Synthesis and evaluation of new bisphosphonate-functionalized (meth) acrylates for biomedical applications

In the first part of this work, new urea dimethacrylates functionalized with bisphosphonate (1a, 1b) and bisphosphonic acid (2a, 2b) groups were synthesized and evaluated for dental applications. Monomers 1a and 1b were synthesized from 2-isocyanatoethyl methacrylate (IEM) and two bisphosphonated amines (BPA1 and BPA2, prepared by the reaction of 1,4-butanediamine and 1,6-hexanediamine with ethylidene bisphosphonate, respectively). Selective cleavage of the bisphosphonate ester groups of 1a and 1b was achieved using trimethylsilyl bromide (TMSBr) to give monomers 2a and 2b. These acid monomers were found to be hydrolytically stable and have pH values (1.73 and 1.81) in the range expected for mild self-etching dental adhesives. Monomers were copolymerized with 2-hydroxyethyl methacrylate (HEMA), triethylene glycol dimethacrylate (TEGDMA) and bisphenol A-glycolate methacrylate (Bis-GMA) using real time FT-IR with 2,2'-dimethoxy-2-phenyl acetophenone (DMPA) as photoinitiator. Conversions obtained for the bisphosphonic acid monomer formulations were about the same as the bisphosphosphonate formulations, but the polymerization rates were faster due to hydrogen bonding. XRD spectrum of HAP treated with 2a/EtOH/H2O solutions proved formation of hydrolytically stable monomer Ca salts and CaHPO4.2H2O (DCPD) induced by demineralization. Also these monomers were found show no significant toxicity. All these properties indicated that the synthesized monomers are suitable candidates for dental materials. In the second part of this work, four novel bisphosphonate-functionalized poly(-amino ester) (PBAE) macromers were synthesized through aza-Michael addition of 1,6-hexane diol diacrylate (HDDA) or poly(ethylene glycol) diacrylate (PEGDA, Mn=575), and BPA1 or BPA2. The macromers were homo- and co polymerized with HEMA in the presence of DMPA as photoinitiator to give biodegradable gels and their properties were studied (degradation). The mass loss of the homopolymers were found to be similar and around 53-69% at 37 °C in 1 day. It was shown that PBAE macromers can be used as crosslinkers for the synthesis of HEMA hydrogels. These hydrogels showed higher and mass loss than those made with PEGDA crosslinkers. These materials have potential in tissue engineering applications.