Toby Gould

Controlled release of BMP-2 from a sintered polymer scaffold enhances bone repair in a mouse calvarial defect model.

Sustained and controlled delivery of growth factors, such as bone morphogenetic protein 2 (BMP‐2), from polymer scaffolds has excellent potential for enhancing bone regeneration. The present study investigated the use of novel sintered polymer scaffolds prepared using temperature‐sensitive PLGA/PEG particles. Growth factors can be incorporated into these scaffolds by mixing the reconstituted growth factor with the particles prior to sintering. The ability of the PLGA/PEG scaffolds to deliver BMP‐2 in a controlled and sustained manner was assessed and the osteogenic potential of these scaffolds was determined in a mouse calvarial defect model. BMP‐2 was released from the scaffolds in vitro over 3 weeks. On average, ca. 70% of the BMP‐2 loaded into the scaffolds was released by the end of this time period. The released BMP‐2 was shown to be active and to induce osteogenesis when used in a cell culture assay. A substantial increase in new bone volume of 55% was observed in a mouse calvarial defect model for BMP‐2‐loaded PLGA/PEG scaffolds compared to empty defect controls. An increase in new bone volume of 31% was observed for PLGA/PEG scaffolds without BMP‐2, compared to empty defect controls. These results demonstrate the potential of novel PLGA/PEG scaffolds for sustained BMP‐2 delivery for bone‐regeneration applications. Copyright

A novel technique for the production of electrospun scaffolds with tailored three-dimensional micro-patterns employing additive manufacturing

Electrospinning is a common technique used to fabricate fibrous scaffolds for tissue engineering applications. There is now growing interest in assessing the ability of collector plate design to influence the patterning of the fibres during the electrospinning process. In this study, we investigate a novel method to generate hybrid electrospun scaffolds consisting of both random fibres and a defined three-dimensional (3D) micro-topography at the surface, using patterned resin formers produced by rapid prototyping (RP). Poly(D,L-lactide-co-glycolide) was electrospun onto the engineered RP surfaces and the ability of these formers to influence microfibre patterning in the resulting scaffolds visualized by scanning electron microscopy. Electrospun scaffolds with patterns mirroring the microstructures of the formers were successfully fabricated. The effect of the resulting fibre patterns and 3D geometries on mammalian cell adhesion and proliferation was investigated by seeding enhanced green fluorescent protein labelled 3T3 fibroblasts onto the scaffolds. Following 24 h and four days of culture, the seeded scaffolds were visually assessed by confocal macro- and microscopy. The patterning of the fibres guided initial cell adhesion to the scaffold with subsequent proliferation over the geometry resulting in the cells being held in a 3D micro-topography. Such patterning could be designed to replicate a specific in vivo structure; we use the dermal papillae as an exemplar here. In conclusion, a novel, versatile and scalable method to produce hybrid electrospun scaffolds has been developed. The 3D directional cues of the patterned fibres have been shown to influence cell behaviour and could be used to culture cells within a similar 3D micro-topography as experienced in vivo.

A thermoresponsive and magnetic colloid for 3D cell expansion and reconfiguration

A dual thermoresponsive and magnetic colloidal gel matrix is described for enhanced stem-cell culture. The combined properties of the material allow enzyme-free passaging and expansion of mesenchymal stem cells, as well as isolation of cells postculture by the simple process of lowering the temperature and applying an external magnetic field. The colloidal gel can be reconfigured with thermal and magnetic stimuli to allow patterning of cells in discrete zones and to control movement of cells within the porous matrix during culture.

Development of a porous poly(DL-lactic acid-co-glycolic acid)-based scaffold for mastoid air-cell regeneration.

To develop a porous, biodegradable scaffold for mastoid air‐cell regeneration.

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

INTRODUCTION The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma. METHODS Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model. RESULTS Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour. CONCLUSIONS Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.

OP22SIMULTANEOUS INTRA-CAVITY DELIVERY OF MULTIPLE CHEMOTHERAPEUTICS FROM A MOULDABLE NEUROSURGICALLY-APPLIED POLYMER PASTE

INTRODUCTION: A thermo-setting biomaterial containing a depot of clinically relevant chemotherapeutics applied to the post-surgical resection cavity offers an opportunity for localised control of residual malignant glioma. Here we evaluate mouldable polymer matrices of poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) microparticles for tailored combination drug release. METHOD: Clinically-approved or experimental chemotherapeutics, alone and in combination, were loaded onto PLGA/PEG microparticle matrices, or encapsulated inside PLGA microspheres. Mono- and dual-therapy release rates were measured by liquid chromatography and stability verified by mass spectrometry. Cytotoxicity of released drugs was assessed using patient-derived invasive margin cells and flank mouse xenografts. RESULTS: Temozolomide (TMZ), etoposide (ETO) and methotrexate were released from PLGA/PEG alone or in dual combinations over 2 weeks in vitro, whilst irinotecan, cilengitide and imatinib released over a similar period as monotherapies. Cytotoxicity was not impaired by polymer interaction. Drug encapsulation in PLGA microspheres dampens the rapid burst release. PLGA/PEG overcomes TMZ instability, resulting in a 10-day release where the AIC active component was measured. In vivo ETO release markedly reduced glioma bioluminescence with longer-term survivors relative to resection-only controls. CONCLUSION: We have developed a PLGA-based platform technology to deliver multiple clinically relevant chemotherapy agents, including TMZ, from a single matrix. Prolonged release kinetics can be achieved by drug encapsulating drugs, potentially filling the 3 week therapy gap that currently exists between surgery and radiotherapy commencement.

Development of a porous PLGA-based scaffold for mastoid air cell regeneration

To develop a porous, biodegradable scaffold for mastoid air‐cell regeneration.

Development of a porous poly(DL-lactic acid-co-glycolic acid)-based scaffold for mastoid air-cell regeneration: Scaffold for Mastoid Regeneration

To develop a porous, biodegradable scaffold for mastoid air‐cell regeneration.