A Tribute to Professor Nicholas Peppas

It is our greatest pleasure to organize this special issue of Advanced Healthcare Materials (AHM) in honor of our mentor, colleague, and friend Nicholas Peppas, professor and director of the Institute for Biomaterials, Drug Delivery and Regenerative Medicine at the University of Texas, Austin. Since its debut in 2010, AHM has published more than 2500 manuscripts from over 60 countries in many research areas, including biomaterials, biointerfaces, biofabrication, tissue engineering, nanomedicine, regenerative medicine, and diagnostic devices. Over the past several decades, Peppas has made pioneering and sustained contributions to most of these areas. Peppas is a pioneer in the synthesis, characterization, and modeling of the dynamic behavior of polymer networks, especially water-swollen hydrogels. His influential work includes the use of hydrogels and their biomaterial applications in bionanotechnology, molecular recognition processes, biosensing, and drug delivery. With respect to the latter, Peppas has developed many of the leading theories and equations that matured the field of controlled release and led to new developments, including seminal contributions to the development of feedback-controlled biomedical devices. His work is characterized by an elegant blending of modern molecular and cellular biology with biomolecular engineering to generate next-generation biomaterials and devices with enhanced function, longevity, reliability, and performance. This special issue contains 20 timely contributions from researchers around the world. Some of the corresponding authors received Ph.D. degrees or postdoctoral training under the tutelage of Peppas, but it is a fair statement that all the authors should have been inspired by and/or benefited from the pioneering work of Peppas in biomaterials. The contributed manuscripts can be broadly divided into four categories: drug delivery, tissue engineering, biofabrication, and advanced therapeutics. In the context of drug delivery, Mark E. Byrne and co-workers report a successful demonstration of sustained, week-long release of a small molecule therapeutic from extended-wear silicone hydrogel contact lenses in a rabbit model (2101263). The authors could keep all commercial properties of the lens while achieving controlled release of the drug at therapeutically relevant concentrations for the duration of wear. This work highlights the enormous potential of contact lenses as a viable delivery platform for the post-cataract, uveitis, post-LASIK, and corneal abrasion treatment. Chien-Chi Lin and co-workers report an injectable, acylhydrazone-linked polymer hydrogel for sustained protein release and cell encapsulation (2101284). As the acylhydrazone bond is pH sensitive, the hydrogel could be hydrolytically degraded in a mild acidic environment and the degradation rate could be controlled by tuning the ketone/hydrazide ratio. Significantly, the injectable hydrogel is cytocompatible and can be formulated for the encapsulation of cells and pH-responsive release of proteins. Mark W. Tibbitt, Ratchaneewan Aunpad, and co-workers report the development of a network of biopolymer nanoparticles for the protection and local delivery of antimicrobial peptides (2101426). Specifically, an antimicrobial peptide, PA13, was electrostatically trapped in a network of positively- and negatively-charged nanoparticles made of chitosan and dextran sulfate, respectively. The moldable and biodegradable network of nanoparticles could protect the bioactive peptide from enzymatic degradation while having it released locally. Upon exposure to proteolytic enzymes, the network loaded with PA-13 could be used to eliminate Pseudomonas aeruginosa during in vitro culture and in an ex vivo porcine skin model, holding promises for would healing and related applications. Kinam Park and co-workers investigated the initial formation of a skin layer on poly(lactide-co-glycolide) (PLGA) microparticles, which are extensively used in making injectable, long-acting formulations for drug delivery (2101427). The PLGA microparticles were formed by injecting an oil phase consisting of a mixture of the drug and PLGA in an organic solvent into a water phase. Their data suggested that the initial contact time between the oil and the water phases in the range of a few seconds played the most important role in determining the properties of the skin layer formed on the microparticles. Parastoo Khoshakhlagh, Han-Jun Kim, Ali Khademhosseini, and co-workers review recent advances in utilizing Laponite-based nanomaterials as a versatile platform for the sustained release and targeted delivery of various therapeutics (2102054). In the form of disc-shaped crystalline nanoparticles, Laponite possesses a large and highly ionic surface area, making it attractive for drug delivery through the adsorption/intercalation and dissolution of biomolecules. Its coagulation capacity and cation exchangeability can both be engineered to control the drug encapsulation efficiency and release profile. Its innate physicochemical properties and architecture can also be leveraged to develop tunable, pH-responsive drug delivery systems. Under the theme of tissue engineering, Stephanie Seidlits and co-workers review recent progress in engineering neural tissues of the central nervous system, with a focus on the interface between conductive biomaterials and neural stem/progenitor cells (2101577). Conductive biomaterials can be used to provide electrical stimulation to help direct neural stem/progenitor cell maturation into functional neuronal networks. The authors highlight recent technological advances in conductive biomaterials, which hold the key to the development of engineered tissues with integrated physiological and electrical functionalities. They also discuss steps researchers can take to move the materials and technologies one step closer to clinical translation. In another review article, Brendan A. C. Harley and co-workers highlight recent advances in engineering biomaterials and systems to replicate the dynamic interactions within the hematopoietic stem cell (HSC) niche (2102130). The biomaterials can be designed to provide stimuli and cues from co-cultured, niche-associated cells to support HSC encapsulation and expansion. When upgraded to systems, the inherent coupling of material properties, biotransport of cell-secreted factors, and cell-mediated remodeling can all be leveraged to engineer a temporally evolving tissue microenvironment. The materials, tools, and methods are also amenable to the broader stem cell engineering community. April M. Kloxin and co-workers report a rational synthesis of hydrogel networks with dynamic mechanical properties to mimic the remodeling events of extracellular matrix (2101947). They achieved pseudo reversible modulation of the mechanical properties of a synthetic hydrogel by integrating two orthogonal features — enzymatically-triggered degradation of crosslinking units and light-triggered photopolymerization stiffening. The as-obtained hydrogels could be sequentially soften and stiffen to mimic matrix remodeling events within loose connective tissues. As a class of synthetically accessible and cell compatible biomaterials, the hydrogels provide a general route to 3D dynamic property modulation. Danielle S. W. Benoit and co-workers report a method to maintain tissue structure and function by encapsulating primary salivary gland acinar cell clusters and intercalated ducts (AIDUCs) in hydrogels degradable by matrix metalloproteinase (2101948). The encapsulation promoted the assembly of AIDUCs into salivary gland mimetics (SGm) with an acinar-like structure. The secretory function was maintained, as indicated by the observation of a robust carbachol and ATP-stimulated calcium flux within the SGm for up to 14 days after encapsulation. An integration of the hydrogel microenvironment with the cell–cell interactions maintained within AIDUCs offers a promising platform for salivary gland regenerative strategies. Natalie Artzi and co-workers report the development of a co-culture spheroid model for osteosarcoma to help understand the divergent relationship between tumor elimination and bone regeneration (2101296). The modelled cancer state (early/late ) could be varied by manipulating the ratio of stromal to osteosarcoma cells, as indicated by the increase in tumor growth rate and an upregulation of a panel of osteosarcoma prognostic genes. The model was further validated by analyzing its ability to mimic the cytotoxic effects of an FDA-approved chemotherapeutic such as Doxorubicin. This multicellular model can be used to screen potential therapeutic options and concentrations of drugs for osteosarcoma prior to the conduction of an animal study. Related to biofabrication, Ali Khademhosseini, Ehsan Toyserkani, and co-workers report a template-directed method for the fabrication of thick, three-dimensional tissues patterned with perfusable macro-channels (2102123). Specifically, a tortuous co-continuous plastic network, designed based on triply periodic minimal surfaces, served as a sacrificial structure to shape the secondary sacrificial gelatin template, which was then used to create a cell-loaded gelatin methacryloyl hydrogel (GelMA) scaffold patterned with a complex interconnected pathway. A superior cell ingrowth into the highly permeable constructs was observed during in vivo evaluation. This fabrication method opens the door to engineering thick and functional tissue constructs through the permeable internal channels. Jason A. Burdick and co-workers investigated extrusion printing into a suspension bath by integrating computational modeling with experimental characterization (2101679). They took rheological data on various hydrogel inks and suspension baths to develop computational printing simulations based on the Carreau constitutive viscosity model for printing an ink into a suspension bath. The results were then compared with the experimental outcomes using custom print designs, in which parameters such as needle translation speed were varied and the printed filament resolution was quantified. In a prototype, the results were used to identify the optimal parameters for printing a GelMA ink into a unique guest-host hyaluronic acid suspension bath. By emphasizing the importance of key rheological properties and print parameters, this work provides a computational model and experimental tools that can be used to inform the selection of print setting for suspension bath printing. Yu Shrike Zhang, Kenneth C. Anderson, Dharminder Chauhan, and co-workers report the use of coaxial extrusion bioprinting to fabricate a high-content multiple myeloma (MM) model (2100884). The 3D-bioprinted model recapitulated some of the characteristic features of the human bone marrow and was able to promote growth and proliferation of the encapsulated MM cells. In a proof of-concept experiment, the patient-derived MM cells could be maintained in the 3D-bioprinted microenvironment with decent viability for up to 7 days. Upon optimization, this model can be potentially used to provide new insights for MM modeling, drug development, and personalized therapy in the future. In the framework of advanced therapeutics, J. Zach Hilt and co-workers review the use of hydrogels and hydrogel nanocomposites to enhance healthcare through human and environmental treatment (2101820). The tunable properties of these biomaterials make them attractive for the removal of environmental contaminants, detoxification and reduction of body burden from exogenous chemical exposures, prevention of disease initiation, and advanced treatment of chronic diseases. They highlight three major junctures where hydrogels and hydrogel nanocomposites have been used to intervene and positively impact human health, including the prevention of exposure to environmental contaminants, inhibition of chronic disease initiation via prophylactic treatments, and treatment of chronic diseases after they have developed. Jordan J. Green and Erin W. Kavanagh provide an overview on the status of utilizing gene transfer nanoparticles as therapeutics (2102145). Gene therapy holds the key to treat the underlying causes of many human diseases with exquisite precision, but its utilization has historically been hindered by the delivery challenges. After an introduction to the state of the field and current challenges in delivery, the authors explicitly discuss opportunities for engineered nanomaterials to meet the current challenges, including the capability to enable long-term therapeutic gene editing. They also highlight clinical applications, including for the treatment of genetic diseases such as cystic fibros. In another review article, Liangfang Zhang, Weiwei Gao, and co-workers highlight their recent efforts in developing white blood cell membrane-coated nanoparticles (WBC-NPs) for biomedical applications (2101349). WBC-NPs are typically prepared by coating the surface of synthetic nanoparticles with the plasma membranes of WBCs, including macrophages, neutrophils, T cells, and natural killer cells. The authors showcase a number of biomedical applications of WBC-NPs, including their use as carriers for drug delivery, as countermeasures for biological neutralization, as vaccines for immune modulation, and as tools for isolation of circulating tumor cells. Kristi S. Anseth and co-workers systematically investigated the impact of collagen triple helix structure on the tumor microenvironment (TME) and thus formation of melanoma cell invadopodia and degradation of extracellular matrix (ECM) upon BRAF inhibitor treatment (2101592). They functionalized poly(ethylene glycol) (PEG) hydrogels with a collagen mimetic peptide (CMP) or embedded whole collagen fibers as an interpenetrating polymer network (IPN), and then investigated the effects of collagen triple helix structure on the morphology, MMP activity, and invasion of melanoma cells using quantitative image analysis and biochemical assays. Their results suggest a route to prevent drug resistance after therapeutic treatment with BRAF inhibitors by inhibiting the interactions between melanoma cells and collagen nanostructure. Maria J. Vicent, Ibane Abasolo, and co-workers report an in vivo evaluation of the anti-tumor and metastatic efficacy of a polyacetyl-based paclitaxel conjugate for prostate cancer treatment (2101544). The authors conjugated paclitaxel to a polyacetal-based nanocarrier to obtain a tert Ser-PTX polyacetal conjugate, which provided sustained release of paclitaxel over two weeks in a pH-responsive manner while achieving a degree of epimerization of paclitaxel to 7-epi paclitaxel. The conjugate effectively inhibited primary tumor growth and hematologic, lymphatic, and coelomic dissemination, as demonstrated by in vivo and ex vivo bioluminescence imaging and histopathological evaluations in mice bearing orthotopic tumors. The results suggest potential application of tert-Ser-PTX as a robust anti-tumor/antimetastatic treatment for prostate cancer. Lola Eniola-Adefeso and co-workers report the use of poly-salicylic acid polymer microparticle decoys to treat acute respiratory distress syndrome (ARDS) (2101534). In a mouse model, it was demonstrated that intravenous salicylic acid-based polymer microparticles could interfere with neutrophils in blood, reducing lung neutrophil infiltration and injury. Importantly, the microparticles were able to reduce multiple inflammatory cytokines in the airway and bacterial load in the bloodstream in a live bacteria lung infection model of ARDS, drastically improving survival. The microparticles based on poly-salicylic acid are anticipated to offer a therapeutic strategy in ARDS, with a rare opportunity for rapid clinical translation. Yi Yan Yang and co-workers investigated the effects of hydrophobicity on the antimicrobial activity, selectivity, and functional mechanism of guanidinium-functionalized polymers (2100482). They synthesized and evaluated a series of guanidinium-functionalized polycarbonate random co-polymers bearing side chains of different hydrophobicity, including ethyl, propyl, isopropyl, benzyl and hexyl. While the polymers had similar minimum inhibitory concentrations, those with a more hydrophobic side chain exhibited a faster rate of bacteria elimination. The co-polymer containing the highly hydrophobic hexyl-functionalized cyclic carbonate killed bacteria through a membrane-disruptive mechanism. This study offers new insights into the design of advanced antimicrobial polymers. We are excited to bring this special issue to the biomaterials community. Unfortunately, a number of invited manuscripts were delayed and cannot be included in this special issue due to the interruption caused by COVID-19. Nevertheless, we hope this special issue still provides a broad spectrum of recent advances in the development of advanced materials for healthcare applications. We also hope that the readers will enjoy the diverse topics presented in this issue and find the inspiration to push this important area of biomedical research to the next level of success. Kristi S. Anseth is a professor of chemical and biological engineering and Associate Faculty Director of the BioFrontiers Institute at the University of Colorado at Boulder. She currently holds the Tisone Professorship and is a distinguished professor. Dr. Anseth came to CU after earning her B.S. degree from Purdue University (1992) and conducing undergraduate research with Nicholas Peppas. She then completed her Ph.D. degree from CU (1994), and post-doctoral research at Purdue with Peppas and at MIT with Robert Langer as an NIH fellow. She is an elected member of the NAE (2009), NAM (2009), NAS (2013), NAI (2016) and AAAS (2019). Most recently, she received the L'Oreal-UNESCO for Women in Science Award in the Life Sciences (2020). Dr. Anseth has served on the Board of Directors and as President of the Materials Research Society, the Board of Governors for Acta Materialia, Inc, the NIH Advisory Council for NIBIB, and as Chair of the NAE US Frontiers of Engineering meetings. 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.