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Current Stem Cell Research & Therapy, 2012, 7, 44-52
Biodegradable Engineering
Bone
Regeneration
Synthetic
Scaffolds
In
Tissue
Salah Hammouche*,1, Dalia Hammouche2 and Michael J. McNicholas1,3 1
Warrington and Halton Hospitals NHS Foundation Trust, Warrington, WA5 1QG, United Kingdom; 2Queen Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, United Kingdom; 3Directorate of Sport, University of Salford, Greater Manchester, M5 4WT, United Kingdom Abstract: A growing array of synthetic bone regeneration scaffolds has been used or investigated over the last century. These scaffolds aim to provide a three-dimensional substrate for bone cells to populate on and function appropriately. To serve this function, these scaffolds should be biocompatible and biodegradable at a rate commensurate with bone remodelling. Their mechanical properties should also be similar to those of the bone regeneration site. In this review, the main families of synthetic bone scaffolds were taxonomised and expounded. The main focus will be on the basic sciences’ principles and properties of clinically available as well as experimental synthetic bone scaffolds. This paper will emphasis on scaffolds developed over the last ten years.
Keywords: Bone regeneration, osteoconductivity, osteoinductivity, scaffold, tissue engineering. INTRODUCTION More than one million patients are treated annually to regenerate bone tissue in sites of congenital defects, tumour resection or fractures; with more than half a million operations require bone grafting in North America alone [1-3]. This regeneration process is very complex and requires the existence of four elements. These are morphogenetic signal, responsive host cells, a viable well-vascularised host bed and a suitable scaffold [4-8]. During fracture healing, scaffold serves as a template for cell interactions and the formation of bone extracellular matrix [9]. It also provides a structural support to the newly formed tissue [10, 11]. Autografts or allografts are used as first-line scaffolds for bone regeneration. However, their use is restricted by donor site shortage and morbidity [12-16]; or by immunologic barriers and infectious diseases’ transmission [17-19]. Thus there is a need for developing tissue-engineered alternatives [10, 17]. A growing array of synthetic scaffolds for bone regeneration has become commercially available over the last century [2, 3, 10, 17, 20-22]. These scaffolds aim to provide a threedimensional substrate for bone cells to populate on and function appropriately. To serve this function, scaffolds should meet certain criteria. They should be biocompatible and biodegradable at a rate commensurate with bone remodelling. Their mechanical properties should be similar to the bone repair site [23-25]. In other words, they should recreate similar environment to that provided by the bone extra-cellular matrix [5, 9, 10, 26-28].
*Address correspondence to this author at the Institute of Medical and Biological Engineering University of Leeds, Leeds, LS2 9JT, United Kingdom; Tel: +44 (0)113 343 2164; Fax: +44 (0)113 242 4611; E-mail:
[email protected]
1574-888X/12 $58.00+.00
This paper is a review article of synthetic bone regeneration scaffolds. Its structure will be similar to that of previous reviews [17, 29-31], while providing more up-to-date information. It will mainly focus on the basic sciences principles and properties of clinically available as well as experimental synthetic bone scaffolds. The main focus would be on newly evolving scaffolds over the last ten years; however, key scaffold families are to be explicated. In this article, bone tissue-engineered synthetic scaffold is defined as a material which acts as a carrier or template for bone cells and induces formation of bone from the surrounding tissue. Due to the word limit, we will exclude scaffolds which are merely used as drug delivery ones without providing a template structure for bone regeneration. We will also exclude non-biodegradable scaffolds which are usually used as permanent fixation plates or screws. This paper will first elucidate the desirable biological and mechanical characteristics of synthetic scaffolds in comparison to those of cortical and cancellous bone. Various types of scaffolds are then taxonomised and expounded. Finally, this article will conclude by our perspectives for prospective scaffolds. DESIRABLE PROPERTIES 1. Scaffolds’ Biological Characteristics Bone regeneration depends on using scaffolds which are osteoconductive as well as osteoinductive scaffolds [10, 22, 31, 32]. Osteoconduction supports in growth of capillaries and cells from the host into a three-dimensional structure to form bone [31]. Osteoconduction supports bone repair in a location that normal healing will eventually occur. On the other hand, osteoinduction is defined as the scaffold’s ability to cause pluripotential cells differentiation, within non-osseous environment, into chondroctyes and osteoblasts © 2012 Bentham Science Publishers
Bone Substitute Scaffolds
culminating in bone formation [31-34]. In fact, an osteoinductive scaffold allows repair in a location that would normally not heal by itself [5]. Although scaffolds serve primarily as osteoconductive moieties, they should preferably induce bone regeneration by osteoinduction. Scaffolds’ osteoinductivity is facilitated by additional properties; scaffolds should incorporate biologically active target molecules and should be able to efficiently deliver natural biological stimuli [30]. Scaffolds have to serve as delivery vehicles for cytokines such as bone morphogenetic proteins, insulin–like growth factors, and transforming growth factors which collectively transform recruited precursor cells into bone matrix producing cells [30]. In addition, scaffolds should serve as a reservoir that releases these factors in soluble form as a function of protein desorption and diffusion. Scaffolds might also incorporate biochemical signals which provide stimuli for cell adhesion, proliferation, differentiation and vascularisation. Some currently-used scaffolds lead to osteogenesis [35]. These scaffolds, which are pre-implanted with potentially– osteogenic stem cells, directly lay down new bone [3]. This is done by harvesting osteogenic cells from the patient preoperatively. These cells are then expanded and seeded on the scaffold [36]. Once implanted in the patient, they would lay down bone extracellular matrix as woven immature bone. This is then remodelled into a mature bone structure while the synthetic scaffold is reabsorbed [36]. Naturally, bone scaffolds should also be biocompatible. They should not elicit any undesirable local or systemic effects in the host [37]. They should be nontoxic, nonimmunogenic and non-carcinogenic [38]. They also have to be biodegradable at a controlled rate which allows deposition of native matrix by growing tissue while providing structural support [30]. 2. Scaffolds’ Geometrical and Mechanical Properties From biomaterial perspective, bone refers to a family of materials; each with a somewhat different structural motif, while sharing the same basic building blocks [39-41]. This building block consists of Dahllite (carbonated apatite) crystals, type I collagen fibrils, and water [39]. Fundamentally, bone is a natural composite of polymer (collagen) and ceramics (bone minerals) [36, 40, 41]. Bone also has a hierarchical structure with a diverse shape reflecting the fine-tuning and functioning adaptation [3, 36, 41, 42]. This complex structure gives bone tissue unique mechanical properties with high stiffness, tensile strength and modulus of elasticity [40, 43]. The estimated modulus of elasticity is 17.0–20.0 GPa in longitudinal direction and 6.0–13.0 GPa in transversal direction. These mechanical characteristics are important for the bone tissue’s supportive function and enable the skeleton to withstand impact. Many papers have stated that synthetic scaffold’s properties should match those of natural bone’s in terms of high stiffness and high elasticity [30, 44, 45]. However, others argued that scaffold strength should be greater than the bone it would be replacing [46]. It is now more widely agreed that the resultant mechanical properties of the composite of bone
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and scaffold should be similar to that of the host bone [47]. These mechanical properties should be maintained within the same order over time as scaffold degrades and bone ingrowth occurs. Synthetic scaffolds should also resemble natural bone complex geometry, one of which is porosity [41]. Pores are a necessary prerequisite in bone scaffolds. Pores allow migration and proliferation of osteoblasts and mesenchymal cells, as well as vascularisation and nutrient and oxygen exchange. Porosity also affects cell recruitment and attachment. A porous surface improves mechanical interlocking between the implant biomaterial and the surrounding natural bone, providing greater mechanical stability at this critical interface [48]. Pore size should correlate with normal bone porosity with an approximate diameter of 100–200 m. Hulbert et al. examined such correlation in vivo in 46% porosity calcium aluminate pellets [49]. They found that the nature of the penetrated tissue is directly related to pores’ sizes. With small pores (10–44 and 44–75 m), the pellets were penetrated by fibrous tissue only. With an increase of pores size to 75–100 m, an ingrowth of unmineralised osteoid tissue started to appear. Not until large pores size pellets (of an order of 100–150 and 150–200 m) were inserted, a substantial bone ingrowth occurred. Utilising macroporous biphasic calcium phosphate ceramics, Gaulthier et al. similarly showed that a pore size of 500 m better supported bone formation compared to 300 m pore size [50]. While the majority of the literature focuses on scaffolds’ macroporosity, less attention has been given to scaffold material design at a microporosity level. Microporosity (pore size
