University of Cambridge > Talks.cam > Departmental Seminar Programme, Department of Veterinary Medicine > DEVELOPMENT OF BIOMATERIALS AND CELL THERAPIES FOR BONE REGENERATION

DEVELOPMENT OF BIOMATERIALS AND CELL THERAPIES FOR BONE REGENERATION

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The use of bone grafts is recommended in numerous surgeries. The autograft is considered to be the technique of choice in bone fusions, for small gaps and in critical defects given the properties of osteoconduction, osteogenic and osteoinduction. Regardless of its unique characteristics, there is an increasing substitution with synthetic bone due to the high morbidity of the harvest and limitations of the volume of autografts. Also the well-known disadvantages of allografts, such as potential risk for transmission of infectious diseases and the induction of adverse immune reactions, have driven the development of synthetic bone grafts for bone regeneration either in human or in veterinary medicine. For those reasons in recent decades there has been an enlargement of the need to use bone grafts. Bonelike® (BL®) (J.D Santos, G.W Hastings, J.C.Knowles, European Patent WO 0068164 ) is a synthetic bone graft substitute, which consisted in the incorporation of P205 CaO glass-based system within the hydroxyapatite (HA) matrix of spherical pellets with 250 – 500 µm of diameter for bone grafting with osteoinductive and osteoconductive proprieties, which overcomes some of the main disadvantages of traditional hydroxyapatite. This biomaterial is a composite composed of a modified HA matrix with α and β-tricalcium phosphate secondary phases, resulting in higher solubility than single HA type of materials. These create better osteoinductive and osteoconductive proprieties that have been confirmed in experimental models of bone regeneration in sheep and recently its application in orthopedic and stomatological pathologies is being tested in small animal (SA) clinics. An ideal bone substitute should also be biocompatible, reabsorbable, with a similar mechanical resistance as the cortical bone, have osteoconductive, osteoinductive and osteogenic properties, should be easily handled and sterilized. The bone substitute should not cause any adverse systemic or local reaction, should provide a favorable environment to be invaded by blood vessels, cells and growth factors. However, no biomaterial developed and used in clinical applications can encompass all of these properties. The perceived drawbacks of some substitutes include poor resorbability, inclusion of processed animal components, inferior handling characteristics, and most of the times, high associated cost. The use of mesenchymal stem cells (MSCs) as candidate of cell-based therapies for treating a variety of pathologies in Veterinary and Human Medicine is based on their qualities for locally modulate the inflammatory response, to produce growth factors, to replace damaged cells and vascularization, and to improve tissue regeneration. Preclinical cell-based products development includes the use of well characterized cell populations whose efficacy and safety are tested in vitro and in appropriate animal models prior to clinical trials and routine clinical application. In the field of orthopedics, there are an increasing number of translational studies that use sheep as an in vivo animal model because of the similarities with humans in size and musculoskeletal architecture. However robust and reproducible methods for the isolation, expansion, manipulation and characterization of ovine and human MSCs from the dental pulp have not been standardized yet. In the present study, DPS Cs isolated from the dental pulp were in vitro characterized and expanded for in vivo application in pre-clinical trials. These studies included flow cytometry, immunocytochemistry analysis, karyotype analysis, metabolic and secretome profile during expansion, and tri-lineage differentiation in at least three cell lines: osteogenic, chondrogenic and adipogenic lineages. The osteogenic potential of DPS Cs derived following this methodology associated to a modified hydroxyapatite bone substitute was further evaluated in vivo in a monocortical ovine model that consists in 5 holes (5 mm Ø), in the femoral diaphysis, with similar bone structure, overlying soft tissue and loading pattern for all defects. This experimental study highlights the importance of including a multidisciplinary team in the development of new biomaterials and cell-based therapies, allowing a close share of knowledge between biomaterials design, cell therapies development and surgeons’ needs. The importance of bringing together collaborative work between medical doctors that promote the transfer of technology to the hospitals; veterinary surgeons, who assure the animal welfare in accordance to International guidelines and introduce these technologies in veterinary medicine; engineers who design, and optimize the biomaterials, and researchers who transfer therapeutic protocols to National and International biotechnology market will be emphasized.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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