Biodegradable and functional aliphatic co-polyesters

2014 - 2015Over the past decades, aliphatic polyesters have found rapidly increasing interest. Linear aliphatic polyesters, such as poly(glycolide) (PGA), poly(lactide) (PLA), poly(ε−caprolactone) (PCL) and their copolymers have found a wide range of practical applications, from packaging to more sophisticated biomedical devices. This class of materials is biocompatible and biodegradable; the degradation products are excreted via the citric acid cycle. The uniqueness of this class of polymers lies in its immense diversity and synthetic versatility. They can be prepared by a variety of monomers via different approaches. The ring-opening polymerization of cyclic esters and lactone is the best strategy. There is still need for improvements to provide materials with enhanced features to address the new requirements of use. A precise control over properties, like hydrophilicity, glass transition, the presence of functional group is important to regulate the biodegradation rate, the thermomechanical properties and it relies on a controlled synthetic pathway. This doctoral thesis was focused on the development of synthetic pathways to obtain aliphatic polyesters with different and controlled microstructures and functional groups by extending the expertise in the ring-opening polymerization of cyclic esters by dimethyl(salicylaldiminato)aluminum compounds. Dimethyl(salicylaldiminato)aluminum compounds with a different steric hindrance at the ortho position of the phenolato ring were tested as catalysts in the ring-opening homo- and co-polymerization of GA, rac-LA and CL. These complexes resulted active for the production of PLGA copolymers with variable microstructure. This copolymer is one of the most used in biomedical field as temporary scaffolds and as drug delivery device. The degradation profile of PLGA is strongly influenced by the microstructure. The copolymerization of GA and LA were performed in bulk and in solution, by varying comonomers ratio, monomer/catalyst feed ratio, temperature, reaction time and solvent. By changing the reaction conditions, copolymers from random, to blocky, to di-block were obtained, demonstrating the versatility of such system in modulating the copolymers microstructure and the related thermal properties. The same catalytic approach was extended to the copolymerization of GA with CL and to the terpolymerization of GA, CL and rac-LA. The formation of random copolymers was favored by the steric hindrance of the catalyst and transesterification reactions contributed to randomize the structure. All the terpolymer samples resulted random and amorphous, the incorporation of the monomers is in this case determined by the bulkiness of the catalyst and by the higher coordination ability of the cyclic esters. While the physical properties can be tailored by copolymerization, the introduction of functional group extends the possible applications to new areas, especially in biomedical field where the binding of biological motifs could enable interactions with cells. Due to the ubiquity of thiol groups in the biological environment and to the pliability of thiol chemistry, an ad hoc lactide-type monomer possessing a pendant thiol-protected group, the 3-methyl-6-(tritylthiomethyl)-1,4-dioxane-2,5-dione was designed and synthetized. Then, this molecule was used as a “building block” for the preparation of functionalized aliphatic co-polyesters by copolymerization with LA and CL promoted by dimethyl(salicylaldiminato)aluminum compounds. After polymerization, the pendant groups incorporated along the chains were converted into pyridyl disulfide functionalities. This derivative was used to prepare porous scaffolds by salt-leaching method after blend with PCLA. The pyridildisulphide groups, which are very reactive in the disulphide exchange reaction, embedded in the 3D porous scaffolds were exploited to graft a cysteine terminated RGD peptide demonstrating the potential of such prepared materials. Finally, dimethyl(salicylaldiminato)aluminum compounds were employed as catalyst in the ring-opening polymerization of an unsaturated large lactone, the ω−6-hexadecenlactone (6HDL). Semicrystalline polyethylene-like unsaturated polyesters were obtained with a good control over the chain growth. The double bonds along the polymeric backbones were used to carry out further modification, which occurred without any change in the degree of polymerization, however, modifying the thermal and structural polymer features. Copolymerization of the 6HDL with the smaller ring size CL produced a true random semicrystalline copolymer. The pseudo-living behaviour of the catalytic system and the absence of transesterification reactions allowed also the preparation of linear block copolymers of 6HDL with CL and/or rac-LA by sequential addition of the monomers. These block copolymers were also semicrystalline. [edited by author]XIV n.s

Engineering 3D degradable, pliable scaffolds toward adipose tissue regeneration; optimized printability, simulations and surface modification

We present a solution to regenerate adipose tissue using degradable, soft, pliable 3D-printed scaffolds made of a medical-grade copolymer coated with polydopamine. The problem today is that while printing, the medical grade copolyesters degrade and the scaffolds become very stiff and brittle, being not optimal for adipose tissue defects. Herein, we have used high molar mass poly(L-lactide-co-trimethylene carbonate) (PLATMC) to engineer scaffolds using a direct extrusion-based 3D printer, the 3D Bioplotter®. Our approach was first focused on how the printing influences the polymer and scaffold’s mechanical properties, then on exploring different printing designs and, in the end, on assessing surface functionalization. Finite element analysis revealed that scaffold’s mechanical properties vary according to the gradual degradation of the polymer as a consequence of the molar mass decrease during printing. Considering this, we defined optimal printing parameters to minimize material’s degradation and printed scaffolds with different designs. We subsequently functionalized one scaffold design with polydopamine coating and conducted in vitro cell studies. Results showed that polydopamine augmented stem cell proliferation and adipogenic differentiation owing to increased surface hydrophilicity. Thus, the present research show that the medical grade PLATMC based scaffolds are a potential candidate towards the development of implantable, resorbable, medical devices for adipose tissue regeneration.publishedVersio

Understanding of how the properties of medical grade lactide based copolymer scaffolds influence adipose tissue regeneration: Sterilization and a systematic in vitro assessment

Aliphatic polyesters are the synthetic polymers most commonly used in the development of resorbable medical implants/devices. Various three-dimensional (3D) scaffolds have been fabricated from these polymers and used in adipose tissue engineering. However, their systematic evaluation altogether lacks, which makes it difficult to select a suitable degradable polymer to design 3D resorbable implants and/or devices able to effectively mimic the properties of adipose tissue. Additionally, the impact of sterilization methods on the medical devices, if any, must be taken into account. We evaluate and compare five different medical-grade resorbable polyesters with l-lactide content ranging from 50 to 100 mol% and exhibiting different physiochemical properties depending on the comonomer (d-lactide, ε-caprolactone, glycolide, and trimethylene carbonate). The salt-leaching technique was used to prepare 3D microporous scaffolds. A comprehensive assessment of physical, chemical, and mechanical properties of the scaffolds was carried out in PBS at 37 °C. The cell-material interactions and the ability of the scaffolds to promote adipogenesis of human adipose tissue-derived stem cells were assessed in vitro. The diverse physical and mechanical properties of the scaffolds, due to the different composition of the copolymers, influenced human adipose tissue-derived stem cells proliferation and differentiation. Scaffolds made from polymers which were above their glass transition temperature and with low degree of crystallinity showed better proliferation and adipogenic differentiation of stem cells. The effect of sterilization techniques (electron beam and ethylene oxide) on the polymer properties was also evaluated. Results showed that scaffolds sterilized with the ethylene oxide method better retained their physical and chemical properties. Overall, the presented research provides (i) a detailed understanding to select a degradable polymer that has relevant properties to augment adipose tissue regeneration and can be further used to fabricate medical devices/implants; (ii) directions to prefer a sterilization method that does not change polymer properties.publishedVersio

Aluminum Alkyl Complexes Bearing Salicylaldiminato Ligands: Versatile Initiators in the Ring-Opening Polymerization of Cyclic Esters

Linear aliphatic polyesters are degradable thermoplastic polymers, which can be obtained by ring-opening polymerization (ROP) of cyclic esters through a coordination-insertion mechanism. Aluminum based organometallic complexes have a leading position as efficient catalysts for this polymerization process. Aluminumalkyl complexes bearing salicylaldiminato ligands, although less explored, have been shown to be efficient and versatile catalysts for the ROP of various cyclic esters. These species have the potential to function as active catalysts in the ROP because of their less coordinatively saturated nature with respect to analogous SALEN-type complexes. They have been used as efficient catalysts in the ROP of commercially available cyclic esters, such as ε-caprolactone, l-lactide, rac-lactide, and glycolide. Moreover, they resulted in efficient catalysts for the ROP of cyclic esters with large ring-size and for the ROP of functionalized lactide. Furthermore, they have been used in the co- and ter-polymerization of various cyclic esters affording well controlled polymerization and a plethora of microstructural architectures, ranging from random to block to multiblock

Aluminum Alkyl Complexes Bearing Salicylaldiminato Ligands: Versatile Initiators in the Ring-Opening Polymerization of Cyclic Esters

Linear aliphatic polyesters are degradable thermoplastic polymers, which can be obtained by ring-opening polymerization (ROP) of cyclic esters through a coordination-insertion mechanism. Aluminum based organometallic complexes have a leading position as efficient catalysts for this polymerization process. Aluminumalkyl complexes bearing salicylaldiminato ligands, although less explored, have been shown to be efficient and versatile catalysts for the ROP of various cyclic esters. These species have the potential to function as active catalysts in the ROP because of their less coordinatively saturated nature with respect to analogous SALEN-type complexes. They have been used as efficient catalysts in the ROP of commercially available cyclic esters, such as ε-caprolactone, l-lactide, rac-lactide, and glycolide. Moreover, they resulted in efficient catalysts for the ROP of cyclic esters with large ring-size and for the ROP of functionalized lactide. Furthermore, they have been used in the co- and ter-polymerization of various cyclic esters affording well controlled polymerization and a plethora of microstructural architectures, ranging from random to block to multiblock

Redox-Responsive Disulfide Cross-Linked PLA–PEG Nanoparticles

We have developed a strategy for the preparation of redox-responsive PEG–PLA-based nanoparticles containing disulfide bonds that can be disassembled in the presence of cellular concentrations of glutathione. Functionalized poly­(lactide)­s were prepared by ring-opening copolymerization of l-lactide and 3-methyl-6-(tritylthio­methyl)-1,4-dioxane-2,5-dione, a monomer bearing a pendant trityl-thiol group, followed by the postpolymerization modification of trityl-thiol into pyridyl disulfide groups. Polymeric networks composed of PLA and PEG blocks linked by disulfide bonds were prepared by a disulfide exchange reaction between the functionalized PLAs and telechelic PEG having thiol groups at both ends, HS-PEG-SH, in DMF. When dialyzed against water, they assembled into dispersible nanoparticles, with a flowerlike structure having a hydrophobic core and a hydrophilic shell, with sizes in the range 167–300 nm that are suitable for drug delivery. The effects of the number of functional groups, molecular weight, and concentration on the nanoparticle size were evaluated. The stability of the nanoparticles after dilution and the redox-responsive behavior in the presence of different concentrations of glutathione were assessed. The hydrophobic molecule Nile red could be encapsulated in the nanoparticles and then released in the presence of glutathione at cellular concentration