Biocompatible poly(methylidene malonate)-made materials for pharmaceutical and biomedical applications.

In the past 20 years, mainly with the sponsorship of Laboratoires UPSA (France) and, afterwards, its spin-off company Virsol (France), several authors have studied methylidene malonate-based polymers used in drug delivery approaches and in the development of novel biomaterials. The present paper aims at summing up the preparation of methylidene malonate monomers, and essentially a novel asymmetric diester structure: 1-ethoxycarbonyl-1-ethoxycarbonylmethylenoxycarbonyl ethene named methylidene malonate 2.1.2. Their polymeric and copolymeric derivatives and a few of their applications which were reported in the literature are also presented. It encompasses the manufacturing of particulate systems such as nano- and macroparticles designed for the delivery of hydrophilic or hydrophobic drugs and biomolecules. This review article also describes their use as biomaterials of interest in the fields of tissue repair, as drug reservoirs or ophthalmology, as implants. Copolymers based on these monomers offer a large range of properties and could be used as new surfactants, micellar vectors, or particulate systems for gene delivery. Therefore, this review, certainly the first dedicated exclusively to methylidene malonate-based materials, highlights the great biomedical and pharmaceutical technology potential of these new materials.

Sustained delivery of growth factors from methylidene malonate 2.1.2-based polymers.

The incorporation of growth factors into new methylidene malonate 2.1.2-based biocompatible polymeric blends of oligomers and polymers to improve their stability and controlled release was investigated. Five growth factors were used in this study: FGF2, PDGF, TGF-beta, NGF and GM-CSF. Formulation in poly(methylidene malonate 2.1.2) blends was achieved by a four-step optimized process, using different oligomers/polymers ratios. Once dried, formulations could be subsequently stored at 4 or 20 degrees C or immediately subjected to degradation in conditioned cell culture medium. Toxicity of blends and their degradation products were evaluated in several cell lines with MTT. Bioactivity and biospecificity of the formulated growth factors were investigated using MTT and immunohistochemical staining. Combined ELISA and crystal violet colorimetric assays were performed to analyze growth factors release. Limited toxicities were observed for unloaded poly(methylidene malonate 2.1.2) blends. Once optimized, growth factors formulations did not reveal lower bioactivities or loss of biospecificity. Moreover, a sustained release over a 21-day period with more than 90% of preserved bioactivity was reached. To conclude, dual growth factor delivery was made possible by the mean of poly(methylidene malonate 2.1.2) blends. These studies demonstrate the ability of methylidene malonate 2.1.2-based polymeric blends for the delivery of growth factors.