Angiogenic Self-Assembling Peptide Scaffolds for Functional Tissue Regeneration Biplab Sarkar, † Peter K. Nguyen, † William Gao, † Akhil Dondapati, † Zain Siddiqui, † and Vivek A. Kumar* ,†,‡,§ † Department of Biomedical Engineering and ‡ Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, New Jersey 07102, United States § Rutgers School of Dental Medicine, Newark, New Jersey 07101, United States ABSTRACT: Implantation of acellular biomimetic scaffolds with proangiogenic motifs may have exciting clinical utility for the treatment of ischemic pathologies such as myocardial infarction. Although direct delivery of angiogenic proteins is a possible treatment option, smaller synthetic peptide-based nanostructured alternatives are being investigated due to favorable factors, such as sustained efficacy and high-density epitope presentation of functional moieties. These peptides may be implanted in vivo at the site of ischemia, bypassing the first-pass metabolism and enabling long-term retention and sustained efficacy. Mimics of angiogenic proteins show tremendous potential for clinical use. We discuss possible approaches to integrate the functionality of such angiogenic peptide mimics into self-assembled peptide scaffolds for application in functional tissue regeneration. ■ INTRODUCTION There is a growing need for regenerative scaffolds for repairing diseased tissues. 1 Biodegradable acellular scaffolds are promis- ing candidates for such application. A major requirement of such regenerative acellular scaffolds is adequate vascularization after implantation. 2 In this review, we discuss salient aspects of the growth factors involved in physiological vascularization and their synthetic mimics. Next, we discuss a promising strategy to deliver and retain such functionality in situ through conjugation with self-assembling peptide scaffolds, which are inherently biodegradable and responsive to programmed manipulation. This therapeutic avenue is worth exploring in treating various ischemic pathologies. ■ ACELLULAR SCAFFOLDS FOR TISSUE REGENERATION Functional tissue regeneration requires recruitment and integration of various cells with concomitant deposition of nonpathologic (nonscar) extracellular matrix components into multilayered and hierarchical functional niches while main- taining the rheological and material properties required for tissue function. 3,4 Xenogeneic and allogeneic tissue transplants for such applications are limited by immunological concerns and batch-to-batch variability. 5-7 Synthetic tissue-mimetic scaffolds are promising alternatives to such biologically derived transplants. 8,9 However, they often have insufficient mechan- ical integrity or inadequate biological signaling. 10-12 A three- dimensional acellular biomimetic scaffold with patterned signals encoded in its overall organization offers a viable compromise, blending together facile, reproducible, and nonimmunogenic formulations with biological signals embed- ded in its structure. Implantation of such functionalized acellular scaffolds may induce and direct spatiotemporal regeneration of specific tissue components. Formation of functional niches via angiogenesis, neurogenesis, or osteo- genesis may allow approximation of the structure and function of native tissue. A few requirements for these regenerative scaffolds are (a) recruitment, segregation, and differentiation of progenitor cells into different cell types within the scaffold, 13-15 (b) a gradient of chemokines or homing signals laid on rationally designed tracks for guiding cells into intended niches, 16,17 (c) material multifunctionality for construction of supports for different cell types, 18-21 (d) tunable porosity and tortuosity in the different domains of the scaffold, 22-24 (e) integration of the different niches within the scaffold such that cells in different locales can interact and communicate, 25,26 (f) mechanical robustness and mimicry of native tissue, 27-29 (g) ability to support the recruited cells through the supply of oxygen and nutrients, 30,31 (h) responsiveness to environmental stimuli, 32-35 and (i) controlled biodegradability. 36-41 Optional aspects could include the presence of sacri ficial components 42, 43 for spatiotemporal remodeling and a cache of sequestered signals 44 activated by rational programming. 45 Researchers have made progress toward meeting the physical requirements of such multicomponent scaffolds Received: July 25, 2018 Revised: August 19, 2018 Published: August 22, 2018 Review pubs.acs.org/Biomac Cite This: Biomacromolecules XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.biomac.8b01137 Biomacromolecules XXXX, XXX, XXX-XXX Biomacromolecules Downloaded from pubs.acs.org by DURHAM UNIV on 08/30/18. For personal use only.