While new biomaterials for regenerative therapies are being reported in the literature, clinical translation is slow. Some existing regenerative approaches rely on high doses of growth factors, such as bone morphogenetic protein‐2 (BMP‐2) in bone regeneration, which can cause serious side effects. An ultralow‐dose growth factor technology is described yielding high bioactivity based on a simple polymer, poly(ethyl acrylate) (PEA), and mechanisms to drive stem cell differentiation and bone regeneration in a critical‐sized murine defect model with translation to a clinical veterinary setting are reported. This material‐based technology triggers spontaneous fibronectin organization and stimulates growth factor signalling, enabling synergistic integrin and BMP‐2 receptor activation in mesenchymal stem cells. To translate this technology, plasma‐polymerized PEA is used on 2D and 3D substrates to enhance cell signalling in vitro, showing the complete healing of a critical‐sized bone injury in mice in vivo. Efficacy is demonstrated in a Münsterländer dog with a nonhealing humerus fracture, establishing the clinical translation of advanced ultralow‐dose growth factor treatment.

No abstract

A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Abstract3D printing is of great interest for tissue engineering scaffolds due to the ability to form complex geometries and control internal structures, including porosity and pore size. The porous structure of scaffolds plays an important role in cell ingrowth and nutrition infusion. Although the internal porosity and pore size of 3D printed scaffolds have been frequently studied, the surface porosity and pore size, which are critical for cell infiltration and mass transport, have not been investigated. The surface geometry can differ considerably from the internal scaffold structure depending on the 3D printing process. It is vital to be able to control the surface geometry of scaffolds as well as the internal structure to fabricate optimal architectures. This work presents a method to control the surface porosity and pore size of 3D printed scaffolds. Six scaffold designs have been printed with surface porosities ranging from 3% -21%. We have characterised the overall scaffold porosity and surface porosity using optical microscopy and microCT. It has been found that surface porosity has a significant impact on cell infiltration and proliferation. In addition, the porosity of the surface has been found to have an effect on mechanical properties and on the forces required to penetrate the scaffold with a surgical suturing needle. To the authors' knowledge, this study is the first to investigate the surface geometry of extrusion-based 3D printed scaffolds and demonstrates the importance of surface geometry in cell infiltration and clinical manipulation.

A robust methodology is presented to identify novel biomaterials suitable for three-dimensional (3D) printing. Currently, the application of additive manufacturing is limited by the availability of functional inks, especially in the area of biomaterials; this is the first time when this method is used to tackle this problem, allowing hundreds of formulations to be readily assessed. Several functional properties, including the release of an antidepressive drug (paroxetine), cytotoxicity, and printability, are screened for 253 new ink formulations in a high-throughput format as well as mechanical properties. The selected candidates with the desirable properties are successfully scaled up using 3D printing into a range of object architectures. A full drug release study and degradability and tensile modulus experiments are presented on a simple architecture to validating the suitability of this methodology to identify printable inks for 3D printing devices with bespoke properties.

This work presents a robust method to achieve the synthesis of low molecular weight polyesters via ring‐opening polymerization (ROP) initiated by 2‐hydroxyethyl‐methacrylate (HEMA) when using triazabicyclodecene (TBD) as catalyst. The effect that the HEMA:TBD ratio has upon the final reaction rate and final polymer molecular architecture is discussed. The optimum HEMA:TBD ratio and reaction conditions required to minimize competing transesterification reactions are determined, in order to synthesize successfully the target ROP macromonomer species containing only a single 2‐methacryloyloxyethyl end‐group. Additionally, to confirm the terminal end‐group fidelity of the product macromonomers and confirm TBD utility for block copolymer manufacture, a small series of di‐block polyesters are synthesized using TBD and shown to exhibit good control over the final polymer structure whilst negating the side transesterification reactions, irrespective of the monomers used.

We investigated the feasibility of using spatially offset Raman spectroscopy (SORS) for nondestructive characterization of bone tissue engineering scaffolds. The deep regions of these scaffolds, or scaffolds implanted subcutaneously in live animals, are typically difficult to measure by confocal Raman spectroscopy techniques because of the limited depth penetration of light caused by the high level of light scattering. Layered samples consisting of bioactive glass foams (IEIC16), three-dimensional (3D)-printed biodegradable poly­(lactic-co-glycolic acid) scaffolds (PLGA), and hydroxyapatite powder (HA) were used to mimic nondestructive detection of biomineralization for intact real-size 3D tissue engineering constructs. SORS spectra were measured with a new SORS instrument using a digital micromirror device (DMD) to allow software selection of the spatial offsets. The results show that HA can be reliably detected at depths of 0–2.3 mm, which corresponds to the maximum accessible spatial offset of the current instrument. The intensity ratio of Raman bands associated with the scaffolds and HA with the spatial offset depended on the depth at which HA was located. Furthermore, we show the feasibility for in vivo monitoring mineralization of scaffold implanted subcutaneously by demonstrating the ability to measure transcutaneously Raman signals of the scaffolds and HA (fresh chicken skin used as a top layer). The ability to measure spectral depth profiles at high speed (5 s acquisition time) and the ease of implementation make SORS a promising approach for noninvasive characterization of cell/tissue development in vitro, and for long-term in vivo monitoring the mineralization in 3D scaffolds subcutaneously implanted in small animals.

No abstract

Low molecular weight additives which can cooperatively self-assemble with supramolecular polyurethanes via complementary hydrogen bonding interactions offer an attractive route to enhancing the properties of addressable polymer networks. Here, we present the design, synthesis, characterisation and mechanical properties of a series of supramolecular polyurethanes with varied loadings of a low molecular weight bis-urea additive. These additives are able to self-assemble with analogous recognition motifs within the supramolecular polyurethanes to form polar 'hard' domains, promoting phase separation within the material and, crucially, increasing the strength of the polymer network. In addition, the bis-urea additive is a by-product within the polymerisation and thus can be synthesised in situ, without the need for complex purification or blending. The mechanical properties of these reinforced polymers were enhanced when compared to the pristine supramolecular polyurethane alone, as a result of higher degrees of order within the polymer matrix. Furthermore, a formulation comprising the small molecule blended with the supramolecular polyurethane was produced to examine the effect of material preparation and filler dispersion within the polymer matrix. Interestingly, the mechanical performance of a blended material was diminished as a result of modest dispersion and incorporation within the polymer matrix. These findings thus demonstrate a facile, one-pot, method that does not require purification to produce reinforced supramolecular polyurethanes. This methodology may find use in industrial applications in which enhancements to the physical and mechanical properties can be easily achieved through the in situ synthesis of low molecular weight additives within the polymerisation.