Three novel bisphosphonate-functionalized secondary diamines are synthesized and incorporated into poly(β-amino ester)s (PBAEs) to investigate the effects of bisphosphonates on biodegradation and toxicity of PBAE polymer networks. These three novel amines, BPA1, BPA2, and BPA3, were prepared from the reactions of 1,4-butanediamine, 1,6-hexanediamine, or 4,9-dioxa-1,12-dodecanediamine with tetraethyl vinylidene bisphosphonate, respectively. The PBAE macromers were obtained from the aza-Michael addition reaction of these amines to 1,6-hexane diol diacrylate (HDDA) and poly(ethylene glycol) diacrylate (PEGDA, M = 575) and photopolymerized to produce biodegradable gels. These gels with different chemistries exhibited similar degradation behavior with mass loss of 53-73% within 24 h, indicating that degradation is mostly governed by the bisphosphonate group. Based on the in vitro cytotoxicity evaluation against NIH 3T3 mouse embryonic fibroblast cells, the degradation products do not exhibit significant toxicity in most cases. It was also shown that PBAE macromers can be used as cross-linkers for the synthesis of 2-hydroxyethyl methacrylate hydrogels, conferring small and customizable degradation rates upon them. The materials reported have potential to be used as nontoxic degradable biomaterials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1412-1421, 2017.
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–Ca 2+ bonds acting as additional cross-links. Cyclic mechanical tests reveal self-recoverability of hydrogels because of reversible nature of BP–Ca 2+ 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.
Novel phosphonic acid-functionalized poly(amido amine) (PAA) macromers are synthesized through aza-Michael addition of 2-aminoethyl phosphonic acid or its mixture with 5-amino-1pentanol at different ratios onto N,N′ -methylene bis(acrylamide) to control the amount of phosphonic acid functionality. The macromers were homo-and copolymerized with 2hydroxyethyl methacrylate at different ratios to obtain hydrogels with various hydrophilicities.The hydrogels' swelling, biodegradation and mineralization properties were evaluated. The swelling and degradation rates of the gels can be tuned by the chemical structure of PAA macromer precursors as well as pH and CaCl2 pre-treatment. The hydrogels show compositiondependent mineralization in SBF and 5xSBF, as evidenced from Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) analyses. The degradation products of the hydrogels have no effect on U-2 OS, Saos-2 and NIH 3T3 cells, suggesting their cytocompatibility. Overall, these materials have potential to be used as nontoxic degradable biomaterials.
Incorporation of bisphosphonate/bisphosphonic acid groups in dental monomer structures should increase interaction of these monomers with dental tissue as these groups have strong affinity for hydroxyapatite. Therefore, new urea dimethacrylates functionalized with bisphosphonate (1a, 1b) and bisphosphonic acid (2a, 2b) groups are synthesized and evaluated for dental applications. Monomers 1a and 1b are synthesized from 2isocyanatoethyl methacrylate (IEM) and two bisphosphonated amines (BPA1 and BPA2), prepared as reported elsewhere. Selective dealkylation of the bisphosphonate ester groups of 1a and 1b using trimethylsilyl bromide (TMSBr) gives monomers (2a and 2b) with bisphosphonic acid functionality. X-ray diffractometer (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS) analyses of monomer-treated HAP particles show that 2a induces formation of stable monomer-calcium salts, similar to 10methacryloyloxydecyl dihydrogen phosphate (MDP), with higher chemical interaction than 2b. The photopolymerization studies indicate good copolymerizability with commercial dental monomers. In vitro studies on NIH 3T3 mouse embryonic fibroblast cells have clearly shown that the tested monomers (1b and 2b) are not toxic according to the MTT standards. All these properties make these monomers suitable as biocompatible cross-linkers/adhesives for dental applications.
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