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. 2018 Aug 2;3(8):8638-8647.
doi: 10.1021/acsomega.8b01103. eCollection 2018 Aug 31.

Bisphosphonic Acid-Functionalized Cross-Linkers to Tailor Hydrogel Properties for Biomedical Applications

Melek N Guven  1 , Merve S Altuncu  1 , Tugba Bal  2 , Dilem C Oran  2 , Umit Gulyuz  3 , Seda Kizilel  2 , Oguz Okay  4 , Duygu Avci  1
Affiliations

Bisphosphonic Acid-Functionalized Cross-Linkers to Tailor Hydrogel Properties for Biomedical Applications

Melek N Guven et al. ACS Omega. .

Abstract

Two bisphosphonic acid-functionalized cross-linkers (one novel) with different spacer chain characteristics were synthesized and incorporated into hydrogels by copolymerization with 2-hydroxyethyl methacrylate at different ratios to control the hydrogels' swelling, mechanical properties, and ability to support mineralization for biomedical applications. The cross-linkers were synthesized by reaction of 2-isocyanatoethyl methacrylate and bisphosphonated diamines followed by selective dealkylation of the bisphosphonate ester groups. The hydrogels provide in vitro growth of carbonated apatite, morphology affected by the cross-linker structure. The hydrogels exhibit a high Young's modulus E (up to 400 kPa) and can sustain up to 10.2 ± 0.1 MPa compressive stresses. E and hence the cross-link density significantly increases upon mineralization reflecting the formation of many bisphosphonate BP-Ca2+ bonds acting as additional cross-links. Cyclic mechanical tests reveal self-recoverability of hydrogels because of reversible nature of BP-Ca2+ bonds. The results suggest that these cross-linkers can add calcium-binding abilities to hydrogels synthesized from any monomer and improve their mechanical, swelling, and mineralization properties and hence are potentially useful materials for biomedical applications.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Synthesis of bisphosphonic acid-functionalized cross-linkers.
Figure 2
Figure 2
1H NMR spectra of 1b and 2b.
Figure 3
Figure 3
13C NMR spectra of 1b and 2b.
Figure 4
Figure 4
IR spectra of 1b and 2b.
Figure 5
Figure 5
SEM images of (top) hydrogels before mineralization, (middle) after 2 weeks of mineralization, and (bottom) after 4 weeks of mineralization. Left column shows the H2a:10:20 hydrogel, right column, H2b:10:20 hydrogel.
Figure 6
Figure 6
SP of the hydrogels.
Figure 7
Figure 7
Ca2+ content of the hydrogels (H2a:10:20 and H2b:10:20) after 4 weeks of mineralization in water (control) and SBF.
Figure 8
Figure 8
EDX analysis of hydrogels after 4 weeks of mineralization in water (control) and SBF: (A,B) show H2a:10:20 hydrogel, (C,D) H2b:10:20 hydrogel.
Figure 9
Figure 9
X-ray diffraction spectra for hydrogels after 2 weeks of mineralization in SBF.
Figure 10
Figure 10
Stress–strain curves of H2a:X:25 (a) and H2b:X:25 hydrogels (b) at various cross-linker contents in water (solid curves) and in aqueous 1 M CaCl2 solution (dashed curves). Nominal stress σnom is plotted against strain ε at a strain rate of 1.8 × 10–2 s–1.
Figure 11
Figure 11
Young’s modulus E and fracture stress σf of the hydrogels in water (circles) and in aqueous 1 M CaCl2 solution (triangles) plotted against the cross-linker (2a) content. Total monomer concentration = 25 wt %.
Figure 12
Figure 12
(a) Stress–strain curves of H2b:10:20 (solid curve) and H2b:10:25 hydrogels (dashed curve) formed at monomer concentrations of 20 and 25 wt %, respectively. (b,c) Cyclic compressive test results with increasing maximum strain εmax from 50 to 90% (b) and for 3 successive cycles up to εmax = 90% (c) for H2b:10:20 hydrogel equilibrium swollen in water. The inset to (c) shows the hysteresis energy Uhys plotted against εmax (circles) and the number of cycles up to εmax = 90% (triangles).
Figure 13
Figure 13
(a,b) Cyclic compressive test results of H2a:10:20 hydrogels immersed in water (a) and in 1 M CaCl2 solution (b) with increasing maximum strain εmax from 50 to 80%. The inset to (a) shows the hysteresis energy Uhys plotted against εmax for the hydrogels in water (circles) and in 1 M CaCl2 solution (triangles). (c) Three successive compressive cycles up to εmax = 80% for H2a:10:20 hydrogels immersed in water and in 1 M CaCl2 solution.
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