Mechanochromic shape memory polymers with simultaneous shape and color change

Abstract

A shape memory polymer that provides a color-based visual cue for shape change. The shape memory polymer can be used for sensing, where a material is designed to change shape in the presence of a specific reagent, whether chemical (such as a particular acid or reactive oxygen species) or biological (such as a particular bacterial or mammalian enzyme). The shape change coupled with the color change will enhance surveillance of the presence of these reagents and would be particularly useful when used in a wound dressing to detect the presence of a bacterial infection. Materials formed from the shape memory polymer may also be used to sense small-scale deformations of surfaces by cells or mechanical forces.

Description

TITLEMECHANOCHROMIC SHAPE MEMORY POLYMERS WITH SIMULTANEOUS SHAPE AND COLOR CHANGEBACKGROUND OF THE INVENTION1. FIELD

[0001] The present disclosure relates to shape memory polymers and, more particularly, to shape memory polymers incorporating chromogenic compounds for variations in fluorescence, color, and shape in response to certain stimuli.2. DESCRIPTION OF THE RELATED ART

[0002] Chronic wounds are difficult to resolve due to a combination of impaired wound physiology and bacterial infections. Infections in chronic wounds prevent healing and are ubiquitous as about 6.5 million are affected annually in the US with a rate of about 3 out of 1000 globally. Treatment of these infections costs over 90 billion USD annually.

[0003] Polyurethane (PUR) based shape memory polymer that change shape in the presence of bacteria to aid in infection surveillance in chronic wounds have been developed. Although such polymers are useful in monitoring wounds, there is a need for a composition that will undergo simultaneous shape and color changes in the presence of bacteria to further enhance the visible detection of infected wounds.BRIEF SUMMARY OF THE INVENTION

[0004] The present invention involves the incorporation of spiropyran (SP) mechanophores into polyurethane PUR shape memory polymers to form SP-containing PUR (PUR / SP) wound dressings that can undergo simultaneous shape and color changes in the presence of bacteria to enhance visible detection of infected wounds.

[0005] In one embodiment, the present invention is a wound dressing formed from a polyurethane shape memory polymer, a substrate of a bacterial protease incorporated into the polyurethane shape memory polymer, and a mechanophore incorporated into the polyurethane shape memory polymer. The polyurethane shape memory polymer may be a reaction product of hexamethylene diisocyanate and polypropylene glycol, wherein the reaction product has been extended with triethylene glycol. The substrate of the bacterial protease may be a peptide that is covalently bound to the polyurethane shape memory polymer. The peptide may be poly(glutamic acid). The mechanophore may be incorporated into the polyurethane by either physical or chemical incorporation. The mechanophore may be a spiropyran mechanophore.122190438. v1 -8 / 26 / 25

[0006] In another embodiment, the present invention is a method of monitoring a wound for an infection. One step involves applying a wound dressing to the wound, wherein the wound dressing has a first shape configuration and a first color and comprises a polyurethane shape memory polymer, a substrate of a bacterial protease incorporated into the polyurethane shape memory polymer, and a mechanophore incorporated into the polyurethane shape memory polymer. Another step entails observing the wound dressing for changes from the first shape configuration and the first color and to at least one of a second configuration and a second color. The polyurethane shape memory polymer may be a reaction product of hexamethylene diisocyanate and polypropylene glycol, wherein the reaction product has been extended with triethylene glycol. The substrate of the bacterial protease may be a peptide that is covalently bound to the polyurethane shape memory polymer. The peptide may be poly(glutamic acid). The mechanophore may be incorporated into the polyurethane by either physical or chemical incorporation. The mechanophore may be a spiropyran mechanophore.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0007] The present invention will be more fully understood and appreciated by reading the following Detailed Description in conjunction with the accompanying drawings, in which:

[0008] FIG. 1 is a series of images showing a bacteria-responsive polyurethane shape memory polymer that responds with a shape change when exposed to bacterial proteases.

[0009] FIG. 2 is a schematic showing an approach for synthesizing polyurethane shape memory polymers that are responsive to bacterial proteases for use as wound dressings.

[0010] FIG. 3 is (A) a diagram of the structure of polyurethane shape memory polymers that are responsive to bacterial proteases and (B) a graph of the Fourier transform infrared spectra of polyurethane shape memory polymers that are responsive to bacterial proteases according to the present invention.

[0011] FIG. 4 is a graph of the shape recovery time of polyurethane shape memory polymers that are responsive to bacterial proteases when exposed to various concentrations of S aureus.

[0012] FIG. 5 is a graph of the percentage of shape recovery of polyurethane shape memory polymers that are responsive to bacterial proteases when exposed to various concentrations of S aureus over varied time frames.222190438. v1 -8 / 26 / 25

[0013] FIG. 6 is a graph of the specificity of polyurethane shape memory polymers that are responsive to bacterial proteases in the presence of different mammalian and bacterial proteases.

[0014] FIG. 7 is a series of images showing the shape recovery of polyurethane shape memory polymers that are responsive to bacterial proteases in representative bacterial and mamallian enzymes.

[0015] FIG. 8 is a pair of images showing the color change of polyurethane (PUR) shape memory polymers that incorporate spiropyran (SP) mechanophores according to the present invention when exposed to white light and UV light.

[0016] FIG. 9 is an image of the color change of polyurethane (PUR) shape memory polymers that incorporate spiropyran (SP) mechanophores according to the present invention upon shape recovery.

[0017] FIG. 10 is a series of images showing the color change of polyurethane (PUR) shape memory polymers that incorporate spiropyran (SP) mechanophores according to the present invention in strained and unstrained configurations.DETAILED DESCRIPTION OF THE INVENTION

[0018] Referring to the figures, wherein like numerals refer to like parts throughout, there is seen in FIG. 1, a series of images of polyurethane (PUR) shape memory polymers that are responsive to exposure to bacteria and thus can be used as wound dressings that change shape to indicate the presence of bacterial proteases. As an example, FIG. 1 shows a PUR shape memory polymer that can be expanded into a first strained shape configuration and used as a wound dressing and will then shrink from that first shape configuration to a second smaller shape configuration when exposed to any bacterial proteases.

[0019] Referring to FIG. 2A and 2B, such shape memory polymers may be synthesized by forming a prepolymer from hexamethylene diisocyanate (HD I) and polypropylene glycol (PPG) in the presence of a catalyst. The prepolymer is then extended with a chain extender, such as triethylene glycol (TEG), and a peptide that is digestible by bacterial proteases, such as poly(glutamic acid). This process can form a PUR-PEP polymer that is responsive to the presence of bacterial proteases, as further seen in FIG. 3 A. The structure of the PUR-PEP was confirmed by the Fourier transform infrared spectra of FIG. 3B.

[0020] Strained PUR-PEP samples (n=3) were incubated in mammalian enzymes (matrix metalloproteinase- 1, trypsin, and lysozyme), and in bacterial enzymes (S. aureus V8 and beta-lactamase) at 37°C for 10 days. Sample dimensions were measured using digital322190438. v1 -8 / 26 / 25calipers every 24 hr, and recovery ratios were determined based on differences in length. Strained PUR-PEP samples (n=3) were also incubated in serial dilutions of S. aureus (1 to 109colony forming units (CFUs)) in stasis buffer for 7 days at 37°C. Samples were imaged daily with a camera, and dimensions were quantified using ImageJ software.

[0021] The material recovered in all tested concentrations of bacteria, and a one-way ANOVA showed no association between bacteria concentration and shape recovery (F (1,5) = 0.68, ns), as shown in FIG. 4. Referring to FIG. 5, the majority of the shape recovery of PUR-PEP polymers when exposed to S. aureus occurred within the first 24 hours. Strained PUR-PEP samples underwent significant shape recovery (-55%) (p<0.05) in both mammalian and bacterial enzymes, as seen in FIG. 6. Referring to FIG. 7, PUR-PEP samples undergo visible shape recovery (-55% in 24 hr) in all tested enzymes. A control PUR was stable (<10% recovery) in all tested enzymes. PUR-PEP shape recovery is therefore not specific to bacterial proteases. PUR-PEP is also sensitive to high and low concentrations of bacteria and thus could be used to detect infections early.

[0022] To incorporate SP, 0.31, 0.63, 1.25 and 2.5 mg of spiropyran (SP) mechanophores were dissolved in a solution of the control PUR in chloroform. The solutions were poured into Teflon dishes, and the solvent was evaporated, leaving PUR / SP films. Films were exposed to visible light for 48 hours. Rectangular samples were cut from the films and heated in an isothermal oven, strained, and cooled. A second set of samples was irradiated with UV light for 24 hours. After imaging on the bench, under fluorescence, and under UV, samples were heated to recover their original shapes and imaged again. Dog bones were cut from films and exposed to tensile force (2 mm / min strain rate) with a 24 N load cell with imaging before / after.

[0023] Referring to FIG. 8, the incorporation of spiropyran (SP) mechanophores into the polyurethane (PUR) shape memory polymers results in a film that turns red when exposed to visible light and back to yellow-brown when exposed to UV light. Strained PUR / SP films turn from brown to red upon shape recovery, as seen in FIG. 9, and strained PUR / SP samples show increased green fluorescence compared to unstrained samples, as seen in FIG. 10. SP- containing PUR could thus additionally provide a color-based surveillance of infection in chronic wounds.

[0024] In summary, PUR-PEP has a high sensitivity to bacterial proteases, such as S. aureus protease and thus the ability to response to and provide a visible detection of low- grade infections in chronic wounds. Moreover, the incorporation of a mechanophore enables simultaneous color and shape change for enhanced infection surveillance.422190438. v1 -8 / 26 / 25

Claims

CLAIMSWhat is claimed is:

1. A wound dressing, comprising: a polyurethane shape memory polymer; a substrate of a bacterial protease incorporated into the polyurethane shape memory polymer; and a mechanophore incorporated into the polyurethane shape memory polymer.

2. The wound dressing of claim 1, wherein the polyurethane shape memory polymer is a reaction product of hexamethylene diisocyanate and polypropylene glycol, wherein the reaction product has been extended with triethylene glycol.

3. The wound dressing of claim 2, wherein the substrate of the bacterial protease is a peptide that is covalently bound to the polyurethane shape memory polymer.

4. The wound dressing of claim 3, wherein the peptide is poly(glutamic acid).

5. The wound dressing of claim 4, wherein the mechanophore is incorporated into the polyurethane by at least one of physical incorporation and chemical incorporation.

6. The wound dressing of claim 5, wherein the mechanophore comprises a spiropyran mechanophore.

7. A method of monitoring a wound for an infection, comprising the steps of: applying a wound dressing to the wound, wherein the wound dressing has a first shape configuration and a first color and comprises a polyurethane shape memory polymer, a substrate of a bacterial protease incorporated into the polyurethane shape memory polymer, and a mechanophore incorporated into the polyurethane shape memory polymer. observing the wound dressing for a change from the first shape configuration and the first color and to at least one of a second configuration and a second color.

8. The method of claim 7, wherein the polyurethane shape memory polymer is a reaction product of hexamethylene diisocyanate and polypropylene glycol, wherein the reaction product has been extended with triethylene glycol.

9. The method of claim 8, wherein the substrate of the bacterial protease is a peptide that is covalently bound to the polyurethane shape memory polymer.

10. The method of claim 9, wherein the peptide is poly(glutamic acid).

11. The method of claim 10, wherein the mechanophore is incorporated into the polyurethane by at least one of physical incorporation and chemical incorporation.

12. The method of claim 11, wherein the mechanophore comprises a spiropyran mechanophore.522190438. v1 -8 / 26 / 25

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