves at 135 μm intervals. Each groove was made with a 0.013 inch end mill, resulting in a structure approximately 300 μm wide and 150 μm deep. A mold for pressing the final multi-channel roll together was made from aluminum. The mold contained two parts that were aligned to form a single 1.6 mm diameter channel that mated with each other.

[0119] Embossing. For embossing, two aluminum blocks and a press mold were heated to 40-50°C before use. The embossing mold was used at a temperature of approximately 21-80°C. A sheet of 2mm foam (Darice) was cut to the size of the embossing mold. Two square press films (e.g., manufactured as described above) were cut to the appropriate size. The first film was placed on the embossing mold and covered with one sheet of foam. This sandwich material was placed between the preheated aluminum blocks and placed in a hydraulic press (Carver). This laminate was pressed with a force of less than 0.4 metric tons. The blocks, with the film lightly adhered to the surface, were gently removed from the laminate. Pre-coated stainless steel wire was placed in the groove of the embossing mold and secured with adhesive tape. In an exemplary embodiment, 16 wires were used to manufacture a 1.6mm diameter device. The second film was placed on top and covered with one sheet of foam. This sandwich material was placed between aluminum blocks on the press. The entire layer was pressed with a force of 1.5 metric tons for 20 seconds, and then removed from the press.

[0120] Device Manufacturing. To form the device, an embossed film with wire spacers was peeled from an embossing block. The film remaining on both sides of the spacers was cut off with a razor. The device was rolled around an axis parallel (or substantially parallel) to the axis of the spacers. This roll was placed in a press mold preheated to 40-50°C. This mold was placed between two aluminum blocks and pressed to a pressure of 1.5-2 metric tons. After removing the press, the mold was opened and the roll was removed. The roll was inserted into an open tube, and the assembly was immersed in water to remove the pologen (NaCl) and PVA coating. The assembly was immersed for 1 hour, with the water changed at least once. After removal from the water, the spacers were removed with tweezers, and the device was air-dried as is.

[0121] Nanoparticles. Porous silicon nanoparticles of desired size were fabricated using electrochemical perforation etching techniques, as previously described (see, for example, Qin et al., (2014), "Size Control of Porous Silicon Nanoparticles by Electrochemical Perforation Etching," Part Part Syst Charact. 31:252-56, incorporated herein). Furthermore, proteins were confined to the porous nanoparticle matrix using oxidative trapping that preserves protein activity, as previously described (see, for example, Kim et al., (2016), "Facile Surface Modification of Hydroxylated Silicon Nanostructures Using Heterocyclic Silanes," Journal of the American Chemical Society 138:15106-9, incorporated herein). During the fabrication steps of the embodiments of the technology described herein, porous silicon nanoparticles (pSiNPs) having a diameter of approximately 200 nm (e.g., 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 nm) were prepared using the method described herein. The pSiNPs were stored at a concentration of 1 mg / ml in ethanol until ready to be loaded with therapeutic agents (e.g., proteins and / or drugs). See also U.S. Patent No. 7,713,778 (incorporated herein), which describes a method for fabricating three-dimensional nanoparticles and depositing materials into the nanoparticle pores used herein.

[0122] Drug / protein loading into nanoparticles. During the preparation steps of embodiments of this technique, lysozyme was used as an experimental model protein to test the delivery of therapeutic agents according to the technique described herein. Specifically, lysozyme was loaded into pSiNPs in a series of steps. First, a lysozyme stock solution of 10 mg / ml lysozyme (Sigma Aldrich) in Tris-buffered saline (TBS) was prepared. Next, pSiNPs were collected from the ethanol storage solution by centrifugation (e.g., 16,000 rcf for 10 minutes) to pelletize the pSiNPs, and the ethanol supernatant was collected and held. This first supernatant was introduced into a new microcentrifuge (e.g., Eppendorf) tube and centrifuged again (e.g., 16,000 rcf for 10 minutes) to collect all nanoparticles present in the first supernatant. The supernatant from the second centrifugation was discarded. Nanoparticles were resuspended in a pre-prepared 10 mg / ml lysozyme stock solution (e.g., 1 mg pSiNP / ml lysozyme stock solution, which is equivalent to 10 mg lysozyme / pSiNP) by sonication for 5 minutes (Cole Parmer 8891). The lysozyme particle suspension was gently vibrated overnight at 4°C to load the nanoparticles with lysozyme. After loading, the particles were washed twice. For washing, the loaded particles were pelletized from the solution by centrifugation (e.g., 16,000 rcf for 10 minutes), the supernatant was removed, and deionized water (DI) was added. The pellet of loaded nanoparticles was sonicated at room temperature for 5 minutes. If particle concentration was required before incorporating the particles into a polymer device (e.g., scaffold), particle concentration was performed using DI water and continuous washing. The pellet was used immediately. The same process, including the following modifications, was used to add growth factors (BDNF, R&D Systems (R&D)) to the nanoparticles. SYSTEMS),248BD005) was loaded: A stock solution of brain-derived growth factor in PBS was prepared as described above, which contained less than 1 wt% bovine serum albumin (BSA). To load BDNF, residual BSA was removed from the outside of the nanoparticles by washing with DI water. During the preparation steps of the embodiments of this technique, experiments showed that residual BSA on the nanoparticles interfered with the formation of the polymer film described herein.

[0123] Introduction of drug-loaded particles into films / scaffolds. To produce polymer films and / or polymer devices (e.g., scaffolds) containing loaded nanoparticles, loaded pSiNPs (containing loaded proteins) were centrifuged in DI water to form pellets, the supernatant was removed, and the pellets were resuspended in ethanol by sonication. The amount of ethanol added was approximately 100-300 μl to maximize the concentration of nanoparticles in the ethanol suspension. This concentrated mixture was transferred to glass vials to prepare a slurry containing polymer and pologen (e.g., salt). A polymer slurry was prepared from 4.5 wt% poly(lactidoglycolide) (85:15 molecular weight 65-95 kDa, Expansorb 10P008; PLGA) in chloroform. As described above, the pologen (NaCl) and polymer slurry were prepared and mixed to produce a slurry with a porosity of 70 vol%.

[0124] PLGA+ salt slurry was added to the loaded nanoparticles to produce films containing nanoparticles at 5, 10, or 15 wt% of the solid portion of the final film. The slurry and nanoparticles were homogenized by sonication at room temperature for 3-5 minutes until the slurry exhibited a homogeneous brown color due to the distribution of nanoparticles throughout the slurry. Next, the slurry was poured onto the film on a glass sheet using the automatic tape caster as described above. The film was air-dried, moistened in ethanol, and then removed from the glass using a razor blade. These films containing pSiNP were stored at 4°C until use.

[0125] A multi-channel device enabling spatial and / or temporal control of therapeutic drug release was fabricated using the embossing method described herein. For example, to fabricate a device containing two different concentrations of nanoparticles and / or therapeutic drugs, two films containing two different concentrations of nanoparticles and / or therapeutic drugs were prepared as described above, and then the two films were placed on an embossing block with a 1 mm overlap. This arrangement determined the spatial distribution of release by the device. The temporal distribution and release of the therapeutic drug were due to the properties of the polymer, film, and their release kinetics. At least one of the films was porous PLGA+pSiNP as described above. A porous PCL film without drug-loading pSiNPs was used in areas of the device where drug release was not desired (prepared as described above). The steps of the embossing process were carried out as described above without any other changes, including the use of pre-coated stainless steel wire (e.g., for channel formation) and the upper layer of porous PCL film. The assembly of the embossed film into the multi-channel device and the insertion of the device into the external conduit were also as described above.

[0126] Material characterization assays. Unless otherwise specified, material characterization was performed on films after removing pologens from the materials. White light interferometry was used to measure the surface roughness of the film. Roughness measurements were obtained using a white light interferometer (Zygo New View 5000) for films with and without 15 wt% pSiNP. Dry samples were measured at 1 cm². 2 It was cut to the following size. The roughness is 640 x 640 μm in area. 2 The roughness was recorded as the root mean square (Rq) of the film over an area of ​​640 × 640 μm. 2 Images of surface roughness were collected over a wide range of periods.

[0127] The tensile strength of PLGA films containing and without 15 wt% pSiNP was tested. Rectangular samples measuring 8 mm x 30 mm were cut from the film, and the samples were hydrated overnight in phosphate-buffered saline (PBS) at 37°C before testing. Tensile tests were performed at room temperature at a rate of 1 mm / min until the material fractured (TA XT plus texture analyzer). The elastic module was calculated as the linear portion of the stress-strain curve.

[0128] Materials were evaluated using a scanning electron microscope (SEM). Dry samples were cut with a razor blade and then placed on aluminum stubs for microscopic examination. For secondary electron imaging (topography only), all samples were sputter coated at 40 mA for 4 minutes, and then imaged using a Hitachi S-3500N operating at 20 keV at a working distance of 10 mm. For backscattered electron imaging, dots of silver paste (PELCO® Colloidal Silver Paste) were placed in the corners of the film, and without further coating, imaged using a MIRA3 Tescan operating at 15 keV at a working distance of 15 mm.

[0129] Experimental details of the reported data: Lysozyme release was measured using lysozyme-loaded pSiNPs incorporated into films at various wt% concentrations. Film samples were washed with tap water for 30 minutes and dried at room temperature. After weighing, the film samples were introduced into Eppendorf tubes. Release experiments were performed in PBS at 37°C. Every 3-4 days, the PBS was removed from the film samples and replaced with fresh PBS. Next, the release of active protein (lysozyme activity kit, Sigma Aldrich, LY0100) and the total released protein (Thermo Scientific Pierce Micro BCA Protein Assay Kit, Thermo Fisher Scientific) were calculated using the supernatant. Lysozyme activity was determined on the day of collection. Total protein calculations were performed on samples left at room temperature for at least 14 days to allow all residual nanoparticles to degrade. Release was recorded per mg of scaffold. Two control films were prepared. The first control film was prepared using pSiNP loaded with lysozyme. The second control film was prepared by directly adding lysozyme-dried lysozyme to a polymer + salt slurry without incorporation into pSiNP, and then sonicating the slurry as in the conventional method.

[0130] BDNF release from pSiNPs was tested in the same manner as lysozyme, with the following modifications: Proteins were released into PBS containing 0.1% BSA, and the supernatant was collected every two days. BDNF concentration was quantified immediately after collection using an ELISA kit.

[0131] Neurite outgrowth was assessed using porous film inserts. Washed film was cut into 12 × 8 mm pieces, sterilized by immersion in 100% ethanol for 5 minutes, and then washed twice with sterile water. The film was assembled into 24-well inserts in a sterile biological cabinet (CELLCROWN, Z681903-12EA). Each sample contained two layers: 1) a bottom layer of non-porous PCL cut into a 24 mm diameter circle; and 2) a porous top layer. After assembly, the insert was placed at the bottom of a 24-well tissue culture plate and 400 μl of sterile water was added. The inserts were stored at room temperature in a sterile hood for 2 days until use. Several hours before neurite inoculation, the film was coated with laminin (natural mouse laminin, Invitrogen, 23017-015). Each insert was incubated with 4 μg of laminin in PBS at room temperature for 1 hour, and then washed with PBS. The inserts were left in PBS at 37°C until inoculation. Dorsal root ganglia (DRGs) were explanted from adult mice, each cut into four small pieces, and left to stand in PBS until inoculation. The explants were placed on the inserts (one per insert) by pipetting 5 μl of PBS + explant onto the film surface. After incubating the explants at 37°C for 2 hours to adhere them to the film, 400 μl of complete cell medium was added to the wells. The medium was changed every 3-4 days. After 7 days of culture, the explants were fixed in 4% paraformaldehyde for 15 minutes. Next, the samples were fluorescently labeled to detect β-tubulin (1:1500, TUJ1, Promega, G7121). Briefly, the film was washed with PBS + 0.1% Tween-20 (PBST), then blocked with 5 wt% BSA in PBST for 1 hour at room temperature. After two washes with PBST, the sample was incubated overnight at 4°C with the primary antibody in 3 wt% BSA in PBST. After two washes with PBST, the sample was incubated with the secondary antibody (1:1000, AlexaFluor) diluted in PBS for 1-2 hours at room temperature.Finally, after washing the samples twice with PBS, they were allowed to stand in a solution of PBS and DAPI staining agent (NucBlue Fixed Cell ReadyProbes Reagent, Thermo Fisher Scientific, R37606, 2 drops / ml PBS). (Cytation 5 Imaging Reader) Inserts containing the explant were imaged using a BioTek imaging reader. Neurite outgrowth was calculated using an Image J plugin called Neurote-J 1.1 (see, for example, Torres-Espin et al., (2014) "Neurite-J: An Image-J plug-in for axonal growth analysis in organotypic cultures," Journal of Neuroscience Methods. 236:26-39). Neurite outgrowth was recorded as the maximum length reached by the neurite (perpendicular to the explant body) and normalized by the distance the cell migrated (calculated from the average distance from the explant body where the cell nucleus was observed). Example 1 - Linear structure and embossed sheet with inherent porosity During the fabrication steps of embodiments of the technology provided herein, experiments were conducted to produce (see, e.g., Materials and Methods), test, and / or characterize embossed sheets having linear structures and inherent porosity. Polymer film sheets were produced by film-forming a composition containing polycaprolactone (PCL) and NaCl as pologen. In exemplary embodiments, the film contained 70 vol% of NaCl pologen that had been pre-ground to a diameter of less than 20 μm. The polymer film sheets were embossed on embossing blocks at 21°C, 40°C, and 60°C (see, e.g., Figure 1). After embossing the polymer film sheets, the NaCl pologen was removed from the film by washing the film with water.

[0132] Measurements of the film revealed that it possessed linear structures remaining after the removal of pologen and inherent porosity. In particular, micrographs of the embossed film showed that the film had linear structures formed by embossing on the embossing block and pores formed by pologen (see, e.g., Figure 2, panels (a)-(g)). Furthermore, the micrographs showed that the film thickness decreased as the embossing temperature increased (see, e.g., Figure 2, panels (a)-(c) and (d)-(f)), and that the embossed structures more closely reproduced the shape of the embossing mold with increasing temperature (see, e.g., Figure 2, panels (a)-(c) and (d)-(f)). Micrographs also showed that the film contained pores after the pologen was washed away (see, e.g., Figure 2, panels (d)-(g)). Example 2 - Embossing including spacer material incorporation During the fabrication steps of embodiments of the technology provided herein, experiments were conducted to form (e.g., linear voids), test, and / or characterize (see, e.g., Materials and Methods). Two sheets of polymer film and a series of spacer wires (placed between the polymer film sheets) were embossed with an embossing block (see, e.g., Materials and Methods). In exemplary embodiments, the wires were stainless steel and coated with polyvinyl alcohol. After applying pressure, the spacer wires were removed.

[0133] Tests of polymer films embossed with spacer wires revealed that introducing spacers (e.g., wire mandrels coated with polyvinyl alcohol (PVA)) into a structure creates a filled pattern, and that removing the spacers creates voids. Figure 3, panel (a) shows wire spacers in the embossed sheet from the side, and Figure 3, panel (b) shows wire spacers in the embossed sheet from the top. Figure 3, panel (c) shows the embossed sheet with voids after the spacer wires have been removed. Example 3 - Embossing device During the fabrication steps of embodiments of the technology provided herein, devices comprising porous polymer materials and microscale structures (see, for example, Figure 5, panels (a) to (c)) were fabricated (see, for example, Materials and Methods; also see Figure 5, panel (a)), tested, and / or experimented with for characterization. Polymer films were fabricated, and materials with voids were fabricated (see, for example, Materials and Methods, and Example 2). Materials were rolled and inserted into tubes to fabricate embossing devices (see, for example, Figure 4, panel (b) and Figure 5, panel (c)).

[0134] Tests of embossed devices (e.g., Figure 4, panel (b)) revealed that they closely resemble microchannel devices manufactured using the dip coating method (e.g., see Figure 4, panel (a)). However, devices manufactured according to the embossing technique described herein offer several advantages over devices manufactured by dip coating. Firstly, materials and devices manufactured according to the technique described herein may include a wider variety of materials and material types than those available in the dip coating method. Secondly, materials and devices manufactured according to the technique described herein can be functionalized and / or modified in many ways compared to materials and devices manufactured by dip coating. Finally, materials and devices manufactured according to the technique described herein have increased lumen volume compared to materials and devices manufactured by dip coating. In particular, measurements have shown that materials and devices manufactured according to the dip coating method have a hollow lumen volume of approximately 50 vol% or less (e.g., approximately 45 vol% to 52 vol% hollow lumen volume) (e.g., see Figure 4, panel (a) and Table 1).

[0135] [Table 1]

[0136] In contrast, embossed materials and devices manufactured according to the techniques described herein have a hollow lumen volume exceeding 60 vol% (see Figure 4, panel (b)). Measurements of the embossed devices revealed that they have a smaller wall thickness than dip-coated materials. In addition, the embossed devices possess more homogeneous characteristics than the dip-coated devices. Both dip-coated and embossed devices have comparable mechanical properties and flexibility.

[0137] During the fabrication steps of the embodiments of the technology described herein, experiments were conducted to fabricate, test, and / or characterize embossed devices made from various polymers. Specifically, embossed devices were fabricated from polycaprolactone (PCL) (Figure 6, panels (a) and (b)) and combinations of PCL and poly(lactide-co-glycolide) (PLGA) (Figure 6, panels (c) and (d)). These devices contained a 300 μm linear structure and were fabricated to have a porosity of 70 vol%. Figure 6 shows microscopic cross-sectional views of the PCL (Figure 6, panel (a)) and PCL / PLGA (Figure 6, panel (c)) devices. Microscopic images show the intrinsic porosity between film layers and close physical bonding for the PCL (Figure 6, panel (b)) and PCL / PLGA (Figure 6, panel (d)) devices.

[0138] During the fabrication steps of the embodiments of the technology described herein, experiments were conducted to characterize the mechanical properties of the embossing device. Specifically, data were collected from the hydrated embossing device under test to measure its response to compression and three-point bending. Using the embossing technique described herein, PCL and PCL / PLGA devices with a diameter of 1.5 mm and a length of 15 mm were manufactured (cross-sectional view shown in Figure 6, panel (a) (PCL) and (c) (PCL / PLGA)). For comparison, similar devices were manufactured from PCL by dip coating. The data showed that the hydrated embossed devices were easily compressible (Figure 7, panel (a)) and bendable (Figure 7, panel (b)). Measurements revealed that the microchannel devices manufactured by the embossing method described herein had compliance equal to or better than that of the dip-coated devices (Figure 7, panels (a) and (b)). In addition, a wide variety of properties were observed depending on the material used. Thus, embodiments of this technique enable the manufacture of materials having specified and / or desired physical structures by selecting appropriate materials to form the embossing apparatus. Example 4A - Embossing device for nerve repair In some embodiments, the embossed devices are fabricated from porous PCL and contain linear microchannels. The entire device has a diameter of 1.6 mm and a length of 10 mm, with 1 mm projections on both sides of the external sheath (e.g., for in-situ suturing at the target). To evaluate the effectiveness of these devices for nerve repair, the devices are tested in a rat sciatic nerve model. Animals were housed with free feeding and water in a facility accredited by the American Association for the Accreditation of Laboratory Animal Care (e.g., 2-3 animals per cage). All animal studies were conducted in accordance with the NIH guidelines for laboratory animal care and safety, adhering to the Institutional Animal Care and Use Committee of the VA Healthcare System (San Diego).

[0139] To implant the embossed device (n=6), the animals were thoroughly anesthetized (e.g., using ketamine (25 mg / mL), xylazine (1300 mg / mL), and acepromazine (0.25 mg / mL)), and a 20 mm long incision was made in the right lateral femur. The right sciatic nerve trunk was exposed by a lateral gluteal muscle incision. The supraarctic connective tissue around the nerve trunk was cut with microscises, and a 6.0 mm long nerve segment was excised. After tissue contraction, the severed nerve ends were further cut to approximately 15 mm; they were protected and hydrated with saline. Using 9-0 Ethicon sutures, the device was positioned at both ends and tied to the nerve. The device was positioned to avoid tension at the connection between the device and the nerve site. After implantation, the muscle was sutured with 5-0 sutures, and the skin was closed with clips. To promote recovery from surgery, antibiotics and analgesics (e.g., vanamine (1 mg / kg) and ampicillin (0.2 mg / kg) in Ringer's lactate solution) are administered during the first three days. After four weeks, the device is retrieved. The animals are perfused with 4% paraformaldehyde (PFA), tissue is collected, and then fixed in PFA for a further 24 hours, followed by 48 hours in 30% sucrose.

[0140] After four weeks, observations are expected to show no signs of device degradation. To assess nerve regeneration throughout the lesion site, tissue sections will be immunolabeled: 1) axon labeling (e.g., to assess axonal regeneration throughout and beyond the injury site) (NF200); and 2) Schwann cells (S100).

[0141] The microchannels in the embossed device allow for the growth of aligned neurites along the length of the scaffold, with the nerves emerging from the apical side of the implant. Unlike more traditional manufacturing methods (e.g., dip coating), the high hollow lumen volume (>50%) provided by this technology allows for the regeneration of numerous neurons due to the reduced volume occupied by the porous wall. Therefore, this technology enables faster healing of nerve lesions along with better functional recovery. Example 4B - Embossing device for nerve repair Embossed multichannel scaffolds were implanted into 1 cm long defects in rat sciatic nerves and compared to sural nerve autografts or open-tube implants. At 4 weeks, the implanted multichannel scaffolds supported linear axonal alignment and accelerated regeneration throughout the injury site. At 6 months, the implanted multichannel scaffolds showed improved connectivity between the spinal cord and the gastrocnemius muscle compared to open-tube treatment and were comparable to autografts. In addition, the multichannel scaffolds supported increased muscle mass, doubling the increase in muscle mass compared to lesions alone or open-tube treatment and being comparable to autografts. See Figure 16, where the embossed multichannel scaffold is referred to as the "NeuroSpan Bridge." Figure 16 shows (A) superior axonal alignment and rate of regeneration across a 1 cm sciatic nerve severance in rats (showing 4 weeks after injury); (B) improved connectivity between spinal motor neurons and muscles, assessed by retrograde tracer (cholera toxin B) injection into the gastrocnemius muscle 6 months after nerve repair; and (C) significantly increased muscle mass. Statistically, the NeuroSpan Bridge is as effective as the sural nerve autograft. N=11 animals / group. Example 5 - Scaling up an embossing device During the fabrication steps of the embodiments of the technology described herein, experiments were conducted to scale up the methods and compositions described in the preceding examples for the purpose of manufacturing larger embossing devices. Specifically, devices with a diameter of 3 mm were manufactured using the same methods as described in Materials and Methods, Example 3, and Figure 5, Panel (a). Data were collected from testing these large embossing devices (Figure 8, Panel (b)) and similar large devices manufactured by traditional methods (e.g., dip coating). From this data, it was found that the technology can be easily scaled up to various aspect ratios and that the manufacturing time is significantly reduced compared to traditional methods (e.g., dip coating) where the size of the structure does not change. Example 6 - Adjustment of the release rate of the therapeutic agent During the fabrication steps of the embodiments of the technology described herein, experiments were conducted to test the release rate of therapeutic agents using lysozyme-loaded pSiNPs embedded in polymer sheets. The delivery vehicle containing the polymer sheet was prepared by film-forming a slurry of poly(lactidoglycolide) (PLGA) containing pologen (NaCl ground to a diameter of <20 μm). Polymer sheets containing pSiNPs were prepared by sonicating the lysozyme-loaded pSiNPs in the polymer / pologen before molding. Pologen was removed from the film by washing with water. Lysozyme was loaded onto the pSiNPs as a model therapeutic agent (before incorporation into the slurry), and then incorporated into the polymer film at 0, 5, 10, and 15 wt% concentrations. Figure 9A is a schematic diagram showing the polymer film containing lysozyme-loaded pSiNPs, and the release of lysozyme from the polymer film and pSiNPs as the polymer film degrades over several days under physiological conditions.

[0142] Data collected during the experiment showed that the time and amount of therapeutic drug released from the film were functions of the amount of pSiNPs embedded in the polymer (Figure 9B). Furthermore, data collected during the experiment revealed that the time of drug release was a function of the polymer degradation kinetics. The data plotted in Figure 9B showed that PLGA films containing lysozyme-loaded pSiNPs released lysozyme over a period of 60 days. The amount of lysozyme released depended on the initial weight of pSiNPs in the film. In particular, the data showed that PLGA films containing 15 wt% lysozyme-loaded pSiNPs actively released lysozyme over periods exceeding 50 days (e.g., 51, 52, 53, 54, or 55 days or longer). Figure 9C is a backscattered electron microscope image of a porous PLGA film containing pSiNPs. Arrows indicate pSiNPs in the porous matrix. Scale bars indicate distances of 10 microns (μm).

[0143] The polymer films were characterized by measuring the elastic module of the hydrated film under tension and by measuring the surface roughness using white light interferometry (Table 2). From the elastic module and roughness measurements, it was found that the embedding of nanoparticles in the polymer film did not significantly change the film properties. Specifically, there was no significant difference in the elastic module and roughness between PLGA containing 0 wt% pSiNP and PLGA containing 15 wt% pSiNP. Figure 10 shows white light interferometry data collected from 640 × 640 μm of PLGA containing 0 wt% pSiNP (left image) and PLGA containing 15 wt% pSiNP (right image).

[0144] [Table 2]

[0145] Example 7 - Delivery of therapeutic agent During the fabrication steps of the embodiments of the technology described herein, experiments were conducted to test the delivery of therapeutic agents (e.g., brain-derived neurotrophic factor (BDNF)) from polymer sheets containing BDNF-loaded pSiNPs. Polymer sheets were prepared by film-forming poly(lactidoglycolide) (PLGA) containing pologen (NaCl ground to a diameter of <20 μm). Polymer sheets containing pSiNPs were prepared by sonicating BDNF-loaded pSiNPs in a polymer / pologen slurry prior to molding. Pologen was removed from the film by washing with water. After loading BDNF as a model therapeutic agent into the pSiNPs (before incorporation into the slurry), the polymer films were incorporated at 0 and 15 wt% concentrations.

[0146] Figure 11 shows the BDNF release rate from a polymer film containing 15 wt% BDNF-loaded pSiNPs. The data showed that the polymer film containing BDNF-loaded pSiNPs delivered 1–2 ng / mg of BDNF per day over 30 days.

[0147] In addition, the biological activity of BDNF was confirmed and quantified by examining neurite outgrowth on the film in vitro after 7 days (Figure 12). In particular, Figure 12 shows data representing the biological activity of growth factor (BDNF) released from PLGA films containing either 0 or 15 wt% therapeutic load pSiNPs. Firstly, a significant difference in neurite growth was measured between films containing 15 wt% pSiNPs and films containing 0 wt% pSiNPs (normalized for cell migration) (Figure 12(a)), **p<0.05). Secondly, neurite outgrowth from mouse dorsal root ganglia (DRGs) was significantly altered by the addition of BDNF-eluting pSiNPs. Figure 12(c) shows increased neurite outgrowth on polymer films containing 15 wt% pBDNF-loaded SiNPs compared to Figure 12(b) (showing limited neurite outgrowth on polymer films containing 0 wt% BDNF-loaded pSiNPs). Nerve processes were visualized using TUJ1 fluorescence staining. The scale bars in Figures 12(b) and 12(c) represent distances of 500 microns (μm). Example 8 - Portable device for therapeutic drug delivery During the fabrication steps of the embodiments of the technology described herein, experiments were conducted to fabricate and test implantable devices (e.g., configured for the delivery of therapeutic drugs) containing therapeutic drug loads pSiNPs. The implantable devices were fabricated using the film forming and embossing methods described herein. Embodiments of implantable devices comprising at least two porous polymer films (e.g., PCL, PLGA, and combinations thereof) were fabricated. In some embodiments, the device comprises at least one porous polymer film containing therapeutic drug loads pSiNPs. In some embodiments, the device comprises a plurality of porous polymer films, each porous polymer film containing a different therapeutic drug and / or different concentrations of the therapeutic drug. The polymer films were fabricated by embodiments of the embossing methods described herein. In some embodiments, the polymer films were fabricated using wire spacers (e.g., pre-coated with a release layer, i.e., poly(vinyl alcohol) (PVA)) to fabricate a device comprising a channel. After fabricating the porous polymer films, the films were rolled as described herein to form a cylinder. In some embodiments, the rolled sheets were inserted into an outer sheath and / or conduit. By removing pologens and spacers, scaffolds with a high hollow lumen volume were fabricated (Figures 13(a) and 13(b)). As shown in Figures 13(a) and 13(b), embodiments of the present technology provide implantable devices comprising a polyester film and pSiNPs. The addition of pSiNPs changes the color of the polymer from white to brown. The portion of the device containing pSiNPs appears dark gray in Figures 13(a) and 13(b). A cross-sectional view of an embossed device with a microchannel structure is shown in Figure 13(a), and a magnified view of the microchannels shown in Figure 13(b) reveals the localization of pSiNPs within the scaffold. The scale bar in Figure 13(a) represents a distance of 250 microns (μm). Example 9 - Device for achieving spatial and temporal control of therapeutic drug delivery During the fabrication steps of the embodiments of this technology, a device was manufactured that achieves control over the temporal and spatial delivery of a therapeutic agent. Films were prepared using embodiments of the embossing technique described herein. Using these films, a device was manufactured that has a high hollow lumen volume and highly manipulated control over the time and location of therapeutic agent release.

[0148] Specifically, we fabricated devices that achieve control over the temporal release (e.g., release rate, release amount, etc.) of therapeutic agents from pSiNPs (e.g., from devices containing pSiNPs). From the data collected during these experiments, it was found that temporal release is controlled by the device structure, including, but not limited to, polymer thickness, polymer degradation kinetics, the amount of pSiNPs embedded in the polymer film, the size of the pSiNPs embedded in the polymer film, and / or the porosity of the pSiNPs embedded in the polymer film. For example, from the data collected during these experiments, it was found that 15 wt% pSiNPs in a porous 85:15 PLGA matrix exhibited maximum therapeutic agent release 30-40 days after implantation, while 15 wt% pSiNPs in a porous PCL matrix did not begin releasing therapeutic agents until 60 days after implantation.

[0149] Embodiments of this technology provide a device manufactured by pressing various films together during an embossing step. Multiple embodiments are characterized in that the spatial arrangement and / or therapeutic agent is determined, and the films are manufactured and arranged accordingly. For example, two or more films are placed on an embossing mold with a 1 mm overlap. After placing a wire spacer and a cover film on top, this assembly is embossed at 1.5 to 2 metric tons. This step forms a continuous microscale structure across the entire device.

[0150] Figure 14 shows a schematic diagram of a device that achieves both temporal and spatial control of therapeutic drug delivery. Films containing different polymers and thus imparting different release kinetics (ng / day released) are distributed along the length of the device. Furthermore, these films may contain various therapeutic drugs and / or different concentrations of therapeutic drugs to achieve spatial control of release. Embodiments of the embossing technique therefore provide a technique for fabricating a device that achieves both temporal and spatial control of therapeutic drug delivery in a single implant. The schematic diagram in Figure 14 shows regions within the device containing different types of therapeutic drugs (shown in varying shades of gray), whose release is controlled by polymer layer thickness, polymer degradation, amount of pSiNPs, pSiNP size, pSiNP pore diameter and porosity, or any combination thereof.

[0151] Figure 15 shows an embodiment of a device that achieves temporal and / or spatial control of therapeutic drug delivery. The embossed, implantable device was fabricated from a polyester containing pSiNPs. The device had a 300 μm linear structure and a porosity of 70 vol%. The device was fabricated so that specific regions of the device contained therapeutic drug-loaded pSiNPs (identifiable by dark gray in Figures 15(a) and (b)). Figure 15(a) is a macro image of the device showing three different regions: two containing therapeutic drug-loaded pSiNPs at the ends, and one region not containing pSiNPs in the center. Figure 15(b) is a photograph showing the boundary between the drug-eluting region (left, gray) and the non-drug-eluting region (right, white). The device contained a coherent structure and physical bonding between the film layers. The scale bar represents a distance of 1 mm in Figure 15(a) and a distance of 250 microns (μm) in Figure 15(b).

[0152] All publications and patents cited in the above specification are incorporated herein by reference in their entirety for all purposes. Various modifications and changes to the compositions, methods, and uses of the described technology will be apparent to those skilled in the art without departing from the scope and spirit of the described technology. Although the technology is described in relation to certain exemplary embodiments, the invention should not be unduly limited to such specific embodiments. In fact, various modifications to the style of description for carrying out the invention will be apparent to those skilled in the art and are intended to be included in the following claims.

Claims

1. (a) A porous film material having two polymer layers and a porosity of at least 60% vol, and defining a plurality of linear microchannels having a diameter of about 100 micrometers to about 200 micrometers, (b) A nerve repair device comprising a sheath surrounding the porous film material.

2. The nerve repair device according to claim 1, wherein the nerve repair device has a hollow lumen volume of at least 60 vol.

3. The nerve repair device according to claim 1, wherein the porous film material comprises a polymer, a biocompatible polymer, a polyester, polycaprolactone, or poly(lactide-coglycolide).

4. The nerve repair device according to claim 1, wherein the plurality of linear microchannels have an aspect ratio of 100 or more.

5. The nerve repair device according to claim 1, wherein the porous film material has a thickness of about 50 to about 200 μm.

6. The nerve repair device according to claim 1, wherein the plurality of linear microchannels have a wall thickness of less than 100 μm.

7. The nerve repair device according to claim 1, wherein the elastic module of the nerve repair device is approximately 22.3 MPa to approximately 55.8 MPa.

8. The nerve repair device according to claim 1, wherein the average pore size of the porous film material is about 10 to 50 micrometers.

9. The nerve repair device according to claim 1, further comprising nanoparticles containing a therapeutic agent, wherein the porous film material comprises the nanoparticles in an amount of about 1% to about 30% by weight.

10. The nerve repair device according to claim 9, wherein the therapeutic agent of the nanoparticles comprises brain-derived neurotrophic factor.

11. The nerve repair device according to claim 9 or 10, wherein the nerve repair device is configured to control the release of the therapeutic agent over a certain period of time, or the nerve repair device is configured to control the release of the therapeutic agent at a release rate of 1 to 1000 ng of therapeutic agent / mg of porous film material / day.

12. The nerve repair device according to claim 1, further comprising a first region containing a first therapeutic agent at a first concentration and a second region containing a second therapeutic agent at a second concentration.

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