2.3 Classification of Smart Materials in Tissue Engineering
2.3.2 Biosynthetic Materials
being investigated for burn treatment.48 the aMp cathelicidin ll-37 is an active molecule, naturally produced by immune cells49 such as macrophages, that contributes not only to protection against bacterial infection, but also has chemotactic effects promoting vascularization and the wound healing process.50 Consistent with the properties attributed to cathelicidin ll-37, preclinical studies using these smart hydrogels showed increased angiogen- esis, a shorter healing time, and increased matrix deposition, compared to the non-conjugated hydrogels.48
the investigation of non-conventional characteristics of polymers, such as conductive properties, is another area of interest in the development of smart materials. Conductive polymers can be considered a hybrid, as they present mechanical properties of traditional degradable polymers as well as con- ductive properties of metallic materials.31,51 Conductive polymers are being widely studied in non-biomedical applications, but the finding that some of these materials have good biocompatibility has raised their biomedical pro- file. the polymers already investigated for tissue engineering applications belong to a group of polyheterocycles that includes polypyrrole, polyani- line, and polythiophene. the potential use that has been focused upon is the reconstruction of electro-active tissues such as the brain, heart, skeletal muscle, and bone.52,53 different molecules carry the charge to be mobilized, tailoring the conductive property of these polymers. Successful approaches involve the use of glycosaminoglycans (GaG) (e.g. chondroitin sulfate and hyaluronic acid) as such “doping” molecules, which also can improve cell integration.31
Currently, in vitro and animal studies have been performed with different modifications of these conductive materials, but to be translated to clinical applications, challenges in the mechanical properties and reproducibility of the manufacturing processes need to be addressed. these materials have been further modified to incorporate specific protein domains to provide cell cues and facilitate cell adhesion and differentiation.31
From the review presented herein, it is obvious that synthetic smart mate- rials are rapidly evolving to simulate the regulatory mechanisms that exist within naturally occurring eCM. in the following sections, the analysis of smart biomaterials derived from naturally occurring materials will provide an alternative approach to cell/tissue modulation applicable in tissue engi- neering approaches.
biomedical applications. their use as homopolymers or co-polymers56 allows tuning of physical and mechanical properties, which expands the spectrum of potential medical uses for these materials. table 2.1 lists some of the most common phas used in medicine.
the phas share several properties with synthetic materials. the biosyn- thetic polymers can be modified by the same techniques applied to synthetic polymers. For example, Fu et al. (2014) explored the use of electrospinning copolymers of p3hB and p4hB (p34hB) to produce scaffolds from unwo- ven nanofibers, with potential for bone tissue engineering applications;56 whereas torun köse et al. (2003) made similar attempts with particle leach- ing to generate a macroporous structure from phBhV.59 the mechanical properties of phas have been well studied62,63 and reported to be analogous to synthetic materials such as polypropylene and polystyrene.64 if the biode- gradability of the phas is considered, some advantages for these materials exist when compared to other degradable synthetic polymers. degradation of phas occurs very slowly by hydrolysis and enzymatic methods, which main- tains the mechanical properties and provides for a gradual transfer of load to support tissue development. the slow rate hydrolysis also avoids abrupt ph changes in the microenvironment, a situation commonly found in polymers like pGa and which can trigger pro-inflammatory events.
recent studies have taken advantage of these inherent properties of phas.
Sun et al. (2015) developed laryngeal cartilage using phBhhx scaffolds by combined methods of casting, compression molding, and leaching. In vitro culture of chondrocytes on the scaffold followed by implantation in a rabbit model allowed the formation of mature cartilage, with increased options for functional repair when combined with a myofascial flap.65
the generation of smart biosynthetic materials has been achieved by var- ious functionalization methods. one of the most common modifications consists of the addition of pendant functional groups that modify the hydro- phobic character of these materials; for example, increased water and pro- tein interactions, as well as swelling of the biosynthetic compounds to form hydrogels.55 Zhan et al. (2015) developed a more complex smart biosynthetic material, able to prevent and control bacterial colonization. in their approach, a self-assembly method was used to generate layers of p34hB interacting Table 2.1 polyhydroxyalkanoates used in medical applications.
name abbreviation applications reference
poly(3-hydroxybutyrate) p3hB Sutures, screws and plates 57 poly(4-hydroxybutyrate) p4hB heart valves, mesh for
hernia repair, sutures 58 poly(3-hydroxybutyrate-
co-3-hydroxyvalerate) phBhV Scaffolds for bone tissue
engineering 59
poly(3-hydroxybutyrate-
co-3-hydroxyhexanoate) phBhhx tissue adhesion barriers 60 poly(3-hydroxybutyrate-
co-3-hydroxyoctanoate) phBho drug carrier nanoparticles 61
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00039
with a bactericidal agent, poly(amidoamine) dendrimers (paMaM), and ha as the anti-adhesion agent66 for potential use in different tissues.
Biosynthetic materials derived from the pha group have an additional and less explored property. due to their bacterial origin, these polymers have shown physiological functions that have an effect not only on the bac- teria from which they were produced, but on a variety of cells in different tissues and different organisms.64 the monomeric forms of p3hB and p4hB, 3-hydroxybutyrate (3hB) and 4-hydroxybutyrate (4hB), respectively, are involved in normal physiologic activities and are produced in the body at low concentrations. Specifically, 3hB can serve as a nutritional supplement to increase ketone levels and control metabolic diseases.67 4hB is associated with functional activity in the central nervous system (CnS)68 and has been proposed for neural applications.64
More recently, pineda Molina et al. (2017) have shown that scaffolds com- posed of p4hB were able to resist deliberate in situ (1 × 108 CFU) Staphylococcus aureus contamination in a rat subcutaneous implantation model.69 the mech- anism of infection resistance appears to be modulation of the host innate immune system rather than direct antimicrobial effects.70 these results show the potential of pha-derived scaffolds in contaminated fields (Figure 2.2).
Figure 2.2 Scaffolds composed of p4hB promote the expression of the antimicro- bial peptide cathelicidin ll-37 (green) in areas surrounding the mesh fiber material in a rat tissue inoculated with the gram-positive bacteria Staphylococcus aureus.
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00039