Bioactive Bone Substitute in a Rabbit Ulna Model: Preclinical Study.

BACKGROUND: Current therapies to effectively treat long-bone defects and extensive bone tissue loss remains limited. In this study, we created a new bone substitute by integrating advanced technologies such as structure patterning, controlled release of a bone growth factor and conjugation system for clinically effective bone regeneration. This novel bioactive bone substitute was evaluated for its safety and efficacy using a rabbit ulna model. METHODS: A three dimensional bone patterned cylindrical structure with 1.5 cm in length and 5 mm in diameter was printed using poly(L-lactic acid)(PLLA) as a weight-bearing support and space-filling scaffold. And a bone morphogenetic protein 2 (BMP2) was employed to enhance bone regeneration, and coated to a 3D PLLA using alginate catechol and collagen to prolong the release kinetics. This novel bone substitute (BS)was evaluated for its physico-chemical and biological properties in vitro, and histological analysis and radiographical analysis such as X-ray, CT and micro-CT image analysis were performed to evaluate new bone formation in vivo. RESULTS: The BS possesses an ideal shape and mechanically suitable proeperties for clinical use, with an easy-to-grab and break-resistant design at both ends, 80 ± 10 MPa of compression strength, and BMP2 release for two months. Histological analysis demonstrated the biocompability of BS with minimal inflammation and immune response, and X-ray, CT and micro-CT demonstrated effective new bone formation in rabbit ulna defect model. CONCLUSION: The preclinical study of a novel bioactive bone substitute has shown its safe and effective properties in an animal model suggesting its clinical potential.

Nanostructured chitosan-polyphenolic patch for remote NIR-photothermal controlled dermal drug delivery.

We describe the synthesis of a nanostructured dermal patch composed of chitosan-tannic acid (CT) that can carry near-infrared (NIR) active Indocyanine green (ICG) dye for performing photothermal heat conversion activity. The NIR-responsive CT-I dermal patch can deliver topical antibiotic drugs (Neomycin). The CT-I and drug-loaded CT-I/N patches have been demonstrated by FTIR, SEM/EDX, TGA, and DSC analysis. The in vitro drug release from the CT-I/N patch are favorable in the dermal environment (pH = 5.5) and significantly increases 25 % more at higher temperatures of 40 to 45 °C. The CT-I/N showed increasing photothermal heat in response to NIR (808 nm) light. The in vivo thermograph demonstrated that the CT-I/N patch can generate >45 °C within 5 min NIR irradiation. As a result, sustained wound healing was shown in H&E (hematoxylin and eosin) staining dermal tissue. Such NIR-active nanostructure film/patch is promising for the future of any sustained on-demand drug delivery system.

rhBMP-2-Conjugated Three-Dimensional-Printed Poly(L-lactide) Scaffold is an Effective Bone Substitute.

BACKGROUND: Bone growth factors, particularly bone morphogenic protein-2 (BMP-2), are required for effective treatment of significant bone loss. Despite the extensive development of bone substitutes, much remains to be desired for wider application in clinical settings. The currently available bone substitutes cannot sustain prolonged BMP-2 release and are inconvenient to use. In this study, we developed a ready-to-use bone substitute by sequential conjugation of BMP to a three-dimensional (3D) poly(L-lactide) (PLLA) scaffold using novel molecular adhesive materials that reduced the operation time and sustained prolonged BMP release. METHODS: A 3D PLLA scaffold was printed and BMP-2 was conjugated with alginate-catechol and collagen. PLLA scaffolds were conjugated with different concentrations of BMP-2 and evaluated for bone regeneration in vitro and in vivo using a mouse calvarial model. The BMP-2 release kinetics were analyzed using ELISA. Histological analysis and micro-CT image analysis were performed to evaluate new bone formation. RESULTS: The 3D structure of the PLLA scaffold had a pore size of 400 µm and grid thickness of 187-230 µm. BMP-2 was released in an initial burst, followed by a sustained release for 14 days. Released BMP-2 maintained osteoinductivity in vitro and in vivo. Micro-computed tomography and histological findings demonstrate that the PLLA scaffold conjugated with 2 µg/ml of BMP-2 induced optimal bone regeneration. CONCLUSION: The 3D-printed PLLA scaffold conjugated with BMP-2 enhanced bone regeneration, demonstrating its potential as a novel bone substitute.

Reversible tissue sticker inspired by chemistry in plant-pathogen relationship.

Plants release phenolic molecules to protect against invading pathogens. In plant-microorganism relationships, phenolics bind to surface oligosaccharides, inactivating microorganism activities. Inspired by phenol-saccharide interactions in plant defense systems, we designed an adhesive sealant. By screening 16 different saccharides, the O-acetyl group, rich in glucomannan (GM), exhibited rapid, robust binding with the galloyl moiety of a model phenolic molecule, tannic acid (TA). Furthermore, the interaction showed both pH and temperature (upper critical solution temperature) sensitivities. Utilizing O-acetyl-galloyl interactions, materials of all dimensions from beads (0D) to strings (1D), films (2D), and objects (3D) could be prepared, as a suitable platform for printing techniques. GMTA films are elastic, adhesive, water-resistant, and effectively sealed perforations, as demonstrated by (1) a lung incision followed by an air inflation model and (2) a thoracic diaphragm model. STATEMENT OF SIGNIFICANCE: In nature, phenolic molecules are 'nearly always' physically bound with polysaccharides, indicating that the phenolics widen the functions of polysaccharides. An example includes that phenolic-polysaccharide interactions are key defense mechanisms against microbial infection in plants whereas polysaccharide alone functions poorly. Despite the ubiquitous biochemistry of polysaccharide-phenolic interactions, efforts on understanding binding chemistry focusing on phenol/polysaccharide interactions is little. This study is important because we found for the first time that O-acetyl group is the moiety in polysaccharides to which phenolic cis-diol and/or cis-triol is spontaneously bound. The phenol-polysaccharide interaction is non-covalent yet robust, kinetically fast, and reversible. Inspired by the interaction chemistry, a simple mixture of phenolic molecules and O-acetyl group containing polysaccharides such as glucomannan opens a promising fabrication strategy toward functional polysaccharide-based material.

Systematic Approach to Mimic Phenolic Natural Polymers for Biofabrication.

In nature, phenolic biopolymers are utilized as functional tools and molecular crosslinkers to control the mechanical properties of biomaterials. Of particular interest are phenolic proteins/polysaccharides from living organisms, which are rich in catechol and/or gallol groups. Their strong underwater adhesion is attributed to the representative phenolic molecule, catechol, which stimulates intermolecular and intramolecular crosslinking induced by oxidative polymerization. Significant efforts have been made to understand the underlying chemistries, and researchers have developed functional biomaterials by mimicking the systems. Owing to their unique biocompatibility and ability to transform their mechanical properties, phenolic polymers have revolutionized biotechnologies. In this review, we highlight the bottom-up approaches for mimicking polyphenolic materials in nature and recent advances in related biomedical applications. We expect that this review will contribute to the rational design and synthesis of polyphenolic functional biomaterials and facilitate the production of related applications.

A Modular Strategy for Functional Pressure Sensitive Adhesives.

A modular approach to synthesizing functional pressure sensitive adhesives (PSAs) was introduced, wherein a modifiable acrylic PSA copolymer was synthesized by copolymerizing common PSA monomers with 6 mol % glycidyl methacrylate, allowing for subsequent functional group modification via the pendant epoxide functionality. This postmodification technique has the advantage of allowing the installation of a variety of functional groups relevant to adhesion, without variation of molecular weight. Because comparisons of cohesive and adhesive performance of candidate PSAs can be complicated by molecular weight differences, this strategy simplifies direct comparisons of the effects of functional groups on performance. As a proof of concept, a mussel-inspired catecholic PSA was synthesized by postreaction of the epoxide scaffold polymer with a thiol-modified catechol, allowing the effect of catechol on underlying structure-property relationships to be determined without variation in molecular weight. The mechanical performance of catecholic PSA was compared to relevant control PSAs by using industry-standard 180° peel and static shear tests, revealing an increase in peel strength achieved through catechol modification. Moreover, we observed an unexpected enhancement in PSA cohesive strength attributed to oxidation of catechol, which cannot be attributed to differences in molecular weight, a common source of changes in PSA cohesive strength.

Laser-induced graphitization of polydopamine leads to enhanced mechanical performance while preserving multifunctionality.

Polydopamine (PDA) is a simple and versatile conformal coating material that has been proposed for a variety of uses; however in practice its performance is often hindered by poor mechanical properties and high roughness. Here, we show that blue-diode laser annealing dramatically improves mechanical performance and reduces roughness of PDA coatings. Laser-annealed PDA (LAPDA) was shown to be >100-fold more scratch resistant than pristine PDA and even better than hard inorganic substrates, which we attribute to partial graphitization and covalent coupling between PDA subunits during annealing. Moreover, laser annealing provides these benefits while preserving other attractive properties of PDA, as demonstrated by the superior biofouling resistance of antifouling polymer-grafted LAPDA compared to PDA modified with the same polymer. Our work suggests that laser annealing may allow the use of PDA in mechanically demanding applications previously considered inaccessible, without sacrificing the functional versatility that is so characteristic of PDA.

Localization of Phenolic Compounds at an Air-Solid Interface in Plant Seed Mucilage: A Strategy to Maximize Its Biological Function?

Given a low concentration of phenols in the naturally occurring aqueous lubricant (mucilage) from hydrated seeds, their biological functions should be severely limited. Here, we introduce an undisclosed natural strategy that enables maximization of phenolic functions through exposing the phenols at the air-seed solid interface. Our findings not only offer a new perspective on plant reproduction physiology but also provide insights into an innovative design of lubricating biomaterials with additional phenolic functions.

Polydopamine-Lysophosphatidate-Functionalised Titanium: A Novel Hybrid Surface Finish for Bone Regenerative Applications.

Aseptic loosening of total joint replacements (TJRs) continues to be the main cause of implant failures. The socioeconomic impact of surgical revisions is hugely significant; in the United Kingdom alone, it is estimated that £135m is spent annually on revision arthroplasties. Enhancing the longevity of titanium implants will help reduce the incidence and overall cost of failed devices. In realising the development of a superior titanium (Ti) technology, we took inspiration from the growing interest in reactive polydopamine thin films for biomaterial surface functionalisations. Adopting a "one-pot" approach, we exposed medical-grade titanium to a mildly alkaline solution of dopamine hydrochloride (DHC) supplemented with (3S)1-fluoro-3-hydroxy-4-(oleoyloxy)butyl-1-phosphonate (FHBP), a phosphatase-resistant analogue of lysophosphatidic acid (LPA). Importantly, LPA and selected LPA analogues like FHBP synergistically cooperate with calcitriol to promote human osteoblast formation and maturation. Herein, we provide evidence that simply immersing Ti in aqueous solutions of DHC-FHBP afforded a surface that was superior to FHBP-Ti at enhancing osteoblast maturation. The facile step we have taken to modify Ti and the biological performance of the final surface finish are appealing properties that may attract the attention of implant manufacturers in the future.

Surface Design for Immobilization of an Antimicrobial Peptide Mimic for Efficient Anti-Biofouling.

Microbial surface attachment negatively impacts a wide range of devices from water purification membranes to biomedical implants. Mimics of antimicrobial peptides (AMPs) constituted from poly(N-substituted glycine) "peptoids" are of great interest as they resist proteolysis and can inhibit a wide spectrum of microbes. We investigate how terminal modification of a peptoid AMP-mimic and its surface immobilization affect antimicrobial activity. We also demonstrate a convenient surface modification strategy for enabling alkyne-azide "click" coupling on amino-functionalized surfaces. Our results verified that the N- and C-terminal peptoid structures are not required for antimicrobial activity. Moreover, our peptoid immobilization density and choice of PEG tether resulted in a "volumetric" spatial separation between AMPs that, compared to past studies, enabled the highest AMP surface activity relative to bacterial attachment. Our analysis suggests the importance of spatial flexibility for membrane activity and that AMP separation may be a controlling parameter for optimizing surface anti-biofouling.

Phenol-Derived Carbon Sealant Inspired by a Coalification Process.

Recently, emerging functions utilizing phenolic molecules, such as surface functionalizing agents or bioadhesives, have attracted significant interest. However, the most important role of phenolic compounds is to produce carbonized plant matter called "coal", which is widely used as an energy source in nearly all countries. Coalification is a long-term, high-temperature process in which phenols are converted into conducting carbonized matter. This study focuses on mimicking coalification processes to create conducting sealants from non-conducting phenolic compounds by heat treatment. We demonstrate that a phenolic adhesive, tri-hydroxybenzene (known as pyrogallol), and polyethylenimine mixture initially acts as an adhesive sealant that can be converted to a conducting carbon sealing material. The conductivity of the phenolic sealant is about 850 Ω-1 cm-1 , which is an approximately two-fold enhancement of the performance of carbon matter. Applications of the biomimetic adhesives described herein include conducting defect sealants in carbon nanomaterials and conducting binders for metal/carbon or ceramic/carbon composites.

Progress in internal/external stimuli responsive fluorescent carbon nanoparticles for theranostic and sensing applications.

In the past decade, fluorescent carbon nanoparticles (FNPs) prepared from natural resources and biomaterials have been attractive due to their various properties, such as unique optical properties, great biocompatibility, water dispersion, and facile surface functionalization. Depending on the properties of the carbon sources and the subsequent carbonization processes, internal/external stimuli responsive carbon nanoparticles have been generated that are useful for theranostic and sensing applications. In this review, we highlight the recent developments in the use of FNPs in nanomedicine in great detail, particularly for FNPs responding to internal stimuli, including redox, pH, and enzymes, and external stimuli, including temperature, light, and magnetic fields, for drug delivery and sensing applications. Furthermore, we hope to provide insight that could stimulate further research aiming for unparalleled useful applications. As a result, there are many possibilities that can be explored from this smart material.

Phenolic condensation and facilitation of fluorescent carbon dot formation: a mechanism study.

Fluorescent carbon dots have received considerable attention as a result of their accessibility and potential applications. Although several prior studies have demonstrated that nearly any organic compound can be converted into carbon dots by chemical carbonization processes, mechanisms explaining the formation of carbon dots still remain unclear. Herein, we propose a seed-growth mechanism of carbon dot formation facilitated by ferulic acid, a widespread and naturally occurring phenolic compound in the seeds of Ocimum basilicum (basil). Ferulic acid triggers the local condensation of polysaccharide chains and forms catalytic core regions resulting in nanoscale carbonization. Our study indicates that carbon dots generated from natural sources might share the similar mechanism of phenolic compound mediated nanoscale condensation followed by core carbonization.

Direct Insulation-to-Conduction Transformation of Adhesive Catecholamine for Simultaneous Increases of Electrical Conductivity and Mechanical Strength of CNT Fibers.

Increase in conductivity and mechanical properties of a carbon nanotube (CNT) fiber inspired by mussel-adhesion chemistry is described. Infiltration of polydopamine into an as-drawn CNT fiber followed by pyrolysis results in a direct insulation-to-conduction transformation of poly(dopamine) into pyrolyzed-poly(dopamine) (py-PDA), retaining the intrinsic adhesive function of catecholamine. The py-PDA enhances both the electrical conductivity and the mechanical strength of the CNT fibers.