This thesis reports research to investigate the mechanical, thermal and acoustic properties of biodegradable foams in block forms based on wheat starch and developed at Brunel University's School of Engineering & Design, in order to exploit the potential environmental benefits of this renewable and biodegradable class of materials. Two emergent novel technologies have been developed based on a combination of the extrusion foaming of starch in conjunction with the natural adhesive characteristics of moistened starch to produce block foams. Regular Packing & Stacking (RPS), and Compression Bonded Loosefill (CBL), are foam fabrication technologies which have both demonstrated the potential to produce bulk foams based on wheat starch with unique structures and properties - a new class of foam materials in the form of macro-composites reinforced by a network of high-density bonding interfaces. This thesis, as part of a Department of Trade & Industry/Technology Strategy Board funded project, reports an investigation into the following areas to address the scientific and technical issues involved in the further development of the materials and their applications. - The basic properties of the raw materials used in the manufacture of CBL and RPS foams are outlined and the fabrication and preparation of these starch-based foams are described. The limitations of these production techniques are discussed with preliminary work and suggestions made for their enhancement. - Research into the mechanical properties of the CBL and RPS foams includes compression, tensile, creep and dynamic impact tests, whilst the mechanical behaviour of the foams subject to high temperature and high humidity conditions is also reported. - Research into the thermal properties of CBL and high density RPS foams includes testing of the material's thermal conductivity. This aspect of the research also involved a case study detailing the use of RPS in a commercial thermal insulation application. - Research into the acoustic properties of CBL and RPS foams includes tests for sound absorption coefficient and sound transmission loss. - Data obtained from these tests are benchmarked against data pertaining to the mechanical, thermal and acoustic properties of conventional polymer foams in order to provide a basis on which to identify the potential cushioning, thermal insulation and acoustic insulation applications of the starch-based materials. The research has demonstrated the following: - Potential cushioning applications include those limited to the range of static loads within the capabilities of the materials, taking into account the resilience of CBL and RPS which is likely to be compromised by successive impacts. - Tensile forces tend to exploit weaknesses in the macrostructure of these materials. By implication the behaviour of the materials under shear forces would be expected to be similarly compromised. - CBL and RPS exhibited dimensional shrinkage, density increase and significantly reduced mechanical properties under conditions of high temperature and humidity. This suggests that neither CBL nor RPS foams would be suitable for applications in regions where tropical conditions may be encountered unless used in conjunction with other protective materials which would not acutely increase the environmental burden of the products. - Low-density RPS and CBL foams exhibit lower thermal conductivities and hence higher thermal insulation properties compared to many commercially available polymer foams of similar densities. As such these foams have the potential to be used in applications in which a measure of thermal insulation is required. A case study based on an existing commercial application in which the temperature of chilled products must be maintained over a 24 hour period reinforced these findings. - The performance of CBL and RPS starch foams would not provide sufficient functionality to be employed in applications in which dedicated acoustic performance is required, although their sound absorption capabilities may facilitate overall marketability for applications in which a degree of acoustic performance is required if used in conjunction with other materials which demonstrate good acoustic performance. It is anticipated that this work will make significant contributions toward advances in the development of these novel technologies, specifically in terms of establishing an understanding of the properties of the starch-based materials and in identifying potential applications. The research results should thus provide a fundamental element in the basis for the industrial development of these renewable and biodegradable materials.

Bone has the capacity to regenerate itself, however for challenging defects such as non-uniform factures, repair can be problematic. A similar challenge is presented in the repair of osteoporotic bone. Osteoporotic bone becomes increasingly porous and brittle and the risk of fracture is greatly increased. A drug mimic, poly(vinyl phosphonic acid – co – acrylic acid)(PVPA), has been incorporated into FDA approved poly(ε-caprolactone)(PCL), and aims to mimic the action of bisphosphonates to reduce the activity of osteoclasts. The PVPA polymer contains pendant phosphonic acid groups which are hypothesised to mimic the P-C-P backbone found in bisphosphonates. The PCL/PVPA scaffold has been found to have sufficient mechanical strength in order to be used as a bone void filler as well as providing a hydrophilic surface for superior cell attachment. The substrate has been found to significantly enhance the deposition of collagen, alkaline phosphatase activity and the expression of osteocalcin. Alizarin red staining revealed an increase in the rate of mineralisation in the presence of the drug mimic. The PCL/PVPA substrates have been suggested to induce osteoblast cells from a proliferative phase to a mineralisation stage. This is believed to be due to the presence of phosphorous within the scaffold which could lead to the critical concentration required for the initiation of mineralisation being reached more rapidly and effectively. The PVPA polymer has been found to mimic the action of bisphosphonates by inducing osteoclast apoptosis in vitro, and its actions of osteoclast apoptosis are comparable to that of Alendronate, a commonly administered bisphosphonate. A critical size defect model has demonstrated that the PVPA polymer has the ability to heal critical size defects; the healing potential was two fold greater than the control PCL substrate. Initial in vivo studies using a subcutaneous model demonstrated an improvement in mineralisation in the presence of PVPA. Untreated PCL/PVPA substrates displayed a high level of branched blood vessel formation, essential for healthy bone formation. However PVPA samples pre-treated with VEGF, hindered blood vessel formation and the infiltration of cells. This suggests that the PVPA alone is capable of inducing neovascularisation without the addition of VEGF. The findings suggest that the PCL/PVPA system could be used to treat challenging bone defects such as non-unions and osteoporotic fractures.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22339号 / 医博第4580号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 髙橋 良輔, 教授 小池 薫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Different structures of non-viral cationic polymer delivery vehicles, including charge center type, molecular weight and degradability, could significantly affect toxicity, release of nucleic acid and transfection efficiency. Poly(glycoamidoamine)s (PGAAs) contained different carbohydrate and secondary amine moieties and showed high transfection efficiency to different cell lines in a nontoxic manner. The "proton sponge hypothesis" has attempted to relate the buffering capacity to endosomal release of polyethylenimine (PEI) based polyplexes, which could contribute to high transfection efficiency. Secondary amine structures rendered PGAAs buffering capacity around physiological pH. To test the feasibility of the mechanism for PGAAs, new no buffering capacity guanidine or methylguanidine containing poly(glycoamidoguanidine)s (PGAGs) were synthesized. PGAGs formed stable polyplexes with pDNA from N/P (# secondary amine or guanidine group on polymer backbone / # phosphate group on pDNA backbone) ratio 3. PGAG based polyplexes expressed low cytotoxicity and were internalized by 90% of cells at N/P 25. Furthermore, two PGAG based polyplexes showed higher transfection efficiency from N/P 5 to 30 than their PGAA based analogs. These data suggested the low transfection could be due to the difficulties to release pDNA from polyplexes; also, the "proton sponge theory" could not explain the higher transfection efficiency by some PGAGs. Degradation of delivery vehicles could potentially release pDNA in cells and increase transfection efficiency. PGAAs degraded rapidly at physiological conditions and the proposed mechanism was amide hydrolysis. Typically, amide groups are stable and hydrolyze slowly in absence of enzyme. Different models mimicking PGAAs were synthesized to study the fast hydrolysis. Amide groups showed asymmetric hydrolysis. Different hydrolysis behaviors suggested neighboring group participation of two terminal groups to induce rapid amide hydrolysis. These new models could potentially be used to design new polymer delivery vehicles with various degradation profiles. / Master of Science

The current clinical treatment for bone deficiencies in clinics includes autografts, allografts and bone graft substitutes. All these treatments, however, still have various limitations. Therefore, in this project, we aim to design, synthesise and characterise a new series of novel polymer networks (PNs) to promote bone formation and offer a new therapeutic solution. An innovative polymerisation technique was used to synthesise the novel polymer-based materials. Various lactone monomers were applied with layered double hydroxides (LDHs) as the initiator for the polymerisation. Copolymerisation was used to control the final product degradation rate, microstructure and biocompatibility. SEM and XRD were used to confirm the formation of the 3D polymer microstructure, PNs indicated interconnected fibrous microstructure (thickness of the fibre ranged from 50-150 nm). Up to 90% polymer yield was achieved using thermogravimetric analysis. Both 1H and 13C nuclear magnetic resonance (NMR) were used to understand the effects of monomer combinations in the polymerisation. The effects of the materials on osteosarcoma cell line Saos-2 were investigated. Representative material compositions and their determined mass concentrations were applied using osteogenic culture medium with Saos-2. The PNs have indicated enhanced osteogenesis using varied assays. A poly(lactide-co-caprolactone) PN (monomer mass ratio 1:1) at 6.25 mg/ml, in particular, resulted in enhanced alkaline phosphate activity not only in growth medium but also in osteogenic medium. Moreover, it indicated the highest bone nodule production in area percentage compared to the other PN samples using Saos-2. Mg-substituted calcified extracellular matrix was formed by the use of PN materials. Therefore, this novel PN could have the possibility to be used as an acellular scaffold or a sprinkle-on powder local to defect site to enhance bone formation in vivo. In addition, this novel technology could be used as a scaffold for tissue engineering.

Vaccines have become an important approach for the treatment of cancer. Cancer vaccines help the immune system to detect and eradicate tumor cells. Also, cancer vaccines are designed to stimulate an effective immune response that can create long-term immune memory to prevent tumor recurrence. This treatment approach involves the administration of a vaccine comprising or encoding an antigen and can often be combined with an adjuvant to further promote the immune response. The goal of this research was to study the effect of the polyanhydride composition of prophylactic cancer vaccine formulations on the tumor-specific immune response. To achieve this goal, three different amphiphilic polyanhydride copolymers were generated comprising different ratios of 1,6-bis-(p-carboxyphenoxy)-hexane (CPH) and 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) or sebacic anhydride (SA) monomers. These copolymers were used to fabricate particles encapsulating a model antigen, ovalbumin (OVA), using a double emulsion solvent evaporation technique. The ability of the three different compositions of amphiphilic polyanhydride copolymers (50:50 CPTEG:CPH, 20:80 CPTEG:CPH, and 20:80 CPH:SA) encapsulating OVA to elicit immune responses was investigated. Further, the impact of soluble unmethylated oligodeoxynucleotides containing deoxycytidyl-deoxyguanosine dinucleotides (CpG ODN), an immunologic adjuvant, on the immune response to the three formulations was also studied. The immune response to cancer vaccines was measured after treatment of C57BL/6J mice with two subcutaneous injections, seven days apart, of 50 μg OVA encapsulated in particles composed of different polyanhydride copolymers with or without 25 μg CpG ODN. In vivo studies showed that 20:80 CPTEG:CPH particles encapsulating OVA significantly stimulated the highest level of CD8+ T lymphocytes, generated the highest serum titers of OVA-specific IgG antibodies, and produced longer survival in comparison to formulations involving the other polyanhydride copolymers. The results also revealed that supplementing the vaccine formulations with CpG ODN did not enhance the immunogenicity of OVA. These results accentuate the crucial role of the copolymer composition of polyanhydrides in stimulating the immune response and improving cancer vaccine efficacy.

Poly(beta-amino esters) are photopolymerizable and biodegradable polymers prepared by the combination of amines with diacrylates. This study aims to fundamentally understand the polymer network formed by poly(ethylene)glycol diacrylate (PEGDA) MW 700 and 3-methoxypropylamine (3MOPA) as well as to characterize the degradation response of this material with and without cyclic loading. The networks were formed by a two-step process; (1) the synthesis of amine-co-peg diacrylate macromers through a step growth reaction, followed by (2) UV initiated chain growth network formation of the diacrylated macromers. Macromer reaction chemistry was confirmed by 1H NMR measurements. UV calorimetric analysis revealed that network formation was dependent on molecular weight of the PEGDA monomer and light intensity, but not temperature in the range of 20 °C to 40 °C. The glass transition temperature of all networks was measured to be in the range of -40 °C to -30°C with a rubbery moduli ranging from 4 to 10 MPa, depending on the molecular weight of the PEGDA monomer. Partial crystallization was discovered to occur in the networks containing higher molecular weight PEGDA only in the presence of humidity and high frequency cyclic loading. Degradation studies were performed with and without applied cyclical stress, and in both cases elastic modulus decrease and mass loss occurred steadily over a 24-hour period. Increasing frequency of applied compressive stress during degradation served to slightly lower degradation rates, especially in samples cycled at high frequency, which crystallized. In all materials, applied cyclic load resulted in catastrophic fracture of the material prior to an appreciable decrease in modulus. The experiments reveal that degradation rate and failure mode can be influenced by the addition of cyclic loading and this should be considered when screening biodegradable polymers for applications that include mechanical loading.

Tissue engineering is an interdisciplinary field that seeks to address the needs by applying the principles of chemistry, biology and engineering for the development of viable substitutes that restore and maintain the function of human bone and cartilage tissues. In tissue engineering, scaffolds play an important role as temporary supports for the transplantation of specific cells and tissues. In this study, poly(ester-urethane)urea (PEUU) and poly(caprolactone) (PCL) scaffolds were fabricated. Scaffolds were characterized by SEM. Porosities of scaffolds vary from 67 % to 80 %. Controlled drug delivery systems release drugs at predetermined rates for extended periods. In this study / firstly poly(lactic-co-glycolicolide/tricalcium phosphate) (PLGA/TCP) and poly(L-lactide)/tricalcium phosphate (PLLA/TCP) composites loaded with Gentamicin or Vancomycin were prepared as controlled drug delivery systems for the local treatment of osteomyelitis. The release behavior of drugs were monitored by UV-VIS spectrometer. It was shown that, Vancomycin loaded samples released higher amounts of drug than the samples loaded with Gentamicin. Secondly, porous ceramic samples were coated with PLGA and PLLA and they were loaded with dexamethasone. The release behavior of samples were monitored by UV-VIS spectrometer.The cubic ceramics released higher amounts of dexamethasone than cylindrical ceramics. When the mechanical properties of porous ceramic samples were concerned, PLLA coated samples had better mechanical properties.

Polymer nanocomposite foams have attracted tremendous interests due to their multifunctional properties in addition to the inherited lightweight benefit of being foamed materials. Polymer nanocomposite foams using high performance polymer and bio-degradable polymer with carbon nanotubes were fabricated, and the effects of foam density and pore size on properties were characterized. Electrical conductivity modeling of polymer nanocomposite foams was conducted to investigate the effects of density and pore size. High performance polymer Polyetherimide (PEI) and multi-walled carbon nanotube (MWCNT) nanocomposites and their foams were fabricated using solvent-casting and solid-state foaming under different foaming conditions. Addition of MWCNTs has little effect on the storage modulus of the nanocomposites. High glass transition temperature of PEI matrix was maintained in the PEI/MWCNT nanocomposites and foams. Volume electrical conductivities of the nanocomposite foams beyond the percolation threshold were within the range of electro-dissipative materials according to the ANSI/ESD standard, which indicates that these lightweight materials could be suitable for electro-static dissipation applications with high temperature requirements. Biodegradable Polylactic acid (PLA) and MWCNT nanocomposites and their foams were fabricated using melt-blending and solid-state foaming under different foaming conditions. Addition of MWCNTs increased the storage modulus of PLA/MWCNT composites. By foaming, the glass transition temperature increased. Volume electrical conductivities of foams with MWCNT contents beyond the percolation threshold were again within the range of electro-dissipative materials according to the ANSI/ESD standard. The foams with a saturation pressure of 2 MPa and foaming temperature of 100 °C showed a weight reduction of 90% without the sacrifice of electrical conductivity. This result is promising in terms of multi-functionality and material saving. At a given CNT loading expressed as volume percent, the electrical conductivity increased significantly as porosity increased. A Monte-Carlo simulation model was developed to understand and predict the electrical conductivity of polymer/MWCNT nanocomposite foams. Two different foam morphologies were considered, designated as Case 1: volume expansion without nanotube rearrangement, and Case 2: nanotube aggregation in cell walls. Simulation results from unfoamed nanocomposites and the Case 1 model were validated with experimental data. The results were in good agreement with those from PEI/MWCNT nanocomposites and their foams, which had a similar microstructure as modeled in Case 1. Porosity effects on electrical conductivity were investigated for both Case 1 and Case 2 models. There was no porosity effect on electrical conductivity at a given volume percent CNT loading for Case 1. However, for Case 2 the electrical conductivity increased as porosity increased. Pore size effect was investigated using the Case 2 model. As pore size increased, the electrical conductivity also increased. Electrical conductivity prediction of foamed polymer nanocomposites using FEM was performed. The results obtained from FEM were compared with those from the Monte-Carlo simulation method. Feasibility of using FEM to predict the electrical conductivity of foamed polymer nanocomposites was discussed. FEM was able to predict the electrical conductivity of polymer nanocomposite foams represented by the Case 2 model with various porosities. However, it could not capture the pore size effect in the electrical conductivity prediction. The FEM simulation can be utilized to predict the electrical conductivity of Case 2 foams when the percolation threshold is determined by Monte-Carlo simulation to save the computational time. This has only been verified when the pore size is small in the range of a few micrometers. / text