A Tribute to Professor Buddy Ratner

As a former colleague for 10 years at the University of Washington (UW), it is my greatest pleasure to organize this special issue to honor Professor Buddy Ratner, the Michael L. & Myrna Darland Endowed Chair in Technology Commercialization (with joint appointments in bioengineering and chemical engineering) at the UW, for his eminent contributions to biomaterials and biointerfaces. Since its debut in 2010, Advanced Healthcare Materials (AHM) has published more than 2500 manuscripts from over 60 countries, covering a broad spectrum of research areas that include biomaterials, biointerfaces, biofabrication, nanomedicine, diagnostic devices, and tissue repair/regeneration. From the very beginning, Ratner has provided invaluable support to AHM by serving on its international advisory board. With a successful and sustainable career spanning almost five decades, Ratner has made outstanding contributions to most of the research areas covered by AHM. His research interests center on the synthesis/fabrication, modification, and characterization of biomaterials/biointerfaces for medical applications. He has been widely recognized for his original and eminent contributions to the understanding of the surface interactions of biological molecules and cells with medical implants. Among his many accomplishments, the book of Biomaterials Science. An Introduction to Materials in Medicine (co-edited by him and three other scholars) deserves special mention. This standard work offers the most comprehensive single text on all aspects of biomaterials. It not only offers a balanced, insightful approach to learning the science and technology of biomaterials but also serves as the key reference for all investigators who explore the applications of materials in medicine. From 1985–1996, Ratner served as the director of the National ESCA and Surface Analysis Center for Biomedical Problems (NESAC/BIO), a research and service facility dedicated to surface analysis. Since 1996, he has led the Research Center for Biomaterials at the University of Washington, a research and education consortium that brings together a cross-disciplinary team of scientists and engineers, as well as industry leaders in the biomaterials field, to address some of the key issues in healthcare. This special issue contains 13 timely contributions from researchers around the world. Most of the corresponding authors are current or former colleagues of Ratner at the UW, or have received graduate and/or postgraduate training under his tutelage. The manuscripts can be broadly divided into four categories: biomaterials/biointerfaces, tissue repair/regeneration, advanced therapeutics, and biofabrication. In the context of biomaterials/biointerfaces, David G. Castner and coworkers report the use of angle-dependent X-ray photoelectron spectroscopy (ADXPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to characterize the surfaces of four biodegradable materials based on poly(peptide-urethaneurea) block copolymers (2100894). The copolymers contain three different blocks: the soft block made of poly(caprolactone diol) (PCL), the hard block consisting of lysine diisocyanate with a hydrazine chain extender, and the oligopeptide block containing proline, hydroxyproline, and glycine. The incorporation of oligopeptide block into the polyurethane backbone is known to result in synthetic polymers with controllable biodegradation profiles. Their results indicate that the surfaces of all four polymers tested are enriched with PCL (i.e., the most hydrophobic component of the three blocks), shedding light on the biodegradation behaviors of these polymers. Stephanie J. Bryant and coworkers mapped macrophage polarization and origin during the progression of the foreign body response (FBR) to a poly(ethylene glycol) (PEG) hydrogel implant (2102209). PEG hydrogels hold promise for in vivo applications but they are known to induce the FBR. Although macrophages play a critical role in the FBR, many questions remain to be answered. The authors mapped temporal changes to the transcriptome of implant-associated monocytes and macrophages. They also examined the origin of macrophages responsible for fibrous encapsulation using wildtype, CCR2-/- mice that lack recruited macrophages and MaFIA mice capable of ablating all macrophages. Their findings demonstrate that implant-associated monocytes and macrophages have temporally distinct transcriptomes during the progression of the FBR and that pro-fibrotic pathways associated with macrophages may be enriched in tissue-resident macrophages. Kim A. Woodrow and Jamie L. Hernandez review the medical applications of porous biomaterials, with a focus on their tissue-specific implications and biocompatibility (2102087). Porosity is an important material feature widely used to engineer implants and tissue scaffolds because the voids allow for the infiltration of cells, achievement of mechanical compliance, and outward diffusion of pharmaceutical agents. Various studies have established that porosity promotes favorable tissue responses (e.g., minimal fibrous encapsulation during the FBR), while causing adverse impacts such as increased biofilm formation and calcification. The authors start with a set of methods commonly used to fabricate porous materials with tunable pore features and then discuss responses from the biological host, including the various stages of the FBR, hemocompatibility, biofilm formation, and calcification. Finally, the host responses are considered in specific tissues, including the subcutis, bone, cardiovascular system, brain, eye, and female reproductive tract. When developing biomaterials for in vivo applications, it is vital to optimize their interactions with the various tissues of the body by paying close attention the porosity and the tissue context. Under the theme of tissue repair/regeneration, Miqin Zhang and coworkers review recent progress in developing injectable natural polymer hydrogels for the treatment of knee osteoarthritis (OA), a serious chronic and degenerative disease that increasingly occurs in the aged population (2101479). Despite the development of novel therapeutic regimen, delivery of therapeutics to the target sites with minimal invasiveness, high retention, and minimal side effects remains a major challenge. The authors start with an overview of the current approaches and challenges in OA treatment and then illustrate how injectable natural polymer hydrogels can serve as a delivery system to overcome some of these challenges. With a focus on the development of injectable polysaccharide-based hydrogels for OA treatment, the unique properties of hydrogels for loading and release of cargos are discussed in detail, together with their current limitations. Younan Xia and coworkers report the fabrication of biomimetic scaffolds with a mineral gradient and funnel-shaped channels for spatially-controlled osteogenesis (2100828). They create a mineral gradient in a biodegradable polymer scaffold by simply swelling a composite film consisting of PCL and hydroxyapatite (HAp) nanoparticles with a PCL solution. During the swelling process, the solvent molecules and PCL polymer chains diffuse into the composite film, generating a gradient in HAp density at the interface. The thickness of the mineral gradient can be tightly controlled by varying the extent of swelling to match the typical length scale (20–60 µm) of the natural tendon-to-bone attachment. When patterned with an array of funnel-shaped channels, the mineral gradient can stimulate the differentiation of stem cells into a graded distribution of cell phenotypes by providing spatial gradations in both biochemical cues (i.e., osteo-inductivity and conductivity associated with the HAp nanoparticles) and mechanical cues (i.e., stiffness of the substrate). This novel class of biomimetic scaffolds can potentially augment the repair/regeneration of the injured tendon-to-bone attachment by stimulating the formation of a functionally-graded interface. In the framework of advanced therapeutics, Xiaohu Gao and co-workers report a new method, termed magneto-endosomalytic therapy (MELT), for cancer treatment by repurposing clinically approved magnetic nanoparticles (2101010). In the presence of a static parallel magnetic field, the intracellular self-assembly of internalized magnetic nanoparticle will lead to cell death in the targeted tissues while leaving other cells and organs intact. This simple and elegant method opens the door to effective and selective cancer treatment by capitalizing on the magnetic nanoparticles that have been approved for clinical use as a MRI contrast agent. Hye Young Lee, Niren Murthy, and coworkers demonstrate that (KVSALKE)5, a coiled-coil forming peptide, can serve as a cell penetrating peptide (CPP) to enhance the intracellular delivery of proteins (2102118). Protein-based therapeutics have the potential to treat a variety of diseases, but safe and effective methods are critically needed in order to have them delivered into the target cells. The authors discover that (KVSALKE)5 can serve as a CCP while being able to form complexes with other proteins that contain its partner peptide E5. According to their data, GFP and Cas9 fused to the peptide show dramatically-enhanced cell uptake by a variety of cell lines, and they are able to edit neurons and astrocytes in the striatum and hippocampus of mice after a direct intracranial injection. This new multifunctional CPP has great potential for improving the delivery of proteins into cells both in vitro and in vivo. Suzie H. Pun and coworkers report the development of a well-defined mannosylated polymer for the delivery of peptide-based vaccines with enhanced antitumor immunity (2101651). Despite their production and safety advantages, the clinical success of peptide-based cancer vaccines has been limited by their intrinsic instability, rapid clearance, and low cellular uptake. The amphiphilic polymer is prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization, and the peptide antigens are then conjugated to the pH-sensitive hydrophobic block through the reversible disulfide linkage for selective release post cell entry. The polymer-peptide conjugates are able to self-assemble into sub-100 nm micelles at physiological pH and dissociate at endosomal pH. Their in vivo data indicate that the mannosylated micelle formulation improves dendritic cell activation and enhances antigen-specific T cell responses, resulting in higher antitumor immunity in tumor-bearing mice relative to free peptide antigen. The mannosylated polymer offers a simple and versatile platform for the effective delivery of peptide-based cancer vaccines. Patrick S. Stayton, Courtney A. Crane, and coworkers report a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering (2101944). Specifically, macrophage and T cell therapeutics are engineered to express a bio-orthogonal single chain variable fragment receptor, which then binds to a fluorescein ligand to direct cell loading with ligand-tagged polymeric prodrugs, termed “drugamers”. The drugamer can be incorporated with a small molecule transgene activator, CMP8, to switch on a degron-tagged gene circuit and thus provide temporal regulation of engineered T cell protein expression. This bio-orthogonal receptor and drugamer system can be potentially used to arm multiple immune cell classes with both anti-tumor and transgene-activating small molecule prodrugs. Satoshi Uchida, Kazunori Kataoka, and coworkers report a method to improve the robustness of polyplex micelles (PMs) for efficient mRNA delivery by bridging mRNA with polycation using RNA oligonucleotide (OligoRNA) derivatives (2102016). Specifically, the OligoRNAs act as a node to bridge ionically complexed mRNA and polycation, thereby stabilizing PM against polyion exchange reaction and ribonuclease attack in extracellular environment. After cellular uptake, the intracellular high concentration of adenosine triphosphate (ATP) triggers the cleavage of phenylboronate ester linkages, releasing the mRNA from PMs. The as-formulated PMs provide efficient introduction of mRNA into cultured cells and mouse lungs after intratracheal administration, holding promise for polyplex-based mRNA delivery. Olof Ramström, Mingdi Yan, and coworkers demonstrate the use of gold nanoclusters (AuNCs) as nano-antibiotic auranofin analogues (2101032). Specifically, phosphine-capped AuNCs are synthesized and glycosylated to yield auranofin analogues with mixed triphenylphosphine monosulfonate (TPPMS)/Ac4 GlcSH ligand shells. The AuNCs are active against both Gram-negative and Gram-positive bacteria, including multidrug-resistant pathogens. Significantly, a mixed-ligand 1.6-nm AuNC shows a higher activity than auranofin against Pseudomonas aeruginosa, while exhibiting lower toxicity against human A549 cells. The enhanced antibacterial activity of the AuNCs can be attributed to a greater uptake of Au by the bacteria relative to the Au(I) complexes. Chuan Yang, Yi Yan Yang, and coworkers report the use of potent antiviral and antimicrobial polymers as safe and effective disinfectants for the prevention of infections (2101898). Specifically, the authors synthesize a series of membrane-disrupting polyionenes comprised of quaternary ammoniums and varying hydrophobic components. These polyionenes are not only effective against bacteria and fungi but also capable of fast acting against clinically isolated drug resistant strains of bacteria. Furthermore, the polyionenes are effective in preventing infections caused by non-enveloped and enveloped viruses. Most importantly, the polyionenes are effective in inhibiting SARS-CoV-2 by >99.999% within 30 seconds. Altogether, the polyionenes can serve as promising active ingredients for the disinfection and prevention of viral/microbial infections. Related to biofabrication, Xunwei Wu, Yu Shrike Zhang and coworkers demonstrate uniaxial and coaxial vertical embedded extrusion bioprinting (2102411). Specifically, they use uniaxial or coaxial nozzles to enable vertical embedded extrusion bioprinting for the fabrication of vertical structures of homogeneous or heterogeneous properties in nature. By adjusting the bioprinting parameters, the characteristics of the bioprinted vertical patterns can be tailored in a controllable fashion. Using this new technique, they demonstrate two proof-of-concept applications in tissue biofabrication by focusing on intestinal villi and hair follicles, two types of line-shaped tissues. The Caco-2 cells in the bioprinted intestinal villus constructs proliferate and aggregate properly, showing functional biomarkers such as ZO-1 and villin. This vertical embedded extrusion bioprinting technique is expected to bring further improvements to the reconstruction of certain human tissues and organs, especially those with a linear structure, potentially leading to widespread use in tissue engineering and drug discovery. I am excited to present this special issue to the AHM community. Unfortunately, a number of invited manuscripts were unable to make into this special issue as a result of the delay caused by COVID-19. Nevertheless, I hope this special issue still provides a snapshot of recent advances in the development of biomaterials, biosurfaces, and devices for healthcare applications. I could not be happier if the readers not only enjoy the diverse topics presented in this issue but also find the inspiration to push this important area of biomedical research to the next level of success. Younan Xia studied at the University of Science and Technology of China (B.S., 1987) and University of Pennsylvania (M.S., 1993) before receiving his Ph.D. from Harvard University in 1996 (with George M. Whitesides). He started as an assistant professor of chemistry at the University of Washington (Seattle) in 1997 and was promoted to associate professor and professor in 2002 and 2004, respectively. He joined the Department of Biomedical Engineering at Washington University in St. Louis in 2007 as the James M. McKelvey Professor. Since 2012, he holds the position of Brock Family Chair and GRA Eminent Scholar in Nanomedicine at the Georgia Institute of Technology.