Novel etheroatom containing aliphatic polyesters for biomedical and environmental applications

Biodegradable polymers for short time applications have attracted much interest all over the world. The reason behind this growing interest is the incompatibility of the polymeric wastes with the environment where they are disposed after usage. Synthetic aliphatic polyesters represent one of the most economically competitive biodegradable polymers. In addition, they gained considerable attention as they combine biodegradability and biocompatibility with interesting physical and chemical properties. In this framework, the present research work focused on the modification by reactive blending and polycondensation of two different aliphatic polyesters, namely poly(butylene succinate) (PBS) and poly(butylene 1,4-cyclohexanedicarboxylate) (PBCE). Both are characterized by good thermal properties, but their mechanical characteristics do not fit the requirements for applications in which high flexibility is requested and, moreover, both show slow biodegradation rate. With the aim of developing new materials with improved characteristics with respect to the parent homopolymers, novel etheroatom containing PBS and PBCE-based fully aliphatic polyesters and copolyesters have been therefore synthesized and carefully characterized. The introduction of oxygen or sulphur atoms along the polymer chains, by acting on chemical composition or molecular architecture, tailored solid-state properties and biodegradation rate: type and amount of comonomeric units and sequence distribution deeply affected the material final properties owing, among all, to the hydrophobic/hydrophilic ratio and to the different ability of the polymer to crystallize. The versatility of the synthesized copolymers has been well proved: as a matter of fact these polymers can be exploited both for biomedical and ecological applications. Feasibility of 3D electrospun scaffolds has been investigated, biocompatibility studies and controlled release of a model molecule showed good responses. As regards ecological applications, barrier properties and eco-toxicological assessments have been conducted with outstanding results. Finally, the ability of the novel polyesters to undergo both hydrolytic and enzymatic degradation has been demonstrated under physiological and environmental conditions.

A General Approach Towards the Synthesis of Amido-Functionalized Biodegradable Polyesters

The thesis presented here describes methodologies to produce pendant group functionalized polyesters from amido-functionalized α-hydroxy acids. The synthetic methods used to produce the functionalized α-hydroxy acids are compatible with a wide array of functional groups, making this technique highly versatile. The synthesis of functionalized polyesters was investigated to develop polymers with properties that may improve the capabilities of existing biodegradable polyesters for applications in controlled release pharmaceuticals. Chemically modified a-hydroxy acids were synthesized by reacting glyoxylic acid with a primary or secondary amide. To demonstrate the utility of this reaction, fourstructurally dissimilar amide substituents were examined including 2-pyrrolidione, benzamide, acetamide and acrylamide. The reaction is synthetically simple, provides high yields and is uniquely flexible, functionalized monomer. The compatibility of this procedure with the collection of functional groups mentioned circumvents the need for syntheses. The amido-functionalized monomers were polymerized by two different techniques: melt polycondensation and solution polymerization. Melt polycondensation was conducted by heating the monomer past its melting temperature under reduced pressure. Oligomeric functionalized polyesters (= 800 g/mol) with low PDIs (= 1.05) were obtained by melt polycondensation. Melt polycondensation was not compatible with all of the synthesized monomers. Two of the monomers (containing benzamide and acrylamide functionalities) degraded before the polycondensation reaction occurred. Thermal gravimetric analysis confirmed that a process other than polyesterification was occurring, indicating that some amido-functionalized α-hydroxy acids cannot be synthesized in the melt.Solution polymerization was conducted to polymerize functionalized α-hydroxy acids that were incompatible with melt polycondensation. Several modified Steglich polyesterifications were tested including p-toluenesulfonic acid mediated and scandium (III) triflate catalyzed. Only oligomeric functionalized polyesters were formed bythis method. A number of possible side reactions including the formation of an N-acylurea and a cyclic polymer ring were possible. The utility of this procedure appears to be limited due to the complexity of the reaction and its inability to produce high molecular weight polymer.

The Use Of Amido- And Imido-Functionalized Alpha Hydroxy Acids In The Creation Of Biodegradable Polyesters: An Exploration Of Va

The purpose of this thesis was to synthesize biodegradable polyesters from a wide array of functionalized ¿-hydroxy acids. The initial strategy was to use amido-functionalized ¿-hydroxy acids and 2-bromopropanoyl bromide to form amido-functionalized cyclic diesters. Then, the resulting cyclic diesters would be used in ring opening polymerization to create biodegradable polyesters. However, the spontaneous rapid degradation of the secondary amido-functionalized cyclic diester structure, as seen with 2-benzamido-hydroxyacetic acid, limited ring formation to tertiary amido-functionalized ¿-hydroxy acids. Also, the hydrophilic nature of most ¿-hydroxy acids allowed water into the crystal structure of the ¿-hydroxy acid. Then, when the ¿-hydroxy acid was used in ring forming reactions, the associated water deactivated reactive reagents and limited cyclic diester synthesis. These issues led to the synthesis of hydrophobic and tertiary amido- and imido-functionalized ¿-hydroxy acids, 2-phthalimido-2-hydroxyacetic acid and 2-(1-oxoisoindolin-2-yl) hydroxyacetic acid. The new ¿-hydroxy acids were used in two new polymerization techniques, melt polycondensation and solution polymerization, instead of ring open polymerization. Melt polycondensation and solution polymerization had shown previous success in forming oligomers of amido-functionalized ¿-hydroxy acids. Melt polycondensation was conducted by heating the monomer past its melting temperature under reduced pressure. The uncatalyzed melt polycondensation of 2-(1-oxoisoindolin-2-yl) hydroxyacetic acid created polyesters (¿ 960 g/mol). The scandium(III) trifluoromethanesulfonate enhanced melt polycondensation polymerization created slightly larger oligomers (¿ 1340 g/mol). However, 2-phthalimido-2-hydroxyacetic acid was not compatible with melt polycondensation because thermal degradation occurred. Thus, solution polymerization was conducted via Steglich esterification. Only oligomeric functionalized polyesters were formed (¿ 1060 g/mol). Future work should focus on optimization of the catalyst and the reaction conditions to obtain higher molecular weight polyesters. Also, 2-(1-oxoisoindolin-2-yl) hydroxyacetic acid should be utilized in the cyclic diester synthesis technique.

The synthesis of novel biodegradable polyesters and copolyesters from anhydrosulfites

This thesis was concerned primarily with the synthesis and the ring-opening polymerisation of anhydrosulfites (1,3,2-dioxa-thiolan-4-one-2-oxides), and secondly with the copolymerisation of anhydrosulfites with -caprolactone. The polyesters and copolyesters synthesised are of considerable interest in medical applications and also for use as environmental friendly packaging. A range of anhydrosulfites were prepared according to an established method. Aliphatic anhydrosulfites were obtained with a level of purity satisfactory for polymerisation whereas aromatic anhydrosulfites decomposed during distillation and purification by chromatographic techniques. Aliphatic anhydrosulfites with a substituent, such as methyl, isopropyl, n-butyl and isobutyl were studied by NMR spectroscopy. Analysis of these spectra revealed that the five-membered anhydrosulfite ring was puckered and that when the substituent was bulky, rotations about the alkyl chains were restricted. A wide range of anionic initiators may be used to initiate anhydrosulfites. Lithium alkyls turned out to be more successful than alkali metal alkoxides and amides. The molecular weights were found to depend on the basicity of the initiator, the monomer-to-initiator ratio, the nature of the solvent and the polymerisation temperature. The molecular weight M0 of poly(L-lactic acid) ranged from (0.5 to 6)x104. Highly crystalline and purely isotactic poly(lactic acid) was synthesised from L-lactic acid anhydrosulfite (L-LAAS) whereas DL-LAAS led to an amorphous polymer with randomly distributed D-and L-lactic units. This indicated that this polymerisation was not stereoselective. However, the bulkiness of the substituent in the anhydrosulfites molecule was found to influence the stereoselectivity of the polymerisation, thus polyesters with isobutyl or n-butyl pendant group were preferentially isotactic. Block-copolymers of ε-caprolactone and several anhydrosulfites were successfully produced. Block-copolymers of LAAS with ε-caprolactone were also synthesised, but the incorporation of caprolactone units was rather small. In contrast, random copolymerisation of LAAS and ε-caprolactone led to polymers with blocky structures similar to those obtained in the block-copolymerisation of LAAS with  ε-caprolactone.

The use of enzyme catalysts in organic media for the synthesis of biodegradable polyesters

The enzyme catalysed polytransesterification of diesters with diols was investigated under various conditions. The most consistent results were obtained using crude porcine pancreatic lipase (PPL) suspended in anhydrous diethyl ether. Addition of molecular sieve to the above system gave higher molecular weight products. The PPL catalysed reaction of bis(2,2,2-trichlorethyl) adipate and glutarate with butane-1,4-diol in anhydrous ether with and without molecular sieve was investigated over a range of times from 8 to 240 hours. The 72 hour adipate reaction with molecular sieve gave the highest molecular weight polymer (Mn 6,500 and Mw 9,400). The glutarate gave the maximum molecular weight polyester after 24 hours (Mn 5,700 and Mw 9,500). Occasionally the glutarate reaction produced very high molecular weight polyester-enzyme complexes. Toluene generally gave lower molecular weight products than diethyl ether. Dichloromethane and tetrahydrofuran gave mainly dimers and trimers. Alternative enzyme and diol systems were also investigated. These yielded no polymeric products. The molecular weights of the polyesters were determined by 1H NMR end-group analysis and by GPC. The molecular weights determined by NMR were on average about twice as great as those determined by GPC. The synthesis of the following diesters is described: i)Bis(2,2,2-trichloroethyl) succinate, glutarate, adipate, trans-3-hexenedioate, and trans-3,4-epoxyadipate. ii) Diphenyl glutarate and adipate.iii)Bis(2,2,2-fluoroethyl) glutarate and trans-3-hexendioate.iv) Divinyl glutarate. v) N,N'Glutaryl dicyclohexanone oxime.The polytransesterification of all the above esters with diols was investigated. The easily synthesised bis(2,2,2-trichloroethyl) glutarate and adipate gave the best results and the work was concentrated on these two esters.

Design, fabrication and characterization of PCL electrospun scaffolds—a review

The expanding interest in electrospinning fibers for bioengineering includes a significant use of polyesters, including poly(3-caprolactone) (PCL). This review summarizes literature on PCL and selected blends, and provides extensive descriptions of the broad range of parameters used in manufacturing such electrospun fibers. Furthermore the chemical, physical and biological approaches for characterizing the electrospun material are described and opinions offered on important information to include in future publications with this electrospun material.

Scaffolds for growth factor delivery as applied to bone tissue engineering

There remains a substantial shortfall in treatment of severe skeletal injuries. The current gold standard of autologous bone grafting from the same patient, has many undesirable side effects associated such as donor site morbidity. Tissue engineering seeks to offer a solution to this problem. The primary requirements for tissue engineered scaffolds have already been well established, and many materials, such as polyesters, present themselves as potential candidates for bone defects; they have comparable structural features, but they often lack the required osteoconductivity to promote adequate bone regeneration. By combining these materials with biological growth factors; which promote the infiltration of cells into the scaffold as well as the differentiation into the specific cell and tissue type, it is possible to increase the formation of new bone. However cost and potential complications associated with growth factors means controlled release is an important consideration in the design of new bone tissue engineering strategies. This review will cover recent research in the area of encapsulation and release of growth factors within a variety of different polymeric scaffolds.

In vitro biocompatibility of different polyester membranes

Nowadays, synthetic biodegradable polymers, such as aliphatic polyesters, are largely used in tissue engineering. They provide several advantages compared to natural materials which use is limited by immunocompatibility, graft availability, etc. In this work, poly(L-lactic) acid (PLLA), poly(DL-lactic) acid (PDLA), poly-epsilon-caprolactone (PCL), poly(L-lactic)-co-caprolactone (molar ratio 70/30) (PLCL) were selected because of their common use in tissue engineering. The membranes were elaborated by solvent casting. Membrane morphology was investigated by atomic force microscopy. The membranes were seeded with human fibroblasts from cell line CRL 2703 in order to evaluate the biocompatibility by the Alamar blue test. The roughness of the membranes ranged from 4 nm for PDLA to 120 nm and they presented very smooth surface except for PCL which beside a macroscopic structure due to its hydrophobicity. Human fibroblasts proliferated over 28 days on the membranes proving the non-in vitro toxicity of the materials and of the processing method. A further step will be the fabrication of three-dimensional scaffold for tissue engineering and the treatment of the scaffolds to augment cell adhesion.

Aligned poly(L-lactic-co-ε-caprolactone) electrospun microfibers and knitted structure: a novel composite scaffold for ligament tissue engineering

We developed a novel technique involving knitting and electrospinning to fabricate a composite scaffold for ligament tissue engineering. Knitted structures were coated with poly(L-lactic-co-e-caprolactone) (PLCL) and then placed onto a rotating cylinder and a PLCL solution was electrospun onto the structure. Highly aligned 2-μm-diameter microfibers covered the space between the stitches and adhered to the knitted scaffolds. The stress–strain tensile curves exhibited an initial toe region similar to the tensile behavior of ligaments. Composite scaffolds had an elastic modulus (150 ± 14 MPa) similar to the modulus of human ligaments. Biological evaluation showed that cells proliferated on the composite scaffolds and they spontaneously orientated along the direction of microfiber alignment. The microfiber architecture also induced a high level of extracellular matrix secretion, which was characterized by immunostaining. We found that cells produced collagen type I and type III, two main components found in ligaments. After 14 days of culture, collagen type III started to form a fibrous network. We fabricated a composite scaffold having the mechanical properties of the knitted structure and the morphological properties of the aligned microfibers. It is difficult to seed a highly macroporous structure with cells, however the technique we developed enabled an easy cell seeding due to presence of the microfiber layer. Therefore, these scaffolds presented attractive properties for a future use in bioreactors for ligament tissue engineering.

A retrospective cohort study of Acticoat™ versus Silvazine™ in a paediatric population

We wished to determine whether changing our centre's practice of using Acticoat instead of Silvazine as our first-line burns dressing provided a better standard of care in terms of efficacy, cost and ease of use. A retrospective cohort study was performed examining 328 Silvazine treated patients from January 2000 to June 2001 and 241 Acticoat treated patients from July 2002 to July 2003. During those periods the respective dressings were used exclusively. There was no significant difference in age, %BSA and mechanism of burn between the groups. In the Silvazine group, 25.6% of children required grafting compared to 15.4% in the Acticoat group (p=0.001). When patients requiring grafting were excluded, the time taken for re-epithelialisation in the Acticoat group (14.9 days) was significantly less than that for the Silvazine group (18.3 days), p=0.047. There were more wounds requiring long term scar management in the Silvazine group (32.6%) compared to the Acticoat group (29.5%), however this was not significant. There was only one positive blood culture in each group, indicating that both Silvazine and Acticoat are potent antimicrobial agents. The use of Acticoat as our primary burns dressing has dramatically changed our clinical practice. Inpatients are now only 18% of the total admissions, with the vast majority of patients treated on an outpatient basis. In terms of cost, Acticoat was demonstrated to be less expensive over the treatment period than Silvazine . We have concluded that Acticoat is a safe, cost-effective, efficacious dressing that reduces the time for re-epithelialisation and the requirement for grafting and long term scar management, compared to Silvazine.