The clinical translation of regenerative therapies, whether in the form of mesenchymal cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses to a target site. We report the development and application of a therapeutic reservoir device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to organs and tissues of interest via a polymer-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the reservoir provided functional compared to a single injection of cells and to no treatment. Recent advances of the system include a multi-port and multi-reservoir system that can be tailored to cargo and application need. The pre-clinical use of our therapeutic reservoir as a research model may enable insights into regenerative orthopaedic therapy, particularly those therapies that require multi-dose approaches.

Autogenous bone grafting limitations have motivated the development of Tissue-Engineered (TE) biomaterials that offer an alternative as bone void fillers. However, the lack of a blood supply within implanted constructs may result in avascular necrosis and construct failure¹. The aim of this project was to investigate the potential of novel TE constructs to promote vascularisation and bone defect repair using two distinct approaches. In Study 1, we investigated the potential of a mesenchymal stem cell (MSC) and endothelial cell (EC) co-culture to stimulate pre-vascularisation of biomaterials prior to in vivo implantation². In Study 2, we investigated the potential of TE hypertrophic cartilage to promote the release of angiogenic factors such as VEGF, vascular invasion and subsequent endochondral bone formation in an in vivo model.

Collagen-only (Coll), collagen-glycosaminoglycan (CG) and collagen-hydroxyapatite (CHA) scaffolds were fabricated by freeze-drying³, seeded with cells and implanted into critical-sized calvarial and femoral defects in immunocompetent rats. In Study 1, Coll and CG scaffolds were initially seeded with ECs, allowed to form capillary-like networks before the delayed addition of MSCs and continued culture prior to calvarial implantation. In Study 2, CG and CHA scaffolds were seeded with MSCs and cultured under chondrogenic and subsequent hypertrophic conditions to form a cartilage pre-cursor prior to calvarial and femoral implantation in vivo.

MicroCT and histomorphometry quantification demonstrated the ability of both systems to support increased bone formation compared to controls. Moreover, the greatest levels of bone formation were observed in the CG groups, notably in those containing cartilage tissue (Study 2). Assessment of the immune response suggests the addition of MSCs promotes the polarisation of macrophages away from inflammation (M1) towards a pro-remodelling phenotype (M2).

We have developed distinct collagen-based systems that promote vascularisation and ultimately enhance bone formation, confirming their potential as advanced strategies for bone repair applications.

Gene-activated scaffolds have shown potential in localised gene delivery resulting in bone tissue regeneration. In this study, the ability of two gene delivery vectors, polyethyleneimine (PEI) and nano-hydroxyapatite (nHA), to act as carriers for the delivery of therapeutic genes when combined with our collagen-nHA (coll-nHA) scaffolds to produce gene-activated scaffolds [1, 2], was determined. In addition, coll-nHA-dual gene scaffolds containing both an angiogenic gene and an osteogenic gene were assessed for bone healing in an in vivo Wistar rat calvarial defect model. When cells were applied to the coll-nHA scaffolds under osteogenic conditions in vitro, the dual scaffolds exhibited significantly superior osteogenic potential when analysed using microCT, calcium quantification and histology compared to single-gene scaffolds and gene-free controls. When the dual scaffolds were assessed in vivo, the nHA dual scaffold outperformed all other groups as early as 4 weeks post-implantation as determined using X-ray, microCT, quantification of new bone volume, histology and vessel formation. This research has demonstrated the potential of using novel coll-nHA scaffolds for therapeutic gene therapy while also being capable of simultaneously delivering numerous genes. This study underlines the effect of specifically tailoring gene-activated scaffolds for bone regeneration applications.

Introduction Significant cortical bone mass has been demonstrated at the proximo-lateral flare of the femur (Fetto et al). Experiments have shown that if a femoral stem has a medial and lateral flare proximally, the loads are transferred to the proximal femur and stress protection in this area is avoided. Furthermore, the results suggested that a stem below the lesser trochanter was unnecessary (Walker et al).

Methodology This paper reports on two cohorts of ten patients that had either a short stemmed fully coated implant (Group I) or an unstemmed metaphyseal implant on which all but the polished tip was coated (Group II). All implants were customised based on pre-operative CT data. All hips had serial post-operative AP and lateral radiographs and bone densitometry was assessed with DEXA scanning.

Results The most recent post-operative radiographs of all patients in Group I revealed buttressing in zone IV with trabeculae streaming from the cortices onto the tip of the stem. Qualitatively there appeared to be osteope-nia in Gruen zones I and VII. The x-rays of the Group II patients revealed good condensation of bone along the textured surface in zone I and VII with preservation of bone density in these regions. These findings were confirmed by the DEXA results which showed a reduction of the BMD in zones I and VII in Group I, while Group II revealed preservation of the BMD in these zones.

Conclusion A conservative prosthesis without a stem which effectively loads both medial and lateral proximal femoral flares not only removes less bone at the index operation but preserves proximal bone stock in the longer term.