Production of self-assembling biomaterials for tissue engineering

Self-assembling peptide-based biomaterials are being developed for use as 3D tissue engineering scaffolds and for therapeutic drug-release applications. Chemical synthesis provides custom-made peptides in small quantities, but production approaches based upon transgenic organisms might be more cost-effective for large-scale peptide production. Long lead times for developing appropriate animal clones or plant lines and potential negative public opinion are obstacles to these routes. Microbes, particularly safe organisms used in the food industry, offer a more rapid route to the large-scale production of recombinant self-assembling biomaterials. In this review, recent advances and challenges in the recombinant production of collagen, elastin and de novo designed self-assembling peptides are discussed. Self-assembling peptide-based biomaterials are being developed for use as 3D tissue engineering scaffolds and for therapeutic drug-release applications. Chemical synthesis provides custom-made peptides in small quantities, but production approaches based upon transgenic organisms might be more cost-effective for large-scale peptide production. Long lead times for developing appropriate animal clones or plant lines and potential negative public opinion are obstacles to these routes. Microbes, particularly safe organisms used in the food industry, offer a more rapid route to the large-scale production of recombinant self-assembling biomaterials. In this review, recent advances and challenges in the recombinant production of collagen, elastin and de novo designed self-assembling peptides are discussed. IntroductionThe concept of self-assemblySelf-assembly is ubiquitous in nature at both macroscopic and microscopic scales and describes the spontaneous association and organization of numerous individual entities into coherent and well-defined structures without external instruction 1Zhang S. Emerging biological materials through molecular self-assembly.Biotechnol. Adv. 2002; 20: 321-339Crossref PubMed Scopus (481) Google Scholar. Molecular self-assembly is characterized by diffusion followed by specific association of molecules through non-covalent interactions, including hydrogen and ionic bonds, and hydrophobic and van der Waals interactions. Individually, such interactions are weak, but their large numbers will dominate the structural and conformational behaviour of the assembly 1Zhang S. Emerging biological materials through molecular self-assembly.Biotechnol. Adv. 2002; 20: 321-339Crossref PubMed Scopus (481) Google Scholar.In bionanotechnology, an understanding of how supramolecular architectures assemble in nature can lead to the design and synthesis of novel biomaterials. A range of complex macromolecules, macromolecular complexes and structural materials including silks 2Mitraki A. van Raaij M.J. Folding of β-structured fibrous proteins and self-assembling peptides.Methods Mol. Biol. 2005; 300: 125-140PubMed Google Scholar, 3Kluge J.A. et al.Spider silks and their applications.Trends Biotechnol. 2008; 26: 244-251Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, collagen 4Köster S. et al.An in situ study of collagen self-assembly processes.Biomacromolecules. 2008; 9: 199-207Crossref PubMed Scopus (55) Google Scholar, bones 5Shapiro F. Bone development and its relation to fracture repair. The role of mesenchymal osteoblasts and surface osteoblasts.Eur. Cell. Mater. 2008; 15: 53-76Crossref PubMed Scopus (355) Google Scholar and teeth 6Chen H. et al.Self-assembly of synthetic hydroxyapatite nanorods into an enamel prism-like structure.J. Colloid Interface Sci. 2005; 288: 97-103Crossref PubMed Scopus (191) Google Scholar all display self-assembly of building blocks.Peptide productionPeptides and proteins have unique biological and self-assembly characteristics that are increasingly being exploited for the development of new bioactive molecules and biomaterials. There are two broad strategies for the production of peptides: chemical synthesis 7Merrifield R.B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide.J. Am. Chem. Soc. 1963; 85: 2149-2154Crossref Scopus (6606) Google Scholar and recombinant production by transgenic organisms ranging from bacteria and fungi to plants and animals. Chemical synthesis is rapid and effective for the production of custom-made peptides in relatively small quantities but can be costly and problematic during process scale-up and as amino acid sequence length increases; sequences over 35 amino acids are not generally considered to be economically feasible 8Sato A.K. et al.Therapeutic peptides: technological advances driving peptides into development.Curr. Opin. Biotechnol. 2006; 17: 638-642Crossref PubMed Scopus (276) Google Scholar. In addition, the process employs chemicals that present potential environmental hazards. Transgenic animals and plants could provide a cost-effective alternative and have been used for structural protein production. However, they are associated with long lead times, the potential for transfer of harmful animal pathogens and/or potential negative public opinion. The use of microbial ‘biofactories’ for protein synthesis is widely employed in industry owing to their ease of use, robustness and lower costs 9Morreale G. et al.Bioprocess-centered molecular design (BMD) for the efficient production of an interfacially active peptide.Biotechnol. Bioeng. 2004; 87: 912-923Crossref PubMed Scopus (14) Google Scholar. Such recombinant systems are superior to chemical synthesis routes for the production of long peptides (>35 amino acids) and proteins, although there are significant challenges for the production and efficient purification of short (10–30 amino acids) self-assembling peptides.In this review we focus upon recombinant self-assembling protein and peptide production. 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Adv. 2002; 20: 321-339Crossref PubMed Scopus (481) Google Scholar have a through their of peptide systems, into the chemical and structural that the self-assembly The peptide systems developed which can scaffolds for tissue which can as molecular and for surface for protein and and for 1Zhang S. Emerging biological materials through molecular self-assembly.Biotechnol. Adv. 2002; 20: 321-339Crossref PubMed Scopus (481) Google Scholar. of self-assembling peptide systems are in of self-assembling peptide systems 1Zhang S. Emerging biological materials through molecular self-assembly.Biotechnol. Adv. 2002; 20: 321-339Crossref PubMed Scopus (481) Google Scholar. Molecular structures through interactions hydrophobic and peptide systems are to ionic with the Molecular their molecular upon in Molecular through a and the peptides can self-assembly to or as of the self-assembling peptides designed by which the of amino acid peptide into a is to and can be in at to can be by an in ionic or by a in peptide been used in a range of including tissue et peptide production and for tissue Sci. S. A. 2002; PubMed Scopus Google Scholar], and A. et self-assembling peptide scaffolds and 3D PubMed Scopus Google Scholar], in H. et in of in 2006; 15: PubMed Scopus Google Scholar] and et peptide for and with of Sci. 2006; PubMed Google over the process of self-assembly is to the design of peptide systems that assemble and with including ionic and for is a relatively for is the self-assembling which is to the and is at but a at by self-assembly of which to will a a at and a of in A. et as a of peptide self-assembly and and Am. Chem. Soc. 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A. 2008; 87: PubMed Scopus Google Scholar, G. et peptide and in Mater. 2008; 87: PubMed Scopus Google Scholar]. The production of short (10–30 self-assembling peptides by recombinant is in its but these can be to and bioactive to provide significant for tissue engineering applications. There is potential for the use of both and self-assembling could peptides the of a by the of more complex self-assembling bioactive by recombinant and which during the self-assembly process to provide an for of short self-assembling peptides been to be feasible microbial with of peptide can be although be to that such as are have been in this are of of protein and have to their use in the food In the recombinant production can be into transgenic animals and particularly transgenic the quantities of peptides that could be relatively in a be IntroductionThe concept of self-assemblySelf-assembly is ubiquitous in nature at both macroscopic and microscopic scales and describes the spontaneous association and organization of numerous individual entities into coherent and well-defined structures without external instruction 1Zhang S. Emerging biological materials through molecular self-assembly.Biotechnol. Adv. 2002; 20: 321-339Crossref PubMed Scopus (481) Google Scholar. Molecular self-assembly is characterized by diffusion followed by specific association of molecules through non-covalent interactions, including hydrogen and ionic bonds, and hydrophobic and van der Waals interactions. Individually, such interactions are weak, but their large numbers will dominate the structural and conformational behaviour of the assembly 1Zhang S. Emerging biological materials through molecular self-assembly.Biotechnol. Adv. 2002; 20: 321-339Crossref PubMed Scopus (481) Google Scholar.In bionanotechnology, an understanding of how supramolecular architectures assemble in nature can lead to the design and synthesis of novel biomaterials. A range of complex macromolecules, macromolecular complexes and structural materials including silks 2Mitraki A. van Raaij M.J. Folding of β-structured fibrous proteins and self-assembling peptides.Methods Mol. Biol. 2005; 300: 125-140PubMed Google Scholar, 3Kluge J.A. et al.Spider silks and their applications.Trends Biotechnol. 2008; 26: 244-251Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, collagen 4Köster S. et al.An in situ study of collagen self-assembly processes.Biomacromolecules. 2008; 9: 199-207Crossref PubMed Scopus (55) Google Scholar, bones 5Shapiro F. Bone development and its relation to fracture repair. The role of mesenchymal osteoblasts and surface osteoblasts.Eur. Cell. Mater. 2008; 15: 53-76Crossref PubMed Scopus (355) Google Scholar and teeth 6Chen H. et al.Self-assembly of synthetic hydroxyapatite nanorods into an enamel prism-like structure.J. Colloid Interface Sci. 2005; 288: 97-103Crossref PubMed Scopus (191) Google Scholar all display self-assembly of building blocks.Peptide productionPeptides and proteins have unique biological and self-assembly characteristics that are increasingly being exploited for the development of new bioactive molecules and biomaterials. There are two broad strategies for the production of peptides: chemical synthesis 7Merrifield R.B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide.J. Am. Chem. Soc. 1963; 85: 2149-2154Crossref Scopus (6606) Google Scholar and recombinant production by transgenic organisms ranging from bacteria and fungi to plants and animals. Chemical synthesis is rapid and effective for the production of custom-made peptides in relatively small quantities but can be costly and problematic during process scale-up and as amino acid sequence length increases; sequences over 35 amino acids are not generally considered to be economically feasible 8Sato A.K. et al.Therapeutic peptides: technological advances driving peptides into development.Curr. Opin. Biotechnol. 2006; 17: 638-642Crossref PubMed Scopus (276) Google Scholar. In addition, the process employs chemicals that present potential environmental hazards. Transgenic animals and plants could provide a cost-effective alternative and have been used for structural protein production. However, they are associated with long lead times, the potential for transfer of harmful animal pathogens and/or potential negative public opinion. The use of microbial ‘biofactories’ for protein synthesis is widely employed in industry owing to their ease of use, robustness and lower costs 9Morreale G. et al.Bioprocess-centered molecular design (BMD) for the efficient production of an interfacially active peptide.Biotechnol. Bioeng. 2004; 87: 912-923Crossref PubMed Scopus (14) Google Scholar. Such recombinant systems are superior to chemical synthesis routes for the production of long peptides (>35 amino acids) and proteins, although there are significant challenges for the production and efficient purification of short (10–30 amino acids) self-assembling peptides.In this review we focus upon recombinant self-assembling protein and peptide production. Initially, we deal with natural self-assembling collagen and elastin systems, which have demonstrated utility for tissue engineering applications. we de novo designed short self-assembling