Development of Polyurethane/Peptide-Based Carriers with Self-Healing Properties

Abstract

In situ-forming gels with self-assembling and self-healing properties are materials of high interest for various biomedical applications, especially for drug delivery systems and tissue regeneration. The main goal of this research was the development of an innovative gel carrier based on dynamic inter- and intramolecular interactions between amphiphilic polyurethane and peptide structures. The polyurethane architecture was adapted to achieve the desired amphiphilicity for self-assembly into an aqueous solution and to facilitate an array of connections with peptides through physical interactions, such as hydrophobic interactions, dipole-dipole, electrostatic, π-π stacking, or hydrogen bonds. The mechanism of the gelation process and the macromolecular conformation in water were evaluated with DLS, ATR-FTIR, and rheological measurements at room and body temperatures. The DLS measurements revealed a bimodal distribution of small (~30-40 nm) and large (~300-400 nm) hydrodynamic diameters of micelles/aggregates at 25 °C for all samples. The increase in the peptide content led to a monomodal distribution of the peaks at 37 °C (~25 nm for the sample with the highest content of peptide). The sol-gel transition occurs very quickly for all samples (within 20-30 s), but the equilibrium state of the gel structure is reached after 1 h in absence of peptide and required more time as the content of peptide increases. Moreover, this system presented self-healing properties, as was revealed by rheological measurements. In the presence of peptide, the structure recovery after each cycle of deformation is a time-dependent process, the recovery is complete after about 300 s. Thus, the addition of the peptide enhanced the polymer chain entanglement through intermolecular interactions, leading to the preparation of a well-defined gel carrier. Undoubtedly, this type of polyurethane/peptide-based carrier, displaying a sol-gel transition at a biologically relevant temperature and enhanced viscoelastic properties, is of great interest in the development of medical devices for minimally invasive procedures or precision medicine.

Keywords: amphiphilic polyurethane structure; polyurethane/peptide gel; self-assembly; self-healing carrier; viscoelastic behavior.

Figure 1

(a) Synthesis route and (b) IR spectrum of APU.

Figure 2

Illustration of self-assembly behavior of polyurethane/peptide-based gel: (a) Optical images of tub inverted test containing samples at 25 °C and 37 °C; (b) Self-assembling representation in sol and gel states; (c) Some physical inter- and intramolecular interactions during gel formation.

Figure 3

Dynamic light scattering data of polyurethane/peptide-based carriers: (a–d) Size distribution of micelles for M and P3 samples at 25 and 37 °C, respectively; The influence of the polyurethane/peptide mass ratio on the (e) Z-average and (f) zeta potential at 25 and 37 °C.

Figure 4

ATR-FTIR spectra of solutions (25 °C) and gels (37 °C) for the investigated samples compared with raw APU and peptide spectra.

Figure 5

Variation of the peak area between (a) 3616 and 3330 cm⁻¹ and (b) 1760 and 1639 cm⁻¹ as a function of increasing temperature for the investigated samples.

Figure 6

G′ variation during gelation induced by temperature increase at different heating rates (a) 1 °C/min (full symbols) and 0.5 °C/min (lines); (b) viscoelastic parameters for sample P3 as a function of temperature for a heating rate of 0.5 °C/min.

Figure 7

(a,b) Evolution of G′ during gelation at 37 °C for all investigated samples; (c,d) Viscoelastic parameters G′, G″ and tanδ during gelation for sample P2. The samples were first tested at 25 °C for 120 s, then the temperature was suddenly switched to 37 °C, and in situ gelation was monitored through the rheological parameters. (b,d) detail the behavior of the systems at the beginning of gelation.

Figure 8

The elastic modulus (a) and loss tangent (b) during the experiments at low and high successive step strains applied every 300 s.

Figure 9

Plots of apparent viscosity as a function of shear rate for all investigated samples in stationary shear conditions (a) at increasing shear rate; (b) curves of apparent viscosity for samples M and P3 at increasing (full symbol) and decreasing (open symbol) shear rate.

Figure 10

The behavior of gel samples (M, P1, P2 and P3) during creep at 2 Pa (a) strain during creep and recovery tests (b) J(t) during creep tests.

Figure 11

(a,b) Strain and (c) creep compliance during creep and recovery tests for P3 gel sample submitted successively to increasing shear stress values.

Figure 12

Stability profile for polyurethane/peptide-based carriers at 37 °C in PBS. Statistical significance: *** p < 0.001; ** 0.001 < p < 0.01; * 0.01 < p < 0.05.