De Novo Synthesis of Collagen-Like Polymers for Biomedical Applications - Project Summary
Collagen has been used for biomedical applications for many decades due to its unsurpassed biocompatibility
and chemically tunable mechanical properties. There is a growing need for processible collagen due to rapidly
developing tissue and organ engineering. The major source of raw collagen is animal tissue; thus, safety and
possible contamination are major concerns. Current attempts to make synthetic collagen-like materials start from
collagen-like peptides synthesized by classical solid-phase peptide synthesis, and thus, is not suitable for large-
scale preparation and has little potential for clinical translation. We propose to develop a new approach to
address an unmet need in synthesis of peptide polymers: controlling the polymer sequence and at the same
time generating high molecular weight polymers. More specifically, we aim to develop collagen-like polymers by
de novo synthesis starting from tripeptide ProHypGly-N-carboxyanhydride (NCA) and by ring opening lead to
polymerization via kinetically controlled polycondensation. The ring opening polymerization of NCA is a very well-
established method of synthetizing peptide polymers from single amino acids. The polymer synthesis can be
controlled to yield high molecular weight homopolymers, block-copolymers, and branched and functional
polymers. However, the problem of controlling the sequence of amino acids within the polymer has not been
resolved. We outline two synthetic routes to synthesize the monomer N-Boc-ProHyp(OtBu)Gly-NCA for the
synthesis of collagen-like polymers. Moreover, we propose the simultaneous deprotection of Boc group in
tripeptide NCA revealing an open N-terminus, as well as the initiation of kinetically controlled polycondensation
leading to collagen-like polymer. While the monodisperse polymers are viewed as better suited for clinical
translation, we postulate that having a polydisperse collagen-like polymer will enable self-assembly into the triple
helix conformation that is required for mechanical stability of collagen-like matrix. The helical structure of the
collagen-like polymers will be observed with Circular Dichroism Spectroscopy. The biocompatibility of the
collagen polymer will be evaluated with Human Dermal Fibroblast cell culture and mechanical characterization
will be performed at UC San Diego Materials Research Science and Engineering Center. The proposed synthesis
and characterization methods have been evaluated for safety and accessibility, because all experiments and
data analysis will be performed by undergraduate and MS graduate students. We envision that the development
of this novel approach will open the door to synthesis of many types of polymer peptides with short repeatable
peptide sequences (e.g., elastin-like and RGD peptides).
