CONCLUSIONES Y RECOMENDACIONES 8.1 Resumen y conclusiones

A range of different approaches to addressing bone repair are under continuing investigation. Some of these can be categorised into factor, cell, ceramic, or polymer-based approaches. Expander/extender materials for use with autograft or allograft can be used both to improve treatment/bone repair, and to reduce the volume of bone graft required for treatment, but are not discussed here.

1.3.1 Factor-based

Bone repair is controlled by a large number of cytokines, growth factors (GFs), and hormones that provide cellular signals to trigger healing responses and promote both migration of osteoprogenitor cells and specific lineage differentiation [68]. A growing body of research investigates the use of growth factors to promote bone regeneration. Results vary due to differing potency and efficacy of GFs used, physiological system variety, in addition to bone type and function, and bone defect type studied [69].

Bioactive molecules investigated include:

• Bone morphogenetic proteins, BMPs. BMPs are widely used osteoinductive factors in bone tissue engineering for a variety of roles that include acting as an osteoblastic differentiation factor for mesenchymal stem cells, MSCs.

• Insulin-like Growth Factors, IGFs. IGFs are a group of autocrine, endocrine, and paracrine polypeptide growth factors that play a role in bone metabolism and are known to stim- ulate proliferation and chemotactic migration of cells originating from periodontal ligaments [69,70].

• Fibroblast growth factor-2, FGF-2. FGF-2 has been shown to have a positive effect on bone healing [71,72] and to inhibit osteogenesis of stromal cells while maintaining

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osteogenic potential state [73].

• Vascular endothelial growth factor, VEGF. VEGF plays an important role in bone an- giogenesis (development of new blood vessels) and its administration has been shown to enhance blood vessel formation and ossification in bone damage models [74]. Studies investigating a variety of delivery mechanisms have been carried out and include investigation of a variety of polymer materials acting as carriers to deliver these bioactive molecules in 3D scaffolds, microparticles, or hydrogels. A review by Lee et al. [69] provides a more detailed overview of the role of bioactive molecules in bone regeneration.

1.3.2 Cell-based

Preclinical in vivo studies have been carried out investigating the use of various cell types as potential methods to improve bone regeneration with generally positive findings. Evidence that showed that MSCs, periosteal cells, and osteoblasts are capable of enhancing bone repair was reported [75,76]. Osseous tissue reconstruction involves cells undergoing a progression from undifferentiated progenitors to fully differentiated adult cells which explains how a tissue engineering approach for improving osseous healing can be approached through different stages of the bone healing process [77].

MSCs are of particular interest for a cell-based approach to bone healing as they can be harvested easily through the iliac crest and expanded to produce a large enough population for a clinical therapy. Additionally, their ability to differentiate down different cell lineages and the presence of research and evidence demonstrating control of the differentiation paths down which they mature make MSCs particularly relevant in this field [77].

1.3.3 Ceramic-based

The main inorganic component in bone is HA, a calcium apatite with a crystal form and chemical formula Ca10(PO4)6(OH)2. Ceramic-based bone graft substitutes are formed from

calcium phosphates, calcium sulphates and/or Bioglass (a range of bioactive glass ceram-R

ics, commercially available, with different compositions of SiO2, Na2O, CaO, and P2O5[78])

due to the similarity with a large part of the natural components found in bone. These materials are both osteoconductive and biocompatible [79], both of which are important in scaffolds for this application. Similarity to natural hydroxyapatite and their ability to

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act as sources of calcium and phosphate ions for bone remodelling and mineralisation are drivers for their use. Additionally researchers have shown bonding of new bone to synthetic hydroxyapatite [80]. A large number of bone graft substitutes are commercially available that are based on calcium sulphates, calcium phosphates and bioactive glasses: Osteograf R

(Dentsply Friadent, Germany), Norian SRS R (Synthes, USA), Pro Osteron R 200R and 500R

(Biomet, USA), Osteoset R (Wright Medical Technology, USA), Chronos R (Synthes, USA),

Actifuse ABX R (Apatech, Germany), Vitoss R (Othovita, USA), Tutoplast R (Tutogen Medi-

cal, Germany).

1.3.4 Polymer-based

A range of different polymeric materials have been used in some form for bone repair. A wide array of polymeric materials with many different properties allow for tailoring of scaffolds for different applications. Polymeric materials that have been investigated in this field vary from natural to synthetic. Those of natural origins include collagen, silk fibroin, chitosan, hyaluronic acid, alginates, cellulose, and dextrans. A review of polymers of natural origins and their role as scaffolds in tissue engineering was carried out by Malafaya et al. [81]. These roles include commercially available bone graft replacements such as Healos RBone

Graft Replacement (DePuy Orthopaedics, USA). Healos is a matrix of cross-linked collagenR

fibres coated with HA and has been approved for clinical use as a bone graft substitute in spinal fusions [81].

Synthetic polymers used in this field include poly (α-hydroxyacids), poly (ǫ-caprolactone), poly (urethane)s, poly (propylene fumarate), poly (phosphazenes), and poly (1,4-butylene succinate). Poly (α-hydroxyacids) include poly (glycolide) (PGA), poly (lactide) (PLA), and poly (ǫ-caprolactone) (PCL), and there is a large body of knowledge about these polymers. These polymers and their copolymers have FDA approval for a variety of clinical applica- tions, and as such are the most commonly used polymers for investigation within the tissue engineering and regenerative medicine field [82]. Various reviews of the many different porous scaffolds under investigation for the application of bone tissue engineering have been reported within the literature [17,82]. The use of a polymeric based scaffold for bone tissue engineering provides great opportunity to incorporate bioactive molecules, cells, and ceramic materials to form a composite tissue engineering solution that combines benefits of each approach. The innovative combination of the most promising technologies will build

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towards optimum solutions for different problems within this field.