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Biologics are increasingly vital medicines that significantly reduce morbidity as well as mortality, yet access continues to be an issue even in apparently wealthy countries, such as the USA. While patient access is expected to improve with the introduction of biosimilars, misperceptions in a significant part based on terminology continue to make a sustained contribution by biosimilars difficult. Patients are and will continue to suffer needlessly if biosimilars continue to be impugned. Consequently, it is increasingly urgent that semantics are clarified, and in particular, the implication that interchangeable biologics are better biosimilars dismissed. This paper distinguishes between the real differences between biologics that matter clinically to patients and discusses the actual meaning of a US Food and Drug Administration designation of interchangeability for a biosimilar product. This will help highlight where there is need for further Food and Drug Administration education and which stakeholders likely need that education the most.

The potential for pharmacodynamic (PD) biomarkers to improve the efficiency of biosimilar product development and regulatory approval formed the premise for the virtual workshop Pharmacodynamic Biomarkers for Biosimilar Development and Approval hosted by the US Food and Drug Administration (FDA) and Duke Margolis, September 2021. Although the possibility of PD biomarkers replacing the to-date routine comparative phase III confirmatory study currently expected by the FDA was discussed, the motivation and feasibility for biosimilar sponsors developing such markers and the regulatory risks entailed largely were not. Even more fundamental is the already established greater comparative value of the pharmacokinetic (PK) study as the most sensitive clinical assay for detecting subtle differences between two products. Consequently, the comparative analytical assessment and the head-to-head PKs will have already answered the core questions as to the biosimilarity of the candidate product to its reference. No further actionable information is obtained with either a PD study or a comparative clinical phase III study even as they may provide some reassurance of what is already known. When a suitable PD biomarker is available for the originator reference product they have already been used for biosimilar development. We must carefully consider the core requirements and timelines inherent in biosimilar development and how they occur in parallel rather than in the series we see for originator products. In order to improve the efficiency of biosimilar development, we need to ask the right questions based on a full understanding of how biosimilars have been developed to date and can be in the future.

Mussel-inspired adhesion chemistry provides a useful alternative to the use of fibrin glues., Since the first report of underwater adhesive proteins of marine mussels in 1981, numerous studies have reported mussel-inspired synthetic adhesive polymers. However, none of them have developed up to human-level translational studies. Here, we report a sticky polysaccharide that effectively promotes hemostasis from animal bleeding models to first-in-human hepatectomy. We found that the hemostatic material instantly generates a barrier layer that seals hemorrhaging sites. The barrier is created within a few seconds by in situ interactions with abundant plasma proteins. Therefore, as long as patient blood contains proper levels of plasma proteins, hemostasis should always occur even in coagulopathic conditions. To date, insufficient tools have been developed to arrest coagulopathic bleedings originated from genetic disorders, chronic diseases, or surgical settings such as organ transplantations. Mussel-inspired adhesion chemistry described here provides a useful alternative to the use of fibrin glues up to a human-level biomedical application.

Tyrosinase is a monooxygenase that catalyzes both the hydroxylation of p-hydroxyphenyl moieties to o-catechols and the oxidation of o-catechols to o-quinones. Apart from its critical functionality in melanogenesis and the synthesis of various neurotransmitters, this enzyme is also used in a variety of biotechnological applications, most notably mediating covalent cross-linking between polymers containing p-hydroxyphenyl groups, forming a hydrogel. Tyrosinases from the genus Streptomyces are usually secreted as a complex with their caddie protein. In this study, we report an increased secretion efficiency observed when the Streptomyces antibioticus tyrosinase gene melC2 was introduced into Pseudomonas fluorescens along with its caddie protein gene melC1, which has the DNA sequence for the Tat (twin-arginine translocation) signal. IMPORTANCE We observed that the S. antibioticus extracellular tyrosinase secretion level was even higher in its nonnatural translationally conjugated fusion protein form than in the natural complex of two separated polypeptides. The results of this study demonstrate that tyrosinase-expressing P. fluorescens can be a stable source of bacterial tyrosinase through exploiting the secretory machinery of P. fluorescens.

A new insect-cuticle- and fruit-browning-mimetic film exhibiting simultaneous self-healing and self-sealing properties only by ambient oxygen without external stimuli is developed. The film is formed at the liquid/air interface via crosslinking of phenolic compounds and poly(amine) chains. The film can be self-healed over a hundred times under ambient air at room temperature without exogenous materials and stimuli.

Mussel-inspired adhesive coatings on biomedical devices have attracted significant interest due to their unique properties such as substrate independency and high efficiency. The key molecules for mussel-inspired adhesive coatings are catechol and amine groups. Along with the understanding of catechol chemistry, chitosan-catechol has also been developed as a representative mussel-inpired adhesive polymer that contains catechol and amine groups for adhesiveness. Herein, we demonstrated the direct writability of chitosan-catechol as a bioink for 3D printing, one of the additive techniques. The use of chitosan-catechol bioink results in the formation of 3D constructs in normal culture media via rapid complexation of this bioink with serum proteins; in addition, the metal/catechol combination containing tiny amounts of vanadyl ions, in which the ratio of metal to catechol is 0.0005, dramatically enhances the mechanical strength and printability of the cell-encapsulated inks, showing a cell viability of approximately 90%. These findings for mussel-inspired bioinks will be a promising way to design a biocompatible 3D bioink cross-linked without any external stimuli.

For the increasing demand of soft materials with wide ranges of applications, hydrogels have been developed exhibiting variety of functions (e.g., stretchable, self-healing, stimuli-responsive, and etc.). So far, add-in components such as inorganic nanoparticles, carbon materials, clays, and many others to main polymers have been used to achieve various unique functions of hydrogels. The multicomponent hydrogel systems often exhibit batch-dependent inconsistent results and problems in multicomponent mixings, require labors during preparations, and accompany unpredictable cross-talk between the added components. Here, we developed 'single polymeric component', alginate-boronic acid (alginate-BA) hydrogel to overcome the aforementioned problems. It exhibits unprecedented multifunctionalities simultaneously, such as high stretchability, self-healing, shear-thinning, pH- and glucose-sensitivities, adhesive properties, and reshaping properties. Multifunctionalities of alginate-BA hydrogel is resulted from the reversible inter- and intramolecular interactions by dynamic equilibrium of boronic acid-diol complexation and dissociation, which was proved by single molecule level Atomic Force Microscopy (AFM) pulling experiments. We also found that the alginate-BA gel showed enhanced in vivo retentions along gastrointestinal (GI) tract. Our findings suggest that rational polymer designs can result in minimizing the number of a participating component for multifunctional hydrogels, instead of increasing complexity by adding various additional components.

Vitamins are non-toxic compounds that perform a variety of biological functions and also available in a large quantity. Other than the usage as food supplements, few attempts have been made to use them as functional materials. In this study, we report that vitamin B6, pyridoxal 5′-phosphate (PLP), is a multi-functional molecule for oxide surface chemistry. PLP-immobilized surfaces exhibit superhydrophilicity and even hemophilicity, enhancing proliferation, migration, and differentiation of mammalian cells. Unlike existing molecules used so far in surface modification, PLP has an intrinsic chemical reactivity toward biomacromolecules due to the presence of the aldehyde group. In fact, RGD peptide is covalently tethered onto PLP surfaces directly in one step without any chemical activation. Furthermore, PLP-functionalized implant device showed rapid bone healing. As vitamin B6 is a FDA approved molecule for human usage, the surface chemistry of vitamin B6 potentially allows a fast route for surface functionalized medical devices into clinic.

Joseph P. Park, Mi-Young Koh, Pil Soo Sung, Keumyeon Kim, Min Sun Kim, Moon Sue Lee, Eui-Cheol Shin*, Ki Hong Kim*, and Haeshin Lee* 1Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea 2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea 3R & D Center, InnoTherapy Inc., Daejeon 305-732, Korea 4Department of Aquatic Life Medicine, Pukyoug National University, Busan 608-737, Korea

DNA has emerged as a novel material in many areas of materials science due to its programmability. Especially, DNA hydrogels have been studied to incorporate new functions into gels. To date, only a few methods have been developed for fabricating DNA hydrogels, such as the use of complementary sequences or covalent bond. Herein, it is demonstrated that one of the most well-known plant-derived polyphenols, tannic acid (TA), can form a DNA hydrogel which is named TNA hydrogel (TA + DNA). TA plays a role as a “molecular glue” by a new mode of action reversibly connecting between phosphodiester bonds, which is different from the crosslinking utilizing complementary sequences. TA intrinsically degrades due to ester bonds connecting between pyrogallol groups, causing a degradable DNA hydrogel. Furthermore, TNA gel is multifunctional in that the gel is extensible upon pulling and adhesive to tissues because of the rich polyphenol groups in TA (ten phenols per TA). Unexpectedly, TNA gel exhibits superior in vivo hemostatic ability that can be useful for biomedical applications. This new DNA hydrogel preparation method represents a new technique for fabricating a large amount of DNA-based hemostatic hydrogel without chemically modifying DNA or requiring the crosslinking by complementary sequences.

In general, mechanical properties and gelation kinetics exhibit a positive correlation with the amount of gelation reagents used. Similarly, for catechol-containing hydrogels, which have attracted significant attention, because of their unique dual properties of cohesion and adhesion, increased amounts of cross-linking agents, such as organic oxidants and/or transition metals (Fe3+), result in enhanced mechanical strength and more rapid gelation kinetics. Here, we report a new metal–ligand cross-linking chemistry, inspired by mussels and ascidians, that defies the aforementioned conventional stoichiometric concept. When a small amount of vanadium is present in the catechol-functionalized polymer solution (i.e., [V] ≪ [catechol]), organic radicals are rapidly generated that trigger the gelation reaction. However, when a large amount of the ion is added to the same solution (i.e., [V] ≫ [catechol]), the catechol remains chemically intact by coordination that inhibits gelation. Thus, a large amount of cross-...

This study reports polysaccharide-based fibers that can be utilized as biocompatible functional sutures. Fibers are spontaneously formed by spinning at the interface between two oppositely charged polysaccharide solutions. Unlike the common belief that polysaccharide fibers prepared by electrostatic interactions would exhibit weak mechanical strength, it is demonstrated that fibers spun at the interface between two droplets of positively charged chitosan and negatively charged heparin can exhibit high mechanical strength through spontaneous wet-state fusion of interfiber strands at a spinning wheel. Dry solidification results in multistranded fibers that were ≈100 µm in diameter with a tensile strength of ≈220 MPa. Post fibrous manipulation yields various morphology with straight or twisted fibers, fabrics, or springs. To demonstrate application of the fiber, it is applied as a medical suture. As heparin has a unique ability to bind adeno-associated virus (AAV), a therapeutic, biocompatible suture exhibiting localized AAV-mediated gene delivery function can be prepared. This study shows that multistrand fusion of fibers, formed by weak, electrostatic interactions and followed by drying solidification counterintuitively results in mechanically strong, functional fibers with various potential applications.

M13 bacteriophage (phage) was engineered for the use as a versatile template for preparing various nanostructured materials via genetic engineering coupled to enzymatic chemical conversions. First, we engineered the M13 phage to display TyrGluGluGlu (YEEE) on the pVIII coat protein and then enzymatically converted the Tyr residue to 3,4-dihydroxyl-l-phenylalanine (DOPA). The DOPA-displayed M13 phage could perform two functions: assembly and nucleation. The engineered phage assembles various noble metals, metal oxides, and semiconducting nanoparticles into one-dimensional arrays. Furthermore, the DOPA-displayed phage triggered the nucleation and growth of gold, silver, platinum, bimetallic cobalt–platinum, and bimetallic iron–platinum nanowires. This versatile phage template enables rapid preparation of phage-based prototype devices by eliminating the screening process, thus reducing effort and time.

Mussels attach to virtually all types of inorganic and organic surfaces in aqueous environments, and catecholamines composed of 3,4-dihydroxy- l -phenylalanine (DOPA), lysine, and histidine in mussel adhesive proteins play a key role in the robust adhesion. DOPA is an unusual catecholic amino acid, and its side chain is called catechol. In this study, we displayed the adhesive moiety of DOPA-histidine on Escherichia coli surfaces using outer membrane protein W as an anchoring motif for the first time. Localization of catecholamines on the cell surface was confirmed by Western blot and immunofluorescence microscopy. Furthermore, cell-to-cell cohesion (i.e., cellular aggregation) induced by the displayed catecholamine and synthesis of gold nanoparticles on the cell surface support functional display of adhesive catecholamines. The engineered E. coli exhibited significant adhesion onto various material surfaces, including silica and glass microparticles, gold, titanium, silicon, poly(ethylene terephthalate), poly(urethane), and poly(dimethylsiloxane). The uniqueness of this approach utilizing the engineered sticky E. coli is that no chemistry for cell attachment are necessary, and the ability of spontaneous E. coli attachment allows one to immobilize the cells on challenging material surfaces such as synthetic polymers. Therefore, we envision that mussel-inspired catecholamine yielded sticky E. coli that can be used as a new type of engineered microbe for various emerging fields, such as whole living cell attachment on versatile material surfaces, cell-to-cell communication systems, and many others.

Titanium is the most biocompatible inorganic biomaterial with a long history of use in orthopedic and dental implants. However, promoting rapid and effective bone formation and integration onto etched, rough TiO2 surfaces has been a challenging topic. Here, 21 commercially available molecules are examined that met the following criteria: (1) contain phosphonic acid for stable immobilization onto TiO2 surfaces and (2) have a molecular weight less than 500 Da for negligible coating thickness. Of these molecules, the surface immobilization of pyridoxal 5'-phosphate (PLP), an active form of vitamin B6 , dramatically increases the hemophilic property of the surface and accelerated osteointegration in vivo. Analysis shows that PLP promotes surface binding of serum albumin and other plasma proteins by Schiff-base formations via its aldehyde group, providing a platform suitable for osteoblast adhesion. PLP also retards blood coagulation more than the widely used citric acid at the TiO2 surface. As PLP is capable of maintaining an inactivated status of surface-adsorbed platelets, delayed coagulation at the implant-blood interface allows for sufficient supply of growth factors from blood plasma and migration of osteoblasts. The results suggest that PLP can be widely applicable as a biocompatible, effective coating compound to promote osteointegration of titanium-based implants.