In Vivo Degradation Mechanism and Biocompatibility of a Biodegradable Aliphatic Polycarbonate: Poly(Trimethylene Carbonate-co-5-Hydroxy Trimethylene Carbonate).

A recently developed viscous liquid aliphatic polycarbonate, poly(trimethylene carbonate-co-5-hydroxy trimethylene carbonate), has advantageous properties for the delivery of acid-sensitive drugs such as proteins and peptides. This copolymer degrades in vitro via an alkaline-catalyzed intramolecular cyclization reaction yielding oligo (trimethylene carbonate), glycerol, and carbon dioxide, but its in vivo degradation mechanisms are presently unknown. The in vivo degradation mechanism and tissue response to this copolymer were investigated following subcutaneous implantation in Wistar rats. The molecular weight and composition of the copolymer varied in the same manner following subcutaneous implantation as observed in vitro. These findings suggest that the copolymer also degraded in vivo principally via intramolecular cyclization. The tissue response in terms of the inflammatory zone cell density, fibrous capsule thickness, and macrophage response was intermediate to that of two clinically used biodegradable sutures, Vicryl and Monocryl, indicating that the copolymer can be considered biotolerable. Collectively, the data show that further development of this copolymer as a drug delivery material is warranted.

Formulation parameters governing sustained protein delivery from degradable viscous liquid aliphatic polycarbonates.

Viscous liquid degradable polymers have advantages as drug depots for sustained protein delivery. We have created a new aliphatic polycarbonate for this purpose, poly(trimethylene carbonate-co-5-hydroxy trimethylene carbonate), which upon degradation retains a near neutral micro-environmental pH. As such, this copolymer is highly suited to the delivery of acid sensitive proteins. We show that the mechanism of protein release from this liquid copolymer is consistent with the formation of super-hydrated regions as a result of the osmotic activity of the solution formed upon distributed protein particle dissolution. Protein release can be manipulated by controlling polymer hydrophobicity which can be adjusted by molecular weight and choice of initiator. Moreover, protein release is highly dependent on protein solubility which impacts the osmotic activity of the solution formed upon dissolution of the protein particles while protein molecular size and isoelectric point are not as influential. As demonstrated by the release of highly bioactive vascular endothelial growth factor, formulations of this copolymer are suitable for prolonged delivery of protein therapeutics.

Liquid Degradable Poly(trimethylene-carbonate-co-5-hydroxy-trimethylene carbonate): An Injectable Drug Delivery Vehicle for Acid-Sensitive Drugs.

Liquid, injectable hydrophobic polymers have advantages as degradable drug delivery vehicles; however, polymers examined for this purpose to date form acidic degradation products that may damage acid-sensitive drugs. Herein, we report on a new viscous liquid vehicle, poly(trimethylene carbonate-co-5-hydroxy-trimethylene carbonate), which degrades through intramolecular cyclization producing glycerol, carbon dioxide, and water-soluble trimethylene carbonate. Copolymer degradation durations from weeks to months were achieved with the 5-hydroxy-trimethylene carbonate (HTMC) content of the oligomer having the greatest impact on the degradation rate, with oligomers possessing a higher HTMC content degrading fastest. The degradation products were non-cytotoxic towards 3T3 fibroblasts and RAW 264.7 macrophages. These copolymers can be injected manually through standard gauge needles and, importantly, during in vitro degradation, the microenvironmental pH within the oligomers remained near neutral. Complete and sustained release of the acid-sensitive protein vascular endothelial growth factor was achieved, with the protein remaining highly bioactive throughout the release period. These copolymers represent a promising formulation for local and sustained release of acid sensitive drugs.

Proliferation and differentiation of mesenchymal stem cell on collagen sponge reinforced with polypropylene/polyethylene terephthalate blend fibers.

Although tissue-engineered scaffolds made from collagen sponge are suitable for cell infiltrating, easily supplying oxygen and nutrients to cells, and removing the waste products, their mechanical properties are not satisfactory to be used as scaffold materials for tissue engineering applications. To improve mechanical properties of collagen, a novel porous scaffold for bone tissue engineering was prepared with collagen sponge reinforced by polypropylene/polyethylene terephthalate (PP/PET) fibers. Collagen solution (6.33 mg/mL) with PP/PET fibers (collagen/fiber ratio [w/w]: 1.27, 0.63, 0.42, 0.25) was freeze-dried, followed by cross-linking of combined dehydrothermal and glutaraldehyde. A scanning electron microscopy-based analysis of surface of the sponges demonstrated that the sponge with collagen/fiber <0.25 exhibited homogenous and interconnected pore structure with an average pore size of 200 µm. Incorporation of PP/PET fibers significantly enhanced the compressive strength of the collagen sponge. Proliferation and osteogenic differentiation of mesenchymal stem cell in collagen sponges reinforced with PP/PET fibers incorporation were significantly enhanced compared with collagen sponge without PP/PET incorporation. We conclude that incorporation of PP/PET fibers not only improves the mechanical properties of collagen sponge, but also enables mesenchymal stem cells to positively improve their proliferation and differentiation.