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Introduction: Polymeric Biomaterials
Chemical Reviews  (IF60.622),  Pub Date : 2021-09-22, DOI: 10.1021/acs.chemrev.1c00354
Matthew L. Becker, Jason A. Burdick

This article is part of the Polymeric Biomaterials special issue. In the last 18 months, a global health crisis due to the rise, spread, and epidemiology of SARS (CoV-2) COVID19 has ravaged all of mankind. Fortunately, fundamental advances in materials, molecular biology, bioengineering, and advanced manufacturing have provided the understanding and ability to identify the pathogen, characterize the protein coat structure, and formulate a new mRNA vaccine and delivery strategy that has likely changed global health forever. Although currently focused primarily on the single target of COVID19, this technology will lead to foundational changes in the approach of researchers in their ongoing efforts to develop therapeutics against AIDS, cancer, and numerous other diseases. Key to the success of the COVID19 vaccine strategy was a material approach to package, stabilize, traffic, and deliver mRNA, which in very short order transitioned from discovery to laboratory curiosity to clinical trials and ultimate regulatory approval and use. Many contributed to this effort over several preceding decades of basic and applied research, with the development of a “new” delivery system providing a critical role in vaccine efficacy. Without this materials innovation, the mRNA vaccines would likely not have succeeded, as existing and widely utilized polymeric formulations and delivery strategies are not compatible with mRNA. Such advances in the development and understanding of biomaterials across widespread applications is the focus of this thematic issue on Polymeric Biomaterials. The past decades have seen extensive growth in our understanding and development of new polymeric biomaterials for various biomedical applications, including in the development of new therapies and biological understanding. Commonly thought to act as inert structural materials that may be degradable, polymeric biomaterials have evolved to induce specific biological responses, act dynamically based on extrinsic signals, traffic through cellular membranes, and be processed using widespread techniques such as with biofabrication tools. Advances in synthetic technologies, as well as materials processing, have opened up material properties and structures that were previously unattainable. These systems are being explored as in vitro platforms for cell culture to uncover new biology, as tissue models to rapidly screen pharmaceutics, or for the development of commercially viable and translationally relevant therapies in applications from tissue adhesives to gene therapy. The use of biomaterials and particularly degradable polymers in medical applications is not a new concept. First reported in the use of resorbable sutures in 1974, poly(lactic acid) (PLA) and subsequently poly(glycolic acid) (PGA), poly(caprolactone) (PCL), and their respective copolymers such as poly(lactic-co-glycolic acid) (PLGA) have been used in applications ranging from solid implantable devices ranging from resorbable bone screws to injectable devices for drug elution. Despite known limitations, over the past 30 years or more, this small library of degradable polymeric materials has dominated the market in products that have gained regulatory approval for commercial use in humans. Considering the advances in polymer science, it is surprising that the diversity of biodegradable materials approved for clinical use is not greater. From a chemical perspective, the design space is limited only by creativity, time, and resources, and hence, surely there are materials better suited to in vivo applications that remain to be discovered or translated to clinical use. While the PLGA family has found, and will continue to find, much success, especially in the area of drug delivery, this focus on the use of these existing and available polyester materials for an ever-increasing range of applications is inherently limiting. In many cases the materials have mechanical and physical properties that do not adequately fit those of the tissues that they are being designed to treat, which from a materials perspective, makes it feel like trying to fit a square peg in a round hole. Thus, the continuing need for a better understanding of biomaterials, as well as their innovation, is clear. This thematic review on Polymeric Biomaterials contains a range of reviews on important topics in this field that we hope will challenge the reader to understand the past and look toward how materials are evolving to meet new biomedical needs. Specifically, we have broken the reviews into three topical areas: (1) Classes of synthetic and naturally derived polymeric biomaterials, (2) advanced methods for the fabrication and characterization of polymeric biomaterials, and (3) applications of polymeric biomaterials. New classes of synthetic and naturally derived materials are needed to advance biomedicine to expand on the available properties of biomaterials (topical area 1). Cooper-White and co-workers provide a comprehensive review on the emergence of high throughput technologies to rapidly synthesize and characterize new biomaterials. These technologies are accelerating the discovery of new biomaterials at previously unimaginable rates, using methods such as automated liquid handling, robotics, and microfluidics. The rapid screening of such biomaterials with cells and tissues and the advancement of tools in the design of experiments, machine learning, and bioinformatics are equally important to advance the field. Focusing on one specific class of biomaterials that has emerged with important properties of biocompatibility and controlled degradation, Dove and co-workers provide an overview of the development of aliphatic polycarbonates. There is great chemical diversity to this class of polymers based on synthetic reagents, resulting in widespread degradation behaviors through hydrolysis, enzymatic breakdown, oxidation, and stimuli-responsive means. Aliphatic polycarbonates have been widely explored for drug and gene therapy, imaging, and scaffolds for tissue repair. Beyond purely synthetic materials, there is great interest in the use of naturally derived polymers in the fabrication of biomaterials, exploiting inherent biofunctionality, such as cell adhesion and degradation. Muir and Burdick provide a detailed review of the range of chemical modifications to biopolymers, including polysaccharides and polypeptides, for the formation of biomedical hydrogels. These chemical modifications allow the linking of biopolymers together and control over hydrogel properties through physical and covalent cross-links for applications as scaffolds fabricated through biofabrication techniques, the delivery of therapeutics, and tissue adhesives. Chen and co-workers then expand on this general class of materials, with a focus on carbohydrates that are found abundantly in the extracellular matrix of animals and the cell walls of plants and bacteria. These include molecules such as polysaccharides, glycopolymers, and glycoproteins and give function to formed biomaterials for widespread application in drug delivery, tissue engineering, and immunology. Weil and co-workers then review the use of DNA in combination with polymers to form functional materials, through techniques such as DNA templating and the fabrication of nanoscale structures with precise designs. DNA offers unique customization at small length scales that is challenging with alternate approaches. Beyond their synthesis, it is important to understand various fabrication techniques to process biomaterials into usable materials, as well as techniques to characterize biomaterial properties (topical area 2). As one approach, cells are often embedded in hydrogels for use as tissue models or for therapeutics and biomaterials provide a range of signals to drive cell behaviors. Bryant and co-workers review both experimental and computational approaches that are being used to understand the fundamentals of hydrogels in these applications, such as their mechanical properties and the resulting cellular behaviors such as mechanosensing, migration, growth, tissue deposition, and matrix elaboration. The review includes a comprehensive overview of published literature, as well as guidance on the integration of experiments and models in these applications. Continuing in the area of hydrogels, Bian and co-workers review the growing area of dynamic hydrogels where properties change over time, such as through biomaterial degradation (e.g., hydrolysis, light-mediated) or through physical interactions between polymers (e.g., ionic bonding, coordination bonds). They further review the applications of dynamic hydrogels, such as in exploring the dynamics of cellular microenvironments in development and disease, fabricating viscoelastic materials to mimic tissue properties, culturing organoids in 3D environments, and for controlled drug delivery. Toward porous biomaterials development, Groll and co-workers provide an overview of the fabrication of electrospun fibrous biomaterials, which exhibit high surface area, high porosity, and structures similar to the natural extracellular matrix. They cover topics related to the verstatile chemistry that has been implemented into electrospun scaffolds, including through the modification of fibers to impart biological functionality into the materials. Further, the review provides extensive information on the various tools that are being used to characterize the functionality of electrospun scaffolds. Becker and co-workers then provide a comprehensive review on various techniques that are used to fabricate scaffolds out of biodegradable materials for widespread applications including tissue engineering, drug delivery, wound healing, and implantable medical devices. A wide range of techniques have emerged, including additive manufacturing (e.g., vat photopolymerization, powder bed fusion), fiber-based scaffold fabrication (e.g., electrospinning), and conventional polymer processing (e.g., molding, poragen leaching). The review further expands on stimuli-responsive materials and the various sterilization approaches that are needed for implantable materials. As a last review in this topical area, Spiller and co-workers cover approaches to characterize and understand inflammatory responses to polymeric biomaterials. This is of course a very important area, to both understand polymeric biomaterials in their intended applications and to also control and improve these interactions with new materials through controlled chemistry and released immunomodulators to promote optimal integration. There are many challenges in this field and a range of new tools and understanding on the horizon to improve biomaterials for therapeutic use. The success of polymeric biomaterials is dependent on controlled inflammatory responses in vivo. Although the prior reviews also mention biomaterials applications, the last set of reviews are focused on specific application areas and how polymeric biomaterials have been designed to meet the needs of biomedicine (topical area 3). To begin, Nam and Mooney review the wide array of polymeric tissue adhesives that have been developed in the past decades for wound healing applications, including wound closure, hemostats, and to promote tissue healing. Such materials have been designed from synthetic polymers, natural polymers, and with inspiration from nature (e.g., mussels, geckos). They end with a discussion of next generation adhesive biomaterials that have added functionality and improved properties. Appel and co-workers provide a review on the translation of hydrogel biomaterials across applications in drug delivery, cell therapies, and surgical applications and include various design criteria for this class of materials with an emphasis on mechanical and rheological properties. Further, they review those injectable hydrogels that have translated to the clinic and provide thoughts on manufacturing steps toward this. Ma and co-workers then describe the emergence of hydrogels in the specific treatment of type 1 diabetes. Hydrogels have been designed for the release of insulin, including with glucose-responsive and pH-sensitive designs and through delivery as patches, injectables, or oral administration. Further, hydrogels have been used for the encapsulation and delivery of insulin-secreting cells to deliver and protect them from the host response. More specific to drug delivery, polymeric biomaterials have made great progress in the delivery of genes and peptides, to overcome limitations in translation and efficacy of prior techniques. Reineke and co-workers review the diverse polymers that have been used in the delivery of nucleic acids, including design features such as polymer structure, molecular weight, charge, and hydrophobicity. They further review the various chemistries used in the formation of engineered multifunctional polyplexes and the challenges in implementing them for cellular transfection. Lastly, Pun and co-workers review the development and design of polymeric carriers to improve intracellular peptide delivery specifically for cancer treatments. Appropriately designed carriers can increase accumulation and uptake of peptides and aid in the targeting of specific organelles for therapy. In summary, there have been many great advances in polymeric biomaterials in recent years that will likely have great impact on fundamental knowledge and patient treatment, such as those now being used to treat COVID-19. As these reviews show, the synthesis, processing, and application of biomaterials involve a wide range of specific polymer chemistries and properties that are likely to make further advances in the future. It is exciting to consider what the future may bring in the area of polymeric biomaterials. Matthew L. Becker is the Hugo L. Blomquist Distinguished Professor at Duke University. His research team is focused on developing novel molecular building blocks, degradable polymeric materials, and additive manufacturing methods for addressing unmet needs at the intersection of chemistry, materials, and medicine. He received a Ph.D. in Organic Chemistry from Washington University in St. Louis and was an NRC Postdoctoral Fellow and then staff member in the Polymers Division at NIST. From 2009–2019, he was the W. Gerald Austen Endowed Chair in Polymer Science and Engineering at the University of Akron. He is a Fellow of the American Chemical Society, the American Institute of Medical and Biomedical Engineering, and the Royal Society of Chemistry. Jason A. Burdick received his Ph.D. in Chemical Engineering from the University of Colorado Boulder and then completed a postdoctoral fellowship at Massachusetts Institute of Technology. He moved to the Department of Bioengineering at the University of Pennsylvania in 2005 where he is now the Robert D. Bent Professor. His expertise is in the development of hydrogel biomaterials and elastomers, their processing through techniques such as electrospinning and 3D bioprinting, and their application in mechanobiology and musculoskeletal and cardiovascular tissue repair. He has also founded several companies for the translation of technology from his laboratory and has been recognized as a fellow of the American Institute for Medical and Biological Engineering, the National Academy of Inventors, the International College of Fellows of Biomaterials Science and Engineering, and the Biomedical Engineering Society. This article has not yet been cited by other publications.