MEDICAL INJECTION APPARATUS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority of Singapore Patent Application No. 10201902092T, filed 8 March 2019, the content of which being hereby incorporated by reference in its entirety for all purposes.

TECHNICAL FIELD

[0002] The present invention generally relates to a polymeric thin film, a method of forming thereof, and a medical injection apparatus comprising the polymeric thin film for delivery into a body of a subject.

BACKGROUND

[0003] Despite recent development in nanosheets-based technologies, polymeric nanosheets have yet to overcome a number of technical challenges to serve as an effective injectable platform, such as, (1) limitation in the size of nanosheets, (2) subop timal mechanical robustness (e.g., ripping during injection), and (3) limited control over shape recovery and limited motion control after delivery into biological sites. Previous studies, for example, demonstrated the use of micro-patterned cell-laden nanosheets (“nanodisks” with the thickness of 170 nm) consisting of poly(lactic-co-glycolic acid) (PLGA)-based biodegradable polymer to perform local delivery of RPE-J cells for the treatment of age- related macular degeneration. In the study, the size of the cell-laden nanosheets was smaller than 1 mm ² (a diameter less than 1 mm). The small size of such nanosheets, among other things, limits the area of lesion that one nanosheet can cover after being injected into a body of a subject. Therefore, to cover a large area, a large number of such nanosheets is required. In another study, magnetic nanoparticles-embedded poly(L-lactic acid) (PLLA) nanosheets (having a thickness of 140 - 200 nm) were used having a maximum lateral size of 15 mm (e.g., corresponding to an area of 2.25 cm ² ). However, the PLLA nanosheets, as well as the PLGA nanosheets, do not have an intrinsic mechanical driving force to expand them after being released or delivered from an injection apparatus. Instead, the expansion (i.e., stretch and spread) of the nanosheets after being delivered had to be promoted by an external stimuli (e.g., using a flux of water/air or external magnetic field). In yet another study, triple-layered polymeric nanosheets were investigated where the strain mismatch between two layers of the triple-layered polymeric nanosheets resulted in the folding of the nanosheets into a cylindrical shape (i.e., cylindrical nanosheets) and the dissolution of the two layers resulted in the unfolding of the nanosheets into a flat shape. However, the radius of curvature (e.g., 0.84 mm) of the cylindrical nanosheets is greater than the inner diameter (I.D.) of commonly used syringe needles. Overall, existing nanosheets have various deficiencies, such as in relation to (1) sheet size (more than 1 cm ² ), (2) injectability and (3) self-expandability.

[0004] A need therefore exists for a polymeric thin film and a method of forming the polymeric thin film that seek to overcome, or at least ameliorate, the above-mentioned deficiencies in conventional nanosheets, for example used for drug delivery. It is against this background that the present invention has been developed.

SUMMARY

[0005] According to a first aspect of the present invention, there is provided a method of forming a polymeric thin film having shape memory properties, comprising:

forming a liquid-soluble supporting layer on a substrate;

depositing a shape memory polymer layer on the liquid- soluble supporting layer, the shape memory polymer layer having a ratio of lateral dimension to thickness of 10 ⁴ or greater; and

removing the shape memory polymer layer from the liquid-soluble supporting layer and the substrate to produce a free-standing polymeric thin film comprising the shape memory polymer layer, of which is free-standing,

wherein said removing the shape memory polymer layer from the liquid-soluble supporting layer and the substrate comprises dissolving the liquid-soluble supporting layer in a liquid to release the shape memory polymer layer from the liquid-soluble supporting layer.

[0006] According to a second aspect of the present invention, there is provided a polymeric thin film having shape memory properties comprising a shape memory polymer layer, the shape memory polymer layer having a ratio of lateral dimension to thickness of 10 ⁴ or greater.

[0007] According to a third aspect of the present invention, there is provided a medical injection apparatus comprising:

a fluid chamber having stored therein a fluid comprising a polymeric thin film; a hollow needle having a first end in fluid communication with the fluid chamber and a second end configured to penetrate a body of a subject; and

a pressure member coupled to the fluid chamber and is operable to pressure the fluid in the fluid chamber comprising the polymeric thin film to discharge through the hollow needle from the second end thereof for delivering the polymeric thin film into the body of the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Embodiments of the present invention will be better understood and readily apparent to one of ordinary skill in the art from the following written description, by way of example only, and in conjunction with the drawings, in which:

FIG. 1 depicts a schematic flow diagram of a method of forming a polymeric thin film having shape memory properties according to various embodiments of the present invention;

FIGS. 2A-2C illustrate exemplary perspective views of a polymeric thin film having shape memory properties according to various embodiments of the present invention;

FIG. 3A depicts a schematic diagram illustrating a medical injection apparatus comprising the polymeric thin film for delivery according to various embodiments of the present invention;

FIG. 3B depicts a schematic flow diagram of a method of delivering a polymeric thin film into a body of a subject using a medical injection apparatus according to various embodiments of the present invention;

FIG. 4A illustrates an exemplary schematic of a process of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention; FIG. 4B illustrates an image of an example polymeric thin film comprising a shape memory polymer layer floating on water;

FIG. 4C illustrates an image of an example polymeric thin film comprising the shape memory polymer layer having a support frame thereon;

FIG. 5A illustrates another exemplary schematic of a process of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention;

FIG. 5B illustrates an image of a film of shape memory polymer layer and liquid- soluble supporting layer being physically peeled off together from a silicon wafer;

FIG. 5C illustrates an image of an example polymeric thin film comprising the shape memory polymer layer of FIG. 5B floating on water;

FIG. 6A illustrates another exemplary schematic of a process of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention;

FIG. 6B illustrates an image of a film of a shape memory polymer layer having magnetic nanoparticles thereon and liquid-soluble supporting layer being physically peeled off together from a silicon wafer;

FIG. 6C shows an AFM topographic image of an edge of a shape memory polymer layer having magnetic nanoparticles thereon with the magnetic nanoparticles on the top, collected on a silicon wafer (left) and the cross-sectional profile along the solid line (right);

FIG. 7 illustrates another exemplary schematic of a process of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention;

FIG. 8A shows a graph illustrating the relationship between the rotational speed for the spin-coating and the thickness of the shape memory polymer layer;

FIG. 8B shows a graph illustrating the relationship between the concentration of the shape memory polymer in solvent and the thickness of the shape memory polymer layer; FIG. 9A illustrates an image of a polymeric thin film according to various embodiments of the present invention being attached to the surface of a chicken muscle; FIG. 9B illustrates images of a polymeric thin film according to various embodiments of the present invention adhering to a piece of chicken skin when attracted by a neodymium magnet;

FIG. 10A shows a graph illustrating the measurements by DMA for polymeric thin films according to various embodiments of the present invention with glass transition temperatures of 25°C and 55°C;

FIG. 10B show images of a polymeric thin film according to various embodiments of the present invention fixed to a tensile test machine before being stretched (left), during being stretched (middle), and after being torn (right);

FIG. IOC shows a graph illustrating the Young’s moduli of polymeric thin films according to various embodiments of the present invention with glass transition temperatures of 25 °C and 55°C at different temperatures;

FIG. 10D shows a table illustrating the Young’s moduli of shape memory polymer layers according to various embodiments of the present invention with glass transition temperatures of 25 °C and 55°C at different temperatures;

FIGS. 11A and 11B show images of polymeric thin films according to various embodiments of the present invention before and after, respectively, placed on the human skin;

FIGS. 12A-12C illustrate SEM images of various polymeric thin films according to various embodiments of the present invention attached to a silicone-based skin replica;

FIG. 12D illustrates a 3D microscopic image of a polymeric thin film according to various embodiments of the present invention conforming to the skin replica;

FIG. 12E illustrates a 2D microscopic image of the polymeric thin film shown in FIG. 12D conforming to the skin replica;

FIG. 12F illustrates a cross-sectional topographic profile of the surface of the skin replica that is partially covered with the polymeric thin film according to various embodiments of the present invention;

FIGS. 12G-12H illustrate images of a polymeric thin film according to various embodiments of the present invention attaching to the surface of the finger;

FIG. 121 shows an image illustrating patterns of a fingerprint transferred to the polymeric thin film according to various embodiments of the present invention; FIG. 12J shows an image illustrating the polymeric thin film according to various embodiments of the present invention losing the transferred fingerprint patterns at 37°C;

FIG. 13 shows an image illustrating a polymeric thin film according to various embodiments of the present invention having microscale -pattern;

FIG. 14A shows schematic illustration for the structure of an exemplary polymeric thin film according to various embodiments of the present invention;

FIG. 14B shows schematic illustration for the structure of a polymeric thin film according to various embodiments of the present invention in a medical injection apparatus;

FIG. 15 A shows an exemplary graph illustrating a height profile (or thickness) of a polymeric thin film according to various embodiments of the present invention and single layered PLGA nanosheet;

FIG. 15B shows an exemplary schematic of a polymeric thin film according to various embodiments of the present invention being injected into a sphere ball using a medical injection apparatus;

FIG. 15C shows an exemplary single layered PLGA nanosheet in water after injection;

FIG. 15D shows an exemplary polymeric thin film according to various embodiments of the present invention in water after injection;

FIG. 15E illustrates a polymeric thin film according to various embodiments of the present invention being guided using an external magnetic field;

FIG. 16 shows an exemplary chemical structure of a shape memory polymer according to various embodiments of the present invention;

FIG. 17 shows an image of an exemplary polymeric thin film according to various embodiments of the present invention;

FIG. 18A shows an image illustrating a medical injection apparatus comprising a polymeric thin film for delivery according to various embodiments of the present invention;

FIG. 18B shows an image illustrating the polymeric thin film of FIG. 18A being ejected from the medical injection apparatus according to various embodiments of the present invention; FIGS. 18C-18D show images illustrating the polymeric thin film of FIG. 18A after being ejected from the medical injection apparatus according to various embodiments of the present invention; and

FIG. 18E shows an image illustrating the polymeric thin film of FIG. 18 A being moved by an external magnetic field according to various embodiments of the present invention.

DETAILED DESCRIPTION

[0009] Various embodiments of the present invention provide a polymeric thin film having shape memory properties, a method of forming thereof, a medical injection apparatus comprising the polymeric thin film for delivery into a body of a subject, and a method of delivering the polymeric thin film into a body of a subject using the medical injection apparatus. The polymeric thin film may be free-standing (i.e., free-standing polymeric thin film). In various embodiments, the polymeric thin film may comprise a shape memory polymer (SMP) layer, the shape memory polymer layer having a ratio of lateral dimension to thickness of 10 ⁴ or greater. In other words, the shape memory polymer layer, and accordingly the polymeric thin film, may have a size-aspect ratio of 10 ⁴ or greater. The above-mentioned lateral dimension may refer to a dimension of the shape memory polymer layer extending in a direction perpendicular to a direction of the thickness of the shape memory polymer layer (i.e., the thickness direction). In various embodiments, the above-mentioned lateral dimension may refer to the maximal lateral dimension of the shape memory polymer layer. In various non-limiting examples, the lateral dimension may be along or parallel to a width, a length, or a diameter of the shape memory polymer layer. The polymeric thin film may also be referred to as a polymeric ultrathin film, a polymeric nanosheet or a polymeric microsheet herein.

[0010] According to various embodiments, a polymer may be a shape memory polymer if an original conformation (or memorized conformation or shape) of the polymer layer is recovered in response to a stimulus. The polymeric thin film may be configurable to be in a temporary conformation (e.g., folded or crumpled), and expandable to the memory conformation from the temporary conformation in response to the stimulus. According to various embodiments, the stimulus may be a predefined temperature or temperature range such as a temperature range provided by body heat.

[0011] FIG. 1 depicts a schematic flow diagram of a method 100 of forming a polymeric thin film having shape memory properties according to various embodiments of the present invention. The method 100 comprises forming (at 102) a liquid-soluble supporting layer on a substrate; depositing (at 104) a shape memory polymer (SMP) layer on the liquid-soluble supporting layer, the shape memory polymer layer having a ratio of lateral dimension to thickness of 10 ⁴ or greater; and removing (at 106) the shape memory polymer layer from the liquid-soluble supporting layer and the substrate to produce a free standing polymeric thin film comprising the shape memory polymer layer. In particular, the above-mentioned removing the shape memory polymer layer from the liquid- soluble supporting layer and the substrate comprises dissolving the liquid-soluble supporting layer in a liquid to release the shape memory polymer layer from the liquid-soluble supporting layer.

[0012] In various embodiments, the method of forming the polymeric thin film having shape memory properties further comprises depositing magnetic nanoparticles (MNPs) (or a magnetic nanoparticle layer) on a surface of the shape memory polymer layer, and the above-mentioned removing the shape memory polymer layer comprises removing the shape memory polymer layer having the magnetic nanoparticles thereon from the liquid- soluble supporting layer and the substrate to produce the free-standing polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon. The magnetic nanoparticles on the surface of the shape memory polymer layer renders the polymeric thin film magnetic and enables the polymeric thin film to be guidable or movable using an external magnetic field. For example, the polymeric thin film may be magnetic to enable non-contact motion control using an external magnetic field.

[0013] In various embodiments, the method of forming the polymeric thin film having shape memory properties further comprises forming a polymer layer on the shape memory polymer layer, the polymer layer functioning as a carrier of a therapeutic substance, and the above-mentioned removing the shape memory polymer layer comprises removing the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer from the liquid-soluble supporting layer and the substrate to produce the free-standing polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer. In various embodiments, the polymer layer may be formed of poly-lactic-co-glycolic acids (PLGAs). For example, the polymer layer may be biodegradable. The polymer layer formed of PLGAs, for example, may be used as a biodegradable platform to release drugs on biological tissues or deliver engineered cells in organs. In various embodiments, the polymer layer may be formed of polylactic acids (PLAs) or polycaprolactones (PCLs).

[0014] In various embodiments, in relation to 102, the above-mentioned liquid-soluble supporting layer may be a water-soluble sacrificial layer. In various embodiments, the above-mentioned dissolving the liquid-soluble supporting layer in the liquid to release the shape memory polymer layer comprises dissolving the water-soluble sacrificial layer in water. In various embodiments, the liquid-soluble supporting layer may be formed of poly(vinyl alcohol) (PVA).

[0015] In various embodiments, in relation to 104, the above-mentioned depositing a shape memory polymer layer on the liquid-soluble supporting layer comprises spin coating a diluted shape memory polymer solution comprising shape memory polymer on the liquid- soluble supporting layer. In various embodiments, the diluted shape memory polymer solution comprises the shape memory polymer in a solvent, the shape memory polymer having a concentration ranging from about 30% to about 50%. In various embodiments, the diluted shape memory polymer solution comprises the shape memory polymer at a concentration of about 30% in the solvent. In various embodiments, the diluted shape memory polymer solution comprises the shape memory polymer at a concentration of about 50% in the solvent. In a non-limiting example, the solvent may be, or include, N,N- dimethylformamide (DMF). In various embodiments, the spin coating may be performed at a rotational speed ranging from about 4000 rpm to about 8000 rpm.

[0016] In various embodiments, the above-mentioned depositing a shape memory polymer layer on the liquid-soluble supporting layer comprises spin coating a shape memory polymer solution comprising shape memory polymer on the liquid-soluble supporting layer. In various embodiments, the shape memory polymer solution may be undiluted, the shape memory polymer having a concentration at about 100%. [0017] The shape memory polymer layer (and accordingly, the polymeric thin film) may be configurable to be in a temporary conformation, and expandable to a memory conformation from the temporary conformation in response to a stimulus. In various embodiments, the stimulus may be a predefined temperature or temperature range such as a temperature range of the body heat in a non-limiting example (e.g., temperature-mediated shape memory effect of the shape memory polymer layer). In various embodiments, the predefined temperature may be about 37°C. Accordingly, the polymeric thin film may be self-expandable into a memory conformation, for example, upon exposure to body heat (self-expandable polymeric thin film mediated by temperature change). In various embodiments, the shape memory polymer layer enables a large change in the Young's moduli by the change in temperature, and shape memory effect (SME) to recover the memorized conformation.

[0018] In various embodiments, the shape memory polymer layer may be formed of polyurethanes. For example, the above-mentioned depositing a shape memory polymer layer on the liquid-soluble supporting layer comprises spin coating a diluted shape memory polymer solution comprising polyurethanes on the liquid-soluble supporting layer.

[0019] In various embodiments, the method of forming the polymeric thin film having shape memory properties further comprises performing a thermal treatment on the shape memory polymer layer.

[0020] In various embodiments, the above-mentioned liquid-soluble supporting layer may be a water-soluble sacrificial layer. In various embodiments, the above-mentioned dissolving the liquid-soluble supporting layer in the liquid to release the shape memory polymer layer comprises dissolving the water-soluble sacrificial layer in water.

[0021] In various embodiments, in relation to 106, the above-mentioned removing the shape memory polymer layer from the liquid-soluble supporting layer and the substrate comprises peeling the shape memory polymer layer and the liquid-soluble supporting layer together from the substrate prior to dissolving the liquid-soluble supporting layer in the liquid.

[0022] In various embodiments, the shape memory polymer layer may have a thickness of less than about 1 pm (e.g., producing an ultrathin film). [0023] In various embodiments, the shape memory polymer layer may have a surface area of about 1 cm ² or larger.

[0024] In various embodiments, the shape memory polymer layer may have a flexural rigidity of about 10 ² nN m or less.

[0025] FIGS. 2A-2C illustrate exemplary perspective views of a polymeric thin film 200 having shape memory properties according to various embodiments of the present invention. The polymeric thin film 200 comprises a shape memory polymer (SMP) layer 210, the shape memory polymer layer 210 having a ratio of lateral dimension to thickness of 10 ⁴ or greater.

[0026] In various embodiments, the polymeric thin film 200 further comprises magnetic nanoparticles (MNP) 220 coated on a surface of the shape memory polymer layer 210, as illustrated in FIG. 2B.

[0027] In various embodiments, the polymeric thin film 200 further comprises a polymer layer 230 arranged on the shape memory polymer layer 210, the polymer layer 230 functioning as a carrier of a therapeutic substance. In various embodiments, the polymer layer 230 may be formed of poly-lactic-co-glycolic acids (PLGAs).

[0028] In various embodiments, the shape memory polymer layer 210 may have a thickness of less than about 1 pm.

[0029] In various embodiments, the shape memory polymer layer 210 may have a surface area of about 1 cm ² or larger.

[0030] In various embodiments, the polymeric thin film 200 may have a flexural rigidity of about 10 ² nN m or less.

[0031] In various example embodiments, the polymeric thin film comprising the shape memory polymer layer may remain robust during the injection and expand after injection in an environment above the predefined temperature such as the glass transition temperature (T _g ) of the shape memory polymer material. In various example embodiments, the low flexural rigidity (e.g., about 10 ² nN m or less) of the polymeric thin film at 37°C (above its glass transition temperature T _g ), derived from its ultrathin thickness (e.g., less than about 1 pm) and low Young’s modulus (e.g., tens of MPa), provided ultra- conformable adhesion to the biological tissue such as skin and muscle without the use of any adhesive reagent or tissue glue. [0032] In various embodiments, there is also provided a medical injection apparatus (which may also be embodied as a device) comprising the polymeric thin film for delivery into a body of a subject. FIG. 3 A shows an exemplary embodiment of a medical injection apparatus 300. In various embodiments, the medical injection apparatus 300 comprises a fluid chamber 310 having stored therein a fluid comprising a polymeric thin film 200 as described herein; a hollow needle 320 having a first end in fluid communication with the fluid chamber 310 and a second end configured to penetrate a body of a subject; and a pressure member 330 coupled to the fluid chamber 310 and operable to pressure the fluid in the fluid chamber comprising the polymeric thin film 200 to discharge through the hollow needle 320 from the second end thereof for delivering the polymeric thin film into the body of the subject. In various embodiments, the medical injection apparatus 300 may be syringe. However, it is understood that the medical injection apparatus is not limited to a syringe, and other types of medical injection apparatus may also be used to deliver the polymeric thin film 200 to a tissue or biological site. For example, other types of medical injection apparatus having a hollow needle 320 configured to penetrate the body of a subject may also be used.

[0033] In various embodiments, there is provided a method of delivering a polymeric thin film into a body of a subject using a medical injection apparatus, such as the medical injection apparatus 300 as described with respect to FIG. 3A. FIG. 3B depicts a schematic flow diagram of a method 360 of delivering a polymeric thin film into a body of a subject using a medical injection apparatus according to various embodiments of the present invention. The method 360 comprises pressuring (at 365), via a pressure member, a fluid comprising a polymeric thin film stored in a fluid chamber to discharge through a hollow needle from a second end thereof for delivering the polymeric thin film into the body of the subject.

[0034] The polymeric thin film as described may exhibit physical properties including temperature-dependent dynamic mechanical modulus, surface conformability (e.g., to the biological tissues), temperature-mediated self-expandability and magnetic guidability. Referring back to FIG. 3A, the polymeric thin film 200 may be injectable through the hollow needle 320 of the medical injection apparatus 300. The polymeric thin film 200 is further expandable to its memorized conformation upon injection from the medical injection apparatus 300 into an environment providing a stimulus for the expansion of the polymeric thin film 200 from a temporary conformation prior to exposure to the stimulus. In various embodiments, the polymeric thin film 200 may be guided by an external magnetic field 350 (i.e., polymeric thin film 200 having magnetic properties).

[0035] The polymeric thin film may provide conformable and long-term stable adhesion to target biological tissues, and serve as a platform to deliver, inter alia, drugs, sensors, cells and engineered tissues to a specific site or lesion in the body for minimally invasive diagnosis and therapy (e.g., in situ delivery of therapeutic substances or materials). Accordingly, various embodiments provide a polymeric thin film which may be advantageously used as minimally invasive implants (e.g., implantable devices, biomaterials, medical devices) for diagnosis, therapy and regenerative medicine. As described, the polymeric thin film may be delivered into the body of a subject using a hollow needle (e.g., injectable through medical needles). For example, according to various embodiments, the polymeric thin film may serve as a syringe-injectable platform to deliver implantable biomaterials and devices to the specific site or lesion in the body of a subject to achieve minimally-invasive diagnosis and therapy.

[0036] It will be appreciated by a person skilled in the art that the terminology used herein is for the purpose of describing various embodiments only and is not intended to be limiting of the present invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising", or the like such as“includes” and/or“including”, when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

[0037] In order that the present invention may be readily understood and put into practical effect, various example embodiments of the present invention will be described hereinafter by way of examples only and not limitations. It will be appreciated by a person skilled in the art that the present invention may, however, be embodied in various different forms or configurations and should not be construed as limited to the example embodiments set forth hereinafter. Rather, these example embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the present invention to those skilled in the art.

[0038] In particular, for better understanding of the present invention and without limitation or loss of generality, various example embodiments of the present invention will now be described with respect to a polymeric thin film which may be delivered into the body of a subject using a medical injection apparatus such as a syringe, however, it will be appreciated by a person skilled in the art that the polymeric thin film which may be delivered using other types medical injection apparatus or device.

[0039] The free-standing polymeric thin film comprising the shape memory polymer layer may be fabricated with a thickness in the range of micro-to-nano orders.

Preparation of polymeric thin film comprising the shape memory polymer layer (polymeric microsheets)

[0040] FIG. 4A illustrates an exemplary schematic of a process 400 of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention. A substrate or wafer 405, such as a silicon wafer in a non-limiting example, may be provided. For example, the substrate may be a 3” silicon wafer. A liquid-soluble supporting layer 410 may be formed on the substrate 405. In various example embodiments, the liquid-soluble supporting layer 410 may be a water- soluble sacrificial layer. For example, a sacrificial layer of PVA may be coated on the substrate 405 prior to the depositing the shape memory polymer layer. In the case of the polymeric thin film being a microsheet (e.g., thickness of the polymeric thin film about 4 - 7 pm), a PVA aqueous solution (e.g., 10 mg/mL) may be spin-coated (e.g., at a rotational speed of 500 rpm and a duration of 10 sec, followed by a rotational speed of 2000 rpm and a duration of 40 sec) on the substrate 405. A shape memory polymer (SMP) solution comprising shape memory polymer (e.g., a mixture of a base polymer and a curing reagent) may then be spin-coated (e.g., at a rotational speed of 500 rpm, and duration of 10 sec followed by a rotational speed of 4000, 6000 or 8000 rpm, and duration of 60 sec) on the liquid-soluble supporting layer 410. After curing the shape memory polymer layer on a hotplate (80°C) for 15 min, the substrate 405 coated with a bilayered film of shape memory polymer layer 210 and liquid-soluble supporting layer 410 may be released into water to dissolve the liquid- soluble supporting layer 410 to obtain the free-standing polymeric thin film 200 comprising the shape memory polymer layer 210 (e.g., shape memory polymer microsheet). In other words, the liquid-soluble supporting layer 410 may be dissolved by water (e.g., water having a temperature below the glass transition temperature T _g of the shape memory polymer layer such as but not limited to 20°C), and the shape memory polymer layer 210 may be released from the substrate. In various example embodiments, at a spin-coating rotational speed of about 8000 rpm, the thickness of the shape memory polymer layer 210 may be 4.2 ± 0.1 pm and 4.6 ± 0.3 pm for two types of shape memory polymer (e.g., shape memory polymer having a glass transition temperature T _g of 25°C and shape memory polymer having a glass transition temperature T _g of 55°C), respectively.

[0041] FIG. 4B illustrates an image 440 of a polymeric thin film 200 comprising the shape memory polymer layer 210 (e.g., polymeric microsheet) with the size of 3“ silicon wafer floating on water. In various example embodiments, a support frame 450 (e.g., adhesive tape frame) may be formed on the shape memory polymer layer 210, as illustrated in FIG. 4C. The support frame 450 may be formed on the shape memory polymer layer 210 before immersing the substrate 405 into the water and releasing the shape memory polymer layer 210.

Preparation of polymeric thin film comprising the shape memory polymer layer (polymeric nanosheets)

[0042] FIGS. 5A-5B illustrate another exemplary schematic of a process 500 of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention. In various example embodiments, to reduce the thickness of the polymeric thin film further down to less than about 1 pm, the shape memory polymer solution comprising shape memory polymer may be diluted in a solvent, such as N,N-dimethylformamide (DMF) in a non-limiting example, before spin coating. Similar to the process 400 described in FIG. 4A, a liquid-soluble supporting layer 410 may be formed on the substrate 405. To avoid the mechanical stress applied to the prepared nanosheet and the resulting fracture upon the release from the silicon wafer, a thick liquid-soluble supporting layer 410 may be formed on the substrate 405. The liquid- soluble supporting layer 410 may formed of PVA. In various example embodiments, a layer of PVA with a thickness of about 10 mih may be formed using an aqueous solution of PVA (10 mg/mL). For example, a PVA aqueous solution (10 mg/mL) may be cast- coated and the substrate 405 may be dried on a hotplate (e.g., temperature of about 60°C for about 60 min) to form a thick liquid-soluble supporting layer 410 (e.g., PVA film) having a thickness of about 1 Opm. This thick supporting layer may serve to maintain the integrity of the deposited shape memory polymer layer.

[0043] A shape memory polymer solution comprising shape memory polymer (e.g., a mixture of a base polymer and a curing reagent) diluted in DMF (e.g., polymer concentration: 30 wt% or 50 wt%) may then be spin-coated on the liquid- soluble supporting layer 410 (e.g., diluted shape memory polymer solution comprising shape memory polymer material). For example, the diluted shape memory polymer solution comprising shape memory polymer may be spin coated on the liquid-soluble supporting layer 410 (at a rotational speed of 500 rpm and a duration of 10 sec, followed by a rotational speed of 8000 rpm and a duration of 60 sec). A thermal treatment (or curing) may then be performed for the shape memory polymer layer to be cured (e.g., on a hotplate at a temperature of about 80°C and duration of about 15 min). After performing thermal treatment on the shape memory polymer layer, a bilayered film of shape memory polymer and liquid-soluble supporting (e.g., PVA) may be physically peeled off from the silicon wafer with a tweezer in the air, as illustrated in FIG. 5B. In various example embodiments, the film may be released into water to dissolve the PVA layer to obtain a free-standing polymeric thin film comprising the shape memory polymer layer (e.g., polymeric nanosheet).

[0044] FIG. 5C illustrates an image 550 of a polymeric thin film 200 comprising the shape memory polymer layer 210 (e.g., shape memory polymer nanosheet) with the size of 3“ silicon wafer floating on water.

Preparation of polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon (MNP-SMP nanosheets)

[0045] FIGS. 6A-6B illustrates another exemplary schematic of a process 600 of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention. Similar to the processes 400 and 500 as described in FIG. 4A and FIG. 5A, a liquid-soluble supporting layer 410 may be formed on the substrate (or wafer) 405. For example, a PVA aqueous solution (e.g., 10 mg/mL) may be cast-coated and the substrate 405 may be dried on a hotplate (e.g., at a temperature of about 60°C for a duration of about 60 min) to form the liquid-soluble supporting layer 410 (e.g., a 1 Opm-thick PVA film). A shape memory polymer solution comprising shape memory polymer (e.g., a mixture of a base polymer and a curing reagent) diluted in solvent such as DMF (diluted shape memory polymer solution) may then be spin-coated (e.g., at a rotational speed of 500 rpm, and duration of lOsec followed by a rotational speed of 8000 rpm, and duration of 60 sec) on the liquid-soluble supporting layer 410. After curing the shape memory polymer layer 210 on a hotplate (e.g., at a temperature of about 80°C for a duration of about 15 min), magnetic nanoparticles (MNPs) 220 may be deposited on a surface of the shape memory polymer layer 210. In various example embodiments, a magnetic nanoparticle -based ferrofluid such as EFH-1 (e.g., ferrofluid based on magnetic nanoparticle dispersion) may be spin-coated (e.g., at a rotational speed of 500 rpm, and duration of lOsec followed by a rotational speed of 8000 rpm, and duration of 60 sec) on the shape memory polymer layer 210. For example, the EFH-1 ferrofluid may comprise superparamagnetic iron oxide nanoparticles. For example, in the case where N,N- dimethylformamide (DMF) is used as a solvent for depositing the shape memory polymer layer 210 (which may be an unsuitable carrier for magnetic nanoparticles), the shape memory polymer solution and the ferrofluid may be spin-coated separately to form a bilayered structure. The formed MNP-SMP-PVA trilayered film 610 may be dried at room temperature for a duration of about 60 min and may be peeled off from the silicon wafer with a tweezer, as illustrated in FIG. 6B. In various example embodiments, the trilayered film 610 may be cut into a square-shape (e.g., having a lateral dimension such as a width of about 15 mm) or a round-shape (e.g., having a lateral dimension such as a diameter of about 15 mm) with scissors. Referring back to FIG. 6A, the MNP-SMP-PVA trilayered film 610 may be movable by an external magnetc field such as lifted by a neodymium magnet 620.The MNP-SMP-PVA trilayered film 610 may be released into water to dissolve the liquid-soluble supporting layer 410 to obtain a free-standing polymeric thin film 200 comprising the shape memory polymer layer having the magnetic nanoparticles thereon (MNP-SMP nanosheet). In various example embodiments, the thickness of the free-standing polymeric thin film 200 (MNP-SMP nanosheet) may be about 710 ± 33 nm (e.g., measured from an atomic force microscope (AFM) topographic image of the dried sample collected on a silicon wafer using a scanning range area of 20 pm x 20 pm, which included the surface of both nanosheet and silicon wafer).

[0046] FIG. 6C shows an AFM topographic image of the edge of the MNP-SMP nanosheet with MNP layer on the top, collected on a silicon wafer (left) and the cross- sectional profile along the solid line 610 in the left panel (right).

Preparation of polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer (PLGA-MNP-SMP nanosheets)

[0047] FIG. 7 illustrates another exemplary schematic of a process 700 of forming a polymeric thin film having shape memory properties according to various example embodiments of the present invention. Similar to the processes 400, 500 and 600 as described in FIG. 4A, FIG. 5 A and FIG. 6A, a liquid-soluble supporting layer 410 may be formed on the substrate 405. For example, a PVA aqueous solution (e.g., 10 mg/mL) may be cast-coated and the substrate 405 may be dried on a hotplate (e.g., at a temperature of about 60°C for a duration of about 60 min) to form the liquid-soluble supporting layer 410 (e.g., a 1 Opm-thick PVA film). A shape memory polymer solution (a mixture of a base polymer and a curing reagent) diluted in solvent such as DMF (diluted shape memory polymer solution) may then spin-coated (e.g., at a rotational speed of 500 rpm, and duration of lOsec followed by a rotational speed of 8000 rpm, and duration of 60 sec) on the liquid- soluble supporting layer 410. After curing the shape memory polymer layer 210 on a hotplate (e.g., at a temperature of about 80°C for a duration of about 15 min), magnetic nanoparticles (MNPs) 220 may be deposited on a surface of the shape memory polymer layer 210. In various example embodiments, a magnetic nanoparticle-based ferrofluid such as EFH-1 may be spin-coated (e.g., at a rotational speed of 500 rpm, and duration of 10 sec followed by a rotational speed of 8000 rpm, and duration of 60 sec) on the shape memory polymer layer 210. A polymer layer 230 may be formed on the shape memory polymer layer 210, the polymer layer 230 functioning as a carrier of a therapeutic substance. In various example embodiments, the polymer layer 230 may be formed of PLGAs. For example, a PLGA (e.g., 20 mg/mL)/Rhodamine B (1 mg/mL) solution in dichloromethane (DCM) may be spin-coated (e.g., at a rotational speed of 500 rpm, and duration of 10 sec followed by a rotational speed of 4000 rpm, and duration of 40 sec) on the magnetic nanoparticle layer 220. The formed PLGA-MNP-SMP-PVA tetralayered film 710 may be peeled off from the substrate 405 with a tweezer. The film 710 may be cut into a square- shape (e.g., having a lateral dimension such as a width of about 10 mm) with scissors. The PLGA-MNP-SMP-PVA tetralayered film 710 may be released into water to dissolve the liquid-soluble supporting layer 410 to obtain a free-standing polymeric thin film 200 comprising the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer (e.g., PLGA-MNP-SMP nanosheet).

Characterization of thickness of the polymeric thin film

[0048] According to various embodiments, the polymeric thin film may be a nanosheet-based platform which may be injectable, self-expandable and conformable to biological surfaces. The polymeric thin film may also be functionalized with additional materials such as magnetic nanoparticles and biodegradable polymers without compromising other properties. For example, to achieve syringe-injectability and ultra- conformability, the thickness and flexural rigidity of shape memory polymer-based films is reduced. The surface conformability of the polymeric thin film (or thin film materials) may depend on its flexural rigidity ( D ). A low flexural rigidity provides mechanically conformable adhesion to the rough surface of biological tissues. The flexural rigidity D may be determined as follows:

Et ³

^{D ~} 12(1 - v ² )

where E, t, and v are Young’s modulus, thickness, and Poisson’s ratio of the polymeric thin film (or thin film materials), respectively. Since the flexural rigidity is in proportion to Young’s modulus and the cube of the thickness, the reduction of the thickness can drastically decrease the flexural rigidity and should be the most effective approach to enhance the conformability. In various example embodiments, the shape memory polymer layer, accordingly, the free-standing polymeric thin film, may have a thickness of less than about 1 pm, resulting in flexural rigidity of about 10 ² nN m or less above their glass transition temperature T _g . For example, the mechanical property (Young’s modulus) of the shape memory polymer may dramatically decrease around the glass transition temperature T _g . The flexural rigidity is in proportion to the Young’s modulus, and thus decrease around the glass transition temperature T _g . Accordingly, the flexural rigidity of the shape memory polymer layer (and the free-standing polymeric thin film) becomes about 10 ^L -2 nN m or less when the temperature is above the glass transition temperature T _g . To demonstrate self-expandability of the nanosheet at 37°C, a shape memory polymer having the glass transition temperature T _g of 25 °C may be selected for the shape memory polymer layer. Functionalization with magnetic nanoparticles conferred an ability to control the location of the implanted devices in remote and minimally invasive manners. To integrate the magnetic property to the shape memory polymer layer (and accordingly, the free-standing polymeric thin film), a magnetic nanoparticle -based ferrofluid was coated on the surface of the shape memory polymer layer to form a magnetic nanoparticle- shape memory polymer (MNP-SMP) bilayered structure. The fabricated devices were characterized for the physical properties and tested for the proposed capabilities.

[0049] Measurement of the thickness of the SMP microsheet was carried out on a specimen collected on a substrate (e.g., silicon wafer) using a surface profilometer (e.g., AlphaStep® D-600 Stylus Profiler (KLA-Tencor, Milpitas, CA)). Measurement of the thickness of the polymeric thin film formed of the shape memory polymer layer (SMP nanosheet) and polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon (MNP-SMP nanosheet) was carried out on a specimen collected on the silicon wafer using an atomic force microscopy (e.g., AFM5000II (Hitachi High-Technologies Co., Ltd, Tokyo, Japan) with a cantilever tip; PRC-DF40P).

[0050] FIG. 8A shows a graph illustrating the relationship between the rotational speed for the spin-coating and the thickness of the shape memory polymer layer (e.g., SMP microsheets) with glass transition temperature T _g of 25°C and 55°C. The thickness of the shape memory polymer layer may be dependent on the rotational speed of the spin-coater (i.e., the thickness decreased as the rotational speed increased). FIG. 8B shows a graph illustrating the relationship between the concentration of the shape memory polymer material in DMF solvent and the thickness of the shape memory polymer layer with glass transition temperatures T _g of 25°C and 55°C. For example, the rotational speed for the spin- coating was fixed at 8000 rpm. Under the constant rotational speed of spin-coating (e.g., 8000 rpm), the thickness of the shape memory polymer layer was dependent on the concentration of the shape memory polymer in DMF solvent (i.e., the thickness decreased as the concentration decreased). At 30 wt%, the thickness of the shape memory polymer layer was 617 ± 16 nm and 864 ± 15 nm for the two types of shape memory polymer material, having glass transition temperatures T _g of 25°C and 55°C, respectively. Accordingly, the liquid-soluble supporting layer method (including water-soluble sacrificial layer method) are effective ways to collect large-scale (e.g., the size of silicon wafers) free-standing polymeric ultrathin film comprising a shape memory polymer layer (with the thickness of micrometers and nanometers, respectively) without losing the integrity after spin-coating and detachment of the shape memory polymer layer from the wafer.

[0051] Tissue adhesion of the polymeric thin film (e.g., MNP-SMP nanosheet) was demonstrated by attaching the nanosheet to the surface of the chicken muscle without the skin, as illustrated in FIG. 9A. In an example experiment, the square-shaped nanosheet (e.g., having a dimension of about 15 mm x 15 mm) remained attached on the chicken muscle with vigorous shaking. This result suggested that the polymeric thin film would adhere to the surface of the biological tissues without any adhesive and stably remain at the same location in the body, making them as a promising candidate for implantable devices. The guidability of the polymeric thin film in an external magnetic field was demonstrated in a 50-mL-tube filled with 37°C water, where a piece of chicken skin (e.g., having a dimension of about 25 mm x 25 mm, and thickness of about 1 mm) was fixed on the wall using an instant adhesive. The polymeric thin filmadhered to the site of the chicken skin when attracted by a neodymium magnet attached outside of the tube, as illustrated in FIG. 9B. The polymeric thin film maintained to stick to the surface of the chicken skin after the magnet was released from the wall and the tube was laid aside. This demonstration indicated that the polymeric thin film was magnetically responsive and tissue-adhesive. When the tube was vigorously shaken by hands, however, the nanosheet was detached from the chicken skin. To enhance the tissue adhesion of the polymeric thin film to the wet biological surface, a mussel-inspired polydopamine (PDA)-modification has been demonstrated to be an effective way. Temperature-dependent mechanical properties

[0052] To confirm that the prepared polymeric thin film comprising the shape memory polymer layer exhibit the dynamic thermomechanical properties (i.e., the temperature- dependent dynamic change in their modulus), the mechanical properties of the shape memory polymer layers (e.g., SMP microsheets) with a thickness of 4.2 ± 0.1 pm and 4.6 ± 0.3 pm for the glass transition temperatures T _g of 25°C and 55°C, respectively, was evaluated by the dynamic mechanical analysis (DMA). DMA of shape memory polymer layers was carried out using a dynamic mechanical analyzer (e.g., DMA Q800 (TA Instruments, Newcastle, DE) in a tensile mode). The storage modulus E’ and the loss modulus E” represent the modulus of the elastic and viscous portion of the sample, respectively. The tangent delta, defined as the ratio of E”/E represents the damping capacity of the sample. Amorphous and semi-crystalline polymers having glassy and rubbery states decrease their stiffness drastically with the increment of viscosity around their transition state including the glass transition temperature T _g . Thus, the storage modulus dramatically drops, and the loss modulus reaches the maximum at the glass transition temperature T _g . The specimen was cut into the rectangular shape with the width of 10 mm and the length of 5 mm, of which the top and bottom edges were supported by an adhesive tape to be held by the clamps of the instrument. During the measurement, a sinusoidal load (e.g., frequency of about 1 Hz) was applied to the sample while the temperature inside the chamber was gradually increased from -20°C to 100°C at a constant ramp speed of 5°C/min.

[0053] The storage modulus, loss modulus and tangent delta was recorded for the two types of shape memory polymer layers with the glass transition temperatures T _g of 25°C and 55°C. FIG. 10A shows a graph 1000 illustrating the measurements by DMA for the shape memory polymer layers (e.g., SMP microsheets) with glass transition temperatures T _g of 25 °C and 55°C. The storage modulus and the loss modulus of the shape memory polymer layers dropped from several GPa to the order of tens to hundreds of MPa, and reached the maximum peak around their glass transition temperature T _g (25°C and 55°C), respectively. For the shape memory polymer layer with the glass transition temperature T _g of 25°C, the storage modulus in its rubbery state (e.g., 115 MPa at 50°C) was smaller by 38 times than that in its glassy state (e.g., 4.4 GPa at 0°C). In the same manner, for the shape memory polymer layer with the glass transition temperature T _g of 55°C, the storage modulus in its rubbery state (e.g., 93 MPa at 80°C) was nearly 30 times smaller than that in its glassy state (e.g., 2.8 GPa at 30°C).

[0054] Young’s moduli of the shape memory polymer layers (e.g., SMP microsheets) at different temperatures were also measured using the same instrument. In an example measurement, the temperature inside the chamber was held constant and a tensile test (tensile speed: 2% strain/min) was carried out for the sample to obtain the stress-strain relationship until the sample was torn off. The size of the samples was the same as that used for the DMA test. FIG. 10B show images of a shape memory polymer layer (e.g., SMP microsheet) fixed to a tensile test machine before being stretched (left), during being stretched (middle), and after being torn (right). Dotted lines 1010 represent the contours of the shape memory polymer layers, while arrows 1020 represent the direction of tensile force. For both shape memory polymer layers with the glass transition temperature T _g of 25°C and 55°C, it was found that the initial slope of the stress/strain decreased as the temperature increased, and the rate of drop was drastic around their glass transition temperatures T _g . The Young’s moduli of the shape memory polymer layers for each temperature were calculated from the initial slope (the range of strain about 1 to about 2%) of the stress/strain relationship. FIG. IOC shows a graph illustrating the Young’s moduli of the shape memory polymer layers with glass transition temperatures T _g of25°C and 55°C at different temperatures. FIG. 10D shows a Table 1 illustrating the Young’s moduli of the shape memory polymer layers (e.g., SMP microsheet) with glass transition temperatures T _g of 25 °C and 55°C at different temperatures.

[0055] It was found that the Young’s modulus of the shape memory polymer layer with the glass transition temperature T _g of 25°C in its rubbery state (e.g., 18 ± 5 MPa at 60°C) was smaller by 70 times than that in its glassy state (e.g., 1.3 ± 0.2 GPa at 0°C). In the same manner, the Young’s modulus of the shape memory polymer layer with the glass transition temperature T _g of 55°C in its rubbery state (e.g., 7 ± 2 MPa at 80°C) was smaller by 210 times than that in its glassy state (e.g., 1.5 ± 0.2 GPa at 20°C). Notably, the shape memory polymer layer with the glass transition temperature T _g of 25°C, owing to its low Young’s modulus (e.g., 20-30 MPa) at 37°C, became soft (e.g., having flexural rigidity of about 0.1- 0.2 nN m) when attached to the human skin and spontaneously conformed to the surface of the skin. In contrast, the shape memory polymer layer with the glass transition temperature T _g of 55°C exhibited high values of Young’s modulus (e.g., about 1 GPa) and flexural rigidity (e.g., 10 nN m) on the human skin at 37°C. As the result, it did not adhere to the human skin conformally. FIGS. 11A and 11B show images of the shape memory polymer layers with glass transition temperatures T _g of 25°C and 55°C before and after, respectively, placed on the human skin (e.g., human skin having temperature of about at 37°C). These suggests that the conformability of the sheet-type materials with similar thicknesses is strongly attributed to their mechanical properties (i.e., Young’s modulus and flexural rigidity). Importantly, the maximum tensile elongation at break of the shape memory polymer layers was the highest around their glass transition temperatures T _g . This profile correlated with corresponding loss modulus that represent the viscous characteristics of the shape memory polymer layers. Referring back to FIG. 10A, the graph 1000 shows that the loss modulus of both shape memory polymer layers with glass transition temperatures T _g of 25 and 55°C increased over the glass transition around each glass transition temperature T _g . The shape memory polymer layers with glass transition temperature T _g of 25 °C showed the elongation of 72% before rapturing at 40°C. This value was higher than the maximum induced tensile strain of the human skin on bending the elbow joint (e.g., the human skin can be at maximum stretched at 63% strain (1.63-fold) when the elbow is bent), suggesting the applicability of the developed platform for skin- contact devices.

Shape memory effect and surface conformability

[0056] In various example embodiments, the polymeric thin film comprising the shape memory polymer layer (e.g., SMP microsheet) with the glass transition temperature T _g of 25°C was crumpled after being immersed in water having a temperature of about 37°C. When the crumpled sheet was placed in an ice water at 0°C (below the glass transition temperature T _g of the shape memory polymer layer), the crumpled shape of the polymeric thin film was temporarily arrested (fixed) (e.g., providing the temporary conformation). When the crumpled sheet was immersed in water having a temperature of about 37°C again, the polymeric thin film expanded spontaneously to the memorized conformation (e.g., flat shape) without any external force because of the SME of the material of the shape memory polymer layer. This observation suggested that the SME of the material of the shape memory polymer layer ensured the self-expandability of the polymeric thin film.

[0057] The surface conformability of the shape memory polymer layers (or polymeric thin film comprising the shape memory polymer layer) (for example having a glass transition temperature T _g of about 25 °C) to the replica of the human skin made of polydimethylsiloxane (PDMS) was evaluated by a scanning electron microscope (SEM). The free-standing polymeric thin film (e.g., SMP microsheet and nanosheet) with different thickness (e.g., 4.2 ± 0.1 pm and 617 ± 16 nm, respectively) were placed on the surface of the silicone-based skin replica. The texture of the replica was transferred from the fingerprint, and the surface of the skin replica was observed with the SEM. The thickness- dependence of the shape conformability was demonstrated. FIG. 12A illustrates an SEM image 1200 of the 4.2pm-thick polymeric thin film (e.g., SMP microsheet) (with glass transition temperature T _g of 25 °C) attaching to the silicone-based skin replica, while FIG. 12B illustrates an SEM image 1210 of the 617nm-thick polymeric thin film (e.g., SMP nanosheet) (with glass transition temperature T _g of 25 °C) conforming to the silicone-based skin replica. Each image 1200, 1210 shows the polymeric thin films with a thickness of 4.2 ± 0.1 pm and 617 ± 16 nm attaching to the skin replica, respectively. The 617nm-thick polymeric thin film conformed well to the microrelief structure with a maximum depth of 100 pm of the skin replica, while the 4.2pm-thick polymeric thin film did not exhibit such conformity. This experiment suggested the surface conformability of the polymeric thin film can be attained by the decrease in the thickness of the sheets, as predicted by the decrease in its flexural rigidity. FIG. 12C illustrates an SEM image 1220 of the 710nm- thick polymeric thin film comprising the shape memory polymer layer having magnetic nanoparticles thereon (e.g., MNP-SMP nanosheet) (with glass transition temperature T _g of 25°C) conforming to the silicone-based skin replica.

Functionalization with MNP and surface conformability

[0058] Envisaging the in vivo applications of the polymeric thin film comprising the shape memory polymer layer as a platform for syringe-injectable devices, the location of the polymeric thin film comprising the shape memory polymer layer after injection should be remotely controlled with an external force. In various example embodiments, magnetic property may be added to the polymeric thin film as described above with respect to FIG. 6A by loading magnetic nanoparticles (MNPs) on the film. Notably, after dissolution of the liquid-soluble supporting layer (e.g., PVA layer in water), the magnetic nanoparticle layer did not detach from the shape memory polymer layer and the magnetic property was maintained. Comparing the thickness of the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon (MNP-SMP nanosheet) (e.g., thickness of about 710 ± 33 nm) with that of the pristine polymeric thin film formed of the shape memory polymer layer (SMP nanosheet) (e.g., thickness of about 617 ± 16 nm) without the magnetic nanoparticles, the thickness of the magnetic nanoparticle layer was estimated as 93 ± 37 nm by calculating the difference in thickness of each nanosheet (e.g., thickness of MNP-SMP nanosheet against thickness of SMP nanosheet). The thickness of the magnetic nanoparticle layer did not affect the conformability of the shape memory polymer layer, as apparent from the MNP-SMP nanosheet following the microrelief structure of the silicone skin replica, as illustrated in FIG. 12C.

[0059] Three-dimensional (3D) and two-dimensional (2D) microscopic images also displayed the conformability of the MNP-SMP nanosheet to the surface with microscale patterns. FIG. 12D illustrates the 3D microscopic image 1230 of the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon conforming to the skin replica, while FIG. 12E illustrates the 2D microscopic image 1240 of the polymeric thin film conforming to the skin replica. FIG. 12F illustrates a cross- sectional topographic profile 1250 of the surface of the skin replica that is partially covered with the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon (e.g., MNP-SMP nanosheet). The cross-sectional topographic profile 1250 shows that the MNP-SMP nanosheet conformed to the microrelief of the skin replica on the order of 100 pm.

[0060] The change of the modulus by temperature offers a unique capability to control the adhesion and removal of the polymeric thin film on the biological surfaces. The transfer of fingerprints is studied utilizing a round-shaped polymeric thin film (MNP-SMP nanosheet) (e.g., having a diameter of about 15 mm), and removal of the polymeric thin film from the skin. The polymeric thin film floating on water was scooped by the index finger and dried for about 1 min. At the body temperature of about 37°C higher than the glass transition temperature T _g of the shape memory polymer layer (e.g., 25 °C), the polymeric thin film became elastic and physically conformed to the pattern of the fingerprint. FIG. 12G illustrates an image 1260 of a polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon (e.g., MNP-SMP nanosheet) attaching to the surface of the finger, well-conforming to the pattern of the fingerprint. When the finger was immersed in ice water (e.g., at a temperature of 0°C, lower than the glass transition temperature T _g of the shape memory polymer layer), the polymeric thin film spontaneously detached from the skin due to the intrusion of water between the nanosheet and skin and floated on the water, as illustrated in image 1270 in FIG. 12H. The immediate detachment of the nanosheet occurred because of the change of the Young’s modulus (e.g., Young’s modulus more than 1 GPa at 0°C, according to Table 1 as shown in FIG. 10D). At 0°C, the flexural rigidity of the polymeric thin film increased, resulting in the reduction of the conformability. The transferred pattern of the fingerprint was arrested on the nanosheet at 0°C. FIG. 121 shows an image 1280 illustrating patterns of the fingerprint transferred to the polymeric thin film. Due to shape memory effect of the shape memory polymer layer, the polymeric thin film lost the transferred patterns at 37°C, as illustrated in image 1290 in FIG. 12J. The same experiment was repeated 10 times without noticeable difference in shape, conformability and thickness of the polymeric thin films. The thickness of the polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon remained the same after 10 times of repeated experiments. There was no physical damage to the sheet (or film), and the transferred patterns also remained indistinguishable. This experiment suggests that the ultra- conformability, owing to the nanometer thickness and the shape memory effect of the shape memory polymer layer, enabled the precise and rapid transfer of the micro-scale textures. The transferred pattern may be removed by the change of the temperature. This experiment also suggested that the presence of magnetic nanoparticles did not compromise the conformability of the developed polymeric thin films. It is noted that controlled detachment of the adhered polymeric thin films from biological surfaces have not been demonstrated previously, which would be difficult to achieve using conventional polymeric thin films having a constant modulus. [0061] In various example embodiments, the shape of the shape memory polymer layer may be modified before being released. In various example embodiments, the free-standing MNP-SMP-PVA trilayered film (e.g., film comprising the liquid-soluble supporting layer and the shape memory polymer layer having magnetic nanoparticles), with the presence of the mechanical liquid-soluble supporting layer of PVA, may be patterned using a cutting plotter or laser cutter without damaging the film. As an example, well-defined patterns were created on the trilayered film using a cutting plotter. After removing an area surrounded by the cutting pattern, a patterned MNP-SMP-PVA trilayered film may be obtained. After dissolving the liquid-soluble supporting layer in water, a free-standing MNP-SMP nanosheet with the microscale -pattern was obtained as shown in FIG. 13. This suggests that above-mentioned method of forming a polymeric thin film having shape memory properties may be combined with the simple modification of the shape using readily available methods of digital fabrication.

Syringe-injectability, self-expandability and magnet guidability of MNP-SMP nanosheets

[0062] The polymeric thin films (e.g., MNP-SMP nanosheets) were tested for the syringe-injectability, self-expandability and magnet guidability in continuous experiments. The film comprising the liquid-soluble supporting layer and the shape memory polymer layer having magnetic nanoparticles (e.g., MNP-SMP-PVA trilayered film) fabricated on a 3” silicon wafer was peeled off from the silicon wafer and cut into a square with a lateral dimension of 15 mm. The magnetic property of the obtained film was confirmed by attaching a neodymium magnet to the film. The free-standing polymeric thin film (e.g., MNP-SMP nanosheet) was collected in a syringe after dissolving the PVA layer in water. The MNP-SMP nanosheet floating in 37°C water was placed in a 5mL-volume syringe equipped with a 20G needle (e.g., outer diameter, O.D. = 0.9 mm and inner diameter, I.D. = 0.6 mm). The MNP-SMP nanosheet maintained its flat structure in water at the temperature of 37°C (above the glass transition temperature 77 of 25 °C), which suggested that the presence of the magnetic nanoparticle layer did not compromise the shape memory effect of the device. The MNP-SMP nanosheet was ejected from the syringe through the 20G needle under manual pressure applied to the syringe. When ejected into the water at 37°C, the MNP-SMP nanosheet was self-expanded to the memorized conformation (e.g., original flat sheet) immediately due to its shape memory effect. This experiment was repeated at least ten times for one nanosheet without losing its integrity, suggesting that the nanosheet possessed robustness sufficient for injection. On the other hand, when ejected into ice water at 0 °C (below the glass transition temperature 77 of the shape memory polymer layer), the MNP-SMP nanosheet did not expand and remained crumpled (temporary conformation). When the ejection to the ice water was repeated, the nanosheet eventually ruptured at the nozzle (which was in contact with the ice-water). Importantly, these observations suggested that the self-expandability of the MNP-SMP nanosheet was driven only by temperature-mediated shape memory effect, not by other factors such as structural and mechanical properties of the MNP-SMP nanosheet and/or the shear forces due to the flow associated with the ejection of the nanosheet. Once it is released in water, magnetic guidability of the MNP-SMP nanosheet was demonstrated using a neodymium magnet. The location of the MNP-SMP nanosheets floating in 37°C water may be readily controlled by the neodymium magnet at 1 cm away from the sheet.

Functionalization with PLGA nanosheet

[0063] In various example embodiments, the polymeric thin film may comprise the shape memory polymer layer having the magnetic nanoparticles thereon and a polymer layer functioning as a carrier of a therapeutic substance (e.g., trilayered film). In various example embodiments, the polymer layer may be formed of poly-lactic-co-glycolic acids (PLGAs). For example, the trilayered polymeric thin film may comprise a shape memory polymer layer, magnetic nanoparticles thereon, and the polymer layer formed of PLGAs. The trilayered polymeric thin film may be used for delivery of molecular drugs or cellular constructs into internal organs. For example, the polymer layer functioning as a carrier of a therapeutic substance may be a biodegradable platform to release drugs on biological tissues or deliver engineered cells in organs. In various example embodiments, the trilayered polymeric thin film may be a syringe-injectable, self-expandable and magnetic guidable thin film platform. FIG. 14A shows schematic illustration for the structure of an exemplary polymeric thin film 200. The polymeric thin film 200 may be formed of the shape memory polymer layer 210 having the magnetic nanoparticles 220 thereon and the polymer layer 230 functioning as a carrier of a therapeutic substance (e.g., PLGA-MNP- SMP nanosheet).

[0064] The polymer layer 230 functioning as a carrier of a therapeutic substance may be stained using a staining agent such as Rhodamine B. The polymer layer 230 may be formed onto the magnetic nanoparticle layer 220 on the shape memory polymer layer 210. In various example embodiments, the polymer layer 230 may be formed by spin-coating a PLGA/Rhodamine B solution in dichlorome thane. The free-standing polymeric thin film 200 comprising the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer (e.g., PLGA-MNP-SMP nanosheet) may be ejected from a medical ejection apparatus. FIG. 14B shows an exemplary free-standing polymeric thin film 200 comprising the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer (e.g., PLGA-MNP-SMP nanosheet) stored in a fluid chamber 310 of a medical injection apparatus 300. In particular, FIG. 14B shows a free standing PLGA-MNP-SMP nanosheet (e.g., having dimension of 10 mm x 10 mm) floating in a 5mL- volume syringe filled with the water at 37°C. For example, the free-standing polymeric thin film 200 may be prepared with the memorized conformation being a square shape. However, it will be appreciated by a person skilled in the art that other memorized conformation, such as rectangular or oval shapes, may also be used. In an example, the free-standing polymeric thin film may have a surface area dimension of 10 mm x 10 mm, and a thickness of about 917 ± 34 nm. The medical injection apparatus 300 may have a hollow needle 320 through which the free-standing polymeric thin film 200 may be readily ejected under manual pressure. For example, the hollow needle 320 may be a 20G needle.

[0065] A single layered PLGA nanosheet was fabricated (e.g., thickness of about 214 ± 5 nm) as a negative control for the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon (e.g., MNP-SMP layer). The difference of the thickness between the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon (e.g., thickness of about 710 ± 33 nm) and the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer, e.g., PLGA-MNP-SMP nanosheet, (e.g., thickness of about 917 ± 34 nm) enabled the thickness of the PLGA layer of the PLGA-MNP-SMP nanosheet to be estimated. The thickness of the PLGA layer of the PLGA-MNP-SMP nanosheet was estimated to be 207 ± 47 nm, which was comparable to the thickness of a single layered PLGA nanosheet. FIG. 15A shows an exemplary graph 1530 illustrating the height profile (or thickness) of PLGA-MNP-SMP nanosheet 1535 and single-layered PLGA nanosheet 1537 collected on a silicon wafer.

[0066] To observe the functionality of the injected polymeric thin film, a sphere ball 1540 (e.g., transparent) may be fabricated as a simple model of an internal organ, as illustrated in FIG. 15B. For example, the sphere ball 1540 may include a calcium alginate membrane filled water. The polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon and a polymer layer (e.g., PLGA-MNP-SMP nanosheet) may be injected into the water- contained calcium alginate ball in a 37 °C water bath using the medical injection apparatus 300. FIG. 15C shows an image of a crumpled PLGA single-layered nanosheet ejected from a syringe through a 20G needle in water. As shown in FIG. 15C, the single layered PLGA nanosheet did not expand to a memorized conformation (e.g., flat sheet) after the injection into the ball 1540 containing water. FIG. 15D shows an image of a polymeric thin film comprising a shape memory polymer layer having the magnetic nanoparticles thereon and a polymer layer (e.g., PLGA-MNP-SMP nanosheet). In particular, FIG. 15D shows the PLGA-MNP-SMP nanosheet expanded to a memorized conformation (e.g., flat sheet) immediately after the injection (e.g., from a syringe through a 20G needle in water). FIG. 15E illustrates the polymeric thin film being guided using an external magnetic field. In particular, FIG. 15D shows an image of a PLGA-MNP-SMP nanosheet attached to the inner wall of the calcium alginate ball guided by a neodymium magnet placed to the outer wall. For example, the PLGA-MNP-SMP nanosheet was successfully guided to the intended location of the inner surface of the ball with a neodymium magnet placed outside of the ball. These demonstrations confirmed that the polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon (e.g., MNP-SMP nanosheet) may be functionalized with the polymer layer (e.g., PLGA layer) (e.g., with 200nm thickness) without compromising its self expandability and magnetic guidability. It is found that the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon (e.g., MNP- SMP nanosheet) conferred the same capabilities to the polymeric thin film formed of the shape memory polymer layer having the magnetic nanoparticles thereon and the polymer layer (e.g., PLGA-MNP-SMP nanosheet), suggesting the vast potentials of the developed polymeric thin film for drug and cell delivery. The polymeric thin film comprising the shape memory polymer layer having the magnetic nanoparticles thereon may overcome the limitation of conventional delivery systems based on the syringe injectable nanosheets with regard to large surface area or size, shape recovery ability and motion control after injection.

[0067] FIG. 16 shows an exemplary chemical structure 1600 of a thermoplastic polyurethane shape memory polymer (SMP) which may be used for the shape memory polymer layer.

[0068] FIG. 17 shows an image 1700 of an exemplary polymeric thin film 200 according to various embodiments of the present invention. The polymeric thin film 200 may comprise a shape memory polymer layer having magnetic nanoparticles thereon. In particular, the polymeric thin film 200 as illustrated in image 1700 may be prior to removal from a liquid-soluble supporting layer (e,g„ PVA layer). For example, the image 1700 illustrates a MNP-SMP-PVA trilayered film (e.g., having a dimension of about 15 mm x 15mm).

[0069] FIG. 18A shows an image 1810 illustrating a medical injection apparatus 300 comprising a polymeric thin film 200 for delivery according to various embodiments of the present invention. In particular, the image 1810 illustrates the free-standing polymeric thin film 200 floating in a 5mL-volume syringe filled with water having a temperature of about 37°C. FIG. 18B shows an image 1820 illustrating the polymeric thin film 200 of FIG. 18A being ejected from the medical injection apparatus 300 according to various embodiments of the present invention. In particular, the image 1820 illustrates the polymeric thin film 200 ejected from a 20G needle of the medical injection apparatus 300. FIG. 18C shows an image 1830 illustrating the polymeric thin film 200 of FIG. 18A after being ejected from the medical injection apparatus according to various embodiments of the present invention. In particular, the image 1830 shows an expanded polymeric thin film 200 after being ejected from a syringe through a 20G needle into the water at 31° C. FIG. 18D shows another image 1840 illustrating the polymeric thin film 200 of FIG. 18A after being ejected from the medical injection apparatus 300 according to various embodiments of the present invention. In particular, the image 1840 shows a crumpled polymeric thin film 200 after being ejected from a syringe through a 20G needle at 0°C in ice water. FIG. 18E shows an image 1850 illustrating the polymeric thin film 200 of FIG. 18A being moved by an external magnetic field according to various embodiments of the present invention. In particular, the image 1850 comprises three overlaid images illustrating the polymeric thin film 200 being guided by a neodymium magnet in 37°C water.

[0070] While embodiments of the invention have been particularly shown and described with reference to specific embodiments, it should be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims. The scope of the invention is thus indicated by the appended claims and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced.