Research ArticleDrug Delivery

Temperature-responsive biometamaterials for gastrointestinal applications

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Science Translational Medicine  17 Apr 2019:
Vol. 11, Issue 488, eaau8581
DOI: 10.1126/scitranslmed.aau8581
  • Fig. 1 In vivo evaluation of heat dissipation in the upper GI tract.

    (A) A radiograph showing the position of the 16 temperature probes (green numbers indicate K-type thermocouples, shown magnified in the inset) arranged in the esophagus and stomach of a Yorkshire pig secured in seated position. The pink arrow indicates direction of water delivery. (B) Schematic depicting temperature decay in the upper GI tract when 100 ml of 55°C water (pseudocolored pink) was orally administered. (C) Temperature changes (ΔT) in the upper GI tract during administration of 55°C volumes of water [V = 10, 20, 50, 100, 200, and 250 ml] in 10 s as a function of probe number i, i = 1, 2, …, 16, as shown in (A). Data are reported as means ± SD for n = 3 measurements for each group. *P < 0.05 (versus V = 100 ml at corresponding probe by one-way analysis of variance (ANOVA)].

  • Fig. 2 Esophageal flower-like system.

    Schematic and prototype images of the flower-like system, illustrating the configurations when folded (before administration), deployed in the esophagus, and folded again following temperature triggering. The components of the design including polymeric arms (light gray), elastic recoil elements (dark gray), nitinol springs (orange), and dissoluble millineedles (green) are shown.

  • Fig. 3 Mechanical characterization, in vivo deployment, and ex vivo evaluation of the flower-like prototype.

    (A) Schematic depicting transformable folded and expanded configurations and corresponding recoiling forces of the elastic elements (FcrElastollan) and the nitinol springs (Fcrnitinol). The dimensions of the prototype are shown in millimeters. Fcrnitinol for nitinol springs with a wire diameter ϕ = 0.5 mm reported for differing number of coils (n) and coil diameters (d) in (B). The dashed black line represents FcrElastollan=0.4 N for a given dimension of the prototype. The blue area represents the experimentally observed valid design space. (C) In vivo endoscopic images of the prototype in pig’s esophagus in different configurations: (i) folded, (ii) deployed in direct and reverse directions, and (iii) folded after administration of 100 ml of 55°C water. (D) Radiograph and (E) histology results indicating penetration and dissolution of millineedles. (F) IVIS (in vivo imaging system) visualization of millineedle-administered dextran fluorescence in esophageal tissue. The control needle was devoid of dextran. The inset shows the optical image of the penetration sites highlighted with white circles. (G) Concentration of budesonide delivered to the esophageal tissue for n = 3 prototypes [each prototype is shown by a different color and consisted of one control needle (triangle) and three drug-loaded needles (circles)]. The inset shows a millineedle loaded with 0.1 mg of budesonide at the tip.

  • Fig. 4 Flexible mechanical metamaterial as a macrostructure dosage form.

    The schematic and prototype images of the metamaterial dosage form illustrating the sequence of deployment in stomach and the building components including drug-carrying arms (light gray), elastic hinges (dark gray), and TRLs (orange). The right panel shows temperature-triggered configuration by endoscopically applying warm water (55°C) to trigger the disassembly.

  • Fig. 5 Characterization of metamaterial dosage form in vitro and in vivo.

    (A) In vitro cumulative drug release and ultimate flexural strength and strain of drug-loaded arms for MOX and CAR formulations incubated in 37°C SGF for 14 days. Markers and column bars represent the mean ± SD for n = 3 samples per group. *P < 0.05, one-way ANOVA and post hoc Bonferroni multiple comparison tests were used to determine the significance (days 1, 7, and 14 versus day 0). (B) Representative abdominal radiographs and endoscopic images obtained at various time points after metamaterial dosage form administration. (C) Serum concentration profiles over 15 days and (D) pharmacokinetic analysis of CAR administered as an immediate release formulation (orange) versus macrostructure dosage form (blue). (E) Effect of temperature on ultimate flexural strength and strain of drug-loaded arm segments with TRLs incubated in 37°C SGF for 14 days. Two-sample t tests were used to determine the significance. *P < 0.05 [not exposed to warm water (−) versus exposed to warm water (+)]. (F) In vivo endoscopic images showing the weakening sequence of a TRL for a macrostructure after spraying 200 ml of 55°C water 7 days after gastric metamaterial dosage form deployment in a porcine model.

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/11/488/eaau8581/DC1

    Fig. S1. Temperature testing setup.

    Fig. S2. Evolution of temperature measured while administering warm water.

    Fig. S3. Flower-like prototype.

    Fig. S4. Fabrication and assembly of the flower-like prototype.

    Fig. S5. Heat treatment of shape-memory nitinol.

    Fig. S6. Mechanical characterization of the flower-like prototype.

    Fig. S7. Fabrication of degradable millineedles.

    Fig. S8. Reconfigurable mechanical metamaterial as a macrostructure dosage form.

    Fig. S9. Drug stability and in vitro release of drug-loaded arms.

    Fig. S10. Mechanical characterization of the drug-loaded arms by three-point bending tests.

    Fig. S11. Mechanical characterization of the interfaces between the polymer arms and elastic hinges by uniaxial tension tests.

    Movie S1. In vivo deployment, closure, and passage of the flower-like prototype in the esophagus.

    Movie S2. In vivo deployment, closure, and passage of the flower-like prototype in the esophagus in the reverse direction.

    Data file S1. Primary data (provided as an Excel file).

  • The PDF file includes:

    • Fig. S1. Temperature testing setup.
    • Fig. S2. Evolution of temperature measured while administering warm water.
    • Fig. S3. Flower-like prototype.
    • Fig. S4. Fabrication and assembly of the flower-like prototype.
    • Fig. S5. Heat treatment of shape-memory nitinol.
    • Fig. S6. Mechanical characterization of the flower-like prototype.
    • Fig. S7. Fabrication of degradable millineedles.
    • Fig. S8. Reconfigurable mechanical metamaterial as a macrostructure dosage form.
    • Fig. S9. Drug stability and in vitro release of drug-loaded arms.
    • Fig. S10. Mechanical characterization of the drug-loaded arms by three-point bending tests.
    • Fig. S11. Mechanical characterization of the interfaces between the polymer arms and elastic hinges by uniaxial tension tests.
    • Legends for movies S1 and S2

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mp4 format). In vivo deployment, closure, and passage of the flower-like prototype in the esophagus.
    • Movie S2 (.mp4 format). In vivo deployment, closure, and passage of the flower-like prototype in the esophagus in the reverse direction.
    • Data file S1. Primary data (provided as an Excel file).

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