SPECIAL FEATURE: PERSPECTIVE PERSPECTIVE SPECIAL FEATURE: Progress in material design for biomedical applications Mark W. Tibbitta,1, Christopher B. Rodellb,1, Jason A. Burdickb, and Kristi S. Ansethc,2 aKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; bDepartment of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104; and cDepartment of Chemical and Biological Engineering and the BioFrontiers Institute, University of Colorado, Boulder, CO 80303 Edited by Mark E. Davis, California Institute of Technology, Pasadena, CA, and approved September 1, 2015 (received for review August 14, 2015) Biomaterials that interface with biological systems are used to deliver drugs safely and efficiently; to prevent, detect, and treat disease; to assist the body as it heals; and to engineer functional tissues outside of the body for organ replacement.The field has evolved beyond selecting materials that were originally designed for other applications with a primary focus on properties that enabled restoration of function and mitigation of acute pathology. Biomaterials are now designed rationally with controlled structure and dynamic functionality to integrate with biological complexity and perform tailored, high-level functions in the body. The transition has been from permissive to promoting biomaterials that are no longer bioinert but bioactive. This perspective surveys recent developments in the field of polymeric and soft biomaterials with a specific emphasis on advances in nano- to macroscale control, static to dynamic functionality, and biocomplex materials. biomaterials | soft materials | feature control | dynamics | biocomplex Biomaterials have been used to augment with the design of materials—including hard improved clinical outcomes by facilitating tissue function and treat diseases or injuries materials like metals and ceramics—that fo- osseointegration with bony tissue, and after for thousands of years—whether selecting cused on outcomes such as mechanical prop- the discovery of bone morphogenetic proteins coralorwoodfordentalimplantsorfabric erties and biocompatibility. This approach led and their recombinant production, spinal for sutures, implant materials historically to the clinical implementation of numerous fusion surgeries benefited from material de- originated by evaluating potential materials materials for biomedical applications, such livery systems that enabled their local pre- in our surroundings that could be used for as joint replacement, pacemakers, and or- sentation (e.g., INFUSE). Collectively, these a specific biomedical application. Many times, thodontics. The contemporary age of bio- examples demonstrate how material design this selection process simply involved consid- materials has advanced with a further focus can be used to present biological signals that eration of the mechanical properties of the on surface functionality, where materials are result in new medical devices and implants material to restore basic function at the im- now smarter and interface with their envi- with superior clinical performance. In fact, a plant site; typically, the materials themselves ronment such as by incorporating bioactive recent report estimated the 2012 global bio- were never originally designed to interface signals to achieve multifunctional design. material market at $44.0 billion and fore- with living tissues. Today, this is no longer These strategies are leading to progress casted a 15% compounded annual growth the case, as we now have an advanced tool- and improvements in fields ranging from rate between 2012 and 2017, reaching $88.4 box of synthetic and processing techniques to medical devices, to drug delivery, and to billion by 2017 (2). rationally create, design, and process mate- regenerative medicine. This perspective focuses primarily on re- rials with specific properties in mind. These As one example, vascular stents have been cent developments in polymers and soft advancements have come hand in hand with widely used to open blocked vessels and materials, due to the large technological the integration of theory with experiments, restore blood flow to ischemic tissues, and growth in these systems since the 1990s. This materials chemistry and biology with engi- the design of these stents has significantly review is organized to highlight some of the neering, and basic science with application. evolved with time. With the development of major advances and modern thinking in bio- As highlighted by the announcement of the Nitinol, a metal alloy of nickel and titanium material design, such as the ability to manip- Materials Genome Initiative (1), biomaterial withuniqueshapememoryandsuperelastic ulate and control biomaterial properties at science is often the stealth technology that properties, stent design has improved to be multiple length scales, introduce dynamic enables breakthroughs in medical devices implanted with simpler, minimally-invasive behavior into biomaterials, and capture that improve health care and save lives. procedures and to maintain function for biocomplexity and additive functionalities. In fact, the last few decades of research have longer periods of time. Next-generation stents led to the emergence of numerous biomaterial transitioned from passive mechanical devices Author contributions: M.W.T., C.B.R., J.A.B., and K.S.A. wrote options, along with an increasing sophistica- to those that actively regulate the biological the paper. tion in the ability to tune and manipulate interface by integrating biodegradable poly- The authors declare no conflict of interest. complex physical and biological properties. mer coatings that locally elute drugs to limit This article is a PNAS Direct Submission. Such advances in biomaterial science have not restenosis and resulting stent failure. These This article is part of the special series of PNAS 100th Anniversary articles to commemorate exceptional research published in PNAS only driven and enabled new medical prod- advances enhanced both the functionality and over the last century. ucts, but have served as new tools for in- efficacy of stent technology for clinical use. 1M.W.T. and C.B.R. contributed equally to this work. vestigation of important biological questions. Similarly, the coating of traditional metal 2To whom correspondence should be addressed. Email: Kristi. The modern biomaterial evolution initiated orthopedic implants with bioactive ceramics [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1516247112 PNAS Early Edition | 1of8 Downloaded by guest on September 27, 2021 Although some examples address surface bonds), whereas secondary structures confer trostatic protein-matrix interactions (8). Be- modifications of biomaterials to promote material resilience (e.g., resilin, elastin). Peptide yond the capacity for single molecule–matrix integration, many of the advances that are synthesis recombinant protein production interactions, the general ECM structure discussed focus on bulk modification of and evolution via phage display have become itself is largely the result of self-assembly materials and especially how this influences invaluable tools to recapitulate similar func- (e.g., fibrillar structure of collagen) and can the stability and function of encapsulated tionalities in synthetic biomaterial analogs. be recapitulated, in part, by well-designed molecules and cells. We then conclude with a Likewise, synthetic approaches (e.g., bio- synthetic analogs. These higher-order motifs forward-looking perspective about the cur- orthogonal chemistry) have evolved to enable are exemplified by self-assembling nano- rent challenges and future directions for the fabrication and functionalization of bio- structures from peptide amphiphiles (9, 10) designing the next generation of biomaterials. materials (e.g., hydrogels) that capture aspects (Fig. 1A), although many alternative means of native biological structures (3). Collectively, of biologically inspired supramolecular ma- From Molecular to Macroscopic these techniques have allowed the production terials have been explored, and their impli- Biomaterials fabrication has evolved across all of biomaterials with unique capacities, in- cations toward cell behavior were recently size scales—from molecular to macroscopic— cluding postmodification of cell culture ma- reviewed (11). In addition to such methods of to impart biochemical and biophysical cues trices and to cross-link implantable materials. self-assembly, nanoparticulate-hydrogel com- into cell culture platforms for regenerative Covalent chemistries have dominated the posites are an emergent means of introduc- medicine, to achieve optimal outcomes in biomaterials field since its conception. ing a wide array of functional behaviors (e.g., drug delivery systems, and to improve in vivo However, the emergence of supramolecular toughness and thermal or electrical conductiv- success of medical implants. Our increased chemistry has begun to enhance our under- ity). The development and use of such nano- understanding of native tissue architecture structured, functional composites has likewise – standing of biology and capacity for creating and cell material interactions, as well as the been a topic of recent review (12). development of processing methods and precise, physiologically structured materials. Nobel Laureate Jean-Marie Lehn insightfully chemical syntheses has driven the design of Building at the Mesoscale. Although self- described supramolecular interactions