title: Engineering growth factors for regenerative medicine applications.
abstract: Growth factors are important morphogenetic proteins that instruct cell behavior and guide tissue repair and renewal. Although their therapeutic potential holds great promise in regenerative medicine applications, translation of growth factors into clinical treatments has been hindered by limitations including poor protein stability, low recombinant expression yield, and suboptimal efficacy. This review highlights current tools, technologies, and approaches to design integrated and effective growth factor-based therapies for regenerative medicine applications. The first section describes rational and combinatorial protein engineering approaches that have been utilized to improve growth factor stability, expression yield, biodistribution, and serum half-life, or alter their cell trafficking behavior or receptor binding affinity. The second section highlights elegant biomaterial-based systems, inspired by the natural extracellular matrix milieu, that have been developed for effective spatial and temporal delivery of growth factors to cell surface receptors. Although appearing distinct, these two approaches are highly complementary and involve principles of molecular design and engineering to be considered in parallel when developing optimal materials for clinical applications.
  
  
  CONCLUSIONS
  Growth factors are promising therapeutic proteins that have the ability to modulate morphogenetic behaviors, including cell survival, proliferation, migration and differentiation. However, the translation of growth factors into clinical therapies has been hindered by properties such as poor protein stability, low recombinant expression yield, and non-physiological delivery, which lead to suboptimal efficacy and adverse side effects. To address these needs, researchers are employing clever molecular and material engineering and design strategies to both improve the intrinsic properties of growth factors and effectively control their delivery into tissue. This review highlights examples of interdisciplinary tools and technologies used to augment the therapeutic potential of growth factors for clinical applications in regenerative medicine.
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA, USA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Mitchell
authors.affiliation: Institute for Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Briquez
authors.affiliation: Institute for Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Institute for Molecular Engineering, University of Chicago, Chicago, IL, USA; Materials Science Division, Argonne National Laboratory, Argonne, IL, USA. Electronic address: jhubbell@uchicago.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Chemical Engineering, Stanford University, Stanford, CA, USA. Electronic address: jennifer.cochran@stanford.edu.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Cochran
mesh_terms: D000818:Animals; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D015202:Protein Engineering / Q000379:methods*; D011994:Recombinant Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D044968:Regenerative Medicine
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins
keywords: Biomaterials; Controlled release; Drug delivery systems; Extracellular matrix; Growth factors; High-throughput screening; Mutagenesis; Protein engineering; Protein library; Regenerative medicine