Acknowledgements
7.2 Multi-Functional Biomaterials for Bone Tissue Engineering
7.2.1 Passive Biomaterials for Mechanical Support
the cell and scaffold form the two basic components of engineered bone tissue. Conventionally, this involves a period of culture in vitro, in which the cells and scaffolds are assembled to form engineered constructs.5
Figure 7.1 summary of roles served by biomaterials in bone tissue engineering.
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00169
post-implantation, the engineered bone grafts are assumed to integrate into the host skeleton, and further mature into woven bone. scaffolds per- form primarily to provide structural support for cells, both in vitro and in vivo, with the following key requirements:6 (1) biocompatibility, in that the materials and degradation products of scaffolds should be non-toxic and non-teratogenic without eliciting excessive inflammatory response. (2) suf- ficient mechanical properties to define and protect a physical space for cel- lular growth; these should ideally match the mechanical properties of the surrounding tissue. (3) high porosity (>90%), good interconnectivity, and average pore size between 200 µm and 400 µm to promote host cell infiltra- tion and host integration. (4) appropriate biodegradability with adjustable degradation rates. (5) Feasible sterilization methods that do not interfere with the function of the scaffold or change the chemical composition of scaf- fold biomaterials.
it is important to distinguish at this point the terms “osteoconductive” and
“osteoinductive”. osteoconductivity refers to the ability of a porous scaffold to support the infiltration of host bone cells and blood vessels. as the scaf- fold undergoes degradation, this process ensures the formation of integrated bone tissue. in contrast, osteoinductive scaffolds actively drive osteogene- sis and the formation of bone tissue. these include physical cues, including topography and the nano-/micro-structure of the scaffold’s surface that influ- ence cell proliferation and differentiation on scaffolds.7 in the early years of tissue engineering, scaffolds were almost exclusively comprised of bio-inert materials. these “first generation” scaffolds provided ample mechanical support and room for osteoconduction, with no chemical or physical cues for osteoinduction of seeded cells.8
First generation scaffolds may be grouped into natural or synthetic materials. proteins such as collagen,9 gelatin,10 fibrin11 and silk fibroin,12 polysaccharides like chitosan13 and alginate14 and inorganic materials like coralline apatite15 are derived from natural sources; consequently, they approximate various components of the human bone extracellular matrix, and are observed to be cytocompatible. these materials exhibit various lim- itations, however, including immunological concerns attributed to the use of xenogeneic material and inadequate mechanical properties (due both to source variability and difficulties in modifying inherent properties). addi- tionally, scaffold-forming technologies to handle these materials are limited, necessitating highly-customized set-ups to address these concerns. taking a pure chitosan scaffold as an example, its inadequate mechanical properties result in improper cell attachment and morphology, which in turn affects cell activities. the addition of 1 wt% nano-hydroxyapatite (hap) to form a composite construct significantly improves scaffold stiffness and translates to 50% greater proliferation rate of pre-osteoblastic cells, one week after cell seeding.16
Compared with natural biomaterials, it is usually easier to shape or alter the chemical and mechanical properties of synthetic materials. in particu- lar, polyesters, such as polycaprolactone (pCL), are commonly employed as
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00169
scaffold materials. Bioresorbable polymers have tailored degradation rates, and are designed to be absorbed by the host over time. of course, synthetic materials have their own limitations, like acidolysis associated with scaffold breakdown, and the lack of biologically-recognizable surface motifs, which impedes cellular attachment.17 great efforts have been spent to address these challenges by incorporating tricalcium phosphate (tCp)18 or employing surface-hydrolytic treatments to improve surface wettability, cell adhesion and thereby host tissue ingrowth.19 hap-coated or gelatin-coated pCL films and 3d honeycomb pCL scaffolds have also been designed for the develop- ment of vascularized tissue engineered bone.20,21 the use of co-polymers is another way to control the degradation of scaffold materials. For example, poly(anhydride-co-imides) has a much more adjustable degradation rate than polyanhydride, a surface bioeroding polymer. as a homopolymer, ali- phatic polyanhydride is rapidly degraded in vivo within a few weeks, while aromatic polyanhydride can take years to be fully degraded.22,23 degradation of poly(anhydride-co-imides) on the other hand, can be adjusted between weeks to a few months by simply tuning its monomer ratio.24,25
aside from polymers, ceramics are renowned for their biocompatibility and the ease of forming highly porous structures. Besides hap and tCp, non-degradable ceramics such as alumina and zirconia26 are also applied in scaffold fabrication. several studies have additionally demonstrated the tunable compressive strength of alumina,27,28 with good cytocompatibility and lack of genotoxicity.29 however, due to low fatigue strength, high rigid- ity and brittleness, the processing and application of pure ceramics remain limited.
Finally, metals that have traditionally been associated with orthopaedic reconstructions can perform similarly in bone tissue engineering as perma- nent scaffolds. titanium (ti) is widely applied in fracture fixation and repair of bone defects owing to its good biocompatibility and resistance to fatigue and corrosion.30 ti fiber web scaffolds coated with a thin hap layer showed enhanced stress resistance and osteoconductivity in rabbit mandibular bone reconstruction.31 surface-grafted chitosan may further improve the safety and efficacy of ti scaffolds by promoting cell attachment and reducing bacterial adhesion.32 Composite coatings of chitosan, nano-hap and nano-copper–
zinc alloy have successfully combined the advantages of natural polymers, synthetic ceramics and metal alloys. this composite shows a low degrada- tion rate for maintaining sufficient mechanical strength, increased protein adsorption to facilitate cell adhesion, and anti-bacterial activity.33
in recent years, other bioinert materials have emerged for bone tissue engi- neering applications, including nano-scale materials such as graphene34,35 and carbon nanotubes, which can also provide mechanical reinforcement for scaffold materials. Multi-walled carbon nanotubes loaded on a poly(3- hydroxybutyrate-co-3-hydroxyvalerate) (phBV) cylinder significantly increased the flexural and compressive strengths of a phBV-based scaffold.36 however, safety concerns over carbon nanotube toxicity and detachment from the implantation site remain significant; further research is required to better characterize its nano-toxicity.37
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00169