Ari Rosling

Towards fabrication of 3D printed medical devices to prevent biofilm formation

The use of three-dimensional (3D) printing technologies is transforming the way that materials are turned into functional devices. We demonstrate in the current study the incorporation of anti-microbial nitrofurantoin in a polymer carrier material and subsequent 3D printing of a model structure, which resulted in an inhibition of biofilm colonization. The approach taken is very promising and can open up new avenues to manufacture functional medical devices in the future.

Three-Dimensional Printed PCL-Based Implantable Prototypes of Medical Devices for Controlled Drug Delivery

The goal of the present study was to fabricate drug-containing T-shaped prototypes of intrauterine system (IUS) with the drug incorporated within the entire backbone of the medical device using 3-dimensional (3D) printing technique, based on fused deposition modeling (FDM™). Indomethacin was used as a model drug to prepare drug-loaded poly(ε-caprolactone)-based filaments with 3 different drug contents, namely 5%, 15%, and 30%, by hot-melt extrusion. The filaments were further used to 3D print IUS. The results showed that the morphology and drug solid-state properties of the filaments and 3D prototypes were dependent on the amount of drug loading. The drug release profiles from the printed devices were faster than from the corresponding filaments due to a lower degree of the drug crystallinity in IUS in addition to the differences in the external/internal structure and geometry between the products. Diffusion of the drug from the polymer was the predominant mechanism of drug release, whereas poly(ε-caprolactone) biodegradation had a minor effect. This study shows that 3D printing is an applicable method in the production of drug-containing IUS and can open new ways in the fabrication of controlled release implantable devices.

Calcium phosphate formation and ion dissolution rates in silica gel-PDLLA composites

Sol-gel derived silicas are potential biomaterials both for tissue regeneration and drug delivery applications. In this study, both SiO(2) and calcium and phosphate-containing SiO(2) (CaPSiO(2)) are combined with poly-(DL-lactide) to form a composite. The main properties studied are the ion release rates of biologically important ions (soluble SiO(2) and Ca(2+)) and the formation of bone mineral-like calcium phosphate (CaP) on the composite surface. These properties are studied by varying the quality, content and granule size of silica gel in the composite, and porosity of the polymer. The results indicate that release rates of SiO(2) and Ca(2+) depend mostly on the formed CaP layer, but in some extent also on the granule size of silicas and polymer porosity. The formation of the bone mineral-like CaP is suggested to be induced by a thin SiO(-) layer on the composite surface. However, due to absence of active SiO(2) or CaPSiO(2) granules on the outermost surface, the suitable nanoscale dimensions do not contribute the nucleation and growth and an extra source for calcium is needed instead. The result show also that all composites with varying amount of CaPSiO(2) (10-60 wt%) formed bone mineral-like CaP on their surfaces, which provides possibilities to optimise the mechanical properties of composites.

Fate of Bone Marrow-Derived Stromal Cells after Intraperitoneal Infusion or Implantation into Femoral Bone Defects in the Host Animal

The fate of intraperitoneally injected or implanted male rat bone marrow-derived stromal cells inside female sibling host animals was traced using Y-chromosome-sensitive PCR. When injected intraperitoneally, Y-chromosome-positive cells were found in all studied organs: heart muscle, lung, thymus, liver, spleen, kidney, skin, and femoral bone marrow with a few exceptions regardless of whether they had gone through osteogenic differentiation or not. In the implant experiments, expanded donor cells were seeded on poly(lactide-co-glycolide) scaffolds and grown under three different conditions (no additives, in osteogenic media for one or two weeks) prior to implantation into corticomedullar femoral defects. Although the impact of osteogenic in vitro cell differentiation on cell migration was more obvious in the implantation experiments than in the intraperitoneal experiments, the donor cells stay alive when injected intraperitoneally or grown in an implant and migrate inside the host. However, when the implants contained bioactive glass, no signs of Y-chromosomal DNA were observed in all studied organs including the implants indicating that the cells had been eliminated.

Improved dimensional stability with bioactive glass fibre skeleton in poly(lactide-co-glycolide) porous scaffolds for tissue engineering

Bone tissue engineering requires highly porous three-dimensional (3D) scaffolds with preferable osteoconductive properties, controlled degradation, and good dimensional stability. In this study, highly porous 3D poly(d,l-lactide-co-glycolide) (PLGA) - bioactive glass (BG) composites (PLGA/BG) were manufactured by combining highly porous 3D fibrous BG mesh skeleton with porous PLGA in a freeze-drying process. The 3D structure of the scaffolds was investigated as well as in vitro hydrolytic degradation for 10weeks. The effect of BG on the dimensional stability, scaffold composition, pore structure, and degradation behaviour of the scaffolds was evaluated. The composites showed superior pore structure as the BG fibres inhibited shrinkage of the scaffolds. The BG was also shown to buffer the acidic degradation products of PLGA. These results demonstrate the potential of these PLGA/BG composites for bone tissue engineering, but the ability of this kind of PLGA/BG composites to promote bone regeneration will be studied in forthcoming in vivo studies.

Tailored approaches in drug development and diagnostics:from molecular design to biological model systems

Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer-aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century.

Bulk composites from microfibrillated cellulose-reinforced thermoset starch made from enzymatically degraded allyl glycidyl ether-modified starch

Microfibrillated cellulose consists of nanoscale bundles of elementary microfibrils prepared, e.g. by the defibrillation of delignified wood pulp fibres in high-pressure homogenizers. In this study, microfibrillated cellulose was used to reinforce a thermoset starch plastic. The starch was modified with allyl glycidyl ether with a degree of substitution of 1.3, which was further hydrolyzed with α-amylase for 18 h yielding significantly improved processing properties. Dry premixes of all constituents were prepared by a stepwise drying process before sample manufacturing. The composite was cured by ethylene glycol dimethacrylate initiated with benzoyl peroxide during compression moulding at 150°C. Scanning electron microscopy revealed some degree of porosity in the samples, where the dispersed microfibrillated cellulose network was detectable. Microfibrillated cellulose, even in relatively small additions (2 wt%, 5 wt% and 10 wt%), resulted in composites with rather good hygromechanical properties. The ultimate strength increased with microfibrillated cellulose content and reached values of comparable composites with 40 wt% softwood fibre. Importantly, the dimensional stability in water was much improved compared to similar composites reinforced with substantially larger weight fractions of softwood fibres.

Drug Release from Poly(D, L-Lactide) / SiO2 Composites

The aim was to develop a biodegradable carrier system for toremif ene citrate based on poly(D,L-lactide) and sol-gel derived SiO 2. Two molecular weights of P(D,L-LA) (LMW 130 000 g/mol and HMW 240 000 g/mol) were used in the composites. The release rate of toremifene citrate from P(D,L-LA)/SiO2 composites was evaluated by in vitro dissolution tests. It was shown that it is possible to prepare a controlled release system of toremifene citrate by adding SiO2 particles and/or pores to the used polymer. Release of toremifene citrate can be adjusted from 30 days to 6 months. Introduction Polylactides have been used as matrix materials for drug rel ease [1], but the clear and sudden changes in structure, e.g., steep decrease in molecular weight ca used by enhanced autocatalytic degradation [2], is a problem with respect to the controlled release of drugs. Biodegradable, sol-gel derived SiO2 is known to be biocombatible and it has been used for controlled drug deli very as such [3]. In this work toremifene citrate (TC) was used as a model dr ug in polymer/silica gel composites. Toremifene citrate is an antiestrogenic compound that has been used i n the systemic treatment of hormone-dependent breast cancer. Local hormone therapy after breast cancer surgery could provide targeted and long-lasting disease control. The purpose of this study was to develop a controlled release form ulation of toremifene citrate using biodegradable delivery systems based on poly(D, Llactide) an d sol-gel derived SiO2 composites. Also the effect of pore forming CO 2 treatment and addition of a fast dissolving mesoporous SiO 2 (MCM-41) on composites was investigated. Furthermore, the effect of the molecular weight of poly(D,Llactide) on release rate of toremifene ci trate was studied. Materials and Methods Silica sol was prepared in a mole ratio of TEOS: H 2O: HCl, 1.0: 14.2: 0.0096. Toremifene citrate (Orion Pharma Ltd, Turku, Finland) was added into the clear hydrolyse d silica sol at room temperature. The pH of the sol was adjusted to 2.4 before spray dry ing with a mini spray dryer (B191, Büchi Labortechnik AG, Switzerland). The theoretical drug concentra tion in the silica sol was 2 wt.%, corresponding to 13,4 wt.% drug in spray dried microparticles (MP). Pore structure of calcified, TEOS-derived MCM-41-type SiO 2 was modified by cetyltrimethylammonium bromide/dimethylhexadecyl amine ratio. HMW and LMW P(D,L-LA) polymers were prepared from racemic l a tide (Purac) recrystallised once from ethylacetate. The racemic D,Dand L,L-lactide w as polymerised in melt using tin octoate as catalyst at 140 °C for 5 hours under N 2 atmosphere and mechanical stirring. Solvent casted PDLLA composite films were prepared by dissolving PDLLA in chloroform mixed with SiO2 microparticles and drug. They contained 40 or 60 wt.% of toremifene citrate containing SiO 2 Key Engineering Materials Online: 2003-12-15 ISSN: 1662-9795, Vols. 254-256, pp 489-492 doi:10.4028/www.scientific.net/KEM.254-256.489

Bioactive Glass (S53P4) and Mesoporous MCM-41-Type SiO2 Adjusting In Vitro Bioactivity of Porous PDLLA

SiO2-based bioceramics, MCM-41-type SiO 2 and the bioactive glass S53P4, in composites with poly(D,L)lactide were studied in the simulated body fluid. The parameters controlling ion dissolutions and calcium phosphate formation were studied a nd the data was used to create multicomposites with locally varying properties ( .g., CaP formation on the other side, uninhibited silica dissolution and possibility to drug release from the other side of com posite)

Renewable poly(δ-decalactone) based block copolymer micelles as drug delivery vehicle: in vitro and in vivo evaluation

Polymers from natural resources are attracting much attention in various fields including drug delivery as green alternatives to fossil fuel based polymers. In this quest, novel block copolymers based on renewable poly(δ-decalactone) (PDL) were evaluated for their drug delivery capabilities and compared with a fossil fuel based polymer i.e. methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL). Using curcumin as a hydrophobic drug model, micelles of PDL block copolymers with different orientation i.e. AB (mPEG-b-PDL), ABA (PDL-b-PEG-b-PDL), ABC (mPEG-b-PDL-b-poly(pentadecalactone) and (mPEG-b-PCL) were prepared by nanoprecipitation method. The size, drug loading and curcumin stability studies results indicated that mPEG-b-PDL micelles was comparable to its counterpart mPEG-b-PCL micelles towards improved delivery of curcumin. Therefore, mixed micelles using these two copolymers were also evaluated to see any change in size, loading and drug release. Drug release studies proposed that sustained release can be obtained using poly(pentadecalactone) as crystalline core whereas rapid release can be achieved using amorphous PDL core. Further, mPEG-b-PDL micelles were found to be non-haemolytic, up to the concentration of 40 mg/mL. In vivo toxicity studies on rats advised low-toxic behaviour of these micelles up to 400 mg/kg dose, as evident by histopathological and biochemical analysis. In summary, it is anticipated that mPEG-b-PDL block copolymer micelles could serve as a renewable alternative for mPEG-b-PCL copolymers in drug delivery applications.