Harri Korhonen

Preparation of poly(ε-caprolactone)-based tissue engineering scaffolds by stereolithography.

A photocrosslinkable poly(ε-caprolactone) (PCL)-based resin was developed and applied using stereolithography. No additional solvents were required during the structure preparation process. Three-armed PCL oligomers of varying molecular weights were synthesized, functionalized with methacrylic anhydride, and photocrosslinked, resulting in high gel content networks. Stereolithography was used to build designed porous scaffolds using the resin containing PCL macromer, Irgacure 369 photoinitiator, inhibitor and dye. A suitable resin viscosity was obtained by heating the resin during the curing process. The scaffolds precisely matched the computer-aided designs, with no observable material shrinkage. The average porosity was 70.5 ± 0.8%, and the average pore size was 465 μm. The pore network was highly interconnected. The photocrosslinkable, biodegradable PCL resin is well suited for the solvent-free fabrication of tissue engineering scaffolds by stereolithography.

Biodegradable and bioactive porous scaffold structures prepared using fused deposition modeling

Three-dimensional printing (3DP) refers to a group of additive manufacturing techniques that can be utilized in tissue engineering applications. Fused deposition modeling (FDM) is a 3DP method capable of using common thermoplastic polymers. However, the scope of materials applicable for FDM has not been fully recognized. The purpose of this study was to examine the creation of biodegradable porous scaffold structures using different materials in FDM and to determine the compressive properties and the fibroblast cell response of the structures. To the best of our knowledge, the printability of a poly(ε-caprolactone)/bioactive glass (PCL/BAG) composite and L-lactide/ε-caprolactone 75/25 mol % copolymer (PLC) was demonstrated for the first time. Scanning electron microscope (SEM) images showed BAG particles at the surface of the printed PCL/BAG scaffolds. Compressive testing showed the possibility of altering the compressive stiffness of a scaffold without changing the compressive modulus. Compressive properties were significantly dependent on porosity level and structural geometry. Fibroblast proliferation was significantly higher in polylactide than in PCL or PCL/BAG composite. Optical microscope images and SEM images showed the viability of the cells, which demonstrated the biocompatibility of the structures.

Novel additive manufactured scaffolds for tissue engineered trachea research

Abstract Conclusions: This study demonstrates proof of concept for controlled manufacturing methods that utilize novel tailored biopolymers (3D photocuring technology) or conventional bioresorbable polymers (fused deposition modeling, FDM) for macroscopic and microscopic geometry control. The manufactured scaffolds could be suitable for tissue engineering research. Objectives: To design novel trachea scaffold prototypes for tissue engineering purposes, and to fabricate them by additive manufacturing. Methods: A commercial 3D model and CT scans of a middle-aged man were obtained for geometrical observations and measurements of human trachea. Model trachea scaffolds with variable wall thickness, interconnected pores, and various degrees of porosity were designed. Photocurable polycaprolactone (PCL) polymer was used with 3D photocuring technology. Thermoplastic polylactide (PLA) and PCL were used with FDM. Cell cultivations were performed for biocompatibility studies. Results: Scaffolds of various sizes and porosities were successfully produced. Both thermoplastic PLA and PCL and photocurable PCL could be used effectively with additive manufacturing technologies to print high-quality tubular porous biodegradable structures. Optical microscopic and SEM images showed the viability of cells. The cells were growing in multiple layers, and biocompatibility of the structures was shown.

Biocompatible photocrosslinked poly(ester anhydride) based on functionalized poly(ε-caprolactone) prepolymer shows surface erosion controlled drug release in vitro and in vivo

Star-shaped poly(epsilon-caprolactone) oligomers functionalized with succinic anhydride were used as prepolymers to prepare photocrosslinked poly(ester anhydride) to evaluate their in vivo drug delivery functionality and biocompatibility. Thus, in this work, erosion, drug release and safety of the photocrosslinked poly(ester anhydride) were examined in vitro and in vivo. A small water-soluble drug, propranolol HCl (M(w) 296 g/mol, solubility 50 mg/ml), was used as the model drug in an evaluation of the erosion controlled release. Drug-free and drug-loaded (10-60% w/w) poly(ester anhydride) discoids eroded in vitro (pH 7.4 buffer, +37 degrees C) linearly within 24-48 h. A strong correlation between the polymer erosion and the linear drug release in vitro was observed, indicating that the release had been controlled by the erosion of the polymer. Similarly, in vivo studies (s.c. implantation of discoids in rats) indicated that surface erosion controlled drug release from the discoids (drug loading 40% w/w). Oligomers did not decrease cell viability in vitro and the implanted discoids (s.c., rats) did not evoke any cytokine activity in vivo. In summary, surface erosion controlled drug release and the safety of photocrosslinked poly(ester anhydride) were demonstrated in this study.

Photocrosslinkable Polyesters and Poly(ester anhydride)s for Biomedical Applications

Crosslinking is a feasible way to prepare biodegradable polymers with potential in biomedical applications such as controlled release of active agents and tissue engineering. A synthesis route in which functional telechelic aliphatic polyester oligomers are used as precursors for the preparation of crosslinked polyesters and poly(ester anhydride)s is described. Mechanical properties, degradation characteristics and rate, and bioactivity can be modified widely by controlling the chemical composition and architecture of the crosslinkable oligomers. In tissue engineering, photocrosslinking allows to use crosslinkable oligomers in advanced manufacturing techniques like micromolding in capillaries, stereolithography and two-photon polymerization.

Photocrosslinked poly(ester anhydride)s for peptide delivery: Effect of oligomer hydrophobicity on PYY3-36 delivery

The treatment for many diseases can be improved by developing more efficient peptide delivery technologies, for example, biodegradable polymers. In this work, photocrosslinked poly(ester anhydride)s based on functionalized poly(ε-caprolactone) oligomers were investigated for their abilities to achieve controlled peptide delivery. The effect of oligomer hydrophobicity on erosion and peptide release from poly(ester anhydride)s was evaluated by developing a sustained subcutaneous delivery system for an antiobesity drug candidate, peptide YY3-36 (PYY3-36). Oligomer hydrophobicity was modified with alkenylsuccinic anhydrides containing a 12-carbon alkenyl chain. PYY3-36 was mixed as a solid powder with methacrylated poly(ester anhydride) precursors, and this mixture was photocrosslinked at room temperature to form an implant for subcutaneous administration in rats. The oligomer hydrophobicity controlled the polymer erosion and PYY3-36 release as the increased hydrophobicity via the alkenyl chain prolonged polymer erosion in vitro and sustained in vivo release of PYY3-36. In addition, photocrosslinked poly(ester anhydride)s increased the bioavailability of PYY3-36 by up to 20-fold in comparison with subcutaneous administration of solution, evidence of remarkably improved delivery. In conclusion, this work demonstrates the suitability of photocrosslinked poly(ester anhydride)s for use in peptide delivery.

Characterization of internal structure, polymer erosion and drug release mechanisms of biodegradable poly(ester anhydride)s by X-ray microtomography

Surface-eroding biodegradable polymers can provide many advantages in drug delivery, such as controllable and zero-order drug release. Photocrosslinkable poly(ester anhydride)s are a recently developed family of surface-eroding polymers with readily modifiable oligomer chemistry allowing tailoring of polymer properties. For example, in vivo release rate of peptide from photocrosslinked poly(ester anhydride)s can be controlled by oligomer hydrophobicity. In this study, X-ray microtomography (micro-CT) was used to gain a deeper understanding on internal structure, polymer erosion and drug release mechanisms of photocrosslinked poly(ester anhydride)s. Micro-CT is non-destructive and able to provide quantitative and qualitative information on the 3D structure of the sample in micrometer resolution. Photocrosslinked poly(ester anhydride) samples with varying drug loading degrees (propranolol HCl 0%, 10% and 60% w/w) and hydrophobicity (with and without 12-carbon alkenyl chain) were prepared. The samples, both freshly prepared and exposed to buffer solution for varying durations were characterized by micro-CT. The results showed that drug release from photocrosslinked poly(ester anhydride)s was primarily controlled by the surface erosion. However, drug diffusion had also a significant role in drug release from less hydrophobic samples with very high (60% w/w) drug loading degrees. In conclusion, micro-CT is a valuable tool in the characterization of surface-eroding polymers.

Synthesis of Novel Chain Extended and Crosslinked Polylactones for Tissue Regeneration and Controlled Release Applications

In addition to ring opening homo- and co-polymerization, chain extension and crosslinking are attractive routes for synthesizing polylactones. Through manipulation of molecular composition and molecular architecture a wide range of mechanical, thermal and degradation properties can be achieved, and using different coupling chemistries, polylactones belonging to many kinds of linear and network-structured polymer families have been synthesized. The poly(ester-urethanes), poly(ester-amides), poly(ester-urethane-amides), polyphosphoesters, poly(ester-anhydrides) and methacrylated crosslinking polyesters polymer families have great potential in biomedical applications such as surgery, tissue-engineering, and controlled active agent release. Mechanical properties, degradation characteristics and rate, and release properties of these polymers can be adjusted within wide ranges. Biopolymers showing bone-like hardness or soft non-creeping elasticity have been synthesized. Poly(ester-anhydrides) in particular combine useful properties of polyesters and polyanhydrides, and have been shown to degrade by surface-erosion, enabling controlled macromolecular active agent release. Photocuring of liquid pre-polymers enables the use of biopolymers in high precision lithographic techniques like micromolding in capillaries, stereolithography and two-photon polymerization. This makes it possible to design and customize complicated scaffold structures, with desired drug release profiles for various biomedical applications.